Neural Correlates of Graphic Cigarette Warning Labels Predict Smoking Cessation Relapse

PubMed Central

Owens, Max M.; MacKillop, James; Gray, Joshua C.; Hawkshead, Brittany E.; Murphy, Cara M.; Sweet, Lawrence H.

2017-01-01

Exposure to graphic warning labels (GWLs) on cigarette packaging has been found to produce heightened activity in brain regions central to emotional processing and higher-order cognitive processes. The current study extends this literature by using functional magnetic resonance imaging (fMRI) to investigate neural activation in response to GWLs and use it to predict relapse in an evidence-based smoking cessation treatment program. Participants were 48 treatment-seeking nicotine-dependent smokers who completed an fMRI paradigm in which they were exposed to GWLs, text-only warning labels (TOLs), and matched control stimuli. Subsequently, they enrolled in smoking cessation treatment and their smoking behavior was monitored. Activation in bilateral amygdala, right dorsolateral prefrontal cortex, right inferior frontal gyrus, left medial temporal gyrus, bilateral occipital lobe, and bilateral fusiform gyrus was greater during GWLs than TOLs. Neural response in the ventromedial prefrontal cortex (vmPFC) during exposure to GWLs (relative to a visual control image) predicted relapse during treatment beyond baseline demographic and dependence severity, but response in the amygdala to GWLs did not. These findings suggest that neurocognitive processes in the vmPFC may be critical to understanding how GWL’s induce behavior change and may be useful as a predictor of smoking cessation treatment prognosis. PMID:28236714

The Alcohol Relapse Risk Assessment: a scoring system to predict the risk of relapse to any alcohol use after liver transplant.

PubMed

Rodrigue, James R; Hanto, Douglas W; Curry, Michael P

2013-12-01

Alcohol relapse after liver transplant heightens concern about recurrent disease, nonadherence to the immunosuppression regimen, and death. To develop a scoring system to stratify risk of alcohol relapse after liver transplant. Retrospective medical record review. All adult liver transplants performed from May 2002 to February 2011 at a single center in the United States. The incidence of return to any alcohol consumption after liver transplant. Thirty-four percent (40/118) of patients with a history of alcohol abuse/dependency relapsed to use of any alcohol after liver transplant. Nine of 25 hypothesized risk factors were predictive of alcohol relapse after liver transplant: absence of hepatocellular carcinoma, tobacco dependence, continued alcohol use after liver disease diagnosis, low motivation for alcohol treatment, poor stress management skills, no rehabilitation relationship, limited social support, lack of nonmedical behavioral consequences, and continued engagement in social activities with alcohol present. Each independent predictor was assigned an Alcohol Relapse Risk Assessment (ARRA) risk value of 1 point, and patients were classified into 1 of 4 groups by ARRA score: ARRA I = 0, ARRA II = 1 to 3, ARRA III = 4 to 6, and ARRA IV = 7 to 9. Patients in the 2 higher ARRA classifications had significantly higher rates of alcohol relapse and were more likely to return to pretransplant levels of drinking. Alcohol relapse rates are moderately high after liver transplant. The ARRA is a valid and practical tool for identifying pretransplant patients with alcohol abuse or dependency at elevated risk of any alcohol use after liver transplant.

Serial semi-quantitative measurement of fecal calprotectin in patients with ulcerative colitis in remission.

PubMed

Garcia-Planella, Esther; Mañosa, Míriam; Chaparro, María; Beltrán, Belén; Barreiro-de-Acosta, Manuel; Gordillo, Jordi; Ricart, Elena; Bermejo, Fernando; García-Sánchez, Valle; Piqueras, Marta; Llaó, Jordina; Gisbert, Javier P; Cabré, Eduard; Domènech, Eugeni

2018-02-01

Fecal calprotectin (FC) correlates with clinical and endoscopic activity in ulcerative colitis (UC), and it is a good predictor of relapse. However, its use in clinical practice is constrained by the need for the patient to deliver stool samples, and for their handling and processing in the laboratory. The availability of hand held devices might spread the use of FC in clinical practice. To evaluate the usefulness of a rapid semi-quantitative test of FC in predicting relapse in patients with UC in remission. Prospective, multicenter study that included UC patients in clinical remission for ≥6 months on maintenance treatment with mesalamine. Patients were evaluated clinically and semi-quantitative FC was measured using a monoclonal immunochromatography rapid test at baseline and every three months until relapse or 12 months of follow-up. One hundred and ninety-one patients had at least one determination of FC. At the end of follow-up, 33 patients (17%) experienced clinical relapse. Endoscopic activity at baseline (p = .043) and having had at least one FC > 60 μg/g during the study period (p = .03) were associated with a higher risk of relapse during follow-up. We obtained a total of 636 semi-quantitative FC determinations matched with a three-month follow-up clinical assessment. Having undetectable FC was inversely associated with early relapse (within three months), with a negative predictive value of 98.6% and a sensitivity of 93.9%. Serial, rapid semi-quantitative measurement of FC may be a useful, easy and cheap monitoring tool for patients with UC in remission.

Implicit attitudes towards smoking predict long-term relapse in abstinent smokers.

PubMed

Spruyt, Adriaan; Lemaigre, Valentine; Salhi, Bihiyga; Van Gucht, Dinska; Tibboel, Helen; Van Bockstaele, Bram; De Houwer, Jan; Van Meerbeeck, Jan; Nackaerts, Kristiaan

2015-07-01

It has previously been argued that implicit attitudes toward substance-related cues drive addictive behavior. Nevertheless, it remains an open question whether behavioral markers of implicit attitude activation can be used to predict long-term relapse. The main objective of this study was to examine the relationship between implicit attitudes toward smoking-related cues and long-term relapse in abstaining smokers. Implicit attitudes toward smoking-related cues were assessed by means of the Implicit Association Test (IAT) and the evaluative priming task (EPT). Both measures were completed by a group of smokers who volunteered to quit smoking (patient group) and a group of nonsmokers (control group). Participants in the patient group completed these measures twice: once prior to smoking cessation and once after smoking cessation. Relapse was assessed by means of short telephone survey, 6 months after completion of the second test session. EPT scores obtained prior to smoking cessation were related to long-term relapse and correlated with self-reported nicotine dependence as well as daily cigarette consumption. In contrast, none of the behavioral outcome measures were found to correlate with the IAT scores. These findings corroborate the idea that implicit attitudes toward substance-related cues are critically involved in long-term relapse. A potential explanation for the divergent findings obtained with the IAT and EPT is provided.

Relapse following antithyroid drug therapy for Graves' hyperthyroidism.

PubMed

Laurberg, Peter; Krejbjerg, Anne; Andersen, Stine Linding

2014-10-01

In most patients with hyperthyroidism caused by Graves' disease, antithyroid drug (ATD) therapy is followed by a gradual amelioration of the autoimmune abnormality, but about half of the patients will experience relapse of hyperthyroidism when the ATDs are withdrawn after a standard 1 to 2 years of therapy. This is a major drawback of ATD therapy, and a major concern to patients. We review current knowledge on how to predict and possibly reduce the risk of such relapse. Several patient and disease characteristics, as well as environmental factors and duration of ATD therapy, may influence the risk of relapse after ATD withdrawal. Depending on the presence of such factors, the risk of relapse after ATD withdrawal may vary from around 10 to 90%. Risk factors for relapse should be taken into account when choosing between therapeutic modalities in a patient with newly diagnosed disease, and also when discussing duration of ATD therapy. Prolonged low-dose ATD therapy may be feasible in patients with high risk of relapse, such as children and patients with active Graves' orbitopathy, and in patients with previous relapse who prefer such therapy rather than surgery or radioiodine.

Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence.

PubMed

Garbusow, Maria; Schad, Daniel J; Sebold, Miriam; Friedel, Eva; Bernhardt, Nadine; Koch, Stefan P; Steinacher, Bruno; Kathmann, Norbert; Geurts, Dirk E M; Sommer, Christian; Müller, Dirk K; Nebe, Stephan; Paul, Sören; Wittchen, Hans-Ulrich; Zimmermann, Ulrich S; Walter, Henrik; Smolka, Michael N; Sterzer, Philipp; Rapp, Michael A; Huys, Quentin J M; Schlagenhauf, Florian; Heinz, Andreas

2016-05-01

In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence. © 2015 Society for the Study of Addiction.

Predicting Relapse among Young Adults: Psychometric Validation of the Advanced Warning of Relapse (AWARE) Scale

PubMed Central

Kelly, John F.; Hoeppner, Bettina B.; Urbanoski, Karen A.; Slaymaker, Valerie

2011-01-01

Objective Failure to maintain abstinence despite incurring severe harm is perhaps the key defining feature of addiction. Relapse prevention strategies have been developed to attenuate this propensity to relapse, but predicting who will, and who will not, relapse has stymied attempts to more efficiently tailor treatments according to relapse risk profile. Here we examine the psychometric properties of a promising relapse risk measure - the Advance WArning of RElapse scale (AWARE) scale (Miller and Harris, 2000) in an understudied but clinically important sample of young adults. Method Inpatient youth (N=303; Age 18-24; 26% female) completed the AWARE scale and the Brief Symptom Inventory-18 (BSI) at the end of residential treatment, and at 1-, 3-, and 6-months following discharge. Internal and convergent validity was tested for each of these four timepoints using confirmatory factor analysis and correlations (with BSI scores). Predictive validity was tested for relapse 1, 3, and 6 months following discharge, as was incremental utility, where AWARE scores were used as predictors of any substance use while controlling for treatment entry substance use severity and having spent time in a controlled environment following treatment. Results Confirmatory factor analysis revealed a single, internally consistent, 25-item factor that demonstrated convergent validity and predicted subsequent relapse alone and when controlling for other important relapse risk predictors. Conclusions The AWARE scale may be a useful and efficient clinical tool for assessing short-term relapse risk among young people and, thus, could serve to enhance the effectiveness of relapse prevention efforts. PMID:21700396

Predicting relapse among young adults: psychometric validation of the Advanced WArning of RElapse (AWARE) scale.

PubMed

Kelly, John F; Hoeppner, Bettina B; Urbanoski, Karen A; Slaymaker, Valerie

2011-10-01

Failure to maintain abstinence despite incurring severe harm is perhaps the key defining feature of addiction. Relapse prevention strategies have been developed to attenuate this propensity to relapse, but predicting who will, and who will not, relapse has stymied attempts to more efficiently tailor treatments according to relapse risk profile. Here we examine the psychometric properties of a promising relapse risk measure-the Advance WArning of RElapse (AWARE) scale (Miller & Harris, 2000) in an understudied but clinically important sample of young adults. Inpatient youth (N=303; Ages 18-24; 26% female) completed the AWARE scale and the Brief Symptom Inventory-18 (BSI) at the end of residential treatment, and at 1-, 3-, and 6-months following discharge. Internal and convergent validity was tested for each of these four timepoints using confirmatory factor analysis and correlations (with BSI scores). Predictive validity was tested for relapse 1, 3, and 6 months following discharge, as was incremental utility, where AWARE scores were used as predictors of any substance use while controlling for treatment entry substance use severity and having spent time in a controlled environment following treatment. Confirmatory factor analysis revealed a single, internally consistent, 25-item factor that demonstrated convergent validity and predicted subsequent relapse alone and when controlling for other important relapse risk predictors. The AWARE scale may be a useful and efficient clinical tool for assessing short-term relapse risk among young people and, thus, could serve to enhance the effectiveness of relapse prevention efforts. Copyright © 2011 Elsevier Ltd. All rights reserved.

Error-related brain activity predicts cocaine use after treatment at 3-month follow-up.

PubMed

Marhe, Reshmi; van de Wetering, Ben J M; Franken, Ingmar H A

2013-04-15

Relapse after treatment is one of the most important problems in drug dependency. Several studies suggest that lack of cognitive control is one of the causes of relapse. In this study, a relative new electrophysiologic index of cognitive control, the error-related negativity, is investigated to examine its suitability as a predictor of relapse. The error-related negativity was measured in 57 cocaine-dependent patients during their first week in detoxification treatment. Data from 49 participants were used to predict cocaine use at 3-month follow-up. Cocaine use at follow-up was measured by means of self-reported days of cocaine use in the last month verified by urine screening. A multiple hierarchical regression model was used to examine the predictive value of the error-related negativity while controlling for addiction severity and self-reported craving in the week before treatment. The error-related negativity was the only significant predictor in the model and added 7.4% of explained variance to the control variables, resulting in a total of 33.4% explained variance in the prediction of days of cocaine use at follow-up. A reduced error-related negativity measured during the first week of treatment was associated with more days of cocaine use at 3-month follow-up. Moreover, the error-related negativity was a stronger predictor of recent cocaine use than addiction severity and craving. These results suggest that underactive error-related brain activity might help to identify patients who are at risk of relapse as early as in the first week of detoxification treatment. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Hazardous Alcohol Drinking as Predictor of Smoking Relapse (3-, 6-, and 12-Months Follow-Up) by Gender.

PubMed

Rodríguez-Cano, Rubén; López-Durán, Ana; Martínez-Vispo, Carmela; Martínez, Úrsula; Fernández Del Río, Elena; Becoña, Elisardo

2016-12-01

Diverse studies have found a relation between alcohol consumption and smoking relapse. Few studies have analyzed the relation of smoking relapse with pretreatment alcohol consumption and gender differences. The main purpose of this study is to analyze the influence of alcohol consumption in smoking relapse over 12 months (3-, 6-, and 12-months follow-up) and to determine possible gender differences. The sample included 374 smokers who quit smoking by participating in a psychological smoking cessation treatment. We assessed hazardous pretreatment alcohol drinking (AUDIT), cigarette consumption (FTND; number of cigarettes) and sociodemographic variables. Higher scores on hazardous pretreatment alcohol drinking predict smoking relapse at 3-, 6-, and 12-months after smoking cessation. In males, higher scores on hazardous pretreatment alcohol drinking predict relapse at 6 and at 12 months. In females, higher scores on hazardous pretreatment alcohol drinking predict tobacco relapse at 3 months. Hazardous pretreatment alcohol drinking predicts relapse at all intervals after smoking cessation (3-, 6-, and 12-months follow-up). However, the influence of hazardous pretreatment alcohol drinking on smoking relapse differs as a function of gender, as it is a short-term predictor in women (3 months) and a long-term predictor in men (6 and 12 months). Copyright © 2016 Elsevier Inc. All rights reserved.

Decreased Plasma Histidine Level Predicts Risk of Relapse in Patients with Ulcerative Colitis in Remission

PubMed Central

Hisamatsu, Tadakazu; Ono, Nobukazu; Imaizumi, Akira; Mori, Maiko; Suzuki, Hiroaki; Uo, Michihide; Hashimoto, Masaki; Naganuma, Makoto; Matsuoka, Katsuyoshi; Mizuno, Shinta; Kitazume, Mina T.; Yajima, Tomoharu; Ogata, Haruhiko; Iwao, Yasushi; Hibi, Toshifumi; Kanai, Takanori

2015-01-01

Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Patients with UC have repeated remission and relapse. Clinical biomarkers that can predict relapse in UC patients in remission have not been identified. To facilitate the prediction of relapse of UC, we investigated the potential of novel multivariate indexes using statistical modeling of plasma free amino acid (PFAA) concentrations. We measured fasting PFAA concentrations in 369 UC patients in clinical remission, and 355 were observed prospectively for up to 1 year. Relapse rate within 1 year was 23% (82 of 355 patients). The age- and gender-adjusted hazard ratio for the lowest quartile compared with the highest quartile of plasma histidine concentration was 2.55 (95% confidence interval: 1.41–4.62; p = 0.0020 (log-rank), p for trend = 0.0005). We demonstrated that plasma amino acid profiles in UC patients in clinical remission can predict the risk of relapse within 1 year. Decreased histidine level in PFAAs was associated with increased risk of relapse. Metabolomics could be promising for the establishment of a non-invasive predictive marker in inflammatory bowel disease. PMID:26474176

Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients.

PubMed

Beck, Anne; Wüstenberg, Torsten; Genauck, Alexander; Wrase, Jana; Schlagenhauf, Florian; Smolka, Michael N; Mann, Karl; Heinz, Andreas

2012-08-01

In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.

Reduced fMRI activity predicts relapse in patients recovering from stimulant dependence.

PubMed

Clark, Vincent P; Beatty, Gregory K; Anderson, Robert E; Kodituwakku, Piyadassa; Phillips, John P; Lane, Terran D R; Kiehl, Kent A; Calhoun, Vince D

2014-02-01

Relapse presents a significant problem for patients recovering from stimulant dependence. Here we examined the hypothesis that patterns of brain function obtained at an early stage of abstinence differentiates patients who later relapse versus those who remain abstinent. Forty-five recently abstinent stimulant-dependent patients were tested using a randomized event-related functional MRI (ER-fMRI) design that was developed in order to replicate a previous ERP study of relapse using a selective attention task, and were then monitored until 6 months of verified abstinence or stimulant use occurred. SPM revealed smaller absolute blood oxygen level-dependent (BOLD) response amplitude in bilateral ventral posterior cingulate and right insular cortex in 23 patients positive for relapse to stimulant use compared with 22 who remained abstinent. ER-fMRI, psychiatric, neuropsychological, demographic, personal and family history of drug use were compared in order to form predictive models. ER-fMRI was found to predict abstinence with higher accuracy than any other single measure obtained in this study. Logistic regression using fMRI amplitude in right posterior cingulate and insular cortex predicted abstinence with 77.8% accuracy, which increased to 89.9% accuracy when history of mania was included. Using 10-fold cross-validation, Bayesian logistic regression and multilayer perceptron algorithms provided the highest accuracy of 84.4%. These results, combined with previous studies, suggest that the functional organization of paralimbic brain regions including ventral anterior and posterior cingulate and right insula are related to patients' ability to maintain abstinence. Novel therapies designed to target these paralimbic regions identified using ER-fMRI may improve treatment outcome. Copyright © 2012 Wiley Periodicals, Inc.

Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease.

PubMed

Kwon, Hyemi; Kim, Won Gu; Jang, Eun Kyung; Kim, Mijin; Park, Suyeon; Jeon, Min Ji; Kim, Tae Yong; Ryu, Jin Sook; Shong, Young Kee; Kim, Won Bae

2016-06-01

Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.

Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease

PubMed Central

Kwon, Hyemi; Jang, Eun Kyung; Kim, Mijin; Park, Suyeon; Jeon, Min Ji; Kim, Tae Yong; Ryu, Jin-Sook; Shong, Young Kee; Kim, Won Bae

2016-01-01

Background Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. Methods This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. Results Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. Conclusion TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease. PMID:27118279

Seasonal variation in onset and relapse of IBD and a model to predict the frequency of onset, relapse, and severity of IBD based on artificial neural network.

PubMed

Peng, Jiang Chen; Ran, Zhi Hua; Shen, Jun

2015-09-01

Previous research has yielded conflicting data as to whether the natural history of inflammatory bowel disease follows a seasonal pattern. The purpose of this study was (1) to determine whether the frequency of onset and relapse of inflammatory bowel disease follows a seasonal pattern and (2) to establish a model to predict the frequency of onset, relapse, and severity of inflammatory bowel disease (IBD) with meteorological data based on artificial neural network (ANN). Patients with diagnosis of ulcerative colitis (UC) or Crohn's disease (CD) between 2003 and 2011 were investigated according to the occurrence of onset and flares of symptoms. The expected onset or relapse was calculated on a monthly basis over the study period. For artificial neural network (ANN), patients from 2003 to 2010 were assigned as training cohort and patients in 2011 were assigned as validation cohort. Mean square error (MSE) and mean absolute percentage error (MAPE) were used to evaluate the predictive accuracy. We found no seasonal pattern of onset (P = 0.248) and relapse (P = 0.394) among UC patients. But, the onset (P = 0.015) and relapse (P = 0.004) of CD were associated with seasonal pattern, with a peak in July and August. ANN had average accuracy to predict the frequency of onset (MSE = 0.076, MAPE = 37.58%) and severity of IBD (MSE = 0.065, MAPE = 42.15%) but high accuracy in predicting the frequency of relapse of IBD (MSE = 0.009, MAPE = 17.1%). The frequency of onset and relapse in IBD showed seasonality only in CD, with a peak in July and August, but not in UC. ANN may have its value in predicting the frequency of relapse among patients with IBD.

Transient impairment of olfactory threshold in acute multiple sclerosis relapse.

PubMed

Bsteh, Gabriel; Hegen, Harald; Ladstätter, Felix; Berek, Klaus; Amprosi, Matthias; Wurth, Sebastian; Auer, Michael; Di Pauli, Franziska; Deisenhammer, Florian; Lutterotti, Andreas; Berger, Thomas

2018-05-18

Impairment of olfactory threshold is a feature of early and active relapsing remitting multiple sclerosis (RRMS). It predicts inflammatory disease activity and was reported to be transient. However, the timing of onset and resolve of olfactory threshold impairment remains unclear. To prospectively assess the development of olfactory threshold in acute MS relapse over time in comparison to stable MS patients. In a prospective observational design, we measured olfactory threshold by performing the Sniffin' Sticks test (minimum score 0, maximum score 16 reflecting optimal olfactory function) at baseline and after 4, 12 and 24 weeks. We included 30 RRMS patients with acute MS relapse and 30 clinically stable RRMS patients (defined as no relapse within the last 12 months) as a control group. Olfactory threshold was impaired in patients with acute MS relapse at baseline (median difference = -3.5; inter-quartile range [IQR] -4.5- - 2.5; p < 0.001), week 4 (-2.5; IQR -3.0 - -2.0; p < 0.001), week 12 (-1.5; IQR -2.0 - -0.5; p = 0.002) and week 24 (-0.5; IQR -1.0 - 0.0; p = 0.159) compared to stable MS patients. Of note, in relapsing patients in whom disease-modifying treatment was initiated or escalated after relapse, threshold did not differ anymore from stable patients at week 12 (-0.5; IQR -1.0 - 0.5; p = 0.247) and week 24 (0.0; IQR -1.0 - 1.0; p = 0.753). Olfactory threshold impairment seems to be a transient bystander feature of MS relapse. It may be correlated to the level of inflammation within the CNS and might be a useful biomarker in this regard. Copyright © 2018 Elsevier B.V. All rights reserved.

Predictors of exercise relapse in a college population.

PubMed

Sullum, J; Clark, M M; King, T K

2000-01-01

Exercise improves physical and mental health. Nevertheless, most 20-year-olds do not exercise, and approximately 50% of the participants in exercise programs drop out in the first 3 to 6 months. In view of the health benefits of exercise, college health educators and clinicians need to be able to identify factors that predict exercise relapse in a student population. The authors administered questionnaires measuring Prochaska's 10 processes of change for exercise, self-efficacy, and decisional balance to 52 physically active undergraduate students. They assessed baseline exercise levels in October and reassessed them about 8 weeks later. At baseline, relapsers had significantly lower self-efficacy scores than those who maintained their exercise levels. The relapsers also had higher perceived negative views of exercise. These findings provide support for applying the transtheoretical model of behavioral change to a college population.

Increased serum brain-derived neurotrophic factor (BDNF) is predictive of cocaine relapse outcomes: A prospective study

PubMed Central

D’Sa, Carrol; Fox, Helen C.; Hong, Adam K.; Dileone, Ralph J.; Sinha, Rajita

2011-01-01

Background Cocaine dependence is associated with high relapse rates but few biological markers associated with relapse outcomes have been identified. Extending preclinical research showing a role for central Brain Derived Neurotrophic Factor (BDNF) in cocaine seeking, we examined whether serum BDNF is altered in abstinent, early recovering, cocaine-dependent individuals and if it is predictive of subsequent relapse risk. Methods Serum samples were collected across three consecutive mornings from 35 treatment-engaged, 3 week abstinent cocaine-dependent inpatients (17M/18F) and 34 demographically matched hospitalized healthy control participants (17M/17F). Cocaine dependent individuals were prospectively followed on days 14, 30 and 90 post-treatment discharge to assess cocaine relapse outcomes. Time to cocaine relapse, number of days of cocaine use (frequency), and amount of cocaine use (quantity) were the main outcome measures. Results High correlations in serum BDNF across days indicated reliable and stable serum BDNF measurements. Significantly higher mean serum BDNF levels were observed for the cocaine-dependent patients compared to healthy control participants (p<.001). Higher serum BDNF levels predicted shorter subsequent time to cocaine relapse (hazard ratio: HR: 1.09, p<.05), greater number of days (p<.05) and higher total amounts of cocaine used (p = .05). Conclusions High serum BDNF levels in recovering cocaine-dependent individuals are predictive of future cocaine relapse outcomes and may represent a clinically relevant marker of relapse risk. These data suggest that serum BDNF levels may provide an indication of relapse risk during early recovery from cocaine dependence. PMID:21741029

Refractory relapsing polychondritis: challenges and solutions

PubMed Central

Lekpa, Fernando Kemta; Chevalier, Xavier

2018-01-01

Relapsing polychondritis is a severe systemic immune-mediated disease characterized by an episodic and progressive inflammatory condition with progressive destruction of cartilaginous structures. This disease has for nearly a century kept secrets not yet explained. The real incidence and prevalence of this rare disease are unknown. The multiple clinical presentations and episodic nature of relapsing polychondritis cause a significant diagnosis delay. No guidelines for the management of patients with relapsing polychondritis have been validated to date. The challenges remain, both in the understanding of its pathophysiology and diagnosis, evaluation of its activity and prognosis, and its treatment. Possible solutions involve the sharing of data for relapsing polychondritis from worldwide reference centers. Thus, we would be able to evolve toward a better knowledge of its pathophysiology, the publication of new diagnosis criteria, which will include biological markers and imaging findings, the prediction of life-threatening or organ-threatening situations, and the publication of therapeutic evidence-based guidelines after performing at randomized controlled trials. PMID:29391837

Gene-Specific DNA Methylation Changes Predict Remission in Patients with ANCA-Associated Vasculitis

PubMed Central

Jones, Britta E.; Yang, Jiajin; Muthigi, Akhil; Hogan, Susan L.; Hu, Yichun; Starmer, Joshua; Henderson, Candace D.; Poulton, Caroline J.; Brant, Elizabeth J.; Pendergraft, William F.; Jennette, J. Charles; Falk, Ronald J.

2017-01-01

ANCA-associated vasculitis is an autoimmune condition characterized by vascular inflammation and organ damage. Pharmacologically induced remission of this condition is complicated by relapses. Potential triggers of relapse are immunologic challenges and environmental insults, both of which associate with changes in epigenetic silencing modifications. Altered histone modifications implicated in gene silencing associate with aberrant autoantigen expression. To establish a link between DNA methylation, a model epigenetic gene silencing modification, and autoantigen gene expression and disease status in ANCA-associated vasculitis, we measured gene-specific DNA methylation of the autoantigen genes myeloperoxidase (MPO) and proteinase 3 (PRTN3) in leukocytes of patients with ANCA-associated vasculitis observed longitudinally (n=82) and of healthy controls (n=32). Patients with active disease demonstrated hypomethylation of MPO and PRTN3 and increased expression of the autoantigens; in remission, DNA methylation generally increased. Longitudinal analysis revealed that patients with ANCA-associated vasculitis could be divided into two groups, on the basis of whether DNA methylation increased or decreased from active disease to remission. In patients with increased DNA methylation, MPO and PRTN3 expression correlated with DNA methylation. Kaplan–Meier estimate of relapse revealed patients with increased DNA methylation at the PRTN3 promoter had a significantly greater probability of a relapse-free period (P<0.001), independent of ANCA serotype. Patients with decreased DNA methylation at the PRTN3 promoter had a greater risk of relapse (hazard ratio, 4.55; 95% confidence interval, 2.09 to 9.91). Thus, changes in the DNA methylation status of the PRTN3 promoter may predict the likelihood of stable remission and explain autoantigen gene regulation. PMID:27821628

Mediators of the Association of Major Depressive Syndrome and Anxiety Syndrome with Postpartum Smoking Relapse

PubMed Central

Correa-Fernández, Virmarie; Ji, Lingyun; Castro, Yessenia; Heppner, Whitney L.; Vidrine, Jennifer Irvin; Costello, Tracy J.; Mullen, Patricia Dolan; Cofta-Woerpel, Ludmila; Velasquez, Mary M.; Greisinger, Anthony; Cinciripini, Paul M.; Wetter, David W.

2012-01-01

Objective Based on conceptual models of addiction and affect regulation, this study examined the mechanisms linking current major depressive syndrome (MDS) and anxiety syndrome (AS) to postpartum smoking relapse. Method Data were collected in a randomized clinical trial from 251 women who quit smoking during pregnancy. Simple and multiple mediation models of the relations of MDS and AS with postpartum relapse were examined using linear regression, continuation ratio logit models, and a Bootstrapping procedure to test the indirect effects. Results Both MDS and AS significantly predicted postpartum smoking relapse. After adjusting for MDS, AS significantly predicted relapse. However, after adjusting for AS, MDS no longer predicted relapse. Situationally-based self-efficacy, expectancies of controlling negative affect by means other than smoking, and various dimensions of primary and secondary tobacco dependence individually mediated the effect of both MDS and AS on relapse. In multiple mediation models, self-efficacy in negative/affective situations significantly mediated the effect of MDS and AS on relapse. Conclusion The findings underscore the negative impact of depression and anxiety on postpartum smoking relapse, and suggest that the effects of MDS on postpartum relapse may be largely explained by comorbid AS. The current investigation provided mixed support for affect regulation models of addiction. Cognitive and tobacco dependence-related aspects of negative and positive reinforcement significantly mediated the relationship of depression and anxiety with relapse, while affect and stress did not. The findings emphasize the unique role of low agency with respect to abstaining from smoking in negative affective situations as a key predictor of postpartum smoking relapse. PMID:22390410

Mediators of the association of major depressive syndrome and anxiety syndrome with postpartum smoking relapse.

PubMed

Correa-Fernández, Virmarie; Ji, Lingyun; Castro, Yessenia; Heppner, Whitney L; Vidrine, Jennifer Irvin; Costello, Tracy J; Mullen, Patricia Dolan; Cofta-Woerpel, Ludmila; Velasquez, Mary M; Greisinger, Anthony; Cinciripini, Paul M; Wetter, David W

2012-08-01

Based on conceptual models of addiction and affect regulation, this study examined the mechanisms linking current major depressive syndrome (MDS) and anxiety syndrome (AS) to postpartum smoking relapse. Data were collected in a randomized clinical trial from 251 women who quit smoking during pregnancy. Simple and multiple mediation models of the relations of MDS and AS with postpartum relapse were examined using linear regression, continuation ratio logit models, and a bootstrapping procedure to test the indirect effects. Both MDS and AS significantly predicted postpartum smoking relapse. After adjusting for MDS, AS significantly predicted relapse. However, after adjusting for AS, MDS no longer predicted relapse. Situationally based self-efficacy, expectancies of controlling negative affect by means other than smoking, and various dimensions of primary and secondary tobacco dependence individually mediated the effect of both MDS and AS on relapse. In multiple mediation models, self-efficacy in negative/affective situations significantly mediated the effect of MDS and AS on relapse. The findings underscore the negative impact of depression and anxiety on postpartum smoking relapse and suggest that the effects of MDS on postpartum relapse may be largely explained by comorbid AS. The current investigation provided mixed support for affect regulation models of addiction. Cognitive and tobacco dependence-related aspects of negative and positive reinforcement significantly mediated the relationship of depression and anxiety with relapse, whereas affect and stress did not. The findings emphasize the unique role of low agency with respect to abstaining from smoking in negative affective situations as a key predictor of postpartum smoking relapse. © 2012 American Psychological Association

Exercise identity and attribution properties predict negative self-conscious emotions for exercise relapse.

PubMed

Flora, Parminder K; Strachan, Shaelyn M; Brawley, Lawrence R; Spink, Kevin S

2012-10-01

Research on exercise identity (EXID) indicates that it is related to negative affect when exercisers are inconsistent or relapse. Although identity theory suggests that causal attributions about this inconsistency elicit negative self-conscious emotions of shame and guilt, no EXID studies have examined this for exercise relapse. Weiner's attribution-based theory of interpersonal motivation (2010) offers a means of testing the attribution-emotion link. Using both frameworks, we examined whether EXID and attributional properties predicted negative emotions for exercise relapse. Participants (n = 224) read an exercise relapse vignette, and then completed EXID, attributions, and emotion measures. Hierarchical multiple regression models using EXID and the attributional property of controllability significantly predicted each of shame and guilt, R² adjusted = .09, ps ≤ .001. Results support identity theory suggestions and Weiner's specific attribution-emotion hypothesis. This first demonstration of an interlinking of EXID, controllability, and negative self-conscious emotions offers more predictive utility using complementary theories than either theory alone.

Cognitive reactivity to sad mood provocation and the prediction of depressive relapse.

PubMed

Segal, Zindel V; Kennedy, Sidney; Gemar, Michael; Hood, Karyn; Pedersen, Rebecca; Buis, Tom

2006-07-01

Episode remission in unipolar major depression, while distinguished by minimal symptom burden, can also be a period of marked sensitivity to emotional stress as well as an increased risk of relapse. To examine whether mood-linked changes in dysfunctional thinking predict relapse in recovered patients who were depressed. In phase 1 of this study, patients with major depressive disorder were randomly assigned to receive either antidepressant medication or cognitive behavior therapy. In phase 2, patients who achieved clinical remission underwent sad mood provocation and were then observed with regular clinical assessments for 18 months. Outpatient psychiatric clinics at the Centre for Addiction and Mental Health, Toronto, Ontario. A total of 301 outpatients with major depressive disorder, aged 18 to 65 years, participated in phase 1 of this study and 99 outpatients with major depressive disorder in remission, aged 18 to 65 years, participated in phase 2. Occurrence of a relapse meeting DSM-IV criteria for a major depressive episode as assessed by the longitudinal interval follow-up evaluation and a Hamilton Depression Rating Scale score of 16 or greater. Patients who recovered through antidepressant medication showed greater cognitive reactivity following the mood provocation than those who received cognitive behavior therapy. Regardless of type of prior treatment, the magnitude of mood-linked cognitive reactivity was a significant predictor of relapse over the subsequent 18 months. Patients whose mood-linked endorsement of dysfunctional attitudes increased by a minimum of 8 points had a significantly shorter time to relapse than those whose scores were not as elevated. The vulnerability of remitted depressed patients for illness relapse may be related to the (re)activation of depressive thinking styles triggered by temporary dysphoric states. This is the first study to link such differences to prognosis following successful treatment for depression. Further understanding of factors predisposing to relapse/recurrence in recovered patients may help to shorten the potentially lifelong course of depression.

Smoking cessation results in a clinical lung cancer screening program.

PubMed

Borondy Kitts, Andrea K; McKee, Andrea B; Regis, Shawn M; Wald, Christoph; Flacke, Sebastian; McKee, Brady J

2016-07-01

Lung cancer screening may provide a "teachable moment" for promoting smoking cessation. This study assessed smoking cessation and relapse rates among individuals undergoing follow-up low-dose chest computed tomography (CT) in a clinical CT lung screening program and assessed the influence of initial screening results on smoking behavior. Self-reported smoking status for individuals enrolled in a clinical CT lung screening program undergoing a follow-up CT lung screening exam between 1st February, 2014 and 31st March, 2015 was retrospectively reviewed and compared to self-reported smoking status using a standardized questionnaire at program entry. Point prevalence smoking cessation and relapse rates were calculated across the entire population and compared with exam results. All individuals undergoing screening fulfilled the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Lung Cancer Screening v1.2012(®) high-risk criteria and had an order for CT lung screening. A total of 1,483 individuals underwent a follow-up CT lung screening exam during the study interval. Smoking status at time of follow-up exam was available for 1,461/1,483 (98.5%). A total of 46% (678/1,461) were active smokers at program entry. The overall point prevalence smoking cessation and relapse rates were 20.8% and 9.3%, respectively. Prior positive screening exam results were not predictive of smoking cessation (OR 1.092; 95% CI, 0.715-1.693) but were predictive of reduced relapse among former smokers who had stopped smoking for 2 years or less (OR 0.330; 95% CI, 0.143-0.710). Duration of program enrollment was predictive of smoking cessation (OR 0.647; 95% CI, 0.477-0.877). Smoking cessation and relapse rates in a clinical CT lung screening program rates are more favorable than those observed in the general population. Duration of participation in the screening program correlated with increased smoking cessation rates. A positive exam result correlated with reduced relapse rates among smokers recently quit smoking.

Clinical trial: factors associated with freedom from relapse of heartburn in patients with healed reflux oesophagitis--results from the maintenance phase of the EXPO study.

PubMed

Labenz, J; Armstrong, D; Zetterstrand, S; Eklund, S; Leodolter, A

2009-06-01

Ability to predict freedom from heartburn relapse during maintenance therapy for healed reflux oesophagitis may facilitate optimal treatment choices for individual patients. To determine factors predicting freedom from heartburn relapse during maintenance proton pump inhibitor therapy in patients with healed reflux oesophagitis. This post-hoc analysis used data from the maintenance phase of the EXPO study (AstraZeneca study code: SH-NEG-0008); 2766 patients with healed reflux oesophagitis and resolved heartburn received once-daily esomeprazole 20 mg or pantoprazole 20 mg for 6 months. Multiple logistic regression analysis determined factors associated with freedom from heartburn relapse. Heartburn relapse rates were lower with esomeprazole than pantoprazole in all subgroups analysed. Esomeprazole treatment was the factor most strongly associated with freedom from heartburn relapse (odds ratio 2.08; P < 0.0001). Other factors significantly associated with freedom from heartburn relapse were Helicobacter pylori infection, greater age, non-obesity, absence of epigastric pain at baseline, pre-treatment nonsevere heartburn and GERD symptom duration < or =5 years. Several factors predict freedom from heartburn relapse during maintenance proton pump inhibitor therapy for healed reflux oesophagitis, the strongest being choice of proton pump inhibitor. These findings outline the importance of optimizing acid control and identifying predictors of relapse for effective long-term symptom management in reflux oesophagitis patients.

Predictors of marijuana relapse in the human laboratory: robust impact of tobacco cigarette smoking status.

PubMed

Haney, Margaret; Bedi, Gillinder; Cooper, Ziva D; Glass, Andrew; Vosburg, Suzanne K; Comer, Sandra D; Foltin, Richard W

2013-02-01

Few marijuana smokers in treatment achieve sustained abstinence, yet factors contributing to high relapse rates are unknown. Study 1: data from five inpatient laboratory studies assessing marijuana intoxication, withdrawal, and relapse were combined to assess factors predicting the likelihood and severity of relapse. Daily, nontreatment-seeking marijuana smokers (n = 51; 10 ± 5 marijuana cigarettes/day) were enrolled. Study 2: to isolate the effects of cigarette smoking, marijuana intoxication, withdrawal, and relapse were assessed in daily marijuana and cigarette smokers (n = 15) under two within-subject, counter-balanced conditions: while smoking tobacco cigarettes as usual (SAU), and after at least 5 days without cigarettes (Quit). Study 1: 49% of participants relapsed the first day active marijuana became available. Tobacco cigarette smokers (75%), who were not abstaining from cigarettes, were far more likely to relapse than non-cigarette smokers (odds ratio: 19, p < .01). Individuals experiencing more positive subjective effects (i.e., feeling "high") after marijuana administration and those with more negative affect and sleep disruption during marijuana withdrawal were more likely to have severe relapse episodes (p < .05). Study 2: most participants (>87%) relapsed to marijuana whether in the SAU or Quit phase. Tobacco cigarette smoking did not significantly influence relapse, nor did it affect marijuana intoxication or most symptoms of withdrawal relative to tobacco cessation. Daily marijuana smokers who also smoke cigarettes have high rates of marijuana relapse, and cigarette smoking versus recent abstinence does not directly influence this association. These data indicate that current cigarette smoking is a clinically important marker for increased risk of marijuana relapse. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Decreased dopamine activity predicts relapse in methamphetamine abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang G. J.; Wang, G.-J.; Smith, L.

2011-01-20

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested withinmore » 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.« less

Decreased dopamine activity predicts relapse in methamphetamine abusers.

PubMed

Wang, G J; Smith, L; Volkow, N D; Telang, F; Logan, J; Tomasi, D; Wong, C T; Hoffman, W; Jayne, M; Alia-Klein, N; Thanos, P; Fowler, J S

2012-09-01

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Biomarker significance of plasma and tumor miR-21, miR-221, and miR-106a in osteosarcoma. | Office of Cancer Genomics

Cancer.gov

Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of surgery and multi-agent chemotherapy, osteosarcoma patients who have a poor response to chemotherapy or develop relapses have a dismal outcome. Identification of biomarkers for active disease may help to monitor tumor burden, detect early relapses, and predict prognosis in these patients. In this study, we examined whether circulating miRNAs can be used as biomarkers in osteosarcoma patients.

Smokers can quit regardless of motivation stage in a worksite smoking cessation programme in Malaysia.

PubMed

Yasin, Siti Munira; Retneswari, Masilamani; Moy, Foong Ming; Koh, David; Isahak, Marzuki

2011-01-01

There is an unclear relationship between smoker's early motivation and success rates. Here we aimed to explore the correlates of motivation and smoking abstinence and relapse in worksite smoking cessation programmes. This prospective cohort study involved employees from two major public universities in Malaysia. Participants were actively recruited into a smoking cessation programme. At the start of treatment, participants were administered a questionnaire on sociodemographic variables, smoking habits and 'stage of change'. Behaviour therapy with free nicotine replacement therapy (NRT) was given as treatment for two months. A similar stage of change questionnaire was given at six months, and their smoking status was determined. There were 185 smokers from both Universities, who joined the programme. At six months, 24 smokers reported sustained abstinence while the others had relapsed. Prior to the programme, the majority of smokers were seriously planning on quitting (59.5%--preparation stage), but over a third had no plans to quit (35.5%--contemplation stage). There was no significant difference noted in changes of motivation stage among the relapsers and the non quitters. In addition, logistic regression showed that sustained abstinence was not predicted by pre-session motivation stage, but this did predict higher relapse for the participants, compared to those in the preparation stage. It is possible to help smokers in the lower motivation groups to quit, provided extra caution is taken to prevent relapse. Healthcare providers' recruitment strategies for cessation programmes should thus encompass smokers in all motivation stages.

Early life adversity influences stress response association with smoking relapse.

PubMed

al'Absi, Mustafa; Lemieux, Andrine; Westra, Ruth; Allen, Sharon

2017-11-01

We examined the hypothesis that stress-related blunting of cortisol in smokers is particularly pronounced in those with a history of severe life adversity. The two aims of this study were first to examine hormonal, craving, and withdrawal symptoms during ad libitum smoking and after the first 24 h of abstinence in smokers who experienced high or low levels of adversity. Second, we sought to examine the relationship between adversity and hypothalamic-pituitary-adrenal (HPA) hormones to predict relapse during the first month of a smoking cessation attempt. Hormonal and self-report measures were collected from 103 smokers (49 women) during ad libitum smoking and after the first 24 h of abstinence. HPA hormones were measured during baseline rest and in response to acute stress in both conditions. All smokers were interested in smoking cessation, and we prospectively used stress response measures to predict relapse during the first 4 weeks of the smoking cessation attempt. The results showed that high adversity was associated with higher distress and smoking withdrawal symptoms. High level of early life adversity was associated with elevated HPA activity, which was found in both salivary and plasma cortisol. Enhanced adrenocorticotropic hormone (ACTH) stress response was evident in high-adversity but not in low-adversity relapsers. This study demonstrated that early life adversity is associated with stress-related HPA responses. The study also demonstrated that, among smokers who experienced a high level of life adversity, heightened ACTH and cortisol responses were linked with increased risk for smoking relapse.

Trait impulsive choice predicts resistance to extinction and propensity to relapse to cocaine seeking: a bidirectional investigation.

PubMed

Broos, Nienke; Diergaarde, Leontien; Schoffelmeer, Anton Nm; Pattij, Tommy; De Vries, Taco J

2012-05-01

Despite the strong association between impulsivity and addiction in humans, it is still a matter of debate whether impulsive choice predisposes to, or results from, drug dependence. Furthermore, it is unknown whether treating impulsivity can protect against relapse propensity. Therefore, this study explored the bidirectional relationship between impulsive choice and cocaine taking and seeking in rat behavioral models. In experiment 1, to determine whether impulsive choice predisposes to cocaine taking or seeking, rats were selected based on trait impulsivity in a delayed reward task and subsequently compared on various stages of cocaine self-administration (SA). To examine the consequence of cocaine intake on impulsive choice, impulsivity was monitored once a week throughout various stages of cocaine SA. To determine whether treating impulsive choice can protect against relapse propensity, in experiment 2, impulsive choice was manipulated by pharmacological interventions and cocaine-associated contextual cues. Trait impulsive choice as determined in experiment 1 predicted high extinction resistance and enhanced propensity to context-induced relapse in the cocaine SA model, whereas cocaine intake did not alter impulsive choice. Furthermore, acute changes in impulsive choice were not related to rates of context-induced relapse. Taken together, the current data indicate that trait impulsive choice predicts persistent cocaine seeking during extinction and enhanced propensity to relapse, whereas acute manipulations of impulsive choice had no favorable outcomes on relapse measures. These observations suggest that trait impulsivity can be used as a predictive factor for addiction liability, but treating this impulsivity does not necessarily protect against relapse.

Comparing early signs and basic symptoms as methods for predicting psychotic relapse in clinical practice.

PubMed

Eisner, Emily; Drake, Richard; Lobban, Fiona; Bucci, Sandra; Emsley, Richard; Barrowclough, Christine

2018-02-01

Early signs interventions show promise but could be further developed. A recent review suggested that 'basic symptoms' should be added to conventional early signs to improve relapse prediction. This study builds on preliminary evidence that basic symptoms predict relapse and aimed to: 1. examine which phenomena participants report prior to relapse and how they describe them; 2. determine the best way of identifying pre-relapse basic symptoms; 3. assess current practice by comparing self- and casenote-reported pre-relapse experiences. Participants with non-affective psychosis were recruited from UK mental health services. In-depth interviews (n=23), verbal checklists of basic symptoms (n=23) and casenote extracts (n=208) were analysed using directed content analysis and non-parametric statistical tests. Three-quarters of interviewees reported basic symptoms and all reported conventional early signs and 'other' pre-relapse experiences. Interviewees provided rich descriptions of basic symptoms. Verbal checklist interviews asking specifically about basic symptoms identified these experiences more readily than open questions during in-depth interviews. Only 5% of casenotes recorded basic symptoms; interviewees were 16 times more likely to report basic symptoms than their casenotes did. The majority of interviewees self-reported pre-relapse basic symptoms when asked specifically about these experiences but very few casenotes reported these symptoms. Basic symptoms may be potent predictors of relapse that clinicians miss. A self-report measure would aid monitoring of basic symptoms in routine clinical practice and would facilitate a prospective investigation comparing basic symptoms and conventional early signs as predictors of relapse. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Predictors of relapse in patients with major depressive disorder in a 52-week, fixed dose, double blind, randomized trial of selegiline transdermal system (STS).

PubMed

Jang, Saeheon; Jung, Sungwon; Pae, Chiun; Kimberly, Blanchard Portland; Craig Nelson, J; Patkar, Ashwin A

2013-12-01

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment. After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥ 14 and a CGI-S score of ≥ 3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse. For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis. While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD. © 2013 Published by Elsevier B.V.

The Tridimensional Personality Questionnaire as a predictor of relapse in detoxified alcohol dependents. The European Fluvoxamine in Alcoholism Study Group.

PubMed

Meszaros, K; Lenzinger, E; Hornik, K; Füreder, T; Willinger, U; Fischer, G; Schönbeck, G; Aschauer, H N

1999-03-01

Personality traits have been found as strong predictors for treatment response in different psychiatric disorders. We administered the Tridimensional Personality Questionnaire, which measures the three personality dimensions: novelty seeking, harm avoidance (HA), and reward dependence, as introduced by Cloninger in a multicenter study (11 centers in the United Kingdom, Eire, Switzerland, and Austria) with detoxified alcohol-dependent patients (n = 521). The objective of this study was to evaluate a possible predictive value of these three dimensions on relapse over 1 -year follow up. A logistic regression analysis showed that novelty seeking is a strong predictor for relapse in detoxified male alcoholics (p = 0.0007; p values adjusted for treatment), but not in females. In both sexes, HA and reward dependence were of no predictive value. However, we found a trend for significance of HA for predicting "early" relapse (4 weeks) in females (p = 0.074). Our results show that Tridimensional Personality Questionnaire personality traits have direct clinical applications for prediction of relapse in detoxified alcohol dependents and indicate the necessity of additional therapeutic treatment in risk groups.

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse.

PubMed

Schmiegelow, K; Heyman, M; Gustafsson, G; Lausen, B; Wesenberg, F; Kristinsson, J; Vettenranta, K; Schroeder, H; Forestier, E; Rosthoej, S

2010-04-01

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Probability and predictors of relapse to smoking: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)

PubMed Central

García-Rodríguez, Olaya; Secades-Villa, Roberto; Flórez-Salamanca, Ludwing; Okuda, Mayumi; Liu, Shang-Min; Blanco, Carlos

2013-01-01

Background The goal of this study was to estimate rates of relapse to smoking in the community and to identify predictors of relapse. Methods Data were drawn from the Waves 1 and 2 of the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC). Logistic regression analyses were used to estimate the probability of relapse at Wave 2 among individuals who were abstinent at Wave 1 given length of abstinence as well as the presence of several sociodemographic, psychopathologic and substance use-related variables at Wave 1. Results The risk for relapse among individuals who had been abstinent for 12 months or less at the baseline assessment was above 50%. Among individuals who had been abstinent for over a year, risk of relapse decreased hyperbolically as a function of time, and stabilized around 10% after 30 years of abstinence. Although several sociodemographic, psychopathologic and tobacco-related variables predicted relapse in univariate analyses, only younger age at cessation and shorter duration of abstinence independently predicted risk of relapse in multivariable analyses. Conclusions The first year after a quit attempt constitutes the period of highest risk for relapse. Although the risk for relapse decreases over time, it never fully disappears. Furthermore, younger age at smoking cessation also increases the risk for relapse. This information may help develop more targeted and effective relapse prevention programs. PMID:23570817

[Application of Competing Risks Model in Predicting Smoking Relapse Following Ischemic Stroke].

PubMed

Hou, Li-Sha; Li, Ji-Jie; Du, Xu-Dong; Yan, Pei-Jing; Zhu, Cai-Rong

2017-07-01

To determine factors associated with smoking relapse in men who survived from their first stroke. Data were collected through face to face interviews with stroke patients in the hospital, and then repeated every three months via telephone over the period from 2010 to 2014. Kaplan-Meier method and competing risk model were adopted to estimate and predict smoking relapse rates. The Kaplan-Meier method estimated a higher relapse rate than the competing risk model. The four-year relapse rate was 43.1% after adjustment of competing risk. Exposure to environmental tobacco smoking outside of home and workplace (such as bars and restaurants) ( P =0.01), single ( P <0.01), and prior history of smoking at least 20 cigarettes per day ( P =0.02) were significant predictors of smoking relapse. When competing risks exist, competing risks model should be used in data analyses. Smoking interventions should give priorities to those without a spouse and those with a heavy smoking history. Smoking ban in public settings can reduce smoking relapse in stroke patients.

The Alcohol Relapse Situation Appraisal Questionnaire: Development and Validation

PubMed Central

Martin, Rosemarie A.; MacKinnon, Selene M.; Johnson, Jennifer E.; Myers, Mark G.; Cook, Travis A. R.; Rohsenow, Damaris J.

2011-01-01

Background The role of cognitive appraisal of the threat of alcohol relapse has received little attention. A previous instrument, the Relapse Situation Appraisal Questionnaire (RSAQ), was developed to assess cocaine users’ primary appraisal of the threat of situations posing a high risk for cocaine relapse. The purpose of the present study was to modify the RSAQ in order to measure primary appraisal in situations involving a high risk for alcohol relapse. Methods The development and psychometric properties of this instrument, the Alcohol Relapse Situation Appraisal Questionnaire (A-RSAQ), were examined with two samples of abstinent adults with alcohol abuse or dependence. Factor structure and validity were examined in Study 1 (N=104). Confirmation of the factor structure and predictive validity were assessed in Study 2 (N=161). Results Results demonstrated construct, discriminant and predictive validity and reliability of the A-RSAQ. Discussion Results support the important role of primary appraisal of degree of risk in alcohol relapse situations. PMID:21237586

Temperament and impulsivity predictors of smoking cessation outcomes.

PubMed

López-Torrecillas, Francisca; Perales, José C; Nieto-Ruiz, Ana; Verdejo-García, Antonio

2014-01-01

Temperament and impulsivity are powerful predictors of addiction treatment outcomes. However, a comprehensive assessment of these features has not been examined in relation to smoking cessation outcomes. Naturalistic prospective study. Treatment-seeking smokers (n = 140) were recruited as they engaged in an occupational health clinic providing smoking cessation treatment between 2009 and 2013. Participants were assessed at baseline with measures of temperament (Temperament and Character Inventory), trait impulsivity (Barratt Impulsivity Scale), and cognitive impulsivity (Go/No Go, Delay Discounting and Iowa Gambling Task). The outcome measure was treatment status, coded as "dropout" versus "relapse" versus "abstinence" at 3, 6, and 12 months endpoints. Participants were telephonically contacted and reminded of follow-up face to face assessments at each endpoint. The participants that failed to answer the phone calls or self-reported discontinuation of treatment and failed to attend the upcoming follow-up session were coded as dropouts. The participants that self-reported continuing treatment, and successfully attended the upcoming follow-up session were coded as either "relapse" or "abstinence", based on the results of smoking behavior self-reports cross-validated with co-oximetry hemoglobin levels. Multinomial regression models were conducted to test whether temperament and impulsivity measures predicted dropout and relapse relative to abstinence outcomes. Higher scores on temperament dimensions of novelty seeking and reward dependence predicted poorer retention across endpoints, whereas only higher scores on persistence predicted greater relapse. Higher scores on the trait dimension of non-planning impulsivity but not performance on cognitive impulsivity predicted poorer retention. Higher non-planning impulsivity and poorer performance in the Iowa Gambling Task predicted greater relapse at 3 and 6 months and 6 months respectively. Temperament measures, and specifically novelty seeking and reward dependence, predict smoking cessation treatment retention, whereas persistence, non-planning impulsivity and poor decision-making predict smoking relapse.

The Impact of Stressful Life Events on Alcohol Relapse: Findings from the Collaborative Longitudinal Personality Disorders Study.

PubMed

Reyes, Christina Delos; Pagano, Maria Elizabeth; Ronis, Robert J

2009-04-01

Alcohol relapse is impacted by a variety of environmental, interpersonal, and intrapersonal factors. We examined the interaction between stressful life events, personality disorder subtype, and alcohol relapse among individuals enrolled in the Collaborative Longitudinal Personality Disorders Study (CLPS). Negative life events predicted relapse in all subjects. In individuals with a history of an alcohol use disorder prior to study entry, positive life events also predicted alcohol relapse. Individuals with Antisocial Personality Disorder (ASPD) were found to be twice as likely to relapse in response to life stressors compared to individuals with Obsessive-Compulsive Personality Disorder (OCPD), who were half as likely to relapse in response to life stressors. Further analysis revealed that individuals with OCPD and no history of an alcohol use disorder were almost 10 times more likely to relapse in the face of a stressful romantic problem, while those with ASPD and a history of an alcohol use disorder were six times more likely to relapse in response to a stressful financial event. These findings have implications for both the assessment and the treatment of individuals who present with co-morbid personality and alcohol use disorders.

The Impact of Stressful Life Events on Alcohol Relapse: Findings from the Collaborative Longitudinal Personality Disorders Study

PubMed Central

Reyes, Christina Delos; Pagano, Maria Elizabeth; Ronis, Robert J.

2009-01-01

Alcohol relapse is impacted by a variety of environmental, interpersonal, and intrapersonal factors. We examined the interaction between stressful life events, personality disorder subtype, and alcohol relapse among individuals enrolled in the Collaborative Longitudinal Personality Disorders Study (CLPS). Negative life events predicted relapse in all subjects. In individuals with a history of an alcohol use disorder prior to study entry, positive life events also predicted alcohol relapse. Individuals with Antisocial Personality Disorder (ASPD) were found to be twice as likely to relapse in response to life stressors compared to individuals with Obsessive-Compulsive Personality Disorder (OCPD), who were half as likely to relapse in response to life stressors. Further analysis revealed that individuals with OCPD and no history of an alcohol use disorder were almost 10 times more likely to relapse in the face of a stressful romantic problem, while those with ASPD and a history of an alcohol use disorder were six times more likely to relapse in response to a stressful financial event. These findings have implications for both the assessment and the treatment of individuals who present with co-morbid personality and alcohol use disorders. PMID:21170176

Predictors of Relapse in Patients with Organizing Pneumonia

PubMed Central

Kim, Minjung; Seo, Hyewon; Shin, Kyung-Min; Lim, Jae-Kwang; Kim, Hyera; Yoo, Seung-Soo; Lee, Jaehee; Lee, Shin-Yup; Kim, Chang-Ho; Park, Jae-Yong

2015-01-01

Background Although organizing pneumonia (OP) responds well to corticosteroid therapy, relapse is common during dose reduction or follow-up. Predictors of relapse in OP patients remain to be established. The aim of the present study was to identify factors related to relapse in OP patients. Methods This study was retrospectively performed in a tertiary referral center. Of 66 OP patients who were improved with or without treatment, 20 (30%) experienced relapse. The clinical and radiologic parameters in the relapse patient group (n=20) were compared to that in the non-relapse group (n=46). Results Multivariate analysis demonstrated that percent predicted forced vital capacity (FVC), PaO2/FiO2, and serum protein level were significant predictors of relapse in OP patients (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.70-0.97; p=0.018; OR, 1.02; 95% CI, 1.00-1.04; p=0.042; and OR, 0.06; 95% CI, 0.01-0.87; p=0.039, respectively). Conclusion This study shows that FVC, PaO2/FiO2 and serum protein level at presentation can significantly predict relapse in OP patients. PMID:26175771

Syphilis and neurosyphilis in a human immunodeficiency virus type-1 seropositive population: evidence for frequent serologic relapse after therapy.

PubMed

Malone, J L; Wallace, M R; Hendrick, B B; LaRocco, A; Tonon, E; Brodine, S K; Bowler, W A; Lavin, B S; Hawkins, R E; Oldfield, E C

1995-07-01

To describe clinical and treatment aspects of syphilis infection among patients seropositive for the human immunodeficiency virus (HIV). Results of serologic tests for syphilis, CD4+ T-lymphocyte counts, and clinical response to therapy were retrospectively monitored in 100 HIV-infected adults with syphilis from a tertiary-care military HIV program. Of the 1,206 HIV-infected patients, 100 (8.3%) in the cohort had syphilis; 61 patients were treated for active syphilis. Serologic or clinical relapse eventually occurred in 10 of the 56 treated patients (17.9%) with follow-up available; 7 of the 10 who relapsed had previously received high-dose intravenous or procaine penicillin therapy. Relapse occurred more than 12 months after initial therapy in 6 of 10 patients (60%) who experienced relapse; 5 patients experienced multiple relapses. The mean CD4+ T-lymphocyte count was not predictive of relapse. Patients with reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test titers (4 of 7 patients [57%]) or the rash of secondary syphilis (4 of 14 patients [29%]) were at highest risk of subsequent relapse or treatment failure when monitored for an average of 2 years. Standard penicillin regimens, including high-dose intravenous penicillin, transiently lowered serum VDRL titers in nearly all cases, but were sometimes inadequate in preventing serologic and clinical relapse in patients infected with HIV type-1, especially among those with secondary syphilis and reactive CSF VDRL titers. Careful long-term follow-up is essential, and repeated courses of therapy may be needed for patients infected with HIV type-1 who have syphilis.

Short-term stress, but not mucosal healing nor depression was predictive for the risk of relapse in patients with ulcerative colitis: a prospective 12-month follow-up study.

PubMed

Langhorst, Jost; Hofstetter, Anna; Wolfe, Fred; Häuser, Winfried

2013-10-01

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Psychological factors such as depression and stress are under debate to contribute to the risk of relapse. The impact of mucosal healing to reduce the risk of relapse had not been studied prospectively. The aim of this study was to identify whether depression and stress increase and mucosal healing reduces the risk of clinical relapse in patients with UC in clinical remission. Patients in clinical remission were followed prospectively for 1 year, or less if they relapsed. Endoscopy and histology score and long-term perceived stress (Perceived Stress Questionnaire) were measured at baseline. Mucosal healing was defined by a Mayo Endoscopy score of 0-1. Depression (Hospital Anxiety and Depression Scale) and acute perceived stress (Cohen Perceived Stress Scale) were measured at baseline and after 1, 3, 6, 9, and 12 months. A time-dependent multivariate Cox regression model determined the predictors of time to relapse. Seventy-five patients were included into final analysis, of which 28 (37.3%) relapsed. Short-term stress at the last visit before relapse (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.10) and male gender (HR = 2.38, 95% CI = 1.01-5.61), but not baseline mucosal healing (HR = 0.86, 95% CI = 0.35-2.11), baseline long-term stress (HR = 0.20, 95% CI = 0.01-3.31), and depression at the last visit before relapse (HR = 1.08, 95% CI = 0.95-1.22) were predictive for a relapse. Short-term stress but not depression nor mucosal healing was predictive for the risk of relapse in patients with UC in clinical remission. Larger multicentre studies are necessary to confirm our findings.

[Clinical and biological prognostic factors in relapsed acute myeloid leukemia patients].

PubMed

Yébenes-Ramírez, Manuel; Serrano, Josefina; Martínez-Losada, Carmen; Sánchez-García, Joaquín

2016-09-02

Acute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Despite recent advances in the characterization of pathogenesis of AML, the cure rates are under 40%, being leukemia relapse the most common cause of treatment failure. Leukaemia relapse occurs due to clonal evolution or clonal escape. In this study, we aimed to analyze the clinical and biological factors influencing outcomes in patients with AML relapse. We included a total of 75 AML patients who experienced leukaemia relapse after achieving complete remission. We performed complete immunophenotyping and conventional karyotyping in bone marrow aspirates obtained at diagnosis and at leukemia relapse. Overall survival (OS) of the series was 3.7%±2.3, leukaemia progression being the most common cause of death. Patients relapsing before 12 months and those with adverse cytogenetic-molecular risk had statistically significant worse outcomes. A percentage of 52.5 of patients showed phenotypic changes and 50% cytogenetic changes at relapse. We did not find significant clinical factors predicting clonal evolution. The presence of clonal evolution at relapse did not have a significant impact on outcome. Patients with relapsed AML have a dismal prognosis, especially those with early relapse and adverse cytogenetic-molecular risk. Clonal evolution with phenotypic and cytogenetic changes occurred in half of the patients without predictive clinical factors or impact on outcome. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

[Open narcissism, covered narcissism and personality disorders as predictive factors of treatment response in an out-patient Drug Addiction Unit].

PubMed

Salazar-Fraile, José; Ripoll-Alandes, Carmen; Bobes, Julio

2010-01-01

Although a high prevalence of personality disorders has been reported in substance users, the literature on their value for predicting treatment response is controversial. On the other hand, while the predictive validity of personality traits as predictors of response to drug abuse or dependence has been studied, research on the validity of narcissistic personality traits is scarce. To study the predictive value of personality disorders, narcissistic personality traits and self-esteem for predicting treatment response. We assessed 78 patients attended at an addiction treatment unit using personality disorder diagnoses and measures of self-esteem, narcissism and covert (hypersensitive) narcissism. These variables were used in a Cox survival model as predictive variables of time to relapse into drug use. Hypersensitive (covert) narcissism and borderline and passive-aggressive personality disorders were risk factors for relapse into drug use, while open narcissism was a protective factor. Self-esteem did not show predictive validity. Personality disorders characterized by impulsivity-instability and passivity-resentfulness show higher risk of relapse into drug abuse. Personality traits characterized by high sensitivity to humiliation increase the risk of relapse, whereas pride and self-confidence are protective factors.

High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study.

PubMed

Yoon, Jae-Ho; Kim, Hee-Je; Kwak, Dae-Hun; Park, Sung-Soo; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2017-01-23

Wilms' tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/10 4 ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. Clinical Research Information Service (CRIS), KCT0002079.

Effects of a GABA-ergic medication combination and initial alcohol withdrawal severity on cue-elicited brain activation among treatment-seeking alcoholics.

PubMed

Schacht, Joseph P; Anton, Raymond F; Randall, Patrick K; Li, Xingbao; Henderson, Scott; Myrick, Hugh

2013-06-01

Many studies have reported medication effects on alcohol cue-elicited brain activation or associations between such activation and subsequent drinking. However, few have combined the methodological rigor of a randomized clinical trial (RCT) with follow-up assessments to determine whether cue-elicited activation predicts relapse during treatment, the crux of alcoholism. This study analyzed functional magnetic resonance imaging (fMRI) data from 48 alcohol-dependent subjects enrolled in a 6-week RCT of an investigational pharmacotherapy. Subjects were randomized, based on their level of alcohol withdrawal (AW) at study entry, to receive either a combination of gabapentin (GBP; up to 1,200 mg for 39 days) and flumazenil (FMZ) infusions (2 days) or two placebos. Midway through the RCT, subjects were administered an fMRI alcohol cue reactivity task. There were no main effects of medication or initial AW status on cue-elicited activation, but these factors interacted, such that the GBP/FMZ/higher AW and placebo/lower AW groups, which had previously been shown to have relatively reduced drinking, demonstrated greater dorsal anterior cingulate cortex (dACC) activation to alcohol cues. Further analysis suggested that this finding represented differences in task-related deactivation and was associated with greater control over alcohol-related thoughts. Among study completers, regardless of medication or AW status, greater left dorsolateral prefrontal cortex (DLPFC) activation predicted more post-scan heavy drinking. These data suggest that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.

Do predictors of smoking relapse change as a function of duration of abstinence? Findings from the United States, Canada, United Kingdom and Australia.

PubMed

Yong, Hua-Hie; Borland, Ron; Cummings, K Michael; Partos, Timea

2018-07-01

To estimate predictors of time to smoking relapse and test if prediction varied by quit duration. Longitudinal cohort data from the International Tobacco Control Four-Country survey with annual follow up collected between 2002 and 2015. Canada, United States, United Kingdom and Australia. A total of 9171 eligible adult smokers who had made at least one quit attempt during the study period. Time to relapse was the main outcome. Predictor variables included pre-quit baseline measures of nicotine dependence, smoking and quitting-related motivations, quitting capacity and social influence, and also two post-quit measures, use of stop-smoking medications and quit duration (1-7 days, 8-14 days, 15-31 days, 1-3 months, 3-6 months, 6-12 months, 1-2 years and 2+ years), along with socio-demographics. All factors were predictive of relapse within the first 6 months of quitting but only wanting to quit, quit intentions and number of friends who smoke were still predictive of relapse in the 6-12-month period of quitting [hazard ratios (HR) = 1.20, P < 0.05; 1.13, P < 0.05; and 1.21, P < 0.001, respectively]. Number of friends smoking was the only remaining predictor of relapse in the 1-2 years quit period (HR = 1.19, P = 0.001) with none predictive beyond the 2-year quit period. Use of stop-smoking medications during quit attempts was related negatively to relapse during the first 2 weeks of quitting (HR = 0.71-0.84), but related positively to relapse in the 1-6-month quit period (HR = 1.29-1.54). Predictive effects of all factors showed significant interaction with quit duration except for perceiving smoking as an important part of life, prematurely stubbing out a cigarette and wanting to quit. Among adult smokers in the United States, Canada, United Kingdom and Australia, factors associated with smoking relapse differ between the early and later stages of a quit attempt, suggesting that the determinants of relapse change as a function of abstinence duration. © 2018 Society for the Study of Addiction.

Characteristics predicting outcomes of allogeneic stem-cell transplantation in relapsed acute myelogenous leukemia.

PubMed

Frazer, J; Couban, S; Doucette, S; Shivakumar, S

2017-04-01

Allogeneic hematopoietic stem-cell transplantation (ahsct) is associated with significant morbidity and mortality, but it can cure carefully selected patients with acute myeloid leukemia (aml) in second remission (cr2). In a cohort of patients with aml who underwent ahsct in cr2, we determined the pre-transplant factors that predicted for overall survival (os), relapse, and non-relapse mortality. We also sought to validate the prognostic risk groups derived by Michelis and colleagues in this independent population. In a retrospective chart review, we obtained data for 55 consecutive patients who underwent ahsct for aml in cr2. Hazard ratios were used to describe the independent effects of pre-transplant variables on outcome, and Kaplan-Meier curves were used to assess outcomes in the three prognostic groups identified by Michelis and colleagues. At 1, 3, and 5 years post-transplant, os was 60%, 45.5%, and 37.5% respectively. Statistically significant differences in os, relapse mortality, and non-relapse mortality were not identified between the prognostic risk groups identified by Michelis and colleagues. Women were less likely than men to relapse, and a modified European Society for Blood and Marrow Transplantation (mebmt) score of 3 or less was associated with a lower non-relapse mortality. The 37.5% 5-year os in this cohort suggests that, compared with other options, ahsct offers patients with aml in cr2 a better chance of cure. Our study supports the use of the mebmt score to predict non-relapse mortality in this population.

SOX9 expression predicts relapse of stage II colon cancer patients.

PubMed

Marcker Espersen, Maiken Lise; Linnemann, Dorte; Christensen, Ib Jarle; Alamili, Mahdi; Troelsen, Jesper T; Høgdall, Estrid

2016-06-01

The aim of this study was to investigate if the protein expression of sex-determining region y-box 9 (SOX9) in primary tumors could predict relapse of stage II colon cancer patients. One hundred forty-four patients with stage II primary colon cancer were retrospectively enrolled in the study. SOX9 expression was evaluated by immunohistochemistry, and mismatch repair status was assessed by both immunohistochemistry and promoter hypermethylation assay. High SOX9 expression at the invasive front was significantly associated with lower risk of relapse when including the SOX9 expression as a continuous variable (from low to high expression) in univariate (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.56-0.94; P = .01) and multivariate Cox proportional hazards analyses (HR, 0.75; 95% CI, 0.58-0.96; P = .02), adjusting for mismatch repair deficiency and histopathologic risk factors. Conversely, low SOX9 expression at the invasive front was significantly associated with high risk of relapse, when including SOX9 expression as a dichotomous variable, in univariate (HR, 2.32; 95% CI, 1.14-4.69; P = .02) and multivariate analyses (HR, 2.32; 95% CI, 1.14-4.69; P = .02), adjusting for histopathologic risk factors and mismatch repair deficiency. In conclusion, high levels of SOX9 of primary stage II colon tumors predict low risk of relapse, whereas low levels of SOX9 predict high risk of relapse. SOX9 may have an important value as a biomarker when evaluating risk of relapse for personalized treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Relapse Risk Assessment for Schizophrenia Patients (RASP): A New Self-Report Screening Tool.

PubMed

Velligan, Dawn; Carpenter, William; Waters, Heidi C; Gerlanc, Nicole M; Legacy, Susan N; Ruetsch, Charles

2018-01-01

The Relapse Assessment for Schizophrenia Patients (RASP) was developed as a six-question self-report screener that measures indicators of Increased Anxiety and Social Isolation to assess patient stability and predict imminent relapse. This paper describes the development and psychometric characteristics of the RASP. The RASP and Positive and Negative Syndrome Scale (PANSS) were administered to patients with schizophrenia (n=166) three separate times. Chart data were collected on a subsample of patients (n=81). Psychometric analyses of RASP included tests of reliability, construct validity, and concurrent validity of items. Factors from RASP were correlated with subscales from PANSS (sensitivity to change and criterion validity [agreement between RASP and evidence of relapse]). Test-retest reliability returned modest to strong agreement at the item level and strong agreement at the questionnaire level. RASP showed good item response curves and internal consistency for the total instrument and within each of the two subscales (Increased Anxiety and Social Isolation). RASP Total Score and subscales showed good concurrent validity when correlated with PANSS Total Score, Positive, Excitement, and Anxiety subscales. RASP correctly predicted relapse in 67% of cases, with good specificity and negative predictive power and acceptable positive predictive power and sensitivity. The reliability and validity data presented support the use of RASP in settings where addition of a brief self-report assessment of relapse risk among patients with schizophrenia may be of benefit. Ease of use and scoring, and the ability to administer without clinical supervision allows for routine administration and assessment of relapse risk.

Smoking cessation results in a clinical lung cancer screening program

PubMed Central

McKee, Andrea B.; Regis, Shawn M.; Wald, Christoph; Flacke, Sebastian; McKee, Brady J.

2016-01-01

Background Lung cancer screening may provide a “teachable moment” for promoting smoking cessation. This study assessed smoking cessation and relapse rates among individuals undergoing follow-up low-dose chest computed tomography (CT) in a clinical CT lung screening program and assessed the influence of initial screening results on smoking behavior. Methods Self-reported smoking status for individuals enrolled in a clinical CT lung screening program undergoing a follow-up CT lung screening exam between 1st February, 2014 and 31st March, 2015 was retrospectively reviewed and compared to self-reported smoking status using a standardized questionnaire at program entry. Point prevalence smoking cessation and relapse rates were calculated across the entire population and compared with exam results. All individuals undergoing screening fulfilled the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Lung Cancer Screening v1.2012® high-risk criteria and had an order for CT lung screening. Results A total of 1,483 individuals underwent a follow-up CT lung screening exam during the study interval. Smoking status at time of follow-up exam was available for 1,461/1,483 (98.5%). A total of 46% (678/1,461) were active smokers at program entry. The overall point prevalence smoking cessation and relapse rates were 20.8% and 9.3%, respectively. Prior positive screening exam results were not predictive of smoking cessation (OR 1.092; 95% CI, 0.715–1.693) but were predictive of reduced relapse among former smokers who had stopped smoking for 2 years or less (OR 0.330; 95% CI, 0.143–0.710). Duration of program enrollment was predictive of smoking cessation (OR 0.647; 95% CI, 0.477–0.877). Conclusions Smoking cessation and relapse rates in a clinical CT lung screening program rates are more favorable than those observed in the general population. Duration of participation in the screening program correlated with increased smoking cessation rates. A positive exam result correlated with reduced relapse rates among smokers recently quit smoking. PMID:27606076

Factors predicting changes in physical activity through adolescence: the Young-HUNT Study, Norway.

PubMed

Rangul, Vegar; Holmen, Turid Lingaas; Bauman, Adrian; Bratberg, Grete H; Kurtze, Nanna; Midthjell, Kristian

2011-06-01

The purpose of this prospective population-based study was to analyze predictors of changes in physical activity (PA) levels from early to late adolescence. Data presented are from 2,348 adolescents and their parents who participated in the Nord-Trøndelag Health study (HUNT 2, 1995-1997) and at follow-up in Young-HUNT 2, 2000-2001 Participants completed a self-reported questionnaire and participated in a clinical examination that included measurements of height and weight. Four patterns of PA emerged in the study: active or inactive at both time points (active maintainers, 13%; inactive maintainers, 59%), inactive and became active (adopters, 12%), active and became inactive (relapsers, 16%). Being overweight, dissatisfied with life, and not actively participating in sports at baseline were significant predictors of change regarding PA among boys at follow-up. For girls, smoking, drinking, low maternal education, and physical inactivity predicted relapsers and inactive maintainers. Higher levels of education and more physically active parents at baseline seemed to protect against decreased PA during follow-up for both genders. Predictors of change in, or maintaining PA status during adolescence differed by gender. These results suggest that PA-promoting interventions should be tailored by gender and focus on encouraging activity for inactive adolescents and maintenance of PA in those already active. Copyright © 2011 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Histologic Normalization Occurs in Ulcerative Colitis and Is Associated With Improved Clinical Outcomes.

PubMed

Christensen, Britt; Hanauer, Stephen B; Erlich, Jonathan; Kassim, Olufemi; Gibson, Peter R; Turner, Jerrold R; Hart, John; Rubin, David T

2017-10-01

Mucosal healing, determined by histologic analysis, is a potential therapeutic target for patients with ulcerative colitis (UC). However, the histologic features of tissue normalization, as an outcome of treatment, have not been well described. We examined the prevalence and predictive values of normalization of the colonic mucosa, based on histologic analysis (histologic normalization) in patients with UC, and determined its association with risk of clinical relapse, compared with histologic disease quiescence and endoscopic mucosal healing. We performed a retrospective study of 646 patients with confirmed UC who underwent colonoscopy at a tertiary medical center from August 2005 through October 2013. We reviewed reports from pathology analyses of random mucosal biopsies from each colon segment, and categorized them into 3 groups based on histology findings: (1) normalization (completely normal mucosa with no features of chronicity present), (2) quiescence (crypt atrophy or branching without signs of active inflammation including erosions, abscesses, or focal neutrophil infiltration), or (3) active disease (epithelial infiltration by neutrophils, crypt abscesses, erosions, or ulceration). Histology findings were compared with clinical and endoscopic findings. We assessed variables associated with histology findings and, in patients in clinical remission (Simple Clinical Colitis Activity Index score ≤2 and subscore of ≤1 for stool frequency or rectal bleeding), predictive values for clinical relapse at follow-up evaluations 6 months later or more were calculated. Of the 646 patients included in the study, 60% had endoscopic mucosal healing, 40% had histologic quiescence, and 10% had histologic normalization. The level of agreement between mucosal and histologic activity was moderate (agreement for 68% of samples; κ = 0.50; P < .001). On multivariate analysis, only proctitis associated with histologic normalization (P = .002). Of 310 patients in clinical remission at initial review, 25% had a clinical relapse, after a median time of 16 months (interquartile range, 10-23 months). Histologic normalization was independently associated with increased odds of relapse-free survival compared with histologic quiescence (hazard ratio, 4.31; 95% confidence interval, 1.48-12.46; P = .007) and histologic activity (hazard ratio, 6.69; 95% confidence interval, 2.16-20.62; P = .001); mucosal healing was not associated with increased odds of relapse-free survival compared with no mucosal healing (hazard ratio, 1.02; 95% confidence interval, 0.56-1.85; P = .954). Histologic normalization of colonic mucosa can be used as a clinical endpoint for patients with UC. We associated histologic normalization with increased odds of relapse-free survival compared with endoscopic healing or histologic quiescence. Further studies are needed to determine whether histologic normalization should be a goal of treatment for patients with UC. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Peripheral Blood WT1 Expression Predicts Relapse in AML Patients Undergoing Allogeneic Stem Cell Transplantation

PubMed Central

Malagola, Michele; Skert, Cristina; Ruggeri, Giuseppina; Ribolla, Rossella; Bernardi, Simona; Borlenghi, Erika; Pagani, Chiara; Rossi, Giuseppe; Caimi, Luigi; Russo, Domenico

2014-01-01

To evaluate if WT1 expression may predict relapse after allo-SCT, we analyzed WT1 levels on peripheral blood (PB) and bone marrow (BM) before and after allo-SCT in 24 AML patients with WT1 overexpression at diagnosis. Five copies of WT1/ABL × 104 from PB were identified as the threshold value that correlated with relapse after allo-SCT. The same correlation was not identified when WT1 expression was assessed from bone marrow (BM). Eight out of 11 (73%) patients with a pre-allo-SCT PB-WT1 ≥ 5 and 4/13 (31%) patients with a pre-allo-SCT PB-WT1 < 5 relapsed, respectively (P = 0.04). The incidence of relapse was higher in patients with PB-WT1 ≥ 5 measured after allo-SCT, at the 3rd (56% versus 38%; P = 0.43) and at the 6th month (71% versus 20%; P = 0.03). Patients with pretransplant PB-WT1 < 5 had significantly better 2-year OS and LFS than patients with a PB-WT1 ≥ 5 (81% versus 0% and 63% versus 20%) (P = 0.02). Our data suggest the usefulness of WT1 monitoring from PB to predict the relapse in allotransplanted AML patients and to modulate the intensity of conditioning and/or the posttransplant immunosuppression in an attempt to reduce the posttransplant relapse risk. PMID:25202702

Longitudinal Investigation of Smoking Initiation and Relapse Among Younger and Older US Military Personnel

PubMed Central

Trone, Daniel W.; Peterson, Arthur V.; Jacobson, Isabel G.; Littman, Alyson J.; Maynard, Charles; Seelig, Amber D.; Crum-Cianflone, Nancy F.; Bricker, Jonathan B.

2015-01-01

Objectives. We examined whether military service, including deployment and combat experience, were related to smoking initiation and relapse. Methods. We included older (panel 1) and younger (panel 2) participants in the Millennium Cohort Study. Never smokers were followed for 3 to 6 years for smoking initiation, and former smokers were followed for relapse. Complementary log-log regression models estimated the relative risk (RR) of initiation and relapse by military exposure while adjusting for demographic, health, and lifestyle factors. Results. Deployment with combat experience predicted higher initiation rate (panel 1: RR = 1.44; 95% confidence interval [CI] = 1.28, 1.62; panel 2: RR = 1.26; 95% CI = 1.04, 1.54) and relapse rate (panel 1 only: RR = 1.48; 95% CI = 1.36, 1.62). Depending on the panel, previous mental health disorders, life stressors, and other military and nonmilitary characteristics independently predicted initiation and relapse. Conclusions. Deployment with combat experience and previous mental disorder may identify military service members in need of intervention to prevent smoking initiation and relapse. PMID:25880953

Impulsive suicide attempts predict post-treatment relapse in alcohol-dependent patients.

PubMed

Wojnar, Marcin; Ilgen, Mark A; Jakubczyk, Andrzej; Wnorowska, Anna; Klimkiewicz, Anna; Brower, Kirk J

2008-10-01

The present study was designed to examine the influence of suicidality on relapse in alcohol-dependent patients. Specifically, a lifetime suicide attempt at baseline was used to predict relapse in the year after treatment. Also, the unique contribution of impulsive suicide attempts was examined. A total of 154 patients with alcohol dependence, consecutively admitted to four addiction treatment facilities in Warsaw, Poland participated in the study. Of the 154 eligible patients, 118 (76.6%) completed a standardized follow-up assessment at 12 months. Previous suicide attempts were common in adults treated for alcohol dependence with 43% patients in the present sample reporting an attempt at some point during their lifetime. Additionally, more than 62% of those with a lifetime suicide attempt reported making an impulsive attempt. Lifetime suicide attempts were not associated with post-treatment relapse (chi-square=2.37, d.f.=1, p=0.124). However, impulsive suicide attempts strongly predicted relapse (OR=2.81, 95% CI=1.13-6.95, p=0.026) and time to relapse (OR=2.10, 95% CI=1.18-3.74, p=0.012) even after adjusting for other measures of baseline psychopathology, depression, impulsivity, hopelessness and alcohol use severity. This study is the first to document the relationship between pre-treatment impulsive suicide attempts and higher likelihood of post-treatment relapse in alcohol-dependent patents. Clinicians should routinely conduct an assessment for previous suicide attempts in patients with alcohol use disorders, and when impulsive suicidality is reported, they should recognize the increased risk for relapse and formulate their patients' treatment plans accordingly with the goals of reducing both alcoholic relapse and suicide rates.

Global map of physical interactions among differentially expressed genes in multiple sclerosis relapses and remissions.

PubMed

Tuller, Tamir; Atar, Shimshi; Ruppin, Eytan; Gurevich, Michael; Achiron, Anat

2011-09-15

Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory T-cell-mediated disease with a relapsing-remitting course in the majority of patients. In this study, we performed a high-resolution systems biology analysis of gene expression and physical interactions in MS relapse and remission. To this end, we integrated 164 large-scale measurements of gene expression in peripheral blood mononuclear cells of MS patients in relapse or remission and healthy subjects, with large-scale information about the physical interactions between these genes obtained from public databases. These data were analyzed with a variety of computational methods. We find that there is a clear and significant global network-level signal that is related to the changes in gene expression of MS patients in comparison to healthy subjects. However, despite the clear differences in the clinical symptoms of MS patients in relapse versus remission, the network level signal is weaker when comparing patients in these two stages of the disease. This result suggests that most of the genes have relatively similar expression levels in the two stages of the disease. In accordance with previous studies, we found that the pathways related to regulation of cell death, chemotaxis and inflammatory response are differentially expressed in the disease in comparison to healthy subjects, while pathways related to cell adhesion, cell migration and cell-cell signaling are activated in relapse in comparison to remission. However, the current study includes a detailed report of the exact set of genes involved in these pathways and the interactions between them. For example, we found that the genes TP53 and IL1 are 'network-hub' that interacts with many of the differentially expressed genes in MS patients versus healthy subjects, and the epidermal growth factor receptor is a 'network-hub' in the case of MS patients with relapse versus remission. The statistical approaches employed in this study enabled us to report new sets of genes that according to their gene expression and physical interactions are predicted to be differentially expressed in MS versus healthy subjects, and in MS patients in relapse versus remission. Some of these genes may be useful biomarkers for diagnosing MS and predicting relapses in MS patients.

Rates and Predictors of Renewed Quitting After Relapse During a One-Year Follow-Up Among Primary Care Patients

PubMed Central

Bold, Krysten W.; Rasheed, Abdullah S.; McCarthy, Danielle E.; Jackson, Thomas C.; Fiore, Michael C.; Baker, Timothy B.

2014-01-01

Background Most people who quit smoking relapse within a year of quitting. Little is known about what prompts renewed quitting after relapse or how often this results in abstinence. Purpose To identify rates, efficacy, and predictors of renewed quit attempts after relapse during a one-year follow-up. Methods Primary care patients in a comparative effectiveness trial of smoking cessation pharmacotherapies reported daily smoking every 6–12 weeks for 12 months to determine relapse, renewed quitting, and 12-month abstinence rates. Results Of 894 known relapsers, 291 (33%) renewed quitting for at least 24 hours and 99 (34%) of these were abstinent at follow-up. The average latency to renewed quitting was 106 days and longer latencies predicted greater success. Renewed quitting was more likely for older, male, less dependent smokers, and later abstinence was predicted by fewer depressive symptoms and longer past abstinence. Conclusions Renewed quitting is common and produces meaningful levels of cessation. PMID:24796541

Consecutive monitoring of faecal calprotectin during mesalazine suppository therapy for active rectal inflammation in ulcerative colitis.

PubMed

Yamamoto, T; Shimoyama, T; Matsumoto, K

2015-09-01

No studies have monitored the levels of faecal calprotectin (FC) during mesalazine suppository therapy for proctitis in ulcerative colitis (UC). To evaluate the value of consecutive monitoring of FC in patients with UC during mesalazine suppository therapy. One hundred and sixty patients with active inflammation limited to the rectum were treated with mesalazine 1 g suppository once daily for 8 weeks. Patients who achieved clinical remission were advised to maintain the treatment, and were followed up for further 40 weeks. FC levels were measured every 8 weeks during the study. At week 8, 118 patients (74%) went into clinical remission, of whom 88 achieved endoscopic healing. The median FC level significantly decreased in patients with clinical and endoscopic remission (both P < 0.0001), while it did not change significantly in those without remission. Eighty (68%) of the 118 patients with remission continued the treatment. Twenty-four patients (30%) relapsed during the 40-week follow-up. In patients with clinical relapse, the median FC level elevated already 8 weeks before the diagnosis of relapse. In contrast, in patients who maintained remission it remained at a low level and did not significantly change during the follow-up. Elevated FC level (≥55 μg/g) was useful for the early diagnosis of relapse (88% sensitivity and 80% specificity). Faecal calprotectin may represent a useful biomarker for the assessment of disease activity in UC patients treated with mesalazine suppositories. Serial monitoring of faecal calprotectin appears to be valuable for the prediction and early diagnosis of relapse during maintenance therapy. © 2015 John Wiley & Sons Ltd.

Genotype and Phenotype Predictors of Relapse of Graves’ Disease after Antithyroid Drug Withdrawal

PubMed Central

Wang, Pei-Wen; Chen, I-Ya; Juo, Suh-Hang Hank; Hsi, Edward; Liu, Rue-Tsuan; Hsieh, Ching-Jung

2013-01-01

Background For patients with Graves’ disease (GD), the primary goal of antithyroid drug therapy is to temporarily restore the patient to the euthyroid state and wait for a subsequent remission of the disease. This study sought to identify the predictive markers for the relapse of disease. Methods To do this, we studied 262 GD patients with long enough follow-up after drug withdrawal to determine treatment outcome. The patients were divided into three groups by time of relapse: early relapse group (n = 91) had an early relapse within 9 months, late relapse group (n = 65) had a relapse between 10 and 36 months, and long-term remission group (n = 106) were either still in remission after at least 3 years or relapsed after 3 years of drug withdrawal. We assessed the treatment outcome of 23 SNPs of costimulatory genes, phenotype and smoking habits. We used permutation to obtain p values for each SNP as an adjustment for multiple testing. Cox proportional hazards models was performed to assess the strength of association between the treatment outcome and clinical and laboratory variables. Results Four SNPs were significantly associated with disease relapse: rs231775 (OR 1.96, 95% CI 1.18–3.26) at CTLA-4 and rs745307 (OR 7.97, 95% CI 1.01–62.7), rs11569309 (OR 8.09, 95% CI 1.03–63.7), and rs3765457 (OR 2.60, 95% CI 1.08–6.28) at CD40. Combining risk alleles at CTLA-4 and CD40 improved the predictability of relapse. Using 3 years as the cutoff point for multivariate analysis, we found several independent predictors of disease relapse: number of risk alleles (HR 1.30, 95% CI 1.09–1.56), a large goiter size at the end of the treatment (HR 1.30, 95% CI 1.05–1.61), persistent TSH-binding inhibitory Ig (HR 1.64, 95% CI 1.15–2.35), and smoking habit (HR 1.60, 95% CI 1.05–2.42). Conclusion Genetic polymorphism of costimulatory genes, smoking status, persistent goiter, and TSH-binding inhibitory Ig predict disease relapse. PMID:24783027

Genotype and phenotype predictors of relapse of graves' disease after antithyroid drug withdrawal.

PubMed

Wang, Pei-Wen; Chen, I-Ya; Juo, Suh-Hang Hank; Hsi, Edward; Liu, Rue-Tsuan; Hsieh, Ching-Jung

2013-01-01

For patients with Graves' disease (GD), the primary goal of antithyroid drug therapy is to temporarily restore the patient to the euthyroid state and wait for a subsequent remission of the disease. This study sought to identify the predictive markers for the relapse of disease. To do this, we studied 262 GD patients with long enough follow-up after drug withdrawal to determine treatment outcome. The patients were divided into three groups by time of relapse: early relapse group (n = 91) had an early relapse within 9 months, late relapse group (n = 65) had a relapse between 10 and 36 months, and long-term remission group (n = 106) were either still in remission after at least 3 years or relapsed after 3 years of drug withdrawal. We assessed the treatment outcome of 23 SNPs of costimulatory genes, phenotype and smoking habits. We used permutation to obtain p values for each SNP as an adjustment for multiple testing. Cox proportional hazards models was performed to assess the strength of association between the treatment outcome and clinical and laboratory variables. FOUR SNPS WERE SIGNIFICANTLY ASSOCIATED WITH DISEASE RELAPSE: rs231775 (OR 1.96, 95% CI 1.18-3.26) at CTLA-4 and rs745307 (OR 7.97, 95% CI 1.01-62.7), rs11569309 (OR 8.09, 95% CI 1.03-63.7), and rs3765457 (OR 2.60, 95% CI 1.08-6.28) at CD40. Combining risk alleles at CTLA-4 and CD40 improved the predictability of relapse. Using 3 years as the cutoff point for multivariate analysis, we found several independent predictors of disease relapse: number of risk alleles (HR 1.30, 95% CI 1.09-1.56), a large goiter size at the end of the treatment (HR 1.30, 95% CI 1.05-1.61), persistent TSH-binding inhibitory Ig (HR 1.64, 95% CI 1.15-2.35), and smoking habit (HR 1.60, 95% CI 1.05-2.42). Genetic polymorphism of costimulatory genes, smoking status, persistent goiter, and TSH-binding inhibitory Ig predict disease relapse.

Cognitive reactivity versus dysfunctional cognitions and the prediction of relapse in recurrent major depressive disorder.

PubMed

Figueroa, Caroline A; Ruhé, Henricus G; Koeter, Maarten W; Spinhoven, Philip; Van der Does, Willem; Bockting, Claudi L; Schene, Aart H

2015-10-01

Major depressive disorder (MDD) is a burdensome disease that has a high risk of relapse/recurrence. Cognitive reactivity appears to be a risk factor for relapse. It remains unclear, however, whether dysfunctional cognitions alone or the reactivity of such cognitions to mild states of sadness (ie, cognitive reactivity) is the crucial factor that increases relapse risk. We aimed to assess the long-term predictive value of cognitive reactivity versus dysfunctional cognitions and other risk factors for depressive relapse. In a prospective cohort of outpatients (N = 116; studied between 2000-2005) who had experienced ≥ 2 previous major depressive episodes (MDEs) and were in remission (DSM-IV) at the start of follow-up, we measured cognitive reactivity, with the Leiden Index of Depression Sensitivity (LEIDS), and dysfunctional cognitions, with the Dysfunctional Attitudes Scale, simultaneously. Course of illness (with the primary outcome of MDE assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders Patient Edition) and time to relapse were monitored prospectively for 3.5 years. Cognitive reactivity scores were associated with time to relapse over the 3.5-year follow-up and also when corrected for the number of previous MDEs and concurrent depressive symptoms (hazard ratio for 1 standard deviation [(HR(SD)); 20 points of the LEIDS, measuring cognitive reactivity] = 1.47; 95% CI, 1.04-2.09; P = .031). Rumination appeared to be a particularly strong predictor of relapse (HR(SD) = 1.60; 95% CI, 1.13-2.26; P = .007). Dysfunctional cognitions did not predict relapse over 3.5 years (HR(SD) = 1.00; 95% CI, 0.74-1.37; P = .93). Every 20-point increase on the cognitive reactivity scale resulted in a 10% to 15% increase in risk of relapse (corrected for previous MDEs and concurrent depressive symptoms). Cognitive reactivity--and particularly rumination--is a long-term predictor of relapse. Future research should address whether psychological interventions can improve cognitive reactivity scores and thereby prevent depressive relapses. ISRCTN Identifier: 68246470. © Copyright 2015 Physicians Postgraduate Press, Inc.

Illness severity and self-efficacy as course predictors of DSM-IV alcohol dependence in a multisite clinical sample.

PubMed

Langenbucher, J; Sulesund, D; Chung, T; Morgenstern, J

1996-01-01

Illness severity and self-efficacy are two constructs of growing interest as predictors of clinical response in alcoholism. Using alternative measures of illness severity (DSM-IV symptom count, Alcohol Dependence Scale, and Addiction Severity Index) and self-efficacy (brief version of the Situational Confidence Questionnaire) rigorously controlled for theoretically important background variables, we studied their unique contribution to multiple indices of relapse, relapse latency, and use of alternative coping behaviors in a large, heterogeneous clinical sample. The Alcohol Dependence Scale contributed to the prediction of 4 of 5 relapse indicators. The SCQ failed to predict relapse behavior or its precursor, coping response. The findings emphasize the predictive validity of severity of dependence as a course specifier and underline the need for more sensitive and externally valid measures of cognitive processes such as self-efficacy for application in future studies of posttreatment behavior.

Diagnostic value of highly-sensitive chimerism analysis after allogeneic stem cell transplantation.

PubMed

Sellmann, Lea; Rabe, Kim; Bünting, Ivonne; Dammann, Elke; Göhring, Gudrun; Ganser, Arnold; Stadler, Michael; Weissinger, Eva M; Hambach, Lothar

2018-05-02

Conventional analysis of host chimerism (HC) frequently fails to detect relapse before its clinical manifestation in patients with hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Quantitative PCR (qPCR)-based highly-sensitive chimerism analysis extends the detection limit of conventional (short tandem repeats-based) chimerism analysis from 1 to 0.01% host cells in whole blood. To date, the diagnostic value of highly-sensitive chimerism analysis is hardly defined. Here, we applied qPCR-based chimerism analysis to 901 blood samples of 71 out-patients with hematological malignancies after allo-SCT. Receiver operating characteristics (ROC) curves were calculated for absolute HC values and for the increments of HC before relapse. Using the best cut-offs, relapse was detected with sensitivities of 74 or 85% and specificities of 69 or 75%, respectively. Positive predictive values (PPVs) were only 12 or 18%, but the respective negative predictive values were 98 or 99%. Relapse was detected median 38 or 45 days prior to clinical diagnosis, respectively. Considering also durations of steadily increasing HC of more than 28 days improved PPVs to more than 28 or 59%, respectively. Overall, highly-sensitive chimerism analysis excludes relapses with high certainty and predicts relapses with high sensitivity and specificity more than a month prior to clinical diagnosis.

Predicting relapse in major depressive disorder using patient-reported outcomes of depressive symptom severity, functioning, and quality of life in the Individual Burden of Illness Index for Depression (IBI-D).

PubMed

Ishak, Waguih William; Greenberg, Jared M; Cohen, Robert M

2013-10-01

Patients with Major Depressive Disorder (MDD) often experience unexpected relapses, despite achieving remission. This study examines the utility of a single multidimensional measure that captures variance in patient-reported Depressive Symptom Severity, Functioning, and Quality of Life (QOL), in predicting MDD relapse. Complete data from remitted patients at the completion of 12 weeks of citalopram in the STAR*D study were used to calculate the Individual Burden of Illness index for Depression (IBI-D), and predict subsequent relapse at six (n=956), nine (n=778), and twelve months (n=479) using generalized linear models. Depressive Symptom Severity, Functioning, and QOL were all predictors of subsequent relapse. Using Akaike information criteria (AIC), the IBI-D provided a good model for relapse even when Depressive Symptom Severity, Functioning, and QOL were combined in a single model. Specifically, an increase of one in the IBI-D increased the odds ratio of relapse by 2.5 at 6 months (β=0.921 ± 0.194, z=4.76, p<2 × 10(-6)), by 2.84 at 9 months (β=1.045 ± 0.22, z=4.74, p<2.2 × 10(-6)), and by 4.1 at 12 months (β=1.41 ± 0.29, z=4.79, p<1.7 × 10(-6)). Self-report poses a risk to measurement precision. Using highly valid and reliable measures could mitigate this risk. The IBI-D requires time and effort for filling out the scales and index calculation. Technological solutions could help ease these burdens. The sample suffered from attrition. Separate analysis of dropouts would be helpful. Incorporating patient-reported outcomes of Functioning and QOL in addition to Depressive Symptom Severity in the IBI-D is useful in assessing the full burden of illness and in adequately predicting relapse, in MDD. © 2013 Elsevier B.V. All rights reserved.

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy

PubMed Central

Devillier, Raynier; Coso, Diane; Castagna, Luca; Brenot Rossi, Isabelle; Anastasia, Antonella; Chiti, Arturo; Ivanov, Vadim; Schiano, Jean Marc; Santoro, Armando; Chabannon, Christian; Balzarotti, Monica; Blaise, Didier; Bouabdallah, Reda

2012-01-01

Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57–10.73]) and tandem transplantation (hazard ratio: 0.39 [0.19–0.78]) but not risk factors at relapse (hazard ratio: 1.77 [0.80–3.92]) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 [1.38–11.75]). Conclusions In patients with relapsed/refractory Hodgkin’s lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation. PMID:22271893

MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia

PubMed Central

Verboon, Lonneke J.; Obulkasim, Askar; de Rooij, Jasmijn D.E.; Katsman, Jenny E.; Sonneveld, Edwin; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Pieters, Rob; Cloos, Jacqueline; Kaspers, Gertjan J.L.; Klusmann, Jan-Henning; Zwaan, Christian Michel; Fornerod, Maarten; van den Heuvel-Eibrink, Marry M.

2016-01-01

The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements. PMID:27351222

Relapse and Recurrence Prevention in the Treatment for Adolescents with Depression Study

ERIC Educational Resources Information Center

Simons, Anne D.; Rohde, Paul; Kennard, Betsy D.; Robins, Michele

2005-01-01

Relapse and recurrence in adolescent depression are important problems. Much less is known about relapse prevention compared to the acute treatment of depression in adolescents. Based on previous research, theoretical predictions, and clinical experience, the Treatment for Adolescents With Depression Study (TADS) protocol was designed to determine…

Proton Magnetic Resonance Spectroscopic Imaging in Newly Diagnosed Glioblastoma: Predictive Value for the Site of Postradiotherapy Relapse in a Prospective Longitudinal Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laprie, Anne; Laboratory of Biophysics and Medical Imaging, Universite Toulouse III Paul Sabatier, Toulouse; Catalaa, Isabelle

Purpose: To investigate the association between magnetic resonance spectroscopic imaging (MRSI)-defined, metabolically abnormal tumor regions and subsequent sites of relapse in data from patients treated with radiotherapy (RT) in a prospective clinical trial. Methods and Materials: Twenty-three examinations were performed prospectively for 9 patients with newly diagnosed glioblastoma multiforme studied in a Phase I trial combining Tipifarnib and RT. The patients underwent magnetic resonance imaging (MRI) and MRSI before treatment and every 2 months until relapse. The MRSI data were categorized by the choline (Cho)/N-acetyl-aspartate (NAA) ratio (CNR) as a measure of spectroscopic abnormality. CNRs corresponding to T1 and T2more » MRI for 1,207 voxels were evaluated before RT and at recurrence. Results: Before treatment, areas of CNR2 (CNR {>=}2) represented 25% of the contrast-enhancing (T1CE) regions and 10% of abnormal T2 regions outside T1CE (HyperT2). The presence of CNR2 was often an early indicator of the site of relapse after therapy. In fact, 75% of the voxels within the T1CE+CNR2 before therapy continued to exhibit CNR2 at relapse, compared with 22% of the voxels within the T1CE with normal CNR (p < 0.05). The location of new contrast enhancement with CNR2 corresponded in 80% of the initial HyperT2+CNR2 vs. 20.7% of the HyperT2 voxels with normal CNR (p < 0.05). Conclusion: Metabolically active regions represented a small percentage of pretreatment MRI abnormalities and were predictive for the site of post-RT relapse. The incorporation of MRSI data in the definition of RT target volumes for selective boosting may be a promising avenue leading to increased local control of glioblastomas.« less

NEURAL SUBSTRATES OF CUE-REACTIVITY: ASSOCIATION WITH TREATMENT OUTCOMES AND RELAPSE

PubMed Central

Courtney, Kelly E.; Schacht, Joseph P.; Hutchison, Kent; Roche, Daniel J.O.; Ray, Lara A.

2016-01-01

Given the strong evidence for neurological alterations at the basis of drug dependence, functional magnetic resonance imaging (fMRI) represents an important tool in the clinical neuroscience of addiction. fMRI cue-reactivity paradigms represent an ideal platform to probe the involvement of neurobiological pathways subserving the reward/motivation system in addiction and potentially offer a translational mechanism by which interventions and behavioral predictions can be tested. Thus, this review summarizes the research that has applied fMRI cue-reactivity paradigms to the study of adult substance use disorder treatment responses. Studies utilizing fMRI cue-reactivity paradigms for the prediction of relapse, and as a means to investigate psychosocial and pharmacological treatment effects on cue-elicited brain activation are presented within four primary categories of substances: alcohol, nicotine, cocaine, and opioids. Lastly, suggestions for how to leverage fMRI technology to advance addiction science and treatment development are provided. PMID:26435524

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis.

PubMed

Teter, Barbara; Agashivala, Neetu; Kavak, Katelyn; Chouhfeh, Lynn; Hashmonay, Ron; Weinstock-Guttman, Bianca

2014-06-01

Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon β or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation. © The Author(s) 2013.

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

PubMed

Hemmati, Philipp G; Vuong, Lam G; Terwey, Theis H; Jehn, Christian F; le Coutre, Philipp; Penack, Olaf; Na, Il-Kang; Dörken, Bernd; Arnold, Renate

2017-02-01

The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014. The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT [overall P = 0.0064 for disease-free survival (DFS), overall P = 0.003 for relapse]. Patients with an intermediate-1 profile have a significantly elevated 5-yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, [hazard ratio (HR) 2.58, P = 0.048]. An intermediate-1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate-1 patients, the presence of an FLT3 internal tandem duplication (FLT3-ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3-ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate-1 subgroup. The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate-1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

48-Week Outcome after Cessation of Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Patient and the Associated Factors with Relapse.

PubMed

Xu, Wen-Xiong; Zhang, Qian; Zhu, Xiang; Lin, Chao-Shuang; Chen, You-Ming; Deng, Hong; Mei, Yong-Yu; Zhao, Zhi-Xin; Xie, Dong-Ying; Gao, Zhi-Liang; Xie, Chan; Peng, Liang

2018-01-01

We aimed to ascertain the feasibility and safety of NA cessation, the status of patients after cessation, and the predictive factors for relapse and subsequent retreatment. A total of 92 patients were enrolled in this prospective study. Patients were monitored every month for the first 3 months after cessation and every 3 months thereafter. Sixty-two patients finished 48 weeks of follow-up. None died or developed liver failure, cirrhosis, or HCC. The 62 patients could be divided into 4 categories according to the 48-week clinical development of relapse. Virologic relapses occurred in 39 (62.9%) patients, with 72.7% occurring in the first 24 weeks in origin HBeAg positive patients and 82.4% in the first 12 weeks in origin HBeAg negative patients. Age (OR = 1.06, 95% CI = 1.02-1.10; p = 0.003), the HBsAg level (OR = 2.21, 95% CI = 1.47-3.32; p < 0.001), and positive origin HBeAg status (OR = 0.32, 95% CI = 0.14-0.74; p = 0.008) were predictive factors to virologic relapse. HBV DNA level (OR = 1.34, 95% CI = 1.13-1.58; p < 0.001) was predictive factor to retreatment. NA cessation is safe under supervision. Age, HBsAg level, and origin HBeAg status can be predictive factors for virologic relapse. The study was submitted to ClinicalTrials.gov Protocol Registration and Results System with the assigned NCT ID NCT02883647.

Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy

PubMed Central

Chesi, Marta; Matthews, Geoffrey M.; Garbitt, Victoria M.; Palmer, Stephen E.; Shortt, Jake; Lefebure, Marcus; Stewart, A. Keith; Johnstone, Ricky W.

2012-01-01

The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM. PMID:22451422

The motivation to stay abstinent in ex-smokers: comparing the present with the past.

PubMed

Dijkstra, Arie; Borland, Ron; Buunk, Bram P

2007-10-01

Little is known about the motivation of ex-smokers to stay abstinent. In the present study we argue that ex-smokers compare their present to their past when they still smoked to conclude whether they make good progress towards a satisfactory state of continued abstinence. These temporal comparisons are thought to be central in the motivation to stay abstinent in ex-smokers. The power of temporal comparisons to predict relapse was tested in two related samples of ex-smokers (N=152 and N=197), together with two other relevant psychological factors; positive outcome expectations of smoking and self-efficacy expectations. In the first sample of ex-smokers, only temporal comparisons predicted relapse after 2 months. In the second sample of ex-smokers, temporal comparisons mediated the relation between perceived positive outcomes of smoking and relapse after 6 months. In addition, in predicting relapse after 6 months, temporal comparisons interacted with self-efficacy. The present study suggests that temporal comparisons comprise the cognitive aspect of the motivation of ex-smokers to stay abstinent. This conceptualization of the motivation in ex-smokers can be used in practice to prevent relapse.

Gender differences in alcohol and substance use relapse.

PubMed

Walitzer, Kimberly S; Dearing, Ronda L

2006-03-01

This review explores gender differences in relapse and characteristics of relapse events in alcohol and substance use. For alcohol, relapse rates were similar across gender. Although negative mood, childhood sexual abuse, alcohol-related self-efficacy, and poorer coping strategies predicted alcohol relapse, gender did not moderate these effects. Gender did moderate the association between marriage and alcohol relapse. For women, marriage and marital stress were risk factors for alcohol relapse; among men, marriage lowered relapse risk. This gender difference in the role of marriage in relapse may be a result of partner differences in problem drinking. Alcoholic women are more likely to be married to heavy drinking partners than are alcoholic men; thus, alcoholic women may be put at risk of relapse by marriage and alcoholic men may be protected by marriage. There are fewer studies documenting gender differences in substance abuse relapse so conclusions are limited and tentative. In contrast to the lack of gender differences in alcohol relapse rates, women appear less likely to experience relapse to substance use, relative to men. Women relapsing to substance use appear to be more sensitive to negative affect and interpersonal problems. Men, in contrast, may be more likely to have positive experiences prior to relapse.

Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML.

PubMed

Zampini, Matteo; Tregnago, Claudia; Bisio, Valeria; Simula, Luca; Borella, Giulia; Manara, Elena; Zanon, Carlo; Zonta, Francesca; Serafin, Valentina; Accordi, Benedetta; Campello, Silvia; Buldini, Barbara; Pession, Andrea; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina

2018-05-01

The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission. The epigenetic signature, made up of 337 differentially methylated regions, was then integrated with gene and protein expression profiles, leading to a network, where cell-to-cell adhesion and cell-motility pathways were found to be aberrantly activated in relapsed patients. We identified most of these factors as RUNX1-RUNX1T1 targets, with Ras Homolog Family Member (RHOB) overexpression being the core of this network. We documented how RHOB re-organized the actin cytoskeleton through its downstream ROCK-LIMK-COFILIN axis: this increases blast adhesion by stress fiber formation, and reduces mitochondrial apoptotic cell death after chemotherapy treatment. Altogether, our data show an epigenetic heterogeneity within t(8;21)-rearranged AML patients at diagnosis able to influence the program of the chimeric transcript, promoting blast re-emergence and progression to relapse.

Life-event stress induced by the Great East Japan Earthquake was associated with relapse in ulcerative colitis but not Crohn's disease: a retrospective cohort study

PubMed Central

Shiga, Hisashi; Miyazawa, Teruko; Kinouchi, Yoshitaka; Takahashi, Seiichi; Tominaga, Gen; Takahashi, Hiroki; Takagi, Sho; Obana, Nobuya; Kikuchi, Tatsuya; Oomori, Shinya; Nomura, Eiki; Shiraki, Manabu; Sato, Yuichirou; Takahashi, Shuichiro; Umemura, Ken; Yokoyama, Hiroshi; Endo, Katsuya; Kakuta, Yoichi; Aizawa, Hiroki; Matsuura, Masaki; Kimura, Tomoya; Kuroha, Masatake; Shimosegawa, Tooru

2013-01-01

Objective Stress is thought to be one of the triggers of relapses in patients with inflammatory bowel disease (IBD). We examined the rate of relapse in IBD patients before and after the Great East Japan Earthquake. Design A retrospective cohort study. Settings 13 hospitals in Japan. Participants 546 ulcerative colitis (UC) and 357 Crohn's disease (CD) patients who received outpatient and inpatient care at 13 hospitals located in the area that were seriously damaged by the earthquake. Data on patient's clinical characteristics, disease activity and deleterious effects of the earthquake were obtained from questionnaires and hospital records. Primary outcome We evaluated the relapse rate (from inactive to active) across two consecutive months before and two consecutive months after the earthquake. In this study, we defined ‘active’ as conditions with a partial Mayo score=2 or more (UC) or a Harvey-Bradshaw index=6 or more (CD). Results Among the UC patients, disease was active in 167 patients and inactive in 379 patients before the earthquake. After the earthquake, the activity scores increased significantly (p<0.0001). A total of 86 patients relapsed (relapse rate=15.8%). The relapse rate was about twice that of the corresponding period in the previous year. Among the CD patients, 86 patients had active disease and 271 had inactive disease before the earthquake. After the earthquake, the activity indices changed little. A total of 25 patients experienced a relapse (relapse rate=7%). The relapse rate did not differ from that of the corresponding period in the previous year. Multivariate analyses revealed that UC, changes in dietary oral intake and anxiety about family finances were associated with the relapse. Conclusions Life-event stress induced by the Great East Japan Earthquake was associated with relapse in UC but not CD. PMID:23396562

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients

PubMed Central

Levandovsky, Mark; Harvey, Danielle; Lara, Primo; Wun, Ted

2008-01-01

Background Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (TTP-HUS) are related and uncommon disorders with a high fatality and complication rate if untreated. Plasma exchange therapy has been shown to produce high response rates and improve survival in patients with many forms of TTP-HUS. We performed a retrospective cohort study of 178 consecutively treated patients with TTP-HUS and analyzed whether clinical or laboratory characteristics could predict for important short- and long-term outcome measures. Results Overall 30-day mortality was 16% (n = 27). 171 patients (96%) received plasma exchange as the principal treatment, with a mean of 8 exchanges and a mean cumulative infused volume of 42 ± 71 L of fresh frozen plasma. The rate of complete response was 65% or 55% depending on whether this was defined by a platelet count of 100,000/μl or 150,000/μl, respectively. The rate of relapse was 18%. The Clinical Severity Score did not predict for 30-day mortality or relapse. The time to complete response did not predict for relapse. Renal insufficiency at presentation was associated with a decreased risk of relapse, with each unit increase in serum creatinine associated with a 40% decreased odds of relapse. 72% of our cohort had an idiopathic TTP-sporadic HUS, while 17% had an underlying cancer, received a solid organ transplant or were treated with a mitomycin-based therapy. The estimated overall 5-year survival was 55% and was significantly better in those without serious underlying conditions. Conclusion Plasma exchange therapy produced both high response and survival rates in this large cohort of patients with TTP-HUS. The Clinical Severity Score did not predict for 30-day mortality or relapse, contrary to our previous findings. Interestingly, the presence of renal insufficiency was associated with a decreased risk of relapse. The most important predictor of mortality was the presence or absence of a serious underlying disorder. PMID:19046460

Mood Reactivity Rather than Cognitive Reactivity Is Predictive of Depressive Relapse: A Randomized Study with 5.5-Year Follow-Up

ERIC Educational Resources Information Center

van Rijsbergen, Gerard D.; Bockting, Claudi L. H.; Burger, Huibert; Spinhoven, Philip; Koeter, Maarten W. J.; Ruhe, Henricus G.; Hollon, Steven D.; Schene, Aart H.

2013-01-01

Objective: The current study examined whether cognitive reactivity, cognitive extremity reactivity, and mood reactivity following mood provocation predicted relapse in depression over 5.5 years. Additionally, this study was the 1st to examine whether changes in cognitive reactivity and mood reactivity following preventive cognitive therapy (PCT)…

CA-125 AUC as a predictor for epithelial ovarian cancer relapse.

PubMed

Mano, António; Falcão, Amílcar; Godinho, Isabel; Santos, Jorge; Leitão, Fátima; de Oliveira, Carlos; Caramona, Margarida

2008-01-01

The aim of the present work was to evaluate the usefulness of CA-125 normalized in time area under the curve (CA-125 AUC) to signalise epithelial ovarian cancer relapse. Data from a hundred and eleven patients were submitted to two different approaches based on CA-125 AUC increase values to predict patient relapse. In Criterion A total CA-125 AUC normalized in time value (AUC(i)) was compared with the immediately previous one (AUC(i-1)) using the formulae AUC(i) > or = F * AUC(i-1) (several F values were tested) to find the appropriate close related increment associated to patient relapse. In Criterion B total CA-125 AUC normalised in time was calculated and several cut-off values were correlated with patient relapse prediction capacity. In Criterion A the best accuracy was achieved with a factor (F) of 1.25 (increment of 25% from the previous status), while in Criterion B the best accuracies were achieved with cut-offs of 25, 50, 75 and 100 IU/mL. The mean lead time to relapse achieved with Criterion A was 181 days, while with Criterion B they were, respectively, 131, 111, 63 and 11 days. Based on our results we believe that conjugation and sequential application of both criteria in patient relapse detection should be highly advisable. CA-125 AUC rapid burst in asymptomatic patients should be firstly evaluated using Criterion A with a high accuracy (0.85) and with a substantial mean lead time to relapse (181 days). If a negative answer was obtained then Criterion B should performed to confirm the absence of relapse.

When Habits Are Dangerous: Alcohol Expectancies and Habitual Decision Making Predict Relapse in Alcohol Dependence.

PubMed

Sebold, Miriam; Nebe, Stephan; Garbusow, Maria; Guggenmos, Matthias; Schad, Daniel J; Beck, Anne; Kuitunen-Paul, Soeren; Sommer, Christian; Frank, Robin; Neu, Peter; Zimmermann, Ulrich S; Rapp, Michael A; Smolka, Michael N; Huys, Quentin J M; Schlagenhauf, Florian; Heinz, Andreas

2017-12-01

Addiction is supposedly characterized by a shift from goal-directed to habitual decision making, thus facilitating automatic drug intake. The two-step task allows distinguishing between these mechanisms by computationally modeling goal-directed and habitual behavior as model-based and model-free control. In addicted patients, decision making may also strongly depend upon drug-associated expectations. Therefore, we investigated model-based versus model-free decision making and its neural correlates as well as alcohol expectancies in alcohol-dependent patients and healthy controls and assessed treatment outcome in patients. Ninety detoxified, medication-free, alcohol-dependent patients and 96 age- and gender-matched control subjects underwent functional magnetic resonance imaging during the two-step task. Alcohol expectancies were measured with the Alcohol Expectancy Questionnaire. Over a follow-up period of 48 weeks, 37 patients remained abstinent and 53 patients relapsed as indicated by the Alcohol Timeline Followback method. Patients who relapsed displayed reduced medial prefrontal cortex activation during model-based decision making. Furthermore, high alcohol expectancies were associated with low model-based control in relapsers, while the opposite was observed in abstainers and healthy control subjects. However, reduced model-based control per se was not associated with subsequent relapse. These findings suggest that poor treatment outcome in alcohol dependence does not simply result from a shift from model-based to model-free control but is instead dependent on the interaction between high drug expectancies and low model-based decision making. Reduced model-based medial prefrontal cortex signatures in those who relapse point to a neural correlate of relapse risk. These observations suggest that therapeutic interventions should target subjective alcohol expectancies. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Randomized study combining interferon and glatiramer acetate in multiple sclerosis.

PubMed

Lublin, Fred D; Cofield, Stacey S; Cutter, Gary R; Conwit, Robin; Narayana, Ponnada A; Nelson, Flavia; Salter, Amber R; Gustafson, Tarah; Wolinsky, Jerry S

2013-03-01

A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis. A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences. Copyright © 2013 American Neurological Association.

Stress-related increases in risk taking and attentional failures predict earlier relapse to smoking in young adults: A pilot investigation.

PubMed

Schepis, Ty S; Tapscott, Brian E; Krishnan-Sarin, Suchitra

2016-04-01

Substantial evidence links greater impulsivity and stress exposure to poorer smoking cessation outcomes. Results from adolescents also indicate that stress-related change in risk taking can impede cessation attempts. We investigated the effects of stress-related change in impulsivity, risk taking, attention and nicotine withdrawal, and craving in young adult smokers on time to smoking relapse in a relapse analogue paradigm. Twenty-six young adult smokers (50% women; mean age: 20.9 ± 1.8) were exposed to a stress imagery session followed by a contingency management-based relapse analogue paradigm. Participants smoked at least 5 cigarettes daily, with a mean baseline carbon monoxide (CO) level of 13.7 (± 5.1) ppm. Repeated measures analysis of variance (ANOVA) and paired t tests examined stress induction validity and Cox regressions of proportional hazards examined the effects of stress-related changes in nicotine withdrawal, nicotine craving, attention, impulsivity, and risk taking on time to relapse. While stress-related change in impulsivity, nicotine craving and withdrawal did not predict time to relapse (all ps > .10), greater stress-related increases in reaction time (RT) variability (p = .02) were predictive of shorter time to relapse, with trend-level findings for inattention and risk taking. Furthermore, changes in stress-related risk taking affected outcome in women more than in men, with a significant relationship between stress-related change in risk taking only in women (p = .026). Smoking cessation attempts in young adults may be adversely impacted by stress-related increases in risk taking and attentional disruption. Clinicians working with young adults attempting cessation may need to target these stress-related impairments by fostering more adaptive coping and resilience. (c) 2016 APA, all rights reserved).

Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.

PubMed

Kousin-Ezewu, Onajite; Azzopardi, Laura; Parker, Richard A; Tuohy, Orla; Compston, Alastair; Coles, Alasdair; Jones, Joanne

2014-06-17

To test the hypothesis that accelerated peripheral blood mononuclear cell recovery after alemtuzumab treatment of multiple sclerosis is associated with recurrent disease activity and to investigate the claim that CD4 counts greater than 388.5 × 10(6) cells/mL at 12 months can be used to identify patients who may benefit from further treatment. A total of 108 patients were followed for a median of 99 months post alemtuzumab. Patients were classified as active or nonactive after each cycle of treatment based on clinical relapse, increasing disability, or new T2/enhancing MRI lesions. These outcomes were correlated with CD4, CD8, CD19, CD56+ NK, and monocyte counts. Of 108 patients, 56 (52%) relapsed at some point during follow-up. Mean annualized relapse rate after alemtuzumab was 0.17 vs 1.67 prior to treatment (equating to a 90% reduction). Of 108 patients, 28 (26%) met the criteria for sustained accumulation of disability. Median time to the lower limit of normal for CD19, CD8, and CD4 was 3, 19.5, and 32 months, respectively. There was no significant difference in the recovery of any cell population between patients with and without disease activity or accumulation of disability after treatment. This study does not support the use of cell counts as biomarkers for identifying patients at greater risk of active disease following treatment with alemtuzumab. © 2014 American Academy of Neurology.

Psychological and environmental determinants of relapse in crack cocaine smokers.

PubMed

Wallace, B C

1989-01-01

The paper reviews approaches to relapse in the treatment of cocaine abusers. Approaches reveal a common mechanism underlying relapse that involves drug craving, recall of euphoria, environmental cues, denial, myths of being able to sell or use drugs, and painful affect states necessitating use of a multifaceted clinical technique. Empirical validation of a common mechanism underlying relapse establishes a typology of psychological and environmental determinants of relapse for crack cocaine smokers (N = 35) who relapse after hospital detoxification and return a second time. Major findings are that relapse follows a painful emotional state (40%), failure to enter arranged aftercare treatment (37%), or encounters with conditioned environmental stimuli (34%), and involves narcissistic psychopathology and denial (28.5%) and interpersonal stress (24%); 85.7% involve multideterminants. Case examples illustrate the role of multideterminants in relapse. The paper educates clinicians to the integrated theory and multifaceted clinical technique necessary for efficacious treatment of cocaine patients, while the typology predicts probable relapse situations.

Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial.

PubMed

Bader, Peter; Kreyenberg, Hermann; von Stackelberg, Arend; Eckert, Cornelia; Salzmann-Manrique, Emilia; Meisel, Roland; Poetschger, Ulrike; Stachel, Daniel; Schrappe, Martin; Alten, Julia; Schrauder, Andre; Schulz, Ansgar; Lang, Peter; Müller, Ingo; Albert, Michael H; Willasch, Andre M; Klingebiel, Thomas E; Peters, Christina

2015-04-10

To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial. In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group. All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positively correlated with the cumulative incidence of relapse (P < .01). A multivariable Cox model was fitted for each time point, which showed that MRD ≥ 10(-4) leukemic cells was consistently correlated with inferior EFS (P < .003). The accuracy of MRD measurements in predicting relapse was investigated with time-dependent receiver operating curves at days +30, +60, +90, and +180. From day +60 onward, the discriminatory power of MRD detection to predict the probability of relapse after 1, 3, 6, and 9 months was more than 96%, more than 87%, more than 71%, and more than 61%, respectively. MRD after transplantation was a reliable marker for predicting impending relapses and could thus serve as the basis for pre-emptive therapy. © 2015 by American Society of Clinical Oncology.

Effect of local administration of simvastatin on postorthodontic relapse in a rabbit model.

PubMed

AlSwafeeri, Hani; ElKenany, Walid; Mowafy, Mohamed; Karam, Sahar

2018-06-01

Posttreatment relapse is a major challenging clinical issue. The objective of this study was to evaluate the effect of local administration of simvastatin on posttreatment relapse. Orthodontic tooth movement was induced in 10 white New Zealand rabbits. After 21 days of active tooth movement, the orthodontic appliances were removed, and the experimental teeth were allowed to relapse for 21 days. During the relapse phase, 1 mandibular quadrant received local simvastatin administration, and the other received the control vehicle solution on a weekly basis. Three-dimensional models of the experimental teeth were created to allow the measurement of experimental tooth movement and posttreatment relapse. The animals were killed at the end of the relapse phase for histomorphometric analysis of alveolar bone remodeling. The mean relapse percentages were 75.83% in the quadrant receiving the control vehicle solution and 62.01% in the quadrant receiving simvastatin. Neither the relapse magnitude nor the relapse percentage showed a significant difference between the 2 quadrants. Histomorphometric analyses showed that local simvastatin administration yielded a significant reduction in the area of active bone-resorptive lacunae and a significant increase in newly formed bone area. Although local administration of simvastatin aids in bone remodeling associated with posttreatment relapse by reducing the area of active bone resorption and upregulating bone formation, it did not significantly minimize posttreatment relapse. Copyright © 2018 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

Performance evaluation of 4 measuring methods of ground-glass opacities for predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer: a multicenter study.

PubMed

Kakinuma, Ryutaro; Kodama, Ken; Yamada, Kouzo; Yokoyama, Akira; Adachi, Shuji; Mori, Kiyoshi; Fukuyama, Yasuro; Fukuda, Yasuro; Kuriyama, Keiko; Oda, Junichi; Oda, Junji; Noguchi, Masayuki; Matsuno, Yoshihiro; Yokose, Tomoyuki; Ohmatsu, Hironobu; Nishiwaki, Yutaka

2008-01-01

To evaluate the performance of 4 methods of measuring the extent of ground-glass opacities as a means of predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer (NSLC). Ground-glass opacities on thin-section computed tomographic images of 120 peripheral NSLCs were measured at 7 medical institutions by the length, area, modified length, and vanishing ratio (VR) methods. The performance (Az) of each method in predicting the 5-year relapse-free survival was evaluated using receiver operating characteristic analysis. The mean Az value obtained by the length, area, modified length, and VR methods in the receiver operating characteristic analyses was 0.683, 0.702, 0.728, and 0.784, respectively. The differences between the mean Az value obtained by the VR method and by the other 3 methods were significant. Vanishing ratio method was the most accurate predictor of the 5-year relapse-free survival of patients with peripheral NSLC.

Delay of smoking gratification as a laboratory model of relapse: effects of incentives for not smoking, and relationship with measures of executive function.

PubMed

Mueller, Eldon T; Landes, Reid D; Kowal, Benjamin P; Yi, Richard; Stitzer, Maxine L; Burnett, Cody A; Bickel, Warren K

2009-09-01

Nineteen nicotine-deprived cigarette smokers received monetary rewards for each minute they chose not to initiate smoking in 2-h laboratory sessions followed by a 30-min period of enforced abstinence from smoking. Reinforcer amounts were delivered according to one of three schedules: increasing, decreasing, and constant. Relapse time (time until first cigarette) was shortest in the decreasing condition, longest in the increasing condition, and intermediate in the constant condition. All differences were significant except in the constant-decreasing comparison. The relationships between a battery of baseline assessments and relapse times were examined. Relapse times were predicted by delay-discounting coefficients (k) for $10 and $1000 in money and for $1000 of cigarettes. Relapse times were also predicted by the number of cigarettes smoked daily and a Wisconsin Card Sorting Test score. Performance on the Stroop Task and the Fagerström Test for Nicotine Dependence differentiated participants dichotomized into those who relapsed 'earlier' in sessions versus those who first smoked 'later'. The variability in some scores from smoking-urges and affect questionnaires administered after smoking-room sessions was explained by measures related to in-session nicotine intake. Results are discussed as they relate to contingency-management procedures, predictors of relapse, and the competing neurobehavioral decision systems theory of addiction.

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

PubMed Central

Petkau, J; Reingold, SC; Held, U; Cutter, GR; Fleming, TR; Hughes, MD; Miller, DH; McFarland, HF; Wolinsky, JS

2009-01-01

Background Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. Objective The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. Methods We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. Results Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. Conclusions Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy. PMID:18535021

Delay of Smoking Gratification as a Laboratory Model of Relapse: Effects of Incentives for Not Smoking, and Relationship to Measures of Executive Function

PubMed Central

Mueller, E. Terry; Landes, Reid D.; Kowal, Benjamin P.; Yi, Richard; Stitzer, Maxine L.; Burnett, Cody A.; Bickel, Warren K.

2010-01-01

Nineteen nicotine-deprived cigarette smokers received monetary rewards for each minute they choose not to initiate smoking in 2-hour laboratory sessions followed by a 30-min period of enforced abstinence from smoking. Reinforcer amounts were delivered according to one of three schedules: increasing, decreasing, and constant. Relapse time (time until first smoke) was shortest in the decreasing condition, longest in the increasing condition, and intermediate in the constant condition. All differences were significant except in the constant-decreasing comparison. The relationships between a battery of baseline assessments and relapse times were examined. Relapse times were predicted by delay-discounting coefficients (k) for $10 and $1000 in money, and for $1000 of cigarettes. Relapse times were also predicted by the number of cigarettes smoked daily and a Wisconsin Card Sorting Test score. Performance on the Stroop Task and the Fagerström Test for Nicotine Dependence differentiated participants dichotomized into those who relapsed “earlier” in sessions versus those who first smoked “later.” Variability on some scores from smoking-urges and affect questionnaires administered after smoking-room sessions was explained by measures related to in-session nicotine intake. Results are discussed as they relate to contingency-management procedures, predictors of relapse, and the competing neuro-behavioral decision systems theory of addiction. PMID:19741301

Stressful Life Events Predict Eating Disorder Relapse Following Remission: Six-Year Prospective Outcomes

PubMed Central

Grilo, Carlos M.; Pagano, Maria E.; Stout, Robert L.; Markowitz, John C.; Ansell, Emily B.; Pinto, Anthony; Zanarini, Mary C.; Yen, Shirley; Skodol, Andrew E.

2012-01-01

Objective To examine prospectively the natural course of bulimia nervosa (BN) and eating disorder not-otherwise-specified (EDNOS) and test for the effects of stressful life events (SLE) on relapse after remission from these eating disorders. Method 117 female patients with BN (N = 35) or EDNOS (N = 82) were prospectively followed for 72 months using structured interviews performed at baseline, 6- and 12-months, and then yearly thereafter. ED were assessed with the structured clinical interview for DSM-IV, and monitored over time with the longitudinal interval follow-up evaluation. Personality disorders were assessed with the diagnostic interview for DSM-IV-personality-disorders, and monitored over time with the follow-along-version. The occurrence and specific timing of SLE were assessed with the life events assessment interview. Cox proportional-hazard-regression-analyses tested associations between time-varying levels of SLE and ED relapse, controlling for comorbid psychiatric disorders, ED duration, and time-varying personality-disorder status. Results ED relapse probability was 43%; BN and EDNOS did not differ in time to relapse. Negative SLE significantly predicted ED relapse; elevated work and social stressors were significant predictors. Psychiatric comorbidity, ED duration, and time-varying personality-disorder status were not significant predictors. Discussion Higher work and social stress represent significant warning signs for triggering relapse for women with remitted BN and EDNOS. PMID:21448971

Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes.

PubMed

Sinha, Rajita; Fox, Helen C; Hong, Kwang-Ik Adam; Hansen, Julie; Tuit, Keri; Kreek, Mary Jeanne

2011-09-01

Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied. To investigate these responses in treatment-engaged, 1-month-abstinent, recovering alcohol-dependent patients relative to matched controls (study 1) and to assess whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome (study 2). Experimental exposure to stress, alcohol cues, and neutral, relaxing context to provoke alcohol craving, anxiety, and HPA axis responses (corticotropin and cortisol levels and cortisol to corticotropin ratio) and a prospective 90-day follow-up outcome design to assess alcohol relapse and aftercare treatment outcomes. Inpatient treatment in a community mental health center and hospital-based research unit. Treatment-engaged alcohol-dependent individuals and healthy controls. Time to alcohol relapse and to heavy drinking relapse. Significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, was seen in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress-induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed-state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse. These results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress- and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress- and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes.

Could Biomarkers of Bone, Cartilage or Synovium Turnover Be Used for Relapse Prediction in Rheumatoid Arthritis Patients?

PubMed Central

Dénarié, Delphine; Constant, Elodie; Thomas, Thierry

2014-01-01

Objective. The aim of this review is to clarify the usefulness of bone, cartilage, and synovial biomarker in the management of rheumatoid arthritis (RA) therapy in remission. Synovial Biomarkers. High MMP-3 levels are associated with joint progression in RA patients, but there is no data about their utility in clinical remission. IIINys and Glc-Gal-PYD seem to be more specific to synovium, but more studies are required. Cartilage Biomarkers. Unbalance between cartilage break-down biomarkers (urinary CTX II and COMP) and cartilage formation biomarker (PIIANP) was described. This unbalance is also associated with joint destruction and prognosis of destruction. No data are available on patients in remission. Bone Biomarkers. RA activity is correlated with an increase of bone resorption markers such as CTX I, PYD, and TRACP 5b and a decrease of bone formation markers such as OC and BALP. RA therapies seem to improve bone turnover in limiting bone resorption. There is no study about bone marker utility in remission. Conclusion. Biomarkers seem to correlate with RA activity and progression. They also could be used to manage RA therapies, but we need more data on RA remission to predict relapse. PMID:24744505

Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone.

PubMed

Couder, Florence; Massardier, Jérôme; You, Benoît; Abbas, Fatima; Hajri, Touria; Lotz, Jean-Pierre; Schott, Anne-Marie; Golfier, François

2016-07-01

Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86-8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR = 5.96; 95% CI, 1.40-25.4, P = .016), a number of methotrexate courses superior to 5 courses (5-8 courses vs 1-4: HR = 6.19; 95% CI, 1.43-26.8, P = .015; 9 courses and more vs 1-4: HR = 6.80; 95% CI, 1.32-35.1, P = .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR = 1.27; 95% CI, 1.09-1.49, P = .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia (95% CI, 1.98-37.9], P = .0042). A patient who received 5-8 courses of methotrexate had a 6.7 times higher relapse risk than a patient who received 1-4 courses (95% CI, 1.54-29.2, P = .011). A patient who received 9 courses or more had an 8.1 times higher relapse risk than a patient who received 1-4 courses of methotrexate (95% CI, 1.54-42.6, P = .014). Low-risk gestational trophoblastic neoplasia following a delivery and patients who need more than 4 courses of methotrexate to normalization are at a higher risk of relapse than other low-risk patients. Allotting a higher score to the "antecedent pregnancy" FIGO item should be considered for postdelivery gestational trophoblastic neoplasia. Further analysis of the need for consolidation courses is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessment of HPV-mRNA test to predict recurrent disease in patients previously treated for CIN 2/3.

PubMed

Frega, Antonio; Sesti, Francesco; Lombardi, Danila; Votano, Sergio; Sopracordevole, Francesco; Catalano, Angelica; Milazzo, Giusi Natalia; Lombardo, Riccardo; Assorgi, Chiara; Olivola, Sara; Chiusuri, Valentina; Ricciardi, Enzo; French, Deborah; Moscarini, Massimo

2014-05-01

The use of HPV-mRNA test in the follow-up after LEEP is still matter of debate, with regard to its capacity of prediction relapse. The aim of the present study is to evaluate the reliability of HPV-mRNA test to predict the residual and recurrent disease, and its accuracy in the follow-up of patients treated for CIN 2/3. Multicenter prospective cohort study. Patients who underwent LEEP after a biopsy diagnosing CIN 2/3 were followed at 3, 6, 12, 24 and 36 months. Each check up included cytology, colposcopy, HPV-DNA test (LiPA) and HPV-mRNA test (PreTect HPV Proofer Kit NorChip). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), of HPV-DNA test and HPV-mRNA test to predict relapse, recurrent and residual disease. Using multiple logistic regression, the statistical significant variables as assessed in univariate analysis were entered and investigated as predictors of relapse disease. The mRNA-test in predicting a residual disease had a sensitivity of 52% and a NPV of 91%, whereas DNA-test had 100% and 100%, respectively. On the contrary in the prediction of recurrent disease mRNA-test had a sensitivity and a NPV of 73.5% and 97%, whereas DNA-test had 44% and 93%. On the multivariate analysis, age, cytology, HPV DNA and mRNA test achieved the role of independent predictors of relapse. HPV-mRNA test has a higher sensitivity and a higher NPV in predicting recurrent disease, for this reason it should be used in the follow-up of patients treated with LEEP for CIN 2/3 in order to individualize the timing of check up. Copyright © 2014 Elsevier B.V. All rights reserved.

Clinical relevance of endoscopic assessment of inflammation in ulcerative colitis: Can endoscopic evaluation predict outcomes?

PubMed Central

Mohammed, Noor; Subramanian, Venkataraman

2016-01-01

Ulcerative colitis (UC) is a chronic inflammatory bowel condition characterised by a relapsing and remitting course. Symptom control has been the traditional mainstay of medical treatment. It is well known that histological inflammatory activity persists despite adequate symptom control and absence of endoscopic inflammation. Current evidence suggests that presence of histological inflammation poses a greater risk of disease relapse and subsequent colorectal cancer risk. New endoscopic technologies hold promise for developing endoscopic markers of mucosal inflammation. Achieving endoscopic and histological remission appears be the future aim of medical treatments for UC. This review article aims to evaluate the use of endoscopy as a tool in assessment of mucosal inflammation UC and its correlation with disease outcomes. PMID:27895420

Leishmania Antigenuria to Predict Initial Treatment Failure and Relapse in Visceral Leishmaniasis/HIV Coinfected Patients: An Exploratory Study Nested Within a Clinical Trial in Ethiopia.

PubMed

van Griensven, Johan; Mengesha, Bewketu; Mekonnen, Tigist; Fikre, Helina; Takele, Yegnasew; Adem, Emebet; Mohammed, Rezika; Ritmeijer, Koert; Vogt, Florian; Adriaensen, Wim; Diro, Ermias

2018-01-01

Background: Biomarkers predicting the risk of VL treatment failure and relapse in VL/HIV coinfected patients are needed. Nested within a two-site clinical trial in Ethiopia (2011-2015), we conducted an exploratory study to assess whether (1) levels of Leishmania antigenuria measured at VL diagnosis were associated with initial treatment failure and (2) levels of Leishmania antigenuria at the end of treatment (parasitologically-confirmed cure) were associated with subsequent relapse. Methods: Leishmania antigenuria at VL diagnosis and cure was determined using KAtex urine antigen test and graded as negative (0), weak/moderate (grade 1+/2+) or strongly-positive (3+). Logistic regression and Kaplan-Meier methods were used to assess the association between antigenuria and (1) initial treatment failure, and (2) relapse over the 12 months after cure, respectively. Results: The analysis to predict initial treatment failure included sixty-three coinfected adults [median age: 30 years interquartile range (IQR) 27-35], median CD4 count: 56 cells/μL (IQR 38-113). KAtex results at VL diagnosis were negative in 11 (17%), weak/moderate in 17 (27%) and strongly-positive in 35 (36%). Twenty (32%) patients had parasitologically-confirmed treatment failure, with a risk of failure of 9% (1/11) with KAtex-negative results, 0% (0/17) for KAtex 1+/2+ and 54% (19/35) for KAtex 3+ results. Compared to KAtex-negative patients, KAtex 3+ patients were at increased risk of treatment failure [odds ratio 11.9 (95% CI 1.4-103.0); P : 0.025]. Forty-four patients were included in the analysis to predict relapse [median age: 31 years (IQR 28-35), median CD4 count: 116 cells/μL (IQR 95-181)]. When achieving VL cure, KAtex results were negative in 19 (43%), weak/moderate (1+/2+) in 10 (23%), and strongly positive (3+) in 15 patients (34%). Over the subsequent 12 months, eight out of 44 patients (18%) relapsed. The predicted 1-year relapse risk was 6% for KAtex-negative results, 14% for KAtex 1+/2+ and 42% for KAtex 3+ results [hazard ratio of 2.2 (95% CI 0.1-34.9) for KAtex 1+/2+ and 9.8 (95% CI 1.8-82.1) for KAtex 3+, compared to KAtex negative patients; P : 0.03]. Conclusion: A simple field-deployable Leishmania urine antigen test can be used for risk stratification of initial treatment failure and VL relapse in HIV-patients. A dipstick-format would facilitate field implementation.

Myelography and cytology in the treatment of medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deutsch, M.; Reigel, D.H.

1981-06-01

Eight of 22 children with newly diagnosed medulloblastoma had asymptomatic spinal cord involvement detected by myelography. Two additional patients had demonstrable spinal cord lesions at the time of relapse in the posterior fossa. Cerebral spinal fluid (CSF) cytology results were inaccurate in predicting cord involvement. Seven patients have relapsed 9 to 69 months from completion of radiotherapy. Three had initial cord involvement and also had subsequent cord involvement at the time of intracranial relapse or afterwards. Frontal lobe involvement as the initial site of relapse occurred in 3 patients. Computerized tomography has been valuable in the early detection of intracranialmore » relapse. Three children are alive and well 10, 18 and 19 months, respectively, from time of relapse. All were retreated with radiotherapy in conjunction with misonidazole and subsequent chemotherapy.« less

American cutaneous leishmaniasis: use of a skin test as a predictor of relapse after treatment.

PubMed Central

Passos, V. M.; Barreto, S. M.; Romanha, A. J.; Krettli, A. U.; Volpini, A. C.; Lima e Costa, M. F.

2000-01-01

While relapses following clinical cure of American cutaneous leishmaniasis are frequent, no test has been described until now to predict such relapses. A cohort of 318 American cutaneous leishmaniasis patients was followed up for two years after treatment with meglumine antimoniate, during which time 32 relapses occurred, 30 in the first year and two in the second (accumulated risk: 10.5%). No association was found between these relapses and the parasite-specific antibody response before and after treatment, or between the relapses and stratification by sociodemographic and clinical characteristics. However when Leishmania was used as antigen, patients with a negative skin test at the time of diagnosis presented a 3.4-fold higher risk (hazard risk = 3.4; 95% confidence interval, 1.7-7.0) of American cutaneous leishmaniasis relapse, compared with patients with a positive response. This result shows that the skin test can be a predictor of American cutaneous leishmaniasis relapse after treatment. PMID:10994280

Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study.

PubMed

Traboulsee, Anthony; Li, David K B; Cascione, Mark; Fang, Juanzhi; Dangond, Fernando; Miller, Aaron

2018-05-11

On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon β-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial. Exploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS. Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN β-1a SC) 44 μg and 22 μg 3×/week (tiw) than with placebo (p < 0.0001). The presence of ≥4 versus 0 active T2 lesions predicted disability progression at Years 3-4 in the IFN β-1a SC 22 μg group only (p < 0.05), whereas the presence of ≥2 versus 0-1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2-4; p < 0.05) and IFN β-1a SC 22 μg groups (Years 3-4; p < 0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (≥4 vs. 0, Years 1-4; ≥2 vs. 0-1, Years 2-4; p < 0.05), and the presence of T1 Gd + lesions at 6 months predicted disability progression in the IFN β-1a SC 44 μg group only (Year 1; p < 0.05). The presence of ≥2 versus 0-1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN β-1a SC 44 μg group. Active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN β-1a SC 22 μg, but not in those receiving IFN β-1a SC 44 μg. Active T2 lesions at 12 months may predict outcomes in those receiving IFN β-1a SC 44 μg and are possibly more suggestive of poor response to therapy than T2 results at 6 months.

Clinical predictors for the prognosis of myasthenia gravis.

PubMed

Wang, Lili; Zhang, Yun; He, Maolin

2017-04-19

Clinical predictors for myasthenia gravis relapse and ocular myasthenia gravis secondary generalization during the first two years after disease onset remain incompletely identified. This study attempts to investigate the clinical predictors for the prognosis of Myasthenia Gravis. Eighty three patients with myasthenia gravis were concluded in this study. Baseline characteristics were analyzed as predictors. Relapse of myasthenia gravis developed in 26 patients (34%). Generalization developed in 34 ocular myasthenia gravis patients (85%). Other autoimmune diseases were observed more commonly in relapsed myasthenia gravis (P = 0.012). Second generalization group contained more late onset patients (P = 0.021). Ocular myasthenia gravis patients with thymus hyperplasia progressed more rapidly than those with other thymus pathology (P = 0.027). Single onset symptom of ocular myasthenia gravis such as ptosis or diplopia predicted early progression than concurrence of ptosis and diplopia (P = 0.027). Treatment effect including glucocorticoid, pyridostigmine, thymectomy, IVIG, immunosuppressive drugs did not show significant difference between the relapsed and non-relapsed groups. The treatment outcome also showed no difference between the single OMG and second generalized groups. Occurrence of associated autoimmune disease can serve as a potential predictor for myasthenia gravis relapse. Either ptosis or diplopia, as well as thymic hyperplasia can predict generalization in the first six months.

Association of Serum Calprotectin (S100A8/A9) Level With Disease Relapse in Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

PubMed

Pepper, Ruth J; Draibe, Juliana B; Caplin, Ben; Fervenza, Fernando C; Hoffman, Gary S; Kallenberg, Cees G M; Langford, Carol A; Monach, Paul A; Seo, Philip; Spiera, Robert; William St Clair, E; Tchao, Nadia K; Stone, John H; Specks, Ulrich; Merkel, Peter A; Salama, Alan D

2017-01-01

S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group (P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 (P = 0.0043) and baseline and month 6 (P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse (P = 0.028). An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. © 2016, American College of Rheumatology.

Extinction of relapsed fear does not require the basolateral amygdala.

PubMed

Lingawi, Nura W; Westbrook, R Frederick; Laurent, Vincent

2017-03-01

It is well established that extinguished fears are restored with the passage of time or a change in physical context. These fear restoration phenomena are believed to mimic the conditions under which relapse occurs in patients that have been treated for anxiety disorders by means of cue-exposure therapy. Here, we used a rodent model to extinguish relapsed fear and assess whether this new extinction prevents further relapse. We found that activity in the basolateral amygdala (BLA) is required to initially extinguish conditioned fear, but this activity was not necessary to subsequently extinguish relapsed fear. That is, extinction of spontaneously recovered or renewed fear was spared by BLA inactivation. Yet, this BLA-independent learning of extinction did not protect against further relapse: extinction of relapsed fear conducted without BLA activity was still likely to return after the passage of time or a shift in physical context. These findings have important clinical implications. They indicate that pharmacological agents with anxiolytic properties may disrupt initial cue-exposure therapy but may be useful when therapy is again needed due to relapse. However, they also suggest that these agents will not protect against further relapse, implying the need for developing drugs that target other brain regions involved in fear inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

Social settings and addiction relapse.

PubMed

Walton, M A; Reischl, T M; Ramanthan, C S

1995-01-01

Despite addiction theorists' acknowledgment of the impact of environmental factors on relapse, researchers have not adequately investigated these influences. Ninety-six substance users provided data regarding their perceived risk for relapse, exposure to substances, and involvement in reinforcing activities. These three setting attributes were assessed in their home, work, and community settings. Reuse was assessed 3 months later. When controlling for confounding variables, aspects of the home settings significantly distinguished abstainers from reusers; perceived risk for relapse was the strongest predictor of reuse. Exposure to substances and involvement in reinforcing activities were not robust reuse indicators. The work and community settings were not significant determinants of reuse. These findings offer some initial support for the utility of examining social settings to better understand addiction relapse and recovery. Identification of setting-based relapse determinants provides concrete targets for relapse prevention interventions.

Efficacy of assessing circulating cell-free DNA using a simple fluorescence assay in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a prospective observational study

PubMed Central

Park, Kwonoh; Woo, Miyoung; Kim, Jeong Eun; Ahn, Jin-Hee; Jung, Kyung Hae; Roh, Jin; Gong, Gyungyub; Kim, Sung-Bae

2018-01-01

This study aims to assess cell-free DNA (CFD) by a fluorescence assay as a biomarker for early prediction of a pathologic complete response (pCR) and relapse in patients with triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy. Patients with clinical stage II or III TNBC scheduled for neoadjuvant chemotherapy were prospectively enrolled. All patients underwent four cycles of Adriamycin plus cyclophosphamide (AC), followed by four cycles of cisplatin or docetaxel chemotherapy and surgery. Blood samples were obtained before the initial chemotherapy (baseline-CFD) and after four AC neoadjuvant chemotherapy cycles (AC-CFD) to evaluate CFD levels. In total, 72 patients who met the inclusion criteria were enrolled. The mean baseline-CFD and AC-CFD levels were 239 ± 68 and 210 ± 66 ng/mL, respectively, with a significant decline in the CFD levels after AC neoadjuvant chemotherapy (P = 0.001). In the 33.6-month median follow-up, 18 cases of relapse were reported. A ROC curve analysis of baseline-CFD was performed to determine the predictive value for relapse, and an area under the curve of 0.62 (95% CI, 0.46–0.78) at 264 ng/mL was obtained. Patients with baseline-CFD >264 ng/mL were at a higher risk of relapse than those with baseline-CFD ≤264 ng/mL (HR, 2.84; 95% CI, 1.11–7.24; P = 0.029). Multivariate analysis established baseline-CFD as an independent predicting factor for relapse (HR, 3.74; 95% CI, 1.32–10.53; P = 0.013). In conclusion, baseline-CFD measured by a fluorescence assay might be a potential biomarker to predict relapse, which could be useful for risk stratification of TNBC. PMID:29423090

Deep NPM1 Sequencing Following Allogeneic Hematopoietic Cell Transplantation Improves Risk Assessment in Adults with NPM1-Mutated AML.

PubMed

Zhou, Yi; Othus, Megan; Walter, Roland B; Estey, Elihu H; Wu, David; Wood, Brent L

2018-04-21

Relapse is the major cause of death in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT). Measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) before and after HCT is a strong, independent risk factor for relapse. As next-generation sequencing (NGS) is increasingly applied in AML MRD detection, it remains to be determined if NGS can improve prediction of post-HCT relapse. Herein, we investigated pre-HCT MRD detected by MFC and NGS in 59 adult patients with NPM1-mutated AML in morphologic remission; 45 of the 59 had post-HCT MRD determined by MFC and NGS around day 28. Before HCT, MRD detected by MFC was the most significant risk factor for relapse (hazard ratio [HR], 4.63; P < .001), whereas MRD detected only by NGS was not. After HCT, MRD detected by either MFC or NGS was significant risk factor for relapse (HR, 4.96, P = .004 and HR, 4.36, P = .002, respectively). Combining pre- and post-HCT MRD provided the best prediction for relapse (HR, 5.25; P < .001), with a sensitivity at 83%. We conclude that NGS testing of mutated NPM1 post-HCT improves the risk assessment for relapse, whereas pre-HCT MFC testing identifies a subset of high-risk patients in whom additional therapy should be tested. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

CD4+CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study.

PubMed

Tselios, Konstantinos; Sarantopoulos, Alexandros; Gkougkourelas, Ioannis; Boura, Panagiota

2014-01-01

Several studies have reported low numbers of T regulatory cells (Tregs) in active systemic lupus erythematosus (SLE). However, it is not evident if these cells may be utilised as a biomarker in assessing disease activity. Tregs (CD4+CD25highFOXP3+) were prospectively assessed by flow cytometry in 285 separate blood samples from 100 white Caucasian SLE patients and 20 healthy controls. Patients were divided, according to disease activity (as measured by SLEDAI) into groups A (n=39, samples=94, SLEDAI=0), B (n=33, samples=92, SLEDAI=1-5), C (n=10, samples=53, SLEDAI=6-10) and D (n=18, samples=46, SLEDAI>10). Longitudinal measurements were performed in 131 cases (37 relapses, 44 remissions and 50 cases with stable disease activity) during three years. Statistics were performed by Student's t-test or one-way ANOVA; correlations with Pearson co-efficient, while p<0.05 was considered significant. Tregs were found significantly lower in severely active disease (group D), compared to healthy controls, inactive disease, mild and moderate disease activity (0.57±0.16% vs. 1.49±0.19%, 1.19±0.34% and 1.05±0.36%, 0.72±0.21%, p<0.05, respectively). There was a strongly inverse correlation between Tregs and SLEDAI (r=-0.644, p<0.001). Alterations in disease activity were characterised by inverse alterations in Tregs: relapse (from 1.23±0.44% to 0.64±0.19%, p<0.001, mean change 0.59±0.41%), remission (from 0.65±0.27% to 1.17±0.30%, p<0.001, mean change 0.52±0.35%). In cases with unaltered disease activity, Treg numbers remained stable (from 0.98±0.35% to 1.03±0.34%, p=0.245). Tregs were practically halved during relapse (mean reduction 42.6±22.2%), and doubled during remission (mean increment 113±120.9%). Mean change of Tregs in stable disease was significantly lower (7.3±20.6%, p<0.001). A clinically significant change in SLEDAI (sum of cases with relapse and remission, n=81) was followed by a significant (>20%) inverse change in Tregs in 71/81 cases (sensitivity 87.7%). In 50 cases of stable disease activity, Tregs were significantly changed (>20%) in 13 cases (specificity 74%). Positive predictive value (PPV) was 84.5% and negative predictive value (NPV) was 78.7%. CD4+CD25highFOXP3+ T regulatory cells displayed a strongly inverse correlation to disease activity in the long term. Treg alterations reflected changes in SLEDAI with high sensitivity. These cells may be a reliable biomarker for the assessment of disease activity in SLE by longitudinal measurements.

Association between methylenetetrahydrofolate reductase polymorphisms and the relapse of acute lymphoblastic leukemia: a meta-analysis.

PubMed

He, H-R; Chen, S-Y; You, H-S; Hu, S-S; Sun, J-Y; Dong, Y-L; Lu, J

2014-10-01

Relapse is a threat in patients treated for acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) activity may affect the sensitivity of patients to folate-based chemotherapeutic drugs, thus influencing the relapse risk. Two polymorphisms of the gene encoding MTHFR, C677T and A1298C, alter MTHFR enzyme activity and may be associated with ALL relapse. The aim of this meta-analysis was to clarify the correlation between the C677T and A1298C polymorphisms and ALL relapse. To this end, data were collected from studies of the association between these two polymorphisms and ALL relapse. Analysis of the data revealed a serious contradiction among the results. A recessive model demonstrated that the ALL relapse risk was significantly increased in carriers of the 677 TT genotype, especially for pediatric ALL, but was unaffected by the A1298C polymorphism. These findings confirm that the MTHFR C677T polymorphism could be considered as a good marker of the pediatric ALL relapse risk.

CD56bright natural killer cells and response to daclizumab HYP in relapsing-remitting MS

PubMed Central

Sheridan, J.; Amaravadi, L.; Riester, K.; Selmaj, K.; Bielekova, B.; Parr, E.; Giovannoni, G.

2015-01-01

Objective: To assess the relationship between CD56bright natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP). Methods: Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56bright NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate. Results: In DAC HYP–treated patients but not placebo-treated patients, the numbers of CD56bright NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56bright NK cell counts and the annualized relapse rate in DAC HYP–treated patients. DAC HYP–treated patients who showed lower levels of expansion of CD56bright NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment. Conclusions: CD56bright NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes. PMID:25635261

Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort.

PubMed

Höie, Ole; Wolters, Frank; Riis, Lene; Aamodt, Geir; Solberg, Camilla; Bernklev, Tomm; Odes, Selwyn; Mouzas, Iannis A; Beltrami, Marina; Langholz, Ebbe; Stockbrügger, Reinhold; Vatn, Morten; Moum, Bjorn

2007-08-01

Cumulative 10-yr relapse rates in ulcerative colitis (UC) of 70% to almost 100% have been reported in regional studies. The aim of this study was to determine the relapse rate in UC in a European population-based cohort 10 yr after diagnosis and to identify factors that may influence the risk of relapse. From 1991 to 1993, 771 patients with UC from seven European countries and Israel were prospectively included in a population-based inception cohort and followed for 10 yr. A relapse was defined as an increase in UC-related symptoms leading to changes in medical treatment or surgery. The cumulative relapse rate, time to first relapse, and number of relapses in the follow-up period were recorded and possible causative factors were investigated. The cumulative relapse rate of patients with at least one relapse was 0.67 (95% CI 0.63-0.71). The time to first relapse showed a greater hazard ratio (HR) (1.2, CI 1.0-1.5) for women and for patients with a high level of education (1.4, CI 1.1-1.8). The number of relapses decreased with age, and current smokers had a lower relapse rate (0.8, CI 0.6-0.9) than nonsmokers. The relapse rate in women was 1.2 (CI 1.1-1.3) times higher than in men. An inverse relation was found between the time to the first relapse and the total number of relapses. In 67% of patients, there was at least one relapse. Smoking status, level of education, and possibly female gender were found to influence the risk of relapse.

Microbiome interaction with sugar plays an important role in relapse of childhood caries.

PubMed

Tian, Jing; Qin, Man; Ma, Wenli; Xia, Bin; Xu, He; Zhang, Qian; Chen, Feng

Childhood caries have a high relapse rate after full mouth therapy. This study aimed to elucidate the relationship between the microbiome, sugar, and the relapse of childhood caries after therapy. A total of 24 children aged 2-4 years who underwent one caries treatment session participated in this study. Supragingival plaque was collected before therapy and 1 and 7 months after therapy, then sequenced using the 16S rRNA high-throughput approach. We found 11 phyla, 140 genera, and 444 species in 72 samples. The children were divided into relapse-free (n = 13) and relapse (n = 11) groups according to whether they relapsed 7 months after therapy. The bacterial community richness, diversity, structure, and relative abundance of bacterial taxa were significantly different between the two groups 7 months after therapy. The two groups also differed in the relative abundance of bacterial taxa, both before and 1 month after therapy. Bacterial community richness and diversity were lower in the relapse-free group 1 month after therapy. Using different operational taxonomic units between the relapse-free and relapse groups 1 month after therapy, a relapse-risk assessment model was built with 75% accuracy, 0.1905 out-of-bag error, and 66.67% validation accuracy. Patients in the relapse group had higher sugar intake frequencies than those in the relapse-free group during follow-up. Interactions between the microbiome and sugar intake frequency were found through co-occurrence networks. We conclude that the microbiome is significantly different between the relapse-free and relapse groups at the time of relapse. Supragingival plaque collected immediately after therapy can be used to predict the risk of relapse. Furthermore, the correlation between sugar intake frequency and microbiome is associated with the relapse. Copyright © 2015 Elsevier Inc. All rights reserved.

A brief motivational interviewing as an adjunct to periodontal therapy-A potential tool to reduce relapse in oral hygiene behaviours. A three-year study.

PubMed

Stenman, J; Wennström, J L; Abrahamsson, K H

2018-05-01

To evaluate (ii) whether inclusion of a single motivational interviewing (MI) session, as an adjunct to periodontal therapy, might be beneficial for preventing relapse in oral hygiene behaviours among patients treated for chronic periodontitis and (ii) whether individual and clinical characteristics can be of predictive value for retention of sufficient oral hygiene behaviours. This 3-year follow-up of a previously reported randomized controlled trial (RCT) study of 6-month duration included 26 patients. Patients in the test group had received one MI session by a clinical psychologist before initiation of the periodontal treatment. Otherwise, all patients followed the same treatment protocol for conventional educational intervention and non-surgical periodontal therapy. Efficacy variables assessed for evaluation of the standard of self-performed periodontal infection control were marginal bleeding index (MBI; primary efficacy variable) and plaque score (PI). The patterns of change in MBI and PI scores were similar for test and control groups over the observation period. At 3 years, both groups showed a desirable mean full-mouth MBI of 15%, a figure that was comparable to that at the short-term evaluation after active periodontal treatment. The post-treatment MBI was the only variable identified as a predictor of retained adequate oral hygiene behaviours. A single MI session as an adjunct to conventional periodontal therapy could not be proven to be of long-term beneficial additive effect with regard to prevention of relapse in oral hygiene behaviour. Desirable standard of self-performed infection control after active periodontal treatment predicted the retention of sufficient oral hygiene behaviour over time. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Quantifying the Clinical Significance of Cannabis Withdrawal

PubMed Central

Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

2012-01-01

Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

Regional homogeneity changes between heroin relapse and non-relapse patients under methadone maintenance treatment: a resting-state fMRI study.

PubMed

Chang, Haifeng; Li, Wei; Li, Qiang; Chen, Jiajie; Zhu, Jia; Ye, Jianjun; Liu, Jierong; Li, Zhe; Li, Yongbin; Shi, Ming; Wang, Yarong; Wang, Wei

2016-08-18

Methadone maintenance treatment (MMT) is recognized as one of the most effective treatments for heroin addiction but its effect is dimmed by the high incidence of heroin relapse. However, underlying neurobiology mechanism of heroin relapse under MMT is still largely unknown. Here, we took advantage of a resting-state fMRI technique by analysis of regional homogeneity (ReHo), and tried to explore the difference of brain function between heroin relapsers and non-relapsers in MMT. Forty MMT patients were included and received a 12-month follow-up. All patients were given baseline resting-state fMRI scans by using a 3.0 T GE Signa Excite HD whole-body MRI system. Monthly self-report and urine test were used to assess heroin relapse or non-relapse. Subjective craving was measured with visual analog scale. The correlation between ReHo and the degree of heroin relapse was analyzed. Compared with the non-relapsers, ReHo values were increased in the bilateral medial orbitofrontal cortex, right caudate, and right cerebellum of the heroin relapsers while those in the left parahippocampal gyrus, left middle temporal gyrus, right lingual gyrus, and precuneus were decreased in heroin relapsers. Importantly, altered ReHo in the right caudate were positively correlated with heroin relapse rates or subjective craving response. Using the resting-state fMRI technique by analysis of ReHo, we provided the first resting-state fMRI evidence that right caudate may serve as a potential biomarker for heroin relapse prediction and also as a promising target for reducing relapse risk.

Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia.

PubMed

Aplenc, Richard; Thompson, Jennifer; Han, Peggy; La, Mei; Zhao, Huaqing; Lange, Beverly; Rebbeck, Timothy

2005-03-15

A significant portion of patients treated for pediatric acute lymphoblastic leukemia (ALL) relapse. We hypothesized that common polymorphisms with moderate effect sizes and large attributive risks could explain an important fraction of ALL relapses. Methylenetetrahydrofolate reductase (MTHFR) is central to folate metabolism and has two common functional polymorphisms (C677T and A1298G). Methotrexate (MTX), which interrupts folate metabolism, is a mainstay of pediatric ALL therapy. MTX inhibits the synthesis of dTMP needed for DNA replication by blocking the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by MTHFR. We hypothesized that a deactivating MTHFR allele would increase ALL relapse risk by potentially increasing 5,10-methylenetetrahydrofolate and dTMP, enhancing DNA synthesis and thus opposing MTX. To test this hypothesis, we genotyped 520 patients on the Children's Cancer Study Group ALL study, CCG-1891. The MTHFR C677T variant allele was statistically significantly associated with relapse (chi2 = 4.38, P = 0.036). This association remained significant (hazard ratio = 1.82, P = 0.008), controlling for important covariates, and was more predictive of relapse than other predictors, including day 7 bone marrow response. The MTHFR C677T variant allele was not associated with an increased risk of toxicity or infection. The MTHFR A1298G polymorphism was not associated with altered risks of relapse, toxicity, or infection. Haplotype analysis showed six common haplotypes that did not provide additional information predictive for relapse. These data provide evidence that the MTHFR C677T polymorphism is a common genetic variant conferring a moderate relative risk and a high attributable risk for relapse in pediatric ALL patients.

Common genetic variation within miR-146a predicts disease onset and relapse in multiple sclerosis.

PubMed

Zhou, Yuan; Chen, Ming; Simpson, Steve; Lucas, Robyn M; Charlesworth, Jac C; Blackburn, Nicholas; van der Mei, Ingrid; Ponsonby, Anne-Louise; Taylor, Bruce V

2018-02-01

Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.

Predicting Relapse in Patients With Medulloblastoma by Integrating Evidence From Clinical and Genomic Features

PubMed Central

Tamayo, Pablo; Cho, Yoon-Jae; Tsherniak, Aviad; Greulich, Heidi; Ambrogio, Lauren; Schouten-van Meeteren, Netteke; Zhou, Tianni; Buxton, Allen; Kool, Marcel; Meyerson, Matthew; Pomeroy, Scott L.; Mesirov, Jill P.

2011-01-01

Purpose Despite significant progress in the molecular understanding of medulloblastoma, stratification of risk in patients remains a challenge. Focus has shifted from clinical parameters to molecular markers, such as expression of specific genes and selected genomic abnormalities, to improve accuracy of treatment outcome prediction. Here, we show how integration of high-level clinical and genomic features or risk factors, including disease subtype, can yield more comprehensive, accurate, and biologically interpretable prediction models for relapse versus no-relapse classification. We also introduce a novel Bayesian nomogram indicating the amount of evidence that each feature contributes on a patient-by-patient basis. Patients and Methods A Bayesian cumulative log-odds model of outcome was developed from a training cohort of 96 children treated for medulloblastoma, starting with the evidence provided by clinical features of metastasis and histology (model A) and incrementally adding the evidence from gene-expression–derived features representing disease subtype–independent (model B) and disease subtype–dependent (model C) pathways, and finally high-level copy-number genomic abnormalities (model D). The models were validated on an independent test cohort (n = 78). Results On an independent multi-institutional test data set, models A to D attain an area under receiver operating characteristic (au-ROC) curve of 0.73 (95% CI, 0.60 to 0.84), 0.75 (95% CI, 0.64 to 0.86), 0.80 (95% CI, 0.70 to 0.90), and 0.78 (95% CI, 0.68 to 0.88), respectively, for predicting relapse versus no relapse. Conclusion The proposed models C and D outperform the current clinical classification schema (au-ROC, 0.68), our previously published eight-gene outcome signature (au-ROC, 0.71), and several new schemas recently proposed in the literature for medulloblastoma risk stratification. PMID:21357789

Smoker Characteristics and Smoking-Cessation Milestones

PubMed Central

Japuntich, Sandra J.; Leventhal, Adam M.; Piper, Megan E.; Bolt, Daniel M.; Roberts, Linda J.; Fiore, Michael C.; Baker, Timothy B.

2011-01-01

Background Contextual variables often predict long-term abstinence, but little is known about how these variables exert their effects. These variables could influence abstinence by affecting the ability to quit at all, or by altering risk of lapsing, or progressing from a lapse to relapse. Purpose To examine the effect of common predictors of smoking-cessation failure on smoking-cessation processes. Methods The current study (N = 1504, 58% female, 84% Caucasian; recruited from January 2005 to June 2007; data analyzed in 2009) uses the approach advocated by Shiffman et al., (2006), which measures cessation outcomes on three different cessation milestones (achieving initial abstinence, lapse risk, and the lapse-relapse transition) to examine relationships of smoker characteristics (dependence, contextual and demographic factors) with smoking-cessation process. Results High nicotine dependence strongly predicted all milestones: not achieving initial abstinence, and a higher risk of both lapse and transitioning from lapse to complete relapse. Numerous contextual and demographic variables were associated with higher initial cessation rates and/or decreased lapse risk at 6 months post-quit (e.g., ethnicity, gender, marital status, education, smoking in the workplace, number of smokers in the social network, and number of supportive others). However, aside from nicotine dependence, only gender significantly predicted the risk of transition from lapse to relapse. Conclusions These findings demonstrate that: (1) higher nicotine dependence predicted worse outcomes across every cessation milestone; (2) demographic and contextual variables are generally associated with initial abstinence rates and lapse risk and not the lapse-relapse transition. These results identify groups who are at risk for failure at specific stages of the smoking-cessation process, and this may have implications for treatment. PMID:21335259

Surveillance imaging in mantle cell lymphoma in first remission lacks clinical utility.

PubMed

Guidot, Daniel M; Switchenko, Jeffrey M; Nastoupil, Loretta J; Koff, Jean L; Blum, Kristie A; Maly, Joseph; Flowers, Christopher R; Cohen, Jonathon B

2018-04-01

Mantle cell lymphoma (MCL) is a heterogeneous disease with high relapse rates. Limited data guide the use of surveillance imaging following treatment. We constructed a retrospective cohort from two academic institutions of patients with MCL who completed first-line therapy and underwent follow-up for relapse, analyzing the effect of surveillance imaging on survival. Of 217 patients, 102 had documented relapse, with 38 (37%) diagnosed by surveillance imaging and 64 (63%) by other methods. Relapse diagnosis by surveillance imaging had no significant advantage in overall survival from diagnosis date (hazard ratio [HR] = 0.80, p = .39) or relapse date (HR = 0.72, p = .22). Of 801 surveillance images, PET/CT had a positive predictive value (PPV) of 24% and number needed-to-scan/treat (NNT) of 51 to detect one relapse, and CT had a PPV of 49% and NNT of 24. For MCL after first-line therapy, relapse detection by surveillance imaging was not associated with improved survival and lacks clinical benefit.

Changes in circulating peptide YY and ghrelin are associated with early smoking relapse.

PubMed

Lemieux, Andrine M; al'Absi, Mustafa

2018-01-01

Ghrelin and peptide YY (PYY) during ad libitum smoking have been associated with decreased reported craving (ghrelin) and increased positive affect (PYY), and higher baseline ghrelin levels predicted subsequent increased risk of smoking relapse. The current study assessed PYY and ghrelin during ad libitum smoking and again after the initial 48h of a smoking cessation attempt. The data compared smokers who abstained for 28days (n=37), smokers who relapsed (n=54), and nonsmokers (n=37). Plasma samples and subjective measures assessing craving and mood were collected at the beginning of each session. Results showed that relapsers experienced greater levels of distress (ps <0.01). While nonsmokers and abstainers showed no change in ghrelin across the initial 48h, relapsers declined (p <0.01). With PYY, relapsers increased (p <0.05) across the early abstinent phase. PYY and ghrelin may be useful predictors of relapse, specifically in reference to early withdrawal. Copyright © 2017. Published by Elsevier B.V.

Social Resource Characteristics and Adolescent Substance Abuse Relapse.

ERIC Educational Resources Information Center

Vik, Peter W.; And Others

1992-01-01

Examined social resource network characteristics of adolescent substance abusers (n=19). Perceived similarity to one's social network emerged as important moderator of whether social network provided support to remain abstinent or elevated risk for relapse. Increased perceived support predicted continued posttreatment abstinence when recovering…

Evaluation of post-surgical relapse after mandibular setback surgery with minimal orthodontic preparation.

PubMed

Lee, Nam-Ki; Kim, Young-Kyun; Yun, Pil-Young; Kim, Jong-Wan

2013-01-01

The aim of this study was to evaluate of the patterns of post-surgical relapse after mandibular setback surgery with minimal orthodontic preparation (MS-MO). The subjects consisted of 15 patients with minimal pre-surgical orthodontic preparation (1.37 ± 1.69 months). Lateral cephalograms were taken in pre-surgical (T0), post-surgical 1 month (T1) and immediately after debonding (T2) stages. To evaluate the surgical changes (T1-T0) and the relapse (T2-T1), the linear and angular measurements were analyzed using paired t-test. Pearson's correlation coefficients of the horizontal and vertical relapses of Pog and Me to other measurements were calculated. Pog or Me in T1 were displaced rotationally on Ar-Pog or Ar-Me lines in T2 to evaluate the remaining surgical relapse except the rotational relapse from total relapse. The mandible relapsed anteriorly 3.53 mm (Pog) and 4.00 mm (Me) and superiorly 2.72 mm (Pog) and 2.44 mm (Me). FH to Ar-Pog and FH to Ar-Me decreased by about 2°. Pure surgical relapses at Pog and Me, except rotational relapses, were about 0.5 mm anteriorly and inferiorly 0.8 mm. The vertical relapse might induce mandibular rotation with the horizontal relapse. For an accurate prediction after MS-MO, the rotational relapse might be considered. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

The role of family expressed emotion and perceived social support in predicting addiction relapse.

PubMed

Atadokht, Akbar; Hajloo, Nader; Karimi, Masoud; Narimani, Mohammad

2015-03-01

Emotional conditions governing the family and patients' perceived social support play important roles in the treatment or relapse process of the chronic disease. The current study aimed to investigate the role of family expressed emotion and perceived social support in prediction of addiction relapse. The descriptive-correlation method was used in the current study. The study population consisted of the individuals referred to the addiction treatment centers in Ardabil from October 2013 to January 2014. The subjects (n = 80) were randomly selected using cluster sampling method. To collect data, expressed emotion test by Cole and Kazaryan, and Multidimensional Scale of Perceived Social Support (MSPSS) were used, and the obtained data was analyzed using the Pearson's correlation coefficient and multiple regression analyses. Results showed a positive relationship between family expressed emotions and the frequency of relapse (r = 0.26, P = 0.011) and a significant negative relationship between perceived social support and the frequency of relapse (r = -0.34, P = 0.001). Multiple regression analysis also showed that perceived social support from family and the family expressed emotions significantly explained 12% of the total variance of relapse frequency. These results have implications for addicted people, their families and professionals working in addiction centers to use the emotional potential of families especially their expressed emotions and the perceived social support of addicts to increase the success rate of addiction treatment.

Integrity of Literature on Expressed Emotion and Relapse in Patients with Schizophrenia Verified by a p-Curve Analysis.

PubMed

Weintraub, Marc J; Hall, Daniel L; Carbonella, Julia Y; Weisman de Mamani, Amy; Hooley, Jill M

2017-06-01

There is growing concern that much published research may have questionable validity due to phenomena such as publication bias and p-hacking. Within the psychiatric literature, the construct of expressed emotion (EE) is widely assumed to be a reliable predictor of relapse across a range of mental illnesses. EE is an index of the family climate, measuring how critical, hostile, and overinvolved a family member is toward a mentally ill patient. No study to date has examined the evidential value of this body of research as a whole. That is to say, although many studies have shown a link between EE and symptom relapse, the integrity of the literature from which this claim is derived has not been tested. In an effort to confirm the integrity of the literature of EE predicting psychiatric relapse in patients with schizophrenia, we conducted a p-curve analysis on all known studies examining EE (using the Camberwell Family Interview) to predict psychiatric relapse over a 9- to 12-month follow-up period. Results suggest that the body of literature on EE is unbiased and has integrity, as there was a significant right skew of p-values, a nonsignificant left skew of p-values, and a nonsignificant test of flatness. We conclude that EE is a robust and valuable predictor of symptom relapse in schizophrenia. © 2016 Family Process Institute.

Integrity of Literature on Expressed Emotion and Relapse in Patients with Schizophrenia Verified by a p-Curve Analysis

PubMed Central

WEINTRAUB, MARC J.; HALL, DANIEL L.; CARBONELLA, JULIA Y.; DE MAMANI, AMY WEISMAN; HOOLEY, JILL M.

2018-01-01

There is growing concern that much published research may have questionable validity due to phenomena such as publication bias and p-hacking. Within the psychiatric literature, the construct of expressed emotion (EE) is widely assumed to be a reliable predictor of relapse across a range of mental illnesses. EE is an index of the family climate, measuring how critical, hostile, and overinvolved a family member is toward a mentally ill patient. No study to date has examined the evidential value of this body of research as a whole. That is to say, although many studies have shown a link between EE and symptom relapse, the integrity of the literature from which this claim is derived has not been tested. In an effort to confirm the integrity of the literature of EE predicting psychiatric relapse in patients with schizophrenia, we conducted a p-curve analysis on all known studies examining EE (using the Camberwell Family Interview) to predict psychiatric relapse over a 9- to 12-month follow-up period. Results suggest that the body of literature on EE is unbiased and has integrity, as there was a significant right skew of p-values, a nonsignificant left skew of p-values, and a nonsignificant test of flatness. We conclude that EE is a robust and valuable predictor of symptom relapse in schizophrenia. PMID:26875506

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.

PubMed

Göçeroğlu, Arda; Berden, Annelies E; Fiocco, Marta; Floßmann, Oliver; Westman, Kerstin W; Ferrario, Franco; Gaskin, Gill; Pusey, Charles D; Hagen, E Christiaan; Noël, Laure-Hélène; Rasmussen, Niels; Waldherr, Rüdiger; Walsh, Michael; Bruijn, Jan A; Jayne, David R W; Bajema, Ingeborg M

2016-01-01

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse

PubMed Central

Göçeroğlu, Arda; Berden, Annelies E.; Fiocco, Marta; Floßmann, Oliver; Westman, Kerstin W.; Ferrario, Franco; Gaskin, Gill; Pusey, Charles D.; Hagen, E. Christiaan; Noël, Laure-Hélène; Rasmussen, Niels; Waldherr, Rüdiger; Walsh, Michael; Bruijn, Jan A.; Jayne, David R. W.; Bajema, Ingeborg M.

2016-01-01

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild–moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray’s regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8–14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray’s model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different. PMID:27973575

Using decision tree analysis to identify risk factors for relapse to smoking

PubMed Central

Piper, Megan E.; Loh, Wei-Yin; Smith, Stevens S.; Japuntich, Sandra J.; Baker, Timothy B.

2010-01-01

This research used classification tree analysis and logistic regression models to identify risk factors related to short- and long-term abstinence. Baseline and cessation outcome data from two smoking cessation trials, conducted from 2001 to 2002, in two Midwestern urban areas, were analyzed. There were 928 participants (53.1% women, 81.8% white) with complete data. Both analyses suggest that relapse risk is produced by interactions of risk factors and that early and late cessation outcomes reflect different vulnerability factors. The results illustrate the dynamic nature of relapse risk and suggest the importance of efficient modeling of interactions in relapse prediction. PMID:20397871

A nomogram to predict brain metastasis as the first relapse in curatively resected non-small cell lung cancer patients.

PubMed

Won, Young-Woong; Joo, Jungnam; Yun, Tak; Lee, Geon-Kook; Han, Ji-Youn; Kim, Heung Tae; Lee, Jin Soo; Kim, Moon Soo; Lee, Jong Mog; Lee, Hyun-Sung; Zo, Jae Ill; Kim, Sohee

2015-05-01

Development of brain metastasis results in a significant reduction in overall survival. However, there is no an effective tool to predict brain metastasis in non-small cell lung cancer (NSCLC) patients. We conducted this study to develop a feasible nomogram that can predict metastasis to the brain as the first relapse site in patients with curatively resected NSCLC. A retrospective review of NSCLC patients who had received curative surgery at National Cancer Center (Goyang, South Korea) between 2001 and 2008 was performed. We chose metastasis to the brain as the first relapse site after curative surgery as the primary endpoint of the study. A nomogram was modeled using logistic regression. Among 1218 patients, brain metastasis as the first relapse developed in 87 patients (7.14%) during the median follow-up of 43.6 months. Occurrence rates of brain metastasis were higher in patients with adenocarcinoma or those with a high pT and pN stage. Younger age appeared to be associated with brain metastasis, but this result was not statistically significant. The final prediction model included histology, smoking status, pT stage, and the interaction between adenocarcinoma and pN stage. The model showed fairly good discriminatory ability with a C-statistic of 69.3% and 69.8% for predicting brain metastasis within 2 years and 5 years, respectively. Internal validation using 2000 bootstrap samples resulted in C-statistics of 67.0% and 67.4% which still indicated good discriminatory performances. The nomogram presented here provides the individual risk estimate of developing metastasis to the brain as the first relapse site in patients with NSCLC who have undergone curative surgery. Surveillance programs or preventive treatment strategies for brain metastasis could be established based on this nomogram. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Neurophysiological correlates of response inhibition predict relapse in detoxified alcoholic patients: some preliminary evidence from event-related potentials

PubMed Central

Petit, Géraldine; Cimochowska, Agnieszka; Kornreich, Charles; Hanak, Catherine; Verbanck, Paul; Campanella, Salvatore

2014-01-01

Background Alcohol dependence is a chronic relapsing disease. The impairment of response inhibition and alcohol-cue reactivity are the main cognitive mechanisms that trigger relapse. Despite the interaction suggested between the two processes, they have long been investigated as two different lines of research. The present study aimed to investigate the interaction between response inhibition and alcohol-cue reactivity and their potential link with relapse. Materials and methods Event-related potentials were recorded during a variant of a “go/no-go” task. Frequent and rare stimuli (to be inhibited) were superimposed on neutral, nonalcohol-related, and alcohol-related contexts. The task was administered following a 3-week detoxification course. Relapse outcome was measured after 3 months, using self-reported abstinence. There were 27 controls (seven females) and 27 patients (seven females), among whom 13 relapsed during the 3-month follow-up period. The no-go N2, no-go P3, and the “difference” wave (P3d) were examined with the aim of linking neural correlates of response inhibition on alcohol-related contexts to the observed relapse rate. Results Results showed that 1) at the behavioral level, alcohol-dependent patients made significantly more commission errors than controls (P<0.001), independently of context; 2) through the subtraction no-go P3 minus go P3, this inhibition deficit was neurophysiologically indexed in patients with greater P3d amplitudes (P=0.034); and 3) within the patient group, increased P3d amplitude enabled us to differentiate between future relapsers and nonrelapsers (P=0.026). Conclusion Our findings suggest that recently detoxified alcoholics are characterized by poorer response-inhibition skills that demand greater neural resources. We propose that event-related potentials can be used in conjunction with behavioral data to predict relapse; this would identify patients that need a higher level of neural resources when suppressing a response is requested. PMID:24966675

Risk factors for alcohol relapse following orthotopic liver transplantation: a systematic review.

PubMed

Rustad, James K; Stern, Theodore A; Prabhakar, Maithri; Musselman, Dominique

2015-01-01

Each year, 5000-6000 individuals undergo orthotopic liver transplantation (OLT) in the United States, and of these, nearly 18% have alcoholic liver disease. Relapse to alcohol occurs in more than 40% of patients with OLT for alcoholic liver disease. We sought to identify factors that predict relapse to alcohol or medication nonadherence following OLT in patients with alcoholic liver disease and to review what randomized clinical interventions have addressed these factors following OLT. Our hypothesis was that there would be factors before and after OLT that predict relapse to alcohol following OLT, and that these, if targeted, might improve sobriety and associated outcomes of adherence with medications and appointments. We performed a review (focusing on articles published since 2004) with PubMed and MEDLINE searches using the following search terms: liver transplantation, recidivism, alcohol relapse, and predictors of alcohol relapse. We supplemented the online searches with manual reviews of article reference lists and selected relevant articles for further review by author consensus. In largely white populations, prospective studies document that shorter length of pretransplantation sobriety is a significant predictor of time to first drink and time to binge use. Presence of psychiatric comorbidity, high score on standardized High-risk Alcoholism Relapse Scale, and diagnosis of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) alcohol dependence are predictive of posttransplantation alcohol relapse. Pretransplantation alcohol use history variables (e.g., family history of alcoholism) reliably discriminate between complete abstainers and those who drink, while medical and psychosocial characteristics at early post-liver transplantation period (e.g., more bodily pain) maximally discriminate patterns of alcohol use. Alcoholic individuals with early-onset, rapidly accelerating moderate use and early-onset, continuously increasing heavy use have more than double the prevalence of steatohepatitis or rejection on biopsy and graft failure and more frequent mortality resulting from recurrent alcoholic liver disease than late-onset (i.e., peak of heaviest drinking at 6y posttransplantation) alcohol users do. Fortunately, pretransplantation screening combined with a structured pretransplantation management program and a 12-step program attendance reduced recidivism. No randomized clinical trials have been performed that target pretransplantation risk factors in individuals with alcoholic liver disease before or after OLT to improve post-OLT outcomes. Recent research findings suggest that screening can reveal individuals who are vulnerable to alcohol relapse and targeted intervention can prevent their relapse to alcohol. Based on existing addiction treatments (e.g., relapse prevention plan construction), randomized clinical trials tailored to post-OLT patients should be conducted to improve their survival and quality of life. Copyright © 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Immunologic prediction of relapse in patients with pemphigus vulgaris (PV) in clinical remission.

PubMed

Daneshpazhooh, Maryam; Zafarmand Sedigh, Vahid; Balighi, Kamran; Hosseini, S Hamed; Ramezani, Ali; Kalantari, Mohammad-Sadegh; Ghandi, Narges; Ghiasi, Maryam; Nikoo, Azita; Chams-Davatchi, Cheyda

2016-06-01

Pemphigus vulgaris (PV) is characterized by multiple relapses, occurring especially in patients on minimal therapy or off therapy. To identify immunologic predictors (anti-desmoglein [Dsg] 1 and 3 antibodies; direct immunofluorescence [DIF]) for relapse in PV patients. Eighty-nine patients in complete clinical remission for at least 6 months and receiving less than or equal to 10 mg prednisolone daily and no immunosuppressive drugs were evaluated using DIF (n=89) and Dsg ELISA (n=46). They were followed until relapse or for at least 18 months. DIF was positive in 44 of 89 patients (49.5%); anti-Dsg 3 antibodies were detected in 18 of 46 patients (39.1%) and anti-Dsg 1 antibodies were detected in 4 of 46 patients (8.7%). Relapse occurred in 38 patients (42.7%). Mean relapse-free time was significantly shorter in anti-Dsg 3-positive patients compared to anti-Dsg 3- negative patients (P = .015) and in DIF-positive patients compared to DIF-negative patients (P = .047), but not in anti-Dsg 1- positive patients compared to anti-Dsg 1-negative patients (P = .501). Sensitivity and predictive values of neither of these tests were high. Small number of anti-Dsg 1-positive patients and use of conventional ELISA. Positive anti-Dsg 3 ELISA and, to a lesser degree, positive DIF are predictors of relapse in PV patients in clinical remission. Decision on discontinuing treatment should be based on the results of these tests as well as on clinical findings. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

[Community-based prevention of drug abuse in Japan].

PubMed

Shimane, Takuya

2010-08-01

The objective of this article is to review community-based drug abuse prevention and relapse prevention in Japan. Japan has a highly efficient system for the primary prevention of drug abuse; this system includes drug abuse education programs in schools and anti-drug abuse campaigns in communities. On the other hand, relapse prevention activities, such as counseling service at mental health welfare centers, self-help groups for drug addicts, and relapse prevention programs at outpatient clinics, are limited because of zero tolerance policies. Therefore, more relapse prevention activities are required in Japanese communities.

Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up

PubMed Central

Schoindre, Yoland; Jallouli, Moez; Tanguy, Marie-Laure; Ghillani, Pascale; Galicier, Lionel; Aumaître, Olivier; Francès, Camille; Le Guern, Véronique; Lioté, Frédéric; Smail, Amar; Limal, Nicolas; Perard, Laurent; Desmurs-Clavel, Hélène; Thi Huong, Du Le; Asli, Bouchra; Kahn, Jean-Emmanuel; Sailler, Laurent; Ackermann, Félix; Papo, Thomas; Sacré, Karim; Fain, Olivier; Stirnemann, Jérôme; Cacoub, Patrice; Leroux, Gaëlle; Cohen-Bittan, Judith; Hulot, Jean-Sébastien; Lechat, Philippe; Musset, Lucile; Piette, Jean-Charles; Amoura, Zahir; Souberbielle, Jean-Claude; Costedoat-Chalumeau, Nathalie

2014-01-01

Objectives Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. Methods Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). Results The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22). Conclusions We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate. PMID:25379192

Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up.

PubMed

Schoindre, Yoland; Jallouli, Moez; Tanguy, Marie-Laure; Ghillani, Pascale; Galicier, Lionel; Aumaître, Olivier; Francès, Camille; Le Guern, Véronique; Lioté, Frédéric; Smail, Amar; Limal, Nicolas; Perard, Laurent; Desmurs-Clavel, Hélène; Le Thi Huong, Du; Asli, Bouchra; Kahn, Jean-Emmanuel; Sailler, Laurent; Ackermann, Félix; Papo, Thomas; Sacré, Karim; Fain, Olivier; Stirnemann, Jérôme; Cacoub, Patrice; Leroux, Gaëlle; Cohen-Bittan, Judith; Hulot, Jean-Sébastien; Lechat, Philippe; Musset, Lucile; Piette, Jean-Charles; Amoura, Zahir; Souberbielle, Jean-Claude; Costedoat-Chalumeau, Nathalie

2014-01-01

Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22). We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate.

Context-induced relapse to cocaine seeking after punishment-imposed abstinence is associated with activation of cortical and subcortical brain regions.

PubMed

Pelloux, Yann; Hoots, Jennifer K; Cifani, Carlo; Adhikary, Sweta; Martin, Jennifer; Minier-Toribio, Angelica; Bossert, Jennifer M; Shaham, Yavin

2018-03-01

We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. In exp. 1, we trained rats to self-administer cocaine (0.75 mg/kg/infusion, 6 hours/day, 12 days) in context A. Next, we transferred them to context B where for the paired group, but not unpaired group, 50 percent of cocaine-reinforced lever presses caused aversive footshock. We then tested the rats for cocaine seeking under extinction conditions in contexts A and B. We also retested them for relapse after retraining in context A and repunishment in context B. In exp. 2, we used Fos immunoreactivity to determine relapse-associated neuronal activation in brain regions of rats exposed to context A, context B or neither context. Results showed the selective shock-induced suppression of cocaine self-administration and context-induced relapse after punishment-imposed abstinence in rats exposed to paired, but not unpaired, footshock. Additionally, context-induced relapse was associated with selective activation of dorsal and ventral medial prefrontal cortex, anterior insula, dorsal striatum, basolateral amygdala, paraventricular nucleus of the thalamus, lateral habenula, substantia nigra, ventral subiculum, and dorsal raphe, but not nucleus accumbens, central amygdala, lateral hypothalamus, ventral tegmental area and other brain regions. Together, context-induced relapse after punishment-imposed abstinence generalizes to rats with a history of cocaine self-administration and is associated with selective activation of cortical and subcortical regions. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study.

PubMed

Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

2014-05-01

The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; p<0.05) only in the progressive group. In the relapsing patients there was an inverse correlation between PKBPND and BH total lesion volume in whole brain (r=-0.781; p<0.05). When progressive patients were grouped according to the disability outcome at 2years from the PK-PET scan, the total PKBPND in BHs was found to be a significant outcome predictor of disability (p<0.01). Our findings show that relapsing and progressive patients have heterogeneous patterns of PKBPND in T1 BHs and indicate that BHs are not just "holes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression. Copyright © 2014 Elsevier Inc. All rights reserved.

Clinical presentation and outcome prediction of clinical, serological, and histopathological classification schemes in ANCA-associated vasculitis with renal involvement.

PubMed

Córdova-Sánchez, Bertha M; Mejía-Vilet, Juan M; Morales-Buenrostro, Luis E; Loyola-Rodríguez, Georgina; Uribe-Uribe, Norma O; Correa-Rotter, Ricardo

2016-07-01

Several classification schemes have been developed for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with actual debate focusing on their clinical and prognostic performance. Sixty-two patients with renal biopsy-proven AAV from a single center in Mexico City diagnosed between 2004 and 2013 were analyzed and classified under clinical (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], renal limited vasculitis [RLV]), serological (proteinase 3 anti-neutrophil cytoplasmic antibodies [PR3-ANCA], myeloperoxidase anti-neutrophil cytoplasmic antibodies [MPO-ANCA], ANCA negative), and histopathological (focal, crescenteric, mixed-type, sclerosing) categories. Clinical presentation parameters were compared at baseline between classification groups, and the predictive value of different classification categories for disease and renal remission, relapse, renal, and patient survival was analyzed. Serological classification predicted relapse rate (PR3-ANCA hazard ratio for relapse 2.93, 1.20-7.17, p = 0.019). There were no differences in disease or renal remission, renal, or patient survival between clinical and serological categories. Histopathological classification predicted response to therapy, with a poorer renal remission rate for sclerosing group and those with less than 25 % normal glomeruli; in addition, it adequately delimited 24-month glomerular filtration rate (eGFR) evolution, but it did not predict renal nor patient survival. On multivariate models, renal replacement therapy (RRT) requirement (HR 8.07, CI 1.75-37.4, p = 0.008) and proteinuria (HR 1.49, CI 1.03-2.14, p = 0.034) at presentation predicted renal survival, while age (HR 1.10, CI 1.01-1.21, p = 0.041) and infective events during the induction phase (HR 4.72, 1.01-22.1, p = 0.049) negatively influenced patient survival. At present, ANCA-based serological classification may predict AAV relapses, but neither clinical nor serological categories predict renal or patient survival. Age, renal function and proteinuria at presentation, histopathology, and infectious complications constitute the main outcome predictors and should be considered for individualized management.

Alcohol-seeking and relapse: A focus on incentive salience and contextual conditioning.

PubMed

Valyear, Milan D; Villaruel, Franz R; Chaudhri, Nadia

2017-08-01

Environmental stimuli that reliably accompany alcohol intake can become associated with the pharmacological effects of alcohol through classical (Pavlovian) conditioning. Of growing interest to addiction researchers is whether or not this process results in the attribution of incentive salience to alcohol-predictive cues, which could motivate alcohol-seeking behavior and relapse. To evaluate this question, we present a review of rodent behavioral studies that examined the capacity of alcohol-predictive cues to (i) support sign-tracking behavior, (ii) serve as conditioned reinforcers, and (iii) produce Pavlovian-to-instrumental transfer. A second, emerging area of research is focused on delineating the role of context in alcohol-seeking behavior and relapse. Here, we review studies showing that alcohol-associated contexts (i) support conditioned place preference, (ii) renew extinguished alcohol-seeking behavior, and (iii) modulate alcohol-seeking responses elicited by discrete alcohol-predictive cues. These behavioral effects may be mediated by unique psychological processes, and have important implications for cue-reactivity studies and neurobiological research. Copyright © 2017 Elsevier B.V. All rights reserved.

Lower Aerobic Endurance Linked to History of Depression in Multiple Sclerosis: Preliminary Observations.

PubMed

Chapman, Kimberly R; Anderson, Jason R; Calvo, Dayana; Pollock, Brandon S; Petersen, Jennifer; Gerhart, Hayden; Ridgel, Angela; Spitznagel, Mary Beth

2018-06-01

Despite the demonstrated benefits of exercise in multiple sclerosis (MS), this population shows low rates of physical activity. Understanding barriers to exercise in persons with MS is important. The current study examined the relationship between lifetime history of depression, current depressive symptoms, and aerobic endurance in persons with relapsing-remitting MS to determine whether depression might be one such barrier. Thirty-one participants with relapsing-remitting MS self-reported current depressive symptoms and history of depression. Aerobic endurance was assessed via 2-Minute Step Test. Linear regression demonstrated that lifetime history of depression predicted lower aerobic fitness whereas current depressive symptoms did not. Findings suggest a possible role of lifetime depression as a barrier to exercise in MS and highlight the importance of effective treatment of depression in this population to reduce its potential impact on exercise adherence.

Artificial intelligence in predicting bladder cancer outcome: a comparison of neuro-fuzzy modeling and artificial neural networks.

PubMed

Catto, James W F; Linkens, Derek A; Abbod, Maysam F; Chen, Minyou; Burton, Julian L; Feeley, Kenneth M; Hamdy, Freddie C

2003-09-15

New techniques for the prediction of tumor behavior are needed, because statistical analysis has a poor accuracy and is not applicable to the individual. Artificial intelligence (AI) may provide these suitable methods. Whereas artificial neural networks (ANN), the best-studied form of AI, have been used successfully, its hidden networks remain an obstacle to its acceptance. Neuro-fuzzy modeling (NFM), another AI method, has a transparent functional layer and is without many of the drawbacks of ANN. We have compared the predictive accuracies of NFM, ANN, and traditional statistical methods, for the behavior of bladder cancer. Experimental molecular biomarkers, including p53 and the mismatch repair proteins, and conventional clinicopathological data were studied in a cohort of 109 patients with bladder cancer. For all three of the methods, models were produced to predict the presence and timing of a tumor relapse. Both methods of AI predicted relapse with an accuracy ranging from 88% to 95%. This was superior to statistical methods (71-77%; P < 0.0006). NFM appeared better than ANN at predicting the timing of relapse (P = 0.073). The use of AI can accurately predict cancer behavior. NFM has a similar or superior predictive accuracy to ANN. However, unlike the impenetrable "black-box" of a neural network, the rules of NFM are transparent, enabling validation from clinical knowledge and the manipulation of input variables to allow exploratory predictions. This technique could be used widely in a variety of areas of medicine.

Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia.

PubMed

Lehmann-Che, Jacqueline; Bally, Cécile; Letouzé, Eric; Berthier, Caroline; Yuan, Hao; Jollivet, Florence; Ades, Lionel; Cassinat, Bruno; Hirsch, Pierre; Pigneux, Arnaud; Mozziconacci, Marie-Joelle; Kogan, Scott; Fenaux, Pierre; de Thé, Hugues

2018-05-24

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time bias.

PubMed

Pickles, Tom; Kim-Sing, Charmaine; Morris, W James; Tyldesley, Scott; Paltiel, Chuck

2003-09-01

To validate the Houston prostate-specific antigen relapse definition in a mature cohort of men treated with external beam radiotherapy (EBRT) and adjuvant androgen ablation (AA) and men treated with EBRT monotherapy, and to compare these results with the American Society for Therapeutic Radiology and Oncology (ASTRO) and Vancouver prostate-specific antigen relapse (biochemical no evidence of disease) definitions. A prospective database of 1490 men treated with EBRT, with or without AA, was examined. The impact on hazard proportions, as well as the predictive ability, of the Houston, ASTRO, and Vancouver definitions was tested. For all patients, the Houston definition was more accurate (79.5%) than the ASTRO (76.7%) or Vancouver (77.2%) definitions in predicting subsequent clinical relapse. The Houston definition was superior to the ASTRO definition in those treated both with and without AA and equivalent to the Vancouver definition in those receiving AA. The Houston definition demonstrated proportional hazards when categorized for the use of AA, unlike the ASTRO and Vancouver definitions. The effect of inadequate follow-up on the projected relapse rates was negligible with the Houston definition. The Houston relapse definition is favored after EBRT monotherapy or combined EBRT and AA. Use of the Cox proportional hazard multivariate analysis is appropriate with the Houston definition, but not with the ASTRO or Vancouver definitions if AA and non-AA patients are combined.

State anxiety modulates the return of fear.

PubMed

Kuhn, Manuel; Mertens, Gaetan; Lonsdorf, Tina B

2016-12-01

Current treatments for anxiety disorders are effective but limited by the high frequency of clinical relapse. Processes underlying relapse are thought to be experimentally modeled in fear conditioning experiments with return fear (ROF) inductions. Thereby reinstatement-induced ROF might be considered a model to study mechanisms underlying adversity-induced relapse. Previous studies have reported differential ROF (i.e. specific for the danger stimulus) but also generalized ROF (i.e. for safe and danger stimuli), but reasons for these divergent findings are not clear yet. Hence, the response pattern (i.e. differential or generalized) following reinstatement may be of importance for the prediction of risk or resilience for ROF. The aim of this study was to investigate state anxiety as a potential individual difference factor contributing to differentiability or generalization of return of fear. Thirty-six participants underwent instructed fear expression, extinction and ROF induction through reinstatement while physiological (skin conductance response, fear potentiated startle) and subjective measures of fear and US expectancy were acquired. Our data show that, as expected, high state anxious individuals show deficits in SCR discrimination between dangerous and safe cues after reinstatement induced ROF (i.e. generalization) as compared to low state anxious individuals. The ability to maintain discrimination under aversive circumstances is negatively associated with pathological anxiety and predictive of resilient responding while excessive generalization is a hallmark of anxiety disorders. Therefore, we suggest that experimentally induced ROF might prove useful in predicting relapse risk in clinical settings and might have implications for possible interventions for relapse prevention. Copyright © 2016 Elsevier B.V. All rights reserved.

A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.

PubMed

Sutton, Rosemary; Venn, Nicola C; Law, Tamara; Boer, Judith M; Trahair, Toby N; Ng, Anthea; Den Boer, Monique L; Dissanayake, Anuruddhika; Giles, Jodie E; Dalzell, Pauline; Mayoh, Chelsea; Barbaric, Draga; Revesz, Tamas; Alvaro, Frank; Pieters, Rob; Haber, Michelle; Norris, Murray D; Schrappe, Martin; Dalla Pozza, Luciano; Marshall, Glenn M

2018-02-01

To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10 -5 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 +  for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 +  groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL. © 2017 John Wiley & Sons Ltd.

Alcohol craving as a predictor of relapse.

PubMed

Schneekloth, Terry D; Biernacka, Joanna M; Hall-Flavin, Daniel K; Karpyak, Victor M; Frye, Mark A; Loukianova, Larissa L; Stevens, Susanna R; Drews, Maureen S; Geske, Jennifer R; Mrazek, David A

2012-11-01

Alcoholism treatment interventions, both psychosocial and pharmacologic, aim to reduce cravings to drink. Yet, the role of craving in treatment outcomes remains unclear. This study evaluated craving intensity measured with the Penn Alcohol Craving Scale (PACS) at admission and discharge from residential treatment as a predictive factor of relapse after treatment. The study cohort included 314 alcohol-dependent subjects. Associations between relapse after discharge, PACS score, and clinical variables were investigated using time-to-event analyses. The primary analysis, based on the intent-to-treat principle, presumed relapse in those declining follow-up or not responding to contact attempts. Secondary analysis utilized data from 226 subjects successfully contacted after discharge with a median follow-up time of 365 days. The intent-to-treat analysis demonstrated that relapse was associated with higher level of craving at admission (p= .002) and discharge (p < .001). The analysis of data from patients successfully contacted after discharge led to similar results. A multivariable analysis indicated that relapse rates increased as PACS scores increased, and a higher discharge PACS score was significantly associated with relapse (p= .006) even after adjusting for covariates. This study demonstrates that higher PACS scores at the time of admission and discharge are associated with relapse following residential addiction treatment. These data support the role of craving in relapse and the utility of craving measurement as a clinical guide in assessing relapse risk. Copyright © American Academy of Addiction Psychiatry.

Gender differences in trauma history and symptoms as predictors of relapse to alcohol and drug use.

PubMed

Heffner, Jaimee L; Blom, Thomas J; Anthenelli, Robert M

2011-01-01

The objective of this study was to determine whether there are gender-specific associations between trauma exposure and alcohol or drug relapse in alcohol-dependent adults. Participants were 51 men (n = 24) and women (n = 27) with alcohol dependence, 22 (43.1%) of whom relapsed during study participation. Severity of childhood trauma; number of lifetime events evoking fear, helplessness, or horror; and current trauma symptoms all predicted relapse in women, but not in men. These findings highlight the importance of assessing trauma history and providing treatment of trauma-related symptoms for individuals with alcohol and drug dependence, and for women in particular. © American Academy of Addiction Psychiatry.

Gender Differences in Trauma History and Symptoms as Predictors of Relapse to Alcohol and Drug Use

PubMed Central

Heffner, Jaimee L.; Blom, Thomas J.; Anthenelli, Robert M.

2011-01-01

The objective of this study was to determine whether there are gender-specific associations between trauma exposure and alcohol or drug relapse in alcohol dependent adults. Participants were 51 men (n=24) and women (n=27) with alcohol dependence, 22 (43.1%) of whom relapsed during study participation. Severity of childhood trauma; number of lifetime events evoking fear, helplessness, or horror; and current trauma symptoms all predicted relapse in women, but not in men. These findings highlight the importance of assessing trauma history and providing treatment of trauma-related symptoms for individuals with alcohol and drug dependence, and for women in particular. PMID:21679261

Claims-based proxies of patient instability among commercially insured adults with schizophrenia

PubMed Central

Ruetsch, Charles; Un, Hyong; Waters, Heidi C

2018-01-01

Objective Schizophrenia (Sz) patients are among the highest utilizers of hospital-based services. Prevention of relapse is in part a treatment goal in order to reduce hospital admissions. However, predicting relapse is a challenge, particularly for payers and disease management firms with only access to claims data. Understandably, such organizations have had little success predicting relapse. A tool that allows payers to identify patients at elevated risk of relapse could facilitate targeted interventions prior to relapse and avoid rehospitalization. In this study, a series of proxy measures of patient instability, calculated from claims data were examined for their utility in identifying Sz patients at elevated risk of relapse. Methods Aetna claims were used to assess the relationship between instability of Sz patients and valence and magnitude of antipsychotic (AP) medication change during a 2-year period. Six proxies of instability including hospital admissions, emergency department visits, medication utilization patterns, and use of outpatient services were identified. Results were replicated using claims data from Truven MarketScan®. Results Patients who switched AP ingredient had the highest overall instability at the point of switch and the second steepest decline in instability following switch. Those who changed to a long-acting injectable AP showed the second highest level of instability and the steepest decrease in instability following the change. Patients augmented with a second AP showed the smallest increase in instability, up to the switch. Results were directionally consistent between the two data sets. Conclusion Using claims-based proxy measures to estimate instability may provide a viable method to better understand Sz patient markers of change in disease severity. Also, such proxies could be used to identify those individuals with the greatest need for treatment modification preventing relapse, improving patient outcomes, and reducing the burden of illness. PMID:29765242

Transverse Diffusivity of Cerebral Parenchyma Predicts Visual Tracking Performance in Relapsing-Remitting Multiple Sclerosis

ERIC Educational Resources Information Center

Warlop, Nele P.; Achten, Eric; Fieremans, Els; Debruyne, Jan; Vingerhoets, Guy

2009-01-01

This study investigated the relation between cerebral damage related to multiple sclerosis (MS) and cognitive decline as determined by two classical mental tracking tests. Cerebral damage in 15 relapsing-remitting MS patients was measured by diffusion tensor imaging (DTI). Fractional anisotropy, longitudinal and transverse diffusivity were defined…

Relapse of incisor crowding: a visit to the Prince of Salina.

PubMed

López-Areal, Luis; Gandía, Jose-Luis

2013-03-01

The management of the retention period after comprehensive orthodontic treatment is of great importance, as a primary goal of clinician. Considerable controversy still surrounds the problem of stability after the retention period. Many studies analyze factors associated to the presence of crowding or incisor irregularity and find predictive features on its relapse. Most studies have reported little o no correlation between the treatment changes in the biological parameters - clinical, biometric (irregularity index, intermolar width, intercanine width, arch length, overjet, overbite), or cephalometric variables- that ocurred and the posttretament and postretention changes that may predict their future development. This article provides a bibliographical overview on the relapse of dental alignment in treated cases. In a brief historical introduction, the first studies on the long-term stability of orthodontic results are analysed. The article then goes on to assess studies that focus attention on anteroinferior alignment before finally studying relapse of upper crowding. It concludes by making some final comments in the light of the bibliography provided and the differents schools regarding retention needs and methods.

Validation study of the Japanese version of the Obsessive-Compulsive Drinking Scale.

PubMed

Tatsuzawa, Yasutaka; Yoshimasu, Haruo; Moriyama, Yasushi; Furusawa, Teruyuki; Yoshino, Aihide

2002-02-01

The Obsessive-Compulsive Drinking Scale (OCDS) is a self-rating questionnaire that measures cognitive and behavioral aspects of craving for alcohol. The OCDS consists of two subscales: the obsessive thoughts of drinking subscale (OS) and the compulsive drinking subscale (CS). This study aims to validate the Japanese version of the OCDS. First, internal consistency and discriminant validity were evaluated. Second, a prospective longitudinal 3-month outcome study of 67 patients with alcohol dependence who participated in a relapse prevention program was designed to assess the concurrent and predictive validity of the OCDS. The OCDS demonstrated high internal consistency. The OS had high discriminant validity, while the CS did not. Twenty-three patients (34.3%) dropped out of treatment. These patients had significantly higher OS scores than those who completed the program. At 3 months, the relapse group had significantly higher OCDS scores than the no relapse group. Also, the OCDS score was higher in subjects who had early-onset alcohol dependence than late-onset dependence. The OCDS is useful for evaluating cognitive aspect of craving and predicts dropout and relapse.

Cytomegalovirus (CMV) DNA load predicts relapsing CMV infection after solid organ transplantation.

PubMed

Sia, I G; Wilson, J A; Groettum, C M; Espy, M J; Smith, T F; Paya, C V

2000-02-01

Cytomegalovirus (CMV) DNA load was analyzed as a marker for relapse of CMV infection in 24 solid organ transplant patients with CMV infection or disease who received a fixed 14-day course of intravenous ganciclovir. Viral load was measured in blood samples obtained before and at the completion of treatment. Eight (33%) of 24 patients developed relapsing CMV infection. Median pretreatment viral loads were higher in the relapsing group (80,150 copies/106 leukocytes) than in the nonrelapsing group (5500 copies/106 leukocytes; P=.007). The relapsing group also had persistent detectable viral DNA (median, 5810 copies/106 leukocytes) after treatment, whereas it was undetectable in the nonrelapsing group (P<. 0001). Primary CMV infection (seronegative recipients of seropositive organs, D+R-) was an independent marker for CMV relapse (P=.03), and these patients had higher pre- and posttreatment viral loads than did non-D+/R- patients (P<.0001 and P=.0014, respectively). CMV DNA load is a useful marker for individualizing antiviral treatment of CMV infection in solid organ transplant recipients.

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis.

PubMed

Stampanoni Bassi, Mario; Iezzi, Ennio; Marfia, Girolama A; Simonelli, Ilaria; Musella, Alessandra; Mandolesi, Georgia; Fresegna, Diego; Pasqualetti, Patrizio; Furlan, Roberto; Finardi, Annamaria; Mataluni, Giorgia; Landi, Doriana; Gilio, Luana; Centonze, Diego; Buttari, Fabio

2018-04-14

In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a "real world" study.

PubMed

Epperla, Narendranath; Hamadani, Mehdi; Cashen, Amanda F; Ahn, Kwang W; Oak, Eunhye; Kanate, Abraham S; Calzada, Oscar; Cohen, Jonathon B; Farmer, Luke; Ghosh, Nilanjan; Tallarico, Michael; Nabhan, Chadi; Costa, Luciano J; Kenkre, Vaishalee P; Hari, Parameswaran N; Fenske, Timothy S

2017-12-01

Ibrutinib has demonstrated significant activity in relapsed/refractory mantle cell lymphoma (MCL) in clinical trials. However, the impact of hematopoietic cell transplantation on the outcomes of ibrutinib and the predictive factors for ibrutinib response has not been well studied. Hence, we conducted a multicenter retrospective study of MCL patients who received ibrutinib to (1) determine the overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of ibrutinib in routine clinical practice, (2) examine characteristics predictive of response to ibrutinib therapy, and (3) describe the outcomes of patients failing ibrutinib. Ninety-seven patients met the eligibility criteria. Overall response rate and median DOR to ibrutinib were 65% and 17 months, respectively. Only lack of primary refractory disease was predictive of ibrutinib response on multivariate analysis. Twenty-nine patients received postibrutinib therapies, with an ORR of 48% and a median DOR of 3 months. The median OS and PFS for the entire group (n = 97) was 22 and 15 months, respectively. On multivariate analysis, ibrutinib response, low MCL international prognostic index, and absence of primary refractory disease were predictors of better PFS, while ibrutinib response and Eastern Cooperative Oncology Group performance status ≤1 were predictors of better OS. The median OS postibrutinib failure was 2.5 months. Our results confirm the high ORR and DOR of ibrutinib in MCL and that prior hematopoietic cell transplantation does not negatively influence ibrutinib outcomes. Survival following ibrutinib failure is poor with no specific subsequent therapy showing superior activity in this setting. As a result, for select (transplant eligible) patients, allogeneic transplant should be strongly considered soon after ibrutinib response is documented to provide durable responses. Copyright © 2017 John Wiley & Sons, Ltd.

Adherence to medical treatment in relation to pregnancy, birth outcome & breastfeeding behavior among women with Crohn's disease.

PubMed

Julsgaard, Mette

2016-07-01

Crohn's disease (CD) is common among women of fertile age, and it often requires maintenance medical treatment. Adherence to medical treatment among women with CD prior to, during, and after pregnancy has, however, never been examined. Although CD women have increased risk of adverse pregnancy outcomes, little is known about predictors for these outcomes in women with CD. In addition, the impact of breastfeeding on disease activity remains controversial. The aims of this PhD thesis were to determine adherence to treatment and to investigate predictors for and prevalence rates of non-adherence to maintenance medical treatment among women with CD prior to, during, and after pregnancy; to assess pregnancy outcomes among women with CD, taking medical treatment, smoking status, and disease activity into account; to assess breastfeeding rates and the impact of breastfeeding on the risk of relapse. We conducted a population-based prevalence study including 154 women with CD who had given birth within a six-year period. We combined questionnaire data, data from medical records, and medical register data. Among 105 (80%) respondents, more than half reported taking medication with an overall high adherence rate of 69.8%. Counselling, previous pregnancy, and planned pregnancy seemed to decrease the likelihood of non-adherence, whereas smoking seemed to predict non-adherence prior to pregnancy, although our sample size prevented any firm conclusions. During pregnancy, the vast majority (95%) of CD women were in remission. The children's birth weight did not differ in relation to maternal medical treatment, but mean birth weight in children of smokers in medical treatment was 274 g lower than that of children of non-smokers in medical treatment. In our relatively small study CD women in medical treatment were not at increased risk of adverse pregnancy outcomes compared with untreated women with CD. In total, 87.6% of CD women were breastfeeding, and rates did not vary by medical treatment. Smoking and non-adherence seemed to predict relapse in CD during the postpartum period, whereas breastfeeding seemed protective against relapse.   Although we generally had low statistical precision this thesis suggests that counselling regarding medical treatment may be an important factor for medical adherence among CD women of fertile age. In addition CD women in medical treatment did not seem at increased risk of adverse pregnancy outcome, but smoking predicted lower birth weight. Breastfeeding did not seem to increase the risk of relapse in CD.

Geographical variation in Plasmodium vivax relapse

PubMed Central

2014-01-01

Background Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission. Methods A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse. Results Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas. Conclusions The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations. PMID:24731298

18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis.

PubMed

Grayson, Peter C; Alehashemi, Sara; Bagheri, Armin A; Civelek, Ali Cahid; Cupps, Thomas R; Kaplan, Mariana J; Malayeri, Ashkan A; Merkel, Peter A; Novakovich, Elaine; Bluemke, David A; Ahlman, Mark A

2018-03-01

To assess the clinical value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large vessel vasculitis (LVV) and comparator subjects. Patients with Takayasu arteritis and giant cell arteritis were studied, along with a comparator group consisting of patients with hyperlipidemia, patients with diseases that mimic LVV, and healthy controls. Participants underwent clinical evaluation and FDG-PET imaging, and patients with LVV underwent serial imaging at 6-month intervals. We calculated sensitivity and specificity of FDG-PET interpretation for distinguishing patients with clinically active LVV from comparator subjects and from patients with disease in clinical remission. A qualitative summary score based on global arterial FDG uptake, the PET Vascular Activity Score (PETVAS), was used to study associations between activity on PET scan and clinical characteristics and to predict relapse. A total of 170 FDG-PET scans were performed in 115 participants (56 patients with LVV and 59 comparator subjects). FDG-PET distinguished patients with clinically active LVV from comparator subjects with a sensitivity of 85% (95% confidence interval [95% CI] 69, 94) and a specificity of 83% (95% CI 71, 91). FDG-PET scans were interpreted as active vasculitis in most patients with LVV in clinical remission (41 of 71 [58%]). Clinical disease activity status, disease duration, body mass index, and glucocorticoid use were independently associated with activity on PET scan. Among patients who underwent PET during clinical remission, future clinical relapse was more common in patients with a high PETVAS than in those with a low PETVAS (55% versus 11%; P = 0.03) over a median follow-up period of 15 months. FDG-PET provides information about vascular inflammation that is complementary to, and distinct from, clinical assessment in LVV. FDG-PET scan activity during clinical remission was associated with future clinical relapse. © 2017, American College of Rheumatology.

Impact of smoking on the course of Graves' disease after withdrawal of antithyroid drugs.

PubMed

Quadbeck, B; Roggenbuck, U; Janssen, O E; Hahn, S; Mann, K; Hoermann, R

2006-09-01

Cigarette smoking has been reported to alter relapse rate in patients with Graves' disease (GD). However, the predictive effect of smoking in GD patients after withdrawal of antithyroid drug treatment (ATDT) is still controversial. A prospective multicenter trial has previously identified smoking as an independent risk factor for relapse. Based on this study, the present paper gives a more detailed analysis of the impact of smoking on the long-term course of GD after ATDT withdrawal. To this end, 86 smokers and 177 non-smokers were followed during two years after ATDT cessation. At the end of ATDT (visit 1) and four weeks later (visit 2) smokers had significant higher TSH receptor antibody (TRAb) levels than non-smokers (10.0 IU/L+/-1.6; mean+/-SEM vs. 6.4 IU/L+/-0.9; 11.0 IU/L+/-1.8 vs. 6.8 IU/L+/-0.8, p < 0.01, respectively). During follow-up, Kaplan Meier analysis showed a significantly higher relapse rate in smokers than non-smokers. A subset of GD patients with TRAb levels >10 IU/L had the highest risk to develop relapse during follow-up. Among them, smokers more often relapsed than non-smokers irrespective of TRAb levels, p < 0.01. Thus, in smokers with TRAb levels > or =10 IU/L the predictive values of a positive and negative test for relapse was 68% and 73%, respectively (specificity 95%). In conclusion, we identified two effects by which smoking alters the course of GD. First, smoking is implicated to elevate TRAb levels and therefore increase the risk for relapse during follow-up. Second, smoking is an independent risk factor to worsen the clinical course of both, GD patients with low and high immunological risk to experience relapse after a successful outcome of ATDT. Thus, our data suggest that smoking has modifying immunological consequences and an adverse impact on the course of GD after withdrawal of ATDT. Therefore, patients should be encouraged to stop smoking.

Violent Recidivism: A Long-Time Follow-Up Study of Mentally Disordered Offenders

PubMed Central

Nilsson, Thomas; Wallinius, Märta; Gustavson, Christina; Anckarsäter, Henrik; Kerekes, Nóra

2011-01-01

Background In this prospective study, mentally disordered perpetrators of severe violent and/or sexual crimes were followed through official registers for 59 (range 8 to 73) months. The relapse rate in criminality was assessed, compared between offenders sentenced to prison versus forensic psychiatric care, and the predictive ability of various risk factors (criminological, clinical, and of structured assessment instruments) was investigated. Method One hundred perpetrators were consecutively assessed between 1998 and 2001 by a clinical battery of established instruments covering DSM-IV diagnoses, psychosocial background factors, and structured assessment instruments (HCR-20, PCL-R, and life-time aggression (LHA)). Follow-up data was collected from official registers for: (i) recidivistic crimes, (ii) crimes during ongoing sanction. Results Twenty subjects relapsed in violent criminality during ongoing sanctions (n = 6) or after discharge/parole (n = 14). Individuals in forensic psychiatric care spent significantly more time at liberty after discharge compared to those in prison, but showed significantly fewer relapses. Criminological (age at first conviction), and clinical (conduct disorder and substance abuse/dependence) risk factors, as well as scores on structured assessment instruments, were moderately associated with violent recidivism. Logistic regression analyses showed that the predictive ability of criminological risk factors versus clinical risk factors combined with scores from assessment instruments was comparable, with each set of variables managing to correctly classify about 80% of all individuals, but the only predictors that remained significant in multiple models were criminological (age at first conviction, and a history of substance abuse among primary relatives). Conclusions Only one in five relapsed into serious criminality, with significantly more relapses among subjects sentenced to prison as compared to forensic psychiatric care. Criminological risk factors tended to be the best predictors of violent relapses, while few synergies were seen when the risk factors were combined. Overall, the predictive validity of common risk factors for violent criminality was rather weak. PMID:22022445

Technetium uptake predicts remission and relapse in Grave's disease patients on antithyroid drugs for at least 1 year in South Indian subjects

PubMed Central

Singhal, Neha; Praveen, V. P.; Bhavani, Nisha; Menon, Arun S.; Menon, Usha; Abraham, Nithya; Kumar, Harish; JayKumar, R. V.; Nair, Vasantha; Sundaram, Shanmugha; Sundaram, Padma

2016-01-01

Context: Most of the information on remission related factors in Grave's disease are derived from Western literature. It is likely that there may be additional prognostic factors and differences in the postdrug treatment course of Grave's disease in India. Aim: To study factors which predict remission/relapse in Grave's disease patients from South India. Also to establish if technetium (Tc) uptake has a role in predicting remission. Subjects and Methods: Records of 174 patients with clinical, biochemical, and scintigraphic criteria consistent with Grave's disease, seen in our Institution between January 2006 and 2014 were analyzed. Patient factors, drug-related factors, Tc-99m uptake and other clinical factors were compared between the remission and nonremission groups. Statistical Analysis Used: Mann–Whitney U-test and Chi-square tests were used when appropriate to compare the groups. Results: Fifty-seven (32.7%) patients attained remission after at least 1 year of thionamide therapy. Of these, 11 (19.2%) patients relapsed within 1 year. Age, gender, goiter, and presence of extrathyroidal manifestations were not associated with remission. Higher values of Tc uptake were positively associated with remission (P- 0.02). Time to achievement of normal thyroid function and composite dose: Time scores were significantly associated with remission (P - 0.05 and P - 0.01, respectively). Patients with lower FT4 at presentation had a higher chance of remission (P - 0.01). The relapse rates were lower than previously reported in the literature. A higher Tc uptake was found to be significantly associated with relapse also (P - 0.009). Conclusion: The prognostic factors associated with remission in Graves's disease in this South Indian study are not the same as that reported in Western literature. Tc scintigraphy may have an additional role in identifying people who are likely to undergo remission and thus predict the outcome of Grave's disease. PMID:27042408

Technetium uptake predicts remission and relapse in Grave's disease patients on antithyroid drugs for at least 1 year in South Indian subjects.

PubMed

Singhal, Neha; Praveen, V P; Bhavani, Nisha; Menon, Arun S; Menon, Usha; Abraham, Nithya; Kumar, Harish; JayKumar, R V; Nair, Vasantha; Sundaram, Shanmugha; Sundaram, Padma

2016-01-01

Most of the information on remission related factors in Grave's disease are derived from Western literature. It is likely that there may be additional prognostic factors and differences in the postdrug treatment course of Grave's disease in India. To study factors which predict remission/relapse in Grave's disease patients from South India. Also to establish if technetium (Tc) uptake has a role in predicting remission. Records of 174 patients with clinical, biochemical, and scintigraphic criteria consistent with Grave's disease, seen in our Institution between January 2006 and 2014 were analyzed. Patient factors, drug-related factors, Tc-99m uptake and other clinical factors were compared between the remission and nonremission groups. Mann-Whitney U-test and Chi-square tests were used when appropriate to compare the groups. Fifty-seven (32.7%) patients attained remission after at least 1 year of thionamide therapy. Of these, 11 (19.2%) patients relapsed within 1 year. Age, gender, goiter, and presence of extrathyroidal manifestations were not associated with remission. Higher values of Tc uptake were positively associated with remission (P- 0.02). Time to achievement of normal thyroid function and composite dose: Time scores were significantly associated with remission (P - 0.05 and P - 0.01, respectively). Patients with lower FT4 at presentation had a higher chance of remission (P - 0.01). The relapse rates were lower than previously reported in the literature. A higher Tc uptake was found to be significantly associated with relapse also (P - 0.009). The prognostic factors associated with remission in Graves's disease in this South Indian study are not the same as that reported in Western literature. Tc scintigraphy may have an additional role in identifying people who are likely to undergo remission and thus predict the outcome of Grave's disease.

Transmission Dynamics of Visceral Leishmaniasis in the Indian Subcontinent – A Systematic Literature Review

PubMed Central

Boelaert, Marleen; Matlashewski, Greg; Mondal, Dinesh; Arana, Byron; Kroeger, Axel; Olliaro, Piero

2016-01-01

Background As Bangladesh, India and Nepal progress towards visceral leishmaniasis (VL) elimination, it is important to understand the role of asymptomatic Leishmania infection (ALI), VL treatment relapse and post kala-azar dermal leishmaniasis (PKDL) in transmission. Methodology/ Principal Finding We reviewed evidence systematically on ALI, relapse and PKDL. We searched multiple databases to include studies on burden, risk factors, biomarkers, natural history, and infectiveness of ALI, PKDL and relapse. After screening 292 papers, 98 were included covering the years 1942 through 2016. ALI, PKDL and relapse studies lacked a reference standard and appropriate biomarker. The prevalence of ALI was 4–17-fold that of VL. The risk of ALI was higher in VL case contacts. Most infections remained asymptomatic or resolved spontaneously. The proportion of ALI that progressed to VL disease within a year was 1.5–23%, and was higher amongst those with high antibody titres. The natural history of PKDL showed variability; 3.8–28.6% had no past history of VL treatment. The infectiveness of PKDL was 32–53%. The risk of VL relapse was higher with HIV co-infection. Modelling studies predicted a range of scenarios. One model predicted VL elimination was unlikely in the long term with early diagnosis. Another model estimated that ALI contributed to 82% of the overall transmission, VL to 10% and PKDL to 8%. Another model predicted that VL cases were the main driver for transmission. Different models predicted VL elimination if the sandfly density was reduced by 67% by killing the sandfly or by 79% by reducing their breeding sites, or with 4–6y of optimal IRS or 10y of sub-optimal IRS and only in low endemic setting. Conclusion/ Significance There is a need for xenodiagnostic and longitudinal studies to understand the potential of ALI and PKDL as reservoirs of infection. PMID:27490264

α4-integrin receptor desaturation and disease activity return after natalizumab cessation.

PubMed

Derfuss, Tobias; Kovarik, John M; Kappos, Ludwig; Savelieva, Marina; Chhabra, Richa; Thakur, Avinash; Zhang, Ying; Wiendl, Heinz; Tomic, Davorka

2017-09-01

To describe the time course of α4-integrin receptor desaturation and disease activity return in patients with relapsing-remitting MS who discontinued natalizumab and to investigate baseline and on-study predictors for the recurrence of disease activity. In the course of TOFINGO, a 32-week, patient- and rater-blinded multicenter, parallel-group study, we performed MRI, counted relapses, and measured α4-integrin receptor occupancy (RO) at baseline and 8, 12, 16, 20, and 24 weeks. The relationship between RO and total number of new T1 gadolinium-enhancing (Gd+) lesions was modeled using Poisson linear regression. Patients (N = 142) were randomized (1:1:1) to 8-, 12-, or 16-week washout (WO) groups. At randomization, the median RO in the 8-, 12-, and 16-week WO groups was 94.5%, 92.4%, and 90.9%, which declined to 79.8%, 30.7%, and 8.7% after 8, 12, and 16 weeks of WO, respectively. The percentage of patients with new T1 Gd+ lesions increased with longer WO period before commencing fingolimod: 2.1% (8 weeks), 9.1% (12 weeks), and 50.0% (16 weeks). Overall, 71% of patients with first relapse between weeks 6 and 18 had RO values below the time-matched population median. Higher T2 lesion volume (LV) at baseline predicted a higher number of new T1 Gd+ lesions. A faster decline in natalizumab RO, longer WO period, and higher T2 LV at baseline were associated with an increased risk for return of inflammatory disease activity. These results provide a mechanistic rationale and, together with the main outcomes of the TOFINGO study, support initiation of fingolimod within 8 weeks of natalizumab discontinuation. NCT01499667.

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

PubMed Central

Tzoneva, Gannie; Garcia, Arianne Perez; Carpenter, Zachary; Khiabanian, Hossein; Tosello, Valeria; Allegretta, Maddalena; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M.; Tallman, Martin S.; Paganin, Maddalena; Basso, Giuseppe; Hof, Jana; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo

2013-01-01

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease1,2. Using whole exome sequencing, here we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside analog metabolism in disease progression and chemotherapy resistance in ALL. PMID:23377281

Predictors of relapses in ANCA-associated small vessel vasculitis with kidney involvement

PubMed Central

Iuliana, Andreiana; Simona, Stancu; Andreea, Avram; Ludmila, Taran; Gabriel, Mircescu

2014-01-01

Rationale: Almost half of the patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated small vessel vasculitis relapse and their characteristics are still to be defined Objective: We aimed to evaluate the relapse rate and its determinants in a cohort of patients with ANCA associated vasculitis with severe kidney involvement. Methods and results: This is a retrospective study which included 100 patients consecutively admitted in a Nephrology Department with crescentic pauci-immune glomerulonephritis diagnosed by kidney biopsy. ANCAs were assessed by capture ELISA or indirect immunofluorescence (IFI). Patients were followed for a median period of 3.2 [0.1; 5.5] years. The median age was 61.6 years. The clinical condition at presentation was severe (median BVAS 16 and BVAS over 21 in one quarter of patients), mostly because of general, kidney and lung scores. Median creatinine was 5.7 mg/dL and 17% of the patients needed temporary dialysis. Eight patients relapsed (13.8%): one in the lung and seven in the kidney. The median time to relapse was 11.3 [9.2; 19.9] months. None of the investigated parameters allowed for differentiating patients who relapsed from those who did not, except higher hematuria in those who relapsed. Discussion: In our patients with ANCA vasculitis and severe kidney involvement, the relapse rate is low and hematuria but not ANCA specificity or clinical presentation allows the prediction of relapse. PMID:27057255

Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time.

PubMed

Kumar, S K; Dispenzieri, A; Fraser, R; Mingwei, F; Akpek, G; Cornell, R; Kharfan-Dabaja, M; Freytes, C; Hashmi, S; Hildebrandt, G; Holmberg, L; Kyle, R; Lazarus, H; Lee, C; Mikhael, J; Nishihori, T; Tay, J; Usmani, S; Vesole, D; Vij, R; Wirk, B; Krishnan, A; Gasparetto, C; Mark, T; Nieto, Y; Hari, P; D'Souza, A

2018-04-01

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Anti-IgE Monoclonal Antibody (Omalizumab) in Refractory and Relapsing Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss): Data on Seventeen Patients.

PubMed

Jachiet, Marie; Samson, Maxime; Cottin, Vincent; Kahn, Jean-Emmanuel; Le Guenno, Guillaume; Bonniaud, Philippe; Devilliers, Hervé; Bouillet, Laurence; Gondouin, Anne; Makhlouf, Fatma; Meaux-Ruault, Nadine; Gil, Helder; Bienvenu, Boris; Coste, André; Groh, Matthieu; Giraud, Violaine; Dominique, Stéphane; Godeau, Bertrand; Puéchal, Xavier; Khouatra, Chahera; Ruivard, Marc; Le Jeunne, Claire; Mouthon, Luc; Guillevin, Loïc; Terrier, Benjamin

2016-09-01

To describe the efficacy and safety of omalizumab, an anti-IgE monoclonal antibody, in patients with refractory and/or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA). We conducted a nationwide retrospective study including EGPA patients who received omalizumab. Response was defined as the absence of asthma and/or sinonasal exacerbations with a prednisone dosage of ≤7.5 mg/day (complete response) or >7.5 mg/day (partial response). Seventeen patients (median age 45 years) received omalizumab for severe steroid-dependent asthma (88%) and/or sinonasal involvement (18%). After a median follow-up of 22 months, 6 patients (35%) achieved a complete response, 5 patients (30%) achieved a partial response, and 6 patients (35%) had no improvement. The median Birmingham Vasculitis Activity Score decreased from 2.5 at baseline to 0.5 at 12 months. The median number of exacerbations per month decreased from 1 at baseline to 0 at 12 months, and the median forced expiratory volume in 1 second increased from 63% of the percent predicted at baseline to 85% of the percent predicted at 12 months. The median prednisone dosage decreased from 16 mg/day at baseline to 11 mg/day at 6 months and 9 mg/day at 12 months. Omalizumab was discontinued in 8 patients (47%) during follow-up, because of remission (12.5%), adverse event despite disease remission (12.5%), refractory disease (25%), or relapse (50%). Relapses included retrobulbar optic neuritis attributable to EGPA in 2 patients and severe asthma flare in 2 others. The results of this study suggest that omalizumab may have a corticosteroid-sparing effect in EGPA patients with asthmatic and/or sinonasal manifestations, but reducing the corticosteroid dose may also increase the risk of severe EGPA flares, which raises the question of the safety of omalizumab in patients with EGPA. © 2016, American College of Rheumatology.

Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity.

PubMed

Pitchers, Kyle K; Phillips, Kyra B; Jones, Jonte L; Robinson, Terry E; Sarter, Martin

2017-07-26

Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS + and a DS - , respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS + to reinstate cocaine seeking behavior. The DS + was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS + We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered. SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability. Copyright © 2017 the authors 0270-6474/17/377198-11$15.00/0.

Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.

PubMed

Janak, Patricia H; Bowers, M Scott; Corbit, Laura H

2012-03-01

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

PubMed

Wudhikarn, Kitsada; Bunworasate, Udomsak; Julamanee, Jakrawadee; Lekhakula, Arnuparp; Chuncharunee, Suporn; Niparuck, Pimjai; Ekwattanakit, Supachai; Khuhapinant, Archrob; Norasetthada, Lalita; Nawarawong, Weerasak; Makruasi, Nisa; Kanitsap, Nonglak; Sirijerachai, Chittima; Chansung, Kanchana; Wong, Peerapon; Numbenjapon, Tontanai; Prayongratana, Kannadit; Suwanban, Tawatchai; Wongkhantee, Somchai; Praditsuktavorn, Pannee; Intragumtornchai, Tanin

2017-01-01

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

Predicting smoking relapse with a multidimensional versus a single-item tobacco craving measure.

PubMed

Berlin, Ivan; Singleton, Edward G; Heishman, Stephen J

2013-10-01

Research suggests that craving is a predictor of smoking relapse. Craving can be assessed by multiple item or multifactorial scales or by single items. However, no systematic comparisons of their prognostic validity or accuracy have been published. The French versions of the 12-item Tobacco Craving Questionnaire (FTCQ-12) and the single craving item on the Minnesota Nicotine Withdrawal Scale (MNWS) are brief, valid, and reliable self-report measures of tobacco craving. In this secondary study, we analyzed data from French smokers with health-related problems enrolled in the Adjustment of DOses of NIcotine in Smoking (ADONIS) cessation trial. We estimated prediction models for each measure and compared their ability to distinguish correctly participants who relapsed from those who did not at 1-8 weeks after their quit date. Adjusted for all potential confounders FTCQ-12 risk score (RS; Factor 2, Expectancy plus Factor 4, Purposefulness) and MNWS craving were valid predictors of smoking relapse at endpoints measured 1-7 weeks apart. Prognostic accuracy of FTCQ-12 RS was greatest at 1-2 weeks follow-up compared to only 1 week for MNWS craving. Sensitivity for FTCQ-12 RS and MNWS craving was 85% and 53%, respectively. FTCQ-12 RS suggests a relapse process involving urges and desires in anticipation of the positive benefits of smoking linked with intent and planning to smoke. Findings also suggest that FTCQ-12 RS may be a better predictor instrument for smoking relapse than MNWS craving. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Impact of craving on alcohol relapse during, and 12 months following, outpatient treatment.

PubMed

Bottlender, Miriam; Soyka, Michael

2004-01-01

This study investigated the relationship between craving in abstinent alcohol-dependent patients measured by the Obsessive Compulsive Craving Scale (OCDS) (Anton et al., 1995) and relapse during and after completion of an intensive outpatient treatment programme. In a prospective study, participants were interviewed at entry to, and end of, an outpatient treatment programme, and 12 months after the end of the programme. To measuring craving the OCDS total score by Anton et al. (1995) and the three-factor model by Kranzler et al. (1999) were used. OCDS was administered at the beginning of treatment (when all patients were abstinent), and at the end of treatment in those who were abstinent and had completed the programme. Of 103 alcohol-dependent patients, 74 completed the treatment programme and at follow-up after 12 months 97% of these patients were personally re-interviewed. Thirty-two patients (31%) relapsed during the treatment phase. They had significantly higher craving measured by the total OCDS score and a significantly higher score on the subscales 'obsessions' and 'drinking control and consequences' compared to abstinent patients. Of the 74 patients who completed the programme 16% had a major relapse in the next 12 months. Major relapse was predicted by the total OCDS score and the subscale 'obsessions'. OCDS total score predicts relapse in outpatient treatment. Treatment and aftercare of patients with high craving should be intensified. In our study design, the subscales of the three-factor model by Kranzler et al. (1999) provided only little information gain compared to the OCDS total score.

Dysfunctional Default Mode Network in Methadone Treated Patients Who Have a Higher Heroin Relapse Risk.

PubMed

Li, Wei; Li, Qiang; Wang, Defeng; Xiao, Wei; Liu, Kai; Shi, Lin; Zhu, Jia; Li, Yongbin; Yan, Xuejiao; Chen, Jiajie; Ye, Jianjun; Li, Zhe; Wang, Yarong; Wang, Wei

2015-10-15

The purpose of this study was to identify whether heroin relapse is associated with changes in the functional connectivity of the default mode network (DMN) during methadone maintenance treatment (MMT). Resting-state functional magnetic resonance imaging (fMRI) data of chronic heroin relapsers (HR) (12 males, 1 female, age: 36.1 ± 6.9 years) and abstainers (HA) (11males, 2 female; age: 42.1 ± 8.1 years) were investigated with an independent component analysis to address the functional connectivity of their DMN. Group comparison was then performed between the relapsers and abstainers. Our study found that the left inferior temporal gyrus and the right superior occipital gyrus associated with DMN showed decreased functional connectivity in HR when compared with HA, while the left precuneus and the right middle cingulum had increased functional connectivity. Mean intensity signal, extracted from left inferior temporal gyrus of HR patients, showed a significant negative correlation corresponding to the degree of heroin relapse. These findings suggest that altered functional connectivity of DMN may contribute to the potential neurobiological mechanism(s) of heroin relapse and have a predictive value concerning heroin relapse under MMT.

Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.

PubMed

Hohmann, Christopher; Milles, Bianca; Schinke, Michael; Schroeter, Michael; Ulzheimer, Jochen; Kraft, Peter; Kleinschnitz, Christoph; Lehmann, Paul V; Kuerten, Stefanie

2014-09-16

B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

Fear of food prospectively predicts drive for thinness in an eating disorder sample recently discharged from intensive treatment.

PubMed

Levinson, Cheri A; Brosof, Leigh C; Ma, Jackie; Fewell, Laura; Lenze, Eric J

2017-12-01

Fears of food are common in individuals with eating disorders and contribute to the high relapse rates. However, it is unknown how fears of food contribute to eating disorder symptoms across time, potentially contributing to an increased likelihood of relapse. Participants diagnosed with an eating disorder (N=168) who had recently completed intensive treatment were assessed after discharge and one month later regarding fear of food, eating disorder symptoms, anxiety sensitivity, and negative affect. Cross lagged path analysis was utilized to determine if fear of food predicted subsequent eating disorder symptoms one month later. Fear of food-specifically, anxiety about eating and feared concerns about eating-predicted drive for thinness, a core symptom domain of eating disorders. These relationships held while accounting for anxiety sensitivity and negative affect. There is a specific, direct relationship between anxiety about eating and feared concerns about eating and drive for thinness. Future research should test if interventions designed to target fear of food can decrease drive for thinness and thereby prevent relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tracing the origins of relapse in acute myeloid leukaemia to stem cells.

PubMed

Shlush, Liran I; Mitchell, Amanda; Heisler, Lawrence; Abelson, Sagi; Ng, Stanley W K; Trotman-Grant, Aaron; Medeiros, Jessie J F; Rao-Bhatia, Abilasha; Jaciw-Zurakowsky, Ivana; Marke, Rene; McLeod, Jessica L; Doedens, Monica; Bader, Gary; Voisin, Veronique; Xu, ChangJiang; McPherson, John D; Hudson, Thomas J; Wang, Jean C Y; Minden, Mark D; Dick, John E

2017-07-06

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse.

PubMed

Vengeliene, Valentina; Cannella, Nazzareno; Takahashi, Tatiane; Spanagel, Rainer

2016-09-01

The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway. An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse-the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue-induced reinstatement of alcohol- and cocaine-seeking behaviour. Our results show that relapse-like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine-seeking behaviour was also abolished by administration of Ro61-8048. Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic/NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts.

Outcome of treatment after first relapse in younger adults with acute myeloid leukemia initially treated by the ALFA-9802 trial.

PubMed

Thomas, Xavier; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cécile; de Botton, Stéphane; de Revel, Thierry; Reman, Oumedaly; Terré, Christine; Gardin, Claude; Chelghoum, Youcef; Boissel, Nicolas; Quesnel, Bruno; Cordonnier, Catherine; Bourhis, Jean-Henri; Elhamri, Mohamed; Fenaux, Pierre; Preudhomme, Claude; Socié, Gérard; Michallet, Mauricette; Castaigne, Sylvie; Dombret, Hervé

2012-09-01

Forty-seven percent of adults with acute myeloid leukemia (AML) who entered the ALFA-9802 trial and achieved a first complete remission (CR) experienced a first relapse. We examined the outcome of these 190 adult patients. Eighty-four patients (44%) achieved a second CR. The median overall survival (OS) after relapse was 8.9 months with a 2-year OS at 25%. Factors predicting a better outcome after relapse were stem cell transplant (SCT) performed in second CR and a first CR duration >1 year. Risk groups defined at the time of diagnosis and treatment received in first CR also influenced the outcome after relapse. The best results were obtained in patients with core binding factor (CBF)-AML, while patients initially defined as favorable intermediate risk showed a similar outcome after relapse than those initially entering the poor risk group. We conclude that most adult patients with recurring AML could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option at this stage of the disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?

PubMed

Zingrillo, M; D'Aloiso, L; Ghiggi, M R; Di Cerbo, A; Chiodini, I; Torlontano, M; Liuzzi, A

1996-08-01

A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with 'burned-out' disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse. Longitudinal prospective study of previously untreated patients with GD. Thirty-nine consecutive patients aged 10-72 years were treated with methimazole (MMI) for 12-24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal. Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal. Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1 +/- 1.1 vs 2 +/- 0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month. Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.

The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis.

PubMed

Scalfari, Antonio; Romualdi, Chiara; Nicholas, Richard S; Mattoscio, Miriam; Magliozzi, Roberta; Morra, Aldo; Monaco, Salvatore; Muraro, Paolo A; Calabrese, Massimiliano

2018-05-16

To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS). In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS. Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP. Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy. © 2018 American Academy of Neurology.

Gender as a prognostic factor and its impact on the incidence of multiple sclerosis in Lorraine, France.

PubMed

Debouverie, M

2009-11-15

We sought to identify (a) the change of incidence rates among gender from 1990 to 2002 from the LORSEP (Lorraine Multiple Sclerosis) population-based cohort, and (b) the role of gender as a predictive demographic factor of disability during the initial course of the disease among multiple sclerosis (MS) patients. The incidence rates of multiple sclerosis (MS) in Lorraine, France, have significantly increased in women, but not in men, from 1990 to 2002 but this increase in incidence of MS was not related to a better ascertainment of patients with mild disability. A total of 2871 MS patients were analyzed. For relapsing-remitting (RR) patients, a multivariate analysis showed that a shorter time to the assignment of an EDSS score of 3 and 4 was associated with the late onset MS, incomplete recovery from the first relapse and a high number of relapses during the first 5 years after the MS onset. Median times were not influenced by gender or by time between the first two relapses. The data were very different for the time between the assignment of scores of 4 and 6, since the median times were not influenced by any of the predicting variables.

Self-Regulatory Strategies as Correlates of Physical Activity Behavior in Persons With Multiple Sclerosis.

PubMed

Cederberg, Katie L; Balto, Julia M; Motl, Robert W

2018-05-01

To examine self-regulation strategies as correlates of physical activity in persons with multiple sclerosis (MS). Cross-sectional, or survey, study. University-based research laboratory. Convenience sample of persons with MS (N=68). Not applicable. Exercise Self-Efficacy Scale (EXSE), 12-item Physical Activity Self-Regulation Scale (PASR-12), and Godin Leisure-Time Exercise Questionnaire (GLTEQ). Correlation analyses indicated that GLTEQ scores were positively and significantly associated with overall self-regulation (r=.43), self-monitoring (r=.45), goal-setting (r=.27), reinforcement (r=.30), time management (r=.41), and relapse prevention (r=.53) PASR-12 scores. Regression analyses indicated that relapse prevention (B=5.01; SE B=1.74; β=.51) and self-monitoring (B=3.65; SE B=1.71; β=.33) were unique predictors of physical activity behavior, and relapse prevention demonstrated a significant association with physical activity behavior that was accounted for by EXSE. Our results indicate that self-regulatory strategies, particularly relapse prevention, may be important correlates of physical activity behavior that can inform the design of future behavioral interventions in MS. Published by Elsevier Inc.

Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab.

PubMed

Rossi, S; Motta, C; Studer, V; De Chiara, V; Barbieri, F; Monteleone, F; Fornasiero, A; Coarelli, G; Bernardi, G; Cutter, G; Stüve, O; Salvetti, M; Centonze, D

2013-01-01

Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab-GA therapy is not associated with clinical deterioration. Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

The cost-effectiveness of disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis.

PubMed

Bozkaya, Duygu; Livingston, Terrie; Migliaccio-Walle, Kristen; Odom, Tanner

2017-03-01

The safety and efficacy of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has been established; however, it is not clear which provides optimal value, given benefit-risk profiles and costs. To compare the cost-effectiveness of current DMTs for patients with RRMS in the US. A Markov model predicting RRMS course following initiation of a DMT was created comparing outcomes (e.g. relapses, disease progression) and costs of natalizumab (NTZ), dimethyl fumarate (DMF), and peginterferon beta-1a (PEG) with fingolimod (FIN), glatiramer acetate (GA, 20 mg daily), and subcutaneous interferon beta-1a (IFN, 44 mcg), respectively, over 10 years. RRMS and secondary-progressive MS (SPMS) EDSS state transitions were predicted in 3-month cycles in which patients were at risk of death, relapse, or discontinuation. Upon DMT discontinuation, natural history progression and relapse rates were applied. Incremental cost-effectiveness ratios (ICERs) were estimated for the cost per relapse avoided, relapse-free years gained, progression avoided, and progression-free years gained. The impact of model parameters on outcomes was evaluated via one-way sensitivity analyses. Costs ranged from $561,177 (NTZ) to $616,251 (GA). NTZ, DMF, and PEG were dominant (less costly and more effective) compared to FIN, GA, and IFN, respectively, for all ICERs. Variability in drug costs and parameters that affected drug cost accrual (e.g. discontinuation rates and the decision to drop out after SPMS conversion) had a considerable impact on ICERs. Several simplifying assumptions were made that may represent potential limitations of this analysis (e.g. a constant treatment effect over time was assumed). The results from this analysis suggest that the NTZ, DMF, and PEG are cost-effective DMT choices compared to FIN, GA, and IFN, respectively. The actual impact on a particular plan will vary based on drug pricing and other factors affecting drug cost accrual.

Measurable residual disease testing in acute myeloid leukaemia.

PubMed

Hourigan, C S; Gale, R P; Gormley, N J; Ossenkoppele, G J; Walter, R B

2017-07-01

There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD-testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result-directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate end point in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done.

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

PubMed Central

Schwartzman, Omer; Savino, Angela Maria; Gombert, Michael; Palmi, Chiara; Cario, Gunnar; Schrappe, Martin; Eckert, Cornelia; von Stackelberg, Arend; Huang, Jin-Yan; Hameiri-Grossman, Michal; Avigad, Smadar; te Kronnie, Geertruy; Geron, Ifat; Birger, Yehudit; Rein, Avigail; Zarfati, Giulia; Fischer, Ute; Mukamel, Zohar; Stanulla, Martin; Biondi, Andrea; Cazzaniga, Giovanni; Vetere, Amedeo; Wagner, Bridget K.; Chen, Zhu; Chen, Sai-Juan; Tanay, Amos; Borkhardt, Arndt; Izraeli, Shai

2017-01-01

Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic “Philadelphia-like” ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are “relapse driving.” We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2pos, Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT “hypersignaling” may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL. PMID:28461505

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome.

PubMed

Schwartzman, Omer; Savino, Angela Maria; Gombert, Michael; Palmi, Chiara; Cario, Gunnar; Schrappe, Martin; Eckert, Cornelia; von Stackelberg, Arend; Huang, Jin-Yan; Hameiri-Grossman, Michal; Avigad, Smadar; Te Kronnie, Geertruy; Geron, Ifat; Birger, Yehudit; Rein, Avigail; Zarfati, Giulia; Fischer, Ute; Mukamel, Zohar; Stanulla, Martin; Biondi, Andrea; Cazzaniga, Giovanni; Vetere, Amedeo; Wagner, Bridget K; Chen, Zhu; Chen, Sai-Juan; Tanay, Amos; Borkhardt, Arndt; Izraeli, Shai

2017-05-16

Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.

Is there a predictive value of EEG and MRI after a first afebrile seizure in children?

PubMed

Tews, W; Weise, S; Syrbe, S; Hirsch, W; Viehweger, A; Merkenschlager, A; Bertsche, A; Kiess, W; Bernhard, M K

2015-03-01

After a first afebrile seizure, EEG in addition to cMRI is recommended for pediatric patients. Once indications requiring immediate treatment are excluded, it is of interest to determine if the results provide a prognostic tool for seizure relapses. Patients aged between 1 month and 18 years who had a first afebrile seizure between 2006 and 2008 were retrospectively studied and monitored for another 48 months. Out of 248 patients, 62.5% had generalized and 36.3% focal seizures. 34.7% of the EEG results were pathological. 176 patients had a cMRI that showed in 23.3% probable epileptogenic lesions. 3 patients with benign cerebral tumours needed surgical therapy. In the following 48 months 29.4% of the children showed seizure relapses. There was a correlation between epileptic patterns in the EEG and further seizures (p=0.0001). However, the sensitivity of the EEG based diagnoses was 0.6, the specificity 0.78 and the positive predictive value 0.52. There was no correlation between epileptogenic lesions and the probability of seizure relapses. The sensitivity of the cMRI to this effect was 0.36, the specificity 0.74 and the positive predictive value 0.34. The EEG is superior to cMRI for predicting seizure relapses. The percentage of noticeable cMRI findings is high but this has low therapeutic relevance and is assumed to largely represent "incidental findings". It is important to question the value of MRI investigations for sedated small children except in the case of emergencies. The key question is whether the cMRI should be deployed to diagnose epilepsy, the probability of seizure recurrences or to classify the entity of a most likely epilepsy. © Georg Thieme Verlag KG Stuttgart · New York.

Enhanced gamma interferon responses of mouse spleen cells following immunotherapy for tuberculosis relapse.

PubMed

Gil, Olga; Vilaplana, Cristina; Guirado, Evelyn; Díaz, Jorge; Cáceres, Neus; Singh, Mahavir; Cardona, Pere-Joan

2008-11-01

Gamma interferon responses of spleen cells in mice were examined during postchemotherapy relapse of intraperitoneally induced latent tuberculous infection. The mycobacterial extract RUTI, which prevented the relapse, significantly enhanced the immune responses to secreted and structural recombinant mycobacterial antigens, suggesting that RUTI-mediated protection was mediated by activated T cells.

Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents.

PubMed

de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

2017-01-01

Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown. To further address this issue, we investigated the role of PPARγ on the development and expression of morphine withdrawal in mice and the effect of pioglitazone on several forms of heroin relapse in rats. We induced physical dependence to morphine in mice by injecting morphine twice daily for 6 days. Withdrawal syndrome was precipitated on day 6 with an injection of naloxone. In addition, different groups of rats were trained to self-administer heroin and, after the extinction, the relapse was elicited by cues, priming, or stress. The effect of different doses of pioglitazone was tested on these different paradigms. Data show that chronic and acute administration of pioglitazone attenuates morphine withdrawal symptoms, and these effects are mediated by activation of PPARγ receptors. Activation of PPARγ by pioglitazone also abolishes yohimbine-induced reinstatement of heroin seeking and reduces heroin-induced reinstatement, while it does not affect cue-induced relapse. These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.

Patients' Competence in and Performance of Cognitive Therapy Skills: Relation to the Reduction of Relapse Risk Following Treatment for Depression

ERIC Educational Resources Information Center

Strunk, Daniel R.; DeRubeis, Robert J.; Chiu, Angela W.; Alvarez, Jennifer

2007-01-01

Cognitive therapy (CT) for depression is designed to teach patients material that is believed to help prevent relapse following successful treatment. This study of 35 moderately to severely depressed patients who responded to CT provides the 1st evidence to suggest that both development and independent use of these competencies predict reduced…

Relapses vs. reactions in multibacillary leprosy: proposal of new relapse criteria.

PubMed

Linder, Katharina; Zia, Mutaher; Kern, Winfried V; Pfau, Ruth K M; Wagner, Dirk

2008-03-01

To compare a new scoring system for multibacillary (MB) leprosy relapses, which combines time factor, risk factors and clinical presentation at relapse, to WHO criteria. Data were collected on all relapses diagnosed between 1998 and 2004 at the Marie-Adelaide-Centre in Karachi, Pakistan, including case histories, clinical manifestations, follow-up, bacterial indices, treatment and contacts. For the diagnosis of MB relapses a simple scoring system was developed and validated on a data-set of mouse foot pads (MFP)-confirmed relapses (Leprosy Reviews, 76, 2005, 241). Its sensitivity was further evaluated in the Karachi relapse cohort. The P-value was calculated with McNemar's test with continuity correction. The new scoring system that combines time factor, risk factors and clinical presentation at relapse had a higher sensitivity in MFP-confirmed relapses than the WHO-criteria (95%vs. 65%, P < 0.01). The sensitivity of the scoring system was also significantly higher than the WHO criteria in the 57 cases of MB-relapses diagnosed in Karachi (72%vs. 54%, P < 0.05). This new simple scoring system for diagnosing MB-relapses in leprosy should be further validated in a prospective study to confirm its superior sensitivity and to evaluate the specificity of these criteria by using MFP-confirmation for patients presenting with signs of activity after treatment.

Aquaporin-4 antibody titration in NMO patients treated with rituximab: A retrospective study.

PubMed

Valentino, Paola; Marnetto, Fabiana; Granieri, Letizia; Capobianco, Marco; Bertolotto, Antonio

2017-03-01

We undertook an observational retrospective study to investigate the usefulness of aquaporin-4 (AQP4) antibodies (Ab) titration in the management of patients with neuromyelitis optica (NMO) treated with rituximab (RTX) by studying (1) the correlation between AQP4-Ab titer and disease activity, (2) the influence of RTX on antibody levels, and (3) the association between AQP4-Ab levels and responsiveness to RTX. A cell-based assay was used for AQP4-Ab titration in 322 serum samples from 7 patients with NMO treated with RTX (median follow-up 65 months), according to a treatment-to-target approach. Serum samples were collected every month following standardized procedures. (1) In group analysis, AQP4-Ab titers correlated with the disease activity, showing higher titers during and preceding relapses than during remission. However, in individual analysis, an increase in AQP4-Ab titers and CD19+ B cells did not always precede a relapse. (2) A reduction of AQP4-Ab titers in the short-term and long-term period was observed during RTX treatment. (3) Reduction of AQP4-Ab titers was observed in responder patients both 3 months after RTX infusion and in the long-term follow-up. In one nonresponder patient, AQP4-Ab levels never decreased during the treatment period. Titration of AQP4-Abs could be useful in the clinical management of patients with NMO treated with RTX: titration before each reinfusion and 3 months after each reinfusion may provide information about responsiveness to RTX. Although a relationship among AQP4-Ab levels, disease activity, and response to RTX was observed, the usefulness of AQP4-Ab titration to predict relapses is limited.

Active Tobacco Smoking and Distant Metastasis in Patients With Oropharyngeal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

McBride, Sean M.; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Ali, Nawal N.

Purpose: Distant metastasis is the site of first relapse in approximately one-third of patients with locally advanced oropharyngeal carcinoma, irrespective of human papillomavirus status. Yet the risk factors associated with distant metastasis are not well characterized. We sought to characterize the relationship between smoking status and distant metastasis. Methods and Materials: We evaluated the association between tobacco smoking status and distant metastasis in a retrospective cohort study of 132 patients who underwent definitive radiation therapy and chemotherapy for Stage III-IVA/B oropharyngeal cancer. Information on tobacco smoking was prospectively collected by patient questionnaires and physician notes at the time of diagnosis.more » Thirty-three percent of the patients were nonsmokers, 51% were former smokers, 16% were active smokers. The cumulative lifetime tobacco smoking in pack-years was 20 (range, 0-150). Results: With a median follow-up time of 52 months, the overall rate of distant metastasis at 4 years was 8%. Distant metastasis was the most common first site of relapse, occurring in 56% of the patients with recurrences. Active smokers had higher rates of distant metastasis than non-active smokers (including never- and former smokers; 31% vs. 4%, p < 0.001) and former smokers (31% vs. 3%, p < 0.001). There was no statistically significant difference in the risk of distant metastasis for patients with lifetime cumulative pack-years >20 and {<=}20 (10% vs. 4%, p = 0.19). In univariate analysis, active smoking (p = 0.0004) and N category (p = 0.009) were predictive of increased risk of distant metastasis. In multivariate analysis, active smoking was the most significant predictive factor for increased risk of distant metastasis (hazard ratio, 12.7, p < 0.0001). Conclusions: This study identified a strong association between active smoking and distant metastasis in patients with oropharyngeal cancer.« less

Role of Endotoxin in the Pathogenesis of Louse-borne Relapsing Fever and in the Mechanism of the Jarisch-Herxheimer Reaction Following Treatment of Louse-borne Relapsing Fever

DTIC Science & Technology

1977-12-01

therapy and during the Jarisch-Herxheimer-like reaction. Further similarities between relapsing fever and Gram-negative bacteremic diseases were sought by...activated during Gram- negative bacterial infections (11-17). The aims of therapy should be to clear the blood of circulating spirochetes without relapse and...more slowly with more prolonged fever. Single dose therapy with intravenous tetracycline [1,2] and oral doxycycline [18] has been shown effective, but

Pretreatment Endorectal Coil Magnetic Resonance Imaging Findings Predict Biochemical Tumor Control in Prostate Cancer Patients Treated With Combination Brachytherapy and External-Beam Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Riaz, Nadeem; Afaq, Asim; Akin, Oguz

Purpose: To investigate the utility of endorectal coil magenetic resonance imaging (eMRI) in predicting biochemical relapse in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Methods and Materials: Between 2000 and 2008, 279 men with intermediate- or high-risk prostate cancer underwent eMRI of their prostate before receiving brachytherapy and supplemental intensity-modulated radiotherapy. Endorectal coil MRI was performed before treatment and retrospectively reviewed by two radiologists experienced in genitourinary MRI. Image-based variables, including tumor diameter, location, number of sextants involved, and the presence of extracapsular extension (ECE), were incorporated with other established clinical variables to predict biochemical control outcomes.more » The median follow-up was 49 months (range, 1-13 years). Results: The 5-year biochemical relapse-free survival for the cohort was 92%. Clinical findings predicting recurrence on univariate analysis included Gleason score (hazard ratio [HR] 3.6, p = 0.001), PSA (HR 1.04, p = 0.005), and National Comprehensive Cancer Network risk group (HR 4.1, p = 0.002). Clinical T stage and the use of androgen deprivation therapy were not correlated with biochemical failure. Imaging findings on univariate analysis associated with relapse included ECE on MRI (HR 3.79, p = 0.003), tumor size (HR 2.58, p = 0.04), and T stage (HR 1.71, p = 0.004). On multivariate analysis incorporating both clinical and imaging findings, only ECE on MRI and Gleason score were independent predictors of recurrence. Conclusions: Pretreatment eMRI findings predict for biochemical recurrence in intermediate- and high-risk prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Gleason score and the presence of ECE on MRI were the only significant predictors of biochemical relapse in this group of patients.« less

Prognostic Markers in Core-Binding Factor AML and Improved Survival with Multiple Consolidation Cycles of Intermediate/High-dose Cytarabine.

PubMed

Prabahran, Ashvind; Tacey, Mark; Fleming, Shaun; Wei, Andrew; Tate, Courtney; Marlton, Paula; Wight, Joel; Grigg, Andrew; Tuckfield, Annabel; Szer, Jeff; Ritchie, David; Chee, Lynette

2018-05-02

Core-binding factor acute myeloid leukaemia (CBF AML) defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis, however 30-40% of patients still relapse after chemotherapy. We sought to evaluate risk factors for relapse in a de novo CBF AML cohort. A retrospective review of patients from 4 Australian tertiary centres from 2001-2012, comprising 40 t(8;21) and 30 inv(16) AMLs. Multivariate analysis identified age (p=0.032) and WCC>40 (p=0.025) as significant predictors for inferior OS and relapse respectively. Relapse risk was higher in the inv(16) group vs the t(8;21) group (57% vs 18%, HR 4.31, 95% CI: 1.78-10.42, p=0.001). Induction therapy had no bearing on OS or relapse free survival (RFS) however, consolidation treatment with >3 cycles of intermediate/high dose cytarabine improved OS (p=0.035) and relapse-free survival (RFS) (p=0.063). 5 patients demonstrated post-treatment stable q PCR positivity without relapse. (1)>3 consolidation cycles of intermediate/ high-dose cytarabine improves patient outcomes. (2)Age and inv(16) CBF AML subtype are predictors of inferior OS and RFS respectively. (3)Stable low-level MRD by qPCR does not predict relapse. (4)Similar OS in the inv(16) cohort compared to the t(8;21) cohort, despite a higher relapse rate, confirms salvageability of relapsed disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A TSHR-LH/CGR chimera that measures functional thyroid-stimulating autoantibodies (TSAb) can predict remission or recurrence in Graves' patients undergoing antithyroid drug (ATD) treatment.

PubMed

Giuliani, Cesidio; Cerrone, Dominique; Harii, Norikazu; Thornton, Mark; Kohn, Leonard D; Dagia, Nilesh M; Bucci, Ines; Carpentieri, Maria; Di Nenno, Barbara; Di Blasio, Andrea; Vitti, Paolo; Monaco, Fabrizio; Napolitano, Giorgio

2012-07-01

A functional thyroid-stimulating autoantibodies (TSAb) assay using a thyroid-stimulating hormone receptor chimera (Mc4) appears to be clinically more useful than the commonly used assay, a binding assay that measures all the antibodies binding to the thyroid-stimulating hormone receptor without functional discrimination, in diagnosing patient with Graves' disease (GD). The objective of the study was to investigate whether an Mc4 assay can predict relapse/remission of hyperthyroidism after antithyroid drug (ATD) treatment in patients with GD. An Mc4 assay was used to prospectively track TSAb activity in GD patients treated with ATD over a 5-yr period. GD patients from the Chieti University participated in this study. Interventions included the assessment of patients' sera using the Mc4 assay, the Mc4-derivative assay (Thyretain), and a human monoclonal thyroid-stimulating hormone receptor antibody, M22 assay. The Mc4 assay, a sensitive index of remission and recurrence, was used in this study. The TSAb levels significantly decreased only in the remitting group as evidenced by Mc4 assay values at the end of ATD (0.96 ± 1.47, 10.9 ± 26.6. and 24.7 ± 37.5 arbitrary units for the remitting, relapsing, and unsuspended therapy groups, respectively). Additional prognostic help was obtained by thyroid volume measurements at the end of treatment. Although not statistically significant, the Mc4 assay has a trend toward improved positive predictive value (95.4 vs. 84.2 or 87.5%), specificity (96.4 vs. 86.4 and 90.9%), and accuracy (87.3 vs. 83.3 and 80.9%) comparing the Mc4, Thyretain, and M22 assays, respectively. Thyretain has a trend toward improved negative predictive value (82.6 vs. 81.8 and 76.9%) and sensitivity (80 vs. 77.8 and 70%) comparing Thyretain, Mc4, and M22 assays, respectively. The Mc4 assay is a clinically useful index of remission and relapse in patients with GD. Larger studies are required to confirm these findings.

Recurrence due to Relapse or Reinfection With Mycobacterium tuberculosis: A Whole-Genome Sequencing Approach in a Large, Population-Based Cohort With a High HIV Infection Prevalence and Active Follow-up

PubMed Central

Guerra-Assunção, José Afonso; Houben, Rein M. G. J.; Crampin, Amelia C.; Mzembe, Themba; Mallard, Kim; Coll, Francesc; Khan, Palwasha; Banda, Louis; Chiwaya, Arthur; Pereira, Rui P. A.; McNerney, Ruth; Harris, David; Parkhill, Julian; Clark, Taane G.; Glynn, Judith R.

2015-01-01

Background. Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain. Methods. In a population-based study in northern Malawi, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008. Results. Based on our data, a difference of ≤10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004). Conclusions. While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection. PMID:25336729

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

PubMed

Datta, Gourab; Colasanti, Alessandro; Rabiner, Eugenii A; Gunn, Roger N; Malik, Omar; Ciccarelli, Olga; Nicholas, Richard; Van Vlierberghe, Eline; Van Hecke, Wim; Searle, Graham; Santos-Ribeiro, Andre; Matthews, Paul M

2017-11-01

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prognostic significance of cytogenetic abnormalities in patients with chronic myelogenous leukemia.

PubMed

Przepiorka, D; Thomas, E D

1988-03-01

The cytogenetic data for 126 patients with Ph-positive chronic myelogenous leukemia (CML) in accelerated phase or blast crisis were analysed for clonal chromosomal abnormalities in addition to the standard Ph prior to allogeneic or syngeneic bone marrow transplantation (BMT). Additional clonal abnormalities were found in 84%, and 14% had a variant Ph (VPh). In decreasing order of frequency, the most common clonal abnormalities were a second Ph, +8, i(17q), -Y and +19. A second Ph, VPh or +8 occurred more frequently in patients who relapsed following BMT than in those who survived disease-free for at least 1 1/2 years. The presence of an i(17q) alone did not correlate with relapse. The patients with a second Ph, VPh or +8 had a median time to relapse of 19 months, and the risk of relapse at 3 years was 73%. Those with other or no additional clonal abnormalities had not reached a median time to relapse and had a 3-year risk of relapse of 31% (p = 0.002). This analysis suggests that specific cytogenetic abnormalities may be useful indicators of resistance to therapy for CML and should be included in proportional hazard models to predict outcome after BMT.

Seasonal variations of 25-OH vitamin D serum levels are associated with clinical disease activity in multiple sclerosis patients.

PubMed

Hartl, Christina; Obermeier, Viola; Gerdes, Lisa Ann; Brügel, Mathias; von Kries, Rüdiger; Kümpfel, Tania

2017-04-15

Low 25-hydroxy vitamin D (25-[OH]-D) serum concentrations have been associated with higher disease activity in multiple sclerosis (MS) patients. In a large cross-sectional study we assessed the vitamin D status in MS patients in relation to seasonality and relapse rate. 415 MS-patients (355 relapsing-remitting MS and 60 secondary-progressive, 282 female, mean age 39.1years) of whom 25-(OH)-D serum concentrations were determined at visits between 2010 and 2013 were included in the study. All clinical data including relapse at visit and expanded disability status scale were recorded in a standardized manner by an experienced neurologist. Seasonal variations of 25-(OH)-D serum concentrations were modelled by sinusoidal regression and seasonal variability in the prevalence of relapse by cubic regression. The mean 25-(OH)-D serum concentration was 24.8ng/ml (range 8.3-140ng/ml) with peak levels of 32.2ng/ml in July/August and nadir in January/February (17.2ng/ml). The lowest modelled prevalence of relapse was in September/October (28%) and the highest modelled prevalence in March/April (47%). The nadir of 25-(OH)-D serum concentrations preceded the peak in prevalence of relapses by two months. In summary, seasonal variation of 25-(OH)-D serum levels were inversely associated with clinical disease activity in MS patients. Future studies should investigate whether vitamin D supplementation in MS patients may decrease the seasonal risk for MS relapses. Copyright © 2017 Elsevier B.V. All rights reserved.

How to predict clinical relapse in inflammatory bowel disease patients

PubMed Central

Liverani, Elisa; Scaioli, Eleonora; Digby, Richard John; Bellanova, Matteo; Belluzzi, Andrea

2016-01-01

Inflammatory bowel diseases have a natural course characterized by alternating periods of remission and relapse. Disease flares occur in a random way and are currently unpredictable for the most part. Predictors of benign or unfavourable clinical course are required to facilitate treatment decisions and to avoid overtreatment. The present article provides a literature review of the current evidence on the main clinical, genetic, endoscopic, histologic, serologic and fecal markers to predict aggressiveness of inflammatory bowel disease and discuss their prognostic role, both in Crohn’s disease and ulcerative colitis. No single marker seems to be reliable alone as a flare predictor, even in light of promising evidence regarding the role of fecal markers, in particular fecal calprotectin, which has reported good results recently. In order to improve our daily clinical practice, validated prognostic scores should be elaborated, integrating clinical and biological markers of prognosis. Finally, we propose an algorithm considering clinical history and biological markers to intercept patients with high risk of clinical relapse. PMID:26811644

Neural response to catecholamine depletion in remitted bulimia nervosa: Relation to depression and relapse.

PubMed

Mueller, Stefanie Verena; Mihov, Yoan; Federspiel, Andrea; Wiest, Roland; Hasler, Gregor

2017-07-01

Bulimia nervosa has been associated with a dysregulated catecholamine system. Nevertheless, the influence of this dysregulation on bulimic symptoms, on neural activity, and on the course of the illness is not clear yet. An instructive paradigm for directly investigating the relationship between catecholaminergic functioning and bulimia nervosa has involved the behavioral and neural responses to experimental catecholamine depletion. The purpose of this study was to examine the neural substrate of catecholaminergic dysfunction in bulimia nervosa and its relationship to relapse. In a randomized, double-blind and crossover study design, catecholamine depletion was achieved by using the oral administration of alpha-methyl-paratyrosine (AMPT) over 24 h in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. In a follow-up telephone interview, bulimic relapse was assessed. Following AMPT, rBN participants revealed an increased vigor reduction and CBF decreases in the pallidum and posterior midcingulate cortex (pMCC) relative to HC participants showing no CBF changes in these regions. These results indicated that the pallidum and the pMCC are the functional neural correlates of the dysregulated catecholamine system in bulimia nervosa. Bulimic relapse was associated with increased depressive symptoms and CBF reduction in the hippocampus/parahippocampal gyrus following catecholamine depletion. AMPT-induced increased CBF in this region predicted staying in remission. These findings demonstrated the importance of depressive symptoms and the stress system in the course of bulimia nervosa. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Does Tobacco-Control Mass Media Campaign Exposure Prevent Relapse Among Recent Quitters?

PubMed Central

Bowe, Steven J.; Durkin, Sarah J.; Yong, Hua-Hie; Spittal, Matthew J.; Simpson, Julie A.; Borland, Ron

2013-01-01

Objective: To determine whether greater mass media campaign exposure may assist recent quitters to avoid relapse. Method: Using date of data collection and postcode, media market estimates of televised tobacco-control advertising exposure measured by gross ratings points (GRPs) were merged with a replenished cohort study of 443 Australians who had quit in the past year. Participants’ demographic and smoking characteristics prior to quitting, and advertising exposure in the period after quitting, were used to predict relapse 1 year later. Results: In multivariate analysis, each increase in exposure of 100 GRPs (i.e., 1 anti-smoking advertisement) in the three-month period after the baseline quit was associated with a 5% increase in the odds of not smoking at follow-up (OR = 1.05, 95% CI 1.02–1.07, p < 0.001). This relationship was linear and unmodified by length of time quit prior to the baseline interview. At the mean value of 1081 GRPs in the 3 months after the baseline-quit interview, the predicted probability of being quit at follow-up was 52%, whereas it was 41% for the minimum (0) and 74% for the maximum (3,541) GRPs. Conclusion: Greater exposure to tobacco-control mass media campaigns may reduce the likelihood of relapse among recent quitters. PMID:22949574

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

PubMed Central

Vesely, C; Frech, C; Eckert, C; Cario, G; Mecklenbräuker, A; zur Stadt, U; Nebral, K; Kraler, F; Fischer, S; Attarbaschi, A; Schuster, M; Bock, C; Cavé, H; von Stackelberg, A; Schrappe, M; Horstmann, M A; Mann, G; Haas, O A; Panzer-Grümayer, R

2017-01-01

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1’s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias. PMID:27899802

Chronic cocaine disrupts mesocortical learning mechanisms

PubMed Central

Buchta, William C.; Riegel, Arthur C.

2016-01-01

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

Automatic Avoidance Tendencies for Alcohol Cues Predict Drinking After Detoxification Treatment in Alcohol Dependence

PubMed Central

2016-01-01

Alcohol dependence is characterized by conflict between approach and avoidance motivational orientations for alcohol that operate in automatic and controlled processes. This article describes the first study to investigate the predictive validity of these motivational orientations for relapse to drinking after discharge from alcohol detoxification treatment in alcohol-dependent patients. One hundred twenty alcohol-dependent patients who were nearing the end of inpatient detoxification treatment completed measures of self-reported (Approach and Avoidance of Alcohol Questionnaire; AAAQ) and automatic (modified Stimulus-Response Compatibility task) approach and avoidance motivational orientations for alcohol. Their drinking behavior was assessed via telephone follow-ups at 2, 4, and 6 months after discharge from treatment. Results indicated that, after controlling for the severity of alcohol dependence, strong automatic avoidance tendencies for alcohol cues were predictive of higher percentage of heavy drinking days (PHDD) at 4-month (β = 0.22, 95% CI [0.07, 0.43]) and 6-month (β = 0.22, 95% CI [0.01, 0.42]) follow-ups. We failed to replicate previous demonstrations of the predictive validity of approach subscales of the AAAQ for relapse to drinking, and there were no significant predictors of PHDD at 2-month follow-up. In conclusion, strong automatic avoidance tendencies predicted relapse to drinking after inpatient detoxification treatment, but automatic approach tendencies and self-reported approach and avoidance tendencies were not predictive in this study. Our results extend previous findings and help to resolve ambiguities with earlier studies that investigated the roles of automatic and controlled cognitive processes in recovery from alcohol dependence. PMID:27935726

Isolating the Role of Psychological Dysfunction in Smoking Cessation Failure: Relations of Personality and Psychopathology to Attaining Smoking Cessation Milestones

PubMed Central

Leventhal, Adam M.; Japuntich, Sandra J.; Piper, Megan E.; Jorenby, Douglas E.; Schlam, Tanya R.; Baker, Timothy B.

2012-01-01

Research exploring psychological dysfunction as a predictor of smoking cessation success may be limited by nonoptimal predictor variables (i.e., categorical psychodiagnostic measures vs. continuous personality-based manifestations of dysfunction) and imprecise outcomes (i.e., summative point prevalence abstinence vs. constituent cessation milestone measures). Accordingly, this study evaluated the unique and overlapping relations of broad-spectrum personality traits (positive emotionality, negative emotionality, and constraint) and past-year psychopathology (anxiety, mood, and substance use disorder) to point prevalence abstinence and three smoking cessation milestones: (1) initiating abstinence; (2) first lapse; and (3) transition from lapse to relapse. Participants were daily smokers (N=1365) enrolled in a smoking cessation treatment study. In single predictor regression models, each manifestation of internalizing dysfunction (lower positive emotionality, higher negative emotionality, and anxiety and mood disorder) predicted failure at one or more cessation milestone. In simultaneous predictor models, lower positive and higher negative emotionality significantly predicted failure to achieve milestones after controlling for psychopathology. Psychopathology did not predict any outcome when controlling for personality. Negative emotionality showed the most robust and consistent effects, significantly predicting failure to initiate abstinence, earlier lapse, and lower point prevalence abstinence rates. Substance use disorder and constraint did not predict cessation outcomes, and no single variable predicted lapse-to-relapse transition. These findings suggest that personality-related manifestations of internalizing dysfunction are more accurate markers of affective sources of relapse risk than mood and anxiety disorders. Further, individuals with high trait negative emotionality may require intensive intervention to promote the initiation and early maintenance of abstinence. PMID:22642858

Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence.

PubMed

Wojnar, Marcin; Brower, Kirk J; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

2009-04-01

The purpose of this study was to examine relationships between genetic markers of central serotonin (5-HT) and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger. The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.

Association between Val66Met Brain-Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post-Treatment Relapse in Alcohol Dependence

PubMed Central

Wojnar, Marcin; Brower, Kirk J.; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

2009-01-01

Background The purpose of this study was to examine relationships between genetic markers of central serotonin and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. Methods The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately one year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Results Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse (OR = 2.62; p = 0.019), and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (HR = 4.93, p = 0.001) were even stronger. Conclusions The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies. PMID:19170664

Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B.

PubMed

Papatheodoridis, George V; Manolakopoulos, Spilios; Su, Tung-Hung; Siakavellas, Spyros; Liu, Chun-Jen; Kourikou, Anastasia; Yang, Hung-Chih; Kao, Jia-Horng

2017-08-31

Relapses are observed in most hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients who discontinue treatment with nucleos(t)ide analogues (NAs); however, the rates of relapse vary widely among studies, and whether all patients with relapse need retreatment is unclear. The aim of this study was to assess the impact of different definitions on the rates of posttreatment relapse and therefore on the probability of retreatment in patients who have discontinued effective long-term NA therapy. In total, 130 HBeAg-negative chronic hepatitis B patients without cirrhosis and before NA treatment were included. All had on-therapy virological remission for ≥24 months and close follow-up for ≥12 months after stopping NA treatment or until retreatment, which started on stringent predefined criteria. Relapses rates based on several predetermined definitions of virological and perhaps biochemical criteria were assessed. The median duration of therapy was 60 months and the median duration of on-therapy virological remission was 43 months. During a median off-NAs follow-up of 15 months, no patient experienced liver decompensation or died. Cumulative relapse rates were 2%-49%, 4%-73%, 11%-82%, and 16%-90% at 3, 6, 12, and 24 months, respectively, whereas cumulative retreatment rates were 15%, 22%, and 40% at 6, 12, and 24 months, respectively, after discontinuation of NA therapy. No patient characteristic was independently associated with the probability of relapse based on at least two definitions or of retreatment. In HBeAg-negative chronic hepatitis B patients who discontinue NA therapy, the definition of relapse has a great impact on off-NAs relapse rates and potentially on the probability of retreatment. Regardless of definition, off-NAs relapses cannot be easily predicted by patient characteristics. A substantial proportion of such patients may not require retreatment if stringent criteria are adopted. (Hepatology 2017). © 2017 by the American Association for the Study of Liver Diseases.

Central diabetes insipidus as a very late relapse limited to the pituitary stalk in Langerhans cell histiocytosis.

PubMed

Nakagawa, Shunsuke; Shinkoda, Yuichi; Hazeki, Daisuke; Imamura, Mari; Okamoto, Yasuhiro; Kawakami, Kiyoshi; Kawano, Yoshifumi

2016-07-01

Central diabetes insipidus (CDI) and relapse are frequently seen in multifocal Langerhans cell histiocytosis (LCH). We present two females with multifocal LCH who developed CDI 9 and 5 years after the initial diagnosis, respectively, as a relapse limited to the pituitary stalk. Combination chemotherapy with cytarabine reduced the mass in the pituitary stalk. Although CDI did not improve, there has been no anterior pituitary hormone deficiency (APHD), neurodegenerative disease in the central nervous system (ND-CNS) or additional relapse for 2 years after therapy. It was difficult to predict the development of CDI in these cases. CDI might develop very late in patients with multifocal LCH, and therefore strict follow-up is necessary, especially with regard to symptoms of CDI such as polydipsia and polyuria. For new-onset CDI with LCH, chemotherapy with cytarabine might be useful for preventing APHD and ND-CNS.

Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study.

PubMed

Van Den Neste, E; Schmitz, N; Mounier, N; Gill, D; Linch, D; Trneny, M; Bouadballah, R; Radford, J; Bargetzi, M; Ribrag, V; Dührsen, U; Ma, D; Briere, J; Thieblemont, C; Bachy, E; Moskowitz, C H; Glass, B; Gisselbrecht, C

2017-02-01

In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

Response to rituximab and timeframe to relapse in rheumatoid arthritis patients: association with B-cell markers.

PubMed

Pyrpasopoulou, Athina; Douma, Stella; Triantafyllou, Areti; Simoulidou, Elisavet; Samara, Magda; Parapanisiou, Efthymia; Aslanidis, Spyros

2010-02-01

Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5 +/- 127.0 days for the RF+ patients versus 233.3 +/- 59.6 days for the RF- patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 +/- 1.076 in seropositive patients versus 0.94 +/- 1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF- counterparts, despite a significantly lower percentage of CD20+ cells. Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking.

PubMed

Augur, Isabel F; Wyckoff, Andrew R; Aston-Jones, Gary; Kalivas, Peter W; Peters, Jamie

2016-09-28

The ventromedial prefrontal cortex (vmPFC) has been shown to negatively regulate cocaine-seeking behavior, but the precise conditions by which vmPFC activity can be exploited to reduce cocaine relapse are currently unknown. We used viral-mediated gene transfer of designer receptors (DREADDs) to activate vmPFC neurons and examine the consequences on cocaine seeking in a rat self-administration model of relapse. Activation of vmPFC neurons with the Gq-DREADD reduced reinstatement of cocaine seeking elicited by cocaine-associated cues, but not by cocaine itself. We used a retro-DREADD approach to confine the Gq-DREADD to vmPFC neurons that project to the medial nucleus accumbens shell, confirming that these neurons are responsible for the decreased cue-induced reinstatement of cocaine seeking. The effects of vmPFC activation on cue-induced reinstatement depended on prior extinction training, consistent with the reported role of this structure in extinction memory. These data help define the conditions under which chemogenetic activation of extinction neural circuits can be exploited to reduce relapse triggered by reminder cues. The ventromedial prefrontal cortex (vmPFC) projection to the nucleus accumbens shell is important for extinction of cocaine seeking, but its anatomical proximity to the relapse-promoting projection from the dorsomedial prefrontal cortex to the nucleus accumbens core makes it difficult to selectively enhance neuronal activity in one pathway or the other using traditional pharmacotherapy (e.g., systemically administered drugs). Viral-mediated gene delivery of an activating Gq-DREADD to vmPFC and/or vmPFC projections to the nucleus accumbens shell allows the chemogenetic exploitation of this extinction neural circuit to reduce cocaine seeking and was particularly effective against relapse triggered by cocaine reminder cues. Copyright © 2016 the authors 0270-6474/16/3610174-07$15.00/0.

Discontinuation of Buprenorphine Maintenance Therapy: Perspectives and Outcomes

PubMed Central

Bentzley, Brandon S.; Barth, Kelly S.; Back, Sudie E.; Book, Sarah W.

2015-01-01

Buprenorphine maintenance therapy (BMT) is increasingly the preferred opioid maintenance agent due to its reduced toxicity and availability in an office-based setting in the United States. Although BMT has been shown to be highly efficacious, it is often discontinued soon after initiation. No current systematic review has yet investigated providers’ or patients’ reasons for BMT discontinuation or the outcomes that follow. Hence, provider and patient perspectives associated with BMT discontinuation after a period of stable buprenorphine maintenance and the resultant outcomes were systematically reviewed with specific emphasis on pre-buprenorphine-taper parameters predictive of relapse following BMT discontinuation. Few identified studies address provider or patient perspectives associated with buprenorphine discontinuation. Within the studies reviewed providers with residency training in BMT were more likely to favor long term BMT instead of detoxification, and providers were likely to consider BMT discontinuation in the face of medication misuse. Patients often desired to remain on BMT because of fear of relapse to illicit opioid use if they were to discontinue BMT. The majority of patients who discontinued BMT did so involuntarily, often due to failure to follow strict program requirements, and 1 month following discontinuation, rates of relapse to illicit opioid use exceeded 50% in every study reviewed. Only lower buprenorphine maintenance dose, which may be a marker for attenuated addiction severity, predicted better outcomes across studies. Relaxed BMT program requirements and frequent counsel on the high probability of relapse if BMT is discontinued may improve retention in treatment and prevent the relapse to illicit opioid use that is likely to follow BMT discontinuation. PMID:25601365

Predictors of posttreatment drinking outcomes in patients with alcohol dependence.

PubMed

Flórez, Gerardo; Saiz, Pilar A; García-Portilla, Paz; De Cos, Francisco J; Dapía, Sonia; Alvarez, Sandra; Nogueiras, Luis; Bobes, Julio

2015-01-01

This cohort study examined how predictors of alcohol dependence treatment outcomes work together over time by comparing pretreatment and posttreatment predictors. A sample of 274 alcohol-dependent patients was recruited and assessed at baseline, 6 months after treatment initiation (end of the active intervention phase), and 18 months after treatment initiation (end of the 12-month research follow-up phase). At each assessment point, the participants completed a battery of standardized tests [European Addiction Severity Index (EuropASI), Obsessive Compulsive Drinking Scale (OCDS), Alcohol Timeline Followback (TLFB), Fagerström, and International Personality Disorder Examination (IPDE)] that measured symptom severity and consequences; biological markers of alcohol consumption were also tested at each assessment point. A sequential strategy with univariate and multivariate analyses was used to identify how pretreatment and posttreatment predictors influence outcomes up to 1 year after treatment. Pretreatment variables had less predictive power than posttreatment ones. OCDS scores and biological markers of alcohol consumption were the most significant variables for the prediction of posttreatment outcomes. Prior pharmacotherapy treatment and relapse prevention interventions were also associated with posttreatment outcomes. The findings highlight the positive impact of pharmacotherapy during the first 6 months after treatment initiation and of relapse prevention during the first year after treatment and how posttreatment predictors are more important than pretreatment predictors.

Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors.

PubMed

Brecht, Mary-Lynn; Herbeck, Diane

2014-06-01

This paper describes methamphetamine (MA) use patterns, specifically the duration of continuing abstinence ("time to relapse") for periods averaging 5 years post-discharge from treatment for MA use, and the relationship with selected user and treatment characteristics. A sample of 350 treatment admissions from a large county substance use disorder (SUD) treatment system was randomly selected (within gender, race/ethnicity, treatment modality strata). Retrospective self-report data are from natural history interviews (NHI) conducted approximately 3 years after treatment and a follow-up of 2-3 years later. Relapse is defined as any use of MA with time as the number of months of continuous MA abstinence after treatment discharge until relapse. This outcome was constructed from a monthly MA use timeline using NHI data. A Cox model was used to examine time to relapse and predictors. Sixty-one percent of the sample relapsed to MA use within 1 year after treatment discharge and 14% during years 2-5. Significant protective factors predicting longer time to relapse included having experienced serious MA-related psychiatric/behavioral problems (hazard ratio [HR]=0.75, p=0.027), longer duration of the index treatment episode (HR=0.93, p=0.001), and participating in self-help or other treatment during the post-treatment abstinence period (HR=0.29, p<0.001); risk factors for shorter time to relapse included having a parent with alcohol and/or drug use problems (HR=1.35, p=0.020) and involvement in MA sales (HR=1.48, p=0.002). Results contribute a long-term perspective on patterns of MA use following treatment and support a need for early post-treatment and long-term continuing care and relapse-prevention services. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease?

PubMed

Radujkovic, Aleksandar; Guglielmi, Cesare; Bergantini, Stefania; Iacobelli, Simona; van Biezen, Anja; Milojkovic, Dragana; Gratwohl, Alois; Schattenberg, Antonius V M B; Verdonck, Leo F; Niederwieser, Dietger W; de Witte, Theo; Kröger, Nicolaus; Olavarria, Eduardo

2015-07-01

Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD-free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3(+) cells ≥ 50 × 10(6)/kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Pharmacological Strategies in the Prevention of Relapse Following Electroconvulsive Therapy

PubMed Central

Prudic, Joan; Haskett, Roger; McCall, W. Vaughn; Isenberg, Keith; Cooper, Thomas; Rosenquist, Peter B.; Mulsant, Benoit H.; Sackeim, Harold A.

2012-01-01

Objective To determine whether starting antidepressant medication at the start of ECT reduces postECT relapse and to determine whether continuation pharmacotherapy with nortriptyline and lithium (NT-Li) differs in efficacy or side effects from continuation pharmacotherapy with venlafaxine and lithium (VEN-Li). Method During an acute ECT phase, 319 patients were randomized to treatment with moderate dosage bilateral ECT or high dosage right unilateral ECT. They were also randomized to concurrent treatment with placebo, NT, or VEN. Of 181 patients to meet postECT remission criteria, 122 (67.4%) participated in a second continuation pharmacotherapy phase. Patients earlier randomized to NT or VEN continued on the antidepressant, while patients earlier randomized to placebo were now randomized to NT or VEN. Li was added for all patients who were followed until relapse or 6 months. Results Starting an antidepressant medication at the beginning of the ECT course did not impact on the rate or timing of relapse relative to starting pharmacotherapy after ECT completion. The combination of NT-Li did not differ from VEN-Li in any relapse or side effect measure. Older age was strongly associated with lower relapse risk, whereas the type of ECT administered in the acute phase and medication resistance were not predictive. Across sites, 50% of patients relapsed, 33.6% continued in remission 6 months postECT, and 16.4% dropped out. Conclusions Starting an antidepressant medication during ECT does not impact relapse and there are concerns about administering Li during an acute ECT course. Nortriptyline and venlafaxine were equally effective in prolonging remission, although relapse rates following ECT are substantial despite intensive pharmacology. As opposed to the usual abrupt cessation of ECT, the impact of an ECT taper should be evaluated. PMID:23303417

Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons

PubMed Central

Mika, Agnieszka; Bouchet, Courtney A.; Bunker, Preston; Hellwinkel, Justin E.; Spence, Katie G.; Day, Heidi E.W.; Campeau, Serge; Fleshner, Monika

2015-01-01

Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male, F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1 week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory. PMID:26454156

Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons.

PubMed

Mika, Agnieszka; Bouchet, Courtney A; Bunker, Preston; Hellwinkel, Justin E; Spence, Katie G; Day, Heidi E W; Campeau, Serge; Fleshner, Monika; Greenwood, Benjamin N

2015-11-01

Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory. Copyright © 2015 Elsevier Inc. All rights reserved.

Real-World Outcomes in Fingolimod-Treated Patients with Multiple Sclerosis in the Czech Republic: Results from the 12-Month GOLEMS Study.

PubMed

Tichá, Veronika; Kodým, Roman; Počíková, Zuzana; Kadlecová, Pavla

2017-02-01

Once-daily oral fingolimod is approved in the EU as escalation treatment for adult patients with highly active relapsing multiple sclerosis (MS). The efficacy and safety profiles of fingolimod have been well established in a large clinical development programme and several papers reflecting the experience with fingolimod in real-world settings have been published to date. The GOLEMS study was designed to evaluate the efficacy, safety and tolerability of fingolimod and the impact of fingolimod treatment on disability progression and work capability in patients with MS in routine clinical practice in the Czech Republic. GOLEMS was a national, multicentre, non-interventional, single-arm study conducted to analyse the outcomes of a minimum of 12 months of fingolimod therapy on primary and secondary endpoints. The primary endpoint was to assess the proportion of relapse-free patients and severity of MS relapses in patients treated with fingolimod for 12 months. Secondary endpoints included assessment of changes in disability progression evaluated by the Expanded Disability Status Scale (EDSS) score and work capability assessment measured through voluntary completion of the WPAI-GH questionnaire. The predictive factors for relapse-free status during fingolimod treatment were also analysed. Of the 240 enrolled patients, 219 completed the 12-month treatment period at the time of final analysis. In the efficacy set (N = 237), the proportion of relapse-free patients increased from 47 patients (19.6 %; 95 % confidence interval [CI] 14.8-25.2) in the year before fingolimod initiation to 152 patients (64.1 %; 95 % CI 58.0-70.2) after 1 year of fingolimod treatment. Of the 85 patients who experienced at least one relapse after 1 year of fingolimod treatment, 53 (62.4 %; 95 % CI 51.7-71.9) reported only one relapse, while 25 (29.4 %; 95 % CI 20.8-39.8) and seven (8.2 %; 95 % CI 4.0-16.0) patients had ≥2 relapses, respectively. No significant changes were observed in EDSS scores over the 12-month treatment period compared with baseline. The absolute number of relapses during 2 years before initiation of fingolimod treatment and baseline EDSS scores were identified as significant independent predictors for 'being relapse-free' during the 12-month fingolimod treatment period. No trend was established in work capability or number of missed days at work due to the large proportion of missing data. Of 240 enrolled patients, 27 (11.3 %) patients discontinued the study at or before the 12-month visit, 16 (6.7 %) discontinued because of adverse events related to study drug. Only six (2.5 %) patients reported serious adverse events related to the study drug. The results confirm the favourable safety and efficacy profile of fingolimod under real-world conditions, consistent with phase III trials.

Individual differences in nucleus accumbens activity to food and sexual images predict weight gain and sexual behavior.

PubMed

Demos, Kathryn E; Heatherton, Todd F; Kelley, William M

2012-04-18

Failures of self-regulation are common, leading to many of the most vexing problems facing contemporary society, from overeating and obesity to impulsive sexual behavior and STDs. One reason that people may be prone to engaging in unwanted behaviors is heightened sensitivity to cues related to those behaviors; people may overeat because of hyperresponsiveness to food cues, addicts may relapse following exposure to their drug of choice, and some people might engage in impulsive sexual activity because they are easily aroused by erotic stimuli. An open question is the extent to which individual differences in neural cue reactivity relate to actual behavioral outcomes. Here we show that individual differences in human reward-related brain activity in the nucleus accumbens to food and sexual images predict subsequent weight gain and sexual activity 6 months later. These findings suggest that heightened reward responsivity in the brain to food and sexual cues is associated with indulgence in overeating and sexual activity, respectively, and provide evidence for a common neural mechanism associated with appetitive behaviors.

Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS

PubMed Central

Kalincik, Tomas; Jokubaitis, Vilija; Zhang, Annie; Pellegrini, Fabio; Wiendl, Heinz; Belachew, Shibeshih; Hyde, Robert; Verheul, Freek; Lugaresi, Alessandra; Havrdová, Eva; Horáková, Dana; Grammond, Pierre; Duquette, Pierre; Prat, Alexandre; Iuliano, Gerardo; Terzi, Murat; Izquierdo, Guillermo; Hupperts, Raymond M.M.; Boz, Cavit; Pucci, Eugenio; Giuliani, Giorgio; Sola, Patrizia; Spitaleri, Daniele L.A.; Lechner-Scott, Jeannette; Bergamaschi, Roberto; Grand'Maison, François; Granella, Franco; Kappos, Ludwig; Trojano, Maria; Butzkueven, Helmut

2016-01-01

Abstract Background: We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score–matched cohorts from observational multiple sclerosis registries. Methods: The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity. Results: First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28–0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58–0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale–time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. Conclusions: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. Classification of evidence: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA. PMID:27104064

Clinical utility of host genetic IL-28B variants in hepatitis C virus genotype 1 Asian patients retreated with pegylated interferon plus ribavirin.

PubMed

Huang, Chung-Feng; Yeh, Ming-Lun; Hsieh, Meng-Hsuan; Hsieh, Ming-Yen; Lin, Zu-Yau; Chen, Shinn-Cherng; Wang, Liang-Yen; Huang, Jee-Fu; Juo, Suh-Hang Hank; Lin, Yi-Ching; Dai, Chia-Yen; Chuang, Wan-Long; Yu, Ming-Lung

2013-09-01

Host interleukin-28B (IL-28B) genetic variants determine a sustained virological response (SVR) in hepatitis C virus genotype 1 (HCV-1) treatment-naïve patients. Its impact on treatment-experienced Asian patients with peginterferon/ribavirin in is to be elucidated. IL-28B rs8099917 genotype was determined in 70 HCV-1 treatment-experienced patients retreated with 48-week peginterferon/ribavirin. The SVR rate was 60.0% and was significantly higher in previous relapsers than in nonresponders (72.7% and 13.3%, P < 0.001). Multivariate analysis revealed that the most important factor predictive of an SVR was previous relapse (Odds ratio [OR]/95% confidence interval [CI]: 14.76/2.72-80.06, P = 0.002), followed by the carriage of rs8099917 TT genotype (OR/95% C.I.: 7.67/1.27-46.49, P = 0.03). Comparing to patients with TG/GG genotype, those with TT genotype had significantly higher rates of rapid virological response (29.3% vs 0%, P = 0.03), end-of-treatment virological response (86.2% vs 50.0%, P = 0.01), SVR (69.0% vs 16.7%, P = 0.002), and lower relapse rate (22.0 % vs 66.7%, P = 0.04). The SVR rate was similarly low between previous nonresponders with different rs8099917 genotypes (12.5% vs 14.3%, P = 1). On the contrary, previous relapsers with rs8099917 TT genotype had a significantly higher SVR rate than those who carried rs8099917 TG/GG genotype (78.0 % vs 20.0%, P = 0.02). Stepwise logistic regression analysis revealed that the only factor predictive of an SVR in previous relapsers was the carriage of rs809997 TT genotype (OR/95% CI:18.50/1.82-188.39, P = 0.014). Host IL-28B genetic variants played a role in Asian relapsers but not nonresponders retreated with peginterferon/ribavirin. Direct antiviral agents might be possibly avoidable in Asian relapsers with favorable IL-28B genotype. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

MS disease activity in RESTORE

PubMed Central

Cree, Bruce A.C.; De Sèze, Jerome; Gold, Ralf; Hartung, Hans-Peter; Jeffery, Douglas; Kappos, Ludwig; Kaufman, Michael; Montalbán, Xavier; Weinstock-Guttman, Bianca; Anderson, Britt; Natarajan, Amy; Ticho, Barry; Duda, Petra

2014-01-01

Objective: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. Methods: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks. Results: Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%–29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4–8 weeks (n = 2 in weeks 4–8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity. Conclusions: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies. Classification of evidence: This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab. PMID:24682966

MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study.

PubMed

Fox, Robert J; Cree, Bruce A C; De Sèze, Jerome; Gold, Ralf; Hartung, Hans-Peter; Jeffery, Douglas; Kappos, Ludwig; Kaufman, Michael; Montalbán, Xavier; Weinstock-Guttman, Bianca; Anderson, Britt; Natarajan, Amy; Ticho, Barry; Duda, Petra

2014-04-29

RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks. Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity. MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies. This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.

Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience.

PubMed

Chau, C; Cathomas, R; Wheater, M; Klingbiel, D; Fehr, M; Bennett, J; Markham, H; Lee, C; Crabb, S J; Geldart, T

2015-09-01

Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Relapse Prevention in Major Depressive Disorder: Mindfulness-Based Cognitive Therapy Versus an Active Control Condition

PubMed Central

Shallcross, Amanda J.; Gross, James J.; Visvanathan, Pallavi D.; Kumar, Niketa; Palfrey, Amy; Ford, Brett Q.; Dimidjian, Sona; Shirk, Stephen; Holm-Denoma, Jill; Goode, Kari M.; Cox, Erica; Chaplin, William; Mauss, Iris B.

2015-01-01

Objective We evaluated the comparative effectiveness of Mindfulness-based cognitive therapy (MBCT) versus an active control condition (ACC) for depression relapse prevention, depressive symptom reduction, and improvement in life satisfaction. Method Ninety-two participants in remission from Major Depressive Disorder with residual depressive symptoms were randomized to either an 8-week MBCT or a validated ACC that is structurally equivalent to MBCT and controls for non-specific effects (e.g., interaction with a facilitator, perceived social support, treatment outcome expectations). Both interventions were delivered according to their published manuals. Results Intention-to-treat analyses indicated no differences between MBCT and ACC in depression relapse rates or time to relapse over a 60-week follow-up. Both groups experienced significant and equal reductions in depressive symptoms and improvements in life satisfaction. A significant quadratic interaction (group x time) indicated that the pattern of depressive symptom reduction differed between groups. The ACC experienced immediate symptom reduction post-intervention and then a gradual increase over the 60-week follow-up. The MBCT group experienced a gradual linear symptom reduction. The pattern for life satisfaction was identical but only marginally significant. Conclusions MBCT did not differ from an ACC on rates of depression relapse, symptom reduction, or life satisfaction, suggesting that MBCT is no more effective for preventing depression relapse and reducing depressive symptoms than the active components of the ACC. Differences in trajectory of depressive symptom improvement suggest that the intervention-specific skills acquired may be associated with differential rates of therapeutic benefit. This study demonstrates the importance of comparing psychotherapeutic interventions to active control conditions. PMID:26371618

Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies

PubMed Central

Cazzaniga, Giovanni; De Lorenzo, Paola; Alten, Julia; Röttgers, Silja; Hancock, Jeremy; Saha, Vaskar; Castor, Anders; Madsen, Hans O.; Gandemer, Virginie; Cavé, Hélène; Leoni, Veronica; Köhler, Rolf; Ferrari, Giulia M.; Bleckmann, Kirsten; Pieters, Rob; van der Velden, Vincent; Stary, Jan; Zuna, Jan; Escherich, Gabriele; zur Stadt, Udo; Aricò, Maurizio; Conter, Valentino; Schrappe, Martin; Valsecchi, Maria Grazia; Biondi, Andrea

2018-01-01

The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10−4 and 70 with MRD≥5×10−4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis. PMID:29079599

Predicting relapse risk in childhood acute lymphoblastic leukaemia.

PubMed

Teachey, David T; Hunger, Stephen P

2013-09-01

Intensive multi-agent chemotherapy regimens and the introduction of risk-stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower-risk and treated with less intensive therapy relapse, while others deemed higher-risk are probably over-treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk-stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response-based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk-stratify therapy. © 2013 John Wiley & Sons Ltd.

Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse.

PubMed

Feltenstein, Matthew W; Altar, C Anthony; See, Ronald E

2007-03-01

Aripiprazole (Abilify) is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D2 receptors and low side effects. Based on pharmacologic properties that include a stabilization of mesocorticolimbic DA activity, a pathway implicated in addiction, aripiprazole was tested for its ability to prevent relapse to cocaine seeking in rats. We assessed the dose-dependent effects of aripiprazole on conditioned cue-induced and cocaine-primed reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. Aripiprazole potently and dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned-cued reinstatement. Aripiprazole was effective at doses that failed to alter cocaine self-administration, food self-administration, reinstatement of food-seeking behavior, or basal locomotor activity, suggesting selective effects of aripiprazole on motivated drug-seeking behavior. These results in a relapse model show that aripiprazole can block cocaine seeking without affecting other behaviors. The D2 partial agonist properties of aripiprazole likely account for the blockade of reinstatement of cocaine-seeking behavior. Given its established efficacy and tolerability as a treatment for psychosis, aripiprazole may be an excellent therapeutic choice for reducing craving and preventing relapse in people with cocaine dependency.

Automatic avoidance tendencies for alcohol cues predict drinking after detoxification treatment in alcohol dependence.

PubMed

Field, Matt; Di Lemma, Lisa; Christiansen, Paul; Dickson, Joanne

2017-03-01

Alcohol dependence is characterized by conflict between approach and avoidance motivational orientations for alcohol that operate in automatic and controlled processes. This article describes the first study to investigate the predictive validity of these motivational orientations for relapse to drinking after discharge from alcohol detoxification treatment in alcohol-dependent patients. One hundred twenty alcohol-dependent patients who were nearing the end of inpatient detoxification treatment completed measures of self-reported (Approach and Avoidance of Alcohol Questionnaire; AAAQ) and automatic (modified Stimulus-Response Compatibility task) approach and avoidance motivational orientations for alcohol. Their drinking behavior was assessed via telephone follow-ups at 2, 4, and 6 months after discharge from treatment. Results indicated that, after controlling for the severity of alcohol dependence, strong automatic avoidance tendencies for alcohol cues were predictive of higher percentage of heavy drinking days (PHDD) at 4-month (β = 0.22, 95% CI [0.07, 0.43]) and 6-month (β = 0.22, 95% CI [0.01, 0.42]) follow-ups. We failed to replicate previous demonstrations of the predictive validity of approach subscales of the AAAQ for relapse to drinking, and there were no significant predictors of PHDD at 2-month follow-up. In conclusion, strong automatic avoidance tendencies predicted relapse to drinking after inpatient detoxification treatment, but automatic approach tendencies and self-reported approach and avoidance tendencies were not predictive in this study. Our results extend previous findings and help to resolve ambiguities with earlier studies that investigated the roles of automatic and controlled cognitive processes in recovery from alcohol dependence. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Anti-myelin antibodies predict the clinical outcome after a first episode suggestive of MS.

PubMed

Tomassini, V; De Giglio, L; Reindl, M; Russo, P; Pestalozza, I; Pantano, P; Berger, T; Pozzilli, C

2007-11-01

The aim of this study was to test the contribution of anti-myelin antibodies in predicting conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) when considering either Poser's or McDonald's diagnostic criteria. Fifty-one patients with CIS and abnormal brain MRI were imaged monthly for six months and then at 12, 18, 24, 36 months. At baseline serum samples testing antibodies against myelin oligodendrocyte glycoprotein (anti-MOG) and myelin basic protein (anti-MBP) were collected. During the 36-month follow-up, 26 (51%) patients developed a relapse thus becoming clinically definite MS (CDMS) according to Poser's criteria; 46 (90.2%) patients converted to MS according to McDonald's criteria. Out of 51 patients, 28 (54.9%) had either double or single positivity for anti-myelin antibodies. Antibody status significantly predicted MS according to Poser's criteria (P=0.004), but did not according to the McDonald's criteria. When compared to antibody negative patients, the risk of developing a relapse was 8.9 (95% CI: 2.7-29.8; P<0.001) for anti-MBP positive (anti-MBP+) patients and 1.5 (95% CI: 0.4-5.4; P=0.564) for those anti-MOG positive (anti-MOG+); double positive patients (ie, anti-MBP+/anti-MOG+) had a risk of relapse's occurrence equal to 3.4 (95% CI: 1.1-10.2; P=0.031). Also, the antibody status predicted the median time span from CIS to CDMS, that was of 36 months in the anti-MOG-/anti-MBP- group, 33 months in the anti-MOG+/anti-MBP- group, 24 months in the anti-MOG+/anti-MBP+ group and 12 months in the anti-MOG-/anti-MBP+ patients (P=0.003 by ANOVA). Our data support the prognostic value of anti-myelin antibodies in CIS patients at risk of CDMS, with positive patients showing shorter time interval to relapse occurrence than negative patients.

99mTc-CXCL8 SPECT to Monitor Disease Activity in Inflammatory Bowel Disease.

PubMed

Aarntzen, Erik H J G; Hermsen, Rick; Drenth, Joost P H; Boerman, Otto C; Oyen, Wim J G

2016-03-01

Inflammatory bowel diseases (IBDs) are defined as chronic relapsing immune-mediated disorders of the gastrointestinal tract. IBD exacerbations are characterized by recruitment of mainly CXCL8 receptor-expressing activated neutrophils into the intestinal wall, leading to severe damage. Considering its chronic relapsing character, accurate and timely diagnosis of an exacerbation is pivotal for early adaptation of the treatment and reduction of the disease burden. However, endoscopic evaluation is invasive and associated with an increased risk of perforation. We previously developed a (99m)Tc-labeled CXCL8 preparation in preclinical models including colitis and clinical studies. In this study, we investigate the accuracy of (99m)Tc-CXCL8 SPECT to detect and localize disease activity in a prospective series of patients with IBD. Thirty patients (15 Crohns disease, 15 ulcerative colitis) participated, and 92 segmental pairs of histology and (99m)Tc-CXCL8 scans were studied. Imaging was performed after injection of 400 MBq of (99m)Tc-CXCL8. Planar and SPECT images of the abdomen were acquired at 30 min and 4 h after the injection. The overall sensitivity and specificity on a per-patient basis for the detection of active disease were 95% and 44% for (99m)Tc-CXCL8 scan and 71% and 70% for endoscopy. The degree of (99m)Tc-CXCL8 accumulation correlated to the degree of neutrophilic influx in affected mucosa. Sensitivity and specificity on a per-segment basis, calculated from the 92 segmental pairs, were 82% and 72%, negative predictive value was 81%, and overall positive predictive value was 74%. Specificity could be increased at the expense of sensitivity using different cutoffs. In 74 segmental pairs, overall sensitivity and specificity for endoscopy were 74% and 85%, positive predictive value was 81%, and negative predictive value was 79%. (99m)Tc-CXCL8 SPECT provides a novel imaging technique to target neutrophil recruitment to the intestinal wall, especially in moderate to severe exacerbations of IBD. Further validation studies are warranted to potentiate (99m)Tc-CXCL8 SPECT as a biomarker to scale up or step down treatment with immune-modulating drugs in a personalized fashion. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

A panel to predict long-term outcome of infliximab therapy for patients with ulcerative colitis.

PubMed

Arias, Maria Theresa; Vande Casteele, Niels; Vermeire, Séverine; de Buck van Overstraeten, Anthony; Billiet, Thomas; Baert, Filip; Wolthuis, Albert; Van Assche, Gert; Noman, Maja; Hoffman, Ilse; D'Hoore, Andre; Gils, Ann; Rutgeerts, Paul; Ferrante, Marc

2015-03-01

Infliximab is effective for patients with refractory ulcerative colitis (UC), but few factors have been identified that predict long-term outcome of therapy. We aimed to identify a panel of markers associated with outcome of infliximab therapy to help physicians make personalized treatment decisions. We collected data from the first 285 patients with refractory UC (41% female; median age, 39 y) treated with infliximab before July 2012 at University Hospitals Leuven, in Belgium. We performed a Cox regression analysis to identify independent factors that predicted relapse-free and colectomy-free survival, and used these factors to create a panel of markers (risk panel). During a median follow-up period of 5 years, 61% of patients relapsed and 20% required colectomy. Independent predictors of relapse-free survival included short-term complete clinical response (odds ratio [OR], 3.75; 95% confidence interval [CI], 2.35-5.97; P < .001), mucosal healing (OR, 1.87; 95% CI, 1.17-2.98; P = .009), and absence of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) (OR, 1.96; 95% CI, 1.23-3.12; P = .005). Independent predictors of colectomy-free survival included short-term clinical response (OR, 7.74; 95% CI, 2.76-21.68; P < .001), mucosal healing (OR, 4.02; 95% CI, 1.16-13.97; P = .028), baseline level of C-reactive protein (CRP) of 5 mg/L or less (OR, 2.95; 95% CI, 1.26-6.89; P = .012), and baseline level of albumin of 35 g/L or greater (OR, 3.03; 95% CI, 1.12-8.22; P = .029). Based on serologic analysis of a subgroup of 112 patients, levels of infliximab greater than 2.5 μg/mL at week 14 of treatment predicted relapse-free survival (P < .001) and colectomy-free survival (P = .034). A risk panel that included levels of pANCA, CRP, albumin, clinical response, and mucosal healing identified patients at risk for UC relapse or colectomy (both P < .001). Clinical response and mucosal healing were confirmed as independent predictors of long-term outcome from infliximab therapy in patients with UC. We identified additional factors (levels of pANCA, CRP, and albumin) to create a risk panel that predicts long-term outcomes of therapy. Serum levels of infliximab at week 14 of treatment also were associated with patient outcomes. Our risk panel and short-term serum levels of infliximab therefore might be used to guide therapy. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Prognostic Prediction Model for Second Allogeneic Stem-Cell Transplantation in Patients With Relapsed Acute Myeloid Leukemia: Single-Center Report.

PubMed

Park, Sung-Soo; Kim, Hee-Je; Min, Kyoung Il; Min, Gi June; Jeon, Young-Woo; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2018-04-01

To identify factors affecting survival outcomes and to develop a prognostic model for second allogeneic stem-cell transplantation (allo-SCT2) for relapsed acute myeloid leukemia (AML) after the first autologous or allogeneic stem-cell transplantation. Seventy-eight consecutive adult AML patients who received allo-SCT2 were analyzed in this retrospective study. The 4-year overall survival (OS) rate was 28.7%. In multivariate analysis, poor cytogenetic risk at diagnosis, circulating blast ≥ 20% at relapse, duration from first transplantation to relapse < 9 months, and failure to achieve morphologic complete remission after allo-SCT2 were factors associated with poor OS. A prognostic model was developed with the following score system: intermediate and poor cytogenetic risk at diagnosis (0.5 and 1 point), peripheral blast ≥ 20% at relapse (1 point), duration from the first transplantation to relapse < 9 months (1 point), and failure to achieve morphologic complete remission after allo-SCT2 (1 point). The model identified 2 subgroups according to the 4-year OS rate: 51.3% in the low-risk group (score < 2) and 2.8% in the high-risk group (score ≥ 2) (P < .001). This prognostic model might be useful to make an appropriate decision for allo-SCT2 in relapsed AML after the first autologous or allogeneic stem-cell transplantation. Copyright © 2018 Elsevier Inc. All rights reserved.

Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease

PubMed Central

Gross, V; Andus, T; Ecker, K; Raedler, A; Loeschke, K; Plauth, M; Rasenack, J; Weber, A; Gierend, M; Ewe, K; Scholmerich, J; Budesonide, S

1998-01-01

Background—The relapse rate after steroid induced remission in Crohn's disease is high. 
Aims—To test whether oral pH modified release budesonide (3 × 1 mg/day) reduces the relapse rate and to identify patient subgroups with an increased risk of relapse. 
Methods—In a multicentre, randomised, double blind study, 179 patients with steroid induced remission of Crohn's disease received either 3 × 1 mg budesonide (n=84) or placebo (n=95) for one year. The primary study aim was the maintenance of remission of Crohn's disease for one year. 
Results—Patient characteristics at study entry were similar for both groups. The relapse rate was 67% (56/84) in the budesonide group and 65% (62/95) in the placebo group. The relapse curves in both groups were similar. The mean time to relapse was 93.5days in the budesonide group and 67.0 days in the placebo group. No prognostic factors allowing prediction of an increased risk for relapse or definition of patient subgroups who derived benefit from low dose budesonide were found. Drug related side effects were mild and no different between the budesonide and the placebo group. 
Conclusion—Oral pH modified release budesonide at a dose of 3 × 1 mg/day is not effective for maintaining steroid induced remission in Crohn's disease. 

 Keywords: budesonide; Crohn's disease; maintenance of remission PMID:9616309

Response assessment of bevacizumab therapy in GBM with integrated 11C-MET-PET/MRI: a feasibility study.

PubMed

Deuschl, Cornelius; Moenninghoff, Christoph; Goericke, Sophia; Kirchner, Julian; Köppen, Susanne; Binse, Ina; Poeppel, Thorsten D; Quick, Harald H; Forsting, Michael; Umutlu, Lale; Herrmann, Ken; Hense, Joerg; Schlamann, Marc

2017-08-01

The objective of this study was to evaluate the potential of integrated 11C-MET PET/MR for response assessment of relapsed glioblastoma (GBM) receiving bevacizumab treatment. Eleven consecutive patients with relapsed GBM were enrolled for an integrated 11C-MET PET/MRI at baseline and at follow-up. Treatment response for MRI was evaluated according to Response Assessment in Neuro-oncology (RANO) criteria and integrated 11C-MET PET was assessed by the T/N ratio. MRI showed no patient with complete response (CR), six of 11 patients with PR, four of 11 patients with SD, and one of 11 patients with progressive disease (PD). PET revealed metabolic response in five of the six patients with partial response (PR) and in two of the four patients with stable disease (SD), whereas metabolic non-response was detected in one of the six patients with PR, in two of the four patients with SD, and in the one patient with PD. Morphological imaging was predictive for PFS and OS when response was defined as CR, PR, SD, and non-response as PD. Metabolic imaging was predictive when using T/N ratio reduction of >25 as discriminator. Based on the morphologic and metabolic findings of this study a proposal for applying integrated PET/MRI for treatment response in relapsed GBM was developed, which was significantly predictive for PFS and OS (P = 0.010 respectively 0,029, log). This study demonstrates the potential of integrated 11C-MET-PET/MRI for response assessment of GBM and the utility of combined assessment of morphologic and metabolic information with the proposal for assessing relapsed GBM.

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

PubMed Central

Barrett, David M.; Shestova, Olga; Hofmann, Ted J.; Perazzelli, Jessica; Klichinsky, Michael; Aikawa, Vania; Nazimuddin, Farzana; Kozlowski, Miroslaw; Scholler, John; Lacey, Simon F.; Melenhorst, Jan J.; Morrissette, Jennifer J.D.; Christian, David A.; Hunter, Christopher A.; Kalos, Michael; Porter, David L.; June, Carl H.; Grupp, Stephan A.

2016-01-01

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies PMID:27571406

Predictive value of cognition for different domains of outcome in recent-onset schizophrenia.

PubMed

Holthausen, Esther A E; Wiersma, Durk; Cahn, Wiepke; Kahn, René S; Dingemans, Peter M; Schene, Aart H; van den Bosch, Robert J

2007-01-15

The aim of this study was to see whether and how cognition predicts outcome in recent-onset schizophrenia in a large range of domains such as course of illness, self-care, interpersonal functioning, vocational functioning and need for care. At inclusion, 115 recent-onset patients were tested on a cognitive battery and 103 patients participated in the follow-up 2 years after inclusion. Differences in outcome between cognitively normal and cognitively impaired patients were also analysed. Cognitive measures at inclusion did not predict number of relapses, activities of daily living and interpersonal functioning. Time in psychosis or in full remission, as well as need for care, were partly predicted by specific cognitive measures. Although statistically significant, the predictive value of cognition with regard to clinical outcome was limited. There was a significant difference between patients with and without cognitive deficits in competitive employment status and vocational functioning. The predictive value of cognition for different social outcome domains varies. It seems that cognition most strongly predicts work performance, where having a cognitive deficit, regardless of the nature of the deficit, acts as a rate-limiting factor.

Predicting Time-to-Relapse in Breast Cancer Using Neural Networks

DTIC Science & Technology

1997-12-01

CODE 17. SECURITY CLASSIFICATION OF REPORT Unclassified 118. SECURITY CLASSIFICATION OF THIS PAGE Unclassified 19. SECURITY CLASSIFICATION OF...Lowell WE, and Davis GL. A neural network that predicts psychiatric length of stay. MD Computing 10:87-92, 1993. Ebell MH. Artificial neural netowrks

Predictive modeling of addiction lapses in a mobile health application.

PubMed

Chih, Ming-Yuan; Patton, Timothy; McTavish, Fiona M; Isham, Andrew J; Judkins-Fisher, Chris L; Atwood, Amy K; Gustafson, David H

2014-01-01

The chronically relapsing nature of alcoholism leads to substantial personal, family, and societal costs. Addiction-comprehensive health enhancement support system (A-CHESS) is a smartphone application that aims to reduce relapse. To offer targeted support to patients who are at risk of lapses within the coming week, a Bayesian network model to predict such events was constructed using responses on 2,934 weekly surveys (called the Weekly Check-in) from 152 alcohol-dependent individuals who recently completed residential treatment. The Weekly Check-in is a self-monitoring service, provided in A-CHESS, to track patients' recovery progress. The model showed good predictability, with the area under receiver operating characteristic curve of 0.829 in the 10-fold cross-validation and 0.912 in the external validation. The sensitivity/specificity table assists the tradeoff decisions necessary to apply the model in practice. This study moves us closer to the goal of providing lapse prediction so that patients might receive more targeted and timely support. © 2013.

Predictive Modeling of Addiction Lapses in a Mobile Health Application

PubMed Central

Chih, Ming-Yuan; Patton, Timothy; McTavish, Fiona M.; Isham, Andrew; Judkins-Fisher, Chris L.; Atwood, Amy K.; Gustafson, David H.

2013-01-01

The chronically relapsing nature of alcoholism leads to substantial personal, family, and societal costs. Addiction-Comprehensive Health Enhancement Support System (A-CHESS) is a smartphone application that aims to reduce relapse. To offer targeted support to patients who are at risk of lapses within the coming week, a Bayesian network model to predict such events was constructed using responses on 2,934 weekly surveys (called the Weekly Check-in) from 152 alcohol-dependent individuals who recently completed residential treatment. The Weekly Check-in is a self-monitoring service, provided in A-CHESS, to track patients’ recovery progress. The model showed good predictability, with the area under receiver operating characteristic curve of 0.829 in the 10-fold cross-validation and 0.912 in the external validation. The sensitivity/specificity table assists the tradeoff decisions necessary to apply the model in practice. This study moves us closer to the goal of providing lapse prediction so that patients might receive more targeted and timely support. PMID:24035143

Predicting the Initial Lapse Using a Mobile Health Application after Alcohol Detoxification

ERIC Educational Resources Information Center

Chih, Ming-Yuan

2013-01-01

The prediction and prevention of the initial lapse--which is defined as the first lapse after a period of abstinence--is important because the initial lapse often leads to subsequent lapses (within the same lapse episode) or relapse. The prediction of the initial lapse may allow preemptive intervention to be possible. This dissertation reports on…

Utility of the PET-CT in the evaluation of early response to treatment in the diffuse large B-cell lymphoma. Preliminary results.

PubMed

Cortés Romera, M; Gámez Cenzano, C; Caresia Aróztegui, A P; Martín-Comín, J; González-Barca, E; Ricart Brulles, Y; Palacios Abufón, A; Robles Barba, J; Rodríguez-Bel, L; Rossi Seoane, S; Fernández de Sevilla, A

2012-01-01

To assess the role of FDG-PET/CT performed after the first cycles of chemotherapy in the prediction of response to treatment in patients with diffuse large B-cell lymphoma. Twenty patients (mean age: 48 years) were included, 16 initial staging and 4 relapse. All patients underwent PET/CT at 3 times: 1) Baseline, 2) After 1-3 cycles of chemotherapy (early response assessment), and 3) End of treatment (evaluation of final response). Early PET/CT findings were correlated to the end-treatment PET/CT and follow-up. The evaluation of the response was established according to the decrease in uptake of the lesions (SUVmax). In the early assessment, a good response indicator (GRI) was obtained when the lesion disappeared or had more than 50% reduction in SUVmax. At the end of the treatment, a complete metabolic response (CMR) was determined in negative PET scans. Follow-up was superior to 19 months and final outcome was established as progression/relapse or no evidence of disease (NED). At the early treatment evaluation, 16/16 patients of initial staging (100%) and 2/4 of relapse (50%) achieved GRI. At the end of treatment evaluation, 14/16 patients of initial staging with GRI achieved CMR and 1/16 PMR: 14 were alive with NED in the follow-up while 1 relapsed. In the second group, 2/2 patients with GRI achieved CMR (100%): 1 continued with NED in the follow-up and another relapsed. FDG-PET/CT after the first cycles of chemotherapy is useful to monitor treatment due to its high negative predictive value (87.5%), using it to modify treatment early in the non-responders. Copyright © 2011 Elsevier España, S.L. y SEMNIM. All rights reserved.

[Clinical research on clearance of leukemic cell during induction of remission therapy in children with precursor B cell acute lymphoblastic leukemia].

PubMed

Yi, Zhi-gang; Cui, Lei; Gao, Chao; Jin, Mei; Zhang, Rui-dong; Li, Zhi-gang; Wu, Min-yuan

2011-03-01

To investigate the clinical value of clearance of leukemic cell during induction of remission therapy in children with precursor B cell acute lymphoblastic leukemia (BCP-ALL), and to assess the applicative value of different indexes. From April 2005 to April 2008, 206 children with de novo BCP-ALL were admitted. We firstly analyzed the effect of clearance of leukemic cells during induction of remission therapy on relapse-free survival (RFS). Four indexes were used to assess the clearance of leukemic cells including prednisone response on day 8 (d8-PR), percentage of lymphoblast in bone marrow on day 22 (d22-BM) and day 33 (d33-BM), and bone marrow (BM) minimal residual disease (MRD) detection on day 33 (d33-MRD). Then the sensitivity, specificity, positive predictive value and negative predictive value of the four indexes to assess their ability to predict relapse were analyzed. Finally, the consistency between two of the four indexes to explore the relationships among them were analyzed. There were significant differences between RFS of the sub-groups divided according to d8-PR, d22-BM, d33-BM, d33-MRD (P < 0.01); Cox proportional hazard model analysis showed that d33-MRD ≥ 10(-3) and positive BCR/ABL fusion gene were the independent prognostic factors. Sensitivity of d33-MRD was higher than that of morphology detection (d22-BM, d33-BM and d8-PR) in prediction of relapse, and positive predictive value of morphology detection was higher than that of d33-MRD. Sensitivity could be greatly increased by combination with clinical and biological characteristics. Consistency could not be found between d8-PR and d22-BM, d33-BM, d33-MRD, as well as between d22-BM, d33-BM, and d33-MRD. However, all cases of d22-BM, d33-BM M2/M3 were d33-MRD ≥ 10(-3), while the same phenomenon could not be found for patients with poor d8-PR. Clearance of leukemic cell during induction of remission therapy in children with BCP-ALL had important clinical value. Sensitivity of MRD detection after induction of remission therapy was higher than that of morphological analysis to predict relapse. Morphological analysis could only identify a few patients with very high risk of relapse and the sensitivity could be increased by combination with clinical biological characteristics. The simple prednisone response may contain some prognostic information that could not be covered by analysis of BM cells. It may be the best way to assess the clearance of leukemic cells to combine the prednisone response with MRD detection after induction of remission therapy.

Randomized Trial of Behavioral Activation, Cognitive Therapy, and Antidepressant Medication in the Prevention of Relapse and Recurrence in Major Depression

ERIC Educational Resources Information Center

Dobson, Keith S.; Hollon, Steven D.; Dimidjian, Sona; Schmaling, Karen B.; Kohlenberg, Robert J.; Gallop, Robert J.; Rizvi, Shireen L.; Gollan, Jackie K.; Dunner, David L.; Jacobson, Neil S.

2008-01-01

This study followed treatment responders from a randomized controlled trial of adults with major depression. Patients treated with medication but withdrawn onto pill-placebo had more relapse through 1 year of follow-up compared to patients who received prior behavioral activation, prior cognitive therapy, or continued medication. Prior…

Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

PubMed Central

Richardson, Paul G.; Weller, Edie; Jagannath, Sundar; Avigan, David E.; Alsina, Melissa; Schlossman, Robert L.; Mazumder, Amitabha; Munshi, Nikhil C.; Ghobrial, Irene M.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; McKenney, Mary; Delaney, Carol; Mitsiades, Constantine S.; Hideshima, Teru; Dalton, William; Knight, Robert; Esseltine, Dixie-Lee; Anderson, Kenneth C.

2009-01-01

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID:19786667

Initial experience with CMC-544 (inotuzumab ozogamicin) in pediatric patients with relapsed B-cell acute lymphoblastic leukemia.

PubMed

Rytting, Michael; Triche, Lisa; Thomas, Deborah; O'Brien, Susan; Kantarjian, Hagop

2014-02-01

Survival is poor in pediatric patients with relapsed or refractory acute B-cell lymphoblastic leukemia (ALL) and therapeutic options are limited. CMC-544 (inotuzumab ozogamicin) has shown significant activity in adult patients with relapsed and refractory ALL. We evaluated CMC-544 in pediatric patients with multiply relapsed ALL. Five children 4-15 years old with relapsed, CD 22 positive B-cell ALL were enrolled on a phase II non-randomized trial of CMC-544. CMC-544 was initially administered at 1.3 mg/m(2) every 3 weeks. The dose then increased to 1.8 mg/m(2) every 3 weeks. Subsequently, a weekly schedule of CMC-544 given as 0.8 mg/m(2) on day 1 followed by 0.5 mg/m(2) on days 8 and 15 was administered. All five patients had refractory relapsed B-cell ALL. Lymphoblasts for all patients highly expressed CD22. Four patients had two or more relapses before starting the study drug. One patient achieved a complete remission in the bone marrow and normal peripheral counts, and two patients achieved bone marrow morphologic remission with absolute neutrophils >1,000/µl but platelets <100,000/µl. Two patients had no response to the drug. Toxicities consisted of fever, sepsis, and liver enzyme elevation. Single agent CMC-544 given at the single dose of 1.8 mg/m(2) every 3 weeks or given as a split, weekly dose was generally well tolerated considering the inherent risks in this population of patients and showed promising activity in pediatric patients with relapsed and refractory ALL. © 2013 Wiley Periodicals, Inc.

Mother–Child Communication and Maternal Depressive Symptoms in Families of Children With Cancer: Integrating Macro and Micro Levels of Analysis

PubMed Central

Dunn, Madeleine J.; Zuckerman, Teddi; Hughart, Leighann; Vannatta, Kathryn; Gerhardt, Cynthia A.; Saylor, Megan; Schuele, C. Melanie; Compas, Bruce E.

2013-01-01

Objectives This study examines associations between maternal depressive symptoms and macro- and micro-level aspects of mothers’ communication about their children’s cancer. Methods Mothers reported depressive symptoms after diagnosis or relapse (child mean age = 10.4 years; 53% male). Mother–child dyads (N = 94) were subsequently observed discussing the child’s cancer and maternal communication was coded. Results Macro-level indicators (positive and negative communication) were associated with certain micro-level indicators of communication (topic maintenance, reflections, reframes, and imperatives). Higher depressive symptoms predicted lower positive communication and higher negative communication. Maternal reflections and imperatives predicted positive communication, and topic maintenance and reframes predicted negative communication, beyond child age, family income, and depressive symptoms. Conclusions Findings suggest concrete targets for improving communication in families after diagnosis or relapse. PMID:23616622

Extinction of alcohol seeking is enhanced by compound extinction and the noradrenaline reuptake inhibitor atomoxetine.

PubMed

Leung, Hiu T; Corbit, Laura H

2017-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli provides a means for reducing their impact on relapse. However, the expression of extinction can be disrupted by exposure to the previous reinforcer as well as the simple passage of time. We investigated whether augmentation of prediction error or of noradrenaline neurotransmission by the reuptake inhibitor atomoxetine would enhance long-term extinction of alcohol-seeking behavior. Rats received Pavlovian conditioning of multiple stimuli signaling the delivery of an alcohol reward before individual extinction was given to each of these stimuli. Further extinction was then given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg/kg; Experiment 2). Experiment 3 examined whether the compound stimulus effect relied on noradrenergic activity by testing the effects of the β-adrenergic antagonist propranolol, given prior to compound stimulus trials. Long-term retention of extinction learning was assessed a week later. Compound stimulus presentations enhanced long-term extinction as the stimulus extinguished in compound elicited less responding than a stimulus receiving equal extinction alone when tested a week later. This effect was mimicked by atomoxetine and blocked by propranolol given during extinction training. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Both behavioral and neurobiological processes could be exploited to enhance the outcome of extinction-based treatments for alcohol use disorders. © 2015 Society for the Study of Addiction.

A behavioral economic reward index predicts drinking resolutions: moderation revisited and compared with other outcomes.

PubMed

Tucker, Jalie A; Roth, David L; Vignolo, Mary J; Westfall, Andrew O

2009-04-01

Data were pooled from 3 studies of recently resolved community-dwelling problem drinkers to determine whether a behavioral economic index of the value of rewards available over different time horizons distinguished among moderation (n = 30), abstinent (n = 95), and unresolved (n = 77) outcomes. Moderation over 1- to 2-year prospective follow-up intervals was hypothesized to involve longer term behavior regulation processes than abstinence or relapse and to be predicted by more balanced preresolution monetary allocations between short-term and longer term objectives (i.e., drinking and saving for the future). Standardized odds ratios (ORs) based on changes in standard deviation units from a multinomial logistic regression indicated that increases on this "Alcohol-Savings Discretionary Expenditure" index predicted higher rates of abstinence (OR = 1.93, p = .004) and relapse (OR = 2.89, p < .0001) compared with moderation outcomes. The index had incremental utility in predicting moderation in complex models that included other established predictors. The study adds to evidence supporting a behavioral economic analysis of drinking resolutions and shows that a systematic analysis of preresolution spending patterns aids in predicting moderation.

Neurogentics of Dopaminergic Receptor Super-sensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART)

PubMed Central

Downs, B. William; Bowirrat, Abdalla; Waite, Roger L.; Braverman, Eric R.; Madigan, Margaret; Oscar-Berman, Marlene; DiNubile, Nicholas; Gold, Mark

2013-01-01

Background and Hypothesis It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers. Proposal and Conclusion We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).” PMID:19940429

Virologic response to treatment with Pegylated Interferon alfa-2b and Ribavirin for chronic hepatitis C in children.

PubMed

Pawłowska, Malgorzata; Pilarczyk, Malgorzata; Halota, Waldemar

2010-12-01

This study assessed the efficacy and safety of treatment of chronic hepatitis C in children with pegylated interferon alpha and ribavirin. Investigations were performed on 53 children with chronic hepatitis C, aged 8-17 years. Children were divided into 2 groups: naïve (n=29) and retreated (n=24). All children were administered a combined therapy with pegylated interferon (IFN) alpha-2b 1.5 mcg/kg/wk and ribavirin 15 mg/kg/d for 48 weeks. Mean baseline viral load was 0.456×10(6) IU/mL, mean alanine aminotransferase (ALT) activity was 45.8±24.3 IU/mL. No child had liver disease assessed greater than grade 2, stage 2 according to modified Scheuer scale. Serum hepatitis C virus (HCV) RNA in TW 12-EVR, TW 48-ETR, and W 72-sustained virologic response (SVR) with the polymerase chain reaction (PCR) method (Roche TaqMan) were evaluated. Sustained virologic response was achieved in 47% of children. The prevalence of relapses was 7.5%. The most important predictor of SVR in both groups was undetectable HCV RNA at TW 12. All retreated children who achieved partial EVR - (the HCV RNA level decreased more than 2 logs relative to baseline) were relapsers. In responders from both groups, baseline ALT activity was higher and baseline viral load was lower. In all children who achieved SVR, HCV RNA was undetectable 12 months later. Pegylated IFN and ribavirin are effective in treating chronic hepatitis C in children. Complete EVR is predictive of a sustained viral response. And high rate of relapses in retreated patients may suggest a longer duration of retherapy.

Predictors of heroin relapse: Personality traits, impulsivity, COMT gene Val158met polymorphism in a 5-year prospective study in Shanghai, China.

PubMed

Su, Hang; Li, Zhibin; Du, Jiang; Jiang, Haifeng; Chen, Zhikang; Sun, Haiming; Zhao, Min

2015-12-01

Relapse is a typical feature of heroin addiction and rooted in genetic and psychological determinants. The aim of this study was to evaluate the effect of personality traits, impulsivity, and COMT gene polymorphism (rs4680) on relapse to heroin use during 5-year follow up. 564 heroin dependent patients were enrolled in compulsory drug rehabilitation center. 12 months prior to their release, personality traits were measured by BIS-11 (Barratt Impulsiveness Scale-11) and Temperament and Character Inventory (TCI). The COMT gene rs4680 polymorphism was genotyped using a DNA sequence detection system. The heroin use status was evaluated for 5 years after discharged. Among the 564 heroin-dependent patients, 500 were followed for 5 years after discharge and 53.0% (n = 265) were considered as relapsed to heroin use according to a strict monitor system. Univariate analysis showed that age, having ever been in methadone maintenance treatment (MMT), the total scores and non-planning scores of BIS-11, and the COMT rs4680 gene variants were different between relapse and abstinent groups. Logistic regression analysis showed higher BIS total score, having ever been in MMT and younger first heroin use age are the predictors of relapse to heroin use during 5 years follow-up, and the COMT rs4680 gene had an interaction with BIS scores. Our findings indicated that the impulsive personality traits, methadone use history, and onset age could predict relapse in heroin-dependent patients during 5 year's follow up. The COMT gene showed a moderational effect in part the relationship of impulsivity with heroin relapse. © 2015 Wiley Periodicals, Inc.

Preoperative [18F]-fluorodeoxyglucose positron emission tomography standardized uptake value of neck lymph nodes may aid in selecting patients with oral cavity squamous cell carcinoma for salvage therapy after relapse.

PubMed

Liao, Chun-Ta; Chang, Joseph Tung-Chieh; Wang, Hung-Ming; Ng, Shu-Hang; Huang, Shiang-Fu; Chen, I-How; Hsueh, Chuen; Lee, Li-Yu; Lin, Chih-Hung; Cheng, Ann-Joy; Yen, Tzu-Chen

2009-11-01

Relapse of tumours in patients with oral cavity squamous cell carcinoma (OSCC) is associated with a dismal outcome. In this prospective study, we sought to investigate the clinical significance of the preoperative maximal standardized uptake value (SUVmax) at the neck lymph nodes in selecting patients with OSCC for salvage therapy after relapse. Between 2002 and 2007, 108 patients with early relapse of OSCC (n=75) or late relapse of OSCC (n=33) were identified. Salvage therapy was performed in 47 patients. All patients underwent 2-deoxy-2[(18)F]-fluoro-D: -glucose positron emission tomography during the 2 weeks before surgery and neck dissection. All patients were followed for 12 months or more after surgery or until death. The optimal cut-off value for the neck lymph node SUVmax (SUVnodal-max) was selected according to the 5-year disease-specific survival (DSS) rate. Independent risk factors were identified by Cox regression analysis. The mean follow-up for all patients was 20.3 months (41.1 months for surviving patients). In the early relapse group, several prognostic factors were identified in univariate and multivariate analyses, including a SUVnodal-max value of >or=4.2. A scoring system based on univariate analysis was formulated. Patients with a score of 0 had a better 5-year DSS than those with scores of 1 or higher (58% vs. 5%, p=0.0003). In patients with late relapse, a SUVnodal-max value of >or=4.2 had the highest prognostic value for predicting the 5-year DSS (45% vs. 0%, p=0.0005). Among patients with relapsed OSCC, the SUVnodal-max value may aid in selecting patients for salvage therapy.

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

PubMed Central

Ruiz-Peña, Juan Luís; Duque, Pablo; Izquierdo, Guillermo

2008-01-01

Background A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. Methods Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN β1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years. Results We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m – last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m – last visit; CH: 0.29, NCH: 0.13). Conclusion Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression. PMID:18325088

Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence

PubMed Central

Campbell, Erin J.; Whitaker, Leslie R.; Harvey, Brandon K.; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T.; Heins, Robert C.; Prisinzano, Thomas E.; Vardy, Eyal; Bonci, Antonello; Bossert, Jennifer M.

2016-01-01

In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. SIGNIFICANCE STATEMENT In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence. PMID:26985037

Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence.

PubMed

Marchant, Nathan J; Campbell, Erin J; Whitaker, Leslie R; Harvey, Brandon K; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T; Heins, Robert C; Prisinzano, Thomas E; Vardy, Eyal; Bonci, Antonello; Bossert, Jennifer M; Shaham, Yavin

2016-03-16

In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence. Copyright © 2016 the authors 0270-6474/16/363282-14$15.00/0.

Risk-adapted, treosulfan-based therapy with auto- and allo-SCT for relapsed/refractory aggressive NHL: a prospective phase-II trial.

PubMed

Koenigsmann, M; Casper, J; Kahl, C; Basara, N; Sayer, H G; Behre, G; Theurich, S; Christopeit, M; Mohren, M; Reichle, A; Metzner, B; Ganser, A; Stadler, M; Uharek, L; Balleisen, L; Hinke, A; Hinke, R; Niederwieser, D

2014-03-01

Since the outcome of relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (>1 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (P<0.0001). Risk-adapted, treosulfan-based therapy with auto- and allo-SCT is feasible. Long-term survival is possible with allogeneic transplantation.

Use of fingolimod in patients with relapsing remitting multiple sclerosis in Kuwait.

PubMed

Alroughani, R; Ahmed, S F; Behbehani, R; Al-Hashel, J

2014-04-01

Post-marketing studies are important to confirm what was established in clinical trials, and to assess the intermediate and long-term efficacy and safety. To assess efficacy and safety of fingolimod in multiple sclerosis (MS) in Kuwait. We retrospectively evaluated MS patients using the MS registries in 3 MS clinics. Relapsing remitting MS patients according to revised 2010 McDonald criteria who had been treated with fingolimod for at least 12 months were included. Primary endpoint was proportion of relapse-free patients at last follow-up. Secondary endpoints were mean change in EDSS and proportion of patients with MRI activity (gadolinium-enhancing or new/enlarging T2 lesions). 76 patients met the inclusion criteria. Mean age and mean disease duration were 34.43 and 7.82 years respectively. Mean duration of exposure to fingolimod was 18.50 months. Proportion of relapse-free patients was 77.6% at last follow-up. Mean EDSS score significantly improved (2.93 versus 1.95; p<0.0001) while 17.1% of patients continued to have MRI activity versus 77.6% at baseline (p<0.0001). Four patients stopped fingolimod due to disease breakthrough (n=3) and lymphadenitis (n=1). Fingolimod is safe and effective in reducing clinical and radiological disease activity in relapsing remitting MS patients. Our results are comparable to reported results of phase III studies. Copyright © 2014 Elsevier B.V. All rights reserved.

The effect of low-frequency mechanical vibration on retention in an orthodontic relapse model.

PubMed

Yadav, Sumit; Assefnia, Amir; Gupta, Himank; Vishwanath, Meenakshi; Kalajzic, Zana; Allareddy, Veerasathpurush; Nanda, Ravindra

2016-02-01

To investigate the effect of low-frequency mechanical vibration (LFMV) on the prevention of relapse after active orthodontic tooth movement, bone volume fraction (BVF), tissue density, and the integrity of periodontal ligament. Thirty male CD1, 12-week-old mice were used for the study. Mice were randomly divided into three groups: 1. control group, 2. relapse group, and 3. relapse + 30 Hz vibration group. In the control group, first molar was moved mesially for 7 days using nickel-titanium coil spring delivering 10g of force, whereas in relapse and relapse + 30 Hz groups, first molar was moved mesially for 7 days and then orthodontic force was removed and molar was allowed to relapse for 7 days. In relapse + 30 Hz group, LFMVs were applied at 30 Hz. Micro-focus computed tomography (micro-CT) was used for tooth movement measurements (relapse), BVF, and tissue density. Additionally, immunostaining for sclerostin, tartrate-resistant acid phosphatase staining, and picro-sirius red staining were performed on histological sections. LFMV at 30 Hz showed a tendency to decrease relapse but was not statistically significant. Micro-CT analysis showed a trend towards increase in BVF and tissue density with application of LFMV. Sclerostin expression was decreased with 30 Hz vibration. Additionally, the picro-sirius staining showed that LFMV at 30 Hz helped in maintaining the thickness and integrity of collagen fibres in periodontal ligament. This is an animal study and extrapolation of the current findings to the clinical situation must be done with caution, as there is no osteonal remodelling (secondary remodelling) in mice when compared to humans. There was no statistically significant difference in the amount of relapse between the relapse-only and relapse + 30 Hz groups. However, there was a trend of decrease in relapse with 30 Hz mechanical vibration. © The Author 2015. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells.

PubMed

Wildner, Gerhild; Kaufmann, Ulrike

2013-09-01

Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-γ. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

Double blind clinical trial in a series of 115 patients with seborrheic dermatitis: prevention of relapses using a topical modulator of Toll like receptor 2.

PubMed

Ionescu, M A; Baroni, A; Brambilla, L; Cannavò, S P; Cristaudo, A; Vedove, C Dalle; Frasca, M; Girolomoni, G; Gnecchi, L; Peris, K; Trifirò, C; Matta, A M; Robert, G

2011-06-01

Seborrheic dermatitis is a chronic inflammatory disease aggravated by Malassezia species. Toll-like receptors (TLR) are part of innate immune system that can be activated by yeasts. Previous studies showed that an association of Umbelliferae extract with a lipid (TLR2-Regul™) decreases the IL-8 expression in human skin in contact with M. furfur. The aim of this study was to assess the activity of a topical formulated with TLR2-Regul™ in the prevention of seborrheic dermatitis (SD) relapses. Immune-competent SD adult patients were treated for SD (topical imidazoles or steroids). Cleared patients were randomized and received a topical containing TLR2-Regul™ (A) or its vehicle (B). Erythema, scales and pruritus were assessed during two months. The study included 115 patients, mean age 43.4, sex ratio m/f 1.5. At week 4 the relapse rate was 26% (N.=15) in group A and 43% (N.=25) in group B. At W8 the relapse rate was 21% (N.=12) in group A and 40% (N.=23) (P=0.0309). In this series of 115 adults with seborrheic dermatitis, patients treated with a topical containing TLR-Regul™ showed a significantly less relapse rate compared with the excipient group (P<0.05). TLR modulation could represent a new therapeutic approach in the prevention of seborrheic dermatitis relapses.

Actigraphy and motion analysis: new tools for psychiatry.

PubMed

Teicher, M H

1995-01-01

Altered locomotor activity is a cardinal sign of several psychiatric disorders. With advances in technology, activity can now be measured precisely. Contemporary studies quantifying activity in psychiatric patients are reviewed. Studies were located by a Medline search (1965 to present; English language only) cross-referencing motor activity and major psychiatric disorders. The review focused on mood disorders and attention-deficit hyperactivity disorder (ADHD). Activity levels are elevated in mania, agitated depression, and ADHD and attenuated in bipolar depression and seasonal depression. The percentage of low-level daytime activity is directly related to severity of depression, and change in this parameter accurately mirrors recovery. Demanding cognitive tasks elicit fidgeting in children with ADHD, and precise measures of activity and attention may provide a sensitive and specific marker for this disorder. Circadian rhythm analysis enhances the sophistication of activity measures. Affective disorders in children and adolescents are characterized by an attenuated circadian rhythm and an enhanced 12-hour harmonic rhythm (diurnal variation). Circadian analysis may help to distinguish between the activity patterns of mania (dysregulated) and ADHD (intact or enhanced). Persistence of hyperactivity or circadian dysregulation in bipolar patients treated with lithium appears to predict rapid relapse once medication is discontinued. Activity monitoring is a valuable research tool, with the potential to aid clinicians in diagnosis and in prediction of treatment response.

Evolution of acute myelogenous leukemia stem cell properties after treatment and progression.

PubMed

Ho, Tzu-Chieh; LaMere, Mark; Stevens, Brett M; Ashton, John M; Myers, Jason R; O'Dwyer, Kristen M; Liesveld, Jane L; Mendler, Jason H; Guzman, Monica; Morrissette, Jennifer D; Zhao, Jianhua; Wang, Eunice S; Wetzler, Meir; Jordan, Craig T; Becker, Michael W

2016-09-29

Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered. © 2016 by The American Society of Hematology.

Predictors of response to intra-articular steroid injection in psoriatic arthritis.

PubMed

Eder, Lihi; Chandran, Vinod; Ueng, Joanna; Bhella, Sita; Lee, Ker-Ai; Rahman, Proton; Pope, Angela; Cook, Richard J; Gladman, Dafna D

2010-07-01

To assess the effectiveness of IA corticosteroid (IAS) injections in PsA and to determine the association between macrophage migration inhibition factor (MIF) gene polymorphism and response to IAS injections. A cohort analysis of PsA patients who were followed prospectively was performed. Clinical response was defined as no tenderness or effusion in the injected joint at 3 months. Relapse was defined as re-occurrence of joint pain or effusion. MIF 173C > G genotyping (rs755622) was performed. Two hundred and twenty patients with 245 IAS injections were included in the study. The probability of responding at 3 months was 41.6%. Within 12 months, 25.5% of the joints relapsed. Clinical factors that were associated with response included duration of psoriasis [Odds ratio (OR) 1.03] and the use of MTX or anti-TNF agents at the time of injection (OR 2.68). Factors that were associated with relapse included injection into large joints (OR 4.58) and elevated sedimentation rate (OR 15.0), whereas absence of clinical and/or radiographic damage (OR 0.23) and duration of PsA (OR 0.92) reduced risk of relapse. MIF polymorphism was not associated with clinical response, but was associated with relapse (OR 3.2). On multivariate analysis including clinical covariates, the association between MIF polymorphism and relapse was lost. IAS injections are effective in PsA. MIF gene polymorphism is associated with relapse. However, this effect is explained by clinical variables that reflect disease activity, suggesting that MIF gene polymorphism influences inflammatory activity.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect.

PubMed

Voldsgaard, A; Bager, P; Garde, E; Åkeson, P; Leffers, A M; Madsen, C G; Kapel, C; Roepstorff, A; Thamsborg, S M; Melbye, M; Siebner, H; Søndergaard, H B; Sellebjerg, F; Sørensen, P Soelberg

2015-11-01

An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect. © The Author(s), 2015.

Evolution of acute myelogenous leukemia stem cell properties after treatment and progression

PubMed Central

Ho, Tzu-Chieh; LaMere, Mark; Stevens, Brett M.; Ashton, John M.; Myers, Jason R.; O’Dwyer, Kristen M.; Liesveld, Jane L.; Mendler, Jason H.; Guzman, Monica; Morrissette, Jennifer D.; Zhao, Jianhua; Wang, Eunice S.; Wetzler, Meir; Jordan, Craig T.

2016-01-01

Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered. PMID:27421961

Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation.

PubMed

Fakhouri, Fadi; Fila, Marc; Provôt, François; Delmas, Yahsou; Barbet, Christelle; Châtelet, Valérie; Rafat, Cédric; Cailliez, Mathilde; Hogan, Julien; Servais, Aude; Karras, Alexandre; Makdassi, Raifah; Louillet, Feriell; Coindre, Jean-Philippe; Rondeau, Eric; Loirat, Chantal; Frémeaux-Bacchi, Véronique

2017-01-06

The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (<7 days) hematologic remission and a return of serum creatinine to baseline level in a median time of 26 days. At last follow-up, renal function remained unchanged in nonrelapsing and relapsing patients compared with baseline values before eculizumab discontinuation. Pathogenic variants in complement genes were associated with higher risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients. Copyright © 2016 by the American Society of Nephrology.

Comparison of the Liaison® Calprotectin kit with a well established point of care test (Quantum Blue - Bühlmann-Alere®) in terms of analytical performances and ability to detect relapses amongst a Crohn population in follow-up.

PubMed

Delefortrie, Quentin; Schatt, Patricia; Grimmelprez, Alexandre; Gohy, Patrick; Deltour, Didier; Collard, Geneviève; Vankerkhoven, Patrick

2016-02-01

Although colonoscopy associated with histopathological sampling remains the gold standard in the diagnostic and follow-up of inflammatory bowel disease (IBD), calprotectin is becoming an essential biomarker in gastroenterology. The aim of this work is to compare a newly developed kit (Liaison® Calprotectin - Diasorin®) and its two distinct extraction protocols (weighing and extraction device protocol) with a well established point of care test (Quantum Blue® - Bühlmann-Alere®) in terms of analytical performances and ability to detect relapses amongst a Crohn's population in follow-up. Stool specimens were collected over a six month period and were composed of control and Crohn's patients. Amongst the Crohn's population disease activity (active vs quiescent) was evaluated by gastroenterologists. A significant difference was found between all three procedures in terms of calprotectin measurements (weighing protocol=30.3μg/g (median); stool extraction device protocol=36.9μg/g (median); Quantum Blue® (median)=63; Friedman test, P value=0.05). However, a good correlation was found between both extraction methods coupled with the Liaison® analyzer and between the Quantum Blue® (weighing protocol/extraction device protocol Rs=0.844, P=0.01; Quantum Blue®/extraction device protocol Rs=0.708, P=0.01; Quantum Blue®/weighing protocol, Rs=0.808, P=0.01). Finally, optimal cut-offs (and associated negative predictive values - NPV) for detecting relapses were in accordance with above results (Quantum Blue® 183.5μg/g and NPV of 100%>extraction device protocol+Liaison® analyzer 124.5μg/g and NPV of 93.5%>weighing protocol+Liaison® analyzer 106.5μg/g and NPV of 95%). Although all three methods correlated well and had relatively good NPV in terms of detecting relapses amongst a Crohn's population in follow-up, the lack of any international standard is the origin of different optimal cut-offs between the three procedures. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease.

PubMed

Derwa, Y; Gracie, D J; Hamlin, P J; Ford, A C

2017-08-01

Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBD). Evidence implicates disturbances of the gastrointestinal microbiota in their pathogenesis. To perform a systematic review and meta-analysis to examine the efficacy of probiotics in IBD. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (until November 2016). Eligible randomised controlled trials (RCTs) recruited adults with UC or CD, and compared probiotics with 5-aminosalicylates (5-ASAs) or placebo. Dichotomous symptom data were pooled to obtain a relative risk (RR) of failure to achieve remission in active IBD, or RR of relapse of disease activity in quiescent IBD, with 95% confidence intervals (CIs). The search identified 12 253 citations. Twenty-two RCTs were eligible. There was no benefit of probiotics over placebo in inducing remission in active UC (RR of failure to achieve remission=0.86; 95% CI=0.68-1.08). However, when only trials of VSL#3 were considered there appeared to be a benefit (RR=0.74; 95% CI=0.63-0.87). Probiotics appeared equivalent to 5-ASAs in preventing UC relapse (RR=1.02; 95% CI=0.85-1.23). There was no benefit of probiotics in inducing remission of active CD, in preventing relapse of quiescent CD, or in preventing relapse of CD after surgically induced remission. VSL#3 may be effective in inducing remission in active UC. Probiotics may be as effective as 5-ASAs in preventing relapse of quiescent UC. The efficacy of probiotics in CD remains uncertain, and more evidence from RCTs is required before their utility is known. © 2017 John Wiley & Sons Ltd.

Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax.

PubMed

Montero, Joan; Stephansky, Jason; Cai, Tianyu; Griffin, Gabriel K; Cabal-Hierro, Lucia; Togami, Katsuhiro; Hogdal, Leah J; Galinsky, Ilene; Morgan, Elizabeth A; Aster, Jon C; Davids, Matthew S; LeBoeuf, Nicole R; Stone, Richard M; Konopleva, Marina; Pemmaraju, Naveen; Letai, Anthony; Lane, Andrew A

2017-02-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker. Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115. ©2016 American Association for Cancer Research.

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

PubMed Central

Dietrich, Sascha; Okun, Jürgen G.; Schmidt, Kathrin; Falk, Christine S.; Wagner, Andreas H.; Karamustafa, Suzan; Radujkovic, Aleksandar; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter; Luft, Thomas

2014-01-01

Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort. PMID:24142995

Effect of immune modulation in relapsed peripheral T-cell lymphomas after post-allogeneic stem cell transplantation: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

PubMed

Mamez, A C; Lévy, V; Chevallier, P; Blaise, D; Vigouroux, S; Xhaard, A; Fegueux, N; Contentin, N; Beguin, Y; Ifrah, N; Bulabois, C E; Suarez, F; Yakoub-Agha, I; Turlure, P; Deconink, E; Lamy, T; Cahn, J Y; Huynh, A; Maury, S; Fornecker, L M; Ouzegdouh, M; Bay, J O; Guillerm, G; Maillard, N; Michallet, M; Malfuson, J V; Bourhis, J H; Rialland, F; Oumedaly, R; Jubert, C; Leblond, V; Boubaya, M; Mohty, M; Nguyen, S

2016-03-01

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68-48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04-16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17-0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease.

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence.

PubMed

Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

2016-07-02

Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

Reactivity to negative affect in smokers: the role of implicit associations and distress tolerance in smoking cessation.

PubMed

Cameron, Amy; Reed, Kathleen Palm; Ninnemann, Andrew

2013-12-01

Avoidance of negative affect is one motivational factor that explains smoking cessation relapse during cessation attempts. This negative reinforcement model of smoking cessation and relapse has demonstrated the importance of one's ability to tolerate nicotine withdrawal symptoms, particularly negative affect states, in remaining abstinent from smoking. Distress tolerance and implicit associations are two individual constructs that may influence the strength of this relationship. In this pilot study the authors examined implicit associations related to avoidance and negative affect using a modified Implicit Association Test (IAT), a measure designed to examine implicit associations related to negative affect and avoidance, and the relationship of these associations to distress tolerance and smoking relapse. In total, 40 participants were recruited through community flyers as part of a larger smoking cessation study. Participants completed a brief smoking history, behavioral distress tolerance assessments, and the modified IAT. Smoking status was assessed via phone 3days and 6days post-quit date. Results from a Cox proportional hazard model revealed that implicit associations between avoidance and negative affect were significantly negatively correlated with time to relapse after a smoking cessation attempt, whereas the behavioral distress tolerance assessments did not predict time to relapse. This study provides novel information about the cognitive associations that may underlie avoidant behavior in smokers, and may be important for understanding smoking relapse when negative affect states are particularly difficult to tolerate. Authors discuss the importance of implicit associations in understanding smoking relapse and how they can be targeted in treatment. © 2013.

Predictors of 12-Months Relapse After Withdrawal Treatment in Hospitalized Patients With Chronic Migraine Associated With Medication Overuse: A Longitudinal Observational Study.

PubMed

Raggi, Alberto; Giovannetti, Ambra M; Leonardi, Matilde; Sansone, Emanuela; Schiavolin, Silvia; Curone, Marcella; Grazzi, Licia; Usai, Susanna; D'Amico, Domenico

2017-01-01

Studies addressing relapse rates conflate relapse into chronic migraine (CM) and medication overuse (MO), and the consequent need to repeat withdrawal. We aim to identify 12-months predictors of relapse into CM (based on headaches frequency) separately from occurrence of another structured withdrawal. Hospitalized patients with CM-MO under withdrawal were enrolled. Candidate predictors included demographic, disability, quality of life, depression scores, general self-efficacy, social support, headaches frequency and intensity, class of overused medications, history of withdrawal treatment in the three years prior to enrollment, attendance to emergency room (ER) between enrollment and follow-up, nonattendance to outpatient neurological examinations. Logistic regressions was used to address the significant predictors for the two outcomes. Complete data were available for 177 patients: 60 (33.9%) relapsed into CM, 38 (21.5%) underwent another withdrawal treatment. Recent history of withdrawal treatments, ER admission after discharge and high baseline BDI-II scores were significant predictors in both models. In addition to this, high baseline headache frequency predicted relapse into another withdrawal treatment. Predictors or relapse into CM and of occurrence of another withdrawal by 12-months are somehow similar. It is important to assess presence of recent previous withdrawal treatments and to plan regular follow-up afterwards, in particular for patients with high headache frequency and relevant mood disturbances: in this way, it will be more likely that situations requiring further structured withdrawal treatments can be identified before patients have to refer to ER. © 2016 American Headache Society.

Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis.

PubMed

Kalinina Ayuso, Viera; van de Winkel, Evelyne Leonce; Rothova, Aniki; de Boer, Joke Helena

2011-02-01

To evaluate the efficacy of methotrexate (MTX) and the effect of its withdrawal on relapse rate of uveitis associated with juvenile idiopathic arthritis (JIA). Retrospective case series. Data of 22 pediatric JIA patients who were being treated with MTX for active uveitis were studied retrospectively. Relapse rate after the withdrawal of MTX was established. Anterior chamber (AC) inflammation, topical steroid use during the first year of MTX treatment, and associations of relapses after the withdrawal were evaluated statistically. Duration of MTX treatment and its withdrawal was determined individually in collaboration with a rheumatologist with an intention to continue the treatment for at least 1 year and to withdraw in case of inactivity of uveitis and arthritis. Inactivity of uveitis was defined as the presence of ≤0.5+ cells in the AC. Eighteen patients (18/22; 82%) showed improvement of their uveitis with a significant decrease in activity of AC inflammation after a minimal period of 3 months of MTX treatment. A topical steroid-sparing effect was observed when MTX was administered for a period of 3 to 9 months. MTX was discontinued because of inactive uveitis in 13 patients. In 9 patients (8/13; 69%) a relapse of uveitis was observed after a mean time of 7.5 months (± SD 7.3). Six patients (6/13; 46%) had a relapse within the first year after the withdrawal. Relapse-free survival after withdrawal of MTX was significantly longer in patients who had been treated with MTX for more than 3 years (P = .009), children who were older than 8 years at the moment of withdrawal (P = .003), and patients who had an inactivity of uveitis of longer than 2 years before withdrawal of MTX (P = .033). Longer inactivity under MTX therapy was independently protective for relapses after the withdrawal (hazard ratio = 0.07; 95% confidence interval 0.01-0.86; P = .038), which means that 1-year increase of duration of inactive uveitis before the withdrawal of MTX results in a decrease of hazard for new relapse of 93%. A high number of patients with inactive uveitis relapse quickly after the withdrawal of MTX. Our results suggest that a longer period of inactivity prior to withdrawal and a longer treatment period with MTX reduce the chance of relapse after withdrawal. Copyright © 2011 Elsevier Inc. All rights reserved.

Correlates of motivation to change in pathological gamblers completing cognitive-behavioral group therapy.

PubMed

Gómez-Peña, Mónica; Penelo, Eva; Granero, Roser; Fernández-Aranda, Fernando; Alvarez-Moya, Eva; Santamaría, Juan José; Moragas, Laura; Neus Aymamí, Maria; Gunnard, Katarina; Menchón, José M; Jimenez-Murcia, Susana

2012-07-01

The present study analyzes the association between the motivation to change and the cognitive-behavioral group intervention, in terms of dropouts and relapses, in a sample of male pathological gamblers. The specific objectives were as follows: (a) to estimate the predictive value of baseline University of Rhode Island Change Assessment scale (URICA) scores (i.e., at the start of the study) as regards the risk of relapse and dropout during treatment and (b) to assess the incremental predictive ability of URICA scores, as regards the mean change produced in the clinical status of patients between the start and finish of treatment. The relationship between the URICA and the response to treatment was analyzed by means of a pre-post design applied to a sample of 191 patients who were consecutively receiving cognitive-behavioral group therapy. The statistical analysis included logistic regression models and hierarchical multiple linear regression models. The discriminative ability of the models including the four URICA scores regarding the likelihood of relapse and dropout was acceptable (area under the receiver operating haracteristic curve: .73 and .71, respectively). No significant predictive ability was found as regards the differences between baseline and posttreatment scores (changes in R(2) below 5% in the multiple regression models). The availability of useful measures of motivation to change would enable treatment outcomes to be optimized through the application of specific therapeutic interventions. © 2012 Wiley Periodicals, Inc.

Evaluation of expressed emotion in schizophrenia: a comparison of Caucasians and Mexican-Americans.

PubMed

Kopelowicz, Alex; Zarate, Roberto; Gonzalez, Veronica; Lopez, Steven R; Ortega, Paula; Obregon, Nora; Mintz, Jim

2002-05-01

Social desirability, while a recognized source of respondent bias among Mexican-Americans, has not been evaluated as an explanation for the lower rate of high expressed emotion (EE) found in the family members of Mexican-Americans versus Caucasians with schizophrenia. In this study, we tested the hypothesis that the lower rate of high EE (hostility and criticism) among Mexican-Americans was the result of cultural factors impacting on how information was reported by the Mexican-American relative of a patient with schizophrenia. We compared the ratings of EE between Caucasian (N = 17) and Mexican-American (N = 44) patients with schizophrenia or schizoaffective disorder and their key relatives using the level of expressed emotion (LEE) scale (paper and pencil instrument rated by the patient and relative separately) and the Five Minute Speech Sample (observational experimenter rated). The ability of the various measures to predict relapse over two years was also examined. Contrary to our hypothesis, there were no differences between patient and family measures within ethnic group. Mexican-American patients and relatives reported lower rates of high EE than Caucasians across all measures. High EE predicted relapse across measures for Caucasian participants, but did not predict relapse for Mexican-Americans on any of the measurement instruments. We discuss the implications of these findings on cross-cultural research and family interventions for individuals with psychotic disorders.

Optimal use of novel agents in chronic lymphocytic leukemia.

PubMed

Smith, Mitchell R; Weiss, Robert F

2018-05-07

Novel agents are changing therapy for patients with CLL, but their optimal use remains unclear. We model the clinical situation in which CLL responds to therapy, but resistant clones, generally carrying del17p, progress and lead to relapse. Sub-clones of varying growth rates and treatment sensitivity affect predicted therapy outcomes. We explore effects of different approaches to starting novel agent in relation to bendamustine-rituximab induction therapy: at initiation of therapy, at the end of chemo-immunotherapy, at molecular relapse, or at clinical detection of relapse. The outcomes differ depending on the underlying clonal architecture, raising the concept that personalized approaches based on clinical evaluation of each patient's clonal architecture might optimize outcomes while minimizing toxicity and cost. Copyright © 2018 Elsevier Ltd. All rights reserved.

A prognostic mutation panel for predicting cancer recurrence in stages II and III colorectal cancer.

PubMed

Sho, Shonan; Court, Colin M; Winograd, Paul; Russell, Marcia M; Tomlinson, James S

2017-12-01

Approximately 20-40% of stage II/III colorectal cancer (CRC) patients develop relapse. Clinicopathological factors alone are limited in detecting these patients, resulting in potential under/over-treatment. We sought to identify a prognostic tumor mutational profile that could predict CRC recurrence. Whole-exome sequencing data were obtained for 207 patients with stage II/III CRC from The Cancer Genome Atlas. Mutational landscape in relapse-free versus relapsed cohort was compared using Fisher's exact test, followed by multivariate Cox regression to identify genes associated with cancer recurrence. Bootstrap-validation was used to examine internal/external validity. We identified five prognostic genes (APAF1, DIAPH2, NTNG1, USP7, and VAV2), which were combined to form a prognostic mutation panel. Patients with ≥1 mutation(s) within this five-gene panel had worse prognosis (3-yr relapse-free survival [RFS]: 53.0%), compared to patients with no mutation (3-yr RFS: 84.3%). In multivariate analysis, the five-gene panel remained prognostic for cancer recurrence independent of stage and high-risk features (hazard ratio 3.63, 95%CI [1.93-6.83], P < 0.0001). Furthermore, its prognostic accuracy was superior to the American Joint Commission on Cancer classification (concordance-index: 0.70 vs 0.54). Our proposed mutation panel identifies CRC patients at high-risk for recurrence, which may help guide adjuvant therapy and post-operative surveillance protocols. © 2017 Wiley Periodicals, Inc.

Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study.

PubMed

Giovannoni, Gavin; Soelberg Sorensen, Per; Cook, Stuart; Rammohan, Kottil W; Rieckmann, Peter; Comi, Giancarlo; Dangond, Fernando; Hicking, Christine; Vermersch, Patrick

2018-04-01

In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population.

Subacute sclerosing panencephalitis. Changes on CT scan during acute relapse.

PubMed

Modi, G; Campbell, H; Bill, P

1989-01-01

A 19-year-old female patient presented in an acute state of akinetic mutism. Serological analysis of serum and cerebrospinal fluid demonstrated the presence of antibodies to measles virus. CT scan carried out during this acute phase of relapse demonstrated white matter enhancement affecting the cortical white matter of the frontal lobes and corpus callosum. These features indicate that active demyelination occurs during acute relapse in subacute sclerosing panencephalitis (SSPE) and suggest that immunotherapy should be considered during this acute phase.

Changes in Religious Coping and Relapse to Drug Use Among Opioid-Dependent Patients Following Inpatient Detoxification

PubMed Central

Skalski, Linda M.; Meade, Christina S.

2013-01-01

Relapse rates remain high among people with opioid dependence. Identifying psychosocial factors associated with outcomes is important for informing behavioral treatments. This study examined religious coping, opioid use, and 12-step participation among 45 participants receiving inpatient opioid detoxification at baseline and follow-up. At baseline, higher positive coping was related to less frequent opioid use pre-admission (β = −.44, p < .001) and history of 12-step participation (OR = 2.33, p < .05). Decreases in negative coping after discharge predicted less opioid use (β = .55, p < .001), and increases in positive coping predicted more frequent 12-step program participation (β = .42, p < .05). Positive religious coping may be protective, while negative religious coping may be a barrier to treatment. PMID:21125425

Opposite Effects of Basolateral Amygdala Inactivation on Context-Induced Relapse to Cocaine Seeking after Extinction versus Punishment.

PubMed

Pelloux, Yann; Minier-Toribio, Angelica; Hoots, Jennifer K; Bossert, Jennifer M; Shaham, Yavin

2018-01-03

Studies using the renewal procedure showed that basolateral amygdala (BLA) inactivation inhibits context-induced relapse to cocaine-seeking after extinction. Here, we determined whether BLA inactivation would also inhibit context-induced relapse after drug-reinforced responding is suppressed by punishment, an animal model of human relapse after self-imposed abstinence due to adverse consequences of drug use. We also determined the effect of central amygdala (CeA) inactivation on context-induced relapse.We trained rats to self-administer cocaine for 12 d (6 h/d) in Context A and then exposed them to either extinction or punishment training for 8 d in Context B. During punishment, 50% of cocaine-reinforced lever-presses produced an aversive footshock of increasing intensity (0.1-0.5 or 0.7 mA). We then tested the rats for relapse to cocaine seeking in the absence of cocaine or shock in Contexts A and B after BLA or CeA injections of vehicle or GABA agonists (muscimol-baclofen). We then retrained the rats for cocaine self-administration in Context A, repunished or re-extinguished lever pressing in Context B, and retested for relapse after BLA or CeA inactivation.BLA or CeA inactivation decreased context-induced relapse in Context A after extinction in Context B. BLA, but not CeA, inactivation increased context-induced relapse in Context A after punishment in Context B. BLA or CeA inactivation provoked relapse in Context B after punishment but not extinction. Results demonstrate that amygdala's role in relapse depends on the method used to achieve abstinence and highlights the importance of studying relapse under abstinence conditions that more closely mimic the human condition. SIGNIFICANCE STATEMENT Relapse to drug use during abstinence is often provoked by re-exposure to the drug self-administration environment or context. Studies using the established extinction-reinstatement rodent model of drug relapse have shown that inactivation of the basolateral amygdala inhibits context-induced drug relapse after extinction of the drug-reinforced responding. Here, we determined whether basolateral amygdala inactivation would also inhibit relapse after drug-reinforced responding is suppressed by punishment, a model of human relapse after self-imposed abstinence. Unexpectedly, we found that basolateral amygdala inactivation had opposite effects on relapse provoked by re-exposure to the drug self-administration environment after extinction versus punishment. Our results demonstrate that depending on the historical conditions that lead to abstinence, amygdala activity can either promote or inhibit relapse. Copyright © 2018 the authors 0270-6474/18/380051-09$15.00/0.

[Latest advances in chronic pancreatitis].

PubMed

Domínguez-Muñoz, J Enrique

2014-09-01

This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the prediction of the fibrosis degree of the gland, the evaluation of patients with asymptomatic hyperenzimemia, the medical and surgical treatment of abdominal pain and the knowledge of the natural history of the autoimmune pancreatitis. In patients with indetermined EUS findings of chronic pancreatitis, a new endoscopic ultrasound examination in the follow-up is of help to confirm or to exclude the disease. Smoking, number of relapses, results of pancreatic function tests and EUS findings allow predicting the degree of pancreatic fibrosis in patients with chronic pancreatitis. Antioxidant therapy has shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Development of intestinal bacterial overgrowth is frequent in patients with chronic pancreatitis, but its impact on symptoms is unknown and deserves further investigations. Finally, autoimmune pancreatitis relapses in about half of the patients with either type 1 or type 2 disease; relapses frequently occur within the first two years of follow-up. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

PubMed

Laubach, J; Garderet, L; Mahindra, A; Gahrton, G; Caers, J; Sezer, O; Voorhees, P; Leleu, X; Johnsen, H E; Streetly, M; Jurczyszyn, A; Ludwig, H; Mellqvist, U-H; Chng, W-J; Pilarski, L; Einsele, H; Hou, J; Turesson, I; Zamagni, E; Chim, C S; Mazumder, A; Westin, J; Lu, J; Reiman, T; Kristinsson, S; Joshua, D; Roussel, M; O'Gorman, P; Terpos, E; McCarthy, P; Dimopoulos, M; Moreau, P; Orlowski, R Z; Miguel, J S; Anderson, K C; Palumbo, A; Kumar, S; Rajkumar, V; Durie, B; Richardson, P G

2016-05-01

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

[Relapse: causes and consequences].

PubMed

Thomas, P

2013-09-01

Relapse after a first episode of schizophrenia is the recurrence of acute symptoms after a period of partial or complete remission. Due to its variable aspects, there is no operational definition of relapse able to modelise the outcome of schizophrenia and measure how the treatment modifies the disease. Follow-up studies based on proxys such as hospital admission revealed that 7 of 10 patients relapsed after a first episode of schizophrenia. The effectiveness of antipsychotic medications on relapse prevention has been widely demonstrated. Recent studies claim for the advantages of atypical over first generation antipsychotic medication. Non-adherence to antipsychotic represents with addictions the main causes of relapse long before some non-consensual factors such as premorbid functioning, duration of untreated psychosis and associated personality disorders. The consequences of relapse are multiple, psychological, biological and social. Pharmaco-clinical studies have demonstrated that the treatment response decreases with each relapse. Relapse, even the first one, will contribute to worsen the outcome of the disease and reduce the capacity in general functionning. Accepting the idea of continuing treatment is a complex decision in which the psychiatrist plays a central role besides patients and their families. The development of integrated actions on modifiable risk factors such as psychosocial support, addictive comorbidities, access to care and the therapeutic alliance should be promoted. Relapse prevention is a major goal of the treatment of first-episode schizophrenia. It is based on adherence to the maintenance treatment, identification of prodromes, family active information and patient therapeutical education. Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.

Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy.

PubMed

Lun, Y; Yang, J-J; Wu, Y

2017-12-01

The mixed lineage leukaemia (MLL) gene translocations are found in approximately 10% of adults with acute myeloid leukaemia (AML) and are markers of poor prognosis. As the best reported response in relapsed and refractory MLL-rearranged AML is around 40%, reinduction treatment is very challenging for those patients. We report a case of relapsed and refractory AML with MLL-AF9, who did not respond to FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) regimen reinduction treatment, but achieved complete response and molecular remission after chidamide-based chemotherapy. Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor that is clinically active in relapsed and refractory peripheral T-cell lymphomas. To the best of our knowledge, successful reinduction treatment on relapsed MLL-AF9 by chidamide-based regimen has not been previously reported. © 2017 John Wiley & Sons Ltd.

Brain structural, neurochemical and neuroinflammatory markers of psychosis onset and relapse: Is there evidence for a psychosis relapse signature?

PubMed

Cropley, Vanessa; Wood, Stephen J; Pantelis, Christos

2013-05-10

Schizophrenia is a debilitating illness that is often associated with progressive clinical deterioration following repeated episodes of illness. Despite the clinical evidence for clinical attrition, the nature of any associated neurobiological pathology has not been examined systematically. This review examines the neurobiological imaging markers associated with psychosis onset and relapse and considers whether these may be potential state markers of acute psychosis. We report several markers of neurobiological changes associated with acute psychosis. These include dynamic changes in brain structure in the frontal and temporal regions, neurochemical alterations in dopamine and glutamate and evidence for neuroinflammation through microglial activation. We propose that with the use of repeat longitudinal assessments of brain imaging markers over the course of a psychosis relapse, the neurobiological trajectory indicative of a 'relapse signature' for psychosis will be identified.

The Anterior Insular Cortex→Central Amygdala Glutamatergic Pathway Is Critical to Relapse after Contingency Management.

PubMed

Venniro, Marco; Caprioli, Daniele; Zhang, Michelle; Whitaker, Leslie R; Zhang, Shiliang; Warren, Brandon L; Cifani, Carlo; Marchant, Nathan J; Yizhar, Ofer; Bossert, Jennifer M; Chiamulera, Cristiano; Morales, Marisela; Shaham, Yavin

2017-10-11

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist. Here we used a novel rat model, in which the availability of a mutually exclusive palatable food maintains prolonged voluntary abstinence from intravenous methamphetamine self-administration, to demonstrate that the activation of monosynaptic glutamatergic projections from anterior insular cortex to central amygdala is critical to relapse after the cessation of contingency management. We identified the anterior insular cortex-to-central amygdala projection as a new addiction- and motivation-related projection and a potential target for relapse prevention. Published by Elsevier Inc.

A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic non-seminomatous germ cell tumor

PubMed Central

Ravi, P.; Gray, K. P.; O'Donnell, E. K.; Sweeney, C. J.

2014-01-01

Background Approximately a quarter of men with metastatic non-seminomatous germ cell tumor (NSGCT) have a residual mass, typically in the retroperitoneum, after chemotherapy. The management of small residual masses (≤1 cm) is controversial, with good outcomes seen with either post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) or surveillance. We sought to review our experience of surveillance and synthesize the cumulative findings with the current literature in the form of a meta-analysis. Patients and methods We searched PubMed, EMBASE and abstracts from ASCO and AUA to identify relevant, English-language studies for the meta-analysis. The DFCI (Dana Farber Cancer Institute) database was constructed from a database of men undergoing cisplatin-based chemotherapy for metastatic NSGCT. The outcomes of interest were the proportion with necrosis, teratoma or active cancer on histology at PC-RPLND (literature) and the total number of relapses, RP-only relapses and overall survival in men undergoing surveillance (literature and DFCI cohort). Results Three of 47 men undergoing post-chemotherapy surveillance at our institution relapsed over a median follow-up of 5.4 years. All three were alive at a median of 4.2 years after relapse. On meta-analysis, the pooled estimates of necrosis, teratoma and active cancer in the 588 men who underwent PC-RPLND were 71, 24 and 4%, respectively. Of the combined 455 men who underwent surveillance, the pooled estimate of the relapse rate was 5%, with an RP-only relapse rate of 3%. Of the 15 men who suffered an RP-only relapse on surveillance, two died of disease. Conclusion Surveillance is a reasonable strategy for men with minimal residual RP disease after chemotherapy and avoids an RPLND in ∼97% of men who are cured with chemotherapy alone. PMID:24276027

Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.

PubMed

Ford, Alexander C; Khan, Khurram J; Sandborn, William J; Kane, Sunanda V; Moayyedi, Paul

2011-12-01

Maintenance therapy with 5-aminosalicylates (5-ASAs) is recommended in patients with quiescent ulcerative colitis (UC), but compliance rates are low. Once-daily dosing may improve adherence, but impact on the relapse of disease activity is unclear as no previous meta-analysis has studied this issue. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through April 2011). Eligible randomized controlled trials (RCTs) recruited adults with quiescent UC, and compared once-daily dosing of 5-ASAs with a more frequent dosing schedule of an identical total daily dose of the same 5-ASA drug. Minimum treatment duration was 6 months. Trials reported a dichotomous assessment of relapse of disease activity at last point of follow-up. Data concerning non-compliance and adverse events were extracted, where reported. Effect of once-daily vs. more frequent dosing schedule was reported as relative risk (RR) of relapse with a 95% confidence interval (CI). The search identified 3,061 citations, and seven RCTs containing 2,745 patients were eligible. All RCTs used mesalamine. Relapse rates were not significantly different between once-daily and conventional dosing schedules for mesalamine (RR of relapse=0.94; 95% CI: 0.82-1.08). Non-compliance (RR=0.87; 95% CI: 0.46-1.66) and adverse events were no more likely with once-daily dosing (RR=1.08; 95% CI: 0.97-1.20). Once-daily dosing with mesalamine is as effective as conventional dosing schedules for the prevention of relapse of quiescent UC, although there is no definitive evidence that compliance with once-daily dosing is better. Adverse events occur at a similar frequency.

Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients.

PubMed

Wesołowska-Andersen, A; Borst, L; Dalgaard, M D; Yadav, R; Rasmussen, K K; Wehner, P S; Rasmussen, M; Ørntoft, T F; Nordentoft, I; Koehler, R; Bartram, C R; Schrappe, M; Sicheritz-Ponten, T; Gautier, L; Marquart, H; Madsen, H O; Brunak, S; Stanulla, M; Gupta, R; Schmiegelow, K

2015-02-01

Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.

The interplay of history of depression and craving in terms of smoking relapse among treatment seeking smokers.

PubMed

Rodríguez-Cano, Rubén; Paulus, Daniel J; López-Durán, Ana; Martínez-Vispo, Carmela; Fernández Del Río, Elena; Becoña, Elisardo; Zvolensky, Michael J

2017-01-01

Although there is an interconnection between history of major depressive disorder and smoking, there has been relatively limited scientific attention oriented on the interplay between history of major depressive disorder and smoking maintenance processes. The current study sought to address whether history of major depressive disorder and post-cessation craving interact in the prediction of relapse among treatment-seeking smokers. Separate models were evaluated as a function of sex. Participants (n = 319, Mage = 41.7, 62.1% female) were treatment-seeking smokers who were abstinent at the end of six weekly 1-hour sessions involving psychosocial treatment for cessation. Participants completed a baseline assessment and reported post-cessation craving. Smoking status was assessed at 1-, 2-, 3-, 6-, and 12-month follow-up after the end of treatment. There was a significant interactive effect evident for females (B = 0.05, OR = 1.05, p = 0.013), but not males. The form of the interaction indicated females with history of major depressive disorder and greater post-treatment craving evinced the highest rate of relapse. Findings suggest that history of major depressive disorder and post-treatment craving are related to increased risk of relapse for female, but not male, smokers. Sex differences play a fundamental role in the explanation of the interaction of history of major depressive disorder and craving post-treatment in smoking relapse. Considering sex differences related to smoking relapse may help to tailor smoking cessation treatments.

The entanglement between relapse and posttreatment criminal justice involvement.

PubMed

Kopak, Albert M; Haugh, Stephanie; Hoffmann, Norman G

2016-09-01

Research has established a connection between substance use and criminal activity, but much less is known about the association between posttreatment relapse and related contact with the criminal justice system. The current study was designed to elucidate this relationship by examining the long-term effects of relapse on arrest. The study also investigated the probability of relapse into substance use as it followed an arrest. Data from 5,822 adults who participated in the Comprehensive Assessment and Treatment Outcome Research (CATOR) system were analyzed. This prospective longitudinal research design included 0-6, 6-12, 12-18, and 18-24 month follow-up data. A series of logistic regression analyses indicated that relapse was associated with posttreatment arrest within the observed follow-up period, but did not significantly influence the likelihood of arrest in future follow-up periods. In comparison, posttreatment arrest in the 6-12 month follow-up period had lasting effects for relapse to substance use in the 12-18 and 18-24 month periods. Arrest in the 0-6 month posttreatment period was also associated with increased risk for relapse in the 18-24 month period. Given the evidence that demonstrated within follow-up period associations between relapse and arrest, relapse prevention is critical to preventing contact with the criminal justice system. In addition, the lasting impact of an arrest must be mitigated to maintain posttreatment recovery from substance use for adults who come into contact with the criminal justice system.

A Behavioral Economic Reward Index Predicts Drinking Resolutions: Moderation Re-visited and Compared with Other Outcomes

PubMed Central

Tucker, Jalie A.; Roth, David L.; Vignolo, Mary J.; Westfall, Andrew O.

2014-01-01

Data were pooled from three studies of recently resolved community-dwelling problem drinkers to determine whether a behavioral economic index of the value of rewards available over different time horizons distinguished among moderation (n = 30), abstinent (n = 95), and unresolved (n = 77) outcomes. Moderation over 1-2 year prospective follow-up intervals was hypothesized to involve longer term behavior regulation processes compared to abstinence or relapse and to be predicted by more balanced pre-resolution monetary allocations between short- and longer-term objectives (i.e., drinking and saving for the future). Standardized odds ratios (OR) based on changes in standard deviation units from a multinomial logistic regression indicated that increases on this “Alcohol-Savings Discretionary Expenditure” index predicted higher rates of both abstinence (OR = 1.93, p = .004) and relapse (OR = 2.89, p < .0001) compared to moderation outcomes. The index had incremental utility in predicting moderation in complex models that included other established predictors. The study adds to evidence supporting a behavioral economic analysis of drinking resolutions and shows that a systematic analysis of pre-resolution spending patterns aids in predicting moderation. PMID:19309182

Implicit but not explicit self-esteem predicts future depressive symptomatology.

PubMed

Franck, Erik; De Raedt, Rudi; De Houwer, Jan

2007-10-01

To date, research on the predictive validity of implicit self-esteem for depressive relapse is very sparse. In the present study, we assessed implicit self-esteem using the Name Letter Preference Task and explicit self-esteem using the Rosenberg self-esteem scale in a group of currently depressed patients, formerly depressed individuals, and never depressed controls. In addition, we examined the predictive validity of explicit, implicit, and the interaction of explicit and implicit self-esteem in predicting future symptoms of depression in formerly depressed individuals and never depressed controls. The results showed that currently depressed individuals reported a lower explicit self-esteem as compared to formerly depressed individuals and never depressed controls. In line with previous research, all groups showed a positive implicit self-esteem not different from each other. Furthermore, after controlling for initial depressive symptomatology, implicit but not explicit self-esteem significantly predicted depressive symptoms at six months follow-up. Although implicit self-esteem assessed with the Name Letter Preference Test was not different between formerly depressed individuals and never depressed controls, the findings suggest it is an interesting variable in the study of vulnerability for depression relapse.

Vaccines and the association with relapses in patients with neuromyelitis optica spectrum disorder.

PubMed

Mealy, Maureen A; Cook, Lawrence J; Pache, Florence; Velez, Diego L; Borisow, Nadja; Becker, Daniel; Arango, Jorge A Jimenez; Paul, Friedemann; Levy, Michael

2018-05-07

It is unknown if vaccines cause non-specific immune activation in patients with neuromyelitis optica spectrum disorder and no consensus on the use of vaccines exists for this population. We investigated the temporal association of vaccinations with relapses in patients with neuromyelitis optica spectrum disorder. This is a multi-center retrospective analysis of patients with neuromyelitis optica spectrum disorder for whom immunization history and clinical records from disease onset were available. Ninety patients who met 2015 diagnostic criteria received a total of 211 vaccinations and experienced 340 relapses over a median disease course of 6.6 years. The likelihood of a relapse occurring within 30, 60, and 90 days of a vaccine was compared to the likelihood of a relapse occurring within each time point of a randomly generated date. We also compared the relapse rate between patients who received any vaccination(s) after disease onset to those who did not. We identified seven patients with neuromyelitis optica spectrum disorder who relapsed within 30 days of a vaccination, six between 31 and 60 days, and four who relapsed between 61 and 90 days. The rate of vaccine-associated relapses within 30, 60, and 90 days was significantly higher than the likelihood of a relapse spontaneously occurring within each of the given time frames (p = 0.034, 0.01, 0.016, respectively) among patients who were not on preventive immunotherapy only. Among those who were on immunotherapy to prevent relapses, there was no significant association of relapse with vaccines. Additionally, among patients on immunotherapy, the annualized relapse rate of those who received routine vaccinations was significantly lower than in unvaccinated patients. The evidence suggests that there may be a risk of vaccination-associated relapses among untreated neuromyelitis optica spectrum disorder patients, however immunosuppressive therapy at time of vaccine may abort the risk; this suggests that the patients who are treated with preventive immune suppression and receive routine vaccinations for common infections may fare better. Further prospective studies are necessary to verify these findings. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of comorbid psychiatric disorders on the outcome of substance abusers: a six year prospective follow-up in two Norwegian counties

PubMed Central

Landheim, Anne Signe; Bakken, Kjell; Vaglum, Per

2006-01-01

Background Most help-seeking substance abusers have comorbid psychiatric disorders. The importance of such disorders for the long-term course of substance abuse is, however, still unclear. The aim of this paper is to describe six-year outcomes regarding death and relapse among alcoholics and poly-substance abusers and to analyse the predictive value of lifetime psychiatric disorders on relapse. Methods A consecutive sample of substance-dependent patients who received treatment in two counties in Norway (n = 287) was followed up after approximately six years. Information on socio-demographics, Axis I (CIDI) and II disorders (MCMI-II) and mental distress (HSCL-25) was gathered at baseline. At follow-up, detailed information regarding socio-demographics, use of substances (AUDIT and DUDIT) and mental distress (HSCL-25) was recorded (response rate: 63%). Results At six-year follow-up, 11% had died, most often male alcoholics (18%). Among the surviving patients, 70% had drug or alcohol related problems the year prior to follow-up. These patients were, classified as "relapsers". There were no significant differences in the relapse rate between women and men and among poly-substance abusers and alcoholics. The relapsers had an earlier onset of a substance use disorder, and more frequently major depression and agoraphobia. Multivariate analysis indicated that both psychiatric disorders (major depression) and substance use factors (early onset of a substance use disorder) were independent predictors of relapse. Conclusion For reducing the risk of long-term relapse, assessment and treatment of major depression (and agoraphobia) are important. In addition, we are in need of a comprehensive treatment and rehabilitation program that also focuses on the addictive behaviour. PMID:17054775

Orbitofrontal structural markers of negative affect in alcohol dependence and their associations with heavy relapse-risk at 6 months post-treatment.

PubMed

Zois, E; Vollstädt-Klein, S; Hoffmann, S; Reinhard, I; Charlet, K; Beck, A; Jorde, A; Kirsch, M; Walter, H; Heinz, A; Kiefer, F

2017-10-01

Alcohol relapse is often occurring to regulate negative affect during withdrawal. On the neurobiological level, alcoholism is associated with gray matter (GM) abnormalities in regions that regulate emotional experience such as the orbitofrontal cortex (OFC). However, no study to our knowledge has investigated the neurobiological unpinning of affect in alcoholism at early withdrawal and the associations of OFC volume with long-term relapse risk. One hundred and eighty-two participants were included, 95 recently detoxified alcohol dependent patients (ADP) and 87 healthy controls (HC). We measured affective states using the positive and negative affect schedule (PANAS). We collected T1-weighted brain structural images and performed Voxel-based morphometry (VBM). Findings revealed GM volume decrease in alcoholics in the prefrontal cortex (including medial OFC), anterior cingulate gyrus, and insula. GM volume in the medial OFC was positively associated with NA in the ADP group. Cox regression analysis predicted that risk to heavy relapse at 6 months increases with decreased GM volume in the medial OFC. Negative affect during alcohol withdrawal was positively associated with OFC volume. What is more, increased GM volume in the OFC also moderated risk to heavy relapse at 6 months. Reduced GM in the OFC poses as risk to recovery from alcohol dependence and provides valuable insights into transient negative affect states during withdrawal that can trigger relapse. Implications exist for therapeutic interventions signifying the OFC as a neurobiological marker to relapse and could explain the inability of ADP to regulate internal negative affective states. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence

PubMed Central

Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

2016-01-01

ABSTRACT Background: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. Case presentation: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Discussion: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. Conclusion: In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration. PMID:27105248

Bridging the gap: using microsociological theory to understand how expressed emotion predicts clinical outcomes.

PubMed

Stanhope, Victoria; Solomon, Phyllis

2007-06-01

Research has shown that expressed emotion (EE) among families is a strong predictor of relapse for people with severe mental illness. Recent studies have also found the presence of EE in consumer-provider relationships. Despite high consistency in the findings related to EE and relapse, the concept has weak validity as little is known about how exactly it triggers relapse. Microsociological theory provides a framework with which to analyze social interaction and, more specifically, understand how interactions relate to the emotions of pride and shame. By identifying the components of interaction rituals, the theory provides insight into the key processes underlying EE and demonstrates how methodologies based on direct observation have the potential to measure EE with greater validity. This article describes how microsociological theory can be applied to the concept of EE.

Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans

PubMed Central

Moberg, Christine A.; Bradford, Daniel E.; Kaye, Jesse T.; Curtin, John J.

2017-01-01

Stress plays a key role in addiction etiology and relapse. Rodent models posit that following repeated periods of alcohol and other drug intoxication, compensatory allostatic changes occur in the central nervous system (CNS) circuits involved in behavioral and emotional response to stressors. We examine a predicted manifestation of this neuroadaptation in recently abstinent alcohol dependent humans. Participants completed a translational laboratory task that uses startle potentiation to unpredictable (vs. predictable) stressors implicated in the putative CNS mechanisms that mediate this neuroadaptation. Alcohol dependent participants displayed significantly greater startle potentiation to unpredictable than predictable stressors relative to non-alcoholic controls. The size of this effect covaried with alcohol-related problems and degree of withdrawal syndrome. This supports the rodent model thesis of a sensitized stress response in abstinent alcoholics. However, this effect could also represent pre-morbid risk or mark more severe and/or comorbid psychopathology. Regardless, pharmacotherapy and psychological interventions may target unpredictable stressor response to reduce stress-induced relapse. PMID:28394145

Lorenz system in the thermodynamic modelling of leukaemia malignancy.

PubMed

Alexeev, Igor

2017-05-01

The core idea of the proposed thermodynamic modelling of malignancy in leukaemia is entropy arising within normal haematopoiesis. Mathematically its description is supposed to be similar to the Lorenz system of ordinary differential equations for simplified processes of heat flow in fluids. The hypothetical model provides a description of remission and relapse in leukaemia as two hierarchical and qualitatively different states of normal haematopoiesis with their own phase spaces. Phase space transition is possible through pitchfork bifurcation, which is considered the common symmetrical scenario for relapse, induced remission and the spontaneous remission of leukaemia. Cytopenia is regarded as an adaptive reaction of haematopoiesis to an increase in entropy caused by leukaemia clones. The following predictions are formulated: a) the percentage of leukaemia cells in marrow as a criterion of remission or relapse is not necessarily constant but is a variable value; b) the probability of remission depends upon normal haematopoiesis reaching bifurcation; c) the duration of remission depends upon the eradication of leukaemia cells through induction or consolidation therapies; d) excessively high doses of chemotherapy in consolidation may induce relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced pain perception prior to smoking cessation is associated with early relapse.

PubMed

Nakajima, Motohiro; al'Absi, Mustafa

2011-09-01

Accumulated evidence suggests that nicotine induces analgesia, and endogenous pain regulatory mechanisms may be altered by chronic smoking. The extent to which individual differences in pain perception are related to smokers' ability to abstain from smoking has not been directly examined. Seventy-one smokers who were interested in quitting completed a pre-cessation laboratory session which included the cold pressor test (CPT). Pain ratings were collected during and after CPT. Also, mood changes, cardiovascular measures, and salivary cortisol samples were evaluated prior to, during, and after CPT. Participants attended 4 weekly follow-up assessment sessions after their quit day. Cox regression analysis revealed that higher pain ratings during and after CPT predicted greater risk for smoking relapse. These results remained significant after affective and physiological responses to CPT were controlled, suggesting that pain ratings prior to smoking cessation are potentially useful in identifying smokers who are at greater risk of early smoking relapse and may reflect underlying putative risk for nicotine dependence and relapse. Copyright © 2011 Elsevier B.V. All rights reserved.

A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data.

PubMed

Spelman, Tim; Gray, Orla; Lucas, Robyn; Butzkueven, Helmut

2015-12-09

This report describes a novel Stata-based application of trigonometric regression modelling to 55 years of multiple sclerosis relapse data from 46 clinical centers across 20 countries located in both hemispheres. Central to the success of this method was the strategic use of plot analysis to guide and corroborate the statistical regression modelling. Initial plot analysis was necessary for establishing realistic hypotheses regarding the presence and structural form of seasonal and latitudinal influences on relapse probability and then testing the performance of the resultant models. Trigonometric regression was then necessary to quantify these relationships, adjust for important confounders and provide a measure of certainty as to how plausible these associations were. Synchronization of graphing techniques with regression modelling permitted a systematic refinement of models until best-fit convergence was achieved, enabling novel inferences to be made regarding the independent influence of both season and latitude in predicting relapse onset timing in MS. These methods have the potential for application across other complex disease and epidemiological phenomena suspected or known to vary systematically with season and/or geographic location.

Expression of FAS-L Differs from Primary to Relapsed Low-grade Gliomas and Predicts Progression-free Survival.

PubMed

Werner, Jan-Michael; Kuhl, Saskia; Stavrinou, Pantelis; Röhn, Gabriele; Krischek, Boris; Blau, Tobias; Goldbrunner, Roland; Timmer, Marco

2017-12-01

The tumor necrosis factor FAS is overexpressed in high-grade gliomas (HGG). Only little is known about FAS or FAS ligand (FAS-L) in low-grade gliomas (LGG). We explored FAS/FAS-L expression in LGG, focusing on differences in primary and relapsed LGG and on its prognostic value. A total of 133 glioma samples (73 LGG, 60 HGG) were collected. The LGG samples included 15 matched pairs of primary and relapsed tumors. RT-PCR was performed to measure FAS/FAS-L expression, using subunit A, flavoprotein variant (SDHA) as housekeeper. Clinical data included progression free- (PFS) and overall survival (OS). LGG showed significantly lower FAS but higher FAS-L expression than HGG. The FAS-L expression was higher in primary compared to relapsed LGG and had a positive prognostic value concerning PFS (median 45.20 vs. 31.37 months). FAS-L could act as a prognostic marker and potential target in primary LGG. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations.

PubMed

Wu, Chenglin; de Miranda, Noel Fcc; Chen, Longyun; Wasik, Agata M; Mansouri, Larry; Jurczak, Wojciech; Galazka, Krystyna; Dlugosz-Danecka, Monika; Machaczka, Maciej; Zhang, Huilai; Peng, Roujun; Morin, Ryan D; Rosenquist, Richard; Sander, Birgitta; Pan-Hammarström, Qiang

2016-06-21

The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.

[Prodromal symptoms in schizophrenic relapse: A descriptive and comparative study].

PubMed

Bouhlel, S; Jones, Y; Khelifa, E; Msolly, M; Melki, W; El-Hechmi, Z

2012-10-01

Schizophrenia is a severe, chronic psychiatric disorder. After recovery from a first psychotic episode, 70% of patients have exacerbations. These exacerbations are preceded in 66 to 100% of cases by early signs. Prevention of relapses is the main object of dealing with schizophrenia. In fact, after a psychotic relapse, 17% of patients develop residual symptoms which did not exist before the relapse. Moreover, symptoms resistant to antipsychotics appear in 35% of patients after a relapse. Each relapse increases the risk of future relapses. Finally, the cost of treating patients with relapses is four times higher than in patients without relapses. Prevention of relapses is possible if we detect early signs. In fact, when specific interventions are applied in time, relapses can be avoided. Surprisingly, there is a scarcity of data on prodromal symptoms of schizophrenic relapses in the literature. In this study, we aimed to describe early signs of schizophrenic relapses, which are comparatively more frequent than those in stabilized outpatients. We conducted a retrospective, descriptive and comparative trial. We included 30 patients with schizophrenia who had recently experienced a psychotic relapse and a member of their families. We also included a control group of 30 stabilized outpatients with schizophrenia. All of the patients were diagnosed schizophrenic according to the DSM IV and had no secondary diagnosis. Only patients aged from 18 to 55 years and having an illness with an episodic evolution were included. The relapse group must have had a period off illness of more than one year and duration of the last remission greater than 3 months. We built a structured interview based on the data of the literature on early symptoms of relapses and on our clinical experience. It contained 93 items describing symptoms and feelings relevant to the period of relapse. The interview lasted about 1h. We collected demographic information from both groups. The relapse group was composed of 21 men and nine women. Their average age was 34 years and their level of education was 9.3 years. The mean number of hospitalizations was 3.8 and 73.3% of patients had interrupted their medication. The stabilized outpatients group included 25 men and five women with an average age of 40.3 years. The mean level of education was 8.3 years, the number of hospitalizations was 2.7 and 16.7% of patients had interrupted their medication. The mean time interval between the beginning of symptoms and the need for hospitalization was 160.5 days. The more frequent symptoms in the relapse group than in stabilized patients were: overinvested ideas/delusions (93.3% of relapsing patients), trouble sleeping (80%), symptoms of disorganization (80%), and excitement/mood changes (73.3%). Globally, non-specific symptoms precede specific symptoms (149.4 days vs. 94.8 days). The earlier signs were influence syndrome (113.4 days before relapse), verbal aggressions against others (108.1 days) and suicidal thoughts (94.8 days). The latest signs were physical aggression against others (37.3 days), unmotivated smiles (35.4 days), aggression against self (35 days), strange thoughts (30.7 days) and breaking things (25.3 days). The time between perception of symptoms and hospitalization in schizophrenic patients in this study was very long (approximately 6 months). Non-psychotic prodromal symptoms precede psychotic symptoms. We recommend a major focus on teaching the patient and his/her family how to recognize early signs of decompensation and what steps to take to ensure effective treatment. We also recommend further research to determine the predictive positive value of early signs of relapse. Copyright © 2011 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Cyclophosphamide's addition in relapsed/refractory multiple myeloma patients with biochemical progression during lenalidomide-dexamethasone treatment.

PubMed

Cesini, Laura; Siniscalchi, Agostina; Grammatico, Sara; Andriani, Alessandro; Fiorini, Alessia; De Rosa, Luca; Za, Tommaso; Rago, Angela; Caravita, Tommaso; Petrucci, Maria Teresa

2018-05-02

The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantation.

PubMed

Wu, Xiaojin; Xie, Yiyu; Wang, Chang; Han, Yue; Bao, Xiebing; Ma, Shoubao; Yilmaz, Ahmet; Yang, Bingyu; Ji, Yuhan; Xu, Jinge; Liu, Hong; Chen, Suning; Zhang, Jianying; Yu, Jianhua; Wu, Depei

2018-05-03

There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study. The changes in serum metabolite levels were investigated using a gas chromatography-mass spectrometry-based metabolomics approach and underwent statistical analysis. Significant metabolic changes were observed on day 7. The stearic acid/palmitic acid (SA/PA) ratio was effective in the diagnosis of grade II-IV aGVHD. Multivariate analysis showed that patients with high SA/PA ratios on day 7 after HSCT were less likely to develop II-IV aGVHD than patients with low SA/PA ratios (odds ratio [OR] = 0.06, 95% CI 0.02-0.18, P < 0.001). After the adjustment for clinical characteristics, the SA/PA ratio had no significant effect on overall survival (hazard ratio [HR] = 1.95, 95% CI 0.92-4.14, P = 0.08), and patients in the high SA/PA ratio group were significantly more likely to relapse than those in the low ratio group (HR = 2.26, 95% CI 1.04-4.91, P = 0.04). Our findings suggest that the SA/PA ratio on day 7 after HSCT is an excellent biomarker to predict both aGVHD and relapse. The serum SA/PA ratio measured on day 7 after transplantation may improve risk stratification for aGVHD and relapse after allogeneic stem cell transplantation. National Natural Science Foundation of China (81470346, 81773361), Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Natural Science Foundation (BK20161204), Innovation Capability Development Project of Jiangsu Province (BM2015004), Jiangsu Medical Junior Talent Person award (QNRC2016707), and NIH (AI129582 and NS106170).

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma.

PubMed

Brown, Sarah; Hinsley, Samantha; Ballesteros, Mónica; Bourne, Sue; McGarry, Paul; Sherratt, Debbie; Flanagan, Louise; Gregory, Walter; Cavenagh, Jamie; Owen, Roger; Williams, Cathy; Kaiser, Martin; Low, Eric; Yong, Kwee

2016-01-01

Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. The trial is registered under ISRCTN17354232, December 2012.

T-category remains an important prognostic factor for oropharyngeal carcinoma in the era of human papillomavirus.

PubMed

Mackenzie, P; Pryor, D; Burmeister, E; Foote, M; Panizza, B; Burmeister, B; Porceddu, S

2014-10-01

To determine prognostic factors for locoregional relapse (LRR), distant relapse and all-cause death in a contemporary cohort of locoregionally advanced oropharyngeal squamous cell carcinoma (OSCC) treated with definitive chemoradiotherapy or radiotherapy alone. OSCC patients treated with definitive radiotherapy between 2005 and 2010 were identified from a prospective head and neck database. Patient age, gender, smoking history, human papillomavirus (HPV) status, T- and N-category, lowest involved nodal level and gross tumour volume of the primary (GTV-p) and nodal (GTV-n) disease were analysed in relation to LRR, distant relapse and death by way of univariate and multivariate analysis. In total, 130 patients were identified, 88 HPV positive, with a median follow-up of 42 months. On multivariate analysis HPV status was a significant predictor of LRR (hazard ratio 0.15; 95% confidence interval 0.05-0.51) and death (hazard ratio 0.29; 95% confidence interval 0.14-0.59) but not distant relapse (hazard ratio 0.53, 95% confidence interval 0.22-1.27). Increasing T-category was associated with a higher risk of LRR (hazard ratio 1.80 for T3/4 versus T1/2; 95% confidence interval 1.08-2.99), death (hazard ratio 1.37, 95% confidence interval 1.06-1.77) and distant relapse (hazard ratio 1.35; 95% confidence interval 1.00-1.83). Increasing GTV-p was associated with increased risk of distant relapse and death. N3 disease and low neck nodes were significant for LRR, distant relapse and death on univariate analysis only. Tumour HPV status was the strongest predictor of LRR and death. T-category is more predictive of distant relapse and may provide additional prognostic value for LRR and death when accounting for HPV status. Copyright © 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Targeted intervention: Computational approaches to elucidate and predict relapse in alcoholism.

PubMed

Heinz, Andreas; Deserno, Lorenz; Zimmermann, Ulrich S; Smolka, Michael N; Beck, Anne; Schlagenhauf, Florian

2017-05-01

Alcohol use disorder (AUD) and addiction in general is characterized by failures of choice resulting in repeated drug intake despite severe negative consequences. Behavioral change is hard to accomplish and relapse after detoxification is common and can be promoted by consumption of small amounts of alcohol as well as exposure to alcohol-associated cues or stress. While those environmental factors contributing to relapse have long been identified, the underlying psychological and neurobiological mechanism on which those factors act are to date incompletely understood. Based on the reinforcing effects of drugs of abuse, animal experiments showed that drug, cue and stress exposure affect Pavlovian and instrumental learning processes, which can increase salience of drug cues and promote habitual drug intake. In humans, computational approaches can help to quantify changes in key learning mechanisms during the development and maintenance of alcohol dependence, e.g. by using sequential decision making in combination with computational modeling to elucidate individual differences in model-free versus more complex, model-based learning strategies and their neurobiological correlates such as prediction error signaling in fronto-striatal circuits. Computational models can also help to explain how alcohol-associated cues trigger relapse: mechanisms such as Pavlovian-to-Instrumental Transfer can quantify to which degree Pavlovian conditioned stimuli can facilitate approach behavior including alcohol seeking and intake. By using generative models of behavioral and neural data, computational approaches can help to quantify individual differences in psychophysiological mechanisms that underlie the development and maintenance of AUD and thus promote targeted intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

The Value of Serum CA125 in the Diagnosis of Borderline Tumors of the Ovary: A Subanalysis of the Prospective Multicenter ROBOT Study.

PubMed

Fotopoulou, Christina; Sehouli, Jalid; Ewald-Riegler, Nina; de Gregorio, Nikolaus; Reuss, Alexander; Richter, Rolf; Mahner, Sven; Kommoss, Friedrich; Schmalfeldt, Barbara; Fehm, Tanja; Hanker, Lars; Wimberger, Pauline; Canzler, Ulrich; Pfisterer, Jacobus; Kommoss, Stefan; Hauptmann, Steffen; du Bois, Andreas

2015-09-01

The value of the serum tumor marker CA125 in borderline tumors of the ovary (BOTs) is not well defined, with unclear benefit in both diagnosis and follow-up. The aim of the present project was to identify the predictive value of CA125 for stage and relapse. CA125 data were extracted from the ROBOT multicenter study of patients with BOT treated between 1998 and 2008 in 24 German centers. While patients' data were retrieved retrospectively from hospital records and clinical tumor registries, follow-up and independent central pathology review were performed prospectively. We identified 127 patients from the ROBOT database fulfilling the eligibility criterion of available CA125 at initial diagnosis. Eighty-three (65.3%) patients had increased CA125 levels (>35 U/L). Of the patients, 85.0% presented with serous and 13.4% with mucinous BOT histology, whereas 29.9% had stage I disease. Fifteen (11.8%) patients experienced a relapse. Multivariate analysis identified raised CA125, young age, and serous histology as independent predictors of peritoneal implants of any type at initial presentation. Raised CA125 at initial diagnosis was, however, not an independent predictor of future relapse. Elevated CA125 seems to be associated with the presence of peritoneal implants of any type at initial diagnosis of serous BOT, but failed to have any independent predictive value on future relapse. Prospective multicenter studies are warranted to evaluate CA125 measurements in the follow-up management of BOT.

A prospective multicenter study of factors associated with hospital admission among adults with acute asthma.

PubMed

Weber, Ellen J; Silverman, Robert A; Callaham, Michael L; Pollack, Charles V; Woodruff, Prescott G; Clark, Sunday; Camargo, Carlos A

2002-10-01

We sought to determine patient characteristics associated with hospital admission after emergency treatment for asthma, and whether disposition guidelines are followed. We performed a prospective multicenter cohort study involving 64 emergency departments in the United States and Canada. Consecutive adult patients with asthma exacerbations were interviewed, and their charts were reviewed using standardized protocols. Telephone follow-up at 2 weeks determined relapse. Of 1805 patients, 363 (20%; 95% confidence interval [CI]: 18% to 22%) were hospitalized. Among patients with severe exacerbations (final peak flow <50% of predicted), 122 (49%; 95% CI: 43% to 55%) were hospitalized. Admission was associated with final peak flow, female sex, nonwhite race, severity of chronic illness, and severity of exacerbation. Admission predictors were similar regardless of hospital funding, region, or size. Among patients with mild or moderate exacerbations of asthma (peak flow >or=50% predicted), the likelihood of admission was associated significantly with the number of predefined risk factors for death from asthma. Of patients who were discharged from the emergency department, 62 (5%; 95% CI: 4% to 6%) relapsed within 72 hours. Relapse was not associated with final peak flow (P = 0.39). Associations between patient characteristics and disposition were similar across sites. Despite guidelines to the contrary, half of patients with final peak flow <50% were discharged. After emergency department treatment and discharge, short-term relapse was uncommon among patients with asthma, suggesting that strict peak flow cutoffs may be unnecessary if risk factors in patients with mild or moderate exacerbations are considered.

Hypersomnia Subtypes, Sleep and Relapse in Bipolar Disorder

PubMed Central

Kaplan, Katherine A.; McGlinchey, Eleanor L.; Soehner, Adriane; Gershon, Anda; Talbot, Lisa S.; Eidelman, Polina; Gruber, June; Harvey, Allison G.

2015-01-01

Background Though poorly defined, hypersomnia is associated with negative health outcomes, and new-onset and recurrence of psychiatric illness. Lack of definition impedes generalizability across studies. The present research clarifies hypersomnia diagnoses in bipolar disorder by exploring possible subgroups and their relationship to prospective sleep data and relapse into mood episodes. Methods A community sample of 159 adults (ages 18–70) with bipolar spectrum diagnoses, euthymic at study entry, were included. Self-report inventories and clinician-administered interviews determined features of hypersomnia. Participants completed sleep diaries and wore wrist actigraphy at home to obtain prospective sleep data. Approximately seven months later, psychiatric status was reassessed. Factor analysis and latent profile analysis explored empirical groupings within hypersomnia diagnoses. Results Factor analyses confirmed two separate subtypes of hypersomnia (‘long sleep’ and ‘excessive sleepiness’) that were uncorrelated. Latent profile analyses suggested a four-class solution, with ‘long sleep’ and ‘excessive sleepiness’ again representing two separate classes. Prospective sleep data suggested that the sleep of ‘long sleepers’ is characterized by long time in bed, not long sleep duration. Longitudinal assessment suggested that ‘excessive sleepiness’ at baseline predicted mania/hypomania relapse. Conclusions This study is the largest of hypersomnia to include objective sleep measurement, and refines our understanding of classification, characterization and associated morbidity. Hypersomnia appears to be comprised of two separate subgroups, long sleep and excessive sleepiness. Long sleep is characterized primarily by long bedrest duration. Excessive sleepiness is not associated with longer sleep or bedrest, but predicts relapse to mania/hypomania. Understanding these entities has important research and treatment implications. PMID:25515854

A conflict rat model of cue-induced relapse to cocaine seeking.

PubMed

Cooper, Ayelet; Barnea-Ygael, Noam; Levy, Dino; Shaham, Yavin; Zangen, Abraham

2007-09-01

Relapse to drug use in humans can be induced by exposure to drug-associated cues. The ability of drug cues to provoke 'relapse' has been studied in laboratory animals using a reinstatement model in which resumption of drug seeking is assessed after extinction of drug-reinforced responding. In this model, there are no adverse consequences of drug-seeking behavior. However, in humans, abstinence is often self-imposed, and relapse episodes likely involve making a choice between the desire for the drug and the negative consequences of pursuing it (a conflict situation). In this paper, we describe a conflict model of cue-induced relapse in rats that approximate the human condition. Rats were trained to lever press for cocaine; infusions were paired with a discrete light cue. An 'electric barrier' was then introduced by electrifying the floor area near the levers. Responding decreased over days with increasing shock intensities, until the rats did not approach the levers for 3 days. Subsequently, the effect of intermittent noncontingent light-cue presentations on resumption of lever responding (relapse) was assessed in extinction tests, with the electric barrier remaining activated; during testing, lever presses led to contingent light-cue presentations. Noncontingent cue exposure led to resumption of lever presses during the relapse tests in 14 of the 24 rats. Surprisingly, 24 h later, 11 of the 24 rats resumed lever responding in a subsequent post-noncontingent cue test under similar extinction conditions. Large individual differences in responding were observed during both tests. At its current stage of development, the conflict relapse model appears particularly suitable for studying individual differences in cue-induced relapse to cocaine seeking or factors that promote this relapse.

Evaluation of the Lactate-to-N-Acetyl-aspartate Ratio Defined With Magnetic Resonance Spectroscopic Imaging Before Radiation Therapy as a New Predictive Marker of the Site of Relapse in Patients With Glioblastoma Multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deviers, Alexandra; UMR; INP

Purpose: Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-{sup 1}H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). Methods and Materials: Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis ofmore » the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. Results: A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm{sup 3}; range: 6-49 cm{sup 3}). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). Conclusions: Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.« less

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.

PubMed

Clappier, Emmanuelle; Gerby, Bastien; Sigaux, François; Delord, Marc; Touzri, Farah; Hernandez, Lucie; Ballerini, Paola; Baruchel, André; Pflumio, Françoise; Soulier, Jean

2011-04-11

Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.

Long-term maintenance therapy for vulvar lichen sclerosus: the results of a randomized study comparing topical vitamin E with an emollient.

PubMed

Virgili, Annarosa; Minghetti, Sara; Borghi, Alessandro; Corazza, Monica

2013-04-01

The chronic and relapsing nature of vulvar lichen sclerosus (VLS) represents a challenge for its long-term management after an effective treatment with topical corticosteroids. To compare the effect of topical vitamin E with that of an emollient in reducing the risk of VLS relapse over a 52-week maintenance treatment. 156 patients with VLS were enrolled in a 12-week active treatment phase on topical 0.1% mometasone furoate ointment once daily. Those who achieved disease remission entered a 52-week maintenance phase in which patients were randomized to apply either an emollient or topical vitamin E once daily. 80 patients entered the maintenance phase. At 52 weeks, for the vitamin E maintenance group, the cumulative crude relapse rate was 27.8% and the cumulative modified crude relapse rate was 55.6%. For the emollient maintenance group, the cumulative crude relapse rate was 22.7% and the cumulative modified crude relapse rate was 50.0%. The median time to relapse was 20 weeks for the vitamin E group and 18.7 weeks for the emollient group. Once VLS has been stabilized with topical corticosteroids, long-term treatment with both vitamin E and emollients may be considered in maintain LS remission.

Association of Physical Activity with Alcohol Abuse and Dependence in a Nationally-Representative U.S. Sample.

PubMed

Damian, April Joy; Mendelson, Tamar

2017-11-10

Alcohol use is a pervasive and costly public health problem in the United States. Relapse rates from alcohol use disorders are high. Although exercise has been proposed as a strategy to prevent relapse, lifestyle modification is the least studied aspect of relapse prevention programs, especially among racial/ethnic minority populations. The current study assessed whether being physically active was associated with remission from alcohol abuse or dependence among Black (African American and Afro Caribbean) adults in the U.S. We utilized data on Black adult participants (n = 4,828) from the nationally representative National Survey of American Life (NSAL) conducted in 2001-2003. Logistic regression models were estimated to assess the odds of being in 12-month remission or currently meeting DSM-IV criteria for alcohol abuse or dependence based on level of physical activity, adjusting for socio-demographic and neighborhood characteristics. People who endorsed being physically active had higher odds of being in 12-month remission from alcohol use problems (OR: 1.67, 95% CI: 1.28, 2.17) than people who were physically inactive, adjusting for individual- and neighborhood-level characteristics. People who were physically active did not differ significantly from those who were inactive with respect to odds of currently meeting DSM-IV criteria for alcohol abuse or dependence. Conclusions/Importance: Physical activity was positively associated with being in 12-month remission from alcohol use problems. Longitudinal studies are needed to establish temporal ordering and to explore exercise as a potential relapse prevention strategy for alcohol use problems.

Evaluation of 5-fluorouracil metabolic enzymes as predictors of response to adjuvant chemotherapy outcomes in patients with stage II/III colorectal cancer: a decision-curve analysis.

PubMed

Shigeta, Kohei; Ishii, Yoshiyuki; Hasegawa, Hirotoshi; Okabayashi, Koji; Kitagawa, Yuko

2014-12-01

The effectiveness of 5-fluorouracil (5-FU)-based adjuvant chemotherapy is reported in patients with colorectal cancer (CRC), but the usefulness of 5-FU metabolic enzymes as predictive biomarkers of the efficacy of this chemotherapy remains unclear. This study aims to verify whether 5-FU metabolic enzymes are predictive biomarkers in the clinical setting of adjuvant chemotherapy for stage II/III CRC. In total, 179 patients with stage II/III CRC who were treated at our institute between 2000 and 2010 were enrolled. Messenger RNA (mRNA) expression of major 5-FU metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase (TP), orotate phosphoribosyl transferase, and β-actin (control) was evaluated using the Danenberg Tumor Profile method. mRNA expression and other clinicopathological data were investigated with regard to CRC relapse. A total of 78 patients underwent surgery alone, while 101 underwent adjuvant chemotherapy (5-FU plus leucovorin [LV] or tegafur plus uracil /LV) following surgery. Relapse-free survival was longer and risk of recurrence was lower in association with high TP mRNA expression than in association with low TP mRNA expression in the adjuvant chemotherapy group (hazard ratio 0.66; 95 % confidence interval 0.47-0.92; p = 0.016), but not in the surgery alone group. mRNA expression of no other enzymes was associated with relapse in both groups. In decision-curve analyses, the predictive efficiency of TP mRNA expression plus clinicopathological factors was slightly better than that of clinicopathological factors only. TP mRNA expression in tumors predicted the effects of adjuvant chemotherapy for stage II/III CRC, although the beneficial effects were marginal.

Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review

PubMed Central

Retsky, Michael; Demicheli, Romano; Hrushesky, William J.M; Forget, Patrice; Kock, Marc De; Gukas, Isaac; Rogers, Rick A; Baum, Michael; Sukhatme, Vikas; Vaidya, Jayant S

2013-01-01

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. PMID:23992307

Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.

PubMed

Rea, Delphine; Henry, Guylaine; Khaznadar, Zena; Etienne, Gabriel; Guilhot, François; Nicolini, Franck; Guilhot, Joelle; Rousselot, Philippe; Huguet, Françoise; Legros, Laurence; Gardembas, Martine; Dubruille, Viviane; Guerci-Bresler, Agnès; Charbonnier, Aude; Maloisel, Frédéric; Ianotto, Jean-Christophe; Villemagne, Bruno; Mahon, François-Xavier; Moins-Teisserenc, Hélène; Dulphy, Nicolas; Toubert, Antoine

2017-08-01

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56 dim subset than had relapsing patients, while CD56 bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56 dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1 + leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985) . Copyright© 2017 Ferrata Storti Foundation.

Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study.

PubMed

Desjonquères, A; Chevallier, P; Thomas, X; Huguet, F; Leguay, T; Bernard, M; Bay, J-O; Tavernier, E; Charbonnier, A; Isnard, F; Hunault, M; Turlure, P; Renaud, M; Bastié, J-N; Himberlin, C; Lepretre, S; Lioure, B; Lhéritier, V; Asnafi, V; Beldjord, K; Lafage-Pochitaloff, M; Béné, M C; Ifrah, N; Dombret, H

2016-12-09

The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ⩾18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients.

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking.

PubMed

Chesworth, Rose; Corbit, Laura H

2017-01-01

One of the principal barriers to overcoming addiction is the propensity to relapse, even after months or years of abstinence. Relapse can be precipitated by cues and contexts associated with drug use; thus, decreasing the conditioned properties of these cues and contexts may assist in preventing relapse. The predictive power of drug cues and contexts can be reduced by repeatedly presenting them in the absence of the drug reinforcer, a process known as extinction. The potential of extinction to limit relapse has generated considerable interest and research over the past few decades. While pre-clinical animal models suggest extinction learning assists relapse prevention, treatment efficacy is often lacking when extinction learning principles are translated into clinical trials. Conklin and Tiffany (Addiction, 2002) suggest the lack of efficacy in clinical practice may be due to limited translation of procedures demonstrated through animal research and propose several methodological improvements to enhance extinction learning for drug addiction. This review will examine recent advances in the behavioural and pharmacological manipulation of extinction learning, based on research from pre-clinical models. In addition, the translation of pre-clinical findings-both those suggested by Conklin and Tiffany () and novel demonstrations from the past 13 years-into clinical trials and the efficacy of these methods in reducing craving and relapse, where available, will be discussed. Finally, we highlight areas where promising pre-clinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods. © 2015 Society for the Study of Addiction.

Activated mesenchymal stem cell administration inhibits chronic alcohol drinking and suppresses relapse-like drinking in high-alcohol drinker rats.

PubMed

Ezquer, Fernando; Quintanilla, María Elena; Morales, Paola; Ezquer, Marcelo; Lespay-Rebolledo, Carolyne; Herrera-Marschitz, Mario; Israel, Yedy

2017-10-18

Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12-17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 10 5 ) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P < 0.001), an effect seen within the first 24 hours of hMSCs administration, and reduced relapse-like drinking by 80% (P < 0.001). In the relapse-like condition, control animals attain blood ethanol ('binge-like') levels >80 mg/dl. The single hMSC administration reduced relapse-like blood ethanol levels to 20 mg/dl. Chronic ethanol intake increased by 250% (P < 0.001) the levels of reactive oxygen species in hippocampus, which were markedly reduced by hMSC administration. Astrocyte glial acidic fibrillary protein immunoreactivity, a hallmark of neuroinflammation, was increased by 60-80% (P < 0.001) by chronic ethanol intake, an effect that was fully abolished by the administration of hMSCs. This study supports the neuroinflammation-chronic ethanol intake hypothesis and suggest that mesenchymal stem cell administration may be considered in the treatment of alcohol use disorders. © 2017 Society for the Study of Addiction.

MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study.

PubMed

Comi, Giancarlo; Cook, Stuart D; Giovannoni, Gavin; Rammohan, Kottil; Rieckmann, Peter; Sørensen, Per Soelberg; Vermersch, Patrick; Hamlett, Anthony C; Viglietta, Vissia; Greenberg, Steven J

2013-04-01

We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (p < 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (p < 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (p < 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (p < 0.001 for all analyses of patients with ≤1 or 2 relapses; p ≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS.

A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma

PubMed Central

Xie, Wanling; Jagannath, Sundar; Jakubowiak, Andrzej; Lonial, Sagar; Raje, Noopur S.; Alsina, Melissa; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Mazumder, Amitabha; Vesole, David H.; Kaufman, Jonathan L.; Colson, Kathleen; McKenney, Mary; Lunde, Laura E.; Feather, John; Maglio, Michelle E.; Warren, Diane; Francis, Dixil; Hideshima, Teru; Knight, Robert; Esseltine, Dixie-Lee; Mitsiades, Constantine S.; Weller, Edie; Anderson, Kenneth C.

2014-01-01

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m2 (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209. PMID:24429336

Yohimbine stress potentiates conditioned cue-induced reinstatement of heroin-seeking in rats.

PubMed

Banna, Kelly M; Back, Sudie E; Do, Phong; See, Ronald E

2010-03-17

Stress and drug-associated cues can trigger craving and relapse in abstinent drug-dependent individuals. Although the role of these two critical factors in relapse has been extensively studied, the interaction between stress and drug-associated cues in relapse has been less well characterized. Using an animal model of relapse, we assessed the effects of the pharmacological stressor, yohimbine (1.25 or 2.5mg/kg), on reinstatement of extinguished heroin-seeking in rats either in the presence or absence of heroin-associated cues. Yohimbine, in the absence of heroin-associated cues, and cues by themselves reliably reinstated heroin-seeking over extinction levels. Notably, animals showed significantly potentiated responding when yohimbine preceded cue-induced reinstatement (3-4x higher over cues or yohimbine alone). These results demonstrate that exposure to heroin-paired cues during yohimbine-induced stress greatly potentiates heroin-seeking, and support the simultaneous targeting of both stress and cue activation during relapse intervention. Copyright 2009 Elsevier B.V. All rights reserved.

Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia.

PubMed

Sutton, Rosemary; Venn, Nicola C; Tolisano, Jonathan; Bahar, Anita Y; Giles, Jodie E; Ashton, Lesley J; Teague, Lochie; Rigutto, Gemma; Waters, Keith; Marshall, Glenn M; Haber, Michelle; Norris, Murray D

2009-08-01

Detection of minimal residual disease (MRD) after induction and consolidation therapy is highly predictive of outcome for childhood acute lymphoblastic leukaemia (ALL) and is used to identify patients at high risk of relapse in several current clinical trials. To evaluate the prognostic significance of MRD at other treatment phases, MRD was measured by real-time quantitative polymerase chain reaction on a selected group of 108 patients enrolled on the Australian and New Zealand Children's Cancer Study Group Study VII including 36 patients with a bone marrow or central nervous system relapse and 72 matched patients in first remission. MRD was prognostic of outcome at all five treatment phases tested: at day 15 (MRD > or = 5 x 10(-2), log rank P < 0.0001), day 35 (> or =1 x 10(-2), P = 0.0001), 4 months (> or =5 x 10(-4), P < 0.0001), 12 months (MRD > or = 1 x 10(-4), P = 0.006) and 24 months (MRD > or = 1 x 10(-4), P < 0.0001). Day 15 was the best early MRD time-point to differentiate between patients with high, intermediate and low risk of relapse. MRD testing at 12 and particularly at 24 months, detected molecular relapses in some patients up to 6 months before clinical relapse. This raised the question of whether a strategy of late monitoring and salvage therapy will improve outcome.

Serotonin at the Nexus of Impulsivity and Cue Reactivity in Cocaine Addiction

PubMed Central

Cunningham, Kathryn A.; Anastasio, Noelle C.

2014-01-01

Cocaine abuse and addiction remain great challenges on the public health agendas in the U.S. and the world. Increasingly sophisticated perspectives on addiction to cocaine and other drugs of abuse have evolved with concerted research efforts over the last 30 years. Relapse remains a particularly powerful clinical problem as, even upon termination of drug use and initiation of abstinence, the recidivism rates can be very high. The cycling course of cocaine intake, abstinence and relapse is tied to a multitude of behavioral and cognitive processes including impulsivity (a predisposition toward rapid unplanned reactions to stimuli without regard to the negative consequences), and cocaine cue reactivity (responsivity to cocaine-associated stimuli) cited as two key phenotypes that contribute to relapse vulnerability even years into recovery. Preclinical studies suggest that serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in key neural circuits may contribute to these interlocked phenotypes well as the altered neurobiological states evoked by cocaine that precipitate relapse events. As such, 5-HT is an important target in the quest to to understand the neurobiology of relapse-predictive phenotypes, to successfully treat this complex disorder and improve diagnostic and prognostic capabilities. This review emphasizes the role of 5-HT and its receptor proteins in key addiction phenotypes and the implications of current findings to the future of therapeutics in addiction. PMID:23850573

Life adversity is associated with smoking relapse after a quit attempt.

PubMed

Lemieux, Andrine; Olson, Leif; Nakajima, Motohiro; Schulberg, Lauren; al'Absi, Mustafa

2016-09-01

Multiple cross-sectional studies have linked adverse childhood events and adult adversities to current smoking, lifetime smoking, and former smoking. To date, however, there have been no direct observational studies assessing the influence of adversities on smoking relapse. We prospectively followed 123 participants, 86 of whom were habitual smokers, from pre-quit ad libitum smoking to four weeks post-quit. Thirty-seven non-smokers were also tested in parallel as a comparison group. Subjects provided biological samples for confirmation of abstinence status and self-report history of adversities such as abuse, neglect, family dysfunction, incarceration, and child-parent separation. They also completed mood and smoking withdrawal symptom measures. The results indicated that within non-smokers and smokers who relapsed within the first month of a quit attempt, but not abstainers, females had significantly higher adversity scores than males. Cigarette craving, which was independent from depressive affect, increased for low adversity participants, but not those with no adversity nor high adversity. These results demonstrate that sex and relapse status interact to predict adversity and that craving for nicotine may be an important additional mediator of relapse. These results add further support to the previous cross-sectional evidence of an adversity and smoking relationship. Further studies to clarify how adversity complicates smoking cessation and impacts smoking behaviors are warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

Longitudinal course of panic disorder with and without agoraphobia using the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

PubMed

Nay, William; Brown, Ruth; Roberson-Nay, Roxann

2013-06-30

Few naturalistic, longitudinal studies of panic disorder with and without agoraphobia (PD/PDA) exist, limiting our knowledge of the temporal rates of incidence, relapse, and chronicity, or the factors that predict category transition. Data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) wave 1 (n=43,093) and wave 2 (n=34,653) were utilized to determine transitional rates, and predictors of category transitions, over a 3-year period. Analyses revealed very high 3-year remission rates for PD and PDA (75% and 67%, respectively), although relapse also was relatively frequent (PD=12%; PDA=21%). Logistic regression revealed previous history of panic attacks, generalized anxiety disorder/major depression (GAD/MDD), nicotine dependence, female sex, younger age, and major financial crises to be reliable predictors of incidence and relapse. The direction and magnitude of association of many predictor variables were similar for PD and PDA, with notable exceptions for social anxiety and romantic relationship factors. Clinicians should be aware of the relapsing-remitting nature of PD and PDA and, thus, take caution to not reduce or eliminate effective treatments prematurely. Similarly, the current study suggests clinicians pay particular attention to concurrent factors relevant to relapse in PD/PDA that may also be clinically addressed (e.g., co-morbid MDD/GAD and nicotine dependence). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura.

PubMed

Bhagirath, Vinai C; Kelton, John G; Moore, Jane; Arnold, Donald M

2012-12-01

Rituximab, an anti-CD20 chimeric monoclonal antibody, has been used successfully to treat patients with relapsed or refractory thrombotic thrombocytopenic purpura (TTP); however, the optimal dose and frequency and the role of rituximab maintenance remain uncertain. We describe a 45-year-old woman with chronic relapsing immune thrombocytopenia who responded to rituximab retreatment administered in four doses over the course of 12 months. Previously, she had received four doses of rituximab and sustained a remission for 19 months. During her latest TTP relapse, multiple treatments were administered including rituximab retreatment. After the first dose (375 mg/m2), she developed serum sickness requiring further doses to be deferred. Three subsequent doses were administered at 4-month intervals over the course of 12 months. ADAMTS13 activity was measured by von Willebrand factor (VWF) digestion. ADAMTS13 inhibition was measured by a modification of the VWF digestion assay and anti-ADAMTS13 antibodies were measured by enzyme-linked immunoassay (enzyme-linked immunosorbent assay, American Diagnostica). Clinical and laboratory remission were achieved after one dose of rituximab, with normalization of ADAMTS13 activity and disappearance of ADAMTS13 inhibitor. Three subsequent doses of rituximab were given without incident and the patient remained in remission after 3.5 years of follow-up (2.5 years since her last dose of rituximab). Maintenance dosing of rituximab should be considered in some patients with relapsing TTP. © 2012 American Association of Blood Banks.

Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies.

PubMed

Place, Andrew E; Goldsmith, Kelly; Bourquin, Jean-Pierre; Loh, Mignon L; Gore, Lia; Morgenstern, Daniel A; Sanzgiri, Yeshwant; Hoffman, David; Zhou, Ying; Ross, Jeremy A; Prine, Betty; Shebley, Mohamad; McNamee, Megan; Farazi, Thalia; Kim, Su Young; Verdugo, Maria; Lash-Fleming, Leanne; Zwaan, C Michel; Vormoor, Josef

2018-03-29

Venetoclax is a highly selective, potent BCL-2 inhibitor that is approved for some patients previously treated for chronic lymphocytic leukemia, and has shown promising activity in adult studies across several hematologic malignancies. Preclinical studies have demonstrated venetoclax activity in pediatric patient-derived xenograft models and cell lines; however, clinical studies in pediatric patients have yet to be conducted. The prognosis is poor for children with most relapsed/refractory malignancies, and limited treatment options result in unmet clinical need. Herein, we describe the rationale and design of the first study of venetoclax in pediatric patients with relapsed/refractory malignancies: a Phase I trial investigating the safety and pharmacokinetics of venetoclax monotherapy followed by the addition of chemotherapy (Trial registration: EudraCT 2017-000439-14; NCT03236857).

Antimalarial activities of new guanidylimidazole and guanidylimidazoline derivatives.

PubMed

Zhang, Liang; Sathunuru, Ramadas; Caridha, Diana; Pybus, Brandon; O'Neil, Michael T; Kozar, Michael P; Lin, Ai J

2011-10-13

A series of new guanidylimidazole derivatives was prepared and evaluated in mice and Rhesus monkeys infected with malarial sporozoites. The majority of the new compounds showed poor metabolic stability and weak in vitro activities in three clones of Plasmodium falciparum. Compounds 8a, 8h, 9a, 16a, and 16e cured the mice infected with sporozoites of P. berghei at 160 and 320 mg/kg/day × 3 po. Compounds 8a showed better causal prophylactic activity than primaquine, tafenoquine, and Malarone in the Rhesus test. In the radical curative test, 8a cured one monkey and delayed relapse of another for 74 days at 30 mg/kg/day × 7 by im. By oral dosing, 8a delayed relapse 81 days for one and 32 days for other vs 11-12 days for control monkeys treated with 10 mg/kg of chloroquine by po alone. Compound 8h, which showed superior activity to 8a in mouse test, delayed the relapse of treated monkeys for 21-26 days at 30 mg/kg/day × 7 by oral.

Dimensions of depressive symptoms and smoking cessation.

PubMed

Leventhal, Adam M; Ramsey, Susan E; Brown, Richard A; LaChance, Heather R; Kahler, Christopher W

2008-03-01

Because different psychopathologic components of depressive symptoms may have distinct etiologies, examining their differential effects on smoking cessation may elucidate mechanisms underlying the smoking-depression relationship. Negative affect (NA), somatic features (SF), low positive affect/anhedonia (PA), and interpersonal disturbance (IP) have been identified as unique dimensions of depression that can be measured using the Center for Epidemiologic Studies Depression Scale (CESD). This study examined common and unique associations between CESD subscales and baseline smoking characteristics, nicotine withdrawal, and relapse in 157 participants enrolled in a smoking cessation trial for heavy social drinkers. Each dimension was univariately associated with negative and positive reinforcement smoking motives. Only SF had unique relations with tolerance smoking motives and univariate associations with nicotine dependence severity. Only PA predicted cessation-related changes in withdrawal symptoms on quit day. Analyses predicting abstinence at 8, 16, and 26 weeks post quit date showed that NA, SF, and PA each univariately predicted relapse, ps< or =.0083. Only low PA predicted poorer outcomes incrementally to the other dimensions, even when controlling for level of nicotine dependence, smoking frequency, and history of major depression, p = .0018. Interventions targeting anhedonia and low positive affect may be useful for smokers trying to quit.

Risk of relapse after natalizumab withdrawal

PubMed Central

Vukusic, Sandra; Casey, Romain; Debard, Nadine; Stankoff, Bruno; Mrejen, Serge; Uhry, Zoe; Van Ganse, Eric; Castot, Anne; Clanet, Michel; Lubetzki, Catherine; Confavreux, Christian

2016-01-01

Objective: To assess disease activity within 12 months after natalizumab (NZ) discontinuation in a large French postmarketing cohort. Methods: In France, patients exposed at least once to NZ were included in the TYSEDMUS observational and multicenter cohort, part of the French NZ Risk Management Plan. Clinical disease activity during the year following NZ discontinuation was assessed in this cohort. Time to first relapse after NZ stop was analyzed using Kaplan-Meier method and potentially associated factors were studied using a multivariate Cox model. Results: Out of the 4,055 patients with multiple sclerosis (MS) included in TYSEDMUS, 1,253 discontinued NZ and 715 of them had relevant data for our study. The probability of relapse within the year after NZ stop was estimated at 45% (95% confidence interval 0.41–0.49). Conclusions: This large and systematic survey of patients with MS after NZ withdrawal allows quantifying the risk of increased disease activity following treatment discontinuation. This study provides large-scale, multicenter, systematic data after NZ cessation in real-life settings. PMID:27844037

Cognitive Therapy Skills Predict Cognitive Reactivity to Sad Mood Following Cognitive Therapy for Depression

PubMed Central

Strunk, Daniel R.; Adler, Abby D.; Hollars, Shannon N.

2013-01-01

Both patients’ competence in the coping skills taught in Cognitive Therapy (CT) and patients’ endorsement of dysfunctional cognitions following a sad mood induction (i.e., their cognitive reactivity) have been found to predict risk of relapse following a successful course of CT for depression. We examined the relationship between these constructs, specifically whether CT skills would be related to less cognitive reactivity following a mood induction among patients who responded to a course of CT. In a sample of 28 depressed patients, post-treatment CT skills were significantly related to less cognitive reactivity in response to a sad mood induction procedure (β = −.29). This relation was not accounted for by individual differences in mood reactivity. We discuss these findings as a key step in developing a more complete understanding of the role of CT coping skills and cognitive reactivity as markers of patients’ vulnerability to relapse. PMID:24363473

Advanced-stage Hodgkin lymphoma: US/chest radiography for detection of relapse in patients in first complete remission--a randomized trial of routine surveillance imaging procedures.

PubMed

Picardi, Marco; Pugliese, Novella; Cirillo, Michele; Zeppa, Pio; Cozzolino, Imma; Ciancia, Giuseppe; Pettinato, Guido; Salvatore, Claudia; Quintarelli, Concetta; Pane, Fabrizio

2014-07-01

To compare the use of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) with the use of a combination of ultrasonography (US) and chest radiography for systematic follow-up of patients with high-risk Hodgkin lymphoma. Institutional review board approval and informed consent were obtained. In a single center between January 2001 and December 2009, patients with advanced-stage Hodgkin lymphoma who had responded completely to first-line treatment were randomly assigned (1:1) to follow-up with either PET/CT or US/chest radiography. Follow-up included clinical and imaging procedures at 4, 8, 12, 16, 20, 24, 30, 36, 48, 60, 84, and 108 months after treatment discontinuation. When clinical and/or imaging results were positive, recurrence was confirmed histologically. The primary endpoint was to compare the sensitivity of the two follow-up imaging approaches. Secondary endpoints were their specificity, positive and negative predictive values, time to recurrence detection, radiation risks, and costs. A total of 300 patients were randomized into the two arms. The study was closed after a median follow-up time of 60 months, with a relapse rate of 27%. Sensitivity for detection of Hodgkin lymphoma was similar for the two follow-up approaches. All of the relapses (40 of 40) were identified with FDG PET/CT (100%) and 39 of 40 relapses were identified with US/chest radiography (97.5%; P = .0001 for the equivalence test). US/chest radiography showed significantly higher specificity and positive predictive value than did PET/CT (96% [106 of 110] vs 86% [95 of 110], respectively; P = .02; and 91% [39 of 43] vs 73% [40 of 55], respectively; P = .01). Exposure to ionizing radiation was estimated to be 14.5 mSv for one PET/CT examination versus 0.1 mSv for one chest radiographic examination. Estimated cost per relapse diagnosed with routine PET/CT was 10-fold higher compared with that diagnosed with routine US/chest radiography. US and chest radiography are diagnostic tools that enable effective, safe, and low-cost routine surveillance imaging for patients at high risk of Hodgkin lymphoma relapse. © RSNA, 2014.

[Motivations for cannabis cessation, coping and adaptation strategies, and perceived benefits: impact on cannabis use relapse and abstinence].

PubMed

Chauchard, E; Septfons, A; Chabrol, H

2013-12-01

While cannabis has been recognized as the most illicit drug use in the world, few studies focusing on cannabis self-change and cannabis relapse or abstinence in adult non-treatment samples have been conducted. The first aim of this study was to understand cannabis self-change motives, coping and adaptation strategies and evaluating perceived benefits from cannabis cessation. The second aim was to compare, in a convenience sample of non-treatment-seeking adult cannabis smokers, motivations to quit smoking cannabis, coping and adaptive strategies, as well as perceived benefit from cessation between cannabis abstinent and participants who relapse. Sixty-three participants (31 men and 32 women) who attempted to quit cannabis in a non-controlled environment without medical help and were enrolled. They completed the Marijuana Quit Questionnaire (MJQQ), a self-report questionnaire collecting information in three areas: sociodemographic characteristics, cannabis use history (including any associated problems), and participants' characteristics regarding their "most difficult" (self-defined) attempt to quit in a non-controlled environment. For this study the index quit attempt was characterized in two areas: reasons for quitting marijuana, coping strategies used while quitting. Two additional questionnaires were added to the MJQQ; the Brief Cope, and a questionnaire assessing perceived benefit of the cannabis quit attempt. The participants were on average 28.5 years old (±5.1), and started using cannabis on average at 15.8 years (±2.8). Seventy-four percent (n=45) of the participants met the DSM-IV criteria for cannabis dependence before cannabis cessation. T-tests were used to compare abstainers and participants who relapsed after the quit attempt. Realizing that cannabis induces disabling cognitive disorders such as affection of memory, concentration and attention were reported by 71% of the participant as a motivation for quitting cannabis use. Then, being more energetic (reported by 68%) and more active during the day (62%), being able to control their life (67%), proving themselves they could quit (60%), saving money (60%), as well being less worried about their health (57%) were also reported as motivations to quit cannabis use. Different coping and adaptation strategies were also reported. First, environmental strategies such as disposing of both cannabis (71%) and equipment to smoke (71%), no longer going to places where cannabis is smoked (33%) or lifestyle changes (68%) were used to cope with cannabis cessation. Then cognitive strategies such as motivation, willingness (71%), self-control and having a positive perception of the situation (68%) were also reported. Regarding coping strategies, participants accepted and learned how to live with the new situation (68%), and social support from family (32%) and friends (30%) were reported. Perceived benefits were linked with motivations for cannabis cessation. Thus, participants reported having more energy (75%), being more active (73%), less tired (70%) and recovering memory (57%) after cannabis cessation. Fifty-two percent of participants relapsed after the quit attempt. Abstainers had significantly higher scores on two subscales: the "negative impact of cannabis use on one's health and on self and social image" (t(61)=-3.84; P<0.001; d=-0.76) and "negative reinforcement (e.g. seeking relief for specific physical symptoms or social problems caused by cannabis)" (t(61)=3.56; P=0.01; d=-0.51) than non-anstainers. Non-abstainers reported significantly less social support from family (t(61)=-3.85; P<0.001, d=-0.76) and friends (t(61)=-2.22; P=00.03, d=-0.51) than abstainers. This study underlines different aspects of cannabis cessation, self-change, relapse, and abstinence. Social and family support, as well as social network appears to be of prime importance in relapses and prevention programs for cannabis use. New perspectives for research on cannabis cessation self-change and relapses are thus highlighted, notably regarding factors that could predict relapse or success in cessation of smoking cannabis. Research on cannabis self-change and relapse are warranted for both prevention and therapeutic programs. Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

The topographical model of multiple sclerosis

PubMed Central

Cook, Karin; De Nino, Scott; Fletcher, Madhuri

2016-01-01

Relapses and progression contribute to multiple sclerosis (MS) disease course, but neither the relationship between them nor the spectrum of clinical heterogeneity has been fully characterized. A hypothesis-driven, biologically informed model could build on the clinical phenotypes to encompass the dynamic admixture of factors underlying MS disease course. In this medical hypothesis, we put forth a dynamic model of MS disease course that incorporates localization and other drivers of disability to propose a clinical manifestation framework that visualizes MS in a clinically individualized way. The topographical model encapsulates 5 factors (localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate), visualized utilizing dynamic 3-dimensional renderings. The central hypothesis is that, like symptom recrudescence in Uhthoff phenomenon and pseudoexacerbations, progression clinically recapitulates prior relapse symptoms and unmasks previously silent lesions, incrementally revealing underlying lesion topography. The model uses real-time simulation software to depict disease course archetypes and illuminate several well-described but poorly reconciled phenomena including the clinical/MRI paradox and prognostic significance of lesion location and burden on disease outcomes. Utilization of this model could allow for earlier and more clinically precise identification of progressive MS and predictive implications can be empirically tested. PMID:27648465

Nonnormality and Divergence in Posttreatment Alcohol Use

PubMed Central

Witkiewitz, Katie; van der Maas, Han L. J.; Hufford, Michael R.; Marlatt, G. Alan

2007-01-01

Alcohol lapses are the modal outcome following treatment for alcohol use disorders, yet many alcohol researchers have encountered limited success in the prediction and prevention of relapse. One hypothesis is that lapses are unpredictable, but another possibility is the complexity of the relapse process is not captured by traditional statistical methods. Data from Project Matching Alcohol Treatments to Client Heterogeneity (Project MATCH), a multisite alcohol treatment study, were reanalyzed with 2 statistical methodologies: catastrophe and 2-part growth mixture modeling. Drawing on previous investigations of self-efficacy as a dynamic predictor of relapse, the current study revisits the self-efficacy matching hypothesis, which was not statistically supported in Project MATCH. Results from both the catastrophe and growth mixture analyses demonstrated a dynamic relationship between self-efficacy and drinking outcomes. The growth mixture analyses provided evidence in support of the original matching hypothesis: Individuals with lower self-efficacy who received cognitive behavior therapy drank far less frequently than did those with low self-efficacy who received motivational therapy. These results highlight the dynamical nature of the relapse process and the importance of the use of methodologies that accommodate this complexity when evaluating treatment outcomes. PMID:17516769

Does maintenance CBT contribute to long-term treatment response of panic disorder with or without agoraphobia? A randomized controlled clinical trial.

PubMed

White, Kamila S; Payne, Laura A; Gorman, Jack M; Shear, M Katherine; Woods, Scott W; Saksa, John R; Barlow, David H

2013-02-01

We examined the possibility that maintenance cognitive behavior therapy (M-CBT) may improve the likelihood of sustained improvement and reduced relapse in a multi-site randomized controlled clinical trial of patients who met criteria for panic disorder with or without agoraphobia. Participants were all patients (N = 379) who first began an open trial of acute-phase CBT. Patients completing and responding to acute-phase treatment were randomized to receive either 9 monthly sessions of M-CBT (n = 79) or assessment only (n = 78) and were then followed for an additional 12 months without treatment. M-CBT produced significantly lower relapse rates (5.2%) and reduced work and social impairment compared to the assessment only condition (18.4%) at a 21-month follow-up. Multivariate Cox proportional hazards models showed that residual symptoms of agoraphobia at the end of acute-phase treatment were independently predictive of time to relapse during 21-month follow-up (hazards ratio = 1.15, p < .01). M-CBT aimed at reinforcing acute treatment gains to prevent relapse and offset disorder recurrence may improve long-term outcome for panic disorder with and without agoraphobia.

Does Maintenance CBT Contribute to Long-Term Treatment Response of Panic Disorder With or Without Agoraphobia? A Randomized Controlled Clinical Trial

PubMed Central

White, Kamila S.; Payne, Laura A.; Gorman, Jack M.; Shear, M. Katherine; Woods, Scott W.; Saksa, John R.; Barlow, David H.

2012-01-01

Objective To examine the possibility that maintenance cognitive behavior therapy (M–CBT) may improve the likelihood of sustained improvement and reduced relapse in a multi-site randomized controlled clinical trial of patients who met criteria for panic disorder with or without agoraphobia. Method Participants were all patients (N = 379) who first began an open trial of acute-phase CBT. Patients completing and responding to acute-phase treatment were randomized to receive either nine monthly sessions of M-CBT (n = 79) or assessment only (n = 78) and were then followed for an additional 12 months without treatment. Results M–CBT produced significantly lower relapse rates (5.2%) and reduced work and social impairment compared to the assessment only condition (18.4%) at a 21-month follow-up (MFU). Multivariate Cox proportional hazards models showed that residual symptoms of agoraphobia at the end of acute-phase treatment were independently predictive of time to relapse during 21-MFU (HR = 1.15, p < .01). Conclusions M–CBT aimed at reinforcing acute treatment gains to prevent relapse and offset disorder recurrence may improve long-term outcome in PD/A. PMID:23127290

Neuroscience of inhibition for addiction medicine: From prediction of initiation to prediction of relapse

PubMed Central

Moeller, Scott J.; Bederson, Lucia; Alia-Klein, Nelly; Goldstein, Rita Z.

2017-01-01

A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior. Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differences from healthy non-addicted controls during tasks of response inhibition accompanied by brain activation abnormalities as revealed by functional neuroimaging. However, it is less clear whether inhibition-related deficits predate the transition to problematic use, and, in turn, whether these deficits predict the transition out of problematic substance use. Here, we review longitudinal studies of response inhibition in children/adolescents with little substance experience and longitudinal studies of already-addicted individuals attempting to sustain abstinence. Results show that response inhibition, and its underlying neural correlates, predict both substance use outcomes (onset and abstinence). Neurally, key roles were observed for multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex). In general, less activation of these regions during response inhibition predicted not only the onset of substance use, but interestingly, also better abstinence-related outcomes among individuals already addicted. The role of subcortical areas, although potentially important, is less clear because of inconsistent results and because these regions are less classically reported in studies of healthy response inhibition. Overall, this review indicates that response inhibition is not simply a manifestation of current drug addiction, but rather a core neurocognitive dimension that predicts key substance use outcomes. Early intervention in inhibitory deficits could have high clinical and public health relevance. PMID:26806776

NCI 1st International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Summary and Recommendations from the Organizing Committee

PubMed Central

Bishop, Michael R.; Alyea, Edwin P.; Cairo, Mitchell S.; Falkenburg, J.H. Frederik; June, Carl H.; Kröger, Nicolaus; Little, Richard F.; Miller, Jeffrey S.; Pavletic, Steven Z.; Porter, David L.; Riddell, Stanley R.; van Besien, Koen; Wayne, Alan S.; Weisdorf, Daniel J.; Wu, Roy S.; Giralt, Sergio

2011-01-01

The First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT). Each of the Workshop’s six working committees have published individual reports of ongoing basic, translational and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention and treatment. This document summarizes each of the committees’ recommendations and suggests three major initiatives for a coordinated research effort to address the problem of relapse after alloHSCT. The first is the need to establish multi-center correlative and clinical trials networks for basic/translational, epidemiological, and clinical research. Second, there is a need for a network of biorepositories for the collection of samples pre- and post-alloHSCT to aid in laboratory and clinical studies. Third, there should be further refinement, implementation, and study of the proposed Workshop disease-specific response and relapse definitions and the recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplant organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse following alloHSCT. PMID:21224011

Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in Ulcerative Colitis: systematic review and meta-analysis.

PubMed

Ford, Alexander C; Khan, Khurram J; Achkar, Jean-Paul; Moayyedi, Paul

2012-02-01

Efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, no recent meta-analysis has studied the relative efficacies of differing routes of administration. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through May 2011). Eligible trials recruited adults with mildly to moderately active UC, or quiescent UC, and compared oral 5-ASAs with either topical 5-ASAs or a combination of oral and topical 5-ASAs. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. The search identified 3,061 citations, and 12 randomized controlled trials (RCTs) were eligible. Four compared topical with oral 5-ASAs in active UC remission, with an RR of no remission with topical 5-ASAs of 0.82 (95% CI=0.52-1.28). Four trials compared combined with oral 5-ASAs in active UC (RR of no remission=0.65; 95% CI=0.47-0.91; NNT=5). Three RCTs compared intermittent topical with oral 5-ASAs in preventing relapse of quiescent UC (RR=0.64; 95% CI=0.43-0.95; NNT=4), and two compared combined with oral 5-ASAs (RR of relapse=0.48; 95% CI=0.17-1.38). Combined 5-ASA therapy appeared superior to oral 5-ASAs for induction of remission of mildly to moderately active UC. Intermittent topical 5-ASAs appeared superior to oral 5-ASAs for preventing relapse of quiescent UC.

Predictors of postretention stability of mandibular dental arch dimensions in patients treated with a lip bumper during mixed dentition followed by fixed appliances.

PubMed

Raucci, Gaetana; Pachêco-Pereira, Camila; Elyasi, Maryam; d'Apuzzo, Fabrizia; Flores-Mir, Carlos; Perillo, Letizia

2017-03-01

To identify which dental and/or cephalometric variables were predictors of postretention mandibular dental arch stability in patients who underwent treatment with transpalatal arch and lip bumper during mixed dentition followed by full fixed appliances in the permanent dentition. Thirty-one patients were divided into stable and relapse groups based on the postretention presence or absence of relapse. Intercuspid, interpremolar, and intermolar widths; arch length and perimeter; crowding; and lower incisor proclination were evaluated before treatment (T0), after lip bumper treatment (T1), after fixed appliance treatment (T2), and a minimum of 3 years after removal of the full fixed appliance (T3). Logistic regression analyses were performed to evaluate the effect of changes between T0 and T1, as predictive variables, on the occurrence of relapse at T3. The model explained 53.5 % of the variance in treatment stability and correctly classified 80.6 % of the sample. Of the seven prediction variables, intermolar and interpremolar changes between T0 and T1 (P = .024 and P = .034, respectively) were statistically significant. For every millimeter of increase in intermolar and interpremolar widths there was a 1.52 and 2.70 times increase, respectively, in the odds of having stability. There was also weak evidence for the effect of sex (P = .047). The best predictors of an average 4-year postretention mandibular dental arch stability after treatment with a lip bumper followed by full fixed appliances were intermolar and interpremolar width increases during lip bumper therapy. The amount of relapse in this crowding could be considered clinically irrelevant.

Prediction of minimal residual viremia in HCV type 1 infected patients receiving interferon-based therapy.

PubMed

Knop, Viola; Teuber, Gerlinde; Klinker, Hartwig; Möller, Bernd; Rasenack, Jens; Hinrichsen, Holger; Gerlach, Tilman; Spengler, Ulrich; Buggisch, Peter; Neumann, Konrad; Sarrazin, Christoph; Zeuzem, Stefan; Berg, Thomas

2013-01-01

Complete suppression of viral replication is crucial in chronic HCV treatment in order to prevent relapse and resistance development. We wanted to find out which factors influence the period from being already HCV RNA negative by bDNA assay (< 615 IU/mL) to become undetectable by the more sensitive TMA test (< 5.3 IU/mL). Evaluated were 433 HCV type 1-infected patients. All of them received 1.5 ug/kg Peg-IFNα-2b plus ribavirin for 18-48 weeks. bDNA was performed weekly during the first 8 weeks and thereafter at weeks 12, 24, and 48. Patients who became bDNA undetectable were additionally analysed by TMA. Of the 309 patients with on-treatment response (< 615 IU/mL), 289 also reached undetectable HCV RNA levels by TMA. Multivariate analysis revealed that viremia ≤ 400,000 IU/mL (p = 0.001), fast initial virologic decline (p = 0.004) and absence of fibrosis (p = 0.035) were independent predictors of an accelerated on-treatment response by TMA assay in already bDNA negative patients. bDNA negative patients becoming HCV RNA undetectable by TMA within the following 3 weeks had a frequency of relapse of 21%, whereas those showing TMA negativity after 3 weeks relapsed in 38% (p = 0.001). In RVR patients (bDNA < 615 IU/mL at week 4) the corresponding relapse rates were 15.3% vs. 37.5%, respectively (p = 0.003). Early viral kinetics, baseline viremia and fibrosis stage are important tools to predict persistent minimal viremia during interferon-based therapy. The data have implications for designing a more refined treatment strategy in HCV infection, even in the setting of protease inhibitor-based triple treatment.

The value of FDG PET/CT for follow-up of patients with melanoma: a retrospective analysis

PubMed Central

Vensby, Philip H; Schmidt, Grethe; Kjær, Andreas; Fischer, Barbara M

2017-01-01

The incidence of melanoma (MM) is among the fastest rising cancers in the western countries. Positron Emission Tomography with Computed Tomography (PET/CT) is a valuable non-invasive tool for the diagnosis and staging of patients with MM. However, research on the value of PET/CT in follow-up of melanoma patients is limited. This study assesses the diagnostic value of PET/CT for follow-up after melanoma surgery. This retrospective study includes patients with MM who performed at least one PET/CT scan after initial surgery and staging. PET/CT findings were compared to histology, MRI or fine needle aspiration (FNA) to estimate the diagnostic accuracy. The diagnostic performance of PET/CT performed in patients with and without a clinical suspicion of relapse was compared. 238 patients (526 scans) were included. Of the 526 scans 130 (25%) scans were PET-positive, 365 (69%) PET-negative, and 28 (5%) had equivocal findings. Sensitivity was 89% [0.82-0.94], specificity 92% [0.89-0.95], positive and negative predictive values of 78% [0.70-0.84] and 97% [0.94-0.98] respectively. When stratified for reason of referral there was no statistical significant difference in the diagnostic accuracy of PET/CT between patients referred with or without a clinical suspicion of relapse. This study demonstrates that PET/CT despite a moderate sensitivity has a high negative predictive value in the follow-up of melanoma patients. Thus, a negative PET/CT-scan essentially rules out relapse. However, the frequency of false positive findings is relatively high, especially among patients undergoing a “routine” PET/CT with no clinical suspicion of relapse, potentially causing anxiety and leading to further diagnostic procedures. PMID:29348980

The value of FDG PET/CT for follow-up of patients with melanoma: a retrospective analysis.

PubMed

Vensby, Philip H; Schmidt, Grethe; Kjær, Andreas; Fischer, Barbara M

2017-01-01

The incidence of melanoma (MM) is among the fastest rising cancers in the western countries. Positron Emission Tomography with Computed Tomography (PET/CT) is a valuable non-invasive tool for the diagnosis and staging of patients with MM. However, research on the value of PET/CT in follow-up of melanoma patients is limited. This study assesses the diagnostic value of PET/CT for follow-up after melanoma surgery. This retrospective study includes patients with MM who performed at least one PET/CT scan after initial surgery and staging. PET/CT findings were compared to histology, MRI or fine needle aspiration (FNA) to estimate the diagnostic accuracy. The diagnostic performance of PET/CT performed in patients with and without a clinical suspicion of relapse was compared. 238 patients (526 scans) were included. Of the 526 scans 130 (25%) scans were PET-positive, 365 (69%) PET-negative, and 28 (5%) had equivocal findings. Sensitivity was 89% [0.82-0.94], specificity 92% [0.89-0.95], positive and negative predictive values of 78% [0.70-0.84] and 97% [0.94-0.98] respectively. When stratified for reason of referral there was no statistical significant difference in the diagnostic accuracy of PET/CT between patients referred with or without a clinical suspicion of relapse. This study demonstrates that PET/CT despite a moderate sensitivity has a high negative predictive value in the follow-up of melanoma patients. Thus, a negative PET/CT-scan essentially rules out relapse. However, the frequency of false positive findings is relatively high, especially among patients undergoing a "routine" PET/CT with no clinical suspicion of relapse, potentially causing anxiety and leading to further diagnostic procedures.

Comparison of the prognostic impact of serum anti-EBV antibody and plasma EBV DNA assays in nasopharyngeal carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Twu, C.-W.; Department of Otorhinolaryngology, Taichung Veterans General Hospital, Taichung; Wang, W.-Y.

Purpose: Nasopharyngeal carcinoma (NPC) has been proven as an Epstein-Barr virus (EBV)-associated cancer. Serum anti-EBV antibodies and plasma EBV DNA have been investigated as surrogate markers for NPC. A comparison of the prognostic impacts of both assays has never been reported. Methods and Materials: Paired serum and plasma samples from 114 previously untreated NPC patients were collected and subjected to an immunofluorescence assay for immunoglobulin (Ig)A and IgG antibodies against the viral capsid antigen (VCA) and a real-time quantitative polymerase chain reaction assay for EBV DNA measurement. The effects of both assays on patient prognosis were thoroughly investigated. Results: Relapsedmore » patients had significantly higher pretreatment EBV DNA concentration than patients without relapse (p 0.0006). No associations of VCA-IgA (p = 0.9669) or VCA-IgG (p = 0.6125) were observed between patients with and without relapse. The 4-year overall survival (60.3% vs. 93.1%, p < 0.0001) and relapse-free survival rates (54.4% vs. 77.9%, p = 0.0009) were significantly lower in patients with higher pretreatment EBV DNA load than in those with lower EBV DNA load. Patients with persistently detectable EBV DNA after treatment had significantly worse 4-year overall (30.8% vs. 84.6%, p < 0.0001) and relapse-free survival rates (15.4% vs. 74.0%, p < 0.0001) than those with undetectable EBV DNA. The VCA-IgA and VCA-IgG titer could not predict survivals (all p > 0.1). Cox multivariate analyses also showed the same results. Conclusion: Plasma EBV DNA is superior to serum EBV VCA antibodies in prognostic predictions for NPC.« less

Association of peripheral inflammation with body mass index and depressive relapse in bipolar disorder.

PubMed

Bond, David J; Andreazza, Ana C; Hughes, John; Dhanoa, Taj; Torres, Ivan J; Kozicky, Jan-Marie; Young, L Trevor; Lam, Raymond W; Yatham, Lakshmi N

2016-03-01

Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cognitive and affective trait and state factors influencing the long-term symptom course in remitted depressed patients.

PubMed

Timm, Christina; Ubl, Bettina; Zamoscik, Vera; Ebner-Priemer, Ulrich; Reinhard, Iris; Huffziger, Silke; Kirsch, Peter; Kuehner, Christine

2017-01-01

Major depressive disorder (MDD) is characterized by a high risk for relapses and chronic developments. Clinical characteristics such as residual symptoms have been shown to negatively affect the long-term course of MDD. However, it is unclear so far how trait repetitive negative thinking (RNT) as well as cognitive and affective momentary states, the latter experienced during daily-life, affect the long-term course of MDD. We followed up 57 remitted depressed (rMDD) individuals six (T2) and 36 (T3) months after baseline. Clinical outcomes were time to relapse, time spent with significant symptoms as a marker of chronicity, and levels of depressive symptoms at T2 and T3. Predictors assessed at baseline included residual symptoms and trait RNT. Furthermore, momentary daily life affect and momentary rumination, and their variation over the day were assessed at baseline using ambulatory assessment (AA). In multiple models, residual symptoms and instability of daily-life affect at baseline independently predicted a faster time to relapse, while chronicity was significantly predicted by trait RNT. Multilevel models revealed that depressive symptom levels during follow-up were predicted by baseline residual symptom levels and by instability of daily-life rumination. Both instability features were linked to a higher number of anamnestic MDD episodes. Our findings indicate that trait RNT, but also affective and cognitive processes during daily life impact the longer-term course of MDD. Future longitudinal research on the role of respective AA-phenotypes as potential transdiagnostic course-modifiers is warranted.

Detailed spectral profile analysis of electrocorticograms during freezing against penicillin-induced epileptiform discharges in the anesthetized rat.

PubMed

Tokiwa, Tatsuji; Zimin, Lev; Inoue, Takao; Nomura, Sadahiro; Suzuki, Michiyasu; Yamakawa, Takeshi

2018-07-01

Cryosurgery is an alternative technique for minimally invasive treatment of lesions. We have recently examined cryosurgery for epilepsy in animal models, and found that penicillin G (PG)-induced epileptiform discharges (EDs) mostly vanished after freezing. However, EDs were provoked again after insufficient freezing. Inadequate freezing is not visually detectable during and just after freezing and is not predictable beforehand. To manage this problem, we examined whether intraoperative monitoring of electrocorticograms (ECoGs) can predict recurrence of EDs after cryosurgery. A palm-sized cryoprobe system was applied to focal seizures in a Wistar rat model in which EDs were induced in advance by intracerebral injection of PG. During stable induction of EDs, the cryoprobe was carefully inserted into the epileptic region and this region was immediately frozen. After the series of prefreezing, freezing, and postfreezing, rats in which PG-induced EDs relapsed within 3 h were defined as the ED-relapsed (EDR) group, and other rats were defined as the ED-vanished (EDV) group. Time-frequency analysis was conducted on the ECoGs in each group through each freezing series. Relapse of PG-induced EDs on ECoG after the freezing series was associated with the remaining power of the delta band in the freezing period more strongly in the EDR group than in the EDV group. Success or failure of the freezing procedure can be predicted by the specificity of the delta band of the ECoG obtained intraoperatively. Copyright © 2018 Elsevier B.V. All rights reserved.

Smoking cessation treatment and outcomes patterns simulation: a new framework for evaluating the potential health and economic impact of smoking cessation interventions.

PubMed

Getsios, Denis; Marton, Jenő P; Revankar, Nikhil; Ward, Alexandra J; Willke, Richard J; Rublee, Dale; Ishak, K Jack; Xenakis, James G

2013-09-01

Most existing models of smoking cessation treatments have considered a single quit attempt when modelling long-term outcomes. To develop a model to simulate smokers over their lifetimes accounting for multiple quit attempts and relapses which will allow for prediction of the long-term health and economic impact of smoking cessation strategies. A discrete event simulation (DES) that models individuals' life course of smoking behaviours, attempts to quit, and the cumulative impact on health and economic outcomes was developed. Each individual is assigned one of the available strategies used to support each quit attempt; the outcome of each attempt, time to relapses if abstinence is achieved, and time between quit attempts is tracked. Based on each individual's smoking or abstinence patterns, the risk of developing diseases associated with smoking (chronic obstructive pulmonary disease, lung cancer, myocardial infarction and stroke) is determined and the corresponding costs, changes to mortality, and quality of life assigned. Direct costs are assessed from the perspective of a comprehensive US healthcare payer ($US, 2012 values). Quit attempt strategies that can be evaluated in the current simulation include unassisted quit attempts, brief counselling, behavioural modification therapy, nicotine replacement therapy, bupropion, and varenicline, with the selection of strategies and time between quit attempts based on equations derived from survey data. Equations predicting the success of quit attempts as well as the short-term probability of relapse were derived from five varenicline clinical trials. Concordance between the five trials and predictions from the simulation on abstinence at 12 months was high, indicating that the equations predicting success and relapse in the first year following a quit attempt were reliable. Predictions allowing for only a single quit attempt versus unrestricted attempts demonstrate important differences, with the single quit attempt simulation predicting 19 % more smoking-related diseases and 10 % higher costs associated with smoking-related diseases. Differences are most prominent in predictions of the time that individuals abstain from smoking: 13.2 years on average over a lifetime allowing for multiple quit attempts, versus only 1.2 years with single quit attempts. Differences in abstinence time estimates become substantial only 5 years into the simulation. In the multiple quit attempt simulations, younger individuals survived longer, yet had lower lifetime smoking-related disease and total costs, while the opposite was true for those with high levels of nicotine dependence. By allowing for multiple quit attempts over the course of individuals' lives, the simulation can provide more reliable estimates on the health and economic impact of interventions designed to increase abstinence from smoking. Furthermore, the individual nature of the simulation allows for evaluation of outcomes in populations with different baseline profiles. DES provides a framework for comprehensive and appropriate predictions when applied to smoking cessation over smoker lifetimes.

Oxidative Stress is Increased in Serum from Mexican Patients with Relapsing-Remitting Multiple Sclerosis

PubMed Central

Ortiz, Genaro Gabriel; Macías-Islas, Miguel Ángel; Pacheco-Moisés, Fermín P.; Cruz-Ramos, José A.; Sustersik, Silvia; Barba, Elías Alejandro; Aguayo, Adriana

2009-01-01

Objective: To determine the oxidative stress markers in serum from patients with relapsing-remitting multiple sclerosis. Methods: Blood samples from healthy controls and 22 patients 15 women (7 aged from 20 to 30 and 8 were > 40 years old) and 7 men (5 aged from 20 to 30 and 2 were > 40 years old) fulfilling the McDonald Criteria and classified as having Relapsing-Remitting Multiple Sclerosis accordingly with Lublin were collected for oxidative stress markers quantification. Results: Nitric oxide metabolites (nitrates/nitrites), lipid peroxidation products (malondialdehyde plus 4-hidroxialkenals), and glutathione peroxidase activity were significantly increased in serum of subjects with relapsing-remitting multiple sclerosis in comparison with that of healthy controls. These data support the hypothesis that multiple sclerosis is a component closely linked to oxidative stress. PMID:19242067

Incidence and Outcomes of Central Nervous System Hemophagocytic Lymphohistiocytosis Relapse after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation.

PubMed

Lounder, Dana T; Khandelwal, Pooja; Chandra, Sharat; Jordan, Michael B; Kumar, Ashish R; Grimley, Michael S; Davies, Stella M; Bleesing, Jack J; Marsh, Rebecca A

2017-05-01

Hemophagocytic lymphohistiocytosis (HLH) is an immune regulatory disorder that commonly presents with central nervous system (CNS) involvement. The only cure for genetic HLH is hematopoietic stem cell transplantation (HSCT), typically treated with reduced-intensity conditioning (RIC) regimens. We sought to estimate the incidence of CNS relapse after RIC HSCT, determine risk factors, and evaluate outcomes. We performed a retrospective chart review of 94 consecutive children and young adults with primary HLH who received RIC HSCT. CNS relapse within 1 year after transplantation was diagnosed by review of clinical symptoms, cerebral spinal fluid (CSF), and radiologic findings. Four (4.25%) patients developed symptoms of possible CNS HLH after HSCT and 3 patients were diagnosed. Eight patients underwent screening lumbar puncture because of history of active CNS disease at the onset of the conditioning regimen and 4 had evidence of continued disease. The overall incidence of CNS relapse and continued CNS disease after RIC HSCT was 8%. All patients with CNS disease after HSCT responded to CNS-directed therapy. Whole blood donor chimerism at the time of CNS relapse was low at 1% to 34%, but it remained high at 88% to 100% for patients with continued CNS disease. Overall survival for patients with CNS relapse was 50%, compared with 75% for patients without CNS disease (P = .079). Our data suggest that a low level of donor chimerism or active CNS disease at the time of transplantation increase the risk of CNS HLH after HSCT. Surveillance CSF evaluation after allogeneic RIC HSCT should be considered in patients with risk factors and CNS-directed treatment should be initiated if appropriate. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Stratification of medulloblastoma on the basis of histopathological grading.

PubMed

Giangaspero, Felice; Wellek, Stefan; Masuoka, Jun; Gessi, Marco; Kleihues, Paul; Ohgaki, Hiroko

2006-07-01

Medulloblastoma (WHO grade IV) is an embryonal tumour of the cerebellum and the most common malignant central nervous system tumour in children. Despite significant advances in treatment, 5-year survival rates are still less than 70%, suggesting the presence of subgroups with different response to radio/chemotherapy. In the present study, we re-evaluated a series of 347 medulloblastomas from the SIOP II clinical trial of the International Society of Paediatric Oncology to identify features predictive of clinical outcome. Relapse free survival for medulloblastomas with severe anaplasia [5-year rate: S(60)=49.5%], was significantly shorter than for tumours with moderate or mild anaplasia S(60)=65.4%; P=0.001). The difference between both groups was even larger when the presence or absence of extensive apoptosis was included (46.5 vs. 66.7%; P=0.0216). Other histological features including nodularity, necrosis, vascular proliferation and the presence of beta-catenin mutations (7% of cases) were not predictive for relapse free survival. These findings indicate that degree of anaplasia is the most significant histologic feature predictive of the survival of medulloblastoma patients.

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients.

PubMed

Ebbo, Mikael; Grados, Aurélie; Samson, Maxime; Groh, Matthieu; Loundou, Anderson; Rigolet, Aude; Terrier, Benjamin; Guillaud, Constance; Carra-Dallière, Clarisse; Renou, Frédéric; Pozdzik, Agnieszka; Labauge, Pierre; Palat, Sylvain; Berthelot, Jean-Marie; Pennaforte, Jean-Loup; Wynckel, Alain; Lebas, Céline; Le Gouellec, Noémie; Quémeneur, Thomas; Dahan, Karine; Carbonnel, Franck; Leroux, Gaëlle; Perlat, Antoinette; Mathian, Alexis; Cacoub, Patrice; Hachulla, Eric; Costedoat-Chalumeau, Nathalie; Harlé, Jean-Robert; Schleinitz, Nicolas

2017-01-01

To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients. Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients. RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.

Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy.

PubMed

Guillevin, R; Menuel, C; Taillibert, S; Capelle, L; Costalat, R; Abud, L; Habas, C; De Marco, G; Hoang-Xuan, K; Chiras, J; Vallée, J-N

2011-06-07

This study was designed to evaluate proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ). This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and (1)H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results. A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated over time (Spearman ρ=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ΔV(n)/V(o)), according to a linear regression (P<0.001) in the 'response/no relapse' patient group, and with the evolution of the mean tumour volume (meanV(n)), according to an exponential regression (P<0.001) in the 'response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Δ(Cho/Cr)(n)/(Cho/Cr)(o)), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)(n)-(Cho/Cr)(n))/(Cho/NAA)(n), at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004). The (1)H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, (1)H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ.

Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy

PubMed Central

Guillevin, R; Menuel, C; Taillibert, S; Capelle, L; Costalat, R; Abud, L; Habas, C; De Marco, G; Hoang-Xuan, K; Chiras, J; Vallée, J-N

2011-01-01

Background: This study was designed to evaluate proton magnetic resonance spectroscopy (1H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ). Methods: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and 1H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results. Results: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)n and mean(Cho/NAA)n, were significantly correlated over time (Spearman ρ=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)n and mean(Cho/NAA)n, were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ΔVn/Vo), according to a linear regression (P<0.001) in the ‘response/no relapse' patient group, and with the evolution of the mean tumour volume (meanVn), according to an exponential regression (P<0.001) in the ‘response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Δ(Cho/Cr)n/(Cho/Cr)o), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)n−(Cho/Cr)n)/(Cho/NAA)n, at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004). Conclusions: The 1H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, 1H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ. PMID:21610707

Soluble thrombomodulin levels in plasma of multiple sclerosis patients and their implication.

PubMed

Festoff, Barry W; Li, Chaoyang; Woodhams, Barry; Lynch, Sharon

2012-12-15

Thrombomodulin (TM) on the cell-surface of cerebrovascular endothelial cells (CECs) is released into blood upon CEC damage. TM promotes activation of protein C (APC), an anticoagulant, anti-inflammatory, neuroprotective molecule that protects CECs and impedes inflammatory cell migration across the blood-brain barrier (BBB). Multiple sclerosis (MS) is associated with CEC damage and BBB dysfunction. We evaluated soluble TM (sTM) levels as a biomarker of BBB integrity and whether glatiramer acetate (GA) influenced sTM levels in MS patients. sTM levels quantified by 2-site ELISA from sera of healthy controls and systemic lupus erythematosus (SLE) patients (CEC-damage positive control) were compared with levels from patients with relapsing-remitting (RRMS) or secondary-progressive MS (SPMS), stratified as: RRMS/GA/no relapse, RRMS/GA/in relapse, RRMS no GA/no relapse, RRMS/no GA/in relapse; and SPMS/no GA. Additionally, soluble endothelial protein C receptor (sEPCR) levels were assessed in the non-stratified MS group, SLE patients, and controls. sTM levels were highest in RRMS patients taking GA with or without relapse, followed in decreasing order by SLE, RRMS/no GA/in relapse, SPMS, RRMS/no GA/no relapse, healthy controls. sEPCR levels were highest in MS patients, then SLE, then controls. sTM may be a useful biomarker of BBB integrity in RRMS patients. Further evaluation of sEPCR is needed. The finding that the highest sTM levels were in RRMS patients taking GA is interesting and warrants further investigation. Published by Elsevier B.V.

Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) enrolled in two prospective trials.

PubMed

Samson, Maxime; Puéchal, Xavier; Devilliers, Hervé; Ribi, Camillo; Cohen, Pascal; Stern, Marc; Pagnoux, Christian; Mouthon, Luc; Guillevin, Loïc

2013-06-01

The purpose of this study was to assess the outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in 2 prospective, randomized, open-label clinical trials (1994-2005), with or without Five-Factor Score (FFS)-defined poor-prognosis factors, focusing on survival, disease-free survival, relapses, clinical and laboratory findings, therapeutic responses, and factors predictive of relapse. Forty-four patients with FFS ≥ 1 were assigned to receive 6 or 12 cyclophosphamide pulses plus corticosteroids and the seventy-four with FFS = 0 received corticosteroids alone, with immunosuppressant adjunction when corticosteroids failed. Patients were followed (2005-2011) under routine clinical care in an extended study and data were recorded prospectively. Mean ± SD follow-up was 81.3 ± 39.6 months. Among the 118 patients studied, 29% achieved long-term remission and 10% died. Among the 115 patients achieving a first remission, 41% experienced ≥1 relapses, 26.1 ± 26.8 months after treatment onset, with 57% of relapses occurring when corticosteroid-tapering reached <10 mg/day. Treatment achieved new remissions in >90%, but relapses recurred in 38%. Overall survival was good, reaching 90% at 7 years, regardless of baseline severity. Age ≥65 years was the only factor associated with a higher risk of death during follow-up. The risk of relapse was higher for patients with anti-myeloperoxidase antibodies and lower for those with >3000 eosinophils/mm(3). Sequelae remained frequent, usually chronic asthma and peripheral neuropathy. In conclusion, EGPA patients' survival rate is very good when treatment is stratified according to the baseline FFS. Relapses are frequent, especially in patients with anti-myeloperoxidase antibodies and baseline eosinophilia <3000/mm(3). Copyright © 2013 Elsevier Ltd. All rights reserved.

The Second Antithyroid Drug Treatment Is Effective in Relapsed Graves' Disease Patients: A Median 11-Year Follow-Up Study.

PubMed

Kim, Ye An; Cho, Sun Wook; Choi, Hoon Sung; Moon, Shinje; Moon, Jae Hoon; Kim, Kyung Won; Park, Do Joon; Yi, Ka Hee; Park, Young Joo; Cho, Bo Youn

2017-04-01

Antithyroid drug (ATD) is a widely used treatment for Graves' disease (GD). However, its long-term efficiency remains unclear. This study investigated the long-term disease prognosis and predictive factors for relapse in ATD-treated GD patients. Newly diagnosed, ATD-treated GD patients with at least four years of follow-up were recruited (n = 187). Remission was defined as maintaining a euthyroid status for more than one year after ATD withdrawal. During 11.1 years (range 4.0-23.7 years) of median follow-up, overall, 51.9% of the newly diagnosed ATD-treated GD patients achieved remission, 32.1% continued ATD treatment, and 13.4% underwent other ablation treatments. The 10-year remission rates were higher in the first (34.2%) and second (25.5%) ATD courses than in any of the other subsequent ATD courses, and decreased as ATD treatments were repeated. The 10-year relapse rate was the highest after the third ATD treatment (71.4%) compared with that after the first (60.5%) and second (58.3%) courses. Longer duration of ATD treatment (odds ratio [OR] = 1.4 [confidence interval (CI) 1.2-1.7], p < 0.001), higher number of relapses (OR = 4.7 [CI 2.3-9.8], p < 0.001), and moderate to severe Graves' ophthalmopathy (OR = 4.1 [CI 1.1-15.2], p = 0.032) were associated with persistent disease status. A second course of ATD can be considered for GD patients after the first relapse because the chance of remission and the relapse rate are similar to the one after the first ATD treatment course. For GD patients with more than two relapses, or with an ATD treatment duration of more than four to five years, low-dose maintenance of ATD or ablative treatment needs to be considered.

The budget impact of introducing delayed-release dimethyl fumarate for treatment of relapse-remitting multiple sclerosis in Canada.

PubMed

Dorman, Emily; Kansal, Anuraag R; Sarda, Sujata

2015-01-01

Multiple sclerosis (MS) causes significant disability globally and is especially prevalent in Canada. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an orally administered disease-modifying treatment (DMT) for patients with relapsing-remitting MS (RRMS) that is currently on the market in the US, Australia, Canada, and Europe. A budget impact model (BIM) was developed to assess the financial consequences of introducing DMF for treatment of RRMS in Canada. A BIM calculated the financial consequences of introducing DMF in Canada over 3 years based on RRMS prevalence, treatment market share, and clinical effects. RRMS prevalence in Canada was derived from published literature and natural relapse rates, and disease state distribution from clinical trial data. It was conservatively assumed that 100% of RRMS patients were treated with a DMT. DMF was assumed to absorb market share proportionally from the following current treatments: interferon beta-1a-IM, interferon beta-1a-SC, interferon beta-1b, and glatiramer acetate. Treatment efficacy, in terms of relapse rate reductions and treatment discontinuation rates, was determined from mixed treatment comparison. Treatment costs (including costs of acquisition, monitoring, and administration) and cost of relapse were considered. Deterministic one-way sensitivity analyses were conducted to assess the most sensitive input parameters. Over 3 years, the introduction of DMF resulted in an average annual increase of CAD417 per treated patient per year, with reductions in costs associated with relapses (CAD192/patient/year) partially offsetting increased drug acquisition costs (CAD602/patient/year). On a population level, the average annual cost increase was CAD24,654,237, a CAD 0.68 increase per population covered by the Canadian healthcare system. The main drivers of budget impact were drop-out rates, proportion of RRMS patients treated, and market share assumptions. The acquisition costs of DMF for treatment of RRMS are predicted to be partially offset by reduced costs of relapses in the Canadian healthcare system.

Depression and eating disorders: treatment and course.

PubMed

Mischoulon, David; Eddy, Kamryn T; Keshaviah, Aparna; Dinescu, Diana; Ross, Stephanie L; Kass, Andrea E; Franko, Debra L; Herzog, David B

2011-05-01

We examined the course of major depressive disorder (MDD) and predictors of MDD recovery and relapse in a longitudinal sample of women with eating disorders (ED). 246 Boston-area women with DSM-IV anorexia nervosa-restricting (ANR; n=51), AN-binge/purge (ANBP; n=85), and bulimia nervosa (BN; n=110) were recruited between 1987 and 1991 and interviewed using the Eating Disorders Longitudinal Interval Follow-up Evaluation (LIFE-EAT-II) every 6-12 months for up to 12 years. 100 participants had MDD at study intake and 45 developed MDD during the study. Psychological functioning and treatment were assessed. Times to MDD onset (1 week-4.3 years), recovery (8 weeks-8.7 years), and relapse (1 week-5.2 years) varied. 70% recovered from MDD, but 65% subsequently relapsed. ANR patients were significantly less likely to recover from MDD than ANBP patients (p=0.029). Better psychological functioning and history of MDD were associated with higher chance of MDD recovery. Higher baseline depressive severity and full recovery from ED were associated with greater likelihood of MDD relapse; increased weight loss was somewhat protective. Adequate antidepressant treatment was given to 72% of patients with MDD and generally continued after MDD recovery. Time on antidepressants did not predict MDD recovery (p=0.27) or relapse (p=0.26). Small ED diagnostic subgroups; lack of non-ED control group. The course of MDD in EDs is protracted; MDD recovery may depend on ED type. Antidepressants did not impact likelihood of MDD recovery, nor protect against relapse, which may impact on treatment strategies for comorbid MDD and EDs. Copyright © 2010 Elsevier B.V. All rights reserved.

Psychometric properties of the Persian version of the Time to Relapse Questionnaire (TRQ) in substance use disorder.

PubMed

Khazaee-Pool, Maryam; Moridi, Minoo; Ponnet, Koen; Turner, Nigel; Pashaei, Tahereh

2016-11-01

Predicting time to relapse provides an opportunity for the development of relapse prevention interventions in drug users. The aim of the present study was to describe the development of the Persian version of the 9-item Time to Relapse Questionnaire (TRQ) and to evaluate its psychometric properties in an Iranian sample of treatment-seeking individuals with substance dependence (n = 150). The forward-backward method was used to translate the TRQ scale from English into Persian. After linguistic validation and a pilot check, a cross-sectional study was performed, and psychometric properties of the Iranian version of the questionnaire were assessed. The reliability was evaluated by Cronbach's alpha and test-retest analyses. In addition, the factor structure of the scale was extracted by applying confirmatory factor analysis. The mean age of participants was 40.52 (SD = 11.30) years. The mean scores for the content validity index (CVI) and the content validity ratio (CVR) were 0.93 and 0.81, respectively. A confirmatory factor analysis (CFA) demonstrated that the three-factor model of the TRQ was a good fit for the data and thus replicated the factor structure of the original English language TRQ. Cronbach's alpha presented good internal consistency (alpha = 0.76), and test-retest reliability of the TRQ instrument with 2-week intervals was appropriate (ICC = 0.84). The findings demonstrate that the Persian version of the TRQ is a reliable and valid scale for measuring time to relapse in Iranian drug users. The TRQ can be applied at the start of treatment so that clinical interventions can be targeted toward the different relapse styles.

MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle.

PubMed

Yang, I-Ping; Tsai, Hsiang-Lin; Hou, Ming-Feng; Chen, Ku-Chung; Tsai, Pei-Chien; Huang, Szu-Wei; Chou, Wen-Wen; Wang, Jaw-Yuan; Juo, Suh-Hang Hank

2012-08-01

Colorectal cancer (CRC) is associated with high recurrence and mortality. Because deregulation of microRNAs is associated with CRC development and recurrence, the expression levels of microRNAs can be a simple and reliable biomarker to detect postoperative early relapse, thereby helping physicians to treat high-risk patients more efficiently. We used microRNA arrays and observed that microRNA-93 had substantially different expression levels in early (recurrence within 12 months after surgery) and non-early relapse CRC patients. The replication study, which included 35 early relapse and 42 non-early relapse subjects, further confirmed overexpression of microRNA-93 in non-early relapse samples. The in vitro and in vivo effects of microRNA-93 were investigated by examining cell proliferation, migration and invasion, as well as cell cycles, target-gene expression and xenograft in null mice. Cellular studies showed that the overexpression of microRNA-93 inhibited colon cancer cell proliferation and migration but not invasion. The cell cycle studies also revealed that microRNA-93 caused an accumulation of the G2 population. However, microRNA-93 could not induce cell apoptosis or necrosis. Functional studies showed that microRNA-93 could suppress CCNB1 protein expression leading to cell cycle arrest in the G2 phase. Moreover, microRNA-93 repressed expression of ERBB2, p21 and VEGF, all of which are involved in cell proliferation. MicroRNA-93 also suppressed tumor growth in null mice. This study showed that microRNA-93 can inhibit tumorigenesis and reduce the recurrence of CRC; these findings may have potential clinical applications for predicting the recurrence of CRC.

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

PubMed

Studer, Valeria; Rocchi, Camilla; Motta, Caterina; Lauretti, Benedetta; Perugini, Jacopo; Brambilla, Laura; Pareja-Gutierrez, Lorena; Camera, Giorgia; Barbieri, Francesca Romana; Marfia, Girolama A; Centonze, Diego; Rossi, Silvia

2017-01-01

Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Hope, coping skills, and the prefrontal cortex in alcohol use disorder recovery.

PubMed

Bradshaw, Spencer D; Shumway, Sterling T; Dsauza, Cynthia M; Morris, Neli; Hayes, Nicholas D

2017-09-01

Alcohol use disorders adversely affect individual and societal health. These disorders are a chronic brain disease, and protective factors against relapse should be studied. Prefrontal cortex (PFC) dysfunction is evident in alcohol use disorders, and research that explores recovery of the PFC in alcohol use disorders is needed, specifically in regard to how psychological and behavioral factors can augment medicalized treatments and protect against relapse. For example, hope or a belief that recovery is possible is an important cognitive construct-thought to precede behavioral action-that has been associated with relapse. In this study, associations between healthy coping skills and hope (psychological/behavioral factors) and PFC regional activation in response to alcohol cue exposure were examined. It was also examined whether such associations were unique to alcohol cues. Forty-two participants, 32 males and nine females in recovery from an alcohol use disorder (AUD), were administered a subjective hope and coping in recovery measure. They also viewed alcohol, positive, negative, and neutral cues during functional near-infrared spectroscopy (fNIR) PFC assessment. Levels of healthy coping skills positively correlated with activation in the right dorsomedial prefrontal cortex (DMPFC) in response to alcohol cues. This finding was unique to alcohol cues. The association between coping skills and activation of the right DMPFC in response to alcohol cues may reflect greater action restraint and top-down PFC control processing that may protect against relapse.

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia.

PubMed

Konopleva, Marina; Pollyea, Daniel A; Potluri, Jalaja; Chyla, Brenda; Hogdal, Leah; Busman, Todd; McKeegan, Evelyn; Salem, Ahmed Hamed; Zhu, Ming; Ricker, Justin L; Blum, William; DiNardo, Courtney D; Kadia, Tapan; Dunbar, Martin; Kirby, Rachel; Falotico, Nancy; Leverson, Joel; Humerickhouse, Rod; Mabry, Mack; Stone, Richard; Kantarjian, Hagop; Letai, Anthony

2016-10-01

We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features. Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106-17. ©2016 AACRSee related commentary by Pullarkat and Newman, p. 1082This article is highlighted in the In This Issue feature, p. 1069. ©2016 American Association for Cancer Research.

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.

PubMed

Topp, Max S; Gökbuget, Nicola; Stein, Anthony S; Zugmaier, Gerhard; O'Brien, Susan; Bargou, Ralf C; Dombret, Hervé; Fielding, Adele K; Heffner, Leonard; Larson, Richard A; Neumann, Svenja; Foà, Robin; Litzow, Mark; Ribera, Josep-Maria; Rambaldi, Alessandro; Schiller, Gary; Brüggemann, Monika; Horst, Heinz A; Holland, Chris; Jia, Catherine; Maniar, Tapan; Huber, Birgit; Nagorsen, Dirk; Forman, Stephen J; Kantarjian, Hagop M

2015-01-01

Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. Amgen. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-leukaemic activity of a novel haploidentical-transplantation approach employing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells in children with refractory/relapsed acute leukaemia.

PubMed

Schuster, Friedhelm R; Meisel, Roland; Führer, Monika; Reuther, Susanne; Hauer, Julia; Tischer, Johanna; Feuchtinger, Tobias; Laws, Hans-Jürgen; Kolb, Hans-Jochem; Borkhardt, Arndt

2013-09-01

The treatment outcome of children with refractory acute leukaemia or relapse post-stem cell transplantation is dismal. We report 10 children (non-remission n = 7) who underwent a new haploidentical transplant approach utilizing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells. Nine patients had successful engraftment and no evidence of leukaemia. Acute and chronic graft-versus-host-disease was observed in five and three patients, respectively; two patients died of treatment-related toxicity. Seven patients relapsed after 7 (range 3-34) months, however two patients are alive at 6·5 and 7·0 years. This approach provides anti-leukaemic activity even in heavily pre-treated children but long-term disease control requires further intervention. © 2013 John Wiley & Sons Ltd.

Killing the hypnozoite – drug discovery approaches to prevent relapse in Plasmodium vivax

PubMed Central

Campo, Brice; Vandal, Omar; Wesche, David L.; Burrows, Jeremy N.

2015-01-01

The eradication of malaria will only be possible if effective, well-tolerated medicines kill hypnozoites in vivax and ovale malaria, and thus prevent relapses in patients. Despite progress in the 8-aminoquinoline series, with tafenoquine in Phase III showing clear benefits over primaquine, the drug discovery challenge to identify hypnozoiticidal or hypnozoite-activating compounds has been hampered by the dearth of biological tools and assays, which in turn has been limited by the immense scientific and logistical challenges associated with accessing relevant human tissue and sporozoites. This review summarises the existing drug discovery series and approaches concerning the goal to block relapse. PMID:25891812

Killing the hypnozoite--drug discovery approaches to prevent relapse in Plasmodium vivax.

PubMed

Campo, Brice; Vandal, Omar; Wesche, David L; Burrows, Jeremy N

2015-05-01

The eradication of malaria will only be possible if effective, well-tolerated medicines kill hypnozoites in vivax and ovale malaria, and thus prevent relapses in patients. Despite progress in the 8-aminoquinoline series, with tafenoquine in Phase III showing clear benefits over primaquine, the drug discovery challenge to identify hypnozoiticidal or hypnozoite-activating compounds has been hampered by the dearth of biological tools and assays, which in turn has been limited by the immense scientific and logistical challenges associated with accessing relevant human tissue and sporozoites. This review summarises the existing drug discovery series and approaches concerning the goal to block relapse.

Collectivism and individualism in Latino recovery homes.

PubMed

Jason, Leonard A; Luna, Roberto D; Alvarez, Josefina; Stevens, Ed

2016-04-26

Research indicates that Latinos underutilize substance abuse interventions; cultural variables may contribute to difficulties accessing and completing treatment for this group. As a result, there is a need to understand the role of cultural constructs in treatment outcomes. The purpose of this study was to investigate how levels of collectivism (COL) and individualism (IND) relate to length of stay and relapse outcomes in self-run recovery homes. We compared Latinos in several culturally modified recovery Oxford Houses to Latinos in traditional recovery Oxford Houses. By examining COL and IND in the OH model, we explored whether aspects of COL and IND led to longer lengths of stay and better substance use outcomes. We hypothesized that higher levels of COL would predict longer stays in an Oxford House and less relapse. COL did not have a main effect on length of stay. However, COL had a significant interaction effect with house type such that COL was positively correlated with length of stay in traditional houses and negatively correlated with length of stay in the culturally modified condition; that is, those with higher collectivism tended to stay longer in traditional houses. When we investigated COL, length of stay, and substance use, COL was negatively correlated with relapse in the culturally modified houses and positively correlated with relapse in the traditional houses. In other words, those with higher COL spent less time and had less relapse in the culturally modified compared to the traditional Oxford Houses. The implications of these findings are discussed.

TEL/AML1 positivity in childhood ALL: average or better prognosis? Czech Paediatric Haematology Working Group.

PubMed

Zuna, J; Hrusák, O; Kalinová, M; Muzíková, K; Starý, J; Trka, J

1999-01-01

The presence of TEL/AML1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) defines a subgroup of patients with better than average outcome. However, the prognostic significance of this aberration has recently been disputed by the Berlin-Frankfurt-Münster (BFM) study group due to its relatively high incidence found in relapsed patients (19.6% and 21.9%, in two cohorts). In contrast, only four out of 45 (8.9%) unselected relapsed patients (all of whom had been treated according to BFM protocols) in the Czech Republic carry this fusion. From March 1995 to June 1998, 41 out of 190 (21.6%) newly diagnosed children with ALL were TEL/AML1-positive. There is a statistically significant difference between the incidence of TEL/AML1 fusion at diagnosis and at relapse within our group (P = 0.035). Interim analysis of the minimal residual disease (MRD) detection shows heterogeneity within the group of newly diagnosed TEL/AML1-positive leukaemias--10 out of 24 patients tested at the end of induction therapy had detectable levels of MRD. However, only one of these patients reached relapse-predictive level (10(-3)) of MRD. In conclusion, we corroborate low frequency of TEL/AML1 positivity among relapsed patients with ALL among Czech children who are treated by the BFM protocols. Moreover, we demonstrate different patterns of bone marrow clean-up in TEL/AML1-positive patients.

Genomic analysis of adult B-ALL identifies potential markers of shorter survival.

PubMed

Patel, Shiven; Mason, Clinton C; Glenn, Martha J; Paxton, Christian N; South, Sara T; Cessna, Melissa H; Asch, Julie; Cobain, Erin F; Bixby, Dale L; Smith, Lauren B; Reshmi, Shalini; Gastier-Foster, Julie M; Schiffman, Joshua D; Miles, Rodney R

2017-05-01

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rates and predictors of relapse after natural and treated remission from alcohol use disorders

PubMed Central

Moos, Rudolf H.; Moos, Bernice S.

2007-01-01

Aims This study examined the rates and predictors of 3-year remission, and subsequent 16-year relapse, among initially untreated individuals with alcohol use disorders who did not obtain help or who participated in treatment and/or Alcoholics Anonymous in the first year after recognizing their need for help. Design and measures A sample of individuals (n = 461) who initiated help-seeking was surveyed at baseline and 1 year, 3 years, 8 years and 16 years later. Participants provided information on their life history of drinking, alcohol-related functioning and life context and coping. Findings Compared to individuals who obtained help, those who did not were less likely to achieve 3-year remission and subsequently were more likely to relapse. Less alcohol consumption and fewer drinking problems, more self-efficacy and less reliance on avoidance coping at baseline predicted 3-year remission; this was especially true of individuals who remitted without help. Among individuals who were remitted at 3 years, those who consumed more alcohol but were less likely to see their drinking as a significant problem, had less self-efficacy, and relied more on avoidance coping, were more likely to relapse by 16 years. These findings held for individuals who initially obtained help and for those who did not. Conclusions Natural remission may be followed by a high likelihood of relapse; thus, preventive interventions may be indicated to forestall future alcohol problems among individuals who cut down temporarily on drinking on their own. PMID:16445550

NEMO Binding Domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory Diffuse Large B-Cell Lymphoma

PubMed Central

Gaurnier-Hausser, Anita; Patel, Reema; Baldwin, Albert S.; May, Michael J.; Mason, Nicola J.

2011-01-01

Purpose Activated B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-κB activity that promotes lymphomagenesis and chemotherapy resistance via over-expression of anti-apoptotic NF-κB target genes. Inhibition of the canonical NF-κB pathway may therefore have therapeutic relevance in ABC-DLBCL. Here we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-κB activity and to determine the therapeutic relevance of NF-κB inhibition in dogs with relapsed, resistant DLBCL. Experimental Design Canonical NF-κB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-κB target gene expression was measured by qRT-PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor Nemo Binding Domain (NBD) peptide, and evaluated for NF-κB activity and apoptosis. NBD peptide was administered intra-nodally to dogs with relapsed B-cell lymphoma and NF-κB target gene expression and tumor burden were evaluated pre and post treatment. Results Constitutive canonical NF-κB activity and increased NF-κB target gene expression was detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intra-tumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF-κB target gene expression and reduced tumor burden. Conclusions This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and demonstrates the therapeutic relevance of NF-κB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients. PMID:21610150

Therapeutic efficacy of monthly subcutaneous injection of daclizumab in relapsing multiple sclerosis

PubMed Central

Cohan, Stanley

2016-01-01

Despite the availability of multiple disease-modifying therapies for relapsing multiple sclerosis (MS), there remains a need for highly efficacious targeted therapy with a favorable benefit–risk profile and attributes that encourage a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Daclizumab treatment leads to antagonism of proinflammatory, activated T lymphocyte function and expansion of immunoregulatory CD56bright natural killer cells, and has the potential to, at least in part, rectify the imbalance between immune tolerance and autoimmunity in relapsing MS. The clinical pharmacology, efficacy, and safety of subcutaneous daclizumab have been evaluated extensively in a large clinical study program. In pivotal studies, daclizumab demonstrated superior efficacy in reducing clinical and radiologic measures of MS disease activity compared with placebo or intramuscular interferon beta-1a, a standard-of-care therapy for relapsing MS. The risk of hepatic disorders, cutaneous events, and infections was modestly increased. The monthly subcutaneous self-injection dosing regimen of daclizumab may be advantageous in maintaining patient adherence to treatment, which is important for optimal outcomes with MS disease-modifying therapy. Daclizumab has been approved in the US and in the European Union and represents an effective new treatment option for patients with relapsing forms of MS, and is currently under review by other regulatory agencies. PMID:27672308

Pharmacological intervention based on fecal calprotectin levels in patients with ulcerative colitis at high risk of a relapse: A prospective, randomized, controlled study

PubMed Central

Öhman, Lena; Stotzer, Per-Ove; Isaksson, Stefan; Überbacher, Otto; Ung, Kjell-Arne; Strid, Hans

2015-01-01

Background Targeted therapy, using biomarkers to assess disease activity in ulcerative colitis (UC), has been proposed. Objective The objective of this study was to evaluate whether pharmacological intervention guided by fecal calprotectin (FC) prolongs remission in patients with UC. Methods A total of 91 adults with UC in remission were randomized to an intervention group or a control group. Analysis of FC was performed monthly, during 18 months. A FC value of 300 µg/g was set as the cut-off for intervention, which was a dose escalation of the oral 5-aminosalicylate (5-ASA) agent. The primary study end-point was the number of patients to have relapsed by month 18. Results There were relapses in 18 (35.3%) and 20 (50.0%) patients in the intervention and the control groups, respectively (p = 0.23); and 28 (54.9%) patients in the intervention group and 28 (70.0%) patients in the control group had a FC > 300 µg/g, of which 8 (28.6%) and 16 (57.1%) relapsed, respectively (p < 0.05). Conclusion Active intervention significantly reduced relapse rates, although no significant difference was reached between the groups overall. Thus, FC-levels might be used to identify patients with UC at risk for a flare, and a dose escalation of their 5-ASA agent is a therapeutic option for these patients. PMID:25653861

Vincristine and irinotecan in children with relapsed hepatoblastoma: a single-institution experience.

PubMed

Zhang, Yu-tong; Feng, Li-hua; Zhong, Xiao-dan; Wang, Li-zhe; Chang, Jian

2015-02-01

This study was to determine the efficacy of vincristine and irinotecan in children with relapsed hepatoblastoma (HB). A total of 10 patients with relapsed HB were enrolled. Three patients were excluded. Patients received irinotecan 50 mg/m(2)/day, day 1-5 and vincristine 1.5 mg/m(2)/day, day 1, repeated every 3 weeks. The maximum cycles were eight. Reevaluation of tumor was performed every two cycles. The primary outcome was the rate of complete resection. Secondary outcomes were event-free survival (EFS) and overall survival (OS). Of the seven patients assessable for response, one patient with normal AFP level showed a progressive disease and withdrew. He finally died 6 months later. Four had PR, all of them underwent a second surgery and achieved complete resection. Two patients had SD, one patient relapsed 6 months after orthotopic liver transplantation and died, the other one undergoing surgery had micro margin positive, he relapsed again but alive. The rate of complete resection was 71.4% (including orthotopic liver transplantation). The 2-year EFS and OS for the whole group were 57.1% (95% CI, 12.7% to 34.2%) and 71.4% (95% CI, 16.39% to 37.4%), respectively. The combination of irinotecan and vincristine has a significant antitumor activity and acceptable toxicity in children with relapsed HB.

Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tahara, Takatoshi, E-mail: taka.t-may7@med.Tottori-u.ac.jp; Fujii, Shinya; Ogawa, Toshihide

Purpose: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases. Methods and Materials: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUV{sub max}) and the pain response, and between SUV{sub max} and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUV{sub max}more » according to the length of time from the completion of RT to pain relapse of the bone metastases. Results: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUV{sub max} differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUV{sub max} relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUV{sub max} (P=.0004/P=.004). Conclusions: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases.« less

Evaluation of Vascular Endothelial Growth Factor as a Prognostic Marker for Local Relapse in Early-Stage Breast Cancer Patients Treated With Breast-Conserving Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moran, Meena S., E-mail: meena.moran@yale.edu; Yang Qifeng; Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, People's Republic of China

2011-12-01

Purpose: Vascular endothelial growth factor (VEGF) is an important protein involved in the process of angiogenesis that has been found to correlate with relapse-free and overall survival in breast cancer, predominantly in locally advanced and metastatic disease. A paucity of data is available on the prognostic implications of VEGF in early-stage breast cancer; specifically, its prognostic value for local relapse after breast-conserving therapy (BCT) is largely unknown. The purpose of our study was to assess VEGF expression in a cohort of early-stage breast cancer patients treated with BCT and to correlate the clinical and pathologic features and outcomes with overexpressionmore » of VEGF. Methods and Materials: After obtaining institutional review board approval, the paraffin specimens of 368 patients with early-stage breast cancer treated with BCT between 1975 and 2005 were constructed into tissue microarrays with twofold redundancy. The tissue microarrays were stained for VEGF and read by a trained pathologist, who was unaware of the clinical details, as positive or negative according the standard guidelines. The clinical and pathologic data, long-term outcomes, and results of VEGF staining were analyzed. Results: The median follow-up for the entire cohort was 6.5 years. VEGF expression was positive in 56 (15%) of the 368 patients. Although VEGF expression did not correlate with age at diagnosis, tumor size, nodal status, histologic type, family history, estrogen receptor/progesterone receptor status, or HER-2 status, a trend was seen toward increased VEGF expression in the black cohort (26% black vs. 13% white, p = .068). Within the margin-negative cohort, VEGF did not predict for local relapse-free survival (RFS) (96% vs. 95%), nodal RFS (100% vs. 100%), distant metastasis-free survival (91% vs. 92%), overall survival (92% vs. 97%), respectively (all p >.05). Subset analysis revealed that VEGF was highly predictive of local RFS in node-positive, margin-negative patients (86% vs. 100%, p = .029) on univariate analysis, but it did not retain its significance on multivariate analysis (hazard ratio, 2.52; 95% confidence interval, 0.804-7.920, p = .113). No other subgroups were identified in which a correlation was found between VEGF expression and local relapse. Conclusion: To our knowledge, our study is the first to assess the prognostic value of VEGF with the endpoint of local relapse in early-stage breast cancer treated with BCT, an important question given the recent increased use of targeted antiangiogenic agents in early-stage breast cancer. Our study results suggest that VEGF is not an independent predictor of local RFS after BCT, but additional, larger studies specifically analyzing the endpoint of VEGF and local relapse are warranted.« less

Implications of Starvation-Induced Change in Right Dorsal Anterior Cingulate Volume in Anorexia Nervosa

PubMed Central

McCormick, Laurie M.; Keel, Pamela K.; Brumm, Michael C.; Bowers, Wayne; Swayze, Victor; Andersen, Arnold; Andreasen, Nancy

2013-01-01

Objective Converging evidence suggests a role for the anterior cingulate cortex (ACC) in the pathophysiology of anorexia nervosa (AN). This study sought to determine whether ACC volume was affected by starvation in active AN and, if so, whether this had any clinical significance. Method Eighteen patients with active AN and age- and gender-matched normal controls underwent magnetic resonance imaging (MRI). Sixteen patients (89%) with AN had intelligence quotients (IQ) testing at intake, 14 (78%) had repeat MRIs after weight normalization, and 10 (56%) had outcome data at 1-year post-hospitalization. Results Right dorsal ACC volume was significantly reduced in active AN patients versus controls and was correlated with lower performance IQ. While ACC normalization occurred with weight restoration, smaller change in right dorsal ACC volume prospectively predicted relapse after treatment. Conclusion Reduced right dorsal ACC volume during active AN relates to deficits in perceptual organization and conceptual reasoning. The degree of right dorsal ACC normalization during treatment is related to outcome. PMID:18473337

Implications of starvation-induced change in right dorsal anterior cingulate volume in anorexia nervosa.

PubMed

McCormick, Laurie M; Keel, Pamela K; Brumm, Michael C; Bowers, Wayne; Swayze, Victor; Andersen, Arnold; Andreasen, Nancy

2008-11-01

Converging evidence suggests a role for the anterior cingulate cortex (ACC) in the pathophysiology of anorexia nervosa (AN). This study sought to determine whether ACC volume was affected by starvation in active AN and, if so, whether this had any clinical significance. Eighteen patients with active AN and age- and gender-matched normal controls underwent magnetic resonance imaging (MRI). Sixteen patients (89%) with AN had intelligence quotients (IQ) testing at intake, 14 (78%) had repeat MRIs after weight normalization, and 10 (56%) had outcome data at 1-year posthospitalization. Right dorsal ACC volume was significantly reduced in active AN patients versus controls and was correlated with lower performance IQ. While ACC normalization occurred with weight restoration, smaller change in right dorsal ACC volume prospectively predicted relapse after treatment. Reduced right dorsal ACC volume during active AN relates to deficits in perceptual organization and conceptual reasoning. The degree of right dorsal ACC normalization during treatment is related to outcome.

[Increased risk of relapse in multiple sclerosis patients after ovarian stimulation for in vitro fertilization].

PubMed

Laplaud, D-A; Lefrère, F; Leray, E; Barrière, P; Wiertlewski, S

2007-10-01

In this preliminary study we analysed the impact of ovarian stimulations and the different protocols used for in vitro fertilizations (IVF) on the clinical activity of multiple sclerosis (MS). By matching the databases on MS and IVF of the past 10 years at the university hospital of Nantes, six patients have been found and, for five of them MS relapse rate seemed to be increased in the three-month period following IVF as compared to the previous three months and to two other control periods of three months (P<0.05, Friedman test). The increased relapse rate mainly concerned patients treated by GnRH agonists but not the patients treated by GnRH antagonists. This preliminary work suggests a possible impact of the treatments used for IVF on MS relapse rate. Further studies are now underway to validate these results on a larger scale, by including all cases reported in France.

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

PubMed

Freedman, Mark S; Selchen, Daniel; Arnold, Douglas L; Prat, Alexandre; Banwell, Brenda; Yeung, Michael; Morgenthau, David; Lapierre, Yves

2013-05-01

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial.

PubMed

St Jean, Pamela L; Xue, Zhengyu; Carter, Nick; Koh, Gavin C K W; Duparc, Stephan; Taylor, Maxine; Beaumont, Claire; Llanos-Cuentas, Alejandro; Rueangweerayut, Ronnatrai; Krudsood, Srivicha; Green, Justin A; Rubio, Justin P

2016-02-18

Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria. PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication. Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ. Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial. The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored. A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy. The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM). The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC). In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes. Metabolite identification experiments were performed using liquid chromatography-mass spectrometry. Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57). In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %). Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems. Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ. As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs. These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.

Early Lapses in a Cessation Attempt: Lapse Contexts, Cessation Success, and Predictors of Early Lapse

PubMed Central

2013-01-01

Introduction: The great majority of smokers relapse when they make quit attempts. Therefore, understanding the process of relapse may guide the development of more effective smoking cessation or relapse prevention treatments. The goal of this research is to extend our understanding of the context of initial lapses that occur within 8 weeks of quitting by using more comprehensive assessments of context, a contemporary sample, and sophisticated analytic techniques. Methods: Participants from a randomized controlled smoking cessation trial completed baseline assessments of demographics and tobacco dependence, a daily smoking calendar to determine latency to lapse and relapse (7 consecutive days of smoking), and an assessment of initial lapse context (affect, location, activity, interpersonal, smoke exposure, and cigarette availability). Latent class analysis (LCA) was used to analyze the 6 early lapse (within the first 8 weeks; N = 551) context dimensions; logistic regression and Cox regression were used to relate context to cessation outcomes. Results: LCA revealed 5 distinct initial lapse context classes (talking, with friends, angry; social; alone; with spouse, angry; and with smoking spouse) that were differentially related to cessation outcome. The easy availability of cigarettes characterized almost 75% of lapses, but being with friends, drinking, and not being at home were associated with a lower likelihood of progression to relapse. Conclusions: Early lapsing is highly related to ultimate relapse, and lapsing in frequently experienced contexts seemed most strongly linked with progression to full relapse. PMID:23780705

Susceptible alleles of the CD40 and CTLA-4 genes are not associated with the relapse after antithyroid withdrawal in Graves' disease.

PubMed

Kim, Kyung Won; Park, Young Joo; Kim, Tae Yong; Park, Do Joon; Park, Kyong Soo; Cho, Bo Youn

2007-12-01

In this study, we investigated whether the CD40 or cytotoxic T lymphocyte-associated molecules-4 (CTLA-4) polymorphisms, which are associated with the susceptibility of Graves' disease (GD), can predict the clinical outcome after antithyroid drug (ATD) withdrawal. All patients with GD were treated with ATD. GD patients were divided into two groups: remission or failure. The remission group was defined as patients who maintained a euthyroid state for 1 year after ATD withdrawal. The failure group was defined as patients who relapsed within 1 year after the discontinuation of ATD or who could not discontinue their ATD treatment within 24 months. The rate of treatment failure after ATD withdrawal was 72.2%. For the susceptible genes, the CC genotype in the CD40, the GG genotype in the CTLA-4 exon 1, and the CC genotype in the CTLA-4 promoter region have shown no significant association with a clinical outcome after ATD withdrawal. However, clinical parameters, such as male gender, severe thyrotoxicosis, high thyroid-stimulating hormone-binding inhibitory immunoglobulin value, and a large goiter, were related to treatment failure. These findings suggest that the genetic markers associated with the development of GD cannot be used to predict the relapse of GD patients in place of clinical parameters.

Lifestyle-related disease in Crohn’s disease: Relapse prevention by a semi-vegetarian diet

PubMed Central

Chiba, Mitsuro; Abe, Toru; Tsuda, Hidehiko; Sugawara, Takeshi; Tsuda, Satoko; Tozawa, Haruhiko; Fujiwara, Katsuhiko; Imai, Hideo

2010-01-01

AIM: To investigate whether semi-vegetarian diet (SVD) has a preventive effect against relapse of Crohn’s disease (CD) in patients who have achieved remission, who are a high-risk group for relapse. METHODS: A prospective, single center, 2-year clinical trial was conducted. Twenty-two adult CD patients who achieved clinical remission either medically (n = 17) or surgically (n = 5) and consumed an SVD during hospitalization were advised to continue with an SVD and avoid known high-risk foods for inflammatory bowel disease. The primary endpoint was clinical relapse defined as the appearance of active symptoms of CD. Kaplan-Meier survival analysis was used to calculate the cumulative proportion of patients who had a relapse. A 2-year analysis of relapse rates of patients who followed an SVD and those who did not (an omnivorous diet group) was undertaken. RESULTS: SVD was continued by 16 patients (compliance 73%). Remission was maintained in 15 of 16 patients (94%) in the SVD group vs two of six (33%) in the omnivorous group. Remission rate with SVD was 100% at 1 year and 92% at 2 years. SVD showed significant prevention in the time to relapse compared to that in the omnivorous group (P = 0.0003, log rank test). The concentration of C-reactive protein was normal at the final visit in more than half of the patients in remission who were taking an SVD, who maintained remission during the study (9/15; 60%), who terminated follow-up (8/12; 67%), and who completed 2 years follow-up (7/10; 70%). There was no untoward effect of SVD. CONCLUSION: SVD was highly effective in preventing relapse in CD. PMID:20503448

Online Social Support for the Prevention of Smoking Relapse: A Content Analysis of the WhatsApp and Facebook Social Groups.

PubMed

Cheung, Yee Tak Derek; Chan, Ching Han Helen; Wang, Man Ping; Li, Ho Cheung William; Lam, Tai-Hing

2017-06-01

Online social groups have been increasingly used for smoking cessation intervention. This study aimed to explore the social support components of the online discussion through WhatsApp and Facebook, how these components addressed the need of relapse prevention, and how the participants evaluated this intervention. We coded and analyzed the posts (N = 467) by the 82 recent quitters in WhatsApp and Facebook social groups, who were recruited from the eight smoking cessation clinics in Hong Kong to participate in a pragmatic randomized trial of relapse prevention. Participants' postintervention feedback was collected from the 13 qualitative interviews after the intervention. The WhatsApp social groups had more participants' posts than the Facebook counterparts. The participants' posts in the online social groups could be classified as sharing views and experiences (55.5%), encouragement (28.7%), and knowledge and information (15.8%). About half of the participants' posts (52.9%) addressed the themes listed in the U.S. Clinical Practice Guideline for preventing smoking relapse. The participants perceived the posts as useful reminders for smoking cessation, but avoidance of reporting relapse, inactive discussions, and uninteresting content were barriers to the success of the intervention. Online social groups provided a useful platform for the delivery of cessation support and encouragement of reporting abstinence, which support relapse prevention. The effectiveness of such intervention can be improved by encouraging more self-report of relapse, active discussions, sharing of interesting content, and using an appropriate discussion platform. Quitters who participate in the online social groups can benefit from peer support and information sharing, and hence prevent smoking relapse.

"Always looking for a new balance": toward an understanding of what it takes to continue working while being diagnosed with relapsing-remitting multiple sclerosis.

PubMed

Meide, Hanneke van der; Gorp, Dennis van; van der Hiele, Karin; Visser, Leo

2017-06-22

The aim of this study was to gain insight into the meaning of work in the everyday lives of people with relapsing-remitting multiple sclerosis, and the barriers and facilitators to staying in work. Nineteen employed adults diagnosed with relapsing-remitting multiple sclerosis participated in narrative interviews. All interviews were transcribed and coded for thematic analysis. For people with relapsing-remitting multiple sclerosis, continuing to work was a precarious balancing act. Five themes influenced this balance: becoming familiar with the disease, adjusting expectations, having an understanding and realistic line manager, seeing work as meaningful life activity and strategic considerations. People receiving a diagnosis of relapsing-remitting multiple sclerosis have to refamiliarize themselves with their own body in a meaningful way to be able to continue their work. Rehabilitation professionals can support them herein by taking into account not merely functional capabilities but also identity aspects of the body. Medication that stabilizes symptoms supports making the necessary adjustments. A trusting relationship with the line manager is vital for this adaptation process. Additionally, a match between being adequately challenged by work, while still having the capacity to meet those work demands, is needed, as is long-term financial stability. Implications for rehabilitation Rehabilitation professionals can support employees with relapsing-remitting multiple sclerosis by taking into account not merely functional capabilities but also identity aspects of the body. A trusting relationship with the line manager, including a timely disclosure of the diagnosis, is vital for people with relapsing-remitting multiple sclerosis to remain at work. For people with relapsing-remitting multiple sclerosis, there is a delicate balance between being adequately challenged by work while still having the capacity to meet work demands.

Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials

PubMed Central

Verhey, Leonard H.; Signori, Alessio; Arnold, Douglas L.; Bar-Or, Amit; Sadovnick, A. Dessa; Marrie, Ruth Ann; Banwell, Brenda

2013-01-01

Objective: To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints. Methods: Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters. Results: Assuming a 50% reduction in new T2 lesions over 6 months, 90 patients/arm are required, whereas 165 patients/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (ϑ), sample sizes range from 70 patients/arm (using ARR) to 105 patients/arm (TTFR) for a 50% reduction in relapses, and 230 patients/arm (ARR) to 365 patients/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative ϑ, 2-year trials using ARR require 45 patients/arm (60 patients/arm for TTFR) for a 50% reduction in relapses and 145 patients/arm (200 patients/arm for TTFR) for a 30% reduction. Conclusion: Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration. PMID:23966255

Systematic review and meta-analysis of secondary prophylaxis for prevention of HIV-related toxoplasmic encephalitis relapse using trimethoprim-sulfamethoxazole.

PubMed

Connolly, Mark P; Haitsma, Gertruud; Hernández, Adrián V; Vidal, José E

2017-09-01

A recent systematic literature and meta-analysis reported relative efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of toxoplasmic encephalitis (TE) in HIV-infected adults. Here, we estimated relapse rates during secondary prophylaxis with TMP-SMX, and further explored differences in relapse rates prior to introduction of highly active antiretroviral therapy (HAART) and the widespread adoption of HAART. A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials yielded 707 studies whereby 663 were excluded after abstract screening, and 38 were excluded after full review leaving 6 studies for extraction. We performed double data extraction with a third-party adjudicator. Study designs varied with only one randomized study, four prospective cohorts and one retrospective cohort. Relapse rates were transformed using the Freeman-Tukey method and pooled using both fixed-effect and random-effects meta-analysis models. The TMP-SMX relapse rate was 16.4% (95% CI = 6.2% to 30.3%) based on random-effects models. When the disaggregated pre-HAART studies (n = 4) were included, the relapse rate was 14.9% (random effects; 95% CI = 3.7% to 31.9%). Analysis of two post-HAART studies indicated a relapse rate of 19.2% (random effects; 95% CI = 2.8% to 45.6%). Comparing the relapse rates between pre- and post-HAART studies were contrary to what might be expected based on known benefits of HAART therapy in this population. Nevertheless, cautious interpretation is necessary considering the heterogeneity of the included studies and a limited number of subjects receiving TMP-SMX reported in the post-HAART era.

Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT.

PubMed

Roundhill, E; Burchill, S

2013-07-09

Primary Ewing's sarcoma family of tumours (ESFTs) may respond to chemotherapy, although many patients experience subsequent disease recurrence and relapse. The survival of ESFT cells following chemotherapy has been attributed to the development of resistant disease, possibly through the expression of ABC transporter proteins. MRP-1 and Pgp mRNA and protein expression in primary ESFTs was determined by quantitative reverse-transcriptase PCR (RT-qPCR) and immunohistochemistry, respectively, and alternative splicing of MRP-1 by RT-PCR. We observed MRP-1 protein expression in 92% (43 out of 47) of primary ESFTs, and cell membrane MRP-1 was highly predictive of both overall survival (P<0.0001) and event-free survival (P<0.0001). Alternative splicing of MRP-1 was detected in primary ESFTs, although the pattern of splicing variants was not predictive of patient outcome, with the exception of loss of exon 9 in six patients, which predicted relapse (P=0.041). Pgp protein was detected in 6% (38 out of 44) of primary ESFTs and was not associated with patient survival. For the first time we have established that cell membrane expression of MRP-1 or loss of exon 9 is predictive of outcome but not the number of splicing events or expression of Pgp, and both may be valuable factors for the stratification of patients for more intensive therapy.

Weight gain as a barrier to smoking cessation among military personnel.

PubMed

Russ, C R; Fonseca, V P; Peterson, A L; Blackman, L R; Robbins, A S

2001-01-01

To assess the relationships between active-duty military status, military weight standards, concern about weight gain, and anticipated relapse after smoking cessation. Cross-sectional study. Hospital-based tobacco cessation program. Two hundred fifty-two enrollees, of 253 eligible, to a tobacco cessation program in 1999 (135 men, 117 women; 43% on active duty in the military). Independent variables included gender, body mass index (weight/height2), and military status. Dependent variables included about weight gain with smoking cessation and anticipated relapse. In multivariate regression analyses that controlled for gender and body mass index, active-duty military status was associated with an elevated level of concern about weight gain (1.9-point increase on a 10-point scale; 95% confidence interval [CI], 1.0- to 2.8-point increase), as well as higher anticipated relapse (odds ratio [OR] = 3.6; 95% CI, 1.3 to 9.8). Among subjects who were close to or over the U.S. Air Force maximum allowable weight for height, the analogous OR for active-duty military status was 6.9 (p = .02). Occupational weight standards or expectations may pose additional barriers for individuals contemplating or attempting smoking cessation, as they do among active-duty military personnel. These barriers are likely to hinder efforts to decrease smoking prevalence in certain groups.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

PubMed

Rae-Grant, Alexander; Day, Gregory S; Marrie, Ruth Ann; Rabinstein, Alejandro; Cree, Bruce A C; Gronseth, Gary S; Haboubi, Michael; Halper, June; Hosey, Jonathan P; Jones, David E; Lisak, Robert; Pelletier, Daniel; Potrebic, Sonja; Sitcov, Cynthia; Sommers, Rick; Stachowiak, Julie; Getchius, Thomas S D; Merillat, Shannon A; Pringsheim, Tamara

2018-04-24

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers. © 2018 American Academy of Neurology.

Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study.

PubMed

Van Den Neste, E; Schmitz, N; Mounier, N; Gill, D; Linch, D; Trneny, M; Milpied, N; Radford, J; Ketterer, N; Shpilberg, O; Dührsen, U; Ma, D; Brière, J; Thieblemont, C; Salles, G; Moskowitz, C H; Glass, B; Gisselbrecht, C

2016-01-01

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia.

PubMed

Li, Sheng; Wang, Chengzhong; Wang, Weikai; Liu, Weidong; Zhang, Guiqin

2018-05-01

This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR-520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL.

Rituximab in refractory myasthenia gravis: extended prospective study results.

PubMed

Beecher, Grayson; Anderson, Dustin; Siddiqi, Zaeem A

2018-05-09

Rituximab appears beneficial in treatment-refractory myasthenia gravis (MG), however, prospective, long-term durability data is lacking. In this prospective, open-label study of rituximab in refractory MG, 22 patients (10 AChR, 9 MuSK, 3 seronegative) received rituximab at baseline, with repeat cycles driven by clinical worsening. Manual muscle testing (MMT) scores and CD19/CD20+ B cell counts were serially monitored. At mean follow-up of 28.8 ± 19.0 months (range=6-66 months), mean MMT scores declined from 10.6 ± 5.4 to 3.3 ± 3.1 (p<0.0001). Mean prednisone dose declined from 25.2 ± 15.1 mg/d to 7.3 ± 7.1 mg/d (p=0.002). Ten relapses occurred, with average time to first relapse of 17.1 ± 5.5 months (range=9-23 months). CD19/CD20+ count recovery did not predict relapse. Three patients experienced prolonged B cell depletion (range=24-45 months) after one cycle. Sustained clinical improvement was associated with rituximab after one cycle, with prolonged time to relapse and reduction in steroid dose. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Allogeneic stem cell transplantation using lymphoablative rather than myeloablative conditioning regimen for relapsed or refractory lymphomas.

PubMed

Yoon, Jae-Ho; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Kim, Hee-Je; Min, Chang-Ki; Lee, Jong-Wook; Min, Woo-Sung; Cho, Seok-Goo

2017-03-01

In relapsed or refractory non-Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides graft-versus-lymphoma activity resulting in fewer incidences of relapse. However, therapy-related mortality (TRM) remains an important challenge. We attempted to introduce our reduced-intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo-HSCT. All were pre-conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B-cell lymphomas, seven peripheral T-cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto-HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo-HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow-up of 24.8 months, 3-year overall survival and disease-free survival were 62.4 and 59.2% and the 3-year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft-versus-host diseases (GVHDs) were identified in 17 (≥Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC-allo-HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

PubMed

Chen, Ray Y; Via, Laura E; Dodd, Lori E; Walzl, Gerhard; Malherbe, Stephanus T; Loxton, André G; Dawson, Rodney; Wilkinson, Robert J; Thienemann, Friedrich; Tameris, Michele; Hatherill, Mark; Diacon, Andreas H; Liu, Xin; Xing, Jin; Jin, Xiaowei; Ma, Zhenya; Pan, Shouguo; Zhang, Guolong; Gao, Qian; Jiang, Qi; Zhu, Hong; Liang, Lili; Duan, Hongfei; Song, Taeksun; Alland, David; Tartakovsky, Michael; Rosenthal, Alex; Whalen, Christopher; Duvenhage, Michael; Cai, Ying; Goldfeder, Lisa C; Arora, Kriti; Smith, Bronwyn; Winter, Jill; Barry Iii, Clifton E

2017-11-06

Background : By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods : This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion : Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. NCT02821832.

Tumour size is the only predictive factor of distant recurrence after pathological complete response to neoadjuvant chemotherapy in patients with large operable or locally advanced breast cancers: a sub-study of EORTC 10994/BIG 1-00 phase III trial.

PubMed

Fei, F; Messina, C; Slaets, L; Chakiba, C; Cameron, D; Bogaerts, J; Bonnefoi, H

2015-02-01

Although achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer predicts a better outcome, some patients still relapse. The objectives of this study were to describe the types of events in this group of patients and to identify predictive factors for relapse. Patients with large operable or locally advanced breast cancers (T4d tumours were excluded) were randomised to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel followed by three cycles of eprirubicin/docetaxel. pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in the primary tumour and axillary lymph nodes at surgery. Two Cox regression analyses were performed to identify predictive factors of relapse: one for recurrence-free interval (RFI) and one for distant recurrence-free interval (DRFI). Out of 283 eligible patients who achieved a pCR, 40 (14.1%) and 28 (9.9%) presented an event of interest for the RFI and DRFI analyses, respectively. Five-year RFI, DRFI and overall survival (OS) were 85.3% (95% confidence interval (CI), 80.1-89.3), 89.6% (95% CI, 85.0-92.9) and 91.9% (95% CI, 87.2-94.9), respectively. No predictors for RFI after pCR were identified. For DRFI, tumour size was the only predictor: Hazard ratio (HR) T3 versus T1-2=3.62 (95% CI, 1.66-7.89); HR T4 versus T1-2: HR, 2.80 (95% CI, 0.62-12.64) p=0.0048. In this study, clinical tumour size emerged as the only predictor for DRFI after pCR, with T3 and T4 tumours having an increased risk for distant recurrence compared to T1-2 tumours. Copyright © 2014 Elsevier Ltd. All rights reserved.

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial

PubMed Central

Chen, Ray Y.; Via, Laura E.; Dodd, Lori E.; Walzl, Gerhard; Malherbe, Stephanus T.; Loxton, André G.; Dawson, Rodney; Wilkinson, Robert J.; Thienemann, Friedrich; Tameris, Michele; Hatherill, Mark; Diacon, Andreas H.; Liu, Xin; Xing, Jin; Jin, Xiaowei; Ma, Zhenya; Pan, Shouguo; Zhang, Guolong; Gao, Qian; Jiang, Qi; Zhu, Hong; Liang, Lili; Duan, Hongfei; Song, Taeksun; Alland, David; Tartakovsky, Michael; Rosenthal, Alex; Whalen, Christopher; Duvenhage, Michael; Cai, Ying; Goldfeder, Lisa C.; Arora, Kriti; Smith, Bronwyn; Winter, Jill; Barry III, Clifton E.

2017-01-01

Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. Trial Registration: NCT02821832 PMID:29528048

Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation

PubMed Central

Koenecke, Christian; Göhring, Gudrun; de Wreede, Liesbeth C.; van Biezen, Anja; Scheid, Christof; Volin, Liisa; Maertens, Johan; Finke, Jürgen; Schaap, Nicolaas; Robin, Marie; Passweg, Jakob; Cornelissen, Jan; Beelen, Dietrich; Heuser, Michael; de Witte, Theo; Kröger, Nicolaus

2015-01-01

The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification. PMID:25552702

Evaluation of mitoguazone in patients with refractory chronic lymphocytic leukemia: a phase II study (P-H482) of the Eastern Cooperative Oncology Group.

PubMed

Wiernik, P H; Gordon, L I; Oken, M M; Harris, J E; O'Connell, M J

1999-10-01

Mitoguazone is a unique antitumor agent that interferes with polyamine synthesis that has been reported to have activity against AIDS-related malignant lymphoma. We, therefore, tested this agent for activity against chronic lymphocytic leukemia (CLL) in this phase II study. Mitoguazone, 500 mg/M2 was given intravenously weekly to 13 patients with relapsed or refractory, previously treated Rai stages 2-4 CLL. There were no complete or partial responses as judged by standard criteria. Toxicity was acceptable. Mitoguazone in the dose and schedule employed in this study has no significant activity as a single agent in patients with relapsed or refractory CLL.

Accurate prediction of cardiorespiratory fitness using cycle ergometry in minimally disabled persons with relapsing-remitting multiple sclerosis.

PubMed

Motl, Robert W; Fernhall, Bo

2012-03-01

To examine the accuracy of predicting peak oxygen consumption (VO(2peak)) primarily from peak work rate (WR(peak)) recorded during a maximal, incremental exercise test on a cycle ergometer among persons with relapsing-remitting multiple sclerosis (RRMS) who had minimal disability. Cross-sectional study. Clinical research laboratory. Women with RRMS (n=32) and sex-, age-, height-, and weight-matched healthy controls (n=16) completed an incremental exercise test on a cycle ergometer to volitional termination. Not applicable. Measured and predicted VO(2peak) and WR(peak). There were strong, statistically significant associations between measured and predicted VO(2peak) in the overall sample (R(2)=.89, standard error of the estimate=127.4 mL/min) and subsamples with (R(2)=.89, standard error of the estimate=131.3 mL/min) and without (R(2)=.85, standard error of the estimate=126.8 mL/min) multiple sclerosis (MS) based on the linear regression analyses. Based on the 95% confidence limits for worst-case errors, the equation predicted VO(2peak) within 10% of its true value in 95 of every 100 subjects with MS. Peak VO(2) can be accurately predicted in persons with RRMS who have minimal disability as it is in controls by using established equations and WR(peak) recorded from a maximal, incremental exercise test on a cycle ergometer. Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints.

PubMed

Bujkiewicz, Sylwia; Thompson, John R; Spata, Enti; Abrams, Keith R

2017-10-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing-remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions.

Similar outcome after allogeneic stem cell transplantation with a modified FLAMSA conditioning protocol substituting 4 Gy TBI with treosulfan in an elderly population with high-risk AML.

PubMed

Holtick, Udo; Herling, Marco; Pflug, Natali; Chakupurakal, Geothy; Leitzke, Silke; Wolf, Dominik; Hallek, Michael; Scheid, Christof; Chemnitz, Jens M

2017-03-01

The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (RIC) protocol has been described to be effective in patients with high-risk and refractory acute myeloic leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (aSCT). To increase safety and tolerability of the conditioning, we previously reported the feasibility to substitute the TBI component by treosulfan in elderly AML patients. We now present long-term follow-up data on patients treated with FLAMSA/treosulfan compared to the original FLAMSA/4Gy TBI protocol. We retrospectively analyzed 130 consecutive patients with high-risk or relapsed AML after aSCT following FLAMSA conditioning at our center. Fifty-eight patients were treated with FLAMSA/treosulfan due to age and/or comorbidities. Seventy-two patients were treated with FLAMSA/TBI. Median age of patients treated with FLAMSA/treosulfan was 60 years compared to 46 years in those treated with FLAMSA/TBI. The cumulative incidence of a non-relapse mortality at 4 years was 28% in FLAMSA/treosulfan patients as compared to 13% in FLAMSA/TBI. Cumulative incidence of relapse was higher in patients treated with FLAMSA/TBI (46 vs. 32%). This difference was even more prominent for patients treated in blast persistence prior to transplant (relapse incidence 70% for TBI vs. 35% for treosulfan). The overall and relapse-free survival rates at 4 years were 47 and 41%, respectively, for patients treated with FLAMSA/TBI as compared to 43 and 40% in patients treated with FLAMSA/treosulfan. These data indicate an anti-leukemic activity by FLAMSA/treosulfan especially in patients with a blast persistence prior to transplant. Older age was an independent factor for a higher non-relapse mortality. Translating FLAMSA/treosulfan to younger patients, a lower non-relapse mortality, and an improved anti-leukemic activity might add up to improved overall survival. Randomized studies are required to demonstrate an improved efficacy of treosulfan- versus TBI-based FLAMSA conditioning.

Efficacy and Pharmacologic Data of Second-Generation Tyrosine Kinase Inhibitor Nilotinib in BCR-ABL-Positive Leukemia Patients with Central Nervous System Relapse after Allogeneic Stem Cell Transplantation

PubMed Central

Reinwald, Mark; Schleyer, Eberhard; Kiewe, Philipp; Blau, Igor Wolfgang; Burmeister, Thomas; Pursche, Stefan; Neumann, Martin; Notter, Michael; Thiel, Eckhard; Hofmann, Wolf-Karsten; Kolb, Hans-Jochem; Burdach, Stefan; Bender, Hans-Ulrich

2014-01-01

Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL+ disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23–1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL+ leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT. PMID:25025064

Is physical activity maintenance from adolescence to young adulthood associated with reduced CVD risk factors, improved mental health and satisfaction with life: the HUNT Study, Norway.

PubMed

Rangul, Vegar; Bauman, Adrian; Holmen, Turid Lingaas; Midthjell, Kristian

2012-12-14

Little is known about the effect maintaining physical activity throughout adolescence has on cardiovascular risk factors and health status in early adulthood. This ten-year prospective longitudinal study investigated whether differences in physical activity patterns from adolescence to young-adulthood showed different associations with subsequent cardio-metabolic risk factors and mental health in young-adulthood. Based on the second and third Norwegian Nord-Trøndelag Health Surveys (HUNT2 and 3), we included 1869 individuals (838 males) participating in Young-HUNT (1995-97), aged 13-19 years and followed-up at HUNT3 (2006-08), aged 23-31. Self-reported physical activity (PA), mental health and perceived health were recorded, along with measurements of body mass index (BMI), waist circumference (WC), total cholesterol (TC), HDL cholesterol, glucose, triglycerides, resting heart rate (HR) and blood pressure. We used separate linear regressions models to investigate associations between physical activity and each CVD risk factor, and logistic regression analysis to examine PA patterns and subsequent mental health. Physically active maintainers were compared to inactive maintainers. Adopters (inactive as adolescents and physically active as young adults) were compared to inactive maintainers and to those who discontinued activity (relapsers). Active maintainers had significantly lower HR, compared to all other PA patterns. Active maintaining men had significantly lower WC than relapsers and inactive maintainers. When adjusted for age and gender, WC, BMI, HR, diastolic blood pressure and HDL-C showed significant differences comparing active maintaining to other PA patterns. Comparing inactive maintainers against adopters, only HR was significantly lower. Male adopters did not differ significantly in CVD risk compared to inactive maintainers and relapsers. Among females adopting was associated with lower HR and TC compared to inactive maintainers. Active maintainers showed better mental health than inactive maintainers. Active maintaining males had an increased likelihood of good mental health compared to adopters. Active maintaining females reported greater satisfaction with life compared to adopters. Those who maintained their physical activity from adolescence to young adulthood demonstrated a significantly lower CVD risk and better mental health, compared to inactive maintainers. Compared to inactivity maintainers and relapsers, adopting physical activity was not significantly associated with lowered CVD risk. Adopting physical activity between adolescence and young adulthood may not necessarily protect against mental distress.

Neuroscience of inhibition for addiction medicine: from prediction of initiation to prediction of relapse.

PubMed

Moeller, Scott J; Bederson, Lucia; Alia-Klein, Nelly; Goldstein, Rita Z

2016-01-01

A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior. Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differences from healthy nonaddicted controls during tasks of response inhibition accompanied by brain activation abnormalities as revealed by functional neuroimaging. However, it is less clear whether inhibition-related deficits predate the transition to problematic use, and, in turn, whether these deficits predict the transition out of problematic substance use. Here, we review longitudinal studies of response inhibition in children/adolescents with little substance experience and longitudinal studies of already addicted individuals attempting to sustain abstinence. Results show that response inhibition and its underlying neural correlates predict both substance use outcomes (onset and abstinence). Neurally, key roles were observed for multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex). In general, less activation of these regions during response inhibition predicted not only the onset of substance use, but interestingly also better abstinence-related outcomes among individuals already addicted. The role of subcortical areas, although potentially important, is less clear because of inconsistent results and because these regions are less classically reported in studies of healthy response inhibition. Overall, this review indicates that response inhibition is not simply a manifestation of current drug addiction, but rather a core neurocognitive dimension that predicts key substance use outcomes. Early intervention in inhibitory deficits could have high clinical and public health relevance. © 2016 Elsevier B.V. All rights reserved.

Deepened extinction following compound stimulus presentation: Noradrenergic modulation

PubMed Central

Janak, Patricia H.; Corbit, Laura H.

2011-01-01

Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes (renewal). The following experiments replicated the demonstration that presenting multiple previously rewarded stimuli in compound during extinction enhances extinction learning. To explore the pharmacological basis for this we next examined the effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the hypothesis that increased noradrenergic activity at the time of extinction training would improve, whereas blockade of noradrenergic activity would impair the extinction of appetitive stimulus–reward memories. Different groups of rats were trained in a discriminative stimulus paradigm to lever-press for food reward. Once stable responding was achieved, responding was extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either saline, yohimbine (α2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol (β-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our results indicate that increasing noradrenergic activity during extinction augments extinction learning resulting in less recovery of responding at test. These results have important implications for models of relapse to drug seeking and the development of extinction-based therapies. PMID:21224211

Post-marketing survey on clinical response to interferon beta in relapsing multiple sclerosis: the Roman experience.

PubMed

Pozzilli, C; Prosperini, L; Sbardella, E; De Giglio, L; Onesti, E; Tomassini, V

2005-12-01

Safety, tolerability and efficacy profiles of interferon beta (IFNbeta) therapy in relapsing multiple sclerosis (MS) has been widely verified both in trial settings and in daily clinical practice. However, for a variable percentage of treated patients, it remains only partially effective. In this study, we reported the post-marketing experience of the efficacy of IFNbeta therapy for a large cohort of MS patients regularly attending the MS Outpatient Clinic of "La Sapienza University" in Rome. In this cohort we also sought clinical and paraclinical variables responsible for the clinical course of MS during IFNbeta therapy. Patients that received treatment with one of the IFNbeta formulations for at least 1 year were included. Clinical outcomes (i. e., relapses and disability score) were monitored throughout the entire study period. Magnetic resonance imaging (MRI) scans were performed twice for each subject: at baseline and after 1 year of therapy. The occurrence of more than one relapse during the study period or a sustained disability progression in the Expanded Disability Status Scale (EDSS) score were considered as criteria for the definition of suboptimal clinical response to IFNbeta therapy. During IFNbeta therapy (number of patients 242, mean length of treatment 4.3+/-2.3 years) a reduction in the annualised relapse rate of 59% (p<0.001) was observed. Eighty-six patients (35%) fulfilled the criterion for defining "suboptimal responder" on the basis of relapses, and 69 (28.5%) did the same on the basis of EDSS sustained progression. Twenty-seven (11.1%) patients showed both an EDSS progression and two or more relapses. The presence of T1-enhancing lesions and new T2 hyperintense lesions on the scan performed after the first year of therapy were the best MRI features associated with both the occurrence of relapses during the treatment period (OR for enhancing lesions and relapses 3.6; OR for new T2 lesion and relapses 2.8). The present post-marketing experience confirms the efficacy of IFNbeta in modifying the natural course of MS and encourages the use of paraclinical variables measuring subclinical disease activity as surrogate markers to monitor the clinical course of MS during IFNbeta therapy.

Pathobiologic Markers of the Ewing Sarcoma Family of Tumors: State of the Art and Prediction of Behaviour

PubMed Central

Pinto, Alfredo; Dickman, Paul; Parham, David

2011-01-01

Over the past three decades, the outcome of Ewing sarcoma family tumor (ESFT) patients who are nonmetastatic at presentation has improved considerably. The prognosis of patients with metastatic disease at the time of diagnosis and recurrence after therapy remains dismal. Drug-resistant disease at diagnosis or at relapse remains a major cause of mortality among patients diagnosed with ESFT. In order to improve the outcome for patients with potential relapse, there is an urgent need to find reliable markers that either predict tumor behaviour at diagnosis or identify therapeutic molecular targets at the time of recurrence. An improved understanding of the cell of origin and the molecular pathways that regulate tumorigenicity in ESFT should aid us in the search for novel therapies for ESFT. The purpose of this paper is thus to outline current concepts of sarcomagenesis in ESFT and to discuss ESFT patterns of differentiation and molecular markers that might affect prognosis or direct future therapeutic development. PMID:20981347

Predictors of Relapse after Discontinuing Systemic Treatment in Childhood Autoimmune Chronic Uveitis.

PubMed

Simonini, Gabriele; Bracaglia, Claudia; Cattalini, Marco; Taddio, Andrea; Brambilla, Alice; De Libero, Cinzia; Pires Marafon, Denise; Caputo, Roberto; Cimaz, Rolando

2017-06-01

To identify clinical predictors of relapse in childhood autoimmune chronic uveitis after stopping systemic treatment. A retrospective, multicenter, cohort study. Ninety-four children in remission, receiving no treatments and with at least a 6-month followup, were enrolled. A higher probability of maintaining remission after discontinuing treatment was shown in idiopathic compared with juvenile idiopathic arthritis uveitis (Mantel-Cox chi-square = 23.21) if inactivity had been obtained within 6 months from starting systemic treatment (Mantel-Cox chi-square = 24.17) and by antitumor necrosis factor-α treatment (Mantel-Cox chi-square = 6.43). Type of disease, time, and type of systemic therapy to achieve inactivity predict different duration of uveitis remission after treatment withdrawal.

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

PubMed Central

Oshima, Koichi; Khiabanian, Hossein; da Silva-Almeida, Ana C.; Tzoneva, Gannie; Abate, Francesco; Ambesi-Impiombato, Alberto; Sanchez-Martin, Marta; Carpenter, Zachary; Penson, Alex; Perez-Garcia, Arianne; Eckert, Cornelia; Nicolas, Concepción; Balbin, Milagros; Sulis, Maria Luisa; Kato, Motohiro; Koh, Katsuyoshi; Paganin, Maddalena; Basso, Giuseppe; Gastier-Foster, Julie M.; Devidas, Meenakshi; Loh, Mignon L.; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A.

2016-01-01

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy. PMID:27655895

Comparative analysis of natalizumab versus fingolimod as second-line treatment in relapsing-remitting multiple sclerosis.

PubMed

Lorscheider, Johannes; Benkert, Pascal; Lienert, Carmen; Hänni, Peter; Derfuss, Tobias; Kuhle, Jens; Kappos, Ludwig; Yaldizli, Özgür

2018-05-01

No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS. Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses. Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9-2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95% confidence interval (CI) 0.3-0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95% CI 1.1-2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95% CI 0.5-1.5, p = 0.62). Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod.

Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse.

PubMed

Feltenstein, Matthew W; Do, Phong H; See, Ronald E

2009-12-01

Aripiprazole (Abilify) is an atypical antipsychotic drug characterized by partial agonist activity at dopamine (DA) D(2)/D(3) receptors and a low side-effect profile. While we previously demonstrated that acute aripiprazole blocked the reinstatement of cocaine seeking in an animal model of relapse, clinical treatment of relapse prevention necessitates testing the effects of aripiprazole following prolonged abstinence, as well as after repeated administration during withdrawal from cocaine. We assessed the effects of repeated aripiprazole treatment on cocaine seeking after abstinence and during conditioned cue-induced and cocaine-primed reinstatement in rats. Rats self-administered intravenous cocaine paired with a light + tone stimulus for 10-14 days, followed by 2 weeks of abstinence. Following post-abstinence relapse testing, lever responding was allowed to extinguish, with subsequent reinstatement testing occurring either in the presence of the conditioned stimulus, or after a cocaine-priming injection (10 mg/kg, intraperitoneal (IP)). Following 3 or 7 days of pretreatment, rats received an injection of aripiprazole (0.25, 0.5, and 1.0 mg/kg, IP) or vehicle prior to post-abstinence relapse and reinstatement testing. Vehicle-pretreated animals showed robust cocaine seeking during relapse and reinstatement testing, an effect that was significantly attenuated by aripiprazole pretreatment, although no lasting effects were found in the absence of acute injection. These findings support the possibility that repeated aripiprazole may be an effective therapeutic agent for the prevention of relapse in abstinent cocaine users. Based on its antipsychotic profile, aripiprazole may be particularly useful for individuals diagnosed with comorbid psychoses, such as schizophrenia or bipolar disorder.

Relapse May Serve as a Mediator Variable in Longitudinal Outcomes in Multiple Sclerosis.

PubMed

Stone, Lael Anne; Cutter, Gary Raymond; Fisher, Elizabeth; Richert, Nancy; McCartin, Jennifer; Ohayon, Joan; Bash, Craig; McFarland, Henry

2016-05-01

Contrast-enhancing lesions (CEL) on magnetic resonance imaging (MRI) are believed to represent inflammatory disease activity in multiple sclerosis (MS), but their relationship to subsequent long-term disability and progression is unclear, particularly at longer time periods such as 8-10 years. Between 1989 and 1994, 111 MS patients were seen at the National Institutes of Health for clinical evaluations and 3 monthly contrast-enhanced MRI scans. Of these, 94 patients were re-evaluated a mean of 8 years later (range 6.1-10.5 years) with a single MRI scan and clinical evaluation. CEL number and volume were determined at baseline and follow-up. The number of relapses was ascertained over the follow-up period and annualized relapse rates were calculated. Other MRI parameters, such as T2 hyperintensity volume, T1 volume, and brain parenchymal fraction, were also calculated. While there was no direct correlation between CEL number or volume at baseline and disability status at follow-up, CEL measures at baseline did correlate with number of relapses observed in the subsequent years, and the number of relapses in turn correlated with subsequent disability as well as transition to progressive MS. While number and volume of CEL at baseline do not directly correlate with disability in the longer term in MS, our data suggest that 1 route to disability involves relapses as a mediator variable in the causal sequence of MS progression from CEL to disability. Further studies using relapse as a mediator variable in a larger data set may be warranted. Copyright © 2015 by the American Society of Neuroimaging.

Change in self-esteem predicts depressive symptoms at follow-up after intensive multimodal psychotherapy for major depression.

PubMed

Dinger, Ulrike; Ehrenthal, Johannes C; Nikendei, Christoph; Schauenburg, Henning

2017-09-01

Reduced self-esteem is a core symptom of depression, but few studies have investigated within-treatment change of self-esteem as a predictor of long-term outcome in depression. This study investigated change in self-esteem during 8 weeks of multimodal, psychodynamically oriented psychotherapy for 40 depressed patients and tested whether it would predict outcome 6 months after termination. Data was drawn from a randomized clinical pilot trial on day-clinic versus inpatient psychotherapy for depression. Findings supported the association between change in self-esteem and follow-up depression severity, even when controlling for within-treatment symptom change. Change in self-esteem was not related to overall symptoms and interpersonal problems at follow-up. Thus, change in self-esteem may be an important variable in preventing relapse for depression. Self-esteem is related to depressive symptoms and interpersonal problems. Improvement of self-esteem during psychotherapy correlates with improvements of symptoms and interpersonal problems. Change of self-esteem during psychotherapy predicts depressive symptoms 6 months after termination of therapy. When treating depressed patients, psychotherapists should work towards an improvement of self-esteem in order to prevent relapse. Copyright © 2017 John Wiley & Sons, Ltd.

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

PubMed

Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

2017-09-01

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

Long-term results of pneumatic dilatation for relapsing symptoms of achalasia after Heller myotomy.

PubMed

Legros, Ludivine; Ropert, Alain; Brochard, Charlène; Bouguen, Guillaume; Pagenault, Maël; Siproudhis, Laurent; Bretagne, Jean-François

2014-09-01

The aim of this study was to assess the efficacy and safety of pneumatic dilatation (PD) to treat symptom recurrence after Heller myotomy (HM). Consecutive patients receiving PD for relapsing symptoms following prior HM were included in this retrospective single-center study. Eckardt score ≤3 and/or ∆ Eckardt (difference between Eckardt score before and after dilatation) ≥3 defined the success of initial dilatation. Patients who maintained response longer than 2 months after initial dilatation were defined as short-term responders. Relapsers were offered further on-demand dilatation. Remission was defined as an Eckardt score ≤3 at the study endpoint. Kaplan-Meier survival curves were used to determine relapse rates. Eighteen patients (11 women, seven men) were included from January 2004 to January 2013. Ten patients had type I achalasia, and seven had type III, according to the Chicago classification. Thirty-nine PDs were performed (1.5 [1-2.25] per patient). All patients had short-term responses. The remission rate at the endpoint, after a median follow-up of 33 months, was 78%, but 44% were treated with on-demand PD during the follow-up interval. The proportions of patients without relapse and subsequent PD were 72% at 12 months, 65% at 24 and 36 months, and 49% at 48 months. No factors predictive of long-term response, particularly the type of achalasia, could be identified in this series. There were no perforations. In treating symptom recurrence following HM, PD was safe and effective over the long term when combined with subsequent PD. © 2014 John Wiley & Sons Ltd.

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia.

PubMed

Sutton, Rosemary; Shaw, Peter J; Venn, Nicola C; Law, Tamara; Dissanayake, Anuruddhika; Kilo, Tatjana; Haber, Michelle; Norris, Murray D; Fraser, Chris; Alvaro, Frank; Revesz, Tamas; Trahair, Toby N; Dalla-Pozza, Luciano; Marshall, Glenn M; O'Brien, Tracey A

2015-02-01

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0·0001) or post-HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy. © 2014 John Wiley & Sons Ltd.

Changes in circulating leptin levels during the initial stage of cessation are associated with smoking relapse.

PubMed

Lemieux, Andrine; Nakajima, Motohiro; Hatsukami, Dorothy K; Allen, Sharon; al'Absi, Mustafa

2015-09-01

Leptin has been linked to tobacco craving and withdrawal-related symptoms. Very few studies have examined leptin prospectively in both male and female nonsmokers and smokers. We examine leptin concentrations prospectively in both male and female nonsmokers and smokers to assess the associations of leptin with psychological symptoms and smoking relapse during ad libitum smoking, the first 48 h post quit, and 4 weeks post-cessation. Self-report psychological, anthropomorphic, and biological measures (cotinine, carbon monoxide, and plasma leptin) were collected before and after 48 h of smoking abstinence. Smokers were stratified at 28 days post quit as abstinent or relapsed if they had smoked daily for seven consecutive days at any point in the 28 days. Leptin concentration (square root transformed ng/ml) increased over the 48-h abstinence, but only in female abstainers. In contrast, leptin was very stable across time for nonsmokers, relapsers, and males. Cox regression supported that increased leptin was associated with decreased risk of relapse. Leptin was correlated negatively with withdrawal symptoms for abstainers only. Females produce more leptin than males and this level increases from ad libitum smoking to 48-h post quit. The current analysis indicates that a leptin increase early in cessation predicts abstinence. The increase in women, but not men, in response to abstinence provides further evidence of important gender differences. The negative correlation between leptin and withdrawal symptoms indicates a possible protective effect of leptin. Further research is ongoing to elucidate the psychological and biological determinants of this effect.

Discrepancy between recurrence-free survival and overall survival in patients with resectable colorectal liver metastases: a potential surrogate endpoint for time to surgical failure.

PubMed

Oba, Masaru; Hasegawa, Kiyoshi; Matsuyama, Yutaka; Shindoh, Junichi; Mise, Yoshihiro; Aoki, Taku; Sakamoto, Yoshihiro; Sugawara, Yasuhiko; Makuuchi, Masatoshi; Kokudo, Norihiro

2014-06-01

Recurrence-free survival (RFS) may not be a surrogate for overall survival (OS) in patients with resectable colorectal liver metastases (CLM). We investigated whether a new composite tool-time to surgical failure (TSF)-is a suitable endpoint. The medical records of consecutive patients who underwent curative resection for CLM at our center over a 17-year period were reviewed. Patients with liver-limited tumors (n = 371) who had not received previous treatment for metastasis were eligible for analysis. TSF was defined as the time until unresectable relapse or death. The correlations between TSF and OS, and between RFS and OS, were assessed for all the eligible patients. The median OS, TSF, and RFS were 5.7, 2.7, and 0.7 years, respectively, and the 5-year OS, TSF, and RFS rates were 52.6, 39.8, and 23.7 %, respectively, for all patients. The rates of first, second, and third relapse were 75.5, 77.6, and 70.8 %, respectively, and repeat resections were performed in 54.3 % (first relapses), 40.7 % (second relapses), and 47.1 % (third relapses) of patients. The concordance proportions of TSF and RFS for OS events were 0.83 and 0.65, respectively. The correlation between TSF and OS was stronger than that between RFS and OS in terms of the predicted probabilities. The correlation between TSF and OS was stronger than that between RFS and OS after curative hepatic resection. TSF could be a suitable endpoint for CLM overall management.

Nicotine Withdrawal Induces Neural Deficits in Reward Processing.

PubMed

Oliver, Jason A; Evans, David E; Addicott, Merideth A; Potts, Geoffrey F; Brandon, Thomas H; Drobes, David J

2017-06-01

Nicotine withdrawal reduces neurobiological responses to nonsmoking rewards. Insight into these reward deficits could inform the development of targeted interventions. This study examined the effect of withdrawal on neural and behavioral responses during a reward prediction task. Smokers (N = 48) attended two laboratory sessions following overnight abstinence. Withdrawal was manipulated by having participants smoke three regular nicotine (0.6 mg yield; satiation) or very low nicotine (0.05 mg yield; withdrawal) cigarettes. Electrophysiological recordings of neural activity were obtained while participants completed a reward prediction task that involved viewing four combinations of predictive and reward-determining stimuli: (1) Unexpected Reward; (2) Predicted Reward; (3) Predicted Punishment; (4) Unexpected Punishment. The task evokes a medial frontal negativity that mimics the phasic pattern of dopaminergic firing in ventral tegmental regions associated with reward prediction errors. Nicotine withdrawal decreased the amplitude of the medial frontal negativity equally across all trial types (p < .001). Exploratory analyses indicated withdrawal increased time to initiate the next trial following unexpected punishment trials (p < .001) and response time on reward trials during withdrawal was positively related to nicotine dependence (p < .001). Nicotine withdrawal had equivocal impact across trial types, suggesting reward processing deficits are unlikely to stem from changes in phasic dopaminergic activity during prediction errors. Effects on tonic activity may be more pronounced. Pharmacological interventions directly targeting the dopamine system and behavioral interventions designed to increase reward motivation and responsiveness (eg, behavioral activation) may aid in mitigating withdrawal symptoms and potentially improving smoking cessation outcomes. Findings from this study indicate nicotine withdrawal impacts reward processing signals that are observable in smokers' neural activity. This may play a role in the subjective aversive experience of nicotine withdrawal and potentially contribute to smoking relapse. Interventions that address abnormal responding to both pleasant and unpleasant stimuli may be particularly effective for alleviating nicotine withdrawal. © The Author 2017. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cost-effectiveness model of long-acting risperidone in schizophrenia in the US.

PubMed

Edwards, Natalie C; Rupnow, Marcia F T; Pashos, Chris L; Botteman, Marc F; Diamond, Ronald J

2005-01-01

Schizophrenia is a devastating and costly illness that affects 1% of the population in the US. Effective pharmacological therapies are available but suboptimal patient adherence to either acute or long-term therapeutic regimens reduces their effectiveness. The availability of a long-acting injection (LAI) formulation of risperidone may increase adherence and improve clinical and economic outcomes for people with schizophrenia. To assess the cost effectiveness of risperidone LAI compared with oral risperidone, oral olanzapine and haloperidol decanoate LAI over a 1-year time period in outpatients with schizophrenia who had previously suffered a relapse requiring hospitalisation. US healthcare system. Published medical literature, unpublished data from clinical trials and a consumer health database, and a clinical expert panel were used to populate a decision-analysis model comparing the four treatment alternatives. The model captured: rates of patient compliance; rates, frequency and duration of relapse; incidence of adverse events (bodyweight gain and extrapyramidal effects); and healthcare resource utilisation and associated costs. Primary outcomes were: the proportion of patients with relapse; the frequency of relapse per patient; the number of relapse days per patient; and total direct medical cost per patient per year. Costs are in year 2002 US dollars. Based on model projections, the proportions of patients experiencing a relapse requiring hospitalisation after 1 year of treatment were 66% for haloperidol decanoate LAI, 41% for oral risperidone and oral olanzapine and 26% for risperidone LAI, while the proportion of patients with a relapse not requiring hospitalisation were 60%, 37%, 37% and 24%, respectively. The mean number of days of relapse requiring hospitalisation per patient per year was 28 for haloperidol decanoate LAI, 18 for oral risperidone and oral olanzapine and 11 for risperidone LAI, while the mean number of days of relapse not requiring hospitalisation was 8, 5, 5 and 3, respectively. This would translate into direct medical cost savings with risperidone LAI compared with oral risperidone, oral olanzapine and haloperidol decanoate LAI of USD 397, USD 1742, and USD 8328, respectively. These findings were supported by sensitivity analyses. The use of risperidone LAI for treatment of outpatients with schizophrenia is predicted in this model to result in better clinical outcomes and lower total healthcare costs over 1 year than its comparators, oral risperidone, oral olanzapine and haloperidol decanoate LAI. Risperidone LAI may therefore be a cost saving therapeutic option for outpatients with schizophrenia in the US healthcare setting.

Resource utilization, costs and treatment patterns of switching and discontinuing treatment of MS patients with high relapse activity.

PubMed

Raimundo, Karina; Tian, Haijun; Zhou, Huanxue; Zhang, Xin; Kahler, Kristijan H; Agashivala, Neetu; Kim, Edward

2013-04-08

Multiple sclerosis (MS) is a chronic disease that affects mainly adults in the prime of their lives. However, few studies report the impact of high annual relapse rates on outcomes. The purpose of this study was to identify high relapse activity (HRA) in patients with MS, comparing differences in outcomes between patients with and without HRA. A retrospective longitudinal study was conducted using the MarketScan® Commercial Claims and Encounters and Medicare Supplemental Database. Patients had to have at least one ICD-9 for MS (340.XX) in 2009 and one in 2008, be older than 18 years, and have continuous enrolment in the years 2009-2010. HRA was defined as having ≥2 relapses in 2009. Multivariate analyses compared all-cause and MS-specific emergency room (ER) visits, hospitalizations, and all-cause costs, excluding disease modifying therapy (DMT) costs, in 2010 between patients with and without HRA, controlling for baseline characteristics. A subgroup analysis using treatment exposure was also performed. 19,219 patients were included: 5.3% (n=1,017) had ≥2 relapses in 2009. Patients with HRA were more likely to have all-cause and MS-specific resource utilization than patients without HRA. Mean total all-cause non DMT costs were $12,057 higher for the HRA group. In the subgroup analysis, HRA treatment-naïve patients were more likely to start treatment, and HRA treatment-experienced patients were more likely to discontinue or switch index DMT (P<0.01). Patients with ≥2 relapses annually have higher resource utilization and costs. The difference in cost was over twice as large in treatment-naïve patients versus treatment-experienced patients. HRA was also associated with an increased likelihood of starting DMT treatment (treatment-naïve patients), and switching or discontinuing DMT therapy (treatment-experienced patients).

Antidepressant monotherapy vs sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression.

PubMed

Segal, Zindel V; Bieling, Peter; Young, Trevor; MacQueen, Glenda; Cooke, Robert; Martin, Lawrence; Bloch, Richard; Levitan, Robert D

2010-12-01

Mindfulness-based cognitive therapy (MBCT) is a group-based psychosocial intervention designed to enhance self-management of prodromal symptoms associated with depressive relapse. To compare rates of relapse in depressed patients in remission receiving MBCT against maintenance antidepressant pharmacotherapy, the current standard of care. Patients who met remission criteria after 8 months of algorithm-informed antidepressant treatment were randomized to receive maintenance antidepressant medication, MBCT, or placebo and were followed up for 18 months. Outpatient clinics at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, and St Joseph's Healthcare, Hamilton, Ontario. One hundred sixty patients aged 18 to 65 years meeting DSM-IV criteria for major depressive disorder with a minimum of 2 past episodes. Of these, 84 achieved remission (52.5%) and were assigned to 1 of the 3 study conditions. Patients in remission discontinued their antidepressants and attended 8 weekly group sessions of MBCT, continued taking their therapeutic dose of antidepressant medication, or discontinued active medication and were switched to placebo. Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression on module A of the Structured Clinical Interview for DSM-IV. Intention-to-treat analyses showed a significant interaction between the quality of acute-phase remission and subsequent prevention of relapse in randomized patients (P = .03). Among unstable remitters (1 or more Hamilton Rating Scale for Depression score >7 during remission), patients in both MBCT and maintenance treatment showed a 73% decrease in hazard compared with placebo (P = .03), whereas for stable remitters (all Hamilton Rating Scale for Depression scores ≤7 during remission) there were no group differences in survival. For depressed patients achieving stable or unstable clinical remission, MBCT offers protection against relapse/recurrence on a par with that of maintenance antidepressant pharmacotherapy. Our data also highlight the importance of maintaining at least 1 long-term active treatment in unstable remitters.

Substance Abuse among High-Risk Sexual Offenders: Do Measures of Lifetime History of Substance Abuse Add to the Prediction of Recidivism over Actuarial Risk Assessment Instruments?

ERIC Educational Resources Information Center

Looman, Jan; Abracen, Jeffrey

2011-01-01

There has been relatively little research on the degree to which measures of lifetime history of substance abuse add to the prediction of risk based on actuarial measures alone among sexual offenders. This issue is of relevance in that a history of substance abuse is related to relapse to substance using behavior. Furthermore, substance use has…

Alemtuzumab Use in Clinical Practice: Recommendations from European Multiple Sclerosis Experts.

PubMed

Berger, Thomas; Elovaara, Irina; Fredrikson, Sten; McGuigan, Chris; Moiola, Lucia; Myhr, Kjell-Morten; Oreja-Guevara, Celia; Stoliarov, Igor; Zettl, Uwe K

2017-01-01

Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.

Daclizumab for the treatment of relapsing-remitting multiple sclerosis.

PubMed

Herwerth, Marina; Hemmer, Bernhard

2017-06-01

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Over the last two decades, the number of therapeutic options for the treatment of relapsing remitting MS (RRMS) has been constantly growing, providing new treatment options to patients. Areas covered: Herein, the authors review the recently approved monoclonal antibody daclizumab for the treatment of RRMS. Based on original articles, they discuss its mode of action and evaluate its efficacy and safety profile compared to other available agents. Expert opinion: The IL-2 receptor modulator daclizumab is a new highly effective agent for the treatment of RRMS with novel immunomodulatory properties. Compared to interferon-beta i.m., daclizumab is more effective in reducing relapse rates and MRI activity. However, its use is limited by the risk of autoimmune disorders and hepatotoxicity. Similar to other monoclonal antibodies for RRMS, therapy with daclizumab needs a strict preselection and monitoring of patients based on individual risk benefit assessment. Given its substantial effectiveness, daclizumab can be an attractive option for patients with highly active MS.

Alone on the Inside: The Impact of Social Isolation and Helping Others on AOD Use and Criminal Activity

PubMed Central

Johnson, Byron R.; Pagano, Maria E.; Lee, Matthew T.; Post, Stephen G.

2015-01-01

Because addiction is a socially isolating disease, social support for recovery is an important element of treatment planning. This study examines the relationship between social isolation, giving and receiving social support in Alcoholics Anonymous during treatment, and post-treatment outcomes among juvenile offenders court-referred to addiction treatment. Adolescents (N = 195) aged 14 to 18 years were prospectively assessed at treatment admission, treatment discharge, 6 months, and 12 months after treatment discharge. The influence of social isolation variables on relapse and severe criminal activity in the 12-months post-treatment was examined using negative binomial logistic regressions and event history methods. Juveniles entering treatment with social estrangement were significantly more likely to relapse, be incarcerated, and commit a violent crime in the 12-months post-treatment. Giving help to others in Alcoholics Anonymous during treatment significantly reduced the risk of relapse, incarceration, and violent crime in the 12-months post-treatment whereas receiving help did not. PMID:29628533

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear.

PubMed

Marek, Roger; Jin, Jingji; Goode, Travis D; Giustino, Thomas F; Wang, Qian; Acca, Gillian M; Holehonnur, Roopashri; Ploski, Jonathan E; Fitzgerald, Paul J; Lynagh, Timothy; Lynch, Joseph W; Maren, Stephen; Sah, Pankaj

2018-03-01

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

PubMed Central

Zorrilla, Eric P.; Heilig, Markus; de Wit, Harriet; Shaham, Yavin

2013-01-01

Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence. PMID:23294766

Activation of the hypnozoite: a part of Plasmodium vivax life cycle and survival.

PubMed

Hulden, Lena; Hulden, Larry

2011-04-16

Plasmodium vivax is the most widespread malaria parasite. It has a dormant stage in the human liver, which makes it difficult to eradicate. It is proposed that a relapse of vivax malaria, besides being genetically determined by the specific strain, is induced by the bites of uninfected vectors. The dormant stage maximizes the possibility for the parasite to reach the vector for sexual reproduction. The advantage would increase if the parasite was able to detect the presence of a new generation of vectors. The sporozoites function both in the vector and in the human hosts. They invade the cells of the salivary gland in the vector and the hepatocytes in the human. Some of the sporozoites develop into hypnozoites in the human liver. It is suggested that the hypnozoite activates when it recognizes the same Anopheles specific protein, which it had previously recognized as a sporozoite to invade the salivary gland in the vector. Another possibility is that the hypnozoite activates upon the bodily reaction by the human on a bite by an Anopheles female. The connection between the relapse and a new generation of vectors can be documented by simultaneous monitoring of both parasitaemia in humans and the presence of uninfective/infective vectors in the same area with seasonal malaria transmission. Experimental studies are needed to find the saliva components, which trigger the relapse. Although P. cynomolgi in monkeys also has hypnozoites and relapses, testing with monkeys might be problematical. These live in a reasonably stable tropical environment where relapses cannot easily be linked to vectors. The importance of the trigger increases in unpredictable variations in the vector season. Artificial triggering of hypnozoites would make the medication more effective and resistance against a protein that the parasite itself uses during its life cycle would not develop. In areas with seasonal vivax malaria it could be used locally for eradication.

Antiminor Histocompatibility Complex (MiHA) T Cells for Patients With Relapsed Hematologic Malignancies Following Matched HSCT (Guided Lymphocyte Immunopeptide Derived Expansion)

ClinicalTrials.gov

2017-12-04

Hematologic Cancer; Relapse Leukemia; Relapsed Adult ALL; Relapsed Adult AML; Relapsed CLL; Relapsed Non Hodgkin Lymphoma; Relapsed Hodgkin's Lymphoma; Relapsed Myelodysplastic Syndromes; Relapsed Multiple Myeloma

Corticosteroid-treated chronic active hepatitis in remission: uncertain prognosis of chronic persistent hepatitis.

PubMed

Czaja, A J; Ludwig, J; Baggenstoss, A H; Wolf, A

1981-01-01

To assess the prognosis of patients with severe chronic hepatitis after histologic examination had shown an improvement to chronic persistent hepatitis, we followed 52 such patients regularly for 54 +/- 4 months after the cessation of corticosteroid therapy. In 24 patients, the condition deteriorated 7 +/- 1 months after therapy and required further treatment with prednisone. Histologic features of chronic active hepatitis, including bridging and multilobular necrosis, were documented in all 14 patients in whom biopsies were performed. In 20 of 24 patients, the disease responded to retreatment, but 13 again had relapses, and cirrhosis developed in two. Of 28 patients who remained asymptomatic for 48 +/- 6 months, 17 retained features of chronic persistent hepatitis, and nine had improvement to normal histologic features. Cirrhosis developed in two patients without clinical manifestations of active inflammation. Findings before and after treatment did not predict outcome. We conclude that severe chronic active hepatitis that has been treated with prednisone and converted to chronic persistent hepatitis will often and unpredictably deteriorate after treatment has been stopped. Cirrhosis develops rarely but may occur with or without clinically overt chronic active hepatitis.

Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells

PubMed Central

Dai, Haiming; Ding, Husheng; Meng, X. Wei; Peterson, Kevin L.; Schneider, Paula A.; Karp, Judith E.; Kaufmann, Scott H.

2015-01-01

Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoactivation plays a key role in regulating the intrinsic apoptotic pathway in intact cells. In particular, we show that up to 80% of BAK (but not BAX) in lymphohematopoietic cell lines is oligomerized and bound to anti-apoptotic BCL2 family members in the absence of exogenous death stimuli. The extent of this constitutive BAK oligomerization is diminished by BAK knockdown and unaffected by BIM or PUMA down-regulation. Further analysis indicates that sensitivity of cells to BH3 mimetics reflects the identity of the anti-apoptotic proteins to which BAK is constitutively bound, with extensive BCLXL•BAK complexes predicting navitoclax sensitivity, and extensive MCL1•BAK complexes predicting A1210477 sensitivity. Moreover, high BAK expression correlates with sensitivity of clinical acute myelogenous leukemia to chemotherapy, whereas low BAK levels correlate with resistance and relapse. Collectively, these results inform current understanding of MOMP and provide new insight into the ability of BH3 mimetics to induce apoptosis without directly activating BAX or BAK. PMID:26494789

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group.

PubMed

Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

2011-05-01

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3-4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity.

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group

PubMed Central

Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

2011-01-01

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3—4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity. PMID:21463120

Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors.

PubMed

Farnedi, Anna; Rossi, Silvia; Bertani, Nicoletta; Gulli, Mariolina; Silini, Enrico Maria; Mucignat, Maria Teresa; Poli, Tito; Sesenna, Enrico; Lanfranco, Davide; Montebugnoli, Lucio; Leonardi, Elisa; Marchetti, Claudio; Cocchi, Renato; Ambrosini-Spaltro, Andrea; Foschini, Maria Pia; Perris, Roberto

2015-05-03

Tumour relapse is recognized to be the prime fatal burden in patients affected by head and neck squamous cell carcinoma (HNSCC), but no discrete molecular trait has yet been identified to make reliable early predictions of tumour recurrence. Expression of cell surface proteoglycans (PGs) is frequently altered in carcinomas and several of them are gradually emerging as key prognostic factors. A PG expression analysis at both mRNA and protein level, was pursued on primary lesions derived from 173 HNSCC patients from whom full clinical history and 2 years post-surgical follow-up was accessible. Gene and protein expression data were correlated with clinical traits and previously proposed tumour relapse markers to stratify high-risk patient subgroups. HNSCC lesions were indeed found to exhibit a widely aberrant PG expression pattern characterized by a variable expression of all PGs and a characteristic de novo transcription/translation of GPC2, GPC5 and NG2/CSPG4 respectively in 36%, 72% and 71% on 119 cases. Importantly, expression of NG2/CSPG4, on neoplastic cells and in the intralesional stroma (Hazard Ratio [HR], 6.76, p = 0.017) was strongly associated with loco-regional relapse, whereas stromal enrichment of SDC2 (HR, 7.652, p = 0.007) was independently tied to lymphnodal infiltration and disease-related death. Conversely, down-regulated SDC1 transcript (HR, 0.232, p = 0.013) uniquely correlated with formation of distant metastases. Altered expression of PGs significantly correlated with the above disease outcomes when either considered alone or in association with well-established predictors of poor prognosis (i.e. T classification, previous occurrence of precancerous lesions and lymphnodal metastasis). Combined alteration of all three PGs was found to be a reliable predictor of shorter survival. An unprecedented PG-based prognostic portrait is unveiled that incisively diversifies disease course in HNSCC patients beyond the currently known clinical and molecular biomarkers.

Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation.

PubMed

Mannis, Gabriel N; Martin, Thomas G; Damon, Lloyd E; Andreadis, Charalambos; Olin, Rebecca L; Kong, Katherine A; Faham, Malek; Hwang, Jimmy; Ai, Weiyun Z; Gaensler, Karin M L; Sayre, Peter H; Wolf, Jeffrey L; Logan, Aaron C

2016-06-01

Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with "high-risk" ALL uniformly require allogeneic (allo) hematopoietic cell transplantation (HCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous (auto) hematopoietic cell transplantation for high-risk patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Philadelphia chromosome-negative (Ph-) B-ALL, and 4 (14%) had T cell ALL. With a median follow-up of 41 months (range, 3 to 217), median relapse-free survival (RFS) and overall survival for the entire cohort were 3.2 and 4.2 years, respectively; at 5 years after transplantation, 42% of patients remain alive and relapse free. Using MRD detection at a threshold of ≥ 1 × 10(-6), median RFS for patients with detectable MRD was 6.5 months and was not reached for patients without detectable disease (P = .0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1 × 10(-6) (odds ratio, 23.8; confidence interval, 1.8 to 312.9; P = .0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Cue reactivity and its relation to craving and relapse in alcohol dependence: a combined laboratory and field study.

PubMed

Witteman, Jurriaan; Post, Hans; Tarvainen, Mika; de Bruijn, Avalon; Perna, Elizabeth De Sousa Fernandes; Ramaekers, Johannes G; Wiers, Reinout W

2015-10-01

The present study investigated the nature of physiological cue reactivity and craving in response to alcohol cues among alcohol-dependent patients (N = 80) who were enrolled in detoxification treatment. Further, the predictive value with regard to future drinking of both the magnitude of the physiological and craving response to alcohol cues while in treatment and the degree of alcohol-cue exposure in patients' natural environment was assessed. Physiological reactivity and craving in response to experimental exposure to alcohol and soft drink advertisements were measured during detoxification treatment using heart rate variability and subjective rating of craving. Following discharge, patients monitored exposure to alcohol advertisements for five consecutive weeks with a diary and were followed up with an assessment of relapse at 5 weeks and 3 months post-discharge. The results indicated that the presence of alcohol cues such as the portrayal of the drug and drinking behaviour induced physiological cue reactivity and craving. Additionally, cue reactivity and craving were positively correlated, and cue reactivity was larger for patients with shorter histories of alcohol dependence. Further, patients reported a substantial daily exposure to alcohol cues. The magnitude of cue reactivity and the craving response to alcohol cues at baseline and degree of exposure to alcohol cues in patients' natural environment did not predict relapse. It is concluded that the presence of alcohol cues such as portrayal of alcoholic beverages and drinking behaviour induces cue reactivity and craving in alcohol dependence through a conditioned appetitive response.

Tobacco Withdrawal Components and Their Relations with Cessation Success

PubMed Central

Piper, Megan E.; Schlam, Tanya R.; Cook, Jessica W.; Sheffer, Megan A.; Smith, Stevens S.; Loh, Wei-Yin; Bolt, Daniel M.; Kim, Su-Young; Kaye, Jesse T.; Hefner, Kathryn R.; Baker, Timothy B.

2011-01-01

Rationale Tobacco withdrawal is a key factor in smoking relapse, but important questions about the withdrawal phenomenon remain. Objectives This research was intended to provide information about two core components of withdrawal (negative affect and craving): 1) how various withdrawal symptom profile dimensions (e.g., mean level, volatility, extreme values) differ between negative affect and craving; and 2) how these dimensions relate to cessation outcome. Methods Adult smokers (N=1504) in a double-blind randomized placebo-controlled smoking cessation trial provided real-time withdrawal symptom data four times per day for 4 weeks (2 weeks pre-quit and 2 weeks post-quit) via palmtop computers. Cessation outcome was biochemically confirmed 8-week point-prevalence abstinence. Results Examination of craving and negative affect dimensions following a cessation attempt revealed that craving symptoms differed from negative affect symptoms, with higher means, greater variability, and a greater incidence of extreme peaks. Regression analyses revealed that abstinence was associated with lower mean levels of both craving and negative affect and fewer incidences of extreme craving peaks. In a multivariate model, the increase in mean craving and negative affect scores each uniquely predicted relapse. Conclusions Real-time reports revealed different patterns of abstinence-related negative affect and craving and that dimensions of both predict cessation outcome, suggesting that negative affect and craving dimensions each has motivational significance. This underscores the complexity of withdrawal as a determinant of relapse and the need to measure its distinct components and dimensions. PMID:21416234

Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group.

PubMed

Oriol, Albert; Vives, Susana; Hernández-Rivas, Jesús-María; Tormo, Mar; Heras, Inmaculada; Rivas, Concepción; Bethencourt, Concepción; Moscardó, Federico; Bueno, Javier; Grande, Carlos; del Potro, Eloy; Guardia, Ramon; Brunet, Salut; Bergua, Juan; Bernal, Teresa; Moreno, Maria-José; Calvo, Carlota; Bastida, Pilar; Feliu, Evarist; Ribera, Josep-Maria

2010-04-01

About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. The median overall survival after relapse was 4.5 months (95% CI, 4-5 months) with a 5-year overall survival of 10% (95% CI, 8%-12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%-30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P<0.022) and a first remission lasting more than 2 years (2-year overall survival of 36% versus 17% among those with a shorter first remission; P<0.001). Patients under 30 years old whose first complete remission lasted longer than 2 years had a 5-year overall survival of 38% (95% CI, 23%-53%) and a 5-year disease-free survival of 53% (95% CI, 34%-72%). The prognosis of adult patients with acute lymphoblastic leukemia who relapse is poor. Those aged less than 30 years with a first complete remission lasting longer than 2 years have reasonable possibilities of becoming long-term survivors while patients over this age or those who relapse early cannot be successfully rescued using the therapies currently available.

Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group

PubMed Central

Oriol, Albert; Vives, Susana; Hernández-Rivas, Jesús-María; Tormo, Mar; Heras, Inmaculada; Rivas, Concepción; Bethencourt, Concepción; Moscardó, Federico; Bueno, Javier; Grande, Carlos; del Potro, Eloy; Guardia, Ramon; Brunet, Salut; Bergua, Juan; Bernal, Teresa; Moreno, Maria-José; Calvo, Carlota; Bastida, Pilar; Feliu, Evarist; Ribera, Josep-Maria

2010-01-01

Background About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. Design and Methods We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. Results The median overall survival after relapse was 4.5 months (95% CI, 4–5 months) with a 5-year overall survival of 10% (95% CI, 8%–12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%–30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P<0.022) and a first remission lasting more than 2 years (2-year overall survival of 36% versus 17% among those with a shorter first remission; P<0.001). Patients under 30 years old whose first complete remission lasted longer than 2 years had a 5-year overall survival of 38% (95% CI, 23%–53%) and a 5-year disease-free survival of 53% (95% CI, 34%–72%). Conclusions The prognosis of adult patients with acute lymphoblastic leukemia who relapse is poor. Those aged less than 30 years with a first complete remission lasting longer than 2 years have reasonable possibilities of becoming long-term survivors while patients over this age or those who relapse early cannot be successfully rescued using the therapies currently available. PMID:20145276

Impact of Social Cognition on Alcohol Dependence Treatment Outcome: Poorer Facial Emotion Recognition Predicts Relapse/Dropout.

PubMed

Rupp, Claudia I; Derntl, Birgit; Osthaus, Friederike; Kemmler, Georg; Fleischhacker, W Wolfgang

2017-12-01

Despite growing evidence for neurobehavioral deficits in social cognition in alcohol use disorder (AUD), the clinical relevance remains unclear, and little is known about its impact on treatment outcome. This study prospectively investigated the impact of neurocognitive social abilities at treatment onset on treatment completion. Fifty-nine alcohol-dependent patients were assessed with measures of social cognition including 3 core components of empathy via paradigms measuring: (i) emotion recognition (the ability to recognize emotions via facial expression), (ii) emotional perspective taking, and (iii) affective responsiveness at the beginning of inpatient treatment for alcohol dependence. Subjective measures were also obtained, including estimates of task performance and a self-report measure of empathic abilities (Interpersonal Reactivity Index). According to treatment outcomes, patients were divided into a patient group with a regular treatment course (e.g., with planned discharge and without relapse during treatment) or an irregular treatment course (e.g., relapse and/or premature and unplanned termination of treatment, "dropout"). Compared with patients completing treatment in a regular fashion, patients with relapse and/or dropout of treatment had significantly poorer facial emotion recognition ability at treatment onset. Additional logistic regression analyses confirmed these results and identified poor emotion recognition performance as a significant predictor for relapse/dropout. Self-report (subjective) measures did not correspond with neurobehavioral social cognition measures, respectively objective task performance. Analyses of individual subtypes of facial emotions revealed poorer recognition particularly of disgust, anger, and no (neutral faces) emotion in patients with relapse/dropout. Social cognition in AUD is clinically relevant. Less successful treatment outcome was associated with poorer facial emotion recognition ability at the beginning of treatment. Impaired facial emotion recognition represents a neurocognitive risk factor that should be taken into account in alcohol dependence treatment. Treatments targeting the improvement of these social cognition deficits in AUD may offer a promising future approach. Copyright © 2017 by the Research Society on Alcoholism.

In vivo measurement of the potential doubling time by flowcytometry in oropharyngeal cancer treated by conventional radiotherapy.

PubMed

Bourhis, J; Wilson, G; Wibault, P; Bosq, J; Chavaudra, N; Janot, F; Luboinski, B; Eschwege, F; Malaise, E P

1993-08-01

Experimental and clinical studies suggest that the pre-treatment potential doubling time could be predictive of tumor control in patients treated by conventional radiotherapy and could help to identify the rapidly growing tumors for which accelerated radiotherapy is required. To test this hypothesis, we studied prospectively 48 patients with a squamous cell carcinoma of the oropharynx and treated by conventional radiotherapy (70 Gy/7 weeks). The duration of S phase, the labeling index and the potential doubling time were obtained by flowcytometry measurements of a tumor biopsy obtained after injection of 200 mg bromodeoxyuridine to the patient. Three parameters were significantly associated with an increased risk of relapse namely the tumors size (T4; p < 0.01), the nodal status (> or = N2; p < 0.05) and the site of the primary within the oropharynx (p = 0.08). The S phase, labeling index, DNA index and potential doubling time were not significantly associated with an increased risk of relapse. However when considering only the T2 subgroup of patients, high labeling indexes and short potential doubling time were associated with an increased risk of relapse: the mean pre-treatment potential doubling time of the tumors which relapsed was 3.21 versus 5.5 days when there was no evidence of local relapse (p < 0.05). The mean labeling index for the group of tumors associated with a tumor recurrence was 11.7% compared to 7.3% when there was no evidence of relapse (p = 0.02). Factors other than proliferation play a role in determining the outcome of oropharyngeal cancers treated by conventional radiotherapy. However there was a significant correlation between short potential doubling time, high labeling index and tumor recurrence in the T2 subgroup of patients. The finding of significance for potential doubling time and labeling index in the T2 subset of tumors may be a reflexion of the more homogeneous nature of these tumors with regard to prognostic variables.

Plasminogen activator inhibitor-2 in patients with monocytic leukemia.

PubMed

Scherrer, A; Kruithof, E K; Grob, J P

1991-06-01

Plasma and tumor cells from 103 patients with leukemia or lymphoma at initial presentation were investigated for the presence of plasminogen activator inhibitor-2 (PAI-2) antigen, a potent inhibitor of urokinase. PAI-2 was detected in plasma and leukemic cells of the 21 patients with leukemia having a monocytic component [acute myelomonocytic (M4), acute monoblastic (M5), and chronic myelomonocytic leukemias], and in the three patients with acute undifferentiated myeloblastic leukemia (M0). In contrast, this serine protease inhibitor was undetectable in 79 patients with other subtypes of acute myeloid leukemia or other hematological malignancies. Serial serum PAI-2 determinations in 16 patients with acute leukemia at presentation, during therapy, remission, and relapse revealed that in the five patients with M4-M5, elevated PAI-2 levels rapidly normalized under therapy and during remission, but increased again in the patients with a relapse associated with an M4-M5 phenotype. Thus, PAI-2 seems to be a marker highly specific for the active stages of monocytic leukemia, i.e. presentation and relapse. The presence of PAI-2 in the plasma and cells of patients with M0 may give a clue to a monocytic origin of these cells.

Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis.

PubMed

Touil, Hanane; Kobert, Antonia; Lebeurrier, Nathalie; Rieger, Aja; Saikali, Philippe; Lambert, Caroline; Fawaz, Lama; Moore, Craig S; Prat, Alexandre; Gommerman, Jennifer; Antel, Jack P; Itoyama, Yasuto; Nakashima, Ichiro; Bar-Or, Amit

2018-04-19

The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

PubMed

Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A; Cornelissen-Steijger, Paulien D M; Geukes Foppen, Marnix H; Kemper, Kristel; Goding, Colin R; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G; Ribas, Antoni; Lo, Roger S; Peeper, Daniel S

2014-12-15

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

PubMed Central

Roundhill, E; Burchill, S

2013-01-01

Background: Primary Ewing's sarcoma family of tumours (ESFTs) may respond to chemotherapy, although many patients experience subsequent disease recurrence and relapse. The survival of ESFT cells following chemotherapy has been attributed to the development of resistant disease, possibly through the expression of ABC transporter proteins. Methods: MRP-1 and Pgp mRNA and protein expression in primary ESFTs was determined by quantitative reverse-transcriptase PCR (RT-qPCR) and immunohistochemistry, respectively, and alternative splicing of MRP-1 by RT-PCR. Results: We observed MRP-1 protein expression in 92% (43 out of 47) of primary ESFTs, and cell membrane MRP-1 was highly predictive of both overall survival (P<0.0001) and event-free survival (P<0.0001). Alternative splicing of MRP-1 was detected in primary ESFTs, although the pattern of splicing variants was not predictive of patient outcome, with the exception of loss of exon 9 in six patients, which predicted relapse (P=0.041). Pgp protein was detected in 6% (38 out of 44) of primary ESFTs and was not associated with patient survival. Conclusion: For the first time we have established that cell membrane expression of MRP-1 or loss of exon 9 is predictive of outcome but not the number of splicing events or expression of Pgp, and both may be valuable factors for the stratification of patients for more intensive therapy. PMID:23799853

Predicting Rapid Relapse Following Treatment for Chemical Dependence: A Matched-Subjects Design.

ERIC Educational Resources Information Center

Svanum, Soren; McAdoo, William George

1989-01-01

Persons who underwent residential treatment for chemical dependency were identified as three-month treatment failures (N=52) or successes (N=52). Subjects were matched on Minnesota Multiphasic Personality Inventory (MMPI) scores. Found posttreatment depression, anxiety, and sleep problems strongly related to failure among psychiatric MMPI group;…

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

PubMed Central

Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

2016-01-01

Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing–remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood–brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

CUE-INDUCED REINSTATEMENT OF ALCOHOL-SEEKING BEHAVIOR IS ASSOCIATED WITH INCREASED ERK1/2 PHOSPHORYLATION IN SPECIFIC LIMBIC BRAIN REGIONS: BLOCKADE BY THE MGLUR5 ANTAGONIST MPEP

PubMed Central

Schroeder, Jason P.; Spanos, Marina; Stevenson, Jennie R.; Besheer, Joyce; Salling, Michael; Hodge, Clyde W.

2008-01-01

Relapse to alcohol use after periods of abstinence is a hallmark behavioral pathology of alcoholism and a major clinical problem. Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate relapse to alcohol-seeking behavior but the molecular mechanisms of this potential therapeutic effect remain unexplored. The extracellular signal-regulated kinase (ERK1/2) pathway is downstream of mGluR5 and has been implicated in addiction. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior, and its reduction by an mGluR5 antagonist, is associated with changes in ERK1/2 activation in reward-related limbic brain regions. Selectively bred alcohol-preferring (P) rats were trained to lever press on a concurrent schedule of alcohol (15% v/v) vs. water reinforcement. Following 9 days of extinction, rats were given an additional extinction trial or injected with the mGluR5 antagonist MPEP (0, 1, 3, or 10 mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10 mg/kg) conditions for analysis of p-ERK1/2, total ERK1/2, and p-ERK5 immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a 3–5 fold increase in p-ERK1/2 IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK1/2 IR. P-ERK1/2 IR in the central amygdala and NAcb core was dissociated with the relapse-like behavior and the pharmacological effect of mGluR5 blockade. No changes in total ERK or p-ERK5 were observed. These results suggest that exposure to cues previously associated with alcohol self-administration is sufficient to produce concomitant increases in relapse-like behavior and ERK1/2 activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cue-induced ERK1/2 activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events. PMID:18619984

Info-gap management of public health Policy for TB with HIV-prevalence and epidemiological uncertainty

PubMed Central

2012-01-01

Background Formulation and evaluation of public health policy commonly employs science-based mathematical models. For instance, epidemiological dynamics of TB is dominated, in general, by flow between actively and latently infected populations. Thus modelling is central in planning public health intervention. However, models are highly uncertain because they are based on observations that are geographically and temporally distinct from the population to which they are applied. Aims We aim to demonstrate the advantages of info-gap theory, a non-probabilistic approach to severe uncertainty when worst cases cannot be reliably identified and probability distributions are unreliable or unavailable. Info-gap is applied here to mathematical modelling of epidemics and analysis of public health decision-making. Methods Applying info-gap robustness analysis to tuberculosis/HIV (TB/HIV) epidemics, we illustrate the critical role of incorporating uncertainty in formulating recommendations for interventions. Robustness is assessed as the magnitude of uncertainty that can be tolerated by a given intervention. We illustrate the methodology by exploring interventions that alter the rates of diagnosis, cure, relapse and HIV infection. Results We demonstrate several policy implications. Equivalence among alternative rates of diagnosis and relapse are identified. The impact of initial TB and HIV prevalence on the robustness to uncertainty is quantified. In some configurations, increased aggressiveness of intervention improves the predicted outcome but also reduces the robustness to uncertainty. Similarly, predicted outcomes may be better at larger target times, but may also be more vulnerable to model error. Conclusions The info-gap framework is useful for managing model uncertainty and is attractive when uncertainties on model parameters are extreme. When a public health model underlies guidelines, info-gap decision theory provides valuable insight into the confidence of achieving agreed-upon goals. PMID:23249291

Info-gap management of public health Policy for TB with HIV-prevalence and epidemiological uncertainty.

PubMed

Ben-Haim, Yakov; Dacso, Clifford C; Zetola, Nicola M

2012-12-19

Formulation and evaluation of public health policy commonly employs science-based mathematical models. For instance, epidemiological dynamics of TB is dominated, in general, by flow between actively and latently infected populations. Thus modelling is central in planning public health intervention. However, models are highly uncertain because they are based on observations that are geographically and temporally distinct from the population to which they are applied. We aim to demonstrate the advantages of info-gap theory, a non-probabilistic approach to severe uncertainty when worst cases cannot be reliably identified and probability distributions are unreliable or unavailable. Info-gap is applied here to mathematical modelling of epidemics and analysis of public health decision-making. Applying info-gap robustness analysis to tuberculosis/HIV (TB/HIV) epidemics, we illustrate the critical role of incorporating uncertainty in formulating recommendations for interventions. Robustness is assessed as the magnitude of uncertainty that can be tolerated by a given intervention. We illustrate the methodology by exploring interventions that alter the rates of diagnosis, cure, relapse and HIV infection. We demonstrate several policy implications. Equivalence among alternative rates of diagnosis and relapse are identified. The impact of initial TB and HIV prevalence on the robustness to uncertainty is quantified. In some configurations, increased aggressiveness of intervention improves the predicted outcome but also reduces the robustness to uncertainty. Similarly, predicted outcomes may be better at larger target times, but may also be more vulnerable to model error. The info-gap framework is useful for managing model uncertainty and is attractive when uncertainties on model parameters are extreme. When a public health model underlies guidelines, info-gap decision theory provides valuable insight into the confidence of achieving agreed-upon goals.