External validation of a Cox prognostic model: principles and methods

PubMed Central

2013-01-01

Background A prognostic model should not enter clinical practice unless it has been demonstrated that it performs a useful role. External validation denotes evaluation of model performance in a sample independent of that used to develop the model. Unlike for logistic regression models, external validation of Cox models is sparsely treated in the literature. Successful validation of a model means achieving satisfactory discrimination and calibration (prediction accuracy) in the validation sample. Validating Cox models is not straightforward because event probabilities are estimated relative to an unspecified baseline function. Methods We describe statistical approaches to external validation of a published Cox model according to the level of published information, specifically (1) the prognostic index only, (2) the prognostic index together with Kaplan-Meier curves for risk groups, and (3) the first two plus the baseline survival curve (the estimated survival function at the mean prognostic index across the sample). The most challenging task, requiring level 3 information, is assessing calibration, for which we suggest a method of approximating the baseline survival function. Results We apply the methods to two comparable datasets in primary breast cancer, treating one as derivation and the other as validation sample. Results are presented for discrimination and calibration. We demonstrate plots of survival probabilities that can assist model evaluation. Conclusions Our validation methods are applicable to a wide range of prognostic studies and provide researchers with a toolkit for external validation of a published Cox model. PMID:23496923

Association of Adjuvant Chemotherapy With Survival in Patients With Stage II or III Gastric Cancer

PubMed Central

Jiang, Yuming; Li, Tuanjie; Liang, Xiaoling; Hu, Yanfeng; Huang, Lei; Liao, Zhenchen; Zhao, Liying; Han, Zhen; Zhu, Shuguang; Wang, Menglan; Xu, Yangwei; Qi, Xiaolong; Liu, Hao; Yang, Yang; Yu, Jiang; Liu, Wei; Cai, Shirong

2017-01-01

Importance The current staging system of gastric cancer is not adequate for defining a prognosis and predicting the patients most likely to benefit from chemotherapy. Objective To construct a survival prediction model based on specific tumor and patient characteristics that enables individualized predictions of the net survival benefit of adjuvant chemotherapy for patients with stage II or stage III gastric cancer. Design, Setting, and Participants In this multicenter retrospective analysis, a survival prediction model was constructed using data from a training cohort of 746 patients with stage II or stage III gastric cancer who satisfied the study’s inclusion criteria and underwent surgery between January 1, 2004, and December 31, 2012, at Nanfang Hospital in Guangzhou, China. Patient and tumor characteristics were included as covariates, and their association with overall survival and disease-free survival with and without adjuvant chemotherapy was assessed. The model was internally validated for discrimination and calibration using bootstrap resampling. To externally validate the model, data were included from a validation cohort of 973 patients with stage II or stage III gastric cancer who met the inclusion criteria and underwent surgery at First Affiliated Hospital in Guangzhou, China, and at West China Hospital of Sichuan Hospital in Chendu, China, between January 1, 2000, and June 30, 2009. Data were analyzed from July 10, 2016, to September 1, 2016. Main Outcomes and Measures Concordance index and decision curve analysis for each measure associated with postoperative overall survival and disease-free survival. Results Of the 1719 patients analyzed, 1183 (68.8%) were men and 536 (31.2%) were women and the median (interquartile range) age was 57 (49-66) years. Age, location, differentiation, carcinoembryonic antigen, cancer antigen 19-9, depth of invasion, lymph node metastasis, and adjuvant chemotherapy were significantly associated with overall survival and disease-free survival, with P < .05. The survival prediction model demonstrated good calibration and discrimination, with relatively high bootstrap-corrected concordance indexes in the training and validation cohorts. In the validation cohort, the concordance index for overall survival was 0.693 (95% CI, 0.671-0.715) and for disease-free survival was 0.704 (95% CI, 0.681-0.728). Two nomograms and a calculating tool were built on the basis of specific input variables to estimate an individual’s net survival gain attributable to adjuvant chemotherapy. Conclusions and Relevance The survival prediction model can be used to make individualized predictions of the expected survival benefit from the addition of adjuvant chemotherapy for patients with stage II or stage III gastric cancer. PMID:28538950

Tumor Surface Regularity at MR Imaging Predicts Survival and Response to Surgery in Patients with Glioblastoma.

PubMed

Pérez-Beteta, Julián; Molina-García, David; Ortiz-Alhambra, José A; Fernández-Romero, Antonio; Luque, Belén; Arregui, Elena; Calvo, Manuel; Borrás, José M; Meléndez, Bárbara; Rodríguez de Lope, Ángel; Moreno de la Presa, Raquel; Iglesias Bayo, Lidia; Barcia, Juan A; Martino, Juan; Velásquez, Carlos; Asenjo, Beatriz; Benavides, Manuel; Herruzo, Ismael; Revert, Antonio; Arana, Estanislao; Pérez-García, Víctor M

2018-07-01

Purpose To evaluate the prognostic and predictive value of surface-derived imaging biomarkers obtained from contrast material-enhanced volumetric T1-weighted pretreatment magnetic resonance (MR) imaging sequences in patients with glioblastoma multiforme. Materials and Methods A discovery cohort from five local institutions (165 patients; mean age, 62 years ± 12 [standard deviation]; 43% women and 57% men) and an independent validation cohort (51 patients; mean age, 60 years ± 12; 39% women and 61% men) from The Cancer Imaging Archive with volumetric T1-weighted pretreatment contrast-enhanced MR imaging sequences were included in the study. Clinical variables such as age, treatment, and survival were collected. After tumor segmentation and image processing, tumor surface regularity, measuring how much the tumor surface deviates from a sphere of the same volume, was obtained. Kaplan-Meier, Cox proportional hazards, correlations, and concordance indexes were used to compare variables and patient subgroups. Results Surface regularity was a powerful predictor of survival in the discovery (P = .005, hazard ratio [HR] = 1.61) and validation groups (P = .05, HR = 1.84). Multivariate analysis selected age and surface regularity as significant variables in a combined prognostic model (P < .001, HR = 3.05). The model achieved concordance indexes of 0.76 and 0.74 for the discovery and validation cohorts, respectively. Tumor surface regularity was a predictor of survival for patients who underwent complete resection (P = .01, HR = 1.90). Tumors with irregular surfaces did not benefit from total over subtotal resections (P = .57, HR = 1.17), but those with regular surfaces did (P = .004, HR = 2.07). Conclusion The surface regularity obtained from high-resolution contrast-enhanced pretreatment volumetric T1-weighted MR images is a predictor of survival in patients with glioblastoma. It may help in classifying patients for surgery. © RSNA, 2018 Online supplemental material is available for this article.

Tumor Surface Regularity at MR Imaging Predicts Survival and Response to Surgery in Patients with Glioblastoma.

PubMed

Pérez-Beteta, Julián; Molina-García, David; Ortiz-Alhambra, José A; Fernández-Romero, Antonio; Luque, Belén; Arregui, Elena; Calvo, Manuel; Borrás, José M; Meléndez, Bárbara; Rodríguez de Lope, Ángel; Moreno de la Presa, Raquel; Iglesias Bayo, Lidia; Barcia, Juan A; Martino, Juan; Velásquez, Carlos; Asenjo, Beatriz; Benavides, Manuel; Herruzo, Ismael; Revert, Antonio; Arana, Estanislao; Pérez-García, Víctor M

2018-04-03

Purpose To evaluate the prognostic and predictive value of surface-derived imaging biomarkers obtained from contrast material-enhanced volumetric T1-weighted pretreatment magnetic resonance (MR) imaging sequences in patients with glioblastoma multiforme. Materials and Methods A discovery cohort from five local institutions (165 patients; mean age, 62 years ± 12 [standard deviation]; 43% women and 57% men) and an independent validation cohort (51 patients; mean age, 60 years ± 12; 39% women and 61% men) from The Cancer Imaging Archive with volumetric T1-weighted pretreatment contrast-enhanced MR imaging sequences were included in the study. Clinical variables such as age, treatment, and survival were collected. After tumor segmentation and image processing, tumor surface regularity, measuring how much the tumor surface deviates from a sphere of the same volume, was obtained. Kaplan-Meier, Cox proportional hazards, correlations, and concordance indexes were used to compare variables and patient subgroups. Results Surface regularity was a powerful predictor of survival in the discovery (P = .005, hazard ratio [HR] = 1.61) and validation groups (P = .05, HR = 1.84). Multivariate analysis selected age and surface regularity as significant variables in a combined prognostic model (P < .001, HR = 3.05). The model achieved concordance indexes of 0.76 and 0.74 for the discovery and validation cohorts, respectively. Tumor surface regularity was a predictor of survival for patients who underwent complete resection (P = .01, HR = 1.90). Tumors with irregular surfaces did not benefit from total over subtotal resections (P = .57, HR = 1.17), but those with regular surfaces did (P = .004, HR = 2.07). Conclusion The surface regularity obtained from high-resolution contrast-enhanced pretreatment volumetric T1-weighted MR images is a predictor of survival in patients with glioblastoma. It may help in classifying patients for surgery. © RSNA, 2018 Online supplemental material is available for this article.

Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates.

PubMed

Focks, Andreas; Belgers, Dick; Boerwinkel, Marie-Claire; Buijse, Laura; Roessink, Ivo; Van den Brink, Paul J

2018-05-01

Exposure patterns in ecotoxicological experiments often do not match the exposure profiles for which a risk assessment needs to be performed. This limitation can be overcome by using toxicokinetic-toxicodynamic (TKTD) models for the prediction of effects under time-variable exposure. For the use of TKTD models in the environmental risk assessment of chemicals, it is required to calibrate and validate the model for specific compound-species combinations. In this study, the survival of macroinvertebrates after exposure to the neonicotinoid insecticide was modelled using TKTD models from the General Unified Threshold models of Survival (GUTS) framework. The models were calibrated on existing survival data from acute or chronic tests under static exposure regime. Validation experiments were performed for two sets of species-compound combinations: one set focussed on multiple species sensitivity to a single compound: imidacloprid, and the other set on the effects of multiple compounds for a single species, i.e., the three neonicotinoid compounds imidacloprid, thiacloprid and thiamethoxam, on the survival of the mayfly Cloeon dipterum. The calibrated models were used to predict survival over time, including uncertainty ranges, for the different time-variable exposure profiles used in the validation experiments. From the comparison between observed and predicted survival, it appeared that the accuracy of the model predictions was acceptable for four of five tested species in the multiple species data set. For compounds such as neonicotinoids, which are known to have the potential to show increased toxicity under prolonged exposure, the calibration and validation of TKTD models for survival needs to be performed ideally by considering calibration data from both acute and chronic tests.

Month of birth and survival to age 105+: evidence from the age validation study of German semi-supercentenarians.

PubMed

Doblhammer, Gabriele; Scholz, Rembrandt; Maier, Heiner

2005-10-01

Using data from Germany, we examine if month of birth influences survival up to age 105. Since age reporting at the highest ages is notoriously unreliable we draw on age-validated information from a huge age validation project of 1487 alleged German semi-supercentenarians aged 105+. We use month of birth as an exogenous indicator for seasonal changes in the environment around the time of birth. We find that the seasonal distribution of birth dates changes with age. For 925 age-validated semi-supercentenarians the seasonality is more pronounced than at the time of their birth (1880-1900). Among the December-born the relative risk of survival from birth to age 105+is 16% higher than the average, among the June-born, 23% lower. The month-of-birth pattern in the survival risk of the German semi-supercentenarians resembles closely the month-of-birth pattern in remaining life expectancy at age 50 in Denmark.

Validation of the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pulmonary hypertension prediction model in a unique population and utility in the prediction of long-term survival.

PubMed

Cogswell, Rebecca; Kobashigawa, Erin; McGlothlin, Dana; Shaw, Robin; De Marco, Teresa

2012-11-01

The Registry to Evaluate Early and Long-Term Pulmonary Arterial (PAH) Hypertension Disease Management (REVEAL) model was designed to predict 1-year survival in patients with PAH. Multivariate prediction models need to be evaluated in cohorts distinct from the derivation set to determine external validity. In addition, limited data exist on the utility of this model in the prediction of long-term survival. REVEAL model performance was assessed to predict 1-year and 5-year outcomes, defined as survival or composite survival or freedom from lung transplant, in 140 patients with PAH. The validation cohort had a higher proportion of human immunodeficiency virus (7.9% vs 1.9%, p < 0.0001), methamphetamine use (19.3% vs 4.9%, p < 0.0001), and portal hypertension PAH (16.4% vs 5.1%, p < 0.0001) compared with the development cohort. The C-index of the model to predict survival was 0.765 at 1 year and 0.712 at 5 years of follow-up. The C-index of the model to predict composite survival or freedom from lung transplant was 0.805 and 0.724 at 1 and 5 years of follow-up, respectively. Prediction by the model, however, was weakest among patients with intermediate-risk predicted survival. The REVEAL model had adequate discrimination to predict 1-year survival in this small but clinically distinct validation cohort. Although the model also had predictive ability out to 5 years, prediction was limited among patients of intermediate risk, suggesting our prediction methods can still be improved. Copyright © 2012. Published by Elsevier Inc.

How do we estimate survival? External validation of a tool for survival estimation in patients with metastatic bone disease-decision analysis and comparison of three international patient populations.

PubMed

Piccioli, Andrea; Spinelli, M Silvia; Forsberg, Jonathan A; Wedin, Rikard; Healey, John H; Ippolito, Vincenzo; Daolio, Primo Andrea; Ruggieri, Pietro; Maccauro, Giulio; Gasbarrini, Alessandro; Biagini, Roberto; Piana, Raimondo; Fazioli, Flavio; Luzzati, Alessandro; Di Martino, Alberto; Nicolosi, Francesco; Camnasio, Francesco; Rosa, Michele Attilio; Campanacci, Domenico Andrea; Denaro, Vincenzo; Capanna, Rodolfo

2015-05-22

We recently developed a clinical decision support tool, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases. After making it publicly available on www.PATHFx.org , we attempted to externally validate it using independent, international data. We collected data from patients treated at 13 Italian orthopaedic oncology referral centers between 2010 and 2013, then applied to PATHFx, which generated a probability of survival at three and 12-months for each patient. We assessed accuracy using the area under the receiver-operating characteristic curve (AUC), clinical utility using Decision Curve Analysis (DCA), and compared the Italian patient data to the training set (United States) and first external validation set (Scandinavia). The Italian dataset contained 287 records with at least 12 months follow-up information. The AUCs for the three-month and 12-month estimates was 0.80 and 0.77, respectively. There were missing data, including the surgeon's estimate of survival that was missing in the majority of records. Physiologically, Italian patients were similar to patients in the training and first validation sets. However notable differences were observed in the proportion of those surviving three and 12-months, suggesting differences in referral patterns and perhaps indications for surgery. PATHFx was successfully validated in an Italian dataset containing missing data. This study demonstrates its broad applicability to European patients, even in centers with differing treatment philosophies from those previously studied.

Fine-tuning convolutional deep features for MRI based brain tumor classification

NASA Astrophysics Data System (ADS)

Ahmed, Kaoutar B.; Hall, Lawrence O.; Goldgof, Dmitry B.; Liu, Renhao; Gatenby, Robert A.

2017-03-01

Prediction of survival time from brain tumor magnetic resonance images (MRI) is not commonly performed and would ordinarily be a time consuming process. However, current cross-sectional imaging techniques, particularly MRI, can be used to generate many features that may provide information on the patient's prognosis, including survival. This information can potentially be used to identify individuals who would benefit from more aggressive therapy. Rather than using pre-defined and hand-engineered features as with current radiomics methods, we investigated the use of deep features extracted from pre-trained convolutional neural networks (CNNs) in predicting survival time. We also provide evidence for the power of domain specific fine-tuning in improving the performance of a pre-trained CNN's, even though our data set is small. We fine-tuned a CNN initially trained on a large natural image recognition dataset (Imagenet ILSVRC) and transferred the learned feature representations to the survival time prediction task, obtaining over 81% accuracy in a leave one out cross validation.

Prediction of Conditional Probability of Survival After Surgery for Gastric Cancer: A Study Based on Eastern and Western Large Data Sets.

PubMed

Zhong, Qing; Chen, Qi-Yue; Li, Ping; Xie, Jian-Wei; Wang, Jia-Bin; Lin, Jian-Xian; Lu, Jun; Cao, Long-Long; Lin, Mi; Tu, Ru-Hong; Zheng, Chao-Hui; Huang, Chang-Ming

2018-04-20

The dynamic prognosis of patients who have undergone curative surgery for gastric cancer has yet to be reported. Our objective was to devise an accurate tool for predicting the conditional probability of survival for these patients. We analyzed 11,551 gastric cancer patients from the Surveillance, Epidemiology, and End Results database. Two-thirds of the patients were selected randomly for the development set and one-third for the validation set. Two nomograms were constructed to predict the conditional probability of overall survival and the conditional probability of disease-specific survival, using conditional survival methods. We then applied these nomograms to the 4,001 patients in the database from Fujian Medical University Union Hospital, Fuzhou, China, one of the most active Chinese institutes. The 5-year conditional probability of overall survival of the patients was 41.6% immediately after resection and increased to 52.8%, 68.2%, and 80.4% at 1, 2, and 3 years after gastrectomy. The 5-year conditional probability of disease-specific survival "increased" from 48.9% at the time of gastrectomy to 59.8%, 74.7%, and 85.5% for patients surviving 1, 2, and 3 years, respectively. Sex; race; age; depth of tumor invasion; lymph node metastasis; and tumor size, site, and grade were associated with overall survival and disease-specific survival (P <.05). Within the Surveillance, Epidemiology, and End Results validation set, the accuracy of the conditional probability of overall survival nomogram was 0.77, 0.81, 0.82, and 0.82 at 1, 3, 5, and 10 years after gastrectomy, respectively. Within the other validation set from the Fujian Medical University Union Hospital (n = 4,001), the accuracy of the conditional probability of overall survival nomogram was 0.76, 0.79, 0.77, and 0.77 at 1, 3, 5, and 10 years, respectively. The accuracy of the conditional probability of disease-specific survival model was also favorable. The calibration curve demonstrated good agreement between the predicted and observed survival rates. Based on the large Eastern and Western data sets, we developed and validated the first conditional nomogram for prediction of conditional probability of survival for patients with gastric cancer to allow consideration of the duration of survivorship. Copyright © 2018 Elsevier Inc. All rights reserved.

Cautions regarding the fitting and interpretation of survival curves: examples from NICE single technology appraisals of drugs for cancer.

PubMed

Connock, Martin; Hyde, Chris; Moore, David

2011-10-01

The UK National Institute for Health and Clinical Excellence (NICE) has used its Single Technology Appraisal (STA) programme to assess several drugs for cancer. Typically, the evidence submitted by the manufacturer comes from one short-term randomized controlled trial (RCT) demonstrating improvement in overall survival and/or in delay of disease progression, and these are the pre-eminent drivers of cost effectiveness. We draw attention to key issues encountered in assessing the quality and rigour of the manufacturers' modelling of overall survival and disease progression. Our examples are two recent STAs: sorafenib (Nexavar®) for advanced hepatocellular carcinoma, and azacitidine (Vidaza®) for higher-risk myelodysplastic syndromes (MDS). The choice of parametric model had a large effect on the predicted treatment-dependent survival gain. Logarithmic models (log-Normal and log-logistic) delivered double the survival advantage that was derived from Weibull models. Both submissions selected the logarithmic fits for their base-case economic analyses and justified selection solely on Akaike Information Criterion (AIC) scores. AIC scores in the azacitidine submission failed to match the choice of the log-logistic over Weibull or exponential models, and the modelled survival in the intervention arm lacked face validity. AIC scores for sorafenib models favoured log-Normal fits; however, since there is no statistical method for comparing AIC scores, and differences may be trivial, it is generally advised that the plausibility of competing models should be tested against external data and explored in diagnostic plots. Function fitting to observed data should not be a mechanical process validated by a single crude indicator (AIC). Projective models should show clear plausibility for the patients concerned and should be consistent with other published information. Multiple rather than single parametric functions should be explored and tested with diagnostic plots. When trials have survival curves with long tails exhibiting few events then the robustness of extrapolations using information in such tails should be tested.

Survival of BPV and Aujeszky's disease viruses in meat wastes subjected to different sanitization processes.

PubMed

Paluszak, Z; Lipowski, A; Ligocka, A

2010-01-01

The effect of composting and anaerobic fermentations under meso- and thermophylic conditions (37 degrees and 55 degrees C) on the survival of bovine parvovirus (BPV) and Aujeszky's disease viruse (ADV) in meat wastes has been examined in this study. Viruses were adsorbed on filters and introduced into carriers which were made of meat fragments of different sizes and bones or in the form of suspension they were introduced into the biomass in the course of processes of waste treatment. Carriers were removed at appropriate time intervals and virus titres were determined. The thermoresistant parvovirus survived for the longest time during mesophylic fermentation (almost 70 days), slightly shorter during composting (7-9.5 days depending on the type of carrier) and for the shortest time--at 55 degrees C (46-76 hours). Its inactivation rate was the fastest in a suspension, slower in meat and bone carriers. ADV inactivation proceeded considerably faster, as compared with BPV. Its active particles were not detected as early as in the 30th minute of thermophylic fermentation, the 6th hour of mesophylic fermentation and at the first sampling time during composting (at the 72nd hour). Total survival time ranged from 50 min to 13 hours. All the tested technologies enabled the effective elimination of ADV and on average twofold decrease in BPV titre. From the study conducted it follows that of both viruses, the BPV should be applied for validation processes of methods used in meat waste processing, particularly if this refers to methods where higher temperature is the factor inactivating pathogens.

Unresectable Hepatocellular Carcinoma: MR Imaging after Intraarterial Therapy. Part I. Identification and Validation of Volumetric Functional Response Criteria

PubMed Central

Bonekamp, Susanne; Li, Zhen; Geschwind, Jean-François H.; Halappa, Vivek Gowdra; Corona-Villalobos, Celia Pamela; Reyes, Diane; Pawlik, Timothy M.; Bonekamp, David; Eng, John

2013-01-01

Purpose: To identify and validate the optimal thresholds for volumetric functional MR imaging response criteria to predict overall survival after intraarterial treatment (IAT) in patients with unresectable hepatocellular carcinoma (HCC). Materials and Methods: Institutional review board approval and waiver of informed consent were obtained. A total of 143 patients who had undergone MR imaging before and 3–4 weeks after the first cycle of IAT were included. MR imaging analysis of one representative HCC index lesion was performed with proprietary software after initial treatment. Subjects were randomly divided into training (n = 114 [79.7%]) and validation (n = 29 [20.3%]) data sets. Uni- and multivariate Cox models were used to determine the best cutoffs, as well as survival differences, between response groups in the validation data set. Results: Optimal cutoffs in the training data set were 23% increase in apparent diffusion coefficient (ADC) and 65% decrease in volumetric enhancement in the portal venous phase (VE). Subsequently, 25% increase in ADC and 65% decrease in VE were used to stratify patients in the validation data set. Comparison of ADC responders (n = 12 [58.6%]) with nonresponders (n = 17 [34.5%]) showed significant differences in survival (25th percentile survival, 11.2 vs 4.9 months, respectively; P = .008), as did VE responders (n = 9 [31.0%]) compared with nonresponders (n = 20 [69.0%]; 25th percentile survival, 11.5 vs 5.1 months, respectively; P = .01). Stratification of patients with a combination of the criteria resulted in significant differences in survival between patients with lesions that fulfilled both criteria (n = 6 [20.7%]; too few cases to determine 25th percentile), one criterion (n = 9 [31.0%]; 25th percentile survival, 6.0 months), and neither criterion (n = 14 [48.3%]; 25th percentile survival, 5.1 months; P = .01). The association between the two criteria and overall survival remained significant in a multivariate analysis that included age, sex, Barcelona Clinic for Liver Cancer stage, and number of follow-up treatments. Conclusion: After IAT for unresectable HCC, patients can be stratified into significantly different survival categories based on responder versus nonresponder status according to MR imaging ADC and VE cutoffs. © RSNA, 2013 PMID:23616631

Characterization of Explosives Processing Waste Decomposition Due to Composting. Phase 2

DTIC Science & Technology

1992-11-01

with Ceriodaphnia (10 replicates, each containing 15 mL of test solution and one neonate ). In each temporal block of tests, Ceriodsnhnia survival and... neonate per replicate). This reference validated the biological quality of the dilution water, the Ceriodaphnia food, the test conditions (e.g...incubation temperature and photoperiod), and the health of the neonates used to initiate the tests. Information about the leachates, including the

Development and validation of a prognostic nomogram for terminally ill cancer patients.

PubMed

Feliu, Jaime; Jiménez-Gordo, Ana María; Madero, Rosario; Rodríguez-Aizcorbe, José Ramón; Espinosa, Enrique; Castro, Javier; Acedo, Jesús Domingo; Martínez, Beatriz; Alonso-Babarro, Alberto; Molina, Raquel; Cámara, Juan Carlos; García-Paredes, María Luisa; González-Barón, Manuel

2011-11-02

Determining life expectancy in terminally ill cancer patients is a difficult task. We aimed to develop and validate a nomogram to predict the length of survival in patients with terminal disease. From February 1, 2003, to December 31, 2005, 406 consecutive terminally ill patients were entered into the study. We analyzed 38 features prognostic of life expectancy among terminally ill patients by multivariable Cox regression and identified the most accurate and parsimonious model by backward variable elimination according to the Akaike information criterion. Five clinical and laboratory variables were built into a nomogram to estimate the probability of patient survival at 15, 30, and 60 days. We validated and calibrated the nomogram with an external validation cohort of 474 patients who were treated from June 1, 2006, through December 31, 2007. The median overall survival was 29.1 days for the training set and 18.3 days for the validation set. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, lymphocyte levels, albumin levels, and time from initial diagnosis to diagnosis of terminal disease were retained in the multivariable Cox proportional hazards model as independent prognostic factors of survival and formed the basis of the nomogram. The nomogram had high predictive performance, with a bootstrapped corrected concordance index of 0.70, and it showed good calibration. External independent validation revealed 68% predictive accuracy. We developed a highly accurate tool that uses basic clinical and analytical information to predict the probability of survival at 15, 30, and 60 days in terminally ill cancer patients. This tool can help physicians making decisions on clinical care at the end of life.

Elemental carbon exposure at residence and survival after acute myocardial infarction.

PubMed

von Klot, Stephanie; Gryparis, Alexandros; Tonne, Cathryn; Yanosky, Jeffrey; Coull, Brent A; Goldberg, Robert J; Lessard, Darleen; Melly, Steven J; Suh, Helen H; Schwartz, Joel

2009-07-01

Particulate air pollution has been consistently related to cardiovascular mortality. Some evidence suggests that particulate matter may accelerate the atherosclerotic process. Effects of within-city variations of particulate air pollution on survival after an acute cardiovascular event have been little explored. We conducted a cohort study of hospital survivors of acute myocardial infarction (MI) from the Worcester, MA, metropolitan area to investigate the long-term effects of within-city variation in traffic-related air pollution on mortality. The study builds on an ongoing community-wide investigation examining changes over time in MI incidence and case-fatality rates. We included confirmed cases of MI in 1995, 1997, 1999, 2001, and 2003. Long-term survival status was ascertained through 2005. A validated spatiotemporal land use regression model for traffic-related air pollution was developed and annual averages of elemental carbon at residence estimated. The effect of estimated elemental carbon on the long-term mortality of patients discharged after MI was analyzed using a Cox proportional hazards model, controlling for a variety of demographic, medical history, and clinical variables. Of the 3895 patients with validated MI, 44% died during follow-up. Exposure to estimated elemental carbon in the year of entry into the study was 0.44 microg/m on average. All-cause mortality increased by 15% (95% confidence interval = 0.03%-29%) per interquartile range increase in estimated yearly elemental carbon (0.24 microg/m) after the second year of survival. No association between traffic-related pollution and all-cause mortality was observed during the first 2 years of follow-up. Chronic traffic-related particulate air pollution is associated with increased mortality in hospital survivors of acute MI after the second year of survival.

The validity of EORTC GBM prognostic calculator on survival of GBM patients in the West of Scotland.

PubMed

Teo, Mario; Clark, Brian; MacKinnon, Mairi; Stewart, Willie; Paul, James; St George, Jerome

2014-06-01

It is now accepted that the addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) significantly improves survival. In 2008, a subanalysis of the original study data was performed, and an online "GBM Calculator" was made available on the European Organisation for Research and Treatment of Cancer (EORTC) website allowing users to estimate patients' survival outcomes. We tested this calculator against actual local survival data to validate its use in our patients. Prospectively collected clinical data were analysed on 105 consecutive patients receiving concurrent chemoradiotherapy following surgical treatment of GBM between December 2004 and February 2009. Using the EORTC online calculator, survival outcomes were generated for these patients and compared with their actual survival. The median overall survival for the entire cohort was 15.3 months (range 2.8-50.5 months), with 1-year and 2-year overall survival of 65.7% and 19%, respectively. This is in comparison to the median overall predictive survival of 21.3 months, with 1-year and 2-year survival of 95% and 39.5%, respectively. Case by case analysis also showed that the survival was overestimated in nearly 80% of patients. Subgroup analyses showed similar overestimation of patients' survival, except calculator Model 3 which utilised MGMT status. Use of the EORTC GBM prognostic calculator would have overestimated the survival of the majority of our patients with GBM. Uncertainty exists as to the cause of overestimation in the cohort although local socioeconomic factors might play a role. The different calculator models yielded different outcomes and the "best" predictor of survival for the cohort under study utilised the tumour MGMT status. We would strongly encourage similar local studies of validity testing prior to employing the online prognostic calculator for other population groups.

Endpoints and surrogate endpoints in colorectal cancer: a review of recent developments.

PubMed

Piedbois, Pascal; Buyse, Marc

2008-07-01

The purpose of this review is to discuss recently published work on endpoints for early and advanced colorectal cancer, as well as the statistical approaches used to validate surrogate endpoints. Most attempts to validate surrogate endpoints have estimated the correlation between the surrogate and the true endpoint, and between the treatment effects on these endpoints. The correlation approach has made it possible to validate disease-free survival and progression-free survival as acceptable surrogates for overall survival in early and advanced disease, respectively. The search for surrogate endpoints will intensify over the coming years. In parallel, efforts to either standardize or extend the endpoints or both will improve the reliability and relevance of clinical trial results.

Selection of Surrogate Bacteria for Use in Food Safety Challenge Studies: A Review.

PubMed

Hu, Mengyi; Gurtler, Joshua B

2017-09-01

Nonpathogenic surrogate bacteria are prevalently used in a variety of food challenge studies in place of foodborne pathogens such as Listeria monocytogenes, Salmonella, Escherichia coli O157:H7, and Clostridium botulinum because of safety and sanitary concerns. Surrogate bacteria should have growth characteristics and/or inactivation kinetics similar to those of target pathogens under given conditions in challenge studies. It is of great importance to carefully select and validate potential surrogate bacteria when verifying microbial inactivation processes. A validated surrogate responds similar to the targeted pathogen when tested for inactivation kinetics, growth parameters, or survivability under given conditions in agreement with appropriate statistical analyses. However, a considerable number of food studies involving putative surrogate bacteria lack convincing validation sources or adequate validation processes. Most of the validation information for surrogates in these studies is anecdotal and has been collected from previous publications but may not be sufficient for given conditions in the study at hand. This review is limited to an overview of select studies and discussion of the general criteria and approaches for selecting potential surrogate bacteria under given conditions. The review also includes a list of documented bacterial pathogen surrogates and their corresponding food products and treatments to provide guidance for future studies.

Development and Validation of a qRT-PCR Classifier for Lung Cancer Prognosis

PubMed Central

Chen, Guoan; Kim, Sinae; Taylor, Jeremy MG; Wang, Zhuwen; Lee, Oliver; Ramnath, Nithya; Reddy, Rishindra M; Lin, Jules; Chang, Andrew C; Orringer, Mark B; Beer, David G

2011-01-01

Purpose This prospective study aimed to develop a robust and clinically-applicable method to identify high-risk early stage lung cancer patients and then to validate this method for use in future translational studies. Patients and Methods Three published Affymetrix microarray data sets representing 680 primary tumors were used in the survival-related gene selection procedure using clustering, Cox model and random survival forest (RSF) analysis. A final set of 91 genes was selected and tested as a predictor of survival using a qRT-PCR-based assay utilizing an independent cohort of 101 lung adenocarcinomas. Results The RSF model built from 91 genes in the training set predicted patient survival in an independent cohort of 101 lung adenocarcinomas, with a prediction error rate of 26.6%. The mortality risk index (MRI) was significantly related to survival (Cox model p < 0.00001) and separated all patients into low, medium, and high-risk groups (HR = 1.00, 2.82, 4.42). The MRI was also related to survival in stage 1 patients (Cox model p = 0.001), separating patients into low, medium, and high-risk groups (HR = 1.00, 3.29, 3.77). Conclusions The development and validation of this robust qRT-PCR platform allows prediction of patient survival with early stage lung cancer. Utilization will now allow investigators to evaluate it prospectively by incorporation into new clinical trials with the goal of personalized treatment of lung cancer patients and improving patient survival. PMID:21792073

Protein profiles associated with survival in lung adenocarcinoma

PubMed Central

Chen, Guoan; Gharib, Tarek G; Wang, Hong; Huang, Chiang-Ching; Kuick, Rork; Thomas, Dafydd G.; Shedden, Kerby A.; Misek, David E.; Taylor, Jeremy M. G.; Giordano, Thomas J.; Kardia, Sharon L. R.; Iannettoni, Mark D.; Yee, John; Hogg, Philip J.; Orringer, Mark B.; Hanash, Samir M.; Beer, David G.

2003-01-01

Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients (P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer. PMID:14573703

Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples.

PubMed

Fekete, Tibor; Rásó, Erzsébet; Pete, Imre; Tegze, Bálint; Liko, István; Munkácsy, Gyöngyi; Sipos, Norbert; Rigó, János; Györffy, Balázs

2012-07-01

Transcriptomic analysis of global gene expression in ovarian carcinoma can identify dysregulated genes capable to serve as molecular markers for histology subtypes and survival. The aim of our study was to validate previous candidate signatures in an independent setting and to identify single genes capable to serve as biomarkers for ovarian cancer progression. As several datasets are available in the GEO today, we were able to perform a true meta-analysis. First, 829 samples (11 datasets) were downloaded, and the predictive power of 16 previously published gene sets was assessed. Of these, eight were capable to discriminate histology subtypes, and none was capable to predict survival. To overcome the differences in previous studies, we used the 829 samples to identify new predictors. Then, we collected 64 ovarian cancer samples (median relapse-free survival 24.5 months) and performed TaqMan Real Time Polimerase Chain Reaction (RT-PCR) analysis for the best 40 genes associated with histology subtypes and survival. Over 90% of subtype-associated genes were confirmed. Overall survival was effectively predicted by hormone receptors (PGR and ESR2) and by TSPAN8. Relapse-free survival was predicted by MAPT and SNCG. In summary, we successfully validated several gene sets in a meta-analysis in large datasets of ovarian samples. Additionally, several individual genes identified were validated in a clinical cohort. Copyright © 2011 UICC.

Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor–Negative Breast Cancer Survival

PubMed Central

Tyrer, Jonathan; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Schulz-Wendtland, Rüdiger; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Milne, Roger L.; Arias, José Ignacio; Menéndez, Primitiva; Benítez, Javier; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia; Couch, Fergus J.; Olson, Janet E.; Fredericksen, Zachary S.; Wang, Xianshu; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Southey, Melissa C.; Devilee, Peter; Tollenaar, Rob A. E. M.; Seynaeve, Caroline; García-Closas, Montserrat; Lissowska, Jolanta; Sherman, Mark E.; Bolton, Kelly L.; Hall, Per; Czene, Kamila; Cox, Angela; Brock, Ian W.; Elliott, Graeme C.; Reed, Malcolm W. R.; Greenberg, David; Anton-Culver, Hoda; Ziogas, Argyrios; Humphreys, Manjeet; Easton, Douglas F.; Caporaso, Neil E.; Pharoah, Paul D. P.

2010-01-01

Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. Methods We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case–control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. Results In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor–negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10−5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10−4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor–negative breast cancer. PMID:20308648

Molecular Signature for Lymphatic Invasion Associated with Survival of Epithelial Ovarian Cancer.

PubMed

Paik, E Sun; Choi, Hyun Jin; Kim, Tae-Joong; Lee, Jeong-Won; Kim, Byoung-Gie; Bae, Duk-Soo; Choi, Chel Hun

2018-04-01

We aimed to develop molecular classifier that can predict lymphatic invasion and their clinical significance in epithelial ovarian cancer (EOC) patients. We analyzed gene expression (mRNA, methylated DNA) in data from The Cancer Genome Atlas. To identify molecular signatures for lymphatic invasion, we found differentially expressed genes. The performance of classifier was validated by receiver operating characteristics analysis, logistic regression, linear discriminant analysis (LDA), and support vector machine (SVM). We assessed prognostic role of classifier using random survival forest (RSF) model and pathway deregulation score (PDS). For external validation,we analyzed microarray data from 26 EOC samples of Samsung Medical Center and curatedOvarianData database. We identified 21 mRNAs, and seven methylated DNAs from primary EOC tissues that predicted lymphatic invasion and created prognostic models. The classifier predicted lymphatic invasion well, which was validated by logistic regression, LDA, and SVM algorithm (C-index of 0.90, 0.71, and 0.74 for mRNA and C-index of 0.64, 0.68, and 0.69 for DNA methylation). Using RSF model, incorporating molecular data with clinical variables improved prediction of progression-free survival compared with using only clinical variables (p < 0.001 and p=0.008). Similarly, PDS enabled us to classify patients into high-risk and low-risk group, which resulted in survival difference in mRNA profiles (log-rank p-value=0.011). In external validation, gene signature was well correlated with prediction of lymphatic invasion and patients' survival. Molecular signature model predicting lymphatic invasion was well performed and also associated with survival of EOC patients.

SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis.

PubMed

Aguirre-Gamboa, Raul; Gomez-Rueda, Hugo; Martínez-Ledesma, Emmanuel; Martínez-Torteya, Antonio; Chacolla-Huaringa, Rafael; Rodriguez-Barrientos, Alberto; Tamez-Peña, José G; Treviño, Victor

2013-01-01

Validation of multi-gene biomarkers for clinical outcomes is one of the most important issues for cancer prognosis. An important source of information for virtual validation is the high number of available cancer datasets. Nevertheless, assessing the prognostic performance of a gene expression signature along datasets is a difficult task for Biologists and Physicians and also time-consuming for Statisticians and Bioinformaticians. Therefore, to facilitate performance comparisons and validations of survival biomarkers for cancer outcomes, we developed SurvExpress, a cancer-wide gene expression database with clinical outcomes and a web-based tool that provides survival analysis and risk assessment of cancer datasets. The main input of SurvExpress is only the biomarker gene list. We generated a cancer database collecting more than 20,000 samples and 130 datasets with censored clinical information covering tumors over 20 tissues. We implemented a web interface to perform biomarker validation and comparisons in this database, where a multivariate survival analysis can be accomplished in about one minute. We show the utility and simplicity of SurvExpress in two biomarker applications for breast and lung cancer. Compared to other tools, SurvExpress is the largest, most versatile, and quickest free tool available. SurvExpress web can be accessed in http://bioinformatica.mty.itesm.mx/SurvExpress (a tutorial is included). The website was implemented in JSP, JavaScript, MySQL, and R.

SurvExpress: An Online Biomarker Validation Tool and Database for Cancer Gene Expression Data Using Survival Analysis

PubMed Central

Aguirre-Gamboa, Raul; Gomez-Rueda, Hugo; Martínez-Ledesma, Emmanuel; Martínez-Torteya, Antonio; Chacolla-Huaringa, Rafael; Rodriguez-Barrientos, Alberto; Tamez-Peña, José G.; Treviño, Victor

2013-01-01

Validation of multi-gene biomarkers for clinical outcomes is one of the most important issues for cancer prognosis. An important source of information for virtual validation is the high number of available cancer datasets. Nevertheless, assessing the prognostic performance of a gene expression signature along datasets is a difficult task for Biologists and Physicians and also time-consuming for Statisticians and Bioinformaticians. Therefore, to facilitate performance comparisons and validations of survival biomarkers for cancer outcomes, we developed SurvExpress, a cancer-wide gene expression database with clinical outcomes and a web-based tool that provides survival analysis and risk assessment of cancer datasets. The main input of SurvExpress is only the biomarker gene list. We generated a cancer database collecting more than 20,000 samples and 130 datasets with censored clinical information covering tumors over 20 tissues. We implemented a web interface to perform biomarker validation and comparisons in this database, where a multivariate survival analysis can be accomplished in about one minute. We show the utility and simplicity of SurvExpress in two biomarker applications for breast and lung cancer. Compared to other tools, SurvExpress is the largest, most versatile, and quickest free tool available. SurvExpress web can be accessed in http://bioinformatica.mty.itesm.mx/SurvExpress (a tutorial is included). The website was implemented in JSP, JavaScript, MySQL, and R. PMID:24066126

Long-Term Survival Prediction for Coronary Artery Bypass Grafting: Validation of the ASCERT Model Compared With The Society of Thoracic Surgeons Predicted Risk of Mortality.

PubMed

Lancaster, Timothy S; Schill, Matthew R; Greenberg, Jason W; Ruaengsri, Chawannuch; Schuessler, Richard B; Lawton, Jennifer S; Maniar, Hersh S; Pasque, Michael K; Moon, Marc R; Damiano, Ralph J; Melby, Spencer J

2018-05-01

The recently developed American College of Cardiology Foundation-Society of Thoracic Surgeons (STS) Collaboration on the Comparative Effectiveness of Revascularization Strategy (ASCERT) Long-Term Survival Probability Calculator is a valuable addition to existing short-term risk-prediction tools for cardiac surgical procedures but has yet to be externally validated. Institutional data of 654 patients aged 65 years or older undergoing isolated coronary artery bypass grafting between 2005 and 2010 were reviewed. Predicted survival probabilities were calculated using the ASCERT model. Survival data were collected using the Social Security Death Index and institutional medical records. Model calibration and discrimination were assessed for the overall sample and for risk-stratified subgroups based on (1) ASCERT 7-year survival probability and (2) the predicted risk of mortality (PROM) from the STS Short-Term Risk Calculator. Logistic regression analysis was performed to evaluate additional perioperative variables contributing to death. Overall survival was 92.1% (569 of 597) at 1 year and 50.5% (164 of 325) at 7 years. Calibration assessment found no significant differences between predicted and actual survival curves for the overall sample or for the risk-stratified subgroups, whether stratified by predicted 7-year survival or by PROM. Discriminative performance was comparable between the ASCERT and PROM models for 7-year survival prediction (p < 0.001 for both; C-statistic = 0.815 for ASCERT and 0.781 for PROM). Prolonged ventilation, stroke, and hospital length of stay were also predictive of long-term death. The ASCERT survival probability calculator was externally validated for prediction of long-term survival after coronary artery bypass grafting in all risk groups. The widely used STS PROM performed comparably as a predictor of long-term survival. Both tools provide important information for preoperative decision making and patient counseling about potential outcomes after coronary artery bypass grafting. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Determinants of Acute Kidney Injury Duration After Cardiac Surgery: An Externally Validated Tool

PubMed Central

Brown, Jeremiah R.; Kramer, Robert S.; MacKenzie, Todd A.; Coca, Steven G.; Sint, Kyaw; Parikh, Chirag R.

2013-01-01

Background Acute kidney injury (AKI) duration following cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what peri-operative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify peri-operative risk factors that predict duration of AKI, a complication that effects short and long term survival. Methods We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline. Duration of AKI was defined by the number of days AKI was present. Step-wise multivariable negative binomial regression analysis was conducted using peri-operative risk factors for AKI duration. C-index was estimated by Kendall’s tau. Results AKI developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had duration of zero days. Independent predictors of AKI duration included baseline patient and disease characteristics, operative and post-operative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (TRIBE-AKI). The C-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort. Conclusion We identified and externally validated peri-operative predictors of AKI duration. These risk-factors will be useful to evaluate a patient’s risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long term survival. The level of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI. PMID:22206952

RF Systems in Space. Volume I. Space Antennas Frequency (SARF) Simulation.

DTIC Science & Technology

1983-04-01

lens SBR designs were investigated. The survivability of an SBR system was analyzed. The design of ground based SBR validation experiments for large...aperture SBR concepts were investigated. SBR designs were investigated for ground target detection. N1’IS GRAMI DTIC TAB E Unannounced E Justificat... designs :~~.~...: .-..:. ->.. - . *.* . ..- . . .. . -. . ..- . .4. To analyze the survivability of space radar 5. To design ground-based validation

Network-based approach to identify prognostic biomarkers for estrogen receptor-positive breast cancer treatment with tamoxifen.

PubMed

Liu, Rong; Guo, Cheng-Xian; Zhou, Hong-Hao

2015-01-01

This study aims to identify effective gene networks and prognostic biomarkers associated with estrogen receptor positive (ER+) breast cancer using human mRNA studies. Weighted gene coexpression network analysis was performed with a complex ER+ breast cancer transcriptome to investigate the function of networks and key genes in the prognosis of breast cancer. We found a significant correlation of an expression module with distant metastasis-free survival (HR = 2.25; 95% CI .21.03-4.88 in discovery set; HR = 1.78; 95% CI = 1.07-2.93 in validation set). This module contained genes enriched in the biological process of the M phase. From this module, we further identified and validated 5 hub genes (CDK1, DLGAP5, MELK, NUSAP1, and RRM2), the expression levels of which were strongly associated with poor survival. Highly expressed MELK indicated poor survival in luminal A and luminal B breast cancer molecular subtypes. This gene was also found to be associated with tamoxifen resistance. Results indicated that a network-based approach may facilitate the discovery of biomarkers for the prognosis of ER+ breast cancer and may also be used as a basis for establishing personalized therapies. Nevertheless, before the application of this approach in clinical settings, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed.

A nomogram to predict the survival of stage IIIA-N2 non-small cell lung cancer after surgery.

PubMed

Mao, Qixing; Xia, Wenjie; Dong, Gaochao; Chen, Shuqi; Wang, Anpeng; Jin, Guangfu; Jiang, Feng; Xu, Lin

2018-04-01

Postoperative survival of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is highly heterogeneous. Here, we aimed to identify variables associated with postoperative survival and develop a tool for survival prediction. A retrospective review was performed in the Surveillance, Epidemiology, and End Results database from January 2004 to December 2009. Significant variables were selected by use of the backward stepwise method. The nomogram was constructed with multivariable Cox regression. The model's performance was evaluated by concordance index and calibration curve. The model was validated via an independent cohort from the Jiangsu Cancer Hospital Lung Cancer Center. A total of 1809 patients with stage IIIA-N2 NSCLC who underwent surgery were included in the training cohort. Age, sex, grade, histology, tumor size, visceral pleural invasion, positive lymph nodes, lymph nodes examined, and surgery type (lobectomy vs pneumonectomy) were identified as significant prognostic variables using backward stepwise method. A nomogram was developed from the training cohort and validated using an independent Chinese cohort. The concordance index of the model was 0.673 (95% confidence interval, 0.654-0.692) in training cohort and 0.664 in validation cohort (95% confidence interval, 0.614-0.714). The calibration plot showed optimal consistency between nomogram predicted survival and observed survival. Survival analyses demonstrated significant differences between different subgroups stratified by prognostic scores. This nomogram provided the individual survival prediction for patients with stage IIIA-N2 NSCLC after surgery, which might benefit survival counseling for patients and clinicians, clinical trial design and follow-up, as well as postoperative strategy-making. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

The roles of Microphthalmia Transcription Factor and pigmentation in melanoma

PubMed Central

Hsiao, Jennifer J; Fisher, David E

2014-01-01

MITF and pigmentation play important roles in both normal melanocyte and transformed melanoma cell biology. MITF is regulated by many pathways and it also regulates many targets, some of which are still being discovered and functionally validated. MITF is involved in a wide range of processes in melanocytes, including pigment synthesis and lineage survival. Pigmentation itself plays an important role as the interface between genetic and environmental factors that contribute to melanoma. PMID:25111671

Infused autograft lymphocyte-to-monocyte ratio and survival in T-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.

PubMed

Porrata, Luis F; Inwards, David J; Ansell, Stephen M; Micallef, Ivana N; Johnston, Patrick B; Hogan, William J; Markovic, Svetomir N

2015-07-03

The infused autograft lymphocyte-to-monocyte ratio (A-LMR) is a prognostic factor for survival in B-cell lymphomas post-autologous peripheral hematopoietic stem cell transplantation (APHSCT). Thus, we set out to investigate if the A-LMR is also a prognostic factor for survival post-APHSCT in T-cell lymphomas. From 1998 to 2014, 109 T-cell lymphoma patients that underwent APHSCT were studied. Receiver operating characteristic (ROC) and area under the curve (AUC) were used to identify the optimal cut-off value of A-LMR for survival analysis and k-fold cross-validation model to validate the A-LMR cut-off value. Univariate and multivariate Cox proportional hazard models were used to assess the prognostic discriminator power of A-LMR. ROC and AUC identified an A-LMR ≥ 1 as the best cut-off value and was validated by k-fold cross-validation. Multivariate analysis showed A-LMR to be an independent prognostic factor for overall survival (OS) and progression-free survival (PFS). Patients with an A-LMR ≥ 1.0 experienced a superior OS and PFS versus patients with an A-LMR < 1.0 [median OS was not reached vs 17.9 months, 5-year OS rates of 87% (95% confidence interval (CI), 75-94%) vs 26% (95% CI, 13-42%), p < 0.0001; median PFS was not reached vs 11.9 months, 5-year PFS rates of 72% (95% CI, 58-83%) vs 16% (95% CI, 6-32%), p < 0.0001]. A-LMR is also a prognostic factor for clinical outcomes in patients with T-cell lymphomas undergoing APHSCT.

Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals.

PubMed

Collette, Laurence; Burzykowski, Tomasz; Carroll, Kevin J; Newling, Don; Morris, Tom; Schröder, Fritz H

2005-09-01

The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa. Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered. The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69). It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).

Clinical decision rules for termination of resuscitation in out-of-hospital cardiac arrest.

PubMed

Sherbino, Jonathan; Keim, Samuel M; Davis, Daniel P

2010-01-01

Out-of-hospital cardiac arrest (OHCA) has a low probability of survival to hospital discharge. Four clinical decision rules (CDRs) have been validated to identify patients with no probability of survival. Three of these rules focus on exclusive prehospital basic life support care for OHCA, and two of these rules focus on prehospital advanced life support care for OHCA. Can a CDR for the termination of resuscitation identify a patient with no probability of survival in the setting of OHCA? Six validation studies were selected from a PubMed search. A structured review of each of the studies is presented. In OHCA receiving basic life support care, the BLS-TOR (basic life support termination of resuscitation) rule has a positive predictive value for death of 99.5% (95% confidence interval 98.9-99.8%), and decreases the transportation of all patients by 62.6%. This rule has been appropriately validated for widespread use. In OHCA receiving advanced life support care, no current rule has been appropriately validated for widespread use. The BLS-TOR rule is a simple rule that identifies patients who will not survive OHCA. Further research is required to identify similarly robust CDRs for patients receiving advanced life support care in the setting of OHCA. Copyright 2010 Elsevier Inc. All rights reserved.

Developing and Validating a Survival Prediction Model for NSCLC Patients Through Distributed Learning Across 3 Countries.

PubMed

Jochems, Arthur; Deist, Timo M; El Naqa, Issam; Kessler, Marc; Mayo, Chuck; Reeves, Jackson; Jolly, Shruti; Matuszak, Martha; Ten Haken, Randall; van Soest, Johan; Oberije, Cary; Faivre-Finn, Corinne; Price, Gareth; de Ruysscher, Dirk; Lambin, Philippe; Dekker, Andre

2017-10-01

Tools for survival prediction for non-small cell lung cancer (NSCLC) patients treated with chemoradiation or radiation therapy are of limited quality. In this work, we developed a predictive model of survival at 2 years. The model is based on a large volume of historical patient data and serves as a proof of concept to demonstrate the distributed learning approach. Clinical data from 698 lung cancer patients, treated with curative intent with chemoradiation or radiation therapy alone, were collected and stored at 2 different cancer institutes (559 patients at Maastro clinic (Netherlands) and 139 at Michigan university [United States]). The model was further validated on 196 patients originating from The Christie (United Kingdon). A Bayesian network model was adapted for distributed learning (the animation can be viewed at https://www.youtube.com/watch?v=ZDJFOxpwqEA). Two-year posttreatment survival was chosen as the endpoint. The Maastro clinic cohort data are publicly available at https://www.cancerdata.org/publication/developing-and-validating-survival-prediction-model-nsclc-patients-through-distributed, and the developed models can be found at www.predictcancer.org. Variables included in the final model were T and N category, age, performance status, and total tumor dose. The model has an area under the curve (AUC) of 0.66 on the external validation set and an AUC of 0.62 on a 5-fold cross validation. A model based on the T and N category performed with an AUC of 0.47 on the validation set, significantly worse than our model (P<.001). Learning the model in a centralized or distributed fashion yields a minor difference on the probabilities of the conditional probability tables (0.6%); the discriminative performance of the models on the validation set is similar (P=.26). Distributed learning from federated databases allows learning of predictive models on data originating from multiple institutions while avoiding many of the data-sharing barriers. We believe that distributed learning is the future of sharing data in health care. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Search Strategy to Identify Dental Survival Analysis Articles Indexed in MEDLINE.

PubMed

Layton, Danielle M; Clarke, Michael

2016-01-01

Articles reporting survival outcomes (time-to-event outcomes) in patients over time are challenging to identify in the literature. Research shows the words authors use to describe their dental survival analyses vary, and that allocation of medical subject headings by MEDLINE indexers is inconsistent. Together, this undermines accurate article identification. The present study aims to develop and validate a search strategy to identify dental survival analyses indexed in MEDLINE (Ovid). A gold standard cohort of articles was identified to derive the search terms, and an independent gold standard cohort of articles was identified to test and validate the proposed search strategies. The first cohort included all 6,955 articles published in the 50 dental journals with the highest impact factors in 2008, of which 95 articles were dental survival articles. The second cohort included all 6,514 articles published in the 50 dental journals with the highest impact factors for 2012, of which 148 were dental survival articles. Each cohort was identified by a systematic hand search. Performance parameters of sensitivity, precision, and number needed to read (NNR) for the search strategies were calculated. Sensitive, precise, and optimized search strategies were developed and validated. The performances of the search strategy maximizing sensitivity were 92% sensitivity, 14% precision, and 7.11 NNR; the performances of the strategy maximizing precision were 93% precision, 10% sensitivity, and 1.07 NNR; and the performances of the strategy optimizing the balance between sensitivity and precision were 83% sensitivity, 24% precision, and 4.13 NNR. The methods used to identify search terms were objective, not subjective. The search strategies were validated in an independent group of articles that included different journals and different publication years. Across the three search strategies, dental survival articles can be identified with sensitivity up to 92%, precision up to 93%, and NNR of less than two articles to identify relevant records. This research has highlighted the impact that variation in reporting and indexing has on article identification and has improved researchers' ability to identify dental survival articles.

Decision curve analysis and external validation of the postoperative Karakiewicz nomogram for renal cell carcinoma based on a large single-center study cohort.

PubMed

Zastrow, Stefan; Brookman-May, Sabine; Cong, Thi Anh Phuong; Jurk, Stanislaw; von Bar, Immanuel; Novotny, Vladimir; Wirth, Manfred

2015-03-01

To predict outcome of patients with renal cell carcinoma (RCC) who undergo surgical therapy, risk models and nomograms are valuable tools. External validation on independent datasets is crucial for evaluating accuracy and generalizability of these models. The objective of the present study was to externally validate the postoperative nomogram developed by Karakiewicz et al. for prediction of cancer-specific survival. A total of 1,480 consecutive patients with a median follow-up of 82 months (IQR 46-128) were included into this analysis with 268 RCC-specific deaths. Nomogram-estimated survival probabilities were compared with survival probabilities of the actual cohort, and concordance indices were calculated. Calibration plots and decision curve analyses were used for evaluating calibration and clinical net benefit of the nomogram. Concordance between predictions of the nomogram and survival rates of the cohort was 0.911 after 12, 0.909 after 24 months and 0.896 after 60 months. Comparison of predicted probabilities and actual survival estimates with calibration plots showed an overestimation of tumor-specific survival based on nomogram predictions of high-risk patients, although calibration plots showed a reasonable calibration for probability ranges of interest. Decision curve analysis showed a positive net benefit of nomogram predictions for our patient cohort. The postoperative Karakiewicz nomogram provides a good concordance in this external cohort and is reasonably calibrated. It may overestimate tumor-specific survival in high-risk patients, which should be kept in mind when counseling patients. A positive net benefit of nomogram predictions was proven.

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

Oberije, Cary, E-mail: cary.oberije@maastro.nl; De Ruysscher, Dirk; Universitaire Ziekenhuizen Leuven, KU Leuven

Purpose: Although patients with stage III non-small cell lung cancer (NSCLC) are homogeneous according to the TNM staging system, they form a heterogeneous group, which is reflected in the survival outcome. The increasing amount of information for an individual patient and the growing number of treatment options facilitate personalized treatment, but they also complicate treatment decision making. Decision support systems (DSS), which provide individualized prognostic information, can overcome this but are currently lacking. A DSS for stage III NSCLC requires the development and integration of multiple models. The current study takes the first step in this process by developing andmore » validating a model that can provide physicians with a survival probability for an individual NSCLC patient. Methods and Materials: Data from 548 patients with stage III NSCLC were available to enable the development of a prediction model, using stratified Cox regression. Variables were selected by using a bootstrap procedure. Performance of the model was expressed as the c statistic, assessed internally and on 2 external data sets (n=174 and n=130). Results: The final multivariate model, stratified for treatment, consisted of age, gender, World Health Organization performance status, overall treatment time, equivalent radiation dose, number of positive lymph node stations, and gross tumor volume. The bootstrapped c statistic was 0.62. The model could identify risk groups in external data sets. Nomograms were constructed to predict an individual patient's survival probability ( (www.predictcancer.org)). The data set can be downloaded at (https://www.cancerdata.org/10.1016/j.ijrobp.2015.02.048). Conclusions: The prediction model for overall survival of patients with stage III NSCLC highlights the importance of combining patient, clinical, and treatment variables. Nomograms were developed and validated. This tool could be used as a first building block for a decision support system.« less

R package PRIMsrc: Bump Hunting by Patient Rule Induction Method for Survival, Regression and Classification

PubMed Central

Dazard, Jean-Eudes; Choe, Michael; LeBlanc, Michael; Rao, J. Sunil

2015-01-01

PRIMsrc is a novel implementation of a non-parametric bump hunting procedure, based on the Patient Rule Induction Method (PRIM), offering a unified treatment of outcome variables, including censored time-to-event (Survival), continuous (Regression) and discrete (Classification) responses. To fit the model, it uses a recursive peeling procedure with specific peeling criteria and stopping rules depending on the response. To validate the model, it provides an objective function based on prediction-error or other specific statistic, as well as two alternative cross-validation techniques, adapted to the task of decision-rule making and estimation in the three types of settings. PRIMsrc comes as an open source R package, including at this point: (i) a main function for fitting a Survival Bump Hunting model with various options allowing cross-validated model selection to control model size (#covariates) and model complexity (#peeling steps) and generation of cross-validated end-point estimates; (ii) parallel computing; (iii) various S3-generic and specific plotting functions for data visualization, diagnostic, prediction, summary and display of results. It is available on CRAN and GitHub. PMID:26798326

Identifying the potential long-term survivors among breast cancer patients with distant metastasis.

PubMed

Lee, E S; Jung, S Y; Kim, J Y; Kim, J J; Yoo, T K; Kim, Y G; Lee, K S; Lee, E S; Kim, E K; Min, J W; Han, W; Noh, D Y; Moon, H G

2016-05-01

We aimed to develop a prediction model to identify long-term survivors after developing distant metastasis from breast cancer. From the institution's database, we collected data of 547 patients who developed distant metastasis during their follow-ups. We developed a model that predicts the post-metastasis overall survival (PMOS) based on the clinicopathologic factors of the primary tumors and the characteristics of the distant metastasis. For validation, the survival data of 254 patients from four independent institutions were used. The median duration of the PMOS was 31.0 months. The characteristics of the initial primary tumor, such as tumor stage, hormone receptor status, and Ki-67 expression level, and the characteristics of the distant metastasis presentation including the duration of disease-free interval, the site of metastasis, and the presence of metastasis-related symptoms were independent prognostic factors determining the PMOS. The association between tumor stage and the PMOS was only seen in tumors with early relapses. The PMOS score, which was developed based on the above six factors, successfully identified patients with superior survival after metastasis. The median PMOS for patients with a PMOS score of <2 and for patients with a PMOS score of >5 were 71.0 and 12 months, respectively. The clinical significance of the PMOS score was further validated using independent multicenter datasets. We have developed a novel prediction model that can classify breast cancer patients with distant metastasis according to their survival after metastasis. Our model can be a valuable tool to identify long-term survivors who can be potential candidates for more intensive multidisciplinary approaches. Furthermore, our model can provide a more reliable survival information for both physicians and patients during their informed decision-making process. © The Author 2016. 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.

Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer.

PubMed

Li, Bailiang; Cui, Yi; Diehn, Maximilian; Li, Ruijiang

2017-11-01

The prevalence of early-stage non-small cell lung cancer (NSCLC) is expected to increase with recent implementation of annual screening programs. Reliable prognostic biomarkers are needed to identify patients at a high risk for recurrence to guide adjuvant therapy. To develop a robust, individualized immune signature that can estimate prognosis in patients with early-stage nonsquamous NSCLC. This retrospective study analyzed the gene expression profiles of frozen tumor tissue samples from 19 public NSCLC cohorts, including 18 microarray data sets and 1 RNA-Seq data set for The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort. Only patients with nonsquamous NSCLC with clinical annotation were included. Samples were from 2414 patients with nonsquamous NSCLC, divided into a meta-training cohort (729 patients), meta-testing cohort (716 patients), and 3 independent validation cohorts (439, 323, and 207 patients). All patients underwent surgery with a negative surgical margin, received no adjuvant or neoadjuvant therapy, and had publicly available gene expression data and survival information. Data were collected from July 22 through September 8, 2016. Overall survival. Of 2414 patients (1205 men [50%], 1111 women [46%], and 98 of unknown sex [4%]; median age [range], 64 [15-90] years), a prognostic immune signature of 25 gene pairs consisting of 40 unique genes was constructed using the meta-training data set. In the meta-testing and validation cohorts, the immune signature significantly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I, IA, IB, or II disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.72 [95% CI, 1.26-2.33; P < .001] to 2.36 [95% CI, 1.47-3.79; P < .001]) after adjusting for clinical and pathologic factors. Several biological processes, including chemotaxis, were enriched among genes in the immune signature. The percentage of neutrophil infiltration (5.6% vs 1.8%) and necrosis (4.6% vs 1.5%) was significantly higher in the high-risk immune group compared with the low-risk groups in TCGA data set (P < .003). The immune signature achieved a higher accuracy (mean concordance index [C-index], 0.64) than 2 commercialized multigene signatures (mean C-index, 0.53 and 0.61) for estimation of survival in comparable validation cohorts. When integrated with clinical characteristics such as age and stage, the composite clinical and immune signature showed improved prognostic accuracy in all validation data sets relative to molecular signatures alone (mean C-index, 0.70 vs 0.63) and another commercialized clinical-molecular signature (mean C-index, 0.68 vs 0.65). The proposed clinical-immune signature is a promising biomarker for estimating overall survival in nonsquamous NSCLC, including early-stage disease. Prospective studies are needed to test the clinical utility of the biomarker in individualized management of nonsquamous NSCLC.

Nomograms for predicting graft function and survival in living donor kidney transplantation based on the UNOS Registry.

PubMed

Tiong, H Y; Goldfarb, D A; Kattan, M W; Alster, J M; Thuita, L; Yu, C; Wee, A; Poggio, E D

2009-03-01

We developed nomograms that predict transplant renal function at 1 year (Modification of Diet in Renal Disease equation [estimated glomerular filtration rate]) and 5-year graft survival after living donor kidney transplantation. Data for living donor renal transplants were obtained from the United Network for Organ Sharing registry for 2000 to 2003. Nomograms were designed using linear or Cox regression models to predict 1-year estimated glomerular filtration rate and 5-year graft survival based on pretransplant information including demographic factors, immunosuppressive therapy, immunological factors and organ procurement technique. A third nomogram was constructed to predict 5-year graft survival using additional information available by 6 months after transplantation. These data included delayed graft function, any treated rejection episodes and the 6-month estimated glomerular filtration rate. The nomograms were internally validated using 10-fold cross-validation. The renal function nomogram had an r-square value of 0.13. It worked best when predicting estimated glomerular filtration rate values between 50 and 70 ml per minute per 1.73 m(2). The 5-year graft survival nomograms had a concordance index of 0.71 for the pretransplant nomogram and 0.78 for the 6-month posttransplant nomogram. Calibration was adequate for all nomograms. Nomograms based on data from the United Network for Organ Sharing registry have been validated to predict the 1-year estimated glomerular filtration rate and 5-year graft survival. These nomograms may facilitate individualized patient care in living donor kidney transplantation.

Prognostic value of purinergic P2X7 receptor expression in patients with hepatocellular carcinoma after curative resection.

PubMed

Liu, Haiou; Liu, Weisi; Liu, Zheng; Liu, Yidong; Zhang, Weijuan; Xu, Le; Xu, Jiejie

2015-07-01

The family of type 2 purinergic (P2) receptors, especially P2X7, is responsible for the direct tumor-killing functions of extracellular adenosine triphosphate (ATP), but the precise role of P2X7 in the progression of hepatocellular carcinoma (HCC) remains elusive. This study aims to evaluate prognostic value of P2X7 expression in HCC patients after surgical resection. Expression of P2X7 was assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissues from 273 patients with HCC who had undergone hepatectomy between 2006 and 2007. Prognostic value of P2X7 expression and clinical outcomes were evaluated. Peritumoral P2X7 expression was significantly higher than intratumoral P2X7 expression. No significant prognostic difference was observed for overall survival for intratumoral P2X7 density, whereas peritumoral P2X7 density indicates unfavorable overall survival in training set and BCLC stage 0-A subset. Besides, peritumoral P2X7 density, which correlated with tumor size, venous invasion, and BCLC stage, was identified as an independent poor prognosticator for overall survival and recurrence-free survival. The association was further validated in validation set. Peritumoral P2X7 is a potential unfavorable prognosticator for overall survival and recurrence free survival in HCC patients after surgical resection. Further external validation and functional analysis should be pursued to evaluate its potential prognostic value and therapeutic significance for HCC patients.

Integrated analysis of long non-coding RNAs in human gastric cancer: An in silico study.

PubMed

Han, Weiwei; Zhang, Zhenyu; He, Bangshun; Xu, Yijun; Zhang, Jun; Cao, Weijun

2017-01-01

Accumulating evidence highlights the important role of long non-coding RNAs (lncRNAs) in a large number of biological processes. However, the knowledge of genome scale expression of lncRNAs and their potential biological function in gastric cancer is still lacking. Using RNA-seq data from 420 gastric cancer patients in The Cancer Genome Atlas (TCGA), we identified 1,294 lncRNAs differentially expressed in gastric cancer compared with adjacent normal tissues. We also found 247 lncRNAs differentially expressed between intestinal subtype and diffuse subtype. Survival analysis revealed 33 lncRNAs independently associated with patient overall survival, of which 6 lncRNAs were validated in the internal validation set. There were 181 differentially expressed lncRNAs located in the recurrent somatic copy number alterations (SCNAs) regions and their correlations between copy number and RNA expression level were also analyzed. In addition, we inferred the function of lncRNAs by construction of a co-expression network for mRNAs and lncRNAs. Together, this study presented an integrative analysis of lncRNAs in gastric cancer and provided a valuable resource for further functional research of lncRNAs in gastric cancer.

Application of High Speed Digital Image Correlation in Rocket Engine Hot Fire Testing

NASA Technical Reports Server (NTRS)

Gradl, Paul R.; Schmidt, Tim

2016-01-01

Hot fire testing of rocket engine components and rocket engine systems is a critical aspect of the development process to understand performance, reliability and system interactions. Ground testing provides the opportunity for highly instrumented development testing to validate analytical model predictions and determine necessary design changes and process improvements. To properly obtain discrete measurements for model validation, instrumentation must survive in the highly dynamic and extreme temperature application of hot fire testing. Digital Image Correlation has been investigated and being evaluated as a technique to augment traditional instrumentation during component and engine testing providing further data for additional performance improvements and cost savings. The feasibility of digital image correlation techniques were demonstrated in subscale and full scale hotfire testing. This incorporated a pair of high speed cameras to measure three-dimensional, real-time displacements and strains installed and operated under the extreme environments present on the test stand. The development process, setup and calibrations, data collection, hotfire test data collection and post-test analysis and results are presented in this paper.

High-Sensitivity C-Reactive Protein Complements Plasma Epstein-Barr Virus Deoxyribonucleic Acid Prognostication in Nasopharyngeal Carcinoma: A Large-Scale Retrospective and Prospective Cohort Study

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

Tang, Lin-Quan; Department of Nasopharyngeal Carcinoma, Sun Yat-sen University, Guangzhou; Li, Chao-Feng

Purpose: To evaluate the effects of combining the assessment of circulating high-sensitivity C-reactive protein (hs-CRP) with that of Epstein-Barr virus DNA (EBV DNA) in the pretherapy prognostication of nasopharyngeal carcinoma (NPC). Patients and Methods: Three independent cohorts of NPC patients (training set of n=3113, internal validation set of n=1556, and prospective validation set of n=1668) were studied. Determinants of disease-free survival, distant metastasis–free survival, and overall survival were assessed by multivariate analysis. Hazard ratios and survival probabilities of the patient groups, segregated by clinical stage (T1-2N0-1M0, T3-4N0-1M0, T1-2N2-3M0, and T3-4N2-3M0) and EBV DNA load (low or high) alone, and alsomore » according to hs-CRP level (low or high), were compared. Results: Elevated hs-CRP and EBV DNA levels were significantly correlated with poor disease-free survival, distant metastasis–free survival, and overall survival in both the training and validation sets. Associations were similar and remained significant after excluding patients with cardiovascular disease, diabetes, and chronic hepatitis B. Patients with advanced-stage disease were segregated by high EBV DNA levels and high hs-CRP level into a poorest-risk group, and participants with either high EBV DNA but low hs-CRP level or high hs-CRP but low EBV DNA values had poorer survival compared with the bottom values for both biomarkers. These findings demonstrate a significant improvement in the prognostic ability of conventional advanced NPC staging. Conclusion: Baseline plasma EBV DNA and serum hs-CRP levels were significantly correlated with survival in NPC patients. The combined interpretation of EBV DNA with hs-CRP levels led to refinement of the risks for the patient subsets, with improved risk discrimination in patients with advanced-stage disease.« less

Finding Risk Groups by Optimizing Artificial Neural Networks on the Area under the Survival Curve Using Genetic Algorithms.

PubMed

Kalderstam, Jonas; Edén, Patrik; Ohlsson, Mattias

2015-01-01

We investigate a new method to place patients into risk groups in censored survival data. Properties such as median survival time, and end survival rate, are implicitly improved by optimizing the area under the survival curve. Artificial neural networks (ANN) are trained to either maximize or minimize this area using a genetic algorithm, and combined into an ensemble to predict one of low, intermediate, or high risk groups. Estimated patient risk can influence treatment choices, and is important for study stratification. A common approach is to sort the patients according to a prognostic index and then group them along the quartile limits. The Cox proportional hazards model (Cox) is one example of this approach. Another method of doing risk grouping is recursive partitioning (Rpart), which constructs a decision tree where each branch point maximizes the statistical separation between the groups. ANN, Cox, and Rpart are compared on five publicly available data sets with varying properties. Cross-validation, as well as separate test sets, are used to validate the models. Results on the test sets show comparable performance, except for the smallest data set where Rpart's predicted risk groups turn out to be inverted, an example of crossing survival curves. Cross-validation shows that all three models exhibit crossing of some survival curves on this small data set but that the ANN model manages the best separation of groups in terms of median survival time before such crossings. The conclusion is that optimizing the area under the survival curve is a viable approach to identify risk groups. Training ANNs to optimize this area combines two key strengths from both prognostic indices and Rpart. First, a desired minimum group size can be specified, as for a prognostic index. Second, the ability to utilize non-linear effects among the covariates, which Rpart is also able to do.

Self-Reported Physical Quality of Life Before Thoracic Operations Is Associated With Long-Term Survival.

PubMed

Al-Ameri, Mamdoh; Bergman, Per; Franco-Cereceda, Anders; Sartipy, Ulrik

2017-02-01

The aim was to analyze the association between baseline self-reported health-related quality of life and long-term survival after thoracic operations. In a prospective population-based cohort study, we included patients scheduled for thoracic operations and obtained information about preoperative health-related quality of life using the validated quality-of-life instrument Short Form-36. Patients were categorized according to higher or lower physical and mental component scores, compared with an age- and sex-matched reference population. The primary outcome measure was all-cause mortality and was ascertained from Swedish national registers. We used Cox regression for estimation of hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between preoperative physical/mental quality of life and long-term survival while adjusting for differences in baseline characteristics, cancer stage, histopathologic process, and other factors. We included 249 patients between 2006 and 2008. During a median follow-up time of 8.0 years, 119 patients (48%) died. Having a physical component summary score less than reference was significantly associated with mortality (multivariable adjusted HR 2.02, 95% CI: 1.34 to 3.06, p = 0.001). A mental component summary score less than reference was not associated with mortality (adjusted HR 1.32, 95% CI: 0.84 to 3.06, p = 0.233). In patients who underwent thoracic operations, a self-reported physical quality of life lower than reference value was associated with significantly worse survival independent of histopathologic process, cancer stage, extent of operations, and other patient-related factors. The preoperative mental component of quality of life was not associated with long-term survival. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Rapid learning in practice: A lung cancer survival decision support system in routine patient care data

PubMed Central

Dekker, Andre; Vinod, Shalini; Holloway, Lois; Oberije, Cary; George, Armia; Goozee, Gary; Delaney, Geoff P.; Lambin, Philippe; Thwaites, David

2016-01-01

Background and purpose A rapid learning approach has been proposed to extract and apply knowledge from routine care data rather than solely relying on clinical trial evidence. To validate this in practice we deployed a previously developed decision support system (DSS) in a typical, busy clinic for non-small cell lung cancer (NSCLC) patients. Material and methods Gender, age, performance status, lung function, lymph node status, tumor volume and survival were extracted without review from clinical data sources for lung cancer patients. With these data the DSS was tested to predict overall survival. Results 3919 lung cancer patients were identified with 159 eligible for inclusion, due to ineligible histology or stage, non-radical dose, missing tumor volume or survival. The DSS successfully identified a good prognosis group and a medium/poor prognosis group (2 year OS 69% vs. 27/30%, p < 0.001). Stage was less discriminatory (2 year OS 47% for stage I–II vs. 36% for stage IIIA–IIIB, p = 0.12) with most good prognosis patients having higher stage disease. The DSS predicted a large absolute overall survival benefit (~40%) for a radical dose compared to a non-radical dose in patients with a good prognosis, while no survival benefit of radical radiotherapy was predicted for patients with a poor prognosis. Conclusions A rapid learning environment is possible with the quality of clinical data sufficient to validate a DSS. It uses patient and tumor features to identify prognostic groups in whom therapy can be individualized based on predicted outcomes. Especially the survival benefit of a radical versus non-radical dose predicted by the DSS for various prognostic groups has clinical relevance, but needs to be prospectively validated. PMID:25241994

Dual Kidney Allocation Score: A Novel Algorithm Utilizing Expanded Donor Criteria for the Allocation of Dual Kidneys in Adults.

PubMed

Johnson, Adam P; Price, Thea P; Lieby, Benjamin; Doria, Cataldo

2016-09-08

BACKGROUND Dual kidney transplantation (DKT) of expanded-criteria donors is a cost-intensive procedure that aims to increase the pool of available deceased organ donors and has demonstrated equivalent outcomes to expanded-criteria single kidney transplantation (eSKT). The objective of this study was to develop an allocation score based on predicted graft survival from historical dual and single kidney donors. MATERIAL AND METHODS We analyzed United Network for Organ Sharing (UNOS) data for 1547 DKT and 26 381 eSKT performed between January 1994 and September 2013. We utilized multivariable Cox regression to identify variables independently associated with graft survival in dual and single kidney transplantations. We then derived a weighted multivariable product score from calculated hazard ratios to model the benefit of transplantation as dual kidneys. RESULTS Of 36 donor variables known at the time of listing, 13 were significantly associated with graft survival. The derived dual allocation score demonstrated good internal validity with strong correlation to improved survival in dual kidney transplants. Donors with scores less than 2.1 transplanted as dual kidneys had a worsened median survival of 594 days (24%, p-value 0.031) and donors with scores greater than 3.9 had improved median survival of 1107 days (71%, p-value 0.002). There were 17 733 eSKT (67%) and 1051 DKT (67%) with scores in between these values and no differences in survival (p-values 0.676 and 0.185). CONCLUSIONS We have derived a dual kidney allocation score (DKAS) with good internal validity. Future prospective studies will be required to demonstrate external validity, but this score may help to standardize organ allocation for dual kidney transplantation.

Working memory load eliminates the survival processing effect.

PubMed

Kroneisen, Meike; Rummel, Jan; Erdfelder, Edgar

2014-01-01

In a series of experiments, Nairne, Thompson, and Pandeirada (2007) demonstrated that words judged for their relevance to a survival scenario are remembered better than words judged for a scenario not relevant on a survival dimension. They explained this survival-processing effect by arguing that nature "tuned" our memory systems to process and remember fitness-relevant information. Kroneisen and Erdfelder (2011) proposed that it may not be survival processing per se that facilitates recall but the richness and distinctiveness with which information is encoded. To further test this account, we investigated how the survival processing effect is affected by cognitive load. If the survival processing effect is due to automatic processes or, alternatively, if survival processing is routinely prioritized in dual-task contexts, we would expect this effect to persist under cognitive load conditions. If the effect relies on cognitively demanding processes like richness and distinctiveness of encoding, however, the survival processing benefit should be hampered by increased cognitive load during encoding. Results were in line with the latter prediction, that is, the survival processing effect vanished under dual-task conditions.

Psychometric Analysis of the Heart Failure Somatic Perception Scale as a Measure of Patient Symptom Perception.

PubMed

Jurgens, Corrine Y; Lee, Christopher S; Riegel, Barbara

Symptoms are known to predict survival among patients with heart failure (HF), but discrepancies exist between patients' and health providers' perceptions of HF symptom burden. The purpose of this study is to quantify the internal consistency, validity, and prognostic value of patient perception of a broad range of HF symptoms using an HF-specific physical symptom measure, the 18-item HF Somatic Perception Scale v. 3. Factor analysis of the HF Somatic Perception Scale was conducted in a convenience sample of 378 patients with chronic HF. Convergent validity was examined using the Physical Limitation subscale of the Kansas City Cardiomyopathy Questionnaire. Divergent validity was examined using the Self-care of HF Index self-care management score. One-year survival based on HF Somatic Perception Scale scores was quantified using Cox regression controlling for Seattle HF Model scores to account for clinical status, therapeutics, and lab values. The sample was 63% male, 85% white, 67% functionally compromised (New York Heart Association class III-IV) with a mean (SD) age of 63 (12.8) years. Internal consistency of the HF Somatic Perception Scale was α = .90. Convergent (r = -0.54, P < .0001) and divergent (r = 0.18, P > .05) validities were supported. Controlling for Seattle HF scores, HF Somatic Perception Scale was a significant predictor of 1-year survival, with those most symptomatic having worse survival (hazard ratio, 1.012; 95% confidence interval, 1.001-1.024; P = .038). Perception of HF symptom burden as measured by the HF Somatic Perception Scale is a significant predictor of survival, contributing additional prognostic value over and above objective Seattle HF Risk Model scores. This analysis suggests that assessment of a broad range of HF symptoms, or those related to dyspnea or early and subtle symptoms, may be useful in evaluating therapeutic outcomes and predicting event-free survival.

Three-Gene Immunohistochemical Panel Adds to Clinical Staging Algorithms to Predict Prognosis for Patients With Esophageal Adenocarcinoma

PubMed Central

Ong, Chin-Ann J.; Shapiro, Joel; Nason, Katie S.; Davison, Jon M.; Liu, Xinxue; Ross-Innes, Caryn; O'Donovan, Maria; Dinjens, Winand N.M.; Biermann, Katharina; Shannon, Nicholas; Worster, Susannah; Schulz, Laura K.E.; Luketich, James D.; Wijnhoven, Bas P.L.; Hardwick, Richard H.; Fitzgerald, Rebecca C.

2013-01-01

Purpose Esophageal adenocarcinoma (EAC) is a highly aggressive disease with poor long-term survival. Despite growing knowledge of its biology, no molecular biomarkers are currently used in routine clinical practice to determine prognosis or aid clinical decision making. Hence, this study set out to identify and validate a small, clinically applicable immunohistochemistry (IHC) panel for prognostication in patients with EAC. Patients and Methods We recently identified eight molecular prognostic biomarkers using two different genomic platforms. IHC scores of these biomarkers from a UK multicenter cohort (N = 374) were used in univariate Cox regression analysis to determine the smallest biomarker panel with the greatest prognostic power with potential therapeutic relevance. This new panel was validated in two independent cohorts of patients with EAC who had undergone curative esophagectomy from the United States and Europe (N = 666). Results Three of the eight previously identified prognostic molecular biomarkers (epidermal growth factor receptor [EGFR], tripartite motif-containing 44 [TRIM44], and sirtuin 2 [SIRT2]) had the strongest correlation with long-term survival in patients with EAC. Applying these three biomarkers as an IHC panel to the validation cohort segregated patients into two different prognostic groups (P < .01). Adjusting for known survival covariates, including clinical staging criteria, the IHC panel remained an independent predictor, with incremental adverse overall survival (OS) for each positive biomarker (hazard ratio, 1.20; 95% CI, 1.03 to 1.40 per biomarker; P = .02). Conclusion We identified and validated a clinically applicable IHC biomarker panel, consisting of EGFR, TRIM44, and SIRT2, that is independently associated with OS and provides additional prognostic information to current survival predictors such as stage. PMID:23509313

Cancer survival for Aboriginal and Torres Strait Islander Australians: a national study of survival rates and excess mortality.

PubMed

Condon, John R; Zhang, Xiaohua; Baade, Peter; Griffiths, Kalinda; Cunningham, Joan; Roder, David M; Coory, Michael; Jelfs, Paul L; Threlfall, Tim

2014-01-31

National cancer survival statistics are available for the total Australian population but not Indigenous Australians, although their cancer mortality rates are known to be higher than those of other Australians. We aimed to validate analysis methods and report cancer survival rates for Indigenous Australians as the basis for regular national reporting. We used national cancer registrations data to calculate all-cancer and site-specific relative survival for Indigenous Australians (compared with non-Indigenous Australians) diagnosed in 2001-2005. Because of limited availability of Indigenous life tables, we validated and used cause-specific survival (rather than relative survival) for proportional hazards regression to analyze time trends and regional variation in all-cancer survival between 1991 and 2005. Survival was lower for Indigenous than non-Indigenous Australians for all cancers combined and for many cancer sites. The excess mortality of Indigenous people with cancer was restricted to the first three years after diagnosis, and greatest in the first year. Survival was lower for rural and remote than urban residents; this disparity was much greater for Indigenous people. Survival improved between 1991 and 2005 for non-Indigenous people (mortality decreased by 28%), but to a much lesser extent for Indigenous people (11%) and only for those in remote areas; cancer survival did not improve for urban Indigenous residents. Cancer survival is lower for Indigenous than other Australians, for all cancers combined and many individual cancer sites, although more accurate recording of Indigenous status by cancer registers is required before the extent of this disadvantage can be known with certainty. Cancer care for Indigenous Australians needs to be considerably improved; cancer diagnosis, treatment, and support services need to be redesigned specifically to be accessible and acceptable to Indigenous people.

Cryopreservation for delayed circulating tumor cell isolation is a valid strategy for prognostic association of circulating tumor cells in gastroesophageal cancer.

PubMed

Brungs, Daniel; Lynch, David; Luk, Alison Ws; Minaei, Elahe; Ranson, Marie; Aghmesheh, Morteza; Vine, Kara L; Carolan, Martin; Jaber, Mouhannad; de Souza, Paul; Becker, Therese M

2018-02-21

To demonstrate the feasibility of cryopreservation of peripheral blood mononuclear cells (PBMCs) for prognostic circulating tumor cell (CTC) detection in gastroesophageal cancer. Using 7.5 mL blood samples collected in EDTA tubes from patients with gastroesopheagal adenocarcinoma, CTCs were isolated by epithelial cell adhesion molecule based immunomagnetic capture using the IsoFlux platform. Paired specimens taken during the same blood draw ( n = 15) were used to compare number of CTCs isolated from fresh and cryopreserved PBMCs. Blood samples were processed within 24 h to recover the PBMC fraction, with PBMCs used for fresh analysis immediately processed for CTC isolation. Cryopreservation of PBMCs lasted from 2 wk to 25.2 mo (median 14.6 mo). CTCs isolated from pre-treatment cryopreserved PBMCs ( n = 43) were examined for associations with clinicopathological variables and survival outcomes. While there was a significant trend to a decrease in CTC numbers associated with cryopreserved specimens (mean number of CTCs 34.4 vs 51.5, P = 0.04), this was predominately in samples with a total CTC count of > 50, with low CTC count samples less affected ( P = 0.06). There was no significant association between the duration of cryopreservation and number of CTCs. In cryopreserved PBMCs from patient samples prior to treatment, a high CTC count (> 17) was associated with poorer overall survival (OS) ( n = 43, HR = 4.4, 95%CI: 1.7-11.7, P = 0.0013). In multivariate analysis, after controlling for sex, age, stage, ECOG performance status, and primary tumor location, a high CTC count remained significantly associated with a poorer OS (HR = 3.7, 95%CI: 1.2-12.4, P = 0.03). PBMC cryopreservation for delayed CTC isolation is a valid strategy to assist with sample collection, transporting and processing.

Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy.

PubMed

Lammers, Willem J; Hirschfield, Gideon M; Corpechot, Christophe; Nevens, Frederik; Lindor, Keith D; Janssen, Harry L A; Floreani, Annarosa; Ponsioen, Cyriel Y; Mayo, Marlyn J; Invernizzi, Pietro; Battezzati, Pier M; Parés, Albert; Burroughs, Andrew K; Mason, Andrew L; Kowdley, Kris V; Kumagi, Teru; Harms, Maren H; Trivedi, Palak J; Poupon, Raoul; Cheung, Angela; Lleo, Ana; Caballeria, Llorenç; Hansen, Bettina E; van Buuren, Henk R

2015-12-01

Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC. We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria. Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P < .0001); levels of bilirubin (hazard ratio = 2.56; 95% CI: 2.22-2.95; P < .0001), albumin (hazard ratio = 0.10; 95% CI: 0.05-0.24; P < .0001), and alkaline phosphatase (hazard ratio = 1.40; 95% CI: 1.18-1.67; P = .0002); and platelet count (hazard ratio/10 units decrease = 0.97; 95% CI: 0.96-0.99; P < .0001) were all independently associated with death or liver transplantation (C-statistic derivation, 0.81; 95% CI: 0.79-0.83, and validation cohort, 0.82; 95% CI: 0.79-0.84). Patients with risk scores >0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P < .0001). The GLOBE score identified patients who would survive for 5 years and 10 years (responders) with positive predictive values of 98% and 88%, respectively. Up to 22% and 21% of events and nonevents, respectively, 10 years after initiation of treatment were correctly reclassified in comparison with earlier proposed criteria. In subgroups of patients aged <45, 45-52, 52-58, 58-66, and ≥66 years, age-specific GLOBE-score thresholds beyond which survival significantly deviated from matched healthy individuals were -0.52, 0.01, 0.60, 1.01 and 1.69, respectively. Transplant-free survival could still be accurately calculated by the GLOBE score with laboratory values collected at 2-5 years after treatment. We developed and validated scoring system (the GLOBE score) to predict transplant-free survival of ursodeoxycholic acid-treated patients with PBC. This score might be used to select strategies for treatment and care. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Prospective Validation of Objective Prognostic Score for Advanced Cancer Inpatients in South Korea: A Multicenter Study.

PubMed

Yoon, Seok Joon; Suh, Sang-Yeon; Lee, Yong Joo; Park, Jeanno; Hwang, Sunwook; Lee, Sanghee Shiny; Ahn, Hong Yup; Koh, Su-Jin; Park, Keon Uk

2017-01-01

Objective Prognostic Score (OPS) was developed as an easy and simple prognosticating tool in South Korea. It has been validated retrospectively in a single center in South Korea. We aimed to validate the OPS prospectively for advanced cancer inpatients in South Korea using a multicenter study. This was a prospective cohort study. We enrolled 243 advanced cancer patients admitted in five palliative care units in South Korea from May 2013 till March 2015. Seven members of the Korean Palliative Medicine Research Network who are experts of palliative care led the study. Clinical variables (dyspnea/anorexia/performance status) and laboratory variables (total leukocyte counts/serum total bilirubin/serum creatinine/lactate dehydrogenase) were collected at the enrollment. Survival time was calculated as days from enrollment to death during admission. A total of 217 patients were included in the final analysis (feasibility: 89.3%). Survival time of the higher OPS group (OPS ≥3) and the lower OPS group (OPS <3) was 10.0 (95% confidence interval (CI) 7.72-12.28) days and 32.0 (95% CI 25.44-38.56) days, respectively. There were significant differences between the 2 groups (p < 0.001). Overall accuracy of OPS ≥3 for predicting survival less than three weeks was 71.0%. OPS was successfully validated using a prospective multicenter study in South Korea. It is a useful method to predict three-week survival of Korean inpatients with advanced cancer.

A method of increasing test range and accuracy of bioindicators: Geobacillus stearothermophilus spores.

PubMed

Lundahl, Gunnel

2003-01-01

Spores of Geobacillus stearothermophilus are very sensitive to changes in temperature. When validating sterilizing processes, the most common bioindicator (BI) is spores of Geobacillus stearothermophilus ATCC12980 and ATCC7953 with about 10(6) spores /BI and a D121-value of about 2 minutes in water. Because these spores of Geobacillus stearothermophilus do not survive at a F0-value above 12 minutes, it has not been possible to evaluate the agreement between the biological F-value (F(BIO)) and physical measurements (time and temperature) when the physical F0-value exceeds that limit. However, it has been proven that glycerin substantially increases the heat resistance of the spores, and it is possible to utilize that property when manufacturing BIs suitable to use in processes with longer sterilization time or high temperature (above 121 degrees C). By the method described, it is possible to make use of the sensitivity and durability of Geobacillus stearothermophilus' spores when glycerin has increased both test range and accuracy. Experience from years of development and validation work with the use of the highly sensitive glycerin-water-spore-suspension sensor (GWS-sensor) is reported. Validation of the steam sterilization process at high temperature has been possible with the use of GWS-sensors. It has also been shown that the spores in suspension keep their characteristics for a period of 19 months when stored cold (8 degrees C).

On an algorithmic definition for the components of the minimal cell.

PubMed

Martínez, Octavio; Reyes-Valdés, M Humberto

2018-01-01

Living cells are highly complex systems comprising a multitude of elements that are engaged in the many convoluted processes observed during the cell cycle. However, not all elements and processes are essential for cell survival and reproduction under steady-state environmental conditions. To distinguish between essential from expendable cell components and thus define the 'minimal cell' and the corresponding 'minimal genome', we postulate that the synthesis of all cell elements can be represented as a finite set of binary operators, and within this framework we show that cell elements that depend on their previous existence to be synthesized are those that are essential for cell survival. An algorithm to distinguish essential cell elements is presented and demonstrated within an interactome. Data and functions implementing the algorithm are given as supporting information. We expect that this algorithmic approach will lead to the determination of the complete interactome of the minimal cell, which could then be experimentally validated. The assumptions behind this hypothesis as well as its consequences for experimental and theoretical biology are discussed.

Quantification of the heterogeneity of prognostic cellular biomarkers in ewing sarcoma using automated image and random survival forest analysis.

PubMed

Bühnemann, Claudia; Li, Simon; Yu, Haiyue; Branford White, Harriet; Schäfer, Karl L; Llombart-Bosch, Antonio; Machado, Isidro; Picci, Piero; Hogendoorn, Pancras C W; Athanasou, Nicholas A; Noble, J Alison; Hassan, A Bassim

2014-01-01

Driven by genomic somatic variation, tumour tissues are typically heterogeneous, yet unbiased quantitative methods are rarely used to analyse heterogeneity at the protein level. Motivated by this problem, we developed automated image segmentation of images of multiple biomarkers in Ewing sarcoma to generate distributions of biomarkers between and within tumour cells. We further integrate high dimensional data with patient clinical outcomes utilising random survival forest (RSF) machine learning. Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms. Each cell nucleus and cytoplasm were identified in relation to DAPI and CD99, respectively, and protein biomarkers (e.g. Ki67, pS6, Foxo3a, EGR1, MAPK) localised relative to nuclear and cytoplasmic regions of each cell in order to generate image feature distributions. The image distribution features were analysed with RSF in relation to known overall patient survival from three separate cohorts (185 informative cases). Variation in pre-analytical processing resulted in elimination of a high number of non-informative images that had poor DAPI localisation or biomarker preservation (67 cases, 36%). The distribution of image features for biomarkers in the remaining high quality material (118 cases, 104 features per case) were analysed by RSF with feature selection, and performance assessed using internal cross-validation, rather than a separate validation cohort. A prognostic classifier for Ewing sarcoma with low cross-validation error rates (0.36) was comprised of multiple features, including the Ki67 proliferative marker and a sub-population of cells with low cytoplasmic/nuclear ratio of CD99. Through elimination of bias, the evaluation of high-dimensionality biomarker distribution within cell populations of a tumour using random forest analysis in quality controlled tumour material could be achieved. Such an automated and integrated methodology has potential application in the identification of prognostic classifiers based on tumour cell heterogeneity.

Multivariable model development and internal validation for prostate cancer specific survival and overall survival after whole-gland salvage Iodine-125 prostate brachytherapy.

PubMed

Peters, Max; van der Voort van Zyp, Jochem R N; Moerland, Marinus A; Hoekstra, Carel J; van de Pol, Sandrine; Westendorp, Hendrik; Maenhout, Metha; Kattevilder, Rob; Verkooijen, Helena M; van Rossum, Peter S N; Ahmed, Hashim U; Shah, Taimur T; Emberton, Mark; van Vulpen, Marco

2016-04-01

Whole-gland salvage Iodine-125-brachytherapy is a potentially curative treatment strategy for localised prostate cancer (PCa) recurrences after radiotherapy. Prognostic factors influencing PCa-specific and overall survival (PCaSS & OS) are not known. The objective of this study was to develop a multivariable, internally validated prognostic model for survival after whole-gland salvage I-125-brachytherapy. Whole-gland salvage I-125-brachytherapy patients treated in the Netherlands from 1993-2010 were included. Eligible patients had a transrectal ultrasound-guided biopsy-confirmed localised recurrence after biochemical failure (clinical judgement, ASTRO or Phoenix-definition). Recurrences were assessed clinically and with CT and/or MRI. Metastases were excluded using CT/MRI and technetium-99m scintigraphy. Multivariable Cox-regression was used to assess the predictive value of clinical characteristics in relation to PCa-specific and overall mortality. PCa-specific mortality was defined as patients dying with distant metastases present. Missing data were handled using multiple imputation (20 imputed sets). Internal validation was performed and the C-statistic calculated. Calibration plots were created to visually assess the goodness-of-fit of the final model. Optimism-corrected survival proportions were calculated. All analyses were performed according to the TRIPOD statement. Median total follow-up was 78months (range 5-139). A total of 62 patients were treated, of which 28 (45%) died from PCa after mean (±SD) 82 (±36) months. Overall, 36 patients (58%) patients died after mean 84 (±40) months. PSA doubling time (PSADT) remained a predictive factor for both types of mortality (PCa-specific and overall): corrected hazard ratio's (HR's) 0.92 (95% CI: 0.86-0.98, p=0.02) and 0.94 (95% CI: 0.90-0.99, p=0.01), respectively (C-statistics 0.71 and 0.69, respectively). Calibration was accurate up to 96month follow-up. Over 80% of patients can survive 8years if PSADT>24months (PCaSS) and >33months (OS). Only approximately 50% survival is achieved with a PSADT of 12months. A PSADT of respectively >24months and >33months can result in >80% probability of PCa- specific and overall survival 8years after whole-gland salvage I-125-brachytherapy. Survival should be weighed against toxicity from a salvage procedure. Larger series and external validation are necessary. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adaptive memory: the survival scenario enhances item-specific processing relative to a moving scenario.

PubMed

Burns, Daniel J; Hart, Joshua; Griffith, Samantha E; Burns, Amy D

2013-01-01

Nairne, Thompson, and Pandeirada (2007) found that retention of words rated for their relevance to survival is superior to that of words encoded under numerous other deep processing conditions. They suggested that our memory systems might have evolved to confer an advantage for survival-relevant information. Burns, Burns, and Hwang (2011) suggested a two-process explanation of the proximate mechanisms responsible for the survival advantage. Whereas most control tasks encourage only one type of processing, the survival task encourages both item-specific and relational processing. They found that when control tasks encouraged both types of processing, the survival processing advantage was eliminated. However, none of their control conditions included non-survival scenarios (e.g., moving, vacation, etc.), so it is not clear how this two-process explanation would explain the survival advantage when scenarios are used as control conditions. The present experiments replicated the finding that the survival scenario improves recall relative to a moving scenario in both a between-lists and within-list design and also provided evidence that this difference was accompanied by an item-specific processing difference, not a difference in relational processing. The implications of these results for several existing accounts of the survival processing effect are discussed.

Theoretical aspects and modelling of cellular decision making, cell killing and information-processing in photodynamic therapy of cancer.

PubMed

Gkigkitzis, Ioannis

2013-01-01

The aim of this report is to provide a mathematical model of the mechanism for making binary fate decisions about cell death or survival, during and after Photodynamic Therapy (PDT) treatment, and to supply the logical design for this decision mechanism as an application of rate distortion theory to the biochemical processing of information by the physical system of a cell. Based on system biology models of the molecular interactions involved in the PDT processes previously established, and regarding a cellular decision-making system as a noisy communication channel, we use rate distortion theory to design a time dependent Blahut-Arimoto algorithm where the input is a stimulus vector composed of the time dependent concentrations of three PDT related cell death signaling molecules and the output is a cell fate decision. The molecular concentrations are determined by a group of rate equations. The basic steps are: initialize the probability of the cell fate decision, compute the conditional probability distribution that minimizes the mutual information between input and output, compute the cell probability of cell fate decision that minimizes the mutual information and repeat the last two steps until the probabilities converge. Advance to the next discrete time point and repeat the process. Based on the model from communication theory described in this work, and assuming that the activation of the death signal processing occurs when any of the molecular stimulants increases higher than a predefined threshold (50% of the maximum concentrations), for 1800s of treatment, the cell undergoes necrosis within the first 30 minutes with probability range 90.0%-99.99% and in the case of repair/survival, it goes through apoptosis within 3-4 hours with probability range 90.00%-99.00%. Although, there is no experimental validation of the model at this moment, it reproduces some patterns of survival ratios of predicted experimental data. Analytical modeling based on cell death signaling molecules has been shown to be an independent and useful tool for prediction of cell surviving response to PDT. The model can be adjusted to provide important insights for cellular response to other treatments such as hyperthermia, and diseases such as neurodegeneration.

Integrative analysis of micro-RNA, gene expression, and survival of glioblastoma multiforme.

PubMed

Huang, Yen-Tsung; Hsu, Thomas; Kelsey, Karl T; Lin, Chien-Ling

2015-02-01

Glioblastoma multiforme (GBM), the most common type of malignant brain tumor, is highly fatal. Limited understanding of its rapid progression necessitates additional approaches that integrate what is known about the genomics of this cancer. Using a discovery set (n = 348) and a validation set (n = 174) of GBM patients, we performed genome-wide analyses that integrated mRNA and micro-RNA expression data from GBM as well as associated survival information, assessing coordinated variability in each as this reflects their known mechanistic functions. Cox proportional hazards models were used for the survival analyses, and nonparametric permutation tests were performed for the micro-RNAs to investigate the association between the number of associated genes and its prognostication. We also utilized mediation analyses for micro-RNA-gene pairs to identify their mediation effects. Genome-wide analyses revealed a novel pattern: micro-RNAs related to more gene expressions are more likely to be associated with GBM survival (P = 4.8 × 10(-5)). Genome-wide mediation analyses for the 32,660 micro-RNA-gene pairs with strong association (false discovery rate [FDR] < 0.01%) identified 51 validated pairs with significant mediation effect. Of the 51 pairs, miR-223 had 16 mediation genes. These 16 mediation genes of miR-223 were also highly associated with various other micro-RNAs and mediated their prognostic effects as well. We further constructed a gene signature using the 16 genes, which was highly associated with GBM survival in both the discovery and validation sets (P = 9.8 × 10(-6)). This comprehensive study discovered mediation effects of micro-RNA to gene expression and GBM survival and provided a new analytic framework for integrative genomics. © 2014 WILEY PERIODICALS, INC.

Modeling and validating the cost and clinical pathway of colorectal cancer.

PubMed

Joranger, Paal; Nesbakken, Arild; Hoff, Geir; Sorbye, Halfdan; Oshaug, Arne; Aas, Eline

2015-02-01

Cancer is a major cause of morbidity and mortality, and colorectal cancer (CRC) is the third most common cancer in the world. The estimated costs of CRC treatment vary considerably, and if CRC costs in a model are based on empirically estimated total costs of stage I, II, III, or IV treatments, then they lack some flexibility to capture future changes in CRC treatment. The purpose was 1) to describe how to model CRC costs and survival and 2) to validate the model in a transparent and reproducible way. We applied a semi-Markov model with 70 health states and tracked age and time since specific health states (using tunnels and 3-dimensional data matrix). The model parameters are based on an observational study at Oslo University Hospital (2049 CRC patients), the National Patient Register, literature, and expert opinion. The target population was patients diagnosed with CRC. The model followed the patients diagnosed with CRC from the age of 70 until death or 100 years. The study focused on the perspective of health care payers. The model was validated for face validity, internal and external validity, and cross-validity. The validation showed a satisfactory match with other models and empirical estimates for both cost and survival time, without any preceding calibration of the model. The model can be used to 1) address a range of CRC-related themes (general model) like survival and evaluation of the cost of treatment and prevention measures; 2) make predictions from intermediate to final outcomes; 3) estimate changes in resource use and costs due to changing guidelines; and 4) adjust for future changes in treatment and trends over time. The model is adaptable to other populations. © The Author(s) 2014.

Prediction of overall survival for metastatic pancreatic cancer: Development and validation of a prognostic nomogram with data from open clinical trial and real-world study.

PubMed

Hang, Junjie; Wu, Lixia; Zhu, Lina; Sun, Zhiqiang; Wang, Ge; Pan, Jingjing; Zheng, Suhua; Xu, Kequn; Du, Jiadi; Jiang, Hua

2018-06-01

It is necessary to develop prognostic tools of metastatic pancreatic cancer (MPC) for optimizing therapeutic strategies. Thus, we tried to develop and validate a prognostic nomogram of MPC. Data from 3 clinical trials (NCT00844649, NCT01124786, and NCT00574275) and 133 Chinese MPC patients were used for analysis. The former 2 trials were taken as the training cohort while NCT00574275 was used as the validation cohort. In addition, 133 MPC patients treated in China were taken as the testing cohort. Cox regression model was used to investigate prognostic factors in the training cohort. With these factors, we established a nomogram and verified it by Harrell's concordance index (C-index) and calibration plots. Furthermore, the nomogram was externally validated in the validation cohort and testing cohort. In the training cohort (n = 445), performance status, liver metastasis, Carbohydrate antigen 19-9 (CA19-9) log-value, absolute neutrophil count (ANC), and albumin were independent prognostic factors for overall survival (OS). A nomogram was established with these factors to predict OS and survival probabilities. The nomogram showed an acceptable discrimination ability (C-index: .683) and good calibration, and was further externally validated in the validation cohort (n = 273, C-index: .699) and testing cohort (n = 133, C-index: .653).The nomogram total points (NTP) had the potential to stratify patients into 3-risk groups with median OS of 11.7, 7.0 and 3.7 months (P < .001), respectively. In conclusion, the prognostic nomogram with NTP can predict OS for patients with MPC with considerable accuracy. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Scoring Systems to Estimate Intracerebral Control and Survival Rates of Patients Irradiated for Brain Metastases;Brain metastases; Radiation therapy; Local control; Survival; Prognostic scores

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

Rades, Dirk, E-mail: Rades.Dirk@gmx.net; Dziggel, Liesa; Haatanen, Tiina

2011-07-15

Purpose: To create and validate scoring systems for intracerebral control (IC) and overall survival (OS) of patients irradiated for brain metastases. Methods and Materials: In this study, 1,797 patients were randomly assigned to the test (n = 1,198) or the validation group (n = 599). Two scoring systems were developed, one for IC and another for OS. The scores included prognostic factors found significant on multivariate analyses. Age, performance status, extracerebral metastases, interval tumor diagnosis to RT, and number of brain metastases were associated with OS. Tumor type, performance status, interval, and number of brain metastases were associated with IC.more » The score for each factor was determined by dividing the 6-month IC or OS rate (given in percent) by 10. The total score represented the sum of the scores for each factor. The score groups of the test group were compared with the corresponding score groups of the validation group. Results: In the test group, 6-month IC rates were 17% for 14-18 points, 49% for 19-23 points, and 77% for 24-27 points (p < 0.0001). IC rates in the validation group were 19%, 52%, and 77%, respectively (p < 0.0001). In the test group, 6-month OS rates were 9% for 15-19 points, 41% for 20-25 points, and 78% for 26-30 points (p < 0.0001). OS rates in the validation group were 7%, 39%, and 79%, respectively (p < 0.0001). Conclusions: Patients irradiated for brain metastases can be given scores to estimate OS and IC. IC and OS rates of the validation group were similar to the test group demonstrating the validity and reproducibility of both scores.« less

Review and evaluation of performance measures for survival prediction models in external validation settings.

PubMed

Rahman, M Shafiqur; Ambler, Gareth; Choodari-Oskooei, Babak; Omar, Rumana Z

2017-04-18

When developing a prediction model for survival data it is essential to validate its performance in external validation settings using appropriate performance measures. Although a number of such measures have been proposed, there is only limited guidance regarding their use in the context of model validation. This paper reviewed and evaluated a wide range of performance measures to provide some guidelines for their use in practice. An extensive simulation study based on two clinical datasets was conducted to investigate the performance of the measures in external validation settings. Measures were selected from categories that assess the overall performance, discrimination and calibration of a survival prediction model. Some of these have been modified to allow their use with validation data, and a case study is provided to describe how these measures can be estimated in practice. The measures were evaluated with respect to their robustness to censoring and ease of interpretation. All measures are implemented, or are straightforward to implement, in statistical software. Most of the performance measures were reasonably robust to moderate levels of censoring. One exception was Harrell's concordance measure which tended to increase as censoring increased. We recommend that Uno's concordance measure is used to quantify concordance when there are moderate levels of censoring. Alternatively, Gönen and Heller's measure could be considered, especially if censoring is very high, but we suggest that the prediction model is re-calibrated first. We also recommend that Royston's D is routinely reported to assess discrimination since it has an appealing interpretation. The calibration slope is useful for both internal and external validation settings and recommended to report routinely. Our recommendation would be to use any of the predictive accuracy measures and provide the corresponding predictive accuracy curves. In addition, we recommend to investigate the characteristics of the validation data such as the level of censoring and the distribution of the prognostic index derived in the validation setting before choosing the performance measures.

Impact of biology knowledge on the conservation and management of large pelagic sharks.

PubMed

Yokoi, Hiroki; Ijima, Hirotaka; Ohshimo, Seiji; Yokawa, Kotaro

2017-09-06

Population growth rate, which depends on several biological parameters, is valuable information for the conservation and management of pelagic sharks, such as blue and shortfin mako sharks. However, reported biological parameters for estimating the population growth rates of these sharks differ by sex and display large variability. To estimate the appropriate population growth rate and clarify relationships between growth rate and relevant biological parameters, we developed a two-sex age-structured matrix population model and estimated the population growth rate using combinations of biological parameters. We addressed elasticity analysis and clarified the population growth rate sensitivity. For the blue shark, the estimated median population growth rate was 0.384 with a range of minimum and maximum values of 0.195-0.533, whereas those values of the shortfin mako shark were 0.102 and 0.007-0.318, respectively. The maturity age of male sharks had the largest impact for blue sharks, whereas that of female sharks had the largest impact for shortfin mako sharks. Hypotheses for the survival process of sharks also had a large impact on the population growth rate estimation. Both shark maturity age and survival rate were based on ageing validation data, indicating the importance of validating the quality of these data for the conservation and management of large pelagic sharks.

The longevity of adaptive memory: evidence for mnemonic advantages of survival processing 24 and 48 hours later.

PubMed

Raymaekers, Linsey H C; Otgaar, Henry; Smeets, Tom

2014-01-01

Prior studies have convincingly demonstrated that survival-related processing of information enhances its subsequent retention. This phenomenon, known as the survival recall advantage, generalises to other stimuli, memory domains, and research populations, thereby underscoring its reliability. As previous studies used only short retention intervals between survival processing and the memory test, an important yet hitherto unanswered issue is whether this effect persists over time. The present experiment therefore examined whether survival processing also produces mnemonic benefits when retention is tested after longer delay periods. Participants (N =81) rated the relevance of words according to a survival and a moving scenario, and were then randomly assigned to the typical immediate (3-minute delay) retention test condition or conditions that included a 24- or 48-hour interval between survival processing and memory testing. In each of these conditions survival processing led to higher surprise free recall and recognition rates than processing words according to the moving scenario. Thus this study provides evidence that illustrates the longevity of survival processing advantages on memory performance.

Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.

PubMed

Saad, E D; Katz, A; Hoff, P M; Buyse, M

2010-01-01

Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.

TU-CD-BRB-08: Radiomic Analysis of FDG-PET Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated with SBRT

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

Cui, Y; Shirato, H; Song, J

2015-06-15

Purpose: This study aims to identify novel prognostic imaging biomarkers in locally advanced pancreatic cancer (LAPC) using quantitative, high-throughput image analysis. Methods: 86 patients with LAPC receiving chemotherapy followed by SBRT were retrospectively studied. All patients had a baseline FDG-PET scan prior to SBRT. For each patient, we extracted 435 PET imaging features of five types: statistical, morphological, textural, histogram, and wavelet. These features went through redundancy checks, robustness analysis, as well as a prescreening process based on their concordance indices with respect to the relevant outcomes. We then performed principle component analysis on the remaining features (number ranged frommore » 10 to 16), and fitted a Cox proportional hazard regression model using the first 3 principle components. Kaplan-Meier analysis was used to assess the ability to distinguish high versus low-risk patients separated by median predicted survival. To avoid overfitting, all evaluations were based on leave-one-out cross validation (LOOCV), in which each holdout patient was assigned to a risk group according to the model obtained from a separate training set. Results: For predicting overall survival (OS), the most dominant imaging features were wavelet coefficients. There was a statistically significant difference in OS between patients with predicted high and low-risk based on LOOCV (hazard ratio: 2.26, p<0.001). Similar imaging features were also strongly associated with local progression-free survival (LPFS) (hazard ratio: 1.53, p=0.026) on LOOCV. In comparison, neither SUVmax nor TLG was associated with LPFS (p=0.103, p=0.433) (Table 1). Results for progression-free survival and distant progression-free survival showed similar trends. Conclusion: Radiomic analysis identified novel imaging features that showed improved prognostic value over conventional methods. These features characterize the degree of intra-tumor heterogeneity reflected on FDG-PET images, and their biological underpinnings warrant further investigation. If validated in large, prospective cohorts, this method could be used to stratify patients based on individualized risk.« less

Twenty-year follow-up study of long-term survival of limited-stage small-cell lung cancer and overview of prognostic and treatment factors.

PubMed

Tai, Patricia; Tonita, Jon; Yu, Edward; Skarsgard, David

2003-07-01

To predict the long-term survival results of clinical trials earlier than using actuarial methods and to assess the factors predictive of long-term cure in patients with limited-stage small-cell lung cancer. Between 1981 and 1998, 1417 new cases of small-cell lung cancer were diagnosed in Saskatchewan, Canada, of which 244 were limited stage and treated with curative intent. They were followed to the end of February 2002. A parametric lognormal statistical model was retrospectively validated to determine whether long-term survival rates could be estimated several years earlier than is possible using the standard life-table actuarial method. The survival time of the uncured group followed a lognormal distribution. Four 2-year periods of diagnosis were combined, and patients were followed as a cohort for an additional 2 years. The estimated 10-year cause-specific survival rate was 13% by the lognormal model. The Kaplan-Meier calculation for 10-year cause-specific survival rate was 15% +/- 3%. The data also showed that the absence of mediastinal lymphadenopathy and higher chest radiotherapy dose were significant prognostic factors on multivariate analysis (p < 0.05). Among the 163 patients given prophylactic cranial irradiation, a higher biologically effective dose to the brain did not improve survival or decrease the incidence of brain metastases. The lognormal model has been validated for the estimation of survival in patients with limited-stage small-cell lung cancer. A higher biologically effective dose to the brain did not improve survival or decrease the incidence of brain metastases.

Development and Validation of a New Scoring System to Predict Survival in Patients With Myotonic Dystrophy Type 1.

PubMed

Wahbi, Karim; Porcher, Raphaël; Laforêt, Pascal; Fayssoil, Abdallah; Bécane, Henri Marc; Lazarus, Arnaud; Sochala, Maximilien; Stojkovic, Tanya; Béhin, Anthony; Leonard-Louis, Sarah; Arnaud, Pauline; Furling, Denis; Probst, Vincent; Babuty, Dominique; Pellieux, Sybille; Clementy, Nicolas; Bassez, Guillaume; Péréon, Yann; Eymard, Bruno; Duboc, Denis

2018-05-01

Life expectancy is greatly shortened in patients presenting with myotonic dystrophy type 1 (DM1), the most common neuromuscular disease. A reliable prediction of survival in patients with DM1 is critically important to plan personalized health supervision. To develop and validate a prognostic score to predict 10-year survival in patients with DM1. In this longitudinal cohort study, between January 2000 and November 2014, we enrolled 1296 adults referred to 4 tertiary neuromuscular centers in France for management of genetically proven DM1, including 1066 patients in the derivation cohort and 230 in the validation cohort. Data were analyzed from December 2016 to March 2017. Factors associated with survival by multiple variable Cox modeling, including 95% confidence intervals, and development of a predictive score validated internally and externally. Mean values are reported with their standard deviations. Of the 1296 included patients, 670 (51.7%) were women, and the mean (SD) age was 39.8 (13.7) years. Among the 1066 patients (82.3%) in the derivation cohort, 241 (22.6%) died over a median (interquartile range) follow-up of 11.7 (7.7-14.3) years. Age, diabetes, need for support when walking, heart rate, systolic blood pressure, first-degree atrioventricular block, bundle-branch block, and lung vital capacity were associated with death. Simplified score points were attributed to each predictor, and adding these points yielded scores between 0 and 20, with 0 indicating the lowest and 20 the highest risk of death. The 10-year survival rate was 96.6% (95% CI, 94.4-98.9) in the group with 0 to 4 points, 92.2% (95% CI, 88.8-95.6) in the group with 5 to 7 points, 80.7% (95% CI, 75.4-86.1) in the group with 8 to 10 points, 57.9% (95% CI, 49.2-66.6) in the group with 11 to 13 points, and 19.4% (95% CI, 8.6-30.1) in the group with 14 points or more. In 230 patients (17.7%) included in the validation cohort, the 10-year survival rates for the groups with 0 to 4, 5 to 7, 8 to 10, 11 to 13, and 14 points or more were 99.3% (95% CI, 95.0-100), 80.6% (95% CI, 67.1-96.7), 79.3% (95% CI, 66.2-95.1), 43.2% (95% CI, 28.2-66.1), and 21.6% (95% CI, 10.0-46.8), respectively. The calibration curves did not deviate from the reference line. The C index was 0.753 (95% CI, 0.722-0.785) in the derivation cohort and 0.806 (95% CI, 0.758-0.855) in the validation cohort. The DM1 prognostic score is associated with long-term survival.

An Easy Tool to Predict Survival in Patients Receiving Radiation Therapy for Painful Bone Metastases

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

Westhoff, Paulien G., E-mail: p.g.westhoff@umcutrecht.nl; Graeff, Alexander de; Monninkhof, Evelyn M.

2014-11-15

Purpose: Patients with bone metastases have a widely varying survival. A reliable estimation of survival is needed for appropriate treatment strategies. Our goal was to assess the value of simple prognostic factors, namely, patient and tumor characteristics, Karnofsky performance status (KPS), and patient-reported scores of pain and quality of life, to predict survival in patients with painful bone metastases. Methods and Materials: In the Dutch Bone Metastasis Study, 1157 patients were treated with radiation therapy for painful bone metastases. At randomization, physicians determined the KPS; patients rated general health on a visual analogue scale (VAS-gh), valuation of life on amore » verbal rating scale (VRS-vl) and pain intensity. To assess the predictive value of the variables, we used multivariate Cox proportional hazard analyses and C-statistics for discriminative value. Of the final model, calibration was assessed. External validation was performed on a dataset of 934 patients who were treated with radiation therapy for vertebral metastases. Results: Patients had mainly breast (39%), prostate (23%), or lung cancer (25%). After a maximum of 142 weeks' follow-up, 74% of patients had died. The best predictive model included sex, primary tumor, visceral metastases, KPS, VAS-gh, and VRS-vl (C-statistic = 0.72, 95% CI = 0.70-0.74). A reduced model, with only KPS and primary tumor, showed comparable discriminative capacity (C-statistic = 0.71, 95% CI = 0.69-0.72). External validation showed a C-statistic of 0.72 (95% CI = 0.70-0.73). Calibration of the derivation and the validation dataset showed underestimation of survival. Conclusion: In predicting survival in patients with painful bone metastases, KPS combined with primary tumor was comparable to a more complex model. Considering the amount of variables in complex models and the additional burden on patients, the simple model is preferred for daily use. In addition, a risk table for survival is provided.« less

Validation of a predictive model for survival and growth of Salmonella Typhimurium DT104 on chicken skin for extrapolation to a previous history of frozen storage

USDA-ARS?s Scientific Manuscript database

A predictive model for survival and growth of Salmonella Typhimurium DT104 on chicken skin was evaluated for its ability to predict survival and growth of the same organism after frozen storage for 6 days at -20 C. Experimental methods used to collect data for model development were the same as tho...

Comparative study of joint analysis of microarray gene expression data in survival prediction and risk assessment of breast cancer patients

PubMed Central

2016-01-01

Abstract Microarray gene expression data sets are jointly analyzed to increase statistical power. They could either be merged together or analyzed by meta-analysis. For a given ensemble of data sets, it cannot be foreseen which of these paradigms, merging or meta-analysis, works better. In this article, three joint analysis methods, Z -score normalization, ComBat and the inverse normal method (meta-analysis) were selected for survival prognosis and risk assessment of breast cancer patients. The methods were applied to eight microarray gene expression data sets, totaling 1324 patients with two clinical endpoints, overall survival and relapse-free survival. The performance derived from the joint analysis methods was evaluated using Cox regression for survival analysis and independent validation used as bias estimation. Overall, Z -score normalization had a better performance than ComBat and meta-analysis. Higher Area Under the Receiver Operating Characteristic curve and hazard ratio were also obtained when independent validation was used as bias estimation. With a lower time and memory complexity, Z -score normalization is a simple method for joint analysis of microarray gene expression data sets. The derived findings suggest further assessment of this method in future survival prediction and cancer classification applications. PMID:26504096

Validity of St Gallen risk categories in prognostication of breast cancer patients in Southern Sri Lanka.

PubMed

Peiris, Harshini; Mudduwa, Lakmini; Thalagala, Neil; Jayatilake, Kamani

2018-01-31

Although, there are many developments in the field of management, breast cancer is still the commonest cause of cancer related deaths in women in Sri Lanka. This emphasizes the need for validation of treatment protocols that are used in Sri Lanka for managing breast cancers. There are no published papers on treatment and survival of breast cancer patients in Sri Lanka. Hence this study was designed to determine the validity of St Gallen risk categories based on the survival outcomes of breast cancer patients in Southern Sri Lanka. This retro-prospective study included all female breast cancer patients who had sought the immunohistochemistry services of our unit from May 2006 to December 2012. Patients who had neo-adjuvant chemotherapy were excluded. Patients were stratified according to the St Gallen risk categories; low-risk (LR), intermediate-risk (IR) and high-risk (HR), which is used in deciding on the adjuvant treatment. IR category was subdivided based on presence/absence of 1-3 positive-nodes (absent-IR1, present-IR2) and HR on the number of positive-nodes(1-3 lymph nodes;HR1,> 3 lymph nodes;HR2). Kaplan-Meier and Cox-regression models were used in the survival analysis. This study included 713breast cancer patients (LR-2%, IR1-45%, IR2-10%, HR1-13%, HR2-30%). Five year breast cancer specific survival (BCSS)wasLR-100%, IR-91%, HR-66% and the recurrence free survival (RFS) was LR-85%, IR-84%, HR-65%. BCSS and RFS curves were significantly different between the three risk categories (p < 0.001). No survival difference was evident between the IR1 and IR2 (BCSS-p = 0.232, RFS-p = 0.118). HR1 and HR2 had a distinctly different BCSS (p = 0.033) with no difference in RFS (p = 0.190). This study validates the St Gallen risk categorization of female breast cancer patients in our setting. However, the HR includes two subsets of patients with a distinct difference in BCSS.

Predictive validity of the Sødring Motor Evaluation of Stroke Patients (SMES).

PubMed

Wyller, T B; Sødring, K M; Sveen, U; Ljunggren, A E; Bautz-Holter, E

1996-12-01

The Sødring Motor Evaluation of Stroke Patients (SMES) has been developed as an instrument for the evaluation by physiotherapists of motor function and activities in stroke patients. The predictive validity of the instrument was studied in a consecutive sample of 93 acute stroke patients, assessed in the acute phase and after one year. The outcome measures were: survival, residence at home or in institution, the Barthel ADL index (dichotomized at 19/20), and the Frenchay Activities Index (FAI) (dichotomized at 9/10). The SMES, scored in the acute phase, demonstrated a marginally significant predictive power regarding survival, but was a highly significant predictor regarding the other outcomes. The adjusted odds ratio for a good versus a poor outcome for patients in the upper versus the lower tertile of the SMES arm subscore was 5.4 (95% confidence interval 0.9-59) for survival, 11.5 (2.1-88) for living at home, 86.3 (11-infinity) for a high Barthel score, and 31.4 (5.2-288) for a high FAI score. We conclude that SMES has high predictive validity.

PITX3 DNA methylation is an independent predictor of overall survival in patients with head and neck squamous cell carcinoma.

PubMed

Sailer, Verena; Holmes, Emily Eva; Gevensleben, Heidrun; Goltz, Diane; Dröge, Freya; Franzen, Alina; Dietrich, Jörn; Kristiansen, Glen; Bootz, Friedrich; Schröck, Andreas; Dietrich, Dimo

2017-01-01

Molecular biomarkers assisting risk-group assignment and subsequent treatment stratification are urgently needed for patients with squamous cell cancer of the head and neck region (HNSCC). Aberrant methylation is a frequent event in cancer and, therefore, a promising source for potential biomarkers. Here, the methylation status of the paired-like homeodomain transcription factor 3 ( PITX3 ) was evaluated in HNSCC. Using a quantitative real-time PCR, PITX3 methylation was assessed in a cohort of 326 HNSCC patients treated for localized or locally advanced disease (training cohort). The results were validated with Infinium HumanMethylation450 BeadChip data from a 528 HNSCC patient cohort (validation cohort) generated by The Cancer Genome Atlas (TCGA) Research Network. PITX3 methylation was significantly higher methylated in tumor compared to normal adjacent tissue (NAT; training cohort: median methylation NAT 32.3%, tumor 71.8%, p  < 0.001; validation cohort: median methylation NAT 16.9%, tumor 35.9%, p  < 0.001). PITX3 methylation was also significantly correlated with lymph node status both in the training ( p  = 0.006) and validation ( p  < 0.001) cohort. PITX3 methylation was significantly higher in HPV-associated (p16-positive) tumors compared to p16-negative tumors (training cohort: 73.7 vs. 66.2%, p  = 0.013; validation cohort: 40.0 vs. 33.1%, p  = 0.015). Hypermethylation was significantly associated with the risk of death (training cohort: hazard ratio (HR) = 1.80, [95% confidence interval (CI) 1.20-2.69], p  = 0.005; validation cohort: HR = 1.43, [95% CI 1.05-1.95], p  = 0.022). In multivariate Cox analyses, PITX3 added independent prognostic information. Messenger RNA (mRNA) expression analysis revealed an inverse correlation with PITX3 methylation in the TCGA cohort. PITX3 DNA methylation is an independent prognostic biomarker for overall survival in patients with HNSCC and might aid in the process of risk stratification for individualized treatment.

Biomarker validation for intraductal papillary mucinous neoplasms of the pancreas | Division of Cancer Prevention

Cancer.gov

A critical component to successful cancer screening is the identification of a lesion for which intervention will result in prolonged survival or cure.The five-year survival of patients with resected stage IA pancreas cancer (the earliest identifiable lesion and |

On the susceptibility of adaptive memory to false memory illusions.

PubMed

Howe, Mark L; Derbish, Mary H

2010-05-01

Previous research has shown that survival-related processing of word lists enhances retention for that material. However, the claim that survival-related memories are more accurate has only been examined when true recall and recognition of neutral material has been measured. In the current experiments, we examined the adaptive memory superiority effect for different types of processing and material, measuring accuracy more directly by comparing true and false recollection rates. Survival-related information and processing was examined using word lists containing backward associates of neutral, negative, and survival-related critical lures and type of processing (pleasantness, moving, survival) was varied using an incidental memory paradigm. Across four experiments, results showed that survival-related words were more susceptible than negative and neutral words to the false memory illusion and that processing information in terms of its relevance to survival independently increased this susceptibility to the false memory illusion. Overall, although survival-related processing and survival-related information resulted in poorer, not more accurate, memory, such inaccuracies may have adaptive significance. These findings are discussed in the context of false memory research and recent theories concerning the importance of survival processing and the nature of adaptive memory. Copyright 2009 Elsevier B.V. All rights reserved.

How can survival processing improve memory encoding?

PubMed

Luo, Meng; Geng, Haiyan

2013-11-01

We investigated the psychological mechanism of survival processing advantage from the perspective of false memory in two experiments. Using a DRM paradigm in combination with analysis based on signal detection theory, we were able to separately examine participants' utilization of verbatim representation and gist representation. Specifically, in Experiment 1, participants rated semantically related words in a survival scenario for a survival condition but rated pleasantness of words in the same DRM lists for a non-survival control condition. The results showed that participants demonstrated more gist processing in the survival condition than in the pleasantness condition; however, the degree of item-specific processing in the two encoding conditions did not significantly differ. In Experiment 2, the control task was changed to a category rating task, in which participants were asked to make category ratings of words in the category lists. We found that the survival condition involved more item-specific processing than did the category condition, but we found no significant difference between the two encoding conditions at the level of gist processing. Overall, our study demonstrates that survival processing can simultaneously promote gist and item-specific representations. When the control tasks only promoted either item-specific representation or gist representation, memory advantages of survival processing occurred.

Recursive Partitioning Analysis for New Classification of Patients With Esophageal Cancer Treated by Chemoradiotherapy

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

Nomura, Motoo, E-mail: excell@hkg.odn.ne.jp; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya; Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya

2012-11-01

Background: The 7th edition of the American Joint Committee on Cancer staging system does not include lymph node size in the guidelines for staging patients with esophageal cancer. The objectives of this study were to determine the prognostic impact of the maximum metastatic lymph node diameter (ND) on survival and to develop and validate a new staging system for patients with esophageal squamous cell cancer who were treated with definitive chemoradiotherapy (CRT). Methods: Information on 402 patients with esophageal cancer undergoing CRT at two institutions was reviewed. Univariate and multivariate analyses of data from one institution were used to assessmore » the impact of clinical factors on survival, and recursive partitioning analysis was performed to develop the new staging classification. To assess its clinical utility, the new classification was validated using data from the second institution. Results: By multivariate analysis, gender, T, N, and ND stages were independently and significantly associated with survival (p < 0.05). The resulting new staging classification was based on the T and ND. The four new stages led to good separation of survival curves in both the developmental and validation datasets (p < 0.05). Conclusions: Our results showed that lymph node size is a strong independent prognostic factor and that the new staging system, which incorporated lymph node size, provided good prognostic power, and discriminated effectively for patients with esophageal cancer undergoing CRT.« less

Development and validation of a prognostic model using blood biomarker information for prediction of survival of non-small-cell lung cancer patients treated with combined chemotherapy and radiation or radiotherapy alone (NCT00181519, NCT00573040, and NCT00572325).

PubMed

Dehing-Oberije, Cary; Aerts, Hugo; Yu, Shipeng; De Ruysscher, Dirk; Menheere, Paul; Hilvo, Mika; van der Weide, Hiska; Rao, Bharat; Lambin, Philippe

2011-10-01

Currently, prediction of survival for non-small-cell lung cancer patients treated with (chemo)radiotherapy is mainly based on clinical factors. The hypothesis of this prospective study was that blood biomarkers related to hypoxia, inflammation, and tumor load would have an added prognostic value for predicting survival. Clinical data and blood samples were collected prospectively (NCT00181519, NCT00573040, and NCT00572325) from 106 inoperable non-small-cell lung cancer patients (Stages I-IIIB), treated with curative intent with radiotherapy alone or combined with chemotherapy. Blood biomarkers, including lactate dehydrogenase, C-reactive protein, osteopontin, carbonic anhydrase IX, interleukin (IL) 6, IL-8, carcinoembryonic antigen (CEA), and cytokeratin fragment 21-1, were measured. A multivariate model, built on a large patient population (N = 322) and externally validated, was used as a baseline model. An extended model was created by selecting additional biomarkers. The model's performance was expressed as the area under the curve (AUC) of the receiver operating characteristic and assessed by use of leave-one-out cross validation as well as a validation cohort (n = 52). The baseline model consisted of gender, World Health Organization performance status, forced expiratory volume, number of positive lymph node stations, and gross tumor volume and yielded an AUC of 0.72. The extended model included two additional blood biomarkers (CEA and IL-6) and resulted in a leave-one-out AUC of 0.81. The performance of the extended model was significantly better than the clinical model (p = 0.004). The AUC on the validation cohort was 0.66 and 0.76, respectively. The performance of the prognostic model for survival improved markedly by adding two blood biomarkers: CEA and IL-6. Copyright © 2011 Elsevier Inc. All rights reserved.

Dying to remember, remembering to survive: mortality salience and survival processing.

PubMed

Burns, Daniel J; Hart, Joshua; Kramer, Melanie E; Burns, Amy D

2014-01-01

Processing items for their relevance to survival improves recall for those items relative to numerous other deep processing encoding techniques. Perhaps related, placing individuals in a mortality salient state has also been shown to enhance retention of items encoded after the morality salience manipulation (e.g., in a pleasantness rating task), a phenomenon we dubbed the "dying-to-remember" (DTR) effect. The experiments reported here further explored the effect and tested the possibility that the DTR effect is related to survival processing. Experiment 1 replicated the effect using different encoding tasks, demonstrating that the effect is not dependent on the pleasantness task. In Experiment 2 the DTR effect was associated with increases in item-specific processing, not relational processing, according to several indices. Experiment 3 replicated the main results of Experiment 2, and tested the effects of mortality salience and survival processing within the same experiment. The DTR effect and its associated difference in item-specific processing were completely eliminated when the encoding task required survival processing. These results are consistent with the interpretation that the mechanisms responsible for survival processing and DTR effects are overlapping.

Development and validation of risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team.

PubMed

Harrison, David A; Patel, Krishna; Nixon, Edel; Soar, Jasmeet; Smith, Gary B; Gwinnutt, Carl; Nolan, Jerry P; Rowan, Kathryn M

2014-08-01

The National Cardiac Arrest Audit (NCAA) is the UK national clinical audit for in-hospital cardiac arrest. To make fair comparisons among health care providers, clinical indicators require case mix adjustment using a validated risk model. The aim of this study was to develop and validate risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team in UK hospitals. Risk models for two outcomes-return of spontaneous circulation (ROSC) for greater than 20min and survival to hospital discharge-were developed and validated using data for in-hospital cardiac arrests between April 2011 and March 2013. For each outcome, a full model was fitted and then simplified by testing for non-linearity, combining categories and stepwise reduction. Finally, interactions between predictors were considered. Models were assessed for discrimination, calibration and accuracy. 22,479 in-hospital cardiac arrests in 143 hospitals were included (14,688 development, 7791 validation). The final risk model for ROSC>20min included: age (non-linear), sex, prior length of stay in hospital, reason for attendance, location of arrest, presenting rhythm, and interactions between presenting rhythm and location of arrest. The model for hospital survival included the same predictors, excluding sex. Both models had acceptable performance across the range of measures, although discrimination for hospital mortality exceeded that for ROSC>20min (c index 0.81 versus 0.72). Validated risk models for ROSC>20min and hospital survival following in-hospital cardiac arrest have been developed. These models will strengthen comparative reporting in NCAA and support local quality improvement. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Development and validation of risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team☆

PubMed Central

Harrison, David A.; Patel, Krishna; Nixon, Edel; Soar, Jasmeet; Smith, Gary B.; Gwinnutt, Carl; Nolan, Jerry P.; Rowan, Kathryn M.

2014-01-01

Aim The National Cardiac Arrest Audit (NCAA) is the UK national clinical audit for in-hospital cardiac arrest. To make fair comparisons among health care providers, clinical indicators require case mix adjustment using a validated risk model. The aim of this study was to develop and validate risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team in UK hospitals. Methods Risk models for two outcomes—return of spontaneous circulation (ROSC) for greater than 20 min and survival to hospital discharge—were developed and validated using data for in-hospital cardiac arrests between April 2011 and March 2013. For each outcome, a full model was fitted and then simplified by testing for non-linearity, combining categories and stepwise reduction. Finally, interactions between predictors were considered. Models were assessed for discrimination, calibration and accuracy. Results 22,479 in-hospital cardiac arrests in 143 hospitals were included (14,688 development, 7791 validation). The final risk model for ROSC > 20 min included: age (non-linear), sex, prior length of stay in hospital, reason for attendance, location of arrest, presenting rhythm, and interactions between presenting rhythm and location of arrest. The model for hospital survival included the same predictors, excluding sex. Both models had acceptable performance across the range of measures, although discrimination for hospital mortality exceeded that for ROSC > 20 min (c index 0.81 versus 0.72). Conclusions Validated risk models for ROSC > 20 min and hospital survival following in-hospital cardiac arrest have been developed. These models will strengthen comparative reporting in NCAA and support local quality improvement. PMID:24830872

Molecular strategies of the Caenorhabditis elegans dauer larva to survive extreme desiccation.

PubMed

Erkut, Cihan; Vasilj, Andrej; Boland, Sebastian; Habermann, Bianca; Shevchenko, Andrej; Kurzchalia, Teymuras V

2013-01-01

Massive water loss is a serious challenge for terrestrial animals, which usually has fatal consequences. However, some organisms have developed means to survive this stress by entering an ametabolic state called anhydrobiosis. The molecular and cellular mechanisms underlying this phenomenon are poorly understood. We recently showed that Caenorhabditis elegans dauer larva, an arrested stage specialized for survival in adverse conditions, is resistant to severe desiccation. However, this requires a preconditioning step at a mild desiccative environment to prepare the organism for harsher desiccation conditions. A systems approach was used to identify factors that are activated during this preconditioning. Using microarray analysis, proteomics, and bioinformatics, genes, proteins, and biochemical pathways that are upregulated during this process were identified. These pathways were validated via reverse genetics by testing the desiccation tolerances of mutants. These data show that the desiccation response is activated by hygrosensation (sensing the desiccative environment) via head neurons. This leads to elimination of reactive oxygen species and xenobiotics, expression of heat shock and intrinsically disordered proteins, polyamine utilization, and induction of fatty acid desaturation pathway. Remarkably, this response is specific and involves a small number of functional pathways, which represent the generic toolkit for anhydrobiosis in plants and animals.

Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

PubMed

Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

2018-01-01

Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

Molecular Strategies of the Caenorhabditis elegans Dauer Larva to Survive Extreme Desiccation

PubMed Central

Erkut, Cihan; Vasilj, Andrej; Boland, Sebastian; Habermann, Bianca; Shevchenko, Andrej; Kurzchalia, Teymuras V.

2013-01-01

Massive water loss is a serious challenge for terrestrial animals, which usually has fatal consequences. However, some organisms have developed means to survive this stress by entering an ametabolic state called anhydrobiosis. The molecular and cellular mechanisms underlying this phenomenon are poorly understood. We recently showed that Caenorhabditis elegans dauer larva, an arrested stage specialized for survival in adverse conditions, is resistant to severe desiccation. However, this requires a preconditioning step at a mild desiccative environment to prepare the organism for harsher desiccation conditions. A systems approach was used to identify factors that are activated during this preconditioning. Using microarray analysis, proteomics, and bioinformatics, genes, proteins, and biochemical pathways that are upregulated during this process were identified. These pathways were validated via reverse genetics by testing the desiccation tolerances of mutants. These data show that the desiccation response is activated by hygrosensation (sensing the desiccative environment) via head neurons. This leads to elimination of reactive oxygen species and xenobiotics, expression of heat shock and intrinsically disordered proteins, polyamine utilization, and induction of fatty acid desaturation pathway. Remarkably, this response is specific and involves a small number of functional pathways, which represent the generic toolkit for anhydrobiosis in plants and animals. PMID:24324795

Development of a five-year mortality model in systemic sclerosis patients by different analytical approaches.

PubMed

Beretta, Lorenzo; Santaniello, Alessandro; Cappiello, Francesca; Chawla, Nitesh V; Vonk, Madelon C; Carreira, Patricia E; Allanore, Yannick; Popa-Diaconu, D A; Cossu, Marta; Bertolotti, Francesca; Ferraccioli, Gianfranco; Mazzone, Antonino; Scorza, Raffaella

2010-01-01

Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. The NBC outperformed the Cox-based classifier and the other data mining algorithms after internal cross-validation (area under receiving operator characteristic curve, AUROC: NBC=0.759; RND-F=0.736; Log-Reg=0.754 and Cox= 0.724). The NBC had also a remarkable and better trade-off between sensitivity and specificity (e.g. Balanced accuracy, BA) than the Cox-based classifier, when tested on an independent population of SSc patients (BA: NBC=0.769, Cox=0.622). The NBC was also superior to domain experts in predicting 5-year survival in this population (AUROC=0.829 vs. AUROC=0.788 and BA=0.769 vs. BA=0.67). We provide a model to make consistent 5-year prognostic predictions in SSc patients. Its internal validity, as well as capability of generalisation and reduced uncertainty compared to human experts support its use at bedside. Available at: http://www.nd.edu/~nchawla/survival.xls.

Picturing survival memories: enhanced memory after fitness-relevant processing occurs for verbal and visual stimuli.

PubMed

Otgaar, Henry; Smeets, Tom; van Bergen, Saskia

2010-01-01

Recent studies have shown that processing words according to a survival scenario leads to superior retention relative to control conditions. Here, we examined whether a survival recall advantage could be elicited by using pictures. Furthermore, in Experiment 1, we were interested in whether survival processing also results in improved memory for details. Undergraduates rated the relevance of pictures in a survival, moving, or pleasantness scenario and were subsequently given a surprise free recall test. We found that survival processing yielded superior retention. We also found that distortions occurred more often in the survival condition than in the pleasantness condition. In Experiment 2, we directly compared the survival recall effect between pictures and words. A comparable survival recall advantage was found for pictures and words. The present findings support the idea that memory is enhanced by processing information in terms of fitness value, yet at the same time, the present results suggest that this may increase the risk for memory distortions.

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

Rubin, Benjamin E.; Wetmore, Kelly M.; Price, Morgan N.

Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ~250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism's 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlapmore » with wellconserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA Leu , which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism's physiology and defines the essential gene set required for the growth of a photosynthetic organism.« less

The essential gene set of a photosynthetic organism

DOE PAGES

Rubin, Benjamin E.; Wetmore, Kelly M.; Price, Morgan N.; ...

2015-10-27

Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ~250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism's 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlapmore » with wellconserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA Leu , which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism's physiology and defines the essential gene set required for the growth of a photosynthetic organism.« less

Genome-wide screen identifies a novel prognostic signature for breast cancer survival

DOE PAGES

Mao, Xuan Y.; Lee, Matthew J.; Zhu, Jeffrey; ...

2017-01-21

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion,more » cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.« less

Genome-wide screen identifies a novel prognostic signature for breast cancer survival

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

Mao, Xuan Y.; Lee, Matthew J.; Zhu, Jeffrey

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion,more » cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.« less

Developmental trends in adaptive memory.

PubMed

Otgaar, Henry; Howe, Mark L; Smeets, Tom; Garner, Sarah R

2014-01-01

Recent studies have revealed that memory is enhanced when information is processed for fitness-related purposes. The main objective of the current experiments was to test developmental trends in the evolutionary foundation of memory using different types of stimuli and paradigms. In Experiment 1, 11-year-olds and adults were presented with neutral, negative, and survival-related DRM word lists. We found a memory benefit for the survival-related words and showed that false memories were more likely to be elicited for the survival-related word lists than for the other lists. Experiment 2 examined developmental trends in the survival processing paradigm using neutral, negative, and survival-related pictures. A survival processing advantage was found for survival-related pictures in adults, for negative pictures in 11/12-year-olds, and for neutral pictures in 7/8-year-olds. In Experiment 3, 11/12-year-olds and adults had to imagine the standard survival scenario or an adapted survival condition (or pleasantness condition) that was designed to reduce the possibilities for elaborative processing. We found superior memory retention for both survival scenarios in children and adults. Collectively, our results evidently show that the survival processing advantage is developmentally invariant and that certain proximate mechanisms (elaboration and distinctiveness) underlie these developmental trends.

A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma.

PubMed

Perry, Anamarija M; Cardesa-Salzmann, Teresa M; Meyer, Paul N; Colomo, Luis; Smith, Lynette M; Fu, Kai; Greiner, Timothy C; Delabie, Jan; Gascoyne, Randy D; Rimsza, Lisa; Jaffe, Elaine S; Ott, German; Rosenwald, Andreas; Braziel, Rita M; Tubbs, Raymond; Cook, James R; Staudt, Louis M; Connors, Joseph M; Sehn, Laurie H; Vose, Julie M; López-Guillermo, Armando; Campo, Elias; Chan, Wing C; Weisenburger, Dennis D

2012-09-13

Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell-like subtype, SPARC (secreted protein, acidic, and rich in cysteine) < 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.

Ion channel gene expression predicts survival in glioma patients

PubMed Central

Wang, Rong; Gurguis, Christopher I.; Gu, Wanjun; Ko, Eun A; Lim, Inja; Bang, Hyoweon; Zhou, Tong; Ko, Jae-Hong

2015-01-01

Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients. PMID:26235283

Surrogate endpoints for overall survival in advanced non-small-cell lung cancer patients with mutations of the epidermal growth factor receptor gene.

PubMed

Yoshino, Reiko; Imai, Hisao; Mori, Keita; Takei, Kousuke; Tomizawa, Mai; Kaira, Kyoichi; Yoshii, Akihiro; Tomizawa, Yoshio; Saito, Ryusei; Yamada, Masanobu

2014-09-01

Subsequent therapies confound the ability to discern the effect of first-line chemotherapy on overall survival (OS). We investigated whether progression-free survival (PFS), post-progression survival (PPS) and tumor response were valid surrogate endpoints for OS following first-line chemotherapy in individual patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor gene mutations. We retrospectively analyzed 35 patients with advanced NSCLC treated with first-line gefitinib. The associations of PFS, PPS and tumor response with OS were analyzed. PPS was found to be strongly correlated with OS, unlike PFS and tumor shrinkage. The factors significantly associated with PPS were performance status (PS) after first-line treatment, best response to second-line treatment and number of regimens used after disease progression. PPS may be a surrogate for OS in this patient population and further therapy after disease progression following first-line chemotherapy may significantly affect OS. However, a larger study is required to validate these results.

Gene Expression-Based Survival Prediction in Lung Adenocarcinoma: A Multi-Site, Blinded Validation Study

PubMed Central

Shedden, Kerby; Taylor, Jeremy M.G.; Enkemann, Steve A.; Tsao, Ming S.; Yeatman, Timothy J.; Gerald, William L.; Eschrich, Steve; Jurisica, Igor; Venkatraman, Seshan E.; Meyerson, Matthew; Kuick, Rork; Dobbin, Kevin K.; Lively, Tracy; Jacobson, James W.; Beer, David G.; Giordano, Thomas J.; Misek, David E.; Chang, Andrew C.; Zhu, Chang Qi; Strumpf, Dan; Hanash, Samir; Shepherd, Francis A.; Ding, Kuyue; Seymour, Lesley; Naoki, Katsuhiko; Pennell, Nathan; Weir, Barbara; Verhaak, Roel; Ladd-Acosta, Christine; Golub, Todd; Gruidl, Mike; Szoke, Janos; Zakowski, Maureen; Rusch, Valerie; Kris, Mark; Viale, Agnes; Motoi, Noriko; Travis, William; Sharma, Anupama

2009-01-01

Although prognostic gene expression signatures for survival in early stage lung cancer have been proposed, for clinical application it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) can be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas. PMID:18641660

Validation of Survivability Validation Protocols

DTIC Science & Technology

1993-05-01

simu- lation fidelityl. Physical testing of P.i SOS, in either aboveground tests (AGTs) or underground test ( UGTs ), will usually be impossible, due...with some simulation fidelity compromises) are possible in UGTs and/orAGTs. Hence proof tests, if done in statistically significant numbers, can...level. Simulation fidelity and AGT/ UGT /threat correlation will be validation issues here. Extrapolation to threat environments will be done via modeling

Prognostic value of circulating microRNAs in upper tract urinary carcinoma

PubMed Central

Ingelmo-Torres, Mercedes; Lozano, Juan José; Capitán, David; Alcaraz, Antonio; Mengual, Lourdes

2018-01-01

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC. PMID:29682178

SU-F-R-24: Identifying Prognostic Imaging Biomarkers in Early Stage Lung Cancer Using Radiomics

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

Zeng, X; Wu, J; Cui, Y

2016-06-15

Purpose: Patients diagnosed with early stage lung cancer have favorable outcomes when treated with surgery or stereotactic radiotherapy. However, a significant proportion (∼20%) of patients will develop metastatic disease and eventually die of the disease. The purpose of this work is to identify quantitative imaging biomarkers from CT for predicting overall survival in early stage lung cancer. Methods: In this institutional review board-approved HIPPA-compliant retrospective study, we retrospectively analyzed the diagnostic CT scans of 110 patients with early stage lung cancer. Data from 70 patients were used for training/discovery purposes, while those of remaining 40 patients were used for independentmore » validation. We extracted 191 radiomic features, including statistical, histogram, morphological, and texture features. Cox proportional hazard regression model, coupled with the least absolute shrinkage and selection operator (LASSO), was used to predict overall survival based on the radiomic features. Results: The optimal prognostic model included three image features from the Law’s feature and wavelet texture. In the discovery cohort, this model achieved a concordance index or CI=0.67, and it separated the low-risk from high-risk groups in predicting overall survival (hazard ratio=2.72, log-rank p=0.007). In the independent validation cohort, this radiomic signature achieved a CI=0.62, and significantly stratified the low-risk and high-risk groups in terms of overall survival (hazard ratio=2.20, log-rank p=0.042). Conclusion: We identified CT imaging characteristics associated with overall survival in early stage lung cancer. If prospectively validated, this could potentially help identify high-risk patients who might benefit from adjuvant systemic therapy.« less

Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study.

PubMed

Kim, Hwi Young; Lee, Dong Hyeon; Lee, Jeong-Hoon; Cho, Young Youn; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

2018-03-20

Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS). This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted. A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P < 0.001). In internal validation, the model maintained good discriminant functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values). This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

MUC1 Expression by Immunohistochemistry Is Associated with Adverse Pathologic Features in Prostate Cancer: A Multi-Institutional Study.

PubMed

Eminaga, Okyaz; Wei, Wei; Hawley, Sarah J; Auman, Heidi; Newcomb, Lisa F; Simko, Jeff; Hurtado-Coll, Antonio; Troyer, Dean A; Carroll, Peter R; Gleave, Martin E; Lin, Daniel W; Nelson, Peter S; Thompson, Ian M; True, Lawrence D; McKenney, Jesse K; Feng, Ziding; Fazli, Ladan; Brooks, James D

2016-01-01

The uncertainties inherent in clinical measures of prostate cancer (CaP) aggressiveness endorse the investigation of clinically validated tissue biomarkers. MUC1 expression has been previously reported to independently predict aggressive localized prostate cancer. We used a large cohort to validate whether MUC1 protein levels measured by immunohistochemistry (IHC) predict aggressive cancer, recurrence and survival outcomes after radical prostatectomy independent of clinical and pathological parameters. MUC1 IHC was performed on a multi-institutional tissue microarray (TMA) resource including 1,326 men with a median follow-up of 5 years. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazard models and the Log-rank test. The presence of MUC1 expression was significantly associated with extracapsular extension and higher Gleason score, but not with seminal vesicle invasion, age, positive surgical margins or pre-operative serum PSA levels. In univariable analyses, positive MUC1 staining was significantly associated with a worse recurrence free survival (RFS) (HR: 1.24, CI 1.03-1.49, P = 0.02), although not with disease specific survival (DSS, P>0.5). On multivariable analyses, the presence of positive surgical margins, extracapsular extension, seminal vesicle invasion, as well as higher pre-operative PSA and increasing Gleason score were independently associated with RFS, while MUC1 expression was not. Positive MUC1 expression was not independently associated with disease specific survival (DSS), but was weakly associated with overall survival (OS). In our large, rigorously designed validation cohort, MUC1 protein expression was associated with adverse pathological features, although it was not an independent predictor of outcome after radical prostatectomy.

Prognostic value of circulating microRNAs in upper tract urinary carcinoma.

PubMed

Montalbo, Ruth; Izquierdo, Laura; Ingelmo-Torres, Mercedes; Lozano, Juan José; Capitán, David; Alcaraz, Antonio; Mengual, Lourdes

2018-03-30

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC.

Cryopreservation for delayed circulating tumor cell isolation is a valid strategy for prognostic association of circulating tumor cells in gastroesophageal cancer

PubMed Central

Brungs, Daniel; Lynch, David; Luk, Alison WS; Minaei, Elahe; Ranson, Marie; Aghmesheh, Morteza; Vine, Kara L; Carolan, Martin; Jaber, Mouhannad; de Souza, Paul; Becker, Therese M

2018-01-01

AIM To demonstrate the feasibility of cryopreservation of peripheral blood mononuclear cells (PBMCs) for prognostic circulating tumor cell (CTC) detection in gastroesophageal cancer. METHODS Using 7.5 mL blood samples collected in EDTA tubes from patients with gastroesopheagal adenocarcinoma, CTCs were isolated by epithelial cell adhesion molecule based immunomagnetic capture using the IsoFlux platform. Paired specimens taken during the same blood draw (n = 15) were used to compare number of CTCs isolated from fresh and cryopreserved PBMCs. Blood samples were processed within 24 h to recover the PBMC fraction, with PBMCs used for fresh analysis immediately processed for CTC isolation. Cryopreservation of PBMCs lasted from 2 wk to 25.2 mo (median 14.6 mo). CTCs isolated from pre-treatment cryopreserved PBMCs (n = 43) were examined for associations with clinicopathological variables and survival outcomes. RESULTS While there was a significant trend to a decrease in CTC numbers associated with cryopreserved specimens (mean number of CTCs 34.4 vs 51.5, P = 0.04), this was predominately in samples with a total CTC count of > 50, with low CTC count samples less affected (P = 0.06). There was no significant association between the duration of cryopreservation and number of CTCs. In cryopreserved PBMCs from patient samples prior to treatment, a high CTC count (> 17) was associated with poorer overall survival (OS) (n = 43, HR = 4.4, 95%CI: 1.7-11.7, P = 0.0013). In multivariate analysis, after controlling for sex, age, stage, ECOG performance status, and primary tumor location, a high CTC count remained significantly associated with a poorer OS (HR = 3.7, 95%CI: 1.2-12.4, P = 0.03). CONCLUSION PBMC cryopreservation for delayed CTC isolation is a valid strategy to assist with sample collection, transporting and processing. PMID:29467551

Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC.

PubMed

Wei, Yongyue; Liang, Junya; Zhang, Ruyang; Guo, Yichen; Shen, Sipeng; Su, Li; Lin, Xihong; Moran, Sebastian; Helland, Åslaug; Bjaanæs, Maria M; Karlsson, Anna; Planck, Maria; Esteller, Manel; Fleischer, Thomas; Staaf, Johan; Zhao, Yang; Chen, Feng; Christiani, David C

2018-01-01

KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes and their roles in lung cancer survival. Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites in KDM genes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation. DNA methylation at sites cg11637544 in KDM2A and cg26662347 in KDM1A were in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival ( HR cg11637544  = 1.32, 95%CI, 1.16-1.50, P  = 1.1 × 10 -4 ; HR cg26662347  = 1.88, 95%CI, 1.37-2.60, P  = 3.7 × 10 -3 ), and correlated with corresponding gene expression (cg11637544 for KDM2A , P  = 1.3 × 10 -10 ; cg26662347 for KDM1A P  = 1.5 × 10 -5 ). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance. These findings highlight the association between somatic DNA methylation in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.

A risk prediction model for determining appropriateness of CEA in patients with asymptomatic carotid artery stenosis.

PubMed

Conrad, Mark F; Kang, Jeanwan; Mukhopadhyay, Shankha; Patel, Virendra I; LaMuraglia, Glenn M; Cambria, Richard P

2013-10-01

The benefit of carotid endarterectomy (CEA) over medical therapy in patients with asymptomatic carotid artery stenosis is predicated upon a life expectancy of at least 5 years after the procedure. The goal of this study was to create a scoring system for prediction of 5-year survival after CEA that can be used to triage patients with ACAS. All patients who underwent CEA for severe asymptomatic carotid stenosis from 1989 to 2005 were identified. Long-term survival was determined by a review of hospital records and the social security death index. Because all patients had at least 5-year follow-up, a logistic regression of predictors of survival at 5 years was performed and the odds ratios associated with particular significant comorbidities were used to create a scoring system to predict survival. The scoring system was then validated within the cohort using the Hosmer-Lemeshow Test and a derivation/validation receiver operating characteristic (ROC) curve. There were 2004 CEA performed in 1791 patients. The average follow-up was 130 ± 49 months. The clinical profile of the cohort data included 84% hypertension, 56% coronary artery disease (CAD), 24% diabetes, and 71% on statins. The 30-day stroke rate was 1.1% and the death rate was 0.7%. The actual 5-year survival was 73%. Logistic regression yielded the following predictors of mortality: age (by decade) (odds ratio [OR] = 1.8, P < 0.0001), CAD (OR = 1.5, P = 0.0007), chronic obstructive pulmonary disease (OR = 2.5; P < 0.0001), diabetes (OR = 1.7, P < 0.0001), neck radiation (OR = 2.6, P = 0.005), no statin (OR = 2.1, P < 0.0001), and creatinine more than 1.5 (OR = 2.6, P < 0.0001). These variables were then assigned a hierarchal point scoring system in accordance with the OR value. The 5-year survival based on the scoring system was as follows: 0 to 5 points = 92.5%, 6 to 8 points = 83.6%, 9 to 11 points = 63.7%, 12 to 14 points = 46.5%, and more than 15 points = 33.8%. The Hosmer-Lemeshow test validated the scoring system (P = 0.26) and there was no difference in the ROC curves (C statistic = 0.74 vs 0.73). This validated scoring system can be a useful tool for determining which patients are likely to benefit most from CEA based on the probability of long-term survival. Given that the 5-year survival of patients in the medical arm of the asymptomatic CEA trials was 60% to 70%, it is reasonable to conclude that patients who score 0 to 8 points are excellent candidates for CEA whereas most patients with ≥12 points should be managed with medical therapy alone.

Nomogram Prediction of Overall Survival After Curative Irradiation for Uterine Cervical Cancer

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

Seo, YoungSeok; Yoo, Seong Yul; Kim, Mi-Sook

Purpose: The purpose of this study was to develop a nomogram capable of predicting the probability of 5-year survival after radical radiotherapy (RT) without chemotherapy for uterine cervical cancer. Methods and Materials: We retrospectively analyzed 549 patients that underwent radical RT for uterine cervical cancer between March 1994 and April 2002 at our institution. Multivariate analysis using Cox proportional hazards regression was performed and this Cox model was used as the basis for the devised nomogram. The model was internally validated for discrimination and calibration by bootstrap resampling. Results: By multivariate regression analysis, the model showed that age, hemoglobin levelmore » before RT, Federation Internationale de Gynecologie Obstetrique (FIGO) stage, maximal tumor diameter, lymph node status, and RT dose at Point A significantly predicted overall survival. The survival prediction model demonstrated good calibration and discrimination. The bootstrap-corrected concordance index was 0.67. The predictive ability of the nomogram proved to be superior to FIGO stage (p = 0.01). Conclusions: The devised nomogram offers a significantly better level of discrimination than the FIGO staging system. In particular, it improves predictions of survival probability and could be useful for counseling patients, choosing treatment modalities and schedules, and designing clinical trials. However, before this nomogram is used clinically, it should be externally validated.« less

Surrogate endpoints for overall survival in lung cancer trials: a review.

PubMed

Fiteni, Frédéric; Westeel, Virginie; Bonnetain, Franck

2017-05-01

Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS. Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials. Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.

Development and validation of the Good Outcome Following Attempted Resuscitation (GO-FAR) score to predict neurologically intact survival after in-hospital cardiopulmonary resuscitation.

PubMed

Ebell, Mark H; Jang, Woncheol; Shen, Ye; Geocadin, Romergryko G

2013-11-11

Informing patients and providers of the likelihood of survival after in-hospital cardiac arrest (IHCA), neurologically intact or with minimal deficits, may be useful when discussing do-not-attempt-resuscitation orders. To develop a simple prearrest point score that can identify patients unlikely to survive IHCA, neurologically intact or with minimal deficits. The study included 51,240 inpatients experiencing an index episode of IHCA between January 1, 2007, and December 31, 2009, in 366 hospitals participating in the Get With the Guidelines-Resuscitation registry. Dividing data into training (44.4%), test (22.2%), and validation (33.4%) data sets, we used multivariate methods to select the best independent predictors of good neurologic outcome, created a series of candidate decision models, and used the test data set to select the model that best classified patients as having a very low (<1%), low (1%-3%), average (>3%-15%), or higher than average (>15%) likelihood of survival after in-hospital cardiopulmonary resuscitation for IHCA with good neurologic status. The final model was evaluated using the validation data set. Survival to discharge after in-hospital cardiopulmonary resuscitation for IHCA with good neurologic status (neurologically intact or with minimal deficits) based on a Cerebral Performance Category score of 1. The best performing model was a simple point score based on 13 prearrest variables. The C statistic was 0.78 when applied to the validation set. It identified the likelihood of a good outcome as very low in 9.4% of patients (good outcome in 0.9%), low in 18.9% (good outcome in 1.7%), average in 54.0% (good outcome in 9.4%), and above average in 17.7% (good outcome in 27.5%). Overall, the score can identify more than one-quarter of patients as having a low or very low likelihood of survival to discharge, neurologically intact or with minimal deficits after IHCA (good outcome in 1.4%). The Good Outcome Following Attempted Resuscitation (GO-FAR) scoring system identifies patients who are unlikely to benefit from a resuscitation attempt should they experience IHCA. This information can be used as part of a shared decision regarding do-not-attempt-resuscitation orders.

Adaptive memory: the comparative value of survival processing.

PubMed

Nairne, James S; Pandeirada, Josefa N S; Thompson, Sarah R

2008-02-01

We recently proposed that human memory systems are "tuned" to remember information that is processed for survival, perhaps as a result of fitness advantages accrued in the ancestral past. This proposal was supported by experiments in which participants showed superior memory when words were rated for survival relevance, at least relative to when words received other forms of deep processing. The current experiments tested the mettle of survival memory by pitting survival processing against conditions that are universally accepted as producing excellent retention, including conditions in which participants rated words for imagery, pleasantness, and self-reference; participants also generated words, studied words with the intention of learning them, or rated words for relevance to a contextually rich (but non-survival-related) scenario. Survival processing yielded the best retention, which suggests that it may be one of the best encoding procedures yet discovered in the memory field.

Development of a survey instrument to investigate the primary care factors related to differences in cancer diagnosis between international jurisdictions

PubMed Central

2014-01-01

Background Survival rates following a diagnosis of cancer vary between countries. The International Cancer Benchmarking Partnership (ICBP), a collaboration between six countries with primary care led health services, was set up in 2009 to investigate the causes of these differences. Module 3 of this collaboration hypothesised that an association exists between the readiness of primary care physicians (PCP) to investigate for cancer – the ‘threshold’ risk level at which they investigate or refer to a specialist for consideration of possible cancer – and survival for that cancer (lung, colorectal and ovarian). We describe the development of an international survey instrument to test this hypothesis. Methods The work was led by an academic steering group in England. They agreed that an online survey was the most pragmatic way of identifying differences between the jurisdictions. Research questions were identified through clinical experience and expert knowledge of the relevant literature. A survey comprising a set of direct questions and five clinical scenarios was developed to investigate the hypothesis. The survey content was discussed and refined concurrently and repeatedly with international partners. The survey was validated using an iterative process in England. Following validation the survey was adapted to be relevant to the health systems operating in other jurisdictions and translated into Danish, Norwegian and Swedish, and into Canadian and Australian English. Results This work has produced a survey with face, content and cross cultural validity that will be circulated in all six countries. It could also form a benchmark for similar surveys in countries with similar health care systems. Conclusions The vignettes could also be used as educational resources. This study is likely to impact on healthcare policy and practice in participating countries. PMID:24938306

Twenty-four signature genes predict the prognosis of oral squamous cell carcinoma with high accuracy and repeatability

PubMed Central

Gao, Jianyong; Tian, Gang; Han, Xu; Zhu, Qiang

2018-01-01

Oral squamous cell carcinoma (OSCC) is the sixth most common type cancer worldwide, with poor prognosis. The present study aimed to identify gene signatures that could classify OSCC and predict prognosis in different stages. A training data set (GSE41613) and two validation data sets (GSE42743 and GSE26549) were acquired from the online Gene Expression Omnibus database. In the training data set, patients were classified based on the tumor-node-metastasis staging system, and subsequently grouped into low stage (L) or high stage (H). Signature genes between L and H stages were selected by disparity index analysis, and classification was performed by the expression of these signature genes. The established classification was compared with the L and H classification, and fivefold cross validation was used to evaluate the stability. Enrichment analysis for the signature genes was implemented by the Database for Annotation, Visualization and Integration Discovery. Two validation data sets were used to determine the precise of classification. Survival analysis was conducted followed each classification using the package ‘survival’ in R software. A set of 24 signature genes was identified based on the classification model with the Fi value of 0.47, which was used to distinguish OSCC samples in two different stages. Overall survival of patients in the H stage was higher than those in the L stage. Signature genes were primarily enriched in ‘ether lipid metabolism’ pathway and biological processes such as ‘positive regulation of adaptive immune response’ and ‘apoptotic cell clearance’. The results provided a novel 24-gene set that may be used as biomarkers to predict OSCC prognosis with high accuracy, which may be used to determine an appropriate treatment program for patients with OSCC in addition to the traditional evaluation index. PMID:29257303

A clinical tool for predicting survival in ALS.

PubMed

Knibb, Jonathan A; Keren, Noa; Kulka, Anna; Leigh, P Nigel; Martin, Sarah; Shaw, Christopher E; Tsuda, Miho; Al-Chalabi, Ammar

2016-12-01

Amyotrophic lateral sclerosis (ALS) is a progressive and usually fatal neurodegenerative disease. Survival from diagnosis varies considerably. Several prognostic factors are known, including site of onset (bulbar or limb), age at symptom onset, delay from onset to diagnosis and the use of riluzole and non-invasive ventilation (NIV). Clinicians and patients would benefit from a practical way of using these factors to provide an individualised prognosis. 575 consecutive patients with incident ALS from a population-based registry in South-East England register for ALS (SEALS) were studied. Their survival was modelled as a two-step process: the time from diagnosis to respiratory muscle involvement, followed by the time from respiratory involvement to death. The effects of predictor variables were assessed separately for each time interval. Younger age at symptom onset, longer delay from onset to diagnosis and riluzole use were associated with slower progression to respiratory involvement, and NIV use was associated with lower mortality after respiratory involvement, each with a clinically significant effect size. Riluzole may have a greater effect in younger patients and those with longer delay to diagnosis. A patient's survival time has a roughly 50% chance of falling between half and twice the predicted median. A simple and clinically applicable graphical method of predicting an individual patient's survival from diagnosis is presented. The model should be validated in an independent cohort, and extended to include other important prognostic factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.

PubMed

Agar, Nita Sally; Wedgeworth, Emma; Crichton, Siobhan; Mitchell, Tracey J; Cox, Michael; Ferreira, Silvia; Robson, Alistair; Calonje, Eduardo; Stefanato, Catherine M; Wain, Elizabeth Mary; Wilkins, Bridget; Fields, Paul A; Dean, Alan; Webb, Katherine; Scarisbrick, Julia; Morris, Stephen; Whittaker, Sean J

2010-11-01

We have analyzed the outcome of mycosis fungoides (MF) and Sézary syndrome (SS) patients using the recent International Society for Cutaneous Lymphomas (ISCL)/European Organisation for Research and Treatment of Cancer (EORTC) revised staging proposal. Overall survival (OS), disease-specific survival (DSS), and risk of disease progression (RDP) were calculated for a cohort of 1,502 patients using univariate and multivariate models. The mean age at diagnosis was 54 years, and 71% of patients presented with early-stage disease. Disease progression occurred in 34%, and 26% of patients died due to MF/SS. A significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Univariate analysis established that (1) advanced skin and overall clinical stage, increased age, male sex, increased lactate dehydrogenase (LDH), and large-cell transformation were associated with reduced survival and increased RDP; (2) hypopigmented MF, MF with lymphomatoid papulosis, and poikilodermatous MF were associated with improved survival and reduced RDP; and (3) folliculotropic MF was associated with an increased RDP. Multivariate analysis established that (1) advanced skin (T) stage, the presence in peripheral blood of the tumor clone without Sézary cells (B0b), increased LDH, and folliculotropic MF were independent predictors of poor survival and increased RDP; (2) large-cell transformation and tumor distribution were independent predictors of increased RDP only; and (3) N, M, and B stages; age; male sex; and poikilodermatous MF were only significant for survival. This study has validated the recently proposed ISCL/EORTC staging system and identified new prognostic factors.

A stochastic evolutionary model generating a mixture of exponential distributions

NASA Astrophysics Data System (ADS)

Fenner, Trevor; Levene, Mark; Loizou, George

2016-02-01

Recent interest in human dynamics has stimulated the investigation of the stochastic processes that explain human behaviour in various contexts, such as mobile phone networks and social media. In this paper, we extend the stochastic urn-based model proposed in [T. Fenner, M. Levene, G. Loizou, J. Stat. Mech. 2015, P08015 (2015)] so that it can generate mixture models, in particular, a mixture of exponential distributions. The model is designed to capture the dynamics of survival analysis, traditionally employed in clinical trials, reliability analysis in engineering, and more recently in the analysis of large data sets recording human dynamics. The mixture modelling approach, which is relatively simple and well understood, is very effective in capturing heterogeneity in data. We provide empirical evidence for the validity of the model, using a data set of popular search engine queries collected over a period of 114 months. We show that the survival function of these queries is closely matched by the exponential mixture solution for our model.

Adaptive Memory: Survival Processing Increases Both True and False Memory in Adults and Children

ERIC Educational Resources Information Center

Otgaar, Henry; Smeets, Tom

2010-01-01

Research has shown that processing information in a survival context can enhance the information's memorability. The current study examined whether survival processing can also decrease the susceptibility to false memories and whether the survival advantage can be found in children. In Experiment 1, adults rated semantically related words in a…

Psychology in Education as Developmental Healthcare: A Proposal for Fundamental Change and Survival.

ERIC Educational Resources Information Center

Bagnato, Stephen J.

The survival of psychologists and psychological services in public education is a pressing concern of critical importance to children, families, and school systems. Psychologists advocate that the critical first step for clients to change behavior and personality is to define the problem and to accept its validity. The main problem facing…

On the Plasticity of the Survival Processing Effect

ERIC Educational Resources Information Center

Kroneisen, Meike; Erdfelder, Edgar

2011-01-01

Nairne, Thompson, and Pandeirada (2007) discovered a strong and rather general memory advantage for word material processed in a survival-related context. One possible explanation of this effect conceives survival processing as a special form of encoding: Nature specifically "tuned" our memory systems to process and remember…

SU-E-T-131: Artificial Neural Networks Applied to Overall Survival Prediction for Patients with Periampullary Carcinoma

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

Gong, Y; Yu, J; Yeung, V

Purpose: Artificial neural networks (ANN) can be used to discover complex relations within datasets to help with medical decision making. This study aimed to develop an ANN method to predict two-year overall survival of patients with peri-ampullary cancer (PAC) following resection. Methods: Data were collected from 334 patients with PAC following resection treated in our institutional pancreatic tumor registry between 2006 and 2012. The dataset contains 14 variables including age, gender, T-stage, tumor differentiation, positive-lymph-node ratio, positive resection margins, chemotherapy, radiation therapy, and tumor histology.After censoring for two-year survival analysis, 309 patients were left, of which 44 patients (∼15%) weremore » randomly selected to form testing set. The remaining 265 cases were randomly divided into training set (211 cases, ∼80% of 265) and validation set (54 cases, ∼20% of 265) for 20 times to build 20 ANN models. Each ANN has one hidden layer with 5 units. The 20 ANN models were ranked according to their concordance index (c-index) of prediction on validation sets. To further improve prediction, the top 10% of ANN models were selected, and their outputs averaged for prediction on testing set. Results: By random division, 44 cases in testing set and the remaining 265 cases have approximately equal two-year survival rates, 36.4% and 35.5% respectively. The 20 ANN models, which were trained and validated on the 265 cases, yielded mean c-indexes as 0.59 and 0.63 on validation sets and the testing set, respectively. C-index was 0.72 when the two best ANN models (top 10%) were used in prediction on testing set. The c-index of Cox regression analysis was 0.63. Conclusion: ANN improved survival prediction for patients with PAC. More patient data and further analysis of additional factors may be needed for a more robust model, which will help guide physicians in providing optimal post-operative care. This project was supported by PA CURE Grant.« less

False memories from survival processing make better primes for problem-solving.

PubMed

Garner, Sarah R; Howe, Mark L

2014-01-01

Previous research has demonstrated that participants remember significantly more survival-related information and more information that is processed for its survival relevance. Recent research has also shown that survival materials and processing result in more false memories, ones that are adaptive inasmuch as they prime solutions to insight-based problems. Importantly, false memories for survival-related information facilitate problem solving more than false memories for other types of information. The present study explores this survival advantage using an incidental rather than intentional memory task. Here participants rated information either in the context of its importance to a survival-processing scenario or to moving to a new house. Following this, participants solved a number of compound remote associate tasks (CRATs), half of which had the solution primed by false memories that were generated during the processing task. Results showed that (a) CRATs were primed by false memories in this incidental task, with participants solving significantly more CRATs when primed than when unprimed, (b) this effect was greatest when participants rated items for survival than moving, and (c) processing items for a survival scenario improved overall problem-solving performance even when specific problems themselves were not primed. Results are discussed with regard to adaptive theories of memory.

Drug targeting of oncogenic pathways in melanoma.

PubMed

Fecher, Leslie A; Amaravadi, Ravi K; Schuchter, Lynn M; Flaherty, Keith T

2009-06-01

Melanoma continues to be one of the most aggressive and morbid malignancies once metastatic. Overall survival for advanced unresectable melanoma has not changed over the past several decades. However, the presence of some long-term survivors of metastatic melanoma highlights the heterogeneity of this disease and the potential for improved outcomes. Current research is uncovering the molecular and genetic scaffolding of normal and aberrant cell function. The known oncogenic pathways in melanoma and the attempts to develop therapy for them are discussed. The targeting of certain cellular processes, downstream of the common genetic alterations, for which the issues of target and drug validation are somewhat distinct, are also highlighted.

Is the Survival-Processing Memory Advantage Due to Richness of Encoding?

ERIC Educational Resources Information Center

Röer, Jan P.; Bell, Raoul; Buchner, Axel

2013-01-01

Memory for words rated according to their relevance in a grassland survival context is exceptionally good. According to Nairne, Thompson, and Pandeirada's (2007) evolutionary-based explanation, natural selection processes have tuned the human memory system to prioritize the processing of fitness-relevant information. The survival-processing memory…

Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis.

PubMed

Cheong, Jae-Ho; Yang, Han-Kwang; Kim, Hyunki; Kim, Woo Ho; Kim, Young-Woo; Kook, Myeong-Cherl; Park, Young-Kyu; Kim, Hyung-Ho; Lee, Hye Seung; Lee, Kyung Hee; Gu, Mi Jin; Kim, Ha Yan; Lee, Jinae; Choi, Seung Ho; Hong, Soonwon; Kim, Jong Won; Choi, Yoon Young; Hyung, Woo Jin; Jang, Eunji; Kim, Hyeseon; Huh, Yong-Min; Noh, Sung Hoon

2018-05-01

Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer. In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival. We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2-92·0), 74·8% (69·9-80·1), and 66·0% (60·1-72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5-87·1] vs 64·5% [56·8-73·3]; univariate hazard ratio 0·47 [95% CI 0·30-0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5-79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8-79·9] in patients who only had surgery; 0·93 [0·62-1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (p interaction =0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort. The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted. Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare. Copyright © 2018 Elsevier Ltd. All rights reserved.

Breast cancer survival in New Zealand women.

PubMed

Campbell, Ian D; Scott, Nina; Seneviratne, Sanjeewa; Kollias, James; Walters, David; Taylor, Corey; Webster, Fleur; Zorbas, Helen; Roder, David M

2015-01-01

The Quality Audit (BQA) of Breast Surgeons of Australia and New Zealand includes a broad range of data and is the largest New Zealand (NZ) breast cancer (BC) database outside the NZ Cancer Registry. We used BQA data to compare BC survival by ethnicity, deprivation, remoteness, clinical characteristic and case load. BQA and death data were linked using the National Health Index. Disease-specific survival for invasive cases was benchmarked against Australian BQA data and NZ population-based survivals. Validity was explored by comparison with expected survival by risk factor. Compared with 93% for Australian audit cases, 5-year survival was 90% for NZ audit cases overall, 87% for Maori, 84% for Pacific and 91% for other. BC survival in NZ appears lower than in Australia, with inequities by ethnicity. Differences may be due to access, timeliness and quality of health services, patient risk profiles, BQA coverage and death-record methodology. © 2014 Royal Australasian College of Surgeons.

Validation of the Retinal Detachment after Open Globe Injury (RD-OGI) Score as an Effective Tool for Predicting Retinal Detachment.

PubMed

Brodowska, Katarzyna; Stryjewski, Tomasz P; Papavasileiou, Evangelia; Chee, Yewlin E; Eliott, Dean

2017-05-01

The Retinal Detachment after Open Globe Injury (RD-OGI) Score is a clinical prediction model that was developed at the Massachusetts Eye and Ear Infirmary to predict the risk of retinal detachment (RD) after open globe injury (OGI). This study sought to validate the RD-OGI Score in an independent cohort of patients. Retrospective cohort study. The predictive value of the RD-OGI Score was evaluated by comparing the original RD-OGI Scores of 893 eyes with OGI that presented between 1999 and 2011 (the derivation cohort) with 184 eyes with OGI that presented from January 1, 2012, to January 31, 2014 (the validation cohort). Three risk classes (low, moderate, and high) were created and logistic regression was undertaken to evaluate the optimal predictive value of the RD-OGI Score. A Kaplan-Meier survival analysis evaluated survival experience between the risk classes. Time to RD. At 1 year after OGI, 255 eyes (29%) in the derivation cohort and 66 eyes (36%) in the validation cohort were diagnosed with an RD. At 1 year, the low risk class (RD-OGI Scores 0-2) had a 3% detachment rate in the derivation cohort and a 0% detachment rate in the validation cohort, the moderate risk class (RD-OGI Scores 2.5-4.5) had a 29% detachment rate in the derivation cohort and a 35% detachment rate in the validation cohort, and the high risk class (RD-OGI scores 5-7.5) had a 73% detachment rate in the derivation cohort and an 86% detachment rate in the validation cohort. Regression modeling revealed the RD-OGI to be highly discriminative, especially 30 days after injury, with an area under the receiver operating characteristic curve of 0.939 in the validation cohort. Survival experience was significantly different depending upon the risk class (P < 0.0001, log-rank chi-square). The RD-OGI Score can reliably predict the future risk of developing an RD based on clinical variables that are present at the time of the initial evaluation after OGI. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis.

PubMed

Niyazi, Maximilian; Adeberg, Sebastian; Kaul, David; Boulesteix, Anne-Laure; Bougatf, Nina; Fleischmann, Daniel F; Grün, Arne; Krämer, Anna; Rödel, Claus; Eckert, Franziska; Paulsen, Frank; Kessel, Kerstin A; Combs, Stephanie E; Oehlke, Oliver; Grosu, Anca-Ligia; Seidlitz, Annekatrin; Lattermann, Annika; Krause, Mechthild; Baumann, Michael; Guberina, Maja; Stuschke, Martin; Budach, Volker; Belka, Claus; Debus, Jürgen

2018-04-01

Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort. The reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients. This score can predict post-recurrence survival (PRS) after reRT. The validation dataset consisted of 212 patients. The RRRS differentiates three prognostic groups. Discrimination and calibration were maintained in the validation group. Median PRS times in the development cohort for the good/intermediate/poor risk categories were 14.2, 9.1, and 5.3 months, respectively. The respective groups within the validation cohort displayed median PRS times of 13.8, 8.8, and 3.8 months, respectively. Uno's C for development data was 0.64 (CI: 0.60-0.69) and for validation data 0.63 (CI: 0.58-0.68). The RRRS has been successfully validated in an independent patient cohort. This linear combination of three easily determined clinicopathological factors allows for a reliable classification of patients and may be used as stratification factor for future trials. Copyright © 2018 Elsevier B.V. All rights reserved.

Expression profiles of loneliness-associated genes for survival prediction in cancer patients.

PubMed

You, Liang-Fu; Yeh, Jia-Rong; Su, Mu-Chun

2014-01-01

Influence of loneliness on human survival has been established epidemiologically, but genomic research remains undeveloped. We identified 34 loneliness-associated genes which were statistically significant for high- lonely and low-lonely individuals. With the univariate Cox proportional hazards regression model, we obtained corresponding regression coefficients for loneliness-associated genes fo individual cancer patients. Furthermore, risk scores could be generated with the combination of gene expression level multiplied by corresponding regression coefficients of loneliness-associated genes. We verified that high-risk score cancer patients had shorter mean survival time than their low-risk score counterparts. Then we validated the loneliness-associated gene signature in three independent brain cancer cohorts with Kaplan-Meier survival curves (n=77, 85 and 191), significantly separable by log-rank test with hazard ratios (HR) >1 and p-values <0.0001 (HR=2.94, 3.82, and 1.78). Moreover, we validated the loneliness-associated gene signature in bone cancer (HR=5.10, p-value=4.69e-3), lung cancer (HR=2.86, p-value=4.71e-5), ovarian cancer (HR=1.97, p-value=3.11e-5), and leukemia (HR=2.06, p-value=1.79e-4) cohorts. The last lymphoma cohort proved to have an HR=3.50, p-value=1.15e-7. Loneliness- associated genes had good survival prediction for cancer patients, especially bone cancer patients. Our study provided the first indication that expression of loneliness-associated genes are related to survival time of cancer patients.

Dying scenarios improve recall as much as survival scenarios.

PubMed

Burns, Daniel J; Hart, Joshua; Kramer, Melanie E

2014-01-01

Merely contemplating one's death improves retention for entirely unrelated material learned subsequently. This "dying to remember" effect seems conceptually related to the survival processing effect, whereby processing items for their relevance to being stranded in the grasslands leads to recall superior to that of other deep processing control conditions. The present experiments directly compared survival processing scenarios with "death processing" scenarios. Results showed that when the survival and dying scenarios are closely matched on key dimensions, and possible congruency effects are controlled, the dying and survival scenarios produced equivalently high recall levels. We conclude that the available evidence (cf. Bell, Roer, & Buchner, 2013; Klein, 2012), while not definitive, is consistent with the possibility of overlapping mechanisms.

Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

PubMed

Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G M; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M

2014-01-01

In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53) to 0.63 (95% CI, 0.60-0.66). The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

Evaluating the predictive accuracy and the clinical benefit of a nomogram aimed to predict survival in node-positive prostate cancer patients: External validation on a multi-institutional database.

PubMed

Bianchi, Lorenzo; Schiavina, Riccardo; Borghesi, Marco; Bianchi, Federico Mineo; Briganti, Alberto; Carini, Marco; Terrone, Carlo; Mottrie, Alex; Gacci, Mauro; Gontero, Paolo; Imbimbo, Ciro; Marchioro, Giansilvio; Milanese, Giulio; Mirone, Vincenzo; Montorsi, Francesco; Morgia, Giuseppe; Novara, Giacomo; Porreca, Angelo; Volpe, Alessandro; Brunocilla, Eugenio

2018-04-06

To assess the predictive accuracy and the clinical value of a recent nomogram predicting cancer-specific mortality-free survival after surgery in pN1 prostate cancer patients through an external validation. We evaluated 518 prostate cancer patients treated with radical prostatectomy and pelvic lymph node dissection with evidence of nodal metastases at final pathology, at 10 tertiary centers. External validation was carried out using regression coefficients of the previously published nomogram. The performance characteristics of the model were assessed by quantifying predictive accuracy, according to the area under the curve in the receiver operating characteristic curve and model calibration. Furthermore, we systematically analyzed the specificity, sensitivity, positive predictive value and negative predictive value for each nomogram-derived probability cut-off. Finally, we implemented decision curve analysis, in order to quantify the nomogram's clinical value in routine practice. External validation showed inferior predictive accuracy as referred to in the internal validation (65.8% vs 83.3%, respectively). The discrimination (area under the curve) of the multivariable model was 66.7% (95% CI 60.1-73.0%) by testing with receiver operating characteristic curve analysis. The calibration plot showed an overestimation throughout the range of predicted cancer-specific mortality-free survival rates probabilities. However, in decision curve analysis, the nomogram's use showed a net benefit when compared with the scenarios of treating all patients or none. In an external setting, the nomogram showed inferior predictive accuracy and suboptimal calibration characteristics as compared to that reported in the original population. However, decision curve analysis showed a clinical net benefit, suggesting a clinical implication to correctly manage pN1 prostate cancer patients after surgery. © 2018 The Japanese Urological Association.

A Gene Signature to Determine Metastatic Behavior in Thymomas

PubMed Central

Gökmen-Polar, Yesim; Wilkinson, Jeff; Maetzold, Derek; Stone, John F.; Oelschlager, Kristen M.; Vladislav, Ioan Tudor; Shirar, Kristen L.; Kesler, Kenneth A.; Loehrer, Patrick J.; Badve, Sunil

2013-01-01

Purpose Thymoma represents one of the rarest of all malignancies. Stage and completeness of resection have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour and optimize patient management. Methods qRT-PCR assay for 23 genes (19 test and four reference genes) was performed on multi-institutional archival primary thymomas (n = 36). Gene expression levels were used to compute a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for metastases. The signature was validated in an independent multi-institutional cohort of patients (n = 75). Results A nine-gene signature that can predict metastatic behavior of thymomas was developed and validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasis-free survival rates were 77% and 26% for predicted low (class 1) and high (class 2) risk of metastasis (P = 0.0047, log-rank), respectively. For the validation set, 5-year metastasis-free survival rates were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank), respectively. The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka stages I/II and III/IV (P = 0.0537, log-rank), respectively. In univariate and multivariate Cox models evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the only independent indicator of metastases (P = 0.036). Conclusion A nine-gene signature was established and validated which predicts the likelihood of metastasis more accurately than traditional staging. This further underscores the biologic determinants of the clinical course of thymoma and may improve patient management. PMID:23894276

Contrasting effects of strong ties on SIR and SIS processes in temporal networks

NASA Astrophysics Data System (ADS)

Sun, Kaiyuan; Baronchelli, Andrea; Perra, Nicola

2015-12-01

Most real networks are characterized by connectivity patterns that evolve in time following complex, non-Markovian, dynamics. Here we investigate the impact of this ubiquitous feature by studying the Susceptible-Infected-Recovered (SIR) and Susceptible-Infected-Susceptible (SIS) epidemic models on activity driven networks with and without memory (i.e., Markovian and non-Markovian). We find that memory inhibits the spreading process in SIR models by shifting the epidemic threshold to larger values and reducing the final fraction of recovered nodes. On the contrary, in SIS processes memory reduces the epidemic threshold and, for a wide range of disease parameters, increases the fraction of nodes affected by the disease in the endemic state. The heterogeneity in tie strengths, and the frequent repetition of strong ties it entails, allows in fact less virulent SIS-like diseases to survive in tightly connected local clusters that serve as reservoir for the virus. We validate this picture by studying both processes on two real temporal networks.

Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study.

PubMed

Tang, Xin-Ran; Li, Ying-Qin; Liang, Shao-Bo; Jiang, Wei; Liu, Fang; Ge, Wen-Xiu; Tang, Ling-Long; Mao, Yan-Ping; He, Qing-Mei; Yang, Xiao-Jing; Zhang, Yuan; Wen, Xin; Zhang, Jian; Wang, Ya-Qin; Zhang, Pan-Pan; Sun, Ying; Yun, Jing-Ping; Zeng, Jing; Li, Li; Liu, Li-Zhi; Liu, Na; Ma, Jun

2018-03-01

Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma. In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival. We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p<0·0001), disease-free survival (HR 3·51, 2·43-5·07; p<0·0001), and overall survival (HR 3·22, 2·18-4·76; p<0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status. The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis. The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities. Copyright © 2018 Elsevier Ltd. All rights reserved.

20 CFR 725.214 - Determination of relationship; surviving spouse.

Code of Federal Regulations, 2010 CFR

2010-04-01

... property; or (d) Such individual went through a marriage ceremony with the miner, resulting in a purported marriage between them which, but for a legal impediment (see § 725.230), would have been a valid marriage, unless such individual entered into the purported marriage with knowledge that it was not a valid...

Survival and Self-Descriptive Processing of Abstract and Concrete Nouns

ERIC Educational Resources Information Center

Caldwell, Jennifer

2010-01-01

Researchers have recently described a new processing task in which rating words on the basis of their survival or fitness relevance leads to better recall and recognition performance than several other well known deep processing tasks. The present study was designed to determine whether this survival processing advantage could be observed when…

Adaptive Memory: Evaluating Alternative Forms of Fitness-Relevant Processing in the Survival Processing Paradigm

PubMed Central

Sandry, Joshua; Trafimow, David; Marks, Michael J.; Rice, Stephen

2013-01-01

Memory may have evolved to preserve information processed in terms of its fitness-relevance. Based on the assumption that the human mind comprises different fitness-relevant adaptive mechanisms contributing to survival and reproductive success, we compared alternative fitness-relevant processing scenarios with survival processing. Participants rated words for relevancy to fitness-relevant and control conditions followed by a delay and surprise recall test (Experiment 1a). Participants recalled more words processed for their relevance to a survival situation. We replicated these findings in an online study (Experiment 2) and a study using revised fitness-relevant scenarios (Experiment 3). Across all experiments, we did not find a mnemonic benefit for alternative fitness-relevant processing scenarios, questioning assumptions associated with an evolutionary account of remembering. Based on these results, fitness-relevance seems to be too wide-ranging of a construct to account for the memory findings associated with survival processing. We propose that memory may be hierarchically sensitive to fitness-relevant processing instructions. We encourage future researchers to investigate the underlying mechanisms responsible for survival processing effects and work toward developing a taxonomy of adaptive memory. PMID:23585858

Development of a clinical prediction model to calculate patient life expectancy: the measure of actuarial life expectancy (MALE).

PubMed

Clarke, M G; Kennedy, K P; MacDonagh, R P

2009-01-01

To develop a clinical prediction model enabling the calculation of an individual patient's life expectancy (LE) and survival probability based on age, sex, and comorbidity for use in the joint decision-making process regarding medical treatment. A computer software program was developed with a team of 3 clinicians, 2 professional actuaries, and 2 professional computer programmers. This incorporated statistical spreadsheet and database access design methods. Data sources included life insurance industry actuarial rating factor tables (public and private domain), Government Actuary Department UK life tables, professional actuarial sources, and evidence-based medical literature. The main outcome measures were numerical and graphical display of comorbidity-adjusted LE; 5-, 10-, and 15-year survival probability; in addition to generic UK population LE. Nineteen medical conditions, which impacted significantly on LE in actuarial terms and were commonly encountered in clinical practice, were incorporated in the final model. Numerical and graphical representations of statistical predictions of LE and survival probability were successfully generated for patients with either no comorbidity or a combination of the 19 medical conditions included. Validation and testing, including actuarial peer review, confirmed consistency with the data sources utilized. The evidence-based actuarial data utilized in this computer program design represent a valuable resource for use in the clinical decision-making process, where an accurate objective assessment of patient LE can so often make the difference between patients being offered or denied medical and surgical treatment. Ongoing development to incorporate additional comorbidities and enable Web-based access will enhance its use further.

The effects of healthy aging on the mnemonic benefit of survival processing

PubMed Central

Stillman, Chelsea M.; Coane, Jennifer H.; Profaci, Caterina P.; Howard, James H.; Howard, Darlene V.

2013-01-01

A number of studies have shown that information is remembered better when it is processed for its survival relevance compared to when it is processed for relevance to other, non-survival-related contexts. Here we conducted three experiments to investigate whether the survival advantage also occurs for healthy older adults. In Experiment 1, older and younger adults rated words for their relevance to a grassland survival or moving scenario and then completed an unexpected free recall test on the words. We replicated the survival advantage in two separate groups of younger adults, one of which was placed under divided-attention conditions, but we did not find a survival advantage in the older adults. We then tested two additional samples of older adults using a between- (Experiment 2) or within-subjects (Experiment 3) design, but still found no evidence of the survival advantage in this age group. These results suggest that, although survival processing is an effective encoding strategy for younger adults, it does not provide the same mnemonic benefit to healthy elders. PMID:23896730

Unbiased and automated identification of a circulating tumour cell definition that associates with overall survival.

PubMed

Ligthart, Sjoerd T; Coumans, Frank A W; Attard, Gerhardt; Cassidy, Amy Mulick; de Bono, Johann S; Terstappen, Leon W M M

2011-01-01

Circulating tumour cells (CTC) in patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. Classification of CTC however remains subjective, as they are morphologically heterogeneous. We acquired digital images, using the CellSearch™ system, from blood of 185 castration resistant prostate cancer (CRPC) patients and 68 healthy subjects to define CTC by computer algorithms. Patient survival data was used as the training parameter for the computer to define CTC. The computer-generated CTC definition was validated on a separate CRPC dataset comprising 100 patients. The optimal definition of the computer defined CTC (aCTC) was stricter as compared to the manual CellSearch CTC (mCTC) definition and as a consequence aCTC were less frequent. The computer-generated CTC definition resulted in hazard ratios (HRs) of 2.8 for baseline and 3.9 for follow-up samples, which is comparable to the mCTC definition (baseline HR 2.9, follow-up HR 4.5). Validation resulted in HRs at baseline/follow-up of 3.9/5.4 for computer and 4.8/5.8 for manual definitions. In conclusion, we have defined and validated CTC by clinical outcome using a perfectly reproducing automated algorithm.

Developing and validating a novel metabolic tumor volume risk stratification system for supplementing non-small cell lung cancer staging.

PubMed

Pu, Yonglin; Zhang, James X; Liu, Haiyan; Appelbaum, Daniel; Meng, Jianfeng; Penney, Bill C

2018-06-07

We hypothesized that whole-body metabolic tumor volume (MTVwb) could be used to supplement non-small cell lung cancer (NSCLC) staging due to its independent prognostic value. The goal of this study was to develop and validate a novel MTVwb risk stratification system to supplement NSCLC staging. We performed an IRB-approved retrospective review of 935 patients with NSCLC and FDG-avid tumor divided into modeling and validation cohorts based on the type of PET/CT scanner used for imaging. In addition, sensitivity analysis was conducted by dividing the patient population into two randomized cohorts. Cox regression and Kaplan-Meier survival analyses were performed to determine the prognostic value of the MTVwb risk stratification system. The cut-off values (10.0, 53.4 and 155.0 mL) between the MTVwb quartiles of the modeling cohort were applied to both the modeling and validation cohorts to determine each patient's MTVwb risk stratum. The survival analyses showed that a lower MTVwb risk stratum was associated with better overall survival (all p < 0.01), independent of TNM stage together with other clinical prognostic factors, and the discriminatory power of the MTVwb risk stratification system, as measured by Gönen and Heller's concordance index, was not significantly different from that of TNM stage in both cohorts. Also, the prognostic value of the MTVwb risk stratum was robust in the two randomized cohorts. The discordance rate between the MTVwb risk stratum and TNM stage or substage was 45.1% in the modeling cohort and 50.3% in the validation cohort. This study developed and validated a novel MTVwb risk stratification system, which has prognostic value independent of the TNM stage and other clinical prognostic factors in NSCLC, suggesting that it could be used for further NSCLC pretreatment assessment and for refining treatment decisions in individual patients.

Performance of a Nomogram Predicting Disease-Specific Survival After an R0 Resection for Gastric Cancer in Patients Receiving Postoperative Chemoradiation Therapy

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

Dikken, Johan L.; Department of Surgery, Leiden University Medical Center, Leiden; Coit, Daniel G.

Purpose: The internationally validated Memorial Sloan-Kettering Cancer Center (MSKCC) gastric carcinoma nomogram was based on patients who underwent curative (R0) gastrectomy, without any other therapy. The purpose of the current study was to assess the performance of this gastric cancer nomogram in patients who received chemoradiation therapy after an R0 resection for gastric cancer. Methods and Materials: In a combined dataset of 76 patients from the Netherlands Cancer Institute (NKI), and 63 patients from MSKCC, who received postoperative chemoradiation therapy (CRT) after an R0 gastrectomy, the nomogram was validated by means of the concordance index (CI) and a calibration plot. Results:more » The concordance index for the nomogram was 0.64, which was lower than the CI of the nomogram for patients who received no adjuvant therapy (0.80). In the calibration plot, observed survival was approximately 20% higher than the nomogram-predicted survival for patients receiving postoperative CRT. Conclusions: The MSKCC gastric carcinoma nomogram significantly underpredicted survival for patients in the current study, suggesting an impact of postoperative CRT on survival in patients who underwent an R0 resection for gastric cancer, which has been demonstrated by randomized controlled trials. This analysis stresses the need for updating nomograms with the incorporation of multimodal strategies.« less

Integrated multigene expression panel to prognosticate patients with gastric cancer.

PubMed

Kanda, Mitsuro; Murotani, Kenta; Tanaka, Haruyoshi; Miwa, Takashi; Umeda, Shinichi; Tanaka, Chie; Kobayashi, Daisuke; Hayashi, Masamichi; Hattori, Norifumi; Suenaga, Masaya; Yamada, Suguru; Nakayama, Goro; Fujiwara, Michitaka; Kodera, Yasuhiro

2018-04-10

Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C-index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506-0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents ( MAGED2, SYT8, BTG1 , and FAM46 ) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1-3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer.

Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models.

PubMed

Vermaat, J S; van der Tweel, I; Mehra, N; Sleijfer, S; Haanen, J B; Roodhart, J M; Engwegen, J Y; Korse, C M; Langenberg, M H; Kruit, W; Groenewegen, G; Giles, R H; Schellens, J H; Beijnen, J H; Voest, E E

2010-07-01

In metastatic renal cell cancer (mRCC), the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model is widely used for clinical trial design and patient management. To improve prognostication, we applied proteomics to identify novel serological proteins associated with overall survival (OS). Sera from 114 mRCC patients were screened by surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Identified proteins were related to OS. Three proteins were subsequently validated with enzyme-linked immunosorbent assays and immunoturbidimetry. Prognostic models were statistically bootstrapped to correct for overestimation. SELDI-TOF MS detected 10 proteins associated with OS. Of these, apolipoprotein A2 (ApoA2), serum amyloid alpha (SAA) and transthyretin were validated for their association with OS (P = 5.5 x 10(-9), P = 1.1 x 10(-7) and P = 0.0004, respectively). Combining ApoA2 and SAA yielded a prognostic two-protein signature [Akaike's Information Criteria (AIC) = 732, P = 5.2 x 10(-7)]. Including previously identified prognostic factors, multivariable Cox regression analysis revealed ApoA2, SAA, lactate dehydrogenase, performance status and number of metastasis sites as independent factors for survival. Using these five factors, categorization of patients into three risk groups generated a novel protein-based model predicting patient prognosis (AIC = 713, P = 4.3 x 10(-11)) more robustly than the MSKCC model (AIC = 729, P = 1.3 x 10(-7)). Applying this protein-based model instead of the MSKCC model would have changed the risk group in 38% of the patients. Proteomics and subsequent validation yielded two novel prognostic markers and survival models which improved prediction of OS in mRCC patients over commonly used risk models. Implementation of these models has the potential to improve current risk stratification, although prospective validation will still be necessary.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach.

PubMed

Scheidegger, Stephan; Fuchs, Hans U; Zaugg, Kathrin; Bodis, Stephan; Füchslin, Rudolf M

2013-01-01

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

Adaptive memory: determining the proximate mechanisms responsible for the memorial advantages of survival processing.

PubMed

Burns, Daniel J; Burns, Sarah A; Hwang, Ana J

2011-01-01

J. S. Nairne, S. R. Thompson, and J. N. S. Pandeirada (2007) suggested that our memory systems may have evolved to help us remember fitness-relevant information and showed that retention of words rated for their relevance to survival is superior to that of words encoded under other deep processing conditions. The authors present 4 experiments that uncover the proximate mechanisms likely responsible. The authors obtained a recall advantage for survival processing compared with conditions that promoted only item-specific processing or only relational processing. This effect was eliminated when control conditions encouraged both item-specific and relational processing. Data from separate measures of item-specific and relational processing generally were consistent with the view that the memorial advantage for survival processing results from the encoding of both types of processing. Although the present study suggests the proximate mechanisms for the effect, the authors argue that survival processing may be fundamentally different from other memory phenomena for which item-specific and relational processing differences have been implicated. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Adaptive Memory: Is Survival Processing Special?

ERIC Educational Resources Information Center

Nairne, James S.; Pandeirada, Josefa N. S.

2008-01-01

Do the operating characteristics of memory continue to bear the imprints of ancestral selection pressures? Previous work in our laboratory has shown that human memory may be specially tuned to retain information processed in terms of its survival relevance. A few seconds of survival processing in an incidental learning context can produce recall…

Adaptive memory: the survival-processing memory advantage is not due to negativity or mortality salience.

PubMed

Bell, Raoul; Röer, Jan P; Buchner, Axel

2013-05-01

Recent research has highlighted the adaptive function of memory by showing that imagining being stranded in the grasslands without any survival material and rating words according to their survival value in this situation leads to exceptionally good memory for these words. Studies examining the role of emotions in causing the survival-processing memory advantage have been inconclusive, but some studies have suggested that the effect might be due to negativity or mortality salience. In Experiments 1 and 2, we compared the survival scenario to a control scenario that implied imagining a hopeless situation (floating in outer space with dwindling oxygen supplies) in which only suicide can avoid the agony of choking to death. Although this scenario was perceived as being more negative than the survival scenario, the survival-processing memory advantage persisted. In Experiment 3, thinking about the relevance of words for survival led to better memory for these words than did thinking about the relevance of words for death. This survival advantage was found for concrete, but not for abstract, words. The latter finding is consistent with the assumption that the survival instructions encourage participants to think about many different potential uses of items to aid survival, which may be a particularly efficient form of elaborate encoding. Together, the results suggest that thinking about death is much less effective in promoting recall than is thinking about survival. Therefore, the survival-processing memory advantage cannot be satisfactorily explained by negativity or mortality salience.

Comment on 'Are survival rates for northern spotted owls biased?'

USGS Publications Warehouse

Franklin, A.B.; Nichols, J.D.; Anthony, R.G.; Burnham, K.P.; White, Gary C.; Forsman, E.D.; Anderson, D.R.

2006-01-01

Loehle et al. recently estimated survival rates from radio-telemetered northern spotted owls (Strix occidentalis caurina (Merriam, 1898)) and suggested that survival rates estimated for this species from capture-recapture studies were negatively biased, which subsequently resulted in the negatively biased estimates of rates of population change (lambda) reported by Anthony et al. (Wildl. Monogr. No. 163, pp. 1-47 (2006)). We argue that their survival estimates were inappropriate for comparison with capture-recapture estimates because (i) the manner in which they censored radio-telemetered individuals had the potential to positively bias their survival estimates, (ii) their estimates of survival were not valid for evaluating bias, and (iii) the size and distribution of their radiotelemetry study areas were sufficiently different from capture-recapture study areas to preclude comparisons. In addition, their inferences of negative bias in rates of population change estimated by Anthony et al. were incorrect and reflected a misunderstanding about those estimators.

Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.

PubMed

Hemdan, Tammer; Malmström, Per-Uno; Jahnson, Staffan; Segersten, Ulrika

2015-12-01

Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response. Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry. Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p<0.001). The values for cancer specific survival were 76% and 56%, respectively (p<0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p=0.23) or cancer specific survival (55% vs 51%, p=0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials. Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Targeting signal transduction in pancreatic cancer treatment.

PubMed

Yeh, Jen Jen; Der, Channing J

2007-05-01

Pancreatic cancer is a lethal disease with a 5-year survival rate of 4%. The only opportunity for improved survival continues to be complete surgical resection for those with localized disease. Although chemotherapeutic options are limited for the few patients with resectable disease, this problem is even more magnified in the majority (85%) of patients with unresectable or metastastic disease. Therefore, there is an urgent need for improved therapeutic options. The recent success of inhibitors of signal transduction for the treatment of other cancers supports the need to identify and validate aberrant signaling pathways important for pancreatic tumor growth. This review focuses on the validation of specific signaling networks and the present status of inhibitors of these pathways as therapeutic approaches for pancreatic cancer treatment.

The future-orientation of memory: Planning as a key component mediating the high levels of recall found with survival processing

PubMed Central

Klein, Stanley B.; Robertson, Theresa E.; Delton, Andrew W.

2013-01-01

In a series of papers, Nairne and colleagues have demonstrated that tasks encouraging participants to judge words for relevance to survival led to better recall than did tasks lacking survival relevance. Klein, Robertson, and Delton (2010) presented data suggesting that the future-directed temporal orientation of the survival task (e.g., planning), rather than survival per se, accounts for the good recall found with the task. In the present studies we manipulated the amount of survival and planning processing encouraged by a set of encoding tasks. Participants performed tasks that encouraged processing stimuli for their relevance to (a) both survival and planning, (b) planning, but not survival, or (c) survival but not planning. We predicted, and found, that recall performance associated with tasks encouraging planning (i.e., survival with planning and planning without survival) should exceed tasks that encouraged survival but not planning (i.e., survival without planning). We draw several conclusions. First, planning is a necessary component of the superior recall found in the survival paradigm. Second, memory, from an evolutionary perspective, is inherently prospective—tailored by natural selection to support future decisions and judgements that cannot be known in advance with certainty. PMID:21229456

Predicting Survival of De Novo Metastatic Breast Cancer in Asian Women: Systematic Review and Validation Study

PubMed Central

Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G. M.; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M.

2014-01-01

Background In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. Materials and Methods We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). Results We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48–0.53) to 0.63 (95% CI, 0.60–0.66). Conclusion The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making. PMID:24695692

Constraints and Approach for Selecting the Mars Surveyor '01 Landing Site

NASA Technical Reports Server (NTRS)

Golombek, M.; Bridges, N.; Gilmore, M.; Haldemann, A.; Parker, T.; Saunders, R.; Spencer, D.; Smith, J.; Weitz, C.

1999-01-01

There are many similarities between the Mars Surveyor '01 (MS '01) landing site selection process and that of Mars Pathfinder. The selection process includes two parallel activities in which engineers define and refine the capabilities of the spacecraft through design, testing and modeling and scientists define a set of landing site constraints based on the spacecraft design and landing scenario. As for Pathfinder, the safety of the site is without question the single most important factor, for the simple reason that failure to land safely yields no science and exposes the mission and program to considerable risk. The selection process must be thorough and defensible and capable of surviving multiple withering reviews similar to the Pathfinder decision. On Pathfinder, this was accomplished by attempting to understand the surface properties of sites using available remote sensing data sets and models based on them. Science objectives are factored into the selection process only after the safety of the site is validated. Finally, as for Pathfinder, the selection process is being done in an open environment with multiple opportunities for community involvement including open workshops, with education and outreach opportunities.

Constraints, Approach and Present Status for Selecting the Mars Surveyor 2001 Landing Site

NASA Technical Reports Server (NTRS)

Golombek, M.; Anderson, F.; Bridges, N.; Briggs, G.; Gilmore, M.; Gulick, V.; Haldemann, A.; Parker, T.; Saunders, R.; Spencer, D.;

Development of comprehensive nomograms for evaluating overall and cancer-specific survival of laryngeal squamous cell carcinoma patients treated with neck dissection

PubMed Central

Shi, Xiao; Hu, Wei-ping; Ji, Qing-hai

2017-01-01

Background Neck dissection for laryngeal squamous cell carcinoma (LSCC) patients could provide complementary prognostic information for AJCC N staging, like lymph node ratio (LNR). The aim of this study was to develop effective nomograms to better predict survival for LSCC patients treated with neck dissection. Results 2752 patients were identified and randomly divided into training (n = 2477) and validation (n = 275) cohorts. The 3- and 5-year probabilities of cancer-specific mortality (CSM) were 30.1% and 37.2% while 3- and 5-year death resulting from other causes (DROC) rate were 6.2% and 11.3%, respectively. 13 significant prognostic factors including LNR for overall (OS) and 12 (except race) for CSS were enrolled in the nomograms. Concordance index as a commonly used indicator of predictive performance, showed the nomograms had superiority over the no-LNR models and TNM classification (Training-cohort: OS: 0.713 vs 0.703 vs 0.667, CSS: 0.725 vs 0.713 vs 0.688; Validation-cohort: OS: 0.704 vs 0.690 vs 0.658, cancer-specific survival (CSS): 0.709 vs 0.693 vs 0.672). All calibration plots revealed good agreement between nomogram prediction and actual survival. Materials and Methods We identified LSCC patients undergoing neck dissection diagnosed between 1988 and 2008 from Surveillance, Epidemiology, and End Results (SEER) database. Optimal cutoff points were determined by X-tile program. Cumulative incidence function was used to analyze cancer-specific mortality (CSM) and death resulting from other causes (DROC). Significant predictive factors were used to establish nomograms estimating overall (OS) and cancer-specific survival (CSS). The nomograms were bootstrapped validated both internally and externally. Conclusions Comprehensive nomograms were constructed to predict OS and CSS for LSCC patients treated with neck dissection more accurately. PMID:28430613

Applications of the Galton Watson process to human DNA evolution and demography

NASA Astrophysics Data System (ADS)

Neves, Armando G. M.; Moreira, Carlos H. C.

2006-08-01

We show that the problem of existence of a mitochondrial Eve can be understood as an application of the Galton-Watson process and presents interesting analogies with critical phenomena in Statistical Mechanics. In the approximation of small survival probability, and assuming limited progeny, we are able to find for a genealogic tree the maximum and minimum survival probabilities over all probability distributions for the number of children per woman constrained to a given mean. As a consequence, we can relate existence of a mitochondrial Eve to quantitative demographic data of early mankind. In particular, we show that a mitochondrial Eve may exist even in an exponentially growing population, provided that the mean number of children per woman Nbar is constrained to a small range depending on the probability p that a child is a female. Assuming that the value p≈0.488 valid nowadays has remained fixed for thousands of generations, the range where a mitochondrial Eve occurs with sizeable probability is 2.0492

Using Loop Heat Pipes to Minimize Survival Heater Power for NASA's Evolutionary Xenon Thruster Power Processing Units

NASA Technical Reports Server (NTRS)

Choi, Michael K.

2017-01-01

A thermal design concept of using propylene loop heat pipes to minimize survival heater power for NASA's Evolutionary Xenon Thruster power processing units is presented. It reduces the survival heater power from 183 W to 35 W per power processing unit. The reduction is 81%.

Vulnerabilities in Older Patients when Cancer Treatment is Initiated: Does a Cognitive Impairment Impact the Two-Year Survival?

PubMed Central

Borghgraef, Cindy; Etienne, Anne-Marie; Merckaert, Isabelle; Paesmans, Marianne; Reynaert, Christine; Roos, Myriam; Slachmuylder, Jean-Louis; Vandenbossche, Sandrine; Bron, Dominique; Razavi, Darius

2016-01-01

Introduction Dementia is a known predictor of shorter survival times in older cancer patients. However, no empirical evidence is available to determine how much a cognitive impairment shortens survival in older patients when cancer treatment is initiated. Purpose To longitudinally investigate how much a cognitive impairment detected at the initiation of cancer treatment influences survival of older patients during a two-year follow-up duration and to compare the predictive value of a cognitive impairment on patients survival with the predictive value of other vulnerabilities associated with older age. Methods Three hundred and fifty-seven consecutive patients (≥65 years old) admitted for breast, prostate, or colorectal cancer surgeries were prospectively recruited. A cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA<26). Socio-demographic, disease-related, and geriatric vulnerabilities were assessed using validated tools. Univariate and subsequent multivariate Cox proportional hazards models stratified for diagnosis (breast/prostate cancer versus colorectal cancer) and disease status (metastatic versus non-metastatic) were used. Results A cognitive impairment was detected in 46% (n = 163) of patients. Survival was significantly influenced by a cognitive impairment (HR = 6.13; 95% confidence interval [CI] = 2.07–18.09; p = 0.001), a loss in instrumental autonomy (IADL ≤7) (HR = 3.06; 95% CI = 1.31–7.11; p = 0.009) and fatigue (Mob-T<5) (HR = 5.98; 95% CI = 2.47–14.44; p <0.001). Conclusions During the two years following cancer treatment initiation, older patients with a cognitive impairment were up to six times more likely to die than patients without. Older patients should be screened for cognitive impairments at cancer treatment initiation to enable interventions to reduce morbidity and mortality. Further studies should address processes underlying the relationship between cognitive impairments and an increased risk of dying in older cancer patients. PMID:27479248

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology.

PubMed

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types.

Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value

PubMed Central

Walker, Michael J.; Zhou, Cong; Backen, Alison; Pernemalm, Maria; Williamson, Andrew J.K.; Priest, Lynsey J.C.; Koh, Pek; Faivre-Finn, Corinne; Blackhall, Fiona H.; Dive, Caroline; Whetton, Anthony D.

2015-01-01

Lung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived > 18 mo were compared to the same time points from patients who survived < 14 mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment. PMID:26425690

Integrated production of lactic acid and biomass on distillery stillage.

PubMed

Djukić-Vuković, Aleksandra P; Mojović, Ljiljana V; Vukašinović-Sekulić, Maja S; Nikolić, Svetlana B; Pejin, Jelena D

2013-09-01

The possibilities of parallel lactic acid and biomass production in batch and fed-batch fermentation on distillery stillage from bioethanol production were studied. The highest lactic acid yield and productivity of 92.3 % and 1.49 g L(-1) h(-1) were achieved in batch fermentation with initial sugar concentration of 55 g L(-1). A significant improvement of the process was achieved in fed-batch fermentation where the concentration of lactic acid was increased to 47.6 % and volumetric productivity for 21 % over the batch process. A high number of Lactobacillus rhamnosus ATCC 7469 viable cells of 10(9) CFU ml(-1) was attained at the end of fed-batch fermentation. The survival of 92.9 % of L. rhamnosus cells after 3 h of incubation at pH 2.5 validated that the fermentation media remained after lactic acid removal could be used as a biomass-enriched animal feed thus making an additional value to the process.

Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer.

PubMed

Zhang, Heng; Liu, Hao; Shen, Zhenbin; Lin, Chao; Wang, Xuefei; Qin, Jing; Qin, Xinyu; Xu, Jiejie; Sun, Yihong

2018-02-01

This study was aimed to investigate the prognostic value of tumor-infiltrating neutrophils (TINs) and to generate a predictive model to refine postoperative risk stratification system for patients with gastric cancer. TIN presents in various malignant tumors, but its clinical significance in gastric cancer remains obscure. The study enrolled 3 independent sets of patients with gastric cancer from 2 institutional medical centers of China. TIN was estimated by immunohistochemical staining of CD66b, and its relationship with clinicopathological features and clinical outcomes were evaluated. Prognostic accuracies were evaluated by C-index and Akaike information criterion. TINs in gastric cancer tissues ranged from 0 to 192 cells/high magnification filed (HPF), 0 to 117 cells/HPF, and 0 to 142 cells/HPF in the training, testing, and validation sets, respectively. TINs were negatively correlated with lymph node classification (P = 0.007, P = 0.041, and P = 0.032, respectively) and tumor stage (P = 0.019, P = 0.013, and P = 0.025, respectively) in the 3 sets. Moreover, multivariate analysis identified TINs and tumor node metastasis (TNM) stage as 2 independent prognostic factors for overall survival. Incorporation of TINs into well-established TNM system generated a predictive model that shows better predictive accuracy for overall survival. More importantly, patients with higher TINs were prone to overall survival benefit from postoperative adjuvant chemotherapy. These results were validated in the independent testing and validation sets. TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer.

Validation and application of a death proxy in adult cancer patients.

PubMed

Mealing, Nicole M; Dobbins, Timothy A; Pearson, Sallie-Anne

2012-07-01

PURPOSE: Fact of death is not always available on data sets used for pharmacoepidemiological research. Proxies may be an appropriate substitute in the absence of death data. The purposes of this study were to validate a proxy for death in adult cancer patients and to assess its performance when estimating survival in two cohorts of cancer patients. METHODS: We evaluated 30-, 60-, 90- and 180-day proxies overall and by cancer type using data from 12 394 Australian veterans with lung, colorectal, breast or prostate cancer. The proxy indicated death if the difference between the last dispensing record and the end of the observational period exceeded the proxy cutoff. We then compared actual survival to 90-day proxy estimates in a subset of 4090 veterans with 'full entitlements' for pharmaceutical items and in 3704 Australian women receiving trastuzumab for HER2+ metastatic breast cancer. RESULTS: The 90-day proxy was optimal with an overall sensitivity of 99.3% (95%CI: 98.4-99.7) and a specificity of 97.6% (95%CI: 91.8-99.4). These measures remained high when evaluated by cancer type and spread of disease. The application of the proxy using the most conservative date of death estimate (date of last dispensing) generally underestimated survival, with estimates up to 3 months shorter than survival based on fact of death. CONCLUSIONS: A 90-day death proxy is a robust substitute to identify death in a chronic population when fact of death is not available. The proxy is likely to be valid across a range of chronic diseases as it relies on the presence of 'regular' dispensing records for individual patients. Copyright © 2011 John Wiley & Sons, Ltd. Copyright © 2011 John Wiley & Sons, Ltd.

A Validation Study of the Rank-Preserving Structural Failure Time Model: Confidence Intervals and Unique, Multiple, and Erroneous Solutions.

PubMed

Ouwens, Mario; Hauch, Ole; Franzén, Stefan

2018-05-01

The rank-preserving structural failure time model (RPSFTM) is used for health technology assessment submissions to adjust for switching patients from reference to investigational treatment in cancer trials. It uses counterfactual survival (survival when only reference treatment would have been used) and assumes that, at randomization, the counterfactual survival distribution for the investigational and reference arms is identical. Previous validation reports have assumed that patients in the investigational treatment arm stay on therapy throughout the study period. To evaluate the validity of the RPSFTM at various levels of crossover in situations in which patients are taken off the investigational drug in the investigational arm. The RPSFTM was applied to simulated datasets differing in percentage of patients switching, time of switching, underlying acceleration factor, and number of patients, using exponential distributions for the time on investigational and reference treatment. There were multiple scenarios in which two solutions were found: one corresponding to identical counterfactual distributions, and the other to two different crossing counterfactual distributions. The same was found for the hazard ratio (HR). Unique solutions were observed only when switching patients were on investigational treatment for <40% of the time that patients in the investigational arm were on treatment. Distributions other than exponential could have been used for time on treatment. An HR equal to 1 is a necessary but not always sufficient condition to indicate acceleration factors associated with equal counterfactual survival. Further assessment to distinguish crossing counterfactual curves from equal counterfactual curves is especially needed when the time that switchers stay on investigational treatment is relatively long compared to the time direct starters stay on investigational treatment.

[Current knowledge on perioperative treatments of non-small cell lung carcinomas].

PubMed

Brosseau, S; Naltet, C; Nguenang, M; Gounant, V; Mordant, P; Milleron, B; Castier, Y; Zalcman, G

2017-06-01

Surgery is still the main treatment in early-stage of non-small cell lung cancer with 5-year survival of stage IA patients exceeding 80%, but 5-year survival of stage II patients rapidly decreasing with tumor size, N status, and visceral pleura invasion. The major metastatic risk in such patients has supported clinical research assessing systemic or loco-regional perioperative treatments. Modern phase 3 trials clearly validated adjuvant or neo-adjuvant platinum-based chemotherapy in resected stage I-III patients as a standard treatment of which value has been reassessed several independent meta-analyses, showing a 5% benefit in 5y-survival, and a decrease of the relative risk for death around from 12 to 25%. Conversely perioperative treatments were not validated for stage IA and IB patients. In more advanced stage patients, neo-adjuvant radio-chemotherapy has not been validated either. Adjuvant radiotherapy for N2 patients is currently tested in the large international phase 3 trial Lung-ART/IFCT-0503. The development of video-assisted thoracic surgery (VATS) has helped adjuvant chemotherapies for elderly patients. Perioperative targeted treatments in NSCLC with EGFR or ALK molecular alterations is currently assessed in the U.S. ALCHEMIST prospective trial. Finally, the role of immune check-points inhibitors is currently evaluated in a large international phase 3 trial testing adjuvant anti-PD-L1 monoclonal antibody, the BR31/IFCT-1401 trial, while a proof-of principle neo-adjuvant trial IONESCO/IFCT-1601, has just begun by the end of the 2016 year, with survival results of both trials expected in 5 to 7 years. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant

PubMed Central

Karaesmen, Ezgi; Rizvi, Abbas A.; Preus, Leah M.; McCarthy, Philip L.; Pasquini, Marcelo C.; Onel, Kenan; Zhu, Xiaochun; Spellman, Stephen; Haiman, Christopher A.; Stram, Daniel O.; Pooler, Loreall; Sheng, Xin; Zhu, Qianqian; Yan, Li; Liu, Qian; Hu, Qiang; Webb, Amy; Brock, Guy; Clay-Gilmour, Alyssa I.; Battaglia, Sebastiano; Tritchler, David; Liu, Song; Hahn, Theresa

2017-01-01

Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at P < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at P < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at P < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes. PMID:28811306

External validation of leukocytosis and neutrophilia as a prognostic marker in anal carcinoma treated with definitive chemoradiation.

PubMed

Schernberg, Antoine; Huguet, Florence; Moureau-Zabotto, Laurence; Chargari, Cyrus; Rivin Del Campo, Eleonor; Schlienger, Michel; Escande, Alexandre; Touboul, Emmanuel; Deutsch, Eric

2017-07-01

To validate the prognostic value of leukocyte disorders in anal squamous cell carcinoma (SCC) patients receiving definitive concurrent chemoradiation. Bi-institutional clinical records from consecutive patients treated between 2001 and 2015 with definitive chemoradiation for anal SCC were retrospectively reviewed. Prognostic value of pretreatment leukocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as leukocyte or neutrophil count exceeding 10G/L and 7G/L, respectively. We identified 133 patients, treated in two institutions. Eight% and 7% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year overall survival (OS) and progression-free survival (PFS) were 88% and 77%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS (p<0.01), locoregional control (LRC) and Distant Metastasis Control (DMC) (p<0.05), also after stratification by each institution. In multivariate analysis, leukocytosis and neutrophilia remained as independent risk factors associated with poorer OS, PFS, LRC and DMC (p<0.05). This study validates leukocytosis and neutrophilia as independent prognostic factors in anal SCC patients treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters are clinically relevant biomarkers to be considered for further clinical investigations. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of age on survival benefit of adjuvant chemotherapy in elderly patients with Stage III colon cancer.

PubMed

Zuckerman, Ilene H; Rapp, Thomas; Onukwugha, Ebere; Davidoff, Amy; Choti, Michael A; Gardner, James; Seal, Brian; Mullins, C Daniel

2009-08-01

To estimate the modifying effect of age on the survival benefit associated with adjuvant chemotherapy receipt in elderly patients with a diagnosis of Stage III colon cancer. Observational, retrospective cohort study using two samples: an overall sample of 7,182 patients to provide externally valid analyses and a propensity score-matched sample of 3,016 patients to provide more internally valid analyses by reducing the presence of treatment endogeneity. An interval-censored survival model with a complementary log-log link was used. Hazard ratios and 95% confidence intervals were obtained for all regressions. Data from the National Cancer Institute's Surveillance, Epidemiology and End Results database and the linked Medicare enrollment and claims database were used. Selected patients were aged 66 and older and had a diagnosis of Stage III colon cancer. Patients were followed from surgery to time of death or censorship. The outcome was colon cancer-specific death during the follow-up period. Receipt of adjuvant chemotherapy was measured according to the presence of a claim for 5-fluorouracil or leucovorin within 6 months after surgery. All elderly patients had a significant survival benefit associated with adjuvant chemotherapy receipt, although the survival benefit of adjuvant chemotherapy was not uniform across all age groups. These findings have important clinical and policy implications for the risk-benefit calculation induced by treatment in older patients with Stage III colon cancer. The results suggest that there is a benefit from chemotherapy, but the benefit is lower with older age.

Infrared radiation and stealth characteristics prediction for supersonic aircraft with uncertainty

NASA Astrophysics Data System (ADS)

Pan, Xiaoying; Wang, Xiaojun; Wang, Ruixing; Wang, Lei

2015-11-01

The infrared radiation (IR) intensity is generally used to embody the stealth characteristics of a supersonic aircraft, which directly affects its survivability in warfare. Under such circumstances, the research on IR signature as an important branch of stealth technology is significant to overcome this threat for survivability enhancement. Considering the existence of uncertainties in material and environment, the IR intensity is indeed a range rather than a specific value. In this paper, subjected to the properties of the IR, an analytic process containing the uncertainty propagation and the reliability evaluation is investigated when taking into account that the temperature of object, the atmospheric transmittance and the spectral emissivity of materials are all regarded as uncertain parameters. For one thing, the vertex method is used to analyze and estimate the dispersion of IR intensity; for another, the safety assessment of the stealth performance for aircraft is conducted by non-probabilistic reliability analysis. For the purpose of the comparison and verification, the Monte Carlo simulation is discussed as well. The validity, usage, and efficiency of the developed methodology are demonstrated by two application examples eventually.

Assessing the utility of cancer-registry-processed cause of death in calculating cancer-specific survival.

PubMed

Hu, Chung-Yuan; Xing, Yan; Cormier, Janice N; Chang, George J

2013-05-15

Cancer registries use algorithms to process cause of death (COD) data from death certificates, but uncertainties remain regarding the accuracy and utility of those data in calculating cancer-specific survival (CSS). Because it is impractical to reconfirm the COD through meticulous review of the primary medical records, the observed cancer deaths could be compared with the number of attributed deaths, as estimated by using a relative survival (RS) approach, to determine utility in CSS estimation. Six major cancer types were evaluated using Surveillance, Epidemiology, and End Results (SEER) data (1988-1999 cohort). The COD utility was quantified by using the observed-to-expected ratio (O/E ratio) approach, which was calculated as the SEER-documented observed number of cancer-specific deaths divided by the number of expected deaths attributed to the malignancies as estimated using a RS approach. Favorable utility would have an O/E ratio close to 1. In total, 338,445 patients were identified; and their O/E ratios were 0.97, 0.98, 0.90, 1.07, 1.02, and 0.92 for breast, colorectal, lung, melanoma, prostate, and pancreas cancer, respectively. O/E ratios varied slightly with patients' age, race, and tumor stage, but not by sex. CSS for patients with lung cancer appeared to be overestimated considerably. Patients with multiple cancer diagnoses had poor O/E ratios compared with those who had only 1 cancer. The utility of COD in calculating CSS depended variously on the risk of cancer-related mortality and nontumor factors. However, the impact of this variation on CSS generally was small. The current results indicated that the COD assigned by cancer registries has acceptable validity, and CSS is considered an acceptable surrogate for RS in most circumstances. Copyright © 2013 American Cancer Society.

FGFR3, as a receptor tyrosine kinase, is associated with differentiated biological functions and improved survival of glioma patients.

PubMed

Wang, Zheng; Zhang, Chuanbao; Sun, Lihua; Liang, Jingshan; Liu, Xing; Li, Guanzhang; Yao, Kun; Zhang, Wei; Jiang, Tao

2016-12-20

Activation of receptor tyrosine kinases is common in Malignancies. FGFR3 fusion with TACC3 has been reported to have transforming effects in primary glioblastoma and display oncogenic activity in vitro and in vivo. We set out to investigate the role of FGFR3 in glioma through transcriptomic analysis. FGFR3 increased in Classical subtype and Neural subtype consistently in CGGA and TCGA cohort. Similar patterns of FGFR3 distribution through subtypes were observed in CGGA and TCGA samples. Gene ontology analysis was performed with genes that were significantly correlated with FGFR3 expression. We found that positively associated biological processes of FGFR3 were focused on differentiated cellular functions and neuronal activities, while negatively correlated biological processes focused on mitosis and cell cycle phase. Clinical investigation showed that higher FGFR3 expression predicted improved survival for glioma patients, especially in Proneural subtype. Moreover, FGFR3 showed very limited relevance with other receptor tyrosine kinases in glioma at transcriptome level. FGFR3 expression data of glioma was obtained from Chinese Glioma Genome Atlas (CGGA) and TCGA (The Cancer Genome Atlas). In total, RNA sequencing data of 325 glioma samples and mRNA microarray data of 301 samples from CGGA dataset were enrolled into this study. To consolidate the findings that we have revealed in CGGA dataset, RNA-seq data of 672 glioma samples from TCGA dataset were used as a validation cohort. R language was used as the main tool to perform statistical analysis and graphical work. FGFR3 expression increased in classical and neural subtypes and was associated with differentiated cellular functions. FGFR3 showed very limited correlation with other common receptor tyrosine kinases, and predicted improved survival for glioma patients.

FGFR3, as a receptor tyrosine kinase, is associated with differentiated biological functions and improved survival of glioma patients

PubMed Central

Wang, Zheng; Zhang, Chuanbao; Sun, Lihua; Liang, Jingshan; Liu, Xing; Li, Guanzhang; Yao, Kun; Zhang, Wei; Jiang, Tao

2016-01-01

Background Activation of receptor tyrosine kinases is common in Malignancies. FGFR3 fusion with TACC3 has been reported to have transforming effects in primary glioblastoma and display oncogenic activity in vitro and in vivo. We set out to investigate the role of FGFR3 in glioma through transcriptomic analysis. Results FGFR3 increased in Classical subtype and Neural subtype consistently in CGGA and TCGA cohort. Similar patterns of FGFR3 distribution through subtypes were observed in CGGA and TCGA samples. Gene ontology analysis was performed with genes that were significantly correlated with FGFR3 expression. We found that positively associated biological processes of FGFR3 were focused on differentiated cellular functions and neuronal activities, while negatively correlated biological processes focused on mitosis and cell cycle phase. Clinical investigation showed that higher FGFR3 expression predicted improved survival for glioma patients, especially in Proneural subtype. Moreover, FGFR3 showed very limited relevance with other receptor tyrosine kinases in glioma at transcriptome level. Materials and Methods FGFR3 expression data of glioma was obtained from Chinese Glioma Genome Atlas (CGGA) and TCGA (The Cancer Genome Atlas). In total, RNA sequencing data of 325 glioma samples and mRNA microarray data of 301 samples from CGGA dataset were enrolled into this study. To consolidate the findings that we have revealed in CGGA dataset, RNA-seq data of 672 glioma samples from TCGA dataset were used as a validation cohort. R language was used as the main tool to perform statistical analysis and graphical work. Conclusions FGFR3 expression increased in classical and neural subtypes and was associated with differentiated cellular functions. FGFR3 showed very limited correlation with other common receptor tyrosine kinases, and predicted improved survival for glioma patients. PMID:27829236

Kidney transplantation process in Brazil represented in business process modeling notation.

PubMed

Peres Penteado, A; Molina Cohrs, F; Diniz Hummel, A; Erbs, J; Maciel, R F; Feijó Ortolani, C L; de Aguiar Roza, B; Torres Pisa, I

2015-05-01

Kidney transplantation is considered to be the best treatment for people with chronic kidney failure, because it improves the patients' quality of life and increases their length of survival compared with patients undergoing dialysis. The kidney transplantation process in Brazil is defined through laws, decrees, ordinances, and resolutions, but there is no visual representation of this process. The aim of this study was to analyze official documents to construct a representation of the kidney transplantation process in Brazil with the use of business process modeling notation (BPMN). The methodology for this study was based on an exploratory observational study, document analysis, and construction of process diagrams with the use of BPMN. Two rounds of validations by specialists were conducted. The result includes the kidney transplantation process in Brazil representation with the use of BPMN. We analyzed 2 digital documents that resulted in 2 processes with 45 total of activities and events, 6 organizations involved, and 6 different stages of the process. The constructed representation makes it easier to understand the rules for the business of kidney transplantation and can be used by the health care professionals involved in the various activities within this process. Construction of a representation with language appropriate for the Brazilian lay public is underway. Copyright © 2015 Elsevier Inc. All rights reserved.

Pancreas retransplantation: a second chance for diabetic patients?

PubMed

Buron, Fanny; Thaunat, Olivier; Demuylder-Mischler, Sandrine; Badet, Lionel; Brunet, Maria; Ber, Charles-Eric; Thivolet, Charles; Martin, Xavier; Berney, Thierry; Morelon, Emmanuel

2013-01-27

If pancreas transplantation is a validated alternative for type 1 diabetic patients with end-stage renal disease, the management of patients who have lost their primary graft is poorly defined. This study aims at evaluating pancreas retransplantation outcome. Between 1976 and 2008, 569 pancreas transplantations were performed in Lyon and Geneva, including 37 second transplantations. Second graft survival was compared with primary graft survival of the same patients and the whole population. Predictive factors of second graft survival were sought. Patient survival and impact on kidney graft function and survival were evaluated. Second pancreas survival of the 17 patients transplanted from 1995 was close to primary graft survival of the whole population (71% vs. 79% at 1 year and 59% vs. 69% at 5 years; P=0.5075) and significantly better than their first pancreas survival (71% vs. 29% at 1 year and 59% vs. 7% at 5 years; P=0.0008) regardless of the cause of first pancreas loss. The same results were observed with all 37 retransplantations. Survival of second simultaneous pancreas and kidney transplantations was better than survival of second pancreas after kidney. Patient survival was excellent (89% at 5 years). Pancreas retransplantation had no impact on kidney graft function and survival (100% at 5 years). Pancreas retransplantation is a safe procedure with acceptable graft survival that should be proposed to diabetic patients who have lost their primary graft.

Impact of sex on prognostic host factors in surgical patients with lung cancer.

PubMed

Wainer, Zoe; Wright, Gavin M; Gough, Karla; Daniels, Marissa G; Choong, Peter; Conron, Matthew; Russell, Prudence A; Alam, Naveed Z; Ball, David; Solomon, Benjamin

2017-12-01

Lung cancer has markedly poorer survival in men. Recognized important prognostic factors are divided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors. Two cohorts of patients treated surgically with curative intent between 2000 and 2009 were utilized. The primary cohort was from Melbourne, Australia, with an independent validation set from the American Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate analyses of validated host-related prognostic factors were performed in both cohorts to investigate the differences in survival between men and women. The Melbourne cohort had 605 patients (61% men) and SEER cohort comprised 55 681 patients (51% men). Disease-specific 5-year survival showed men had statistically significant poorer survival in both cohorts (P < 0.001); Melbourne men at 53.2% compared with women at 68.3%, and SEER 53.3% men and 62.0% women were alive at 5 years. Being male was independently prognostic for disease-specific mortality in the Melbourne cohort after adjustment for ethnicity, smoking history, performance status, age, pathological stage and histology (hazard ratio = 1.54, 95% confidence interval: 1.10-2.16, P = 0.012). Sex differences in non-small cell lung cancer are important irrespective of age, ethnicity, smoking, performance status and tumour, node and metastasis stage. Epidemiological findings such as these should be translated into research and clinical paradigms to determine the factors that influence the survival disadvantage experienced by men. © 2016 Royal Australasian College of Surgeons.

Breslow Density Is a Novel Prognostic Feature That Adds Value to Melanoma Staging.

PubMed

Saldanha, Gerald; Yarrow, Jeremy; Pancholi, Jay; Flatman, Katarina; Teo, Kah Wee; Elsheik, Somaia; Harrison, Rebecca; O'Riordan, Marie; Bamford, Mark

2018-06-01

Histomorphologic prognostic biomarkers that can be measured using only an hematoxylin and eosin stain are very attractive because they are simple and cheap. We conceived an entirely novel biomarker of this type, the Breslow density (BD), which measures invasive melanoma cell density at the site where Breslow thickness (BT) is measured. This study assessed BD's prognostic value. In this study, BD was measured in 1329 melanoma patients. Measurement accuracy and precision was assessed using intraclass correlation coefficient (ICC). Survival was assessed with a primary end-point of melanoma-specific survival (MSS) and also overall survival and metastasis-free survival. We found that BD measurement was accurate compared with gold standard image analysis (ICC, 0.84). Precision was excellent for 3 observers with different experience (ICC, 0.93) and for an observer using only written instructions (ICC, 0.93). BD was a highly significant predictor in multivariable analysis for overall survival, MSS, and metastasis-free survival (each, P<0.001) and it explained MSS better than BT, but BT and BD together had best explanatory capability. A BD cut point of ≥65% was trained in 970 melanomas and validated in 359. This cut point showed promise as a novel way to upstage melanoma from T stage "a" to "b." BD was combined with BT to create a targeted burden score. This was a validated as an adjunct to American Joint Committee on Cancer stage. In summary, BD can be measured accurately and precisely. It demonstrated independent prognostic value and explained MSS better than BT alone. Notably, we demonstrated ways that BD could be used with American Joint Committee on Cancer version 8 staging.

Prognostic factors in patients with advanced cancer: use of the patient-generated subjective global assessment in survival prediction.

PubMed

Martin, Lisa; Watanabe, Sharon; Fainsinger, Robin; Lau, Francis; Ghosh, Sunita; Quan, Hue; Atkins, Marlis; Fassbender, Konrad; Downing, G Michael; Baracos, Vickie

2010-10-01

To determine whether elements of a standard nutritional screening assessment are independently prognostic of survival in patients with advanced cancer. A prospective nested cohort of patients with metastatic cancer were accrued from different units of a Regional Palliative Care Program. Patients completed a nutritional screen on admission. Data included age, sex, cancer site, height, weight history, dietary intake, 13 nutrition impact symptoms, and patient- and physician-reported performance status (PS). Univariate and multivariate survival analyses were conducted. Concordance statistics (c-statistics) were used to test the predictive accuracy of models based on training and validation sets; a c-statistic of 0.5 indicates the model predicts the outcome as well as chance; perfect prediction has a c-statistic of 1.0. A training set of patients in palliative home care (n = 1,164) was used to identify prognostic variables. Primary disease site, PS, short-term weight change (either gain or loss), dietary intake, and dysphagia predicted survival in multivariate analysis (P < .05). A model including only patients separated by disease site and PS with high c-statistics between predicted and observed responses for survival in the training set (0.90) and validation set (0.88; n = 603). The addition of weight change, dietary intake, and dysphagia did not further improve the c-statistic of the model. The c-statistic was also not altered by substituting physician-rated palliative PS for patient-reported PS. We demonstrate a high probability of concordance between predicted and observed survival for patients in distinct palliative care settings (home care, tertiary inpatient, ambulatory outpatient) based on patient-reported information.

Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX.

PubMed

Emile, Jean-François; Julié, Catherine; Le Malicot, Karine; Lepage, Come; Tabernero, Josep; Mini, Enrico; Folprecht, Gunnar; Van Laethem, Jean-Luc; Dimet, Stéphanie; Boulagnon-Rombi, Camille; Allard, Marc-Antoine; Penault-Llorca, Frédérique; Bennouna, Jaafar; Laurent-Puig, Pierre; Taieb, Julien

2017-09-01

The prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use. According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data. Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients. Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

EG-09EPIGENETIC PROFILING REVEALS A CpG HYPERMETHYLATION PHENOTYPE (CIMP) ASSOCIATED WITH WORSE PROGRESSION-FREE SURVIVAL IN MENINGIOMA

PubMed Central

Olar, Adriana; Wani, Khalida; Mansouri, Alireza; Zadeh, Gelareh; Wilson, Charmaine; DeMonte, Franco; Fuller, Gregory; Jones, David; Pfister, Stefan; von Deimling, Andreas; Sulman, Erik; Aldape, Kenneth

2014-01-01

BACKGROUND: Methylation profiling of solid tumors has revealed biologic subtypes, often with clinical implications. Methylation profiles of meningioma and their clinical implications are not well understood. METHODS: Ninety-two meningioma samples (n = 44 test set and n = 48 validation set) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised clustering and analyses for recurrence-free survival (RFS) were performed. RESULTS: Unsupervised clustering of the test set using approximately 900 highly variable markers identified two clearly defined methylation subgroups. One of the groups (n = 19) showed global hypermethylation of a set of markers, analogous to CpG island methylator phenotype (CIMP). These findings were reproducible in the validation set, with 18/48 samples showing the CIMP-positive phenotype. Importantly, of 347 highly variable markers common to both the test and validation set analyses, 107 defined CIMP in the test set and 94 defined CIMP in the validation set, with an overlap of 83 markers between the two datasets. This number is much greater than expected by chance indicating reproducibly of the hypermethylated markers that define CIMP in meningioma. With respect to clinical correlation, the 37 CIMP-positive cases displayed significantly shorter RFS compared to the 55 non-CIMP cases (hazard ratio 2.9, p = 0.013). In an effort to develop a preliminary outcome predictor, a 155-marker subset correlated with RFS was identified in the test dataset. When interrogated in the validation dataset, this 155-marker subset showed a statistical trend (p < 0.1) towards distinguishing survival groups. CONCLUSIONS: This study defines the existence of a CIMP phenotype in meningioma, which involves a substantial proportion (37/92, 40%) of samples with clinical implications. Ongoing work will expand this cohort and examine identification of additional biologic differences (mutational and DNA copy number analysis) to further characterize the aberrant methylation subtype in meningioma. CIMP-positivity with aberrant methylation in recurrent/malignant meningioma suggests a potential therapeutic target for clinically aggressive cases.

Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non–Small-Cell Lung Cancer

PubMed Central

Le Teuff, Gwénaël; Marguet, Sophie; Lantuejoul, Sylvie; Dunant, Ariane; Graziano, Stephen; Pirker, Robert; Douillard, Jean-Yves; Le Chevalier, Thierry; Filipits, Martin; Rosell, Rafael; Kratzke, Robert; Popper, Helmut; Soria, Jean-Charles; Shepherd, Frances A.; Seymour, Lesley; Tsao, Ming Sound

2016-01-01

Purpose Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer. Patients and Methods A discovery set (one trial, n = 824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non–small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set. Results Discovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points). Conclusion Intense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non–small-cell lung cancer. PMID:26834066

Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab.

PubMed

Custodio, A; Carmona-Bayonas, A; Jiménez-Fonseca, P; Sánchez, M L; Viudez, A; Hernández, R; Cano, J M; Echavarria, I; Pericay, C; Mangas, M; Visa, L; Buxo, E; García, T; Rodríguez Palomo, A; Álvarez Manceñido, F; Lacalle, A; Macias, I; Azkarate, A; Ramchandani, A; Fernández Montes, A; López, C; Longo, F; Sánchez Bayona, R; Limón, M L; Díaz-Serrano, A; Hurtado, A; Madero, R; Gómez, C; Gallego, J

2017-06-06

To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination chemotherapy. Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrell's c-index was used to evaluate discrimination. The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5-6.6), 9.4 (95% CI, 8.5-10.6), and 14 months (95% CI, 11.8-16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3-8.1), 12.7 (95% CI, 11.3-14.3), and 18.3 months (95% CI, 14.6-24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591-0.631) and 0.673 (95% CI, 0.636-0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351). We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design.

Development and validation of a radiomics nomogram for progression-free survival prediction in stage IV EGFR-mutant non-small cell lung cancer

NASA Astrophysics Data System (ADS)

Song, Jiangdian; Zang, Yali; Li, Weimin; Zhong, Wenzhao; Shi, Jingyun; Dong, Di; Fang, Mengjie; Liu, Zaiyi; Tian, Jie

2017-03-01

Accurately predict the risk of disease progression and benefit of tyrosine kinase inhibitors (TKIs) therapy for stage IV non-small cell lung cancer (NSCLC) patients with activing epidermal growth factor receptor (EGFR) mutations by current staging methods are challenge. We postulated that integrating a classifier consisted of multiple computed tomography (CT) phenotypic features, and other clinicopathological risk factors into a single model could improve risk stratification and prediction of progression-free survival (PFS) of EGFR TKIs for these patients. Patients confirmed as stage IV EGFR-mutant NSCLC received EGFR TKIs with no resection; pretreatment contrast enhanced CT performed at approximately 2 weeks before the treatment was enrolled. A six-CT-phenotypic-feature-based classifier constructed by the LASSO Cox regression model, and three clinicopathological factors: pathologic N category, performance status (PS) score, and intrapulmonary metastasis status were used to construct a nomogram in a training set of 115 patients. The prognostic and predictive accuracy of this nomogram was then subjected to an external independent validation of 107 patients. PFS between the training and independent validation set is no statistical difference by Mann-Whitney U test (P = 0.2670). PFS of the patients could be predicted with good consistency compared with the actual survival. C-index of the proposed individualized nomogram in the training set (0·707, 95%CI: 0·643, 0·771) and the independent validation set (0·715, 95%CI: 0·650, 0·780) showed the potential of clinical prognosis to predict PFS of stage IV EGFR-mutant NSCLC from EGFR TKIs. The individualized nomogram might facilitate patient counselling and individualise management of patients with this disease.

Development and external validation of a risk-prediction model to predict 5-year overall survival in advanced larynx cancer.

PubMed

Petersen, Japke F; Stuiver, Martijn M; Timmermans, Adriana J; Chen, Amy; Zhang, Hongzhen; O'Neill, James P; Deady, Sandra; Vander Poorten, Vincent; Meulemans, Jeroen; Wennerberg, Johan; Skroder, Carl; Day, Andrew T; Koch, Wayne; van den Brekel, Michiel W M

2018-05-01

TNM-classification inadequately estimates patient-specific overall survival (OS). We aimed to improve this by developing a risk-prediction model for patients with advanced larynx cancer. Cohort study. We developed a risk prediction model to estimate the 5-year OS rate based on a cohort of 3,442 patients with T3T4N0N+M0 larynx cancer. The model was internally validated using bootstrapping samples and externally validated on patient data from five external centers (n = 770). The main outcome was performance of the model as tested by discrimination, calibration, and the ability to distinguish risk groups based on tertiles from the derivation dataset. The model performance was compared to a model based on T and N classification only. We included age, gender, T and N classification, and subsite as prognostic variables in the standard model. After external validation, the standard model had a significantly better fit than a model based on T and N classification alone (C statistic, 0.59 vs. 0.55, P < .001). The model was able to distinguish well among three risk groups based on tertiles of the risk score. Adding treatment modality to the model did not decrease the predictive power. As a post hoc analysis, we tested the added value of comorbidity as scored by American Society of Anesthesiologists score in a subsample, which increased the C statistic to 0.68. A risk prediction model for patients with advanced larynx cancer, consisting of readily available clinical variables, gives more accurate estimations of the estimated 5-year survival rate when compared to a model based on T and N classification alone. 2c. Laryngoscope, 128:1140-1145, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of β2 -microglobulin yields a more accurate GELTAMO-IPI.

PubMed

Montalbán, Carlos; Díaz-López, Antonio; Dlouhy, Ivan; Rovira, Jordina; Lopez-Guillermo, Armando; Alonso, Sara; Martín, Alejandro; Sancho, Juan M; García, Olga; Sánchez, Jose M; Rodríguez, Mario; Novelli, Silvana; Salar, Antonio; Gutiérrez, Antonio; Rodríguez-Salazar, Maria J; Bastos, Mariana; Domínguez, Juan F; Fernández, Rubén; Gonzalez de Villambrosia, Sonia; Queizan, José A; Córdoba, Raul; de Oña, Raquel; López-Hernandez, Andrés; Freue, Julian M; Garrote, Heidys; López, Lourdes; Martin-Moreno, Ana M; Rodriguez, Jose; Abraira, Víctor; García, Juan F

2017-03-01

The study included 1848 diffuse large B-cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and explore the effect of adding high Beta-2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN-IPI variables in order to develop an improved index. Comparing survival curves, NCCN-IPI discriminated better than IPI, separating four risk groups with 5-year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high-risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III-IV, and β2M as independently significant, whereas the NCCN-IPI-selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)-IPI developed here, with 7 points, significantly separated four risk groups (0, 1-3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5-year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN-IPI. In conclusion, GELTAMO-IPI is more accurate than the NCCN-IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high-risk group and is not influenced by primary extranodal presentation or treatments of different intensity. © 2017 John Wiley & Sons Ltd.

Validation of a Proposed Tumor Regression Grading Scheme for Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy as a Prognostic Indicator for Survival.

PubMed

Lee, Sun Mi; Katz, Matthew H G; Liu, Li; Sundar, Manonmani; Wang, Hua; Varadhachary, Gauri R; Wolff, Robert A; Lee, Jeffrey E; Maitra, Anirban; Fleming, Jason B; Rashid, Asif; Wang, Huamin

2016-12-01

Neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Although the College of American Pathologists (CAP) grading scheme for tumor response in posttherapy specimens has been used, its clinical significance has not been validated. Previously, we proposed a 3-tier histologic tumor regression grading (HTRG) scheme (HTRG 0, no viable tumor; HTRG 1, <5% viable tumor cells; HTRG 2, ≥5% viable tumor cells) and showed that the 3-tier HTRG scheme correlated with prognosis. In this study, we sought to validate our proposed HTRG scheme in a new cohort of 167 consecutive PDAC patients who completed neoadjuvant therapy and pancreaticoduodenectomy. We found that patients with HTRG 0 or 1 were associated with a lower frequency of lymph node metastasis (P=0.004) and recurrence (P=0.01), lower ypT (P<0.001) and AJCC stage (P<0.001), longer disease-free survival (DFS, P=0.004) and overall survival (OS, P=0.02) than those with HTRG 2. However, there was no difference in either DFS or OS between the groups with CAP grade 2 and those with CAP grade 3 (P>0.05). In multivariate analysis, HTRG grade 0 or 1 was an independent prognostic factor for better DFS (P=0.03), but not OS. Therefore we validated the proposed HTRG scheme from our previous study. The proposed HTRG scheme is simple and easy to apply in practice by pathologists and might be used as a successful surrogate for longer DFS in patients with potentially resectable PDAC who completed neoadjuvant therapy and surgery.

Validation of a two-tier grading system in an unselected, consecutive cohort of serous ovarian cancer patients.

PubMed

Battista, Marco Johannes; Cotarelo, Cristina; Almstedt, Katrin; Heimes, Anne-Sophie; Makris, Georgios-Marios; Weyer, Veronika; Schmidt, Marcus

2016-09-01

New insights into the carcinogenesis of ovarian cancer (OC) lead to the definition of low-grade and high-grade serous OC. In this study, we validated the MD Anderson Cancer Center (MDACC) two-tier grading system and compared it with the traditional three-tier grading system as suggested by the International Federation of Gynecology and Obstetrics (FIGO). Consecutive patients with serous OC were enrolled. These two grading systems were assessed independently from each other. Kaplan-Meier estimates and Cox-regression analyses were performed to validate and compare their prognostic impact. 143 consecutive patients entered the study. According to the Kaplan-Meier estimates, the MDACC grading system (p = 0.001) predicted the progression free survival (PFS) more precisely than the FIGO system (p = 0.025). The MDACC grading system (p = 0.008) but not the FIGO system (p = 0.329) showed a statistically significant difference in terms of disease specific survival (DSS). Multivariable Cox-regression analyses revealed an independent prognostic impact of the MDACC grading system but not of the FIGO system for PFS (HR 1.570; 95 % CI 1.007-2.449; p = 0.047, and HR 0.712; 95 % CI 0.476-1.066; p = 0.099, respectively). Concerning DSS, the two-tier grading system but not the FIGO system showed a prognostic impact in a univariable Cox-regression analysis (HR 2.152; 95 % CI 1.207-3.835; p = 0.009, and HR 1.258; 95 % CI 0.801-1.975; p = 0.319, respectively). We were able to validate the MDACC grading system in serous OC. Moreover, this grading system was stronger associated with survival than the FIGO system.

Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters

PubMed Central

Carr, Brian I.; Giannini, Edoardo G.; Farinati, Fabio; Ciccarese, Francesca; Rapaccini, Gian Ludovico; Marco, Maria Di; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

2014-01-01

Background Previous work has shown that 2 general processes contribute to hepatocellular cancer (HCC) prognosis. They are: a. liver damage, monitored by indices such as blood bilirubin, prothrombin time and AST; as well as b. tumor biology, monitored by indices such as tumor size, tumor number, presence of PVT and blood AFP levels. These 2 processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied Network Phenotyping Strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Aims To validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Methods Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory based approach, which compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Results Without reference to the actual tumor sizes, patients were classified by NPS into 2 subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-Platelets relationship. These trends were combined with patient age, gender and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual scan data) that patients in L phenotype group had 1.5x larger mean tumor masses relative to S, p=6×10−16. Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7 × longer survival compared to L-phenotype. NPS integrated the liver, tumor and basic demographic factors. Cirrhosis associated thrombocytopenia was typical for smaller S-tumors. In L-tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. Summary NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient. PMID:25023357

The distribution of lung cancer across sectors of society in the United Kingdom: a study using national primary care data.

PubMed

Iyen-Omofoman, Barbara; Hubbard, Richard B; Smith, Chris J P; Sparks, Emily; Bradley, Emma; Bourke, Alison; Tata, Laila J

2011-11-10

There is pressing need to diagnose lung cancer earlier in the United Kingdom (UK) and it is likely that research using computerised general practice records will help this process. Linkage of these records to area-level geo-demographic classifications may also facilitate case ascertainment for public health programmes, however, there have as yet been no extensive studies of data validity for such purposes. To first address the need for validation, we assessed the completeness and representativeness of lung cancer data from The Health Improvement Network (THIN) national primary care database by comparing incidence and survival between 2000 and 2009 with the UK National Cancer Registry and the National Lung Cancer Audit Database. Secondly, we explored the potential of a geo-demographic social marketing tool to facilitate disease ascertainment by using Experian's Mosaic Public Sector ™ classification, to identify detailed profiles of the sectors of society where lung cancer incidence was highest. Overall incidence of lung cancer (41.4/100, 000 person-years, 95% confidence interval 40.6-42.1) and median survival (232 days) were similar to other national data; The incidence rate in THIN from 2003-2006 was found to be just over 93% of the national cancer registry rate. Incidence increased considerably with area-level deprivation measured by the Townsend Index and was highest in the North-West of England (65.1/100, 000 person-years). Wider variations in incidence were however identified using Mosaic classifications with the highest incidence in Mosaic Public Sector ™types 'Cared-for pensioners, ' 'Old people in flats' and 'Dignified dependency' (191.7, 174.2 and 117.1 per 100, 000 person-years respectively). Routine electronic data in THIN are a valid source of lung cancer information. Mosaic ™ identified greater incidence differentials than standard area-level measures and as such could be used as a tool for public health programmes to ascertain future cases more effectively.

Predicting survival in patients receiving continuous flow left ventricular assist devices: the HeartMate II risk score.

PubMed

Cowger, Jennifer; Sundareswaran, Kartik; Rogers, Joseph G; Park, Soon J; Pagani, Francis D; Bhat, Geetha; Jaski, Brian; Farrar, David J; Slaughter, Mark S

2013-01-22

The aim of this study was to derive and validate a model to predict survival in candidates for HeartMate II (HMII) (Thoratec, Pleasanton, California) left ventricular assist device (LVAD) support. LVAD mortality risk prediction is important for candidate selection and communicating expectations to patients and clinicians. With the evolution of LVAD support, prior risk prediction models have become less valid. Patients enrolled into the HMII bridge to transplantation and destination therapy trials (N = 1,122) were randomly divided into derivation (DC) (n = 583) and validation cohorts (VC) (n = 539). Pre-operative candidate predictors of 90-day mortality were examined in the DC with logistic regression, from which the HMII Risk Score (HMRS) was derived. The HMRS was then applied to the VC. There were 149 (13%) deaths within 90 days. In the DC, mortality (n = 80) was higher in older patients (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1 to 1.7 per 10 years), those with greater hypoalbuminemia (OR: 0.49, 95% CI: 0.31 to 0.76 per mg/dl of albumin), renal dysfunction (OR: 2.1, 95% CI: 1.4 to 3.2 per mg/dl creatinine), coagulopathy (OR: 3.1, 95% CI: 1.7 to 5.8 per international normalized ratio unit), and in those receiving LVAD support at less experienced centers (OR: 2.2, 95% CI: 1.2 to 4.4 for <15 trial patients). Mortality in the DC low, medium, and high HMRS groups was 4%, 16%, and 29%, respectively (p < 0.001). In the VC, corresponding mortality was 8%, 11%, and 25%, respectively (p < 0.001). HMRS discrimination was good (area under the receiver-operating characteristic curve: 0.71, 95% CI: 0.66 to 0.75). The HMRS might be useful for mortality risk stratification in HMII candidates and may serve as an additional tool in the patient selection process. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

A gene expression signature associated with survival in metastatic melanoma

PubMed Central

Mandruzzato, Susanna; Callegaro, Andrea; Turcatel, Gianluca; Francescato, Samuela; Montesco, Maria C; Chiarion-Sileni, Vanna; Mocellin, Simone; Rossi, Carlo R; Bicciato, Silvio; Wang, Ena; Marincola, Francesco M; Zanovello, Paola

2006-01-01

Background Current clinical and histopathological criteria used to define the prognosis of melanoma patients are inadequate for accurate prediction of clinical outcome. We investigated whether genome screening by means of high-throughput gene microarray might provide clinically useful information on patient survival. Methods Forty-three tumor tissues from 38 patients with stage III and stage IV melanoma were profiled with a 17,500 element cDNA microarray. Expression data were analyzed using significance analysis of microarrays (SAM) to identify genes associated with patient survival, and supervised principal components (SPC) to determine survival prediction. Results SAM analysis revealed a set of 80 probes, corresponding to 70 genes, associated with survival, i.e. 45 probes characterizing longer and 35 shorter survival times, respectively. These transcripts were included in a survival prediction model designed using SPC and cross-validation which allowed identifying 30 predicting probes out of the 80 associated with survival. Conclusion The longer-survival group of genes included those expressed in immune cells, both innate and acquired, confirming the interplay between immunological mechanisms and the natural history of melanoma. Genes linked to immune cells were totally lacking in the poor-survival group, which was instead associated with a number of genes related to highly proliferative and invasive tumor cells. PMID:17129373

Validation of the Mayo Clinic Staging System in Determining Prognoses of Patients With Perihilar Cholangiocarcinoma.

PubMed

Coelen, Robert J S; Gaspersz, Marcia P; Labeur, Tim A; van Vugt, Jeroen L A; van Dieren, Susan; Willemssen, François E J A; Nio, Chung Y; IJzermans, Jan N M; Klümpen, Heinz-Josef; Groot Koerkamp, Bas; van Gulik, Thomas M

2017-12-01

Most systems for staging perihilar cholangiocarcinoma (PHC) have been developed for the minority of patients with resectable disease. The recently developed Mayo Clinic system for staging PHC requires only clinical and radiologic variables, but has not yet been validated. We performed a retrospective study to validate the Mayo Clinic staging system. We identified consecutive patients with suspected PHC who were evaluated and treated at 2 tertiary centers in The Netherlands, from January 2002 through December 2014. Baseline characteristics (performance status, carbohydrate antigen 19-9 level) used in the staging system were collected from medical records and imaging parameters (tumor size, suspected vascular involvement, and metastatic disease) were reassessed by 2 experienced abdominal radiologists. Overall survival was analyzed using the Kaplan-Meier method and comparison of staging groups was performed using the log-rank test and Cox proportional hazard regression analysis. Discriminative performance was quantified by the concordance index and compared with the radiologic TNM staging of the American Joint Committee on Cancer (7th ed). PHCs from 600 patients were staged according to the Mayo Clinic model (23 stage I, 80 stage II, 357 stage III, and 140 stage IV). The median overall survival time was 11.6 months. The median overall survival times for patients with stages I, II, III, and IV were 33.2 months, 19.7 months, 12.1 months, and 6.0 months, respectively; with hazard ratios of 1.0 (reference), 2.02 (95% confidence interval [CI], 1.14-3.58), 2.71 (95% CI, 1.59-4.64), and 4.00 (95% CI, 2.30-6.95), respectively (P < .001). The concordance index score was 0.59 for the entire cohort (95% CI, 0.56-0.61). The Mayo Clinic model performed slightly better than the radiologic American Joint Committee on Cancer TNM system. In a retrospective study of 600 patients with PHC, we validated the Mayo Clinic system for staging PHC. This 4-tier staging system may aid clinicians in making treatment decisions, such as referral for surgery, and predicting survival times. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Time to Second-line Treatment and Subsequent Relative Survival in Older Patients With Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

PubMed

Ammann, Eric M; Shanafelt, Tait D; Larson, Melissa C; Wright, Kara B; McDowell, Bradley D; Link, Brian K; Chrischilles, Elizabeth A

2017-12-01

Novel targeted therapies offer excellent short-term outcomes in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL). However, there is disagreement over how widely these therapies should be used in place of standard chemo-immunotherapy (CIT). We investigated whether stratification on the length of the interval between first-line (T1) and second-line (T2) treatments could identify a subgroup of older patients with relapsed CLL/SLL with an expectation of normal overall survival, and for whom CIT could be an acceptable treatment choice. Patients with relapsed CLL/SLL who received T2 were identified from the SEER-Medicare Linked Database. Five-year relative survival (RS5; ie, the ratio of observed survival to expected survival based on population life tables) was assessed after stratifying patients on the interval between T1 and T2. We then validated our findings in the Mayo Clinic CLL Database. Among 1974 SEER-Medicare patients (median age = 77 years) who received T2 for relapsed CLL/SLL, longer time-to-retreatment was associated with a modestly improved prognosis (P = .01). However, even among those retreated ≥ 3 years after T1, survival was poor compared with the general population (RS5 = 0.50 or lower in SEER-Medicare). Similar patterns were observed in the younger Mayo validation cohort, although prognosis was better overall among the Mayo patients, and patients with favorable fluorescence in situ hybridization retreated ≥ 3 years after T1 had close to normal expected survival (RS5 = 0.87). Further research is needed to quantify the degree to which targeted therapies provide meaningful improvements over CIT in long-term outcomes for older patients with relapsed CLL/SLL. Copyright © 2017 Elsevier Inc. All rights reserved.

Silencing of Tuberin Enhances Photoreceptor Survival and Function in a Preclinical Model of Retinitis Pigmentosa (An American Ophthalmological Society Thesis)

PubMed Central

Tsang, Stephen H.; Chan, Lawrence; Tsai, Yi-Ting; Wu, Wen-Hsuan; Hsu, Chun-Wei; Yang, Jin; Tosi, Joaquin; Wert, Katherine J.; Davis, Richard J.; Mahajan, Vinit B.

2014-01-01

Purpose: To assess the functional consequences of silencing of tuberin, an inhibitor of the mTOR signaling pathway, in a preclinical model of retinitis pigmentosa (RP) in order to test the hypothesis that insufficient induction of the protein kinase B (PKB)-regulated tuberin/mTOR self-survival pathway initiates apoptosis. Methods: In an unbiased genome-scale approach, kinase peptide substrate arrays were used to analyze self-survival pathways at the onset of photoreceptor degeneration. The mutant Pde6bH620Q/Pde6bH620Q at P14 and P18 photoreceptor outer segment (OS) lysates were labeled with P-ATP and hybridized to an array of 1,164 different synthetic peptide substrates. At this stage, OS of Pde6bH620Q/Pde6bH620Q rods are morphologically normal. In vitro kinase assays and immunohistochemistry were used to validate phosphorylation. Short hairpin RNA (shRNA) gene silencing was used to validate tuberin’s role in regulating survival. Results: At the onset of degeneration, 162 peptides were differentially phosphorylated. Protein kinases A, G, C (AGC kinases), and B exhibited increased activity in both peptide array and in vitro kinase assays. Immunohistochemical data confirmed altered phosphorylation patterns for phosphoinositide-dependent kinase-1 (PDK1), ribosomal protein S6 (RPS6), and tuberin. Tuberin gene silencing rescued photoreceptors from degeneration. Conclusions: Phosphorylation of tuberin and RPS6 is due to the upregulated activity of PKB. PKB/tuberin cell growth/survival signaling is activated before the onset of degeneration. Substrates of the AGC kinases in the PKB/tuberin pathway are phosphorylated to promote cell survival. Knockdown of tuberin, the inhibitor of the mTOR pathway, increased photoreceptor survival and function in a preclinical model of RP. PMID:25646031

Rumor Processes in Random Environment on and on Galton-Watson Trees

NASA Astrophysics Data System (ADS)

Bertacchi, Daniela; Zucca, Fabio

2013-11-01

The aim of this paper is to study rumor processes in random environment. In a rumor process a signal starts from the stations of a fixed vertex (the root) and travels on a graph from vertex to vertex. We consider two rumor processes. In the firework process each station, when reached by the signal, transmits it up to a random distance. In the reverse firework process, on the other hand, stations do not send any signal but they “listen” for it up to a random distance. The first random environment that we consider is the deterministic 1-dimensional tree with a random number of stations on each vertex; in this case the root is the origin of . We give conditions for the survival/extinction on almost every realization of the sequence of stations. Later on, we study the processes on Galton-Watson trees with random number of stations on each vertex. We show that if the probability of survival is positive, then there is survival on almost every realization of the infinite tree such that there is at least one station at the root. We characterize the survival of the process in some cases and we give sufficient conditions for survival/extinction.

Predictors of one and two years' mortality in patients with colon cancer: A prospective cohort study.

PubMed

Quintana, José M; Antón-Ladislao, Ane; González, Nerea; Lázaro, Santiago; Baré, Marisa; Fernández-de-Larrea, Nerea; Redondo, Maximino; Briones, Eduardo; Escobar, Antonio; Sarasqueta, Cristina; García-Gutierrez, Susana; Aróstegui, Inmaculada

2018-01-01

Tools to aid in the prognosis assessment of colon cancer patients in terms of risk of mortality are needed. Goals of this study are to develop and validate clinical prediction rules for 1- and 2-year mortality in these patients. This is a prospective cohort study of patients diagnosed with colon cancer who underwent surgery at 22 hospitals. The main outcomes were mortality at 1 and 2 years after surgery. Background, clinical parameters, and diagnostic tests findings were evaluated as possible predictors. Multivariable multilevel logistic regression and survival models were used in the analyses to create the clinical prediction rules. Models developed in the derivation sample were validated in another sample of the study. American Society of Anesthesiologists Physical Status Classification System (ASA), Charlson comorbidity index (> = 4), age (>75 years), residual tumor (R2), TNM stage IV and log of lymph nodes ratio (> = -0.53) were predictors of 1-year mortality (C-index (95% CI): 0.865 (0.792-0.938)). Adjuvant chemotherapy was an additional predictor. Again ASA, Charlson Index (> = 4), age (>75 years), log of lymph nodes ratio (> = -0.53), TNM, and residual tumor were predictors of 2-year mortality (C-index:0.821 (0.766-0.876). Chemotherapy was also an additional predictor. These clinical prediction rules show very good predictive abilities of one and two years survival and provide clinicians and patients with an easy and quick-to-use decision tool for use in the clinical decision process while the patient is still in the index admission.

Whole blood FPR1 mRNA expression predicts both non‐small cell and small cell lung cancer

PubMed Central

Vachani, Anil; Pass, Harvey I.; Rom, William N.; Ryden, Kirk; Weiss, Glen J.; Hogarth, D. K.; Runger, George; Richards, Donald; Shelton, Troy; Mallery, David W.

2018-01-01

While long‐term survival rates for early‐stage lung cancer are high, most cases are diagnosed in later stages that can negatively impact survival rates. We aim to design a simple, single biomarker blood test for early‐stage lung cancer that is robust to preclinical variables and can be readily implemented in the clinic. Whole blood was collected in PAXgene tubes from a training set of 29 patients, and a validation set of 260 patients, of which samples from 58 patients were prospectively collected in a clinical trial specifically for our study. After RNA was extracted, the expressions of FPR1 and a reference gene were quantified by an automated one‐step Taqman RT‐PCR assay. Elevated levels of FPR1 mRNA in whole blood predicted lung cancer status with a sensitivity of 55% and a specificity of 87% on all validation specimens. The prospectively collected specimens had a significantly higher 68% sensitivity and 89% specificity. Results from patients with benign nodules were similar to healthy volunteers. No meaningful correlation was present between our test results and any clinical characteristic other than lung cancer diagnosis. FPR1 mRNA levels in whole blood can predict the presence of lung cancer. Using this as a reflex test for positive lung cancer screening computed tomography scans has the potential to increase the positive predictive value. This marker can be easily measured in an automated process utilizing off‐the‐shelf equipment and reagents. Further work is justified to explain the source of this biomarker. PMID:29313979

Identifying biomarkers of papillary renal cell carcinoma associated with pathological stage by weighted gene co-expression network analysis.

PubMed

He, Zhongshi; Sun, Min; Ke, Yuan; Lin, Rongjie; Xiao, Youde; Zhou, Shuliang; Zhao, Hong; Wang, Yan; Zhou, Fuxiang; Zhou, Yunfeng

2017-04-25

Although papillary renal cell carcinoma (PRCC) accounts for 10%-15% of renal cell carcinoma (RCC), no predictive molecular biomarker is currently applicable to guiding disease stage of PRCC patients. The mRNASeq data of PRCC and adjacent normal tissue in The Cancer Genome Atlas was analyzed to identify 1148 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Then 11 co-expressed gene modules were identified. The highest association was found between blue module and pathological stage (r = 0.45) by Pearson's correlation analysis. Functional enrichment analysis revealed that biological processes of blue module focused on nuclear division, cell cycle phase, and spindle (all P < 1e-10). All 40 hub genes in blue module can distinguish localized (pathological stage I, II) from non-localized (pathological stage III, IV) PRCC (P < 0.01). A good molecular biomarker for pathological stage of RCC must be a prognostic gene in clinical practice. Survival analysis was performed to reversely validate if hub genes were associated with pathological stage. Survival analysis unveiled that all hub genes were associated with patient prognosis (P < 0.01).The validation cohort GSE2748 verified that 30 hub genes can differentiate localized from non-localized PRCC (P < 0.01), and 18 hub genes are prognosis-associated (P < 0.01).ROC curve indicated that the 17 hub genes exhibited excellent diagnostic efficiency for localized and non-localized PRCC (AUC > 0.7). These hub genes may serve as a biomarker and help to distinguish different pathological stages for PRCC patients.

Prognostic Model for Resected Squamous Cell Lung Cancer: External Multicenter Validation and Propensity Score Analysis exploring the Impact of Adjuvant and Neoadjuvant Treatment.

PubMed

Pilotto, Sara; Sperduti, Isabella; Leuzzi, Giovanni; Chiappetta, Marco; Mucilli, Felice; Ratto, Giovanni Battista; Lococo, Filippo; Filosso, Pier Lugigi; Spaggiari, Lorenzo; Novello, Silvia; Milella, Michele; Santo, Antonio; Scarpa, Aldo; Infante, Maurizio; Tortora, Giampaolo; Facciolo, Francesco; Bria, Emilio

2018-04-01

We developed one of the first clinicopathological prognostic nomograms for resected squamous cell lung cancer (SQLC). Herein, we validate the model in a larger multicenter cohort and we explore the impact of adjuvant and neoadjuvant treatment (ANT). Patients with resected SQLC from January 2002 to December 2012 in six institutions were eligible. Each patient was assigned a prognostic score based on the clinicopathological factors included in the model (age, T descriptor according to seventh edition of the TNM classification, lymph node status, and grading). Kaplan-Meier analysis for disease-free survival, cancer-specific survival (CSS), and overall survival was performed according to a three-class risk model. Harrell's C-statistics were adopted for model validation. The effect of ANT was adjusted with propensity score. Data on 1375 patients were gathered (median age, 68 years; male sex, 86.8%; T descriptor 1 or 2 versus 3 or 4, 71.7% versus 24.9%; nodes negative versus positive, 53.4% versus 46.6%; and grading of 1 or 2 versus 3, 35.0% versus 41.1%). Data for survival analysis were available for 1097 patients. With a median follow-up of 55 months, patients at low risk had a significantly longer disease-free survival than did patients at intermediate risk (hazard ratio [HR] = 1.67, 95% confidence interval [CI]: 1.40-2.01) and patients at high risk (HR = 2.46, 95% CI: 1.90-3.19); they also had a significantly longer CSS (HR = 2.46, 95% CI: 1.80-3.36 versus HR = 4.30, 95% CI: 2.92-6.33) and overall survival (HR = 1.79, 95% CI: 1.48-2.17 versus HR = 2.33, 95% CI: 1.76-3.07). A trend in favor of ANT was observed for intermediate-risk/high-risk patients, particularly for CSS (p = 0.06 [5-year CSS 72.7% versus 60.8%]). A model based on a combination of easily available clinicopathological factors effectively stratifies patients with resected SQLC into three risk classes. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Selection of indigenous indicator micro-organisms for validating desiccation-adapted Salmonella reduction in physically heat-treated poultry litter.

PubMed

Chen, Z; Jiang, X

2017-06-01

The thermal resistance of desiccation-adapted Salmonella Senftenberg 775/W was compared with those of indigenous enterococci and total aerobic bacteria in poultry litter. Aged broiler litter and composted turkey litter with 20, 30, 40 and 50% moisture contents were inoculated with desiccation-adapted Salm. Senftenberg 775/W, and then heat-treated at 75 and 85°C. Compared to total aerobic bacteria, there were better correlations between mean log reductions of desiccation-adapted Salm. Senftenberg 775/W and indigenous enterococci in broiler litter samples with 20, 30, 40 and 50% moisture contents at 75°C (R 2  > 0·91), and 20, 30 and 40% moisture contents at 85°C (R 2  > 0·87). The mean log reductions of Salm. Senftenberg 775/W were better correlated with those of indigenous enterococci in turkey litter samples with 20, 30, 40 and 50% moisture contents at 75°C (R 2  > 0·88), and 20 and 30% moisture contents at 85°C (R 2  = 0·83) than those of total aerobic bacteria, which had a better correlation in turkey litter sample with 40% (R 2  = 0·98) moisture content at 85°C. Indigenous enterococci may be used to validate the thermal processing of poultry litter, as it predicts the survival behaviour of Salmonella under some treatment conditions. This study provides some scientific data for poultry litter processors when validating the effectiveness of thermal processing. © 2017 The Society for Applied Microbiology.

Development and Validation of a High Throughput System for Discovery of Antigens for Autoantibody Detection

PubMed Central

Macdonald, Isabel K.; Allen, Jared; Murray, Andrea; Parsy-Kowalska, Celine B.; Healey, Graham F.; Chapman, Caroline J.; Sewell, Herbert F.; Robertson, John F. R.

2012-01-01

An assay employing a panel of tumor-associated antigens has been validated and is available commercially (EarlyCDT®-Lung) to aid the early detection of lung cancer by measurement of serum autoantibodies. The high throughput (HTP) strategy described herein was pursued to identify new antigens to add to the EarlyCDT-Lung panel and to assist in the development of new panels for other cancers. Two ligation-independent cloning vectors were designed and synthesized, producing fusion proteins suitable for the autoantibody ELISA. We developed an abridged HTP version of the validated autoantibody ELISA, determining that results reflected the performance of the EarlyCDT assay, by comparing results on both formats. Once validated this HTP ELISA was utilized to screen multiple fusion proteins prepared on small-scale, by a HTP expression screen. We determined whether the assay performance for these HTP protein batches was an accurate reflection of the performance of R&D or commercial batches. A HTP discovery platform for the identification and optimal production of tumor- associated antigens which detects autoantibodies has been developed and validated. The most favorable conditions for the exposure of immunogenic epitopes were assessed to produce discriminatory proteins for use in a commercial ELISA. This process is rapid and cost-effective compared to standard cloning and screening technologies and enables rapid advancement in the field of autoantibody assay discovery. This approach will significantly reduce timescale and costs for developing similar panels of autoantibody assays for the detection of other cancer types with the ultimate aim of improved overall survival due to early diagnosis and treatment. PMID:22815807

Adaptive memory: young children show enhanced retention of fitness-related information.

PubMed

Aslan, Alp; Bäuml, Karl-Heinz T

2012-01-01

Evolutionary psychologists propose that human cognition evolved through natural selection to solve adaptive problems related to survival and reproduction, with its ultimate function being the enhancement of reproductive fitness. Following this proposal and the evolutionary-developmental view that ancestral selection pressures operated not only on reproductive adults, but also on pre-reproductive children, the present study examined whether young children show superior memory for information that is processed in terms of its survival value. In two experiments, we found such survival processing to enhance retention in 4- to 10-year-old children, relative to various control conditions that also required deep, meaningful processing but were not related to survival. These results suggest that, already in very young children, survival processing is a special and extraordinarily effective form of memory encoding. The results support the functional-evolutionary proposal that young children's memory is "tuned" to process and retain fitness-related information. Copyright © 2011 Elsevier B.V. All rights reserved.

Mothering and midwifery: sometimes a challenge.

PubMed

Fenwick, J

1998-12-01

This paper attempts to present two levels of argument. Firstly it argues that the use of story, in its entirety, is a valid, relevant and useful tool for informing personal and professional knowing. The second level of debate is elicited by the story itself and the discourse surrounding the challenges of implementing continuity of midwifery care models within the mainstream maternity care system. The author hopes that the telling of the story provides a window through which others can share her experience. It is argued that 'identification' with the challenges involved in implementing innovative models of care is an important and vital step in the process, if these models are to begin, survive and achieve their aim of providing women-centred health care.

Pigment network-based skin cancer detection.

PubMed

Alfed, Naser; Khelifi, Fouad; Bouridane, Ahmed; Seker, Huseyin

2015-08-01

Diagnosing skin cancer in its early stages is a challenging task for dermatologists given the fact that the chance for a patient's survival is higher and hence the process of analyzing skin images and making decisions should be time efficient. Therefore, diagnosing the disease using automated and computerized systems has nowadays become essential. This paper proposes an efficient system for skin cancer detection on dermoscopic images. It has been shown that the statistical characteristics of the pigment network, extracted from the dermoscopic image, could be used as efficient discriminating features for cancer detection. The proposed system has been assessed on a dataset of 200 dermoscopic images of the `Hospital Pedro Hispano' [1] and the results of cross-validation have shown high detection accuracy.

A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival.

PubMed

Botta, C; Di Martino, M T; Ciliberto, D; Cucè, M; Correale, P; Rossi, M; Tagliaferri, P; Tassone, P

2016-12-16

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.

TEAM-HF Cost-Effectiveness Model: A Web-Based Program Designed to Evaluate the Cost-Effectiveness of Disease Management Programs in Heart Failure

PubMed Central

Reed, Shelby D.; Neilson, Matthew P.; Gardner, Matthew; Li, Yanhong; Briggs, Andrew H.; Polsky, Daniel E.; Graham, Felicia L.; Bowers, Margaret T.; Paul, Sara C.; Granger, Bradi B.; Schulman, Kevin A.; Whellan, David J.; Riegel, Barbara; Levy, Wayne C.

2015-01-01

Background Heart failure disease management programs can influence medical resource use and quality-adjusted survival. Because projecting long-term costs and survival is challenging, a consistent and valid approach to extrapolating short-term outcomes would be valuable. Methods We developed the Tools for Economic Analysis of Patient Management Interventions in Heart Failure (TEAM-HF) Cost-Effectiveness Model, a Web-based simulation tool designed to integrate data on demographic, clinical, and laboratory characteristics, use of evidence-based medications, and costs to generate predicted outcomes. Survival projections are based on a modified Seattle Heart Failure Model (SHFM). Projections of resource use and quality of life are modeled using relationships with time-varying SHFM scores. The model can be used to evaluate parallel-group and single-cohort designs and hypothetical programs. Simulations consist of 10,000 pairs of virtual cohorts used to generate estimates of resource use, costs, survival, and incremental cost-effectiveness ratios from user inputs. Results The model demonstrated acceptable internal and external validity in replicating resource use, costs, and survival estimates from 3 clinical trials. Simulations to evaluate the cost-effectiveness of heart failure disease management programs across 3 scenarios demonstrate how the model can be used to design a program in which short-term improvements in functioning and use of evidence-based treatments are sufficient to demonstrate good long-term value to the health care system. Conclusion The TEAM-HF Cost-Effectiveness Model provides researchers and providers with a tool for conducting long-term cost-effectiveness analyses of disease management programs in heart failure. PMID:26542504

Ventilator Dependence Risk Score for the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis/Septic Shock with Respiratory Failure.

PubMed

Chang, Ya-Chun; Huang, Kuo-Tung; Chen, Yu-Mu; Wang, Chin-Chou; Wang, Yi-Hsi; Tseng, Chia-Cheng; Lin, Meng-Chih; Fang, Wen-Feng

2018-04-04

We intended to develop a scoring system to predict mechanical ventilator dependence in patients who survive sepsis/septic shock with respiratory failure. This study evaluated 251 adult patients in medical intensive care units (ICUs) between August 2013 to October 2015, who had survived for over 21 days and received aggressive treatment. The risk factors for ventilator dependence were determined. We then constructed a ventilator dependence (VD) risk score using the identified risk factors. The ventilator dependence risk score was calculated as the sum of the following four variables after being adjusted by proportion to the beta coefficient. We assigned a history of previous stroke, a score of one point, platelet count less than 150,000/μL a score of one point, pH value less than 7.35 a score of two points, and the fraction of inspired oxygen on admission day 7 over 39% as two points. The area under the curve in the derivation group was 0.725 (p < 0.001). We then applied the VD risk score for validation on 175 patients. The area under the curve in the validation group was 0.658 (p = 0.001). VD risk score could be applied to predict prolonged mechanical ventilation in patients who survive sepsis/septic shock.

Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review.

PubMed

Savina, Marion; Gourgou, Sophie; Italiano, Antoine; Dinart, Derek; Rondeau, Virginie; Penel, Nicolas; Mathoulin-Pelissier, Simone; Bellera, Carine

2018-03-01

In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA). We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. Copyright © 2017 Elsevier B.V. All rights reserved.

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology

PubMed Central

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types. PMID:23109809

[Brachytherapy for Prostate Cancer: Potentials and Limitations of Social Health Insurance Data for Benefit Assessment].

PubMed

Horenkamp-Sonntag, D; Linder, R; Engel, S; Verheyen, F

2016-05-01

Due to the insufficient data base the Federal Joint Committee (G-BA) had in 2009 after 7 years of deliberation decided to initiate consultation regarding ambulatory brachytherapy for localised prostate cancer for 10 years from social health insurance (SHI) benefits. The aim is to gain more findings by means of comparative studies. Based on the non-availability of clinical primary data of a methodologically acceptable level, it was analysed to what extent secondary data of the SHI may be used in order to arrive at valid conclusions for benefit aspects. As base approx. 8 million insured of TK with their data of cost reimbursement between 2006 and 2011 were considered. In SHI secondary data no clinical information regarding tumour stage and other prognostic factors are available. Therefore, a novel method with therapy-specific multisectoral inclusion and exclusion criteria, respectively, was developed in order to differentiate between localised and advanced tumours of the prostate. Overall survival, relapse-free survival, event-free survival and side-effects associated to prostate cancer were analysed. Out of 87 822 insured persons with the diagnosis prostate cancer, 795 with PBT, 10 936 with RP and 1 925 with EBRT were investigated in detail. The 4-year event-free survival rate was 73% for RP, 77% for PBT and 71% for EBRT. Many prostate cancer-specific side effects appeared already before intervention. Side effects of the intestinal tract (23.8%) and sexual impairments (26.5%) were more frequent for EBRT than for RP (17.1%/14.8%) and PBT (16.4%/13.2%). By means of SHI secondary data and adequate operationalisation important findings regarding relevant aspects of prostate cancer in healthcare research can be generated. However, these hold methodological limitations and are not suited to draw valid conclusions for benefit assessment. Based solely on SHI routine data valid statements regarding comparative benefit assessment are limited. Limitations could be reduced by applying a record linkage with clinical data. Such primary data should include information on tumour stages as well as therapy assignment and observation of survival time. © Georg Thieme Verlag KG Stuttgart · New York.

Predicting Overall Survival After Stereotactic Ablative Radiation Therapy in Early-Stage Lung Cancer: Development and External Validation of the Amsterdam Prognostic Model

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

Louie, Alexander V., E-mail: Dr.alexlouie@gmail.com; Department of Radiation Oncology, London Regional Cancer Program, University of Western Ontario, London, Ontario; Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts

Purpose: A prognostic model for 5-year overall survival (OS), consisting of recursive partitioning analysis (RPA) and a nomogram, was developed for patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic ablative radiation therapy (SABR). Methods and Materials: A primary dataset of 703 ES-NSCLC SABR patients was randomly divided into a training (67%) and an internal validation (33%) dataset. In the former group, 21 unique parameters consisting of patient, treatment, and tumor factors were entered into an RPA model to predict OS. Univariate and multivariate models were constructed for RPA-selected factors to evaluate their relationship with OS. A nomogrammore » for OS was constructed based on factors significant in multivariate modeling and validated with calibration plots. Both the RPA and the nomogram were externally validated in independent surgical (n=193) and SABR (n=543) datasets. Results: RPA identified 2 distinct risk classes based on tumor diameter, age, World Health Organization performance status (PS) and Charlson comorbidity index. This RPA had moderate discrimination in SABR datasets (c-index range: 0.52-0.60) but was of limited value in the surgical validation cohort. The nomogram predicting OS included smoking history in addition to RPA-identified factors. In contrast to RPA, validation of the nomogram performed well in internal validation (r{sup 2}=0.97) and external SABR (r{sup 2}=0.79) and surgical cohorts (r{sup 2}=0.91). Conclusions: The Amsterdam prognostic model is the first externally validated prognostication tool for OS in ES-NSCLC treated with SABR available to individualize patient decision making. The nomogram retained strong performance across surgical and SABR external validation datasets. RPA performance was poor in surgical patients, suggesting that 2 different distinct patient populations are being treated with these 2 effective modalities.« less

A novel classifier based on three preoperative tumor markers predicting the cancer-specific survival of gastric cancer (CEA, CA19-9 and CA72-4).

PubMed

Guo, Jing; Chen, Shangxiang; Li, Shun; Sun, Xiaowei; Li, Wei; Zhou, Zhiwei; Chen, Yingbo; Xu, Dazhi

2018-01-12

Several studies have highlighted the prognostic value of the individual and the various combinations of the tumor markers for gastric cancer (GC). Our study was designed to assess establish a new novel model incorporating carcino-embryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4). A total of 1,566 GC patients (Primary cohort) between Jan 2000 and July 2013 were analyzed. The Primary cohort was randomly divided into Training set (n=783) and Validation set (n=783). A three-tumor marker classifier was developed in the Training set and validated in the Validation set by multivariate regression and risk-score analysis. We have identified a three-tumor marker classifier (including CEA, CA19-9 and CA72-4) for the cancer specific survival (CSS) of GC (p<0.001). Consistent results were obtained in the both Training set and Validation set. Multivariate analysis showed that the classifier was an independent predictor of GC (All p value <0.001 in the Training set, Validation set and Primary cohort). Furthermore, when the leave-one-out approach was performed, the classifier showed superior predictive value to the individual or two of them (with the highest AUC (Area Under Curve); 0.618 for the Training set, and 0.625 for the Validation set), which ascertained its predictive value. Our three-tumor marker classifier is closely associated with the CSS of GC and may serve as a novel model for future decisions concerning treatments.

Constraints, Approach, and Status of Mars Surveyor 2001 Landing Site Selection

NASA Technical Reports Server (NTRS)

Golombek, M.; Bridges, N.; Briggs, G.; Gilmore, M.; Haldemann, A.; Parker, T.; Saunders, R.; Spencer, D.; Smith, J.; Soderblom, L.

1999-01-01

There are many similarities between the Mars Surveyor '01 (MS '01) landing site selection process and that of Mars Pathfinder. The selection process includes two parallel activities in which engineers define and refine the capabilities of the spacecraft through design, testing and modeling and scientists define a set of landing site constraints based on the spacecraft design and landing scenario. As for Pathfinder, the safety of the site is without question the single most important factor, for the simple reason that failure to land safely yields no science and exposes the mission and program to considerable risk. The selection process must be thorough and defensible and capable of surviving multiple withering reviews similar to the Pathfinder decision. On Pathfinder, this was accomplished by attempting to understand the surface properties of sites using available remote sensing data sets and models based on them. Science objectives are factored into the selection process only after the safety of the site is validated. Finally, as for Pathfinder, the selection process is being done in an open environment with multiple opportunities for community involvement including open workshops, with education and outreach opportunities. Additional information is contained in the original extended abstract.

Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.

PubMed

Schwalbe, Edward C; Lindsey, Janet C; Nakjang, Sirintra; Crosier, Stephen; Smith, Amanda J; Hicks, Debbie; Rafiee, Gholamreza; Hill, Rebecca M; Iliasova, Alice; Stone, Thomas; Pizer, Barry; Michalski, Antony; Joshi, Abhijit; Wharton, Stephen B; Jacques, Thomas S; Bailey, Simon; Williamson, Daniel; Clifford, Steven C

2017-07-01

International consensus recognises four medulloblastoma molecular subgroups: WNT (MB WNT ), SHH (MB SHH ), group 3 (MB Grp3 ), and group 4 (MB Grp4 ), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0-16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3-16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MB WNT remained unchanged and each remaining consensus subgroup was split in two. MB SHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MB SHH-Infant ; n=65) and childhood patients (≥4·3 years; MB SHH-Child ; n=38). MB Grp3 and MB Grp4 were each split into high-risk (MB Grp3-HR [n=65] and MB Grp4-HR [n=85]) and low-risk (MB Grp3-LR [n=50] and MB Grp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82-100]); standard risk (50 [23%] patients; 81% survival [70-94]); high-risk (82 [38%] patients; 42% survival [31-56]); and very high-risk (29 [13%] patients; 28% survival [14-56]). The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK). Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic profiling.

PubMed

Yuan, Yinyin; Failmezger, Henrik; Rueda, Oscar M; Ali, H Raza; Gräf, Stefan; Chin, Suet-Feung; Schwarz, Roland F; Curtis, Christina; Dunning, Mark J; Bardwell, Helen; Johnson, Nicola; Doyle, Sarah; Turashvili, Gulisa; Provenzano, Elena; Aparicio, Sam; Caldas, Carlos; Markowetz, Florian

2012-10-24

Solid tumors are heterogeneous tissues composed of a mixture of cancer and normal cells, which complicates the interpretation of their molecular profiles. Furthermore, tissue architecture is generally not reflected in molecular assays, rendering this rich information underused. To address these challenges, we developed a computational approach based on standard hematoxylin and eosin-stained tissue sections and demonstrated its power in a discovery and validation cohort of 323 and 241 breast tumors, respectively. To deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy number profiles between samples. We next devised a predictor for survival in estrogen receptor-negative breast cancer that integrated both image-based and gene expression analyses and significantly outperformed classifiers that use single data types, such as microarray expression signatures. Image processing also allowed us to describe and validate an independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative, image-based method could benefit any large-scale cancer study by refining and complementing molecular assays of tumor samples.

Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab.

PubMed

Piessevaux, Hubert; Buyse, Marc; Schlichting, Michael; Van Cutsem, Eric; Bokemeyer, Carsten; Heeger, Steffen; Tejpar, Sabine

2013-10-20

Early tumor shrinkage (ETS) is associated with long-term outcome in patients with chemorefractory metastatic colorectal cancer (mCRC) receiving cetuximab. This association was investigated in the first-line setting in the randomized CRYSTAL and OPUS mCRC trials, after controlling for KRAS tumor mutation status. Radiologic assessments at week 8 were used to calculate the relative change in the sum of the longest diameters of the target lesions. Time-dependent receiver operating characteristics provided Cτ-indices (time-dependent c-index). Cox regression models and subpopulation treatment effect pattern plot analysis investigated associations between ETS (radiologic tumor size decrease at week 8) and survival and progression-free survival (PFS). In both trials, in patients with KRAS wild-type mCRC, Cτ values for PFS and survival were higher (P < .001) in those receiving chemotherapy plus cetuximab versus chemotherapy alone, indicating a stronger predictive value of ETS for long-term outcome in these patients. In the CRYSTAL and OPUS trials, respectively, the cutoff value of ETS ≥ 20% (v < 20%) identified patients with KRAS wild-type mCRC receiving chemotherapy plus cetuximab with longer PFS (medians 14.1 v 7.3 months, hazard ratio [HR] = 0.32; P < .001, and medians 11.9 v 5.7 months, HR = 0.22; P < .001) and survival (medians 30.0 v 18.6 months, HR = 0.53; P < .001 and medians 26.0 v 15.7 months, HR = 0.43; P = .006). ETS was significantly associated with long-term outcome in patients with KRAS wild-type mCRC treated first-line with chemotherapy plus cetuximab. Validation in prospective trials is required to assess the value of this on-treatment marker in the clinical decision-making process.

Genome-scale analysis identifies GJB2 and ERO1LB as prognosis markers in patients with pancreatic cancer.

PubMed

Zhu, Tao; Gao, Yuan-Feng; Chen, Yi-Xin; Wang, Zhi-Bin; Yin, Ji-Ye; Mao, Xiao-Yuan; Li, Xi; Zhang, Wei; Zhou, Hong-Hao; Liu, Zhao-Qian

2017-03-28

Pancreatic cancer is a complex and heterogeneous disease with the etiology largely unknown. The deadly nature of pancreatic cancer, with an extremely low 5-year survival rate, renders urgent a better understanding of the molecular events underlying it. The aim of this study is to investigate the gene expression module of pancreatic adenocarcinoma and to identify differentially expressed genes (DEGs) with prognostic potentials. Transcriptome microarray data of five GEO datasets (GSE15471, GSE16515, GSE18670, GSE32676, GSE71989), including 117 primary tumor samples and 73 normal pancreatic tissue samples, were utilized to identify DEGs. The five sets of DEGs had an overlapping subset consisting of 98 genes (90 up-regulated and 8 down-regulated), which were probably common to pancreatic cancer. Gene ontology (GO) analysis of the 98 DEGs showed that cell cycle and cell adhesion were the major enriched processes, and extracellular matrix (ECM)-receptor interaction and p53 signaling pathway were the most enriched pathways according to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Elevated expression of gap junction protein beta 2 (GJB2) and reduced endoplasmic reticulum oxidoreductase 1-like beta (ERO1LB) expression were validated in an independent cohort. Kaplan-Meier survival analysis revealed that GJB2 and ERO1LB levels were significantly associated with the overall survival of pancreatic cancer patients. GJB2 and ERO1LB are implicated in pancreatic cancer progression and can be used to predict patient survival. Therapeutic strategies targeting GJB2 and facilitating ERO1LB expression may deserve evaluation to improve prognosis of pancreatic cancer patients.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

PubMed

Harris, P N A; McNamara, J F; Lye, D C; Davis, J S; Bernard, L; Cheng, A C; Doi, Y; Fowler, V G; Kaye, K S; Leibovici, L; Lipman, J; Llewelyn, M J; Munoz-Price, S; Paul, M; Peleg, A Y; Rodríguez-Baño, J; Rogers, B A; Seifert, H; Thamlikitkul, V; Thwaites, G; Tong, S Y C; Turnidge, J; Utili, R; Webb, S A R; Paterson, D L

2017-08-01

To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. All rights reserved.

Technique Refinement and Validation of Variable Aortic Occlusion via Extracorporeal Flow Circuit in a Pig Model (Sus scrofa) of Uncontrolled Hemorrhage with Subsequent Resuscitation and Critical Care

DTIC Science & Technology

2016-07-24

60th Medical Group (AMC), Travis AFB, CA INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) FINAL REPORT SUMMARY (Please type all information. Use...TRIENNIAL REVISION DATE: N/A FUNDING SOURCE: HQ USAF SG 1. RECORD OF ANIMAL USAGE: Animal Species: Total # Approved # Used this FY Total # Used to...Restraint Training: non-Live Animal Health Promotion Research: Survival (chronic) Prevention x_ Research: non-Survival (acute) Utilization Mgt. Other

Prognostic Metabolite Biomarkers for Soft Tissue Sarcomas Discovered by Mass Spectrometry Imaging

NASA Astrophysics Data System (ADS)

Lou, Sha; Balluff, Benjamin; Cleven, Arjen H. G.; Bovée, Judith V. M. G.; McDonnell, Liam A.

2017-02-01

Metabolites can be an important read-out of disease. The identification and validation of biomarkers in the cancer metabolome that can stratify high-risk patients is one of the main current research aspects. Mass spectrometry has become the technique of choice for metabolomics studies, and mass spectrometry imaging (MSI) enables their visualization in patient tissues. In this study, we used MSI to identify prognostic metabolite biomarkers in high grade sarcomas; 33 high grade sarcoma patients, comprising osteosarcoma, leiomyosarcoma, myxofibrosarcoma, and undifferentiated pleomorphic sarcoma were analyzed. Metabolite MSI data were obtained from sections of fresh frozen tissue specimens with matrix-assisted laser/desorption ionization (MALDI) MSI in negative polarity using 9-aminoarcridine as matrix. Subsequent annotation of tumor regions by expert pathologists resulted in tumor-specific metabolite signatures, which were then tested for association with patient survival. Metabolite signals with significant clinical value were further validated and identified by high mass resolution Fourier transform ion cyclotron resonance (FTICR) MSI. Three metabolite signals were found to correlate with overall survival ( m/z 180.9436 and 241.0118) and metastasis-free survival ( m/z 160.8417). FTICR-MSI identified m/z 241.0118 as inositol cyclic phosphate and m/z 160.8417 as carnitine.

Prognostic models for renal cell carcinoma recurrence: external validation in a Japanese population.

PubMed

Utsumi, Takanobu; Ueda, Takeshi; Fukasawa, Satoshi; Komaru, Atsushi; Sazuka, Tomokazu; Kawamura, Koji; Imamoto, Takashi; Nihei, Naoki; Suzuki, Hiroyoshi; Ichikawa, Tomohiko

2011-09-01

The aim of the present study was to compare the accuracy of three prognostic models in predicting recurrence-free survival among Japanese patients who underwent nephrectomy for non-metastatic renal cell carcinoma (RCC). Patients originated from two centers: Chiba University Hospital (n = 152) and Chiba Cancer Center (n = 65). The following data were collected: age, sex, clinical presentation, Eastern Cooperative Oncology Group performance status, surgical technique, 1997 tumor-node-metastasis stage, clinical and pathological tumor size, histological subtype, disease recurrence, and progression. Three western models, including Yaycioglu's model, Cindolo's model and Kattan's nomogram, were used to predict recurrence-free survival. Predictive accuracy of these models were validated by using Harrell's concordance-index. Concordance-indexes were 0.795 and 0.745 for Kattan's nomogram, 0.700 and 0.634 for Yaycioglu's model, and 0.700 and 0.634 for Cindolo's model, respectively. Furthermore, the constructed calibration plots of Kattan's nomogram overestimated the predicted probability of recurrence-free survival after 5 years compared with the actual probability. Our findings suggest that despite working better than other predictive tools, Kattan's nomogram needs be used with caution when applied to Japanese patients who have undergone nephrectomy for non-metastatic RCC. © 2011 The Japanese Urological Association.

Is the survival-processing memory advantage due to richness of encoding?

PubMed

Röer, Jan P; Bell, Raoul; Buchner, Axel

2013-07-01

Memory for words rated according to their relevance in a grassland survival context is exceptionally good. According to Nairne, Thompson, and Pandeirada's (2007) evolutionary-based explanation, natural selection processes have tuned the human memory system to prioritize the processing of fitness-relevant information. The survival-processing memory advantage has been replicated numerous times, but very little is known about the proximate mechanisms behind it. The richness-of-encoding hypothesis (Kroneisen & Erdfelder, 2011) implies that rating the usefulness of items in a survival context leads to the generation of a large number of ideas that may be used as retrieval cues at test to boost recall. In Experiment 1, the typical survival-processing recall advantage was obtained when words were rated according to their usefulness in 1 of 3 fictional contexts. In Experiment 2, participants were asked to write down any ideas that came to mind when thinking about the usefulness of the words. Consistent with the richness-of-encoding hypothesis, participants generated more ideas in the survival condition than in the fitness-irrelevant control conditions. In Experiment 3, participants generated more ideas for congruent than for incongruent words, demonstrating that the richness-of-encoding hypothesis can also account for the previously obtained congruency effect on recall (Butler, Kang, & Roediger, 2009). In both experiments the number of ideas written down predicted future recall performance well. Our results provide further evidence for the assumption that richness of encoding is an important proximate mechanism involved in memory performance in the survival-processing paradigm. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Cancer and beyond: the question of survivorship.

PubMed

Breaden, K

1997-11-01

Today, more people are surviving cancer as a result of improved treatment and early diagnosis. In Australia, the 5-year survival rate for persons diagnosed with cancer is now approaching 50%. Although there is a growing population of cancer survivors, little is known about what surviving entails. Traditionally, a survivor has been defined as one who has been disease-free for more than 5 years. However, this definition does not take into account the experience nor the process of survival and the aim of this article is to document the process of surviving cancer as reflected in the experiences of cancer survivors. Using a method of hermeneutic phenomenology (as described by van Manen), the study draws on the stories of six women, who by their definition, are surviving cancer. A discussion of themes has been structured according to the everyday experiences of living in a body and living in time. The women describe a survival process that includes: 'feeling whole again'; 'the body as the house of suspicion'; 'the future in question'; 'changes in time'; 'lucky to be alive'; and 'sharing the journey'.

Dynamic frailty models based on compound birth-death processes.

PubMed

Putter, Hein; van Houwelingen, Hans C

2015-07-01

Frailty models are used in survival analysis to model unobserved heterogeneity. They accommodate such heterogeneity by the inclusion of a random term, the frailty, which is assumed to multiply the hazard of a subject (individual frailty) or the hazards of all subjects in a cluster (shared frailty). Typically, the frailty term is assumed to be constant over time. This is a restrictive assumption and extensions to allow for time-varying or dynamic frailties are of interest. In this paper, we extend the auto-correlated frailty models of Henderson and Shimakura and of Fiocco, Putter and van Houwelingen, developed for longitudinal count data and discrete survival data, to continuous survival data. We present a rigorous construction of the frailty processes in continuous time based on compound birth-death processes. When the frailty processes are used as mixtures in models for survival data, we derive the marginal hazards and survival functions and the marginal bivariate survival functions and cross-ratio function. We derive distributional properties of the processes, conditional on observed data, and show how to obtain the maximum likelihood estimators of the parameters of the model using a (stochastic) expectation-maximization algorithm. The methods are applied to a publicly available data set. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Adaptive Memory: Is There a Reproduction-Processing Effect?

PubMed

Seitz, Benjamin M; Polack, Cody W; Miller, Ralph R

2017-12-14

Like all biological systems, human memory is likely to have been influenced by evolutionary processes, and its abilities have been subjected to selective mechanisms. Consequently, human memory should be primed to better remember information relevant to one's evolutionary fitness. Supporting this view, participants asked to rate words based on their relevance to an imaginary survival situation better recall those words (even the words rated low in relevancy) than the same words rated with respect to non-survival situations. This mnemonic advantage is called the "survival-processing effect," and presumably it was selected for because it contributed to evolutionary fitness. The same reasoning suggests that there should be an advantage for recall of information that has been rated for relevancy to reproduction and/or mate seeking, although little evidence has existed to assess this proposition. We used an experimental design similar to that in the original survival-processing effect study (Nairne, Thompson, & Pandeirada, 2007) and across 3 experiments tested several newly designed scenarios to determine whether a reproduction-processing effect could be found in an ancestral environment, a modern mating environment, and an ancestral environment in which the emphasis was on raising offspring as opposed to finding a mate. Our results replicated the survival-processing effect but provided no evidence of a reproduction-processing effect when the scenario emphasized finding a mate. However, when rating items on their relevancy to raising one's offspring in an ancestral environment, a mnemonic advantage comparable to that of the survival-processing effect was found. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma.

PubMed

Tanguturi, Shyam K; Trippa, Lorenzo; Ramkissoon, Shakti H; Pelton, Kristine; Knoff, David; Sandak, David; Lindeman, Neal I; Ligon, Azra H; Beroukhim, Rameen; Parmigiani, Giovanni; Wen, Patrick Y; Ligon, Keith L; Alexander, Brian M

2017-07-01

Biomarkers can improve clinical trial efficiency, but designing and interpreting biomarker-driven trials require knowledge of relationships among biomarkers, clinical covariates, and endpoints. We investigated these relationships across genomic subgroups of glioblastoma (GBM) within our institution (DF/BWCC), validated results in The Cancer Genome Atlas (TCGA), and demonstrated potential impacts on clinical trial design and interpretation. We identified genotyped patients at DF/BWCC, and clinical associations across 4 common GBM genomic biomarker groups were compared along with overall survival (OS), progression-free survival (PFS), and survival post-progression (SPP). Significant associations were validated in TCGA. Biomarker-based clinical trials were simulated using various assumptions. Epidermal growth factor receptor (EGFR)(+) and p53(-) subgroups were more likely isocitrate dehydrogenase (IDH) wild-type. Phosphatidylinositol-3 kinase (PI3K)(+) patients were older, and patients with O6-DNA methylguanine-methyltransferase (MGMT)-promoter methylation were more often female. OS, PFS, and SPP were all longer for IDH mutant and MGMT methylated patients, but there was no independent prognostic value for other genomic subgroups. PI3K(+) patients had shorter PFS among IDH wild-type tumors, however, and no DF/BWCC long-term survivors were either EGFR(+) (0% vs 7%, P = .014) or p53(-) (0% vs 10%, P = .005). The degree of biomarker overlap impacted the efficiency of Bayesian-adaptive clinical trials, while PFS and OS distribution variation had less impact. Biomarker frequency was proportionally associated with sample size in all designs. We identified several associations between GBM genomic subgroups and clinical or molecular prognostic covariates and validated known prognostic factors in all survival periods. These results are important for biomarker-based trial design and interpretation of biomarker-only and nonrandomized trials. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Nonparametric Discrete Survival Function Estimation with Uncertain Endpoints Using an Internal Validation Subsample

PubMed Central

Zee, Jarcy; Xie, Sharon X.

2015-01-01

Summary When a true survival endpoint cannot be assessed for some subjects, an alternative endpoint that measures the true endpoint with error may be collected, which often occurs when obtaining the true endpoint is too invasive or costly. We develop an estimated likelihood function for the situation where we have both uncertain endpoints for all participants and true endpoints for only a subset of participants. We propose a nonparametric maximum estimated likelihood estimator of the discrete survival function of time to the true endpoint. We show that the proposed estimator is consistent and asymptotically normal. We demonstrate through extensive simulations that the proposed estimator has little bias compared to the naïve Kaplan-Meier survival function estimator, which uses only uncertain endpoints, and more efficient with moderate missingness compared to the complete-case Kaplan-Meier survival function estimator, which uses only available true endpoints. Finally, we apply the proposed method to a dataset for estimating the risk of developing Alzheimer's disease from the Alzheimer's Disease Neuroimaging Initiative. PMID:25916510

Genetics and biology of pancreatic ductal adenocarcinoma

PubMed Central

Ying, Haoqiang; Dey, Prasenjit; Yao, Wantong; Kimmelman, Alec C.; Draetta, Giulio F.; Maitra, Anirban; DePinho, Ronald A.

2016-01-01

With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. PMID:26883357

Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response

PubMed Central

Feinerman, Ofer; Jentsch, Garrit; Tkach, Karen E; Coward, Jesse W; Hathorn, Matthew M; Sneddon, Michael W; Emonet, Thierry; Smith, Kendall A; Altan-Bonnet, Grégoire

2010-01-01

Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin-2 (IL-2) signaling in a population of T cells during an immune response by combining in silico modeling and single-cell measurements in vitro. We demonstrate that IL-2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL-2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug-of-war for IL-2 between regulatory (Treg) and effector (Teff) T cells, whereby access to IL-2 can either increase the survival of Teff cells or the suppressive capacity of Treg cells. This tug-of-war is the mechanism enforcing, at the systems level, a core function of Treg cells, namely the specific suppression of survival signals for weakly activated Teff cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of Treg suppression. PMID:21119631

Cancer astrocytes have a more conserved molecular status in long recurrence free survival (RFS) IDH1 wild-type glioblastoma patients: new emerging cancer players

PubMed Central

Franceschi, Sara; Lessi, Francesca; Aretini, Paolo; Ortenzi, Valerio; Scatena, Cristian; Menicagli, Michele; La Ferla, Marco; Civita, Prospero; Zavaglia, Katia; Scopelliti, Claudia; Apollo, Alessandro; Carbone, Francesco Giovanni; Vannozzi, Riccardo; Bevilacqua, Generoso; Pasqualetti, Francesco; Naccarato, Antonio Giuseppe; Mazzanti, Chiara Maria

2018-01-01

Glioblastoma is a devastating disease that despite all the information gathered so far, its optimal management remains elusive due to the absence of validated targets from clinical studies. A better clarification of the molecular mechanisms is needed. In this study, having access to IDH1 wild-type glioblastoma of patients with exceptionally long recurrence free survival (RFS), we decided to compare their mutational and gene expression profile to groups of IDH1 wild-type glioblastoma of patients with shorter RFS, by using NGS technology. The exome analysis revealed that Long-RFS tumors have a lower mutational rate compared to the other groups. A total of 158 genes were found differentially expressed among the groups, 112 of which distinguished the two RFS extreme groups. Overall, the exome data suggests that shorter RFS tumors could be, chronologically, in a more advanced state in the muli-step tumor process of sequential accumulation of mutations. New players in this kind of cancer emerge from the analysis, confirmed at the RNA/DNA level, identifying, therefore, possible oncodrivers or tumor suppressor genes. PMID:29844869

Adaptive memory: enhanced location memory after survival processing.

PubMed

Nairne, James S; Vanarsdall, Joshua E; Pandeirada, Josefa N S; Blunt, Janell R

2012-03-01

Two experiments investigated whether survival processing enhances memory for location. From an adaptive perspective, remembering that food has been located in a particular area, or that potential predators are likely to be found in a given territory, should increase the chances of subsequent survival. Participants were shown pictures of food or animals located at various positions on a computer screen. The task was to rate the ease of collecting the food or capturing the animals relative to a central fixation point. Surprise retention tests revealed that people remembered the locations of the items better when the collection or capturing task was described as relevant to survival. These data extend the generality of survival processing advantages to a new domain (location memory) by means of a task that does not involve rating the relevance of words to a scenario. 2012 APA, all rights reserved

Threats to validity of nonrandomized studies of postdiagnosis exposures on cancer recurrence and survival.

PubMed

Chubak, Jessica; Boudreau, Denise M; Wirtz, Heidi S; McKnight, Barbara; Weiss, Noel S

2013-10-02

Studies of the effects of exposures after cancer diagnosis on cancer recurrence and survival can provide important information to the growing group of cancer survivors. Observational studies that address this issue generally fall into one of two categories: 1) those using health plan automated data that contain "continuous" information on exposures, such as studies that use pharmacy records; and 2) survey or interview studies that collect information directly from patients once or periodically postdiagnosis. Reverse causation, confounding, selection bias, and information bias are common in observational studies of cancer outcomes in relation to exposures after cancer diagnosis. We describe these biases, focusing on sources of bias specific to these types of studies, and we discuss approaches for reducing them. Attention to known challenges in epidemiologic research is critical for the validity of studies of postdiagnosis exposures and cancer outcomes.

Threats to Validity of Nonrandomized Studies of Postdiagnosis Exposures on Cancer Recurrence and Survival

PubMed Central

2013-01-01

Studies of the effects of exposures after cancer diagnosis on cancer recurrence and survival can provide important information to the growing group of cancer survivors. Observational studies that address this issue generally fall into one of two categories: 1) those using health plan automated data that contain “continuous” information on exposures, such as studies that use pharmacy records; and 2) survey or interview studies that collect information directly from patients once or periodically postdiagnosis. Reverse causation, confounding, selection bias, and information bias are common in observational studies of cancer outcomes in relation to exposures after cancer diagnosis. We describe these biases, focusing on sources of bias specific to these types of studies, and we discuss approaches for reducing them. Attention to known challenges in epidemiologic research is critical for the validity of studies of postdiagnosis exposures and cancer outcomes. PMID:23940288

Relative Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor, Dacarbazine, and Glycoprotein 100 in Metastatic Melanoma: An Indirect Treatment Comparison.

PubMed

Quinn, Casey; Ma, Qiufei; Kudlac, Amber; Palmer, Stephen; Barber, Beth; Zhao, Zhongyun

2017-02-01

Advances in the treatment of metastatic melanoma have been achieved in recent years: immunotherapies and targeted therapies have demonstrated survival benefits over older agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF), dacarbazine, and glycoprotein peptide vaccine (gp100) in pivotal phase 3 trials. It is important to compare therapies to guide the treatment decision-making process, and establishing the relationship between older agents can strengthen the networks of evidence for newer therapies. We report the outcome of an indirect comparison of GM-CSF, dacarbazine, and gp100 in metastatic melanoma through meta-analysis of absolute treatment effect. A systematic literature review identified trials for inclusion in the meta-analysis. A valid network meta-analysis was not feasible: treatment-specific meta-analysis was conducted. A published algorithm was used to adjust overall survival estimates from trials of GM-CSF, dacarbazine, and gp100 for heterogeneity in baseline prognostic factors. Survival estimates were compared in three patient groups: stage IIIB-IV M1c, stage IIIB-IV M1a, and stage IV M1b/c. One trial of GM-CSF, four of dacarbazine, and one of gp100 were included in the analysis. After adjusting for differences in baseline prognostic factors, median overall survival (OS) in all patient groups was longer for those receiving GM-CSF than for those receiving dacarbazine or gp100. The observed survival over time for GM-CSF was similar to the adjusted survival for dacarbazine and greater than for gp100 in all patient groups. The relative treatment effect of GM-CSF, dacarbazine, and gp100 has been reliably estimated by adjusting for differences in baseline prognostic factors. Results suggest that OS with GM-CSF is at least as good as with dacarbazine and greater than with gp100. Given the role of these agents as controls in phase 3 trials of new immunotherapies and targeted agents, these results can be used to contextualize the efficacy of newer therapies. Amgen Inc.

Clinical and Pathological Staging Validation in the Eighth Edition of the TNM Classification for Lung Cancer: Correlation between Solid Size on Thin-Section Computed Tomography and Invasive Size in Pathological Findings in the New T Classification.

PubMed

Aokage, Keiju; Miyoshi, Tomohiro; Ishii, Genichiro; Kusumoto, Masahiro; Nomura, Shogo; Katsumata, Shinya; Sekihara, Keigo; Hishida, Tomoyuki; Tsuboi, Masahiro

2017-09-01

The aim of this study was to validate the new eighth edition of the TNM classification and to elucidate whether radiological solid size corresponds to pathological invasive size incorporated in this T factor. We analyzed the data on 1792 patients who underwent complete resection from 2003 to 2011 at the National Cancer Center Hospital East, Japan. We reevaluated preoperative thin-section computed tomography (TSCT) to determine solid size and pathological invasive size using the fourth edition of the WHO classification and reclassified them according to the new TNM classification. The discriminative power of survival curves by the seventh edition was compared with that by the eighth edition by using concordance probability estimates and Akaike's information criteria calculated using a univariable Cox regression model. Pearson's correlation coefficient was calculated to elucidate the correlation between radiological solid size using TSCT and pathological invasive size. The overall survival curves in the eighth edition were well distinct at each clinical and pathological stage. The 5-year survival rates of patients with clinical and pathological stage 0 newly defined were both 100%. The concordance probability estimate and Akaike's information criterion values of the eighth edition were higher than those of the seventh edition in discriminatory power for overall survival. Solid size on TSCT scan and pathological invasive size showed a positive linear relationship, and Pearson's correlation coefficient was calculated as 0.83, which indicated strong correlation. This TNM classification will be feasible regarding patient survival, and radiological solid size correlates significantly with pathological invasive size as a new T factor. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Can the prognosis of individual patients with glioblastoma be predicted using an online calculator?

PubMed Central

Parks, Christopher; Heald, James; Hall, Gregory; Kamaly-Asl, Ian

2013-01-01

Background In an exploratory subanalysis of the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada (EORTC/NCIC) trial data, Gorlia et al. identified a variety of factors that were predictive of overall survival, including therapy administered, age, extent of surgery, mini-mental score, administration of corticosteroids, World Health Organization (WHO) performance status, and O-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Gorlia et al. developed 3 nomograms, each intended to predict the survival times of patients with newly diagnosed glioblastoma on the basis of individual-specific combinations of prognostic factors. These are available online as a “GBM Calculator” and are intended for use in patient counseling. This study is an external validation of this calculator. Method One hundred eighty-seven patients from 2 UK neurosurgical units who had histologically confirmed glioblastoma (WHO grade IV) had their information at diagnosis entered into the GBM calculator. A record was made of the actual and predicted median survival time for each patient. Statistical analysis was performed to assess the accuracy, precision, correlation, and discrimination of the calculator. Results The calculator gives both inaccurate and imprecise predictions. Only 23% of predictions were within 25% of the actual survival, and the percentage bias is 140% in our series. The coefficient of variance is 76%, where a smaller percentage would indicate greater precision. There is only a weak positive correlation between the predicted and actual survival among patients (R2 of 0.07). Discrimination is inadequate as measured by a C-index of 0.62. Conclusions The authors would not recommend the use of this tool in patient counseling. If departments were considering its use, we would advise that a similar validating exercise be undertaken. PMID:23543729

Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model: A Web-based program designed to evaluate the cost-effectiveness of disease management programs in heart failure.

PubMed

Reed, Shelby D; Neilson, Matthew P; Gardner, Matthew; Li, Yanhong; Briggs, Andrew H; Polsky, Daniel E; Graham, Felicia L; Bowers, Margaret T; Paul, Sara C; Granger, Bradi B; Schulman, Kevin A; Whellan, David J; Riegel, Barbara; Levy, Wayne C

2015-11-01

Heart failure disease management programs can influence medical resource use and quality-adjusted survival. Because projecting long-term costs and survival is challenging, a consistent and valid approach to extrapolating short-term outcomes would be valuable. We developed the Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model, a Web-based simulation tool designed to integrate data on demographic, clinical, and laboratory characteristics; use of evidence-based medications; and costs to generate predicted outcomes. Survival projections are based on a modified Seattle Heart Failure Model. Projections of resource use and quality of life are modeled using relationships with time-varying Seattle Heart Failure Model scores. The model can be used to evaluate parallel-group and single-cohort study designs and hypothetical programs. Simulations consist of 10,000 pairs of virtual cohorts used to generate estimates of resource use, costs, survival, and incremental cost-effectiveness ratios from user inputs. The model demonstrated acceptable internal and external validity in replicating resource use, costs, and survival estimates from 3 clinical trials. Simulations to evaluate the cost-effectiveness of heart failure disease management programs across 3 scenarios demonstrate how the model can be used to design a program in which short-term improvements in functioning and use of evidence-based treatments are sufficient to demonstrate good long-term value to the health care system. The Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model provides researchers and providers with a tool for conducting long-term cost-effectiveness analyses of disease management programs in heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.

Fractional differential equations based modeling of microbial survival and growth curves: model development and experimental validation.

PubMed

Kaur, A; Takhar, P S; Smith, D M; Mann, J E; Brashears, M M

2008-10-01

A fractional differential equations (FDEs)-based theory involving 1- and 2-term equations was developed to predict the nonlinear survival and growth curves of foodborne pathogens. It is interesting to note that the solution of 1-term FDE leads to the Weibull model. Nonlinear regression (Gauss-Newton method) was performed to calculate the parameters of the 1-term and 2-term FDEs. The experimental inactivation data of Salmonella cocktail in ground turkey breast, ground turkey thigh, and pork shoulder; and cocktail of Salmonella, E. coli, and Listeria monocytogenes in ground beef exposed at isothermal cooking conditions of 50 to 66 degrees C were used for validation. To evaluate the performance of 2-term FDE in predicting the growth curves-growth of Salmonella typhimurium, Salmonella Enteritidis, and background flora in ground pork and boneless pork chops; and E. coli O157:H7 in ground beef in the temperature range of 22.2 to 4.4 degrees C were chosen. A program was written in Matlab to predict the model parameters and survival and growth curves. Two-term FDE was more successful in describing the complex shapes of microbial survival and growth curves as compared to the linear and Weibull models. Predicted curves of 2-term FDE had higher magnitudes of R(2) (0.89 to 0.99) and lower magnitudes of root mean square error (0.0182 to 0.5461) for all experimental cases in comparison to the linear and Weibull models. This model was capable of predicting the tails in survival curves, which was not possible using Weibull and linear models. The developed model can be used for other foodborne pathogens in a variety of food products to study the destruction and growth behavior.

Attentional Bias to Beauty with Evolutionary Benefits: Evidence from Aesthetic Appraisal of Landscape Architecture

PubMed Central

Zhang, Wei; Tang, Xiaoxiang; He, Xianyou; Lai, Shuxian

2018-01-01

Substantial evidence suggests that beauty is associated with the survival and reproduction of organisms. Landscape architecture is composed of a series of natural elements that have significant evolutionary implications. The present study used one pilot material ratings and three experiments to examine the mechanisms of aesthetic appraisals of landscape architecture. The results confirmed that landscape architecture elicited a sense of beauty and captured visual attention more easily than other types of architecture during explicit aesthetic rating task (Experiment 1) and implicit aesthetic perception task (dot-probe paradigm, Experiment 2). Furthermore, the spatial cueing paradigm revealed that response latencies were significantly faster for landscape architecture than non-landscape architecture on valid trials, but there was no significant difference in this contrast on invalid trials at 150-ms stimulus onset asynchrony (SOA, Experiment 3a). At 500-ms SOA (Experiment 3b), participants responded significantly faster for landscape architecture on valid trials, but reacted significantly slower for landscape architecture on invalid trials. The findings indicated that the beauty of landscape architecture can be perceived implicitly, and only faster orienting of attention, but not delayed disengagement of attention was generated at early stages of the processing of landscape architecture. However, the attentional bias at later stages of attentional processes may be resulted from both faster orienting of attention and delayed disengagement of attention from landscape architecture photographs. PMID:29467696

Attentional Bias to Beauty with Evolutionary Benefits: Evidence from Aesthetic Appraisal of Landscape Architecture.

PubMed

Zhang, Wei; Tang, Xiaoxiang; He, Xianyou; Lai, Shuxian

2018-01-01

Substantial evidence suggests that beauty is associated with the survival and reproduction of organisms. Landscape architecture is composed of a series of natural elements that have significant evolutionary implications. The present study used one pilot material ratings and three experiments to examine the mechanisms of aesthetic appraisals of landscape architecture. The results confirmed that landscape architecture elicited a sense of beauty and captured visual attention more easily than other types of architecture during explicit aesthetic rating task (Experiment 1) and implicit aesthetic perception task (dot-probe paradigm, Experiment 2). Furthermore, the spatial cueing paradigm revealed that response latencies were significantly faster for landscape architecture than non-landscape architecture on valid trials, but there was no significant difference in this contrast on invalid trials at 150-ms stimulus onset asynchrony (SOA, Experiment 3a). At 500-ms SOA (Experiment 3b), participants responded significantly faster for landscape architecture on valid trials, but reacted significantly slower for landscape architecture on invalid trials. The findings indicated that the beauty of landscape architecture can be perceived implicitly, and only faster orienting of attention, but not delayed disengagement of attention was generated at early stages of the processing of landscape architecture. However, the attentional bias at later stages of attentional processes may be resulted from both faster orienting of attention and delayed disengagement of attention from landscape architecture photographs.

Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab

PubMed Central

Custodio, A; Carmona-Bayonas, A; Jiménez-Fonseca, P; Sánchez, M L; Viudez, A; Hernández, R; Cano, J M; Echavarria, I; Pericay, C; Mangas, M; Visa, L; Buxo, E; García, T; Rodríguez Palomo, A; Álvarez Manceñido, F; Lacalle, A; Macias, I; Azkarate, A; Ramchandani, A; Fernández Montes, A; López, C; Longo, F; Sánchez Bayona, R; Limón, M L; Díaz-Serrano, A; Hurtado, A; Madero, R; Gómez, C; Gallego, J

2017-01-01

Background: To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination chemotherapy. Methods: Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrell's c-index was used to evaluate discrimination. Results: The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5–6.6), 9.4 (95% CI, 8.5–10.6), and 14 months (95% CI, 11.8–16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3–8.1), 12.7 (95% CI, 11.3–14.3), and 18.3 months (95% CI, 14.6–24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591–0.631) and 0.673 (95% CI, 0.636–0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351). Conclusions: We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design. PMID:28463962

Extensions of the survival advantage in memory: examining the role of ancestral context and implied social isolation.

PubMed

Kostic, Bogdan; McFarlan, Chastity C; Cleary, Anne M

2012-07-01

Recent work (e.g., Nairne & Pandeirada, 2010) has shown that words are remembered better when they have been processed for their survival value in a grasslands context than when processed in other contexts. It has been suggested that this is because human memory systems were shaped by evolution specifically to help humans survive. Thus far, the survival processing advantage has mainly been shown with grasslands contexts, which are thought to be particularly relevant to human evolution. The present study demonstrated the survival processing advantage with other contexts (e.g., lost in a jungle), including with contexts that should not, in and of themselves, be relevant to human evolution (e.g., lost in outer space). We further examined whether implied social isolation plays a critical role in the survival advantage to memory by comparing scenarios in which the person is alone versus with other people present (e.g., lost at sea alone or with others), and whether the perceived source of danger is social isolation or other human attackers. A survival advantage was shown in both the isolation and the group settings, and whether the primary source of danger was isolation or other human attackers did not matter. These findings suggest that the survival advantage in memory is not dependent on evolutionarily relevant physical contexts (e.g., grasslands) or particular sources of perceived danger (social isolation vs. perceived attackers), showing the advantage to be robust and applicable to a variety of scenarios. 2012 APA, all rights reserved

A Twin Protection Effect? Explaining Twin Survival Advantages with a Two-Process Mortality Model

PubMed Central

2016-01-01

Twin studies that focus on the correlation in age-at-death between twin pairs have yielded important insights into the heritability and role of genetic factors in determining lifespan, but less attention is paid to the biological and social role of zygosity itself in determining survival across the entire life course. Using data from the Danish Twin Registry and the Human Mortality Database, we show that monozygotic twins have greater cumulative survival proportions at nearly every age compared to dizygotic twins and the Danish general population. We examine this survival advantage by fitting these data with a two-process mortality model that partitions survivorship patterns into extrinsic and intrinsic mortality processes roughly corresponding to acute, environmental and chronic, biological origins. We find intrinsic processes confer a survival advantage at older ages for males, while at younger ages, all monozygotic twins show a health protection effect against extrinsic death akin to a marriage protection effect. While existing research suggests an increasingly important role for genetic factors at very advanced ages, we conclude that the social closeness of monozygotic twins is a plausible driver of the survival advantage at ages <65. PMID:27192433

Identification and Construction of Combinatory Cancer Hallmark-Based Gene Signature Sets to Predict Recurrence and Chemotherapy Benefit in Stage II Colorectal Cancer.

PubMed

Gao, Shanwu; Tibiche, Chabane; Zou, Jinfeng; Zaman, Naif; Trifiro, Mark; O'Connor-McCourt, Maureen; Wang, Edwin

2016-01-01

Decisions regarding adjuvant therapy in patients with stage II colorectal cancer (CRC) have been among the most challenging and controversial in oncology over the past 20 years. To develop robust combinatory cancer hallmark-based gene signature sets (CSS sets) that more accurately predict prognosis and identify a subset of patients with stage II CRC who could gain survival benefits from adjuvant chemotherapy. Thirteen retrospective studies of patients with stage II CRC who had clinical follow-up and adjuvant chemotherapy were analyzed. Respective totals of 162 and 843 patients from 2 and 11 independent cohorts were used as the discovery and validation cohorts, respectively. A total of 1005 patients with stage II CRC were included in the 13 cohorts. Among them, 84 of 416 patients in 3 independent cohorts received fluorouracil-based adjuvant chemotherapy. Identification of CSS sets to predict relapse-free survival and identify a subset of patients with stage II CRC who could gain substantial survival benefits from fluorouracil-based adjuvant chemotherapy. Eight cancer hallmark-based gene signatures (30 genes each) were identified and used to construct CSS sets for determining prognosis. The CSS sets were validated in 11 independent cohorts of 767 patients with stage II CRC who did not receive adjuvant chemotherapy. The CSS sets accurately stratified patients into low-, intermediate-, and high-risk groups. Five-year relapse-free survival rates were 94%, 78%, and 45%, respectively, representing 60%, 28%, and 12% of patients with stage II disease. The 416 patients with CSS set-defined high-risk stage II CRC who received fluorouracil-based adjuvant chemotherapy showed a substantial gain in survival benefits from the treatment (ie, recurrence reduced by 30%-40% in 5 years). The CSS sets substantially outperformed other prognostic predictors of stage 2 CRC. They are more accurate and robust for prognostic predictions and facilitate the identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy.

Prediction of cancer specific survival after radical nephroureterectomy for upper tract urothelial carcinoma: development of an optimized postoperative nomogram using decision curve analysis.

PubMed

Rouprêt, Morgan; Hupertan, Vincent; Seisen, Thomas; Colin, Pierre; Xylinas, Evanguelos; Yates, David R; Fajkovic, Harun; Lotan, Yair; Raman, Jay D; Zigeuner, Richard; Remzi, Mesut; Bolenz, Christian; Novara, Giacomo; Kassouf, Wassim; Ouzzane, Adil; Rozet, François; Cussenot, Olivier; Martinez-Salamanca, Juan I; Fritsche, Hans-Martin; Walton, Thomas J; Wood, Christopher G; Bensalah, Karim; Karakiewicz, Pierre I; Montorsi, Francesco; Margulis, Vitaly; Shariat, Shahrokh F

2013-05-01

We conceived and proposed a unique and optimized nomogram to predict cancer specific survival after radical nephroureterectomy in patients with upper tract urothelial carcinoma by merging the 2 largest multicenter data sets reported in this population. The international and the French national collaborative groups on upper tract urothelial carcinoma pooled data on 3,387 patients treated with radical nephroureterectomy for whom full data for nomogram development were available. The merged study population was randomly split into the development cohort (2,371) and the external validation cohort (1,016). Cox regressions were used for univariable and multivariable analyses, and to build different models. The ultimate reduced nomogram was assessed using Harrell's concordance index (c-index) and decision curve analysis. Of the 2,371 patients in the nomogram development cohort 510 (21.5%) died of upper tract urothelial carcinoma during followup. The actuarial cancer specific survival probability at 5 years was 73.7% (95% CI 71.9-75.6). Decision curve analysis revealed that the use of the best model was associated with benefit gains relative to the prediction of cancer specific survival. The optimized nomogram included only 5 variables associated with cancer specific survival on multivariable analysis, those of age (p = 0.001), T stage (p <0.001), N stage (p = 0.001), architecture (p = 0.02) and lymphovascular invasion (p = 0.001). The discriminative accuracy of the nomogram was 0.8 (95% CI 0.77-0.86). Using standard pathological features obtained from the largest data set of upper tract urothelial carcinomas worldwide, we devised and validated an accurate and ultimate nomogram, superior to any single clinical variable, for predicting cancer specific survival after radical nephroureterectomy. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Validation of the CPS + EG Staging System for Disease-Specific Survival in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

PubMed

Abdelsattar, Jad M; Al-Hilli, Zahraa; Hoskin, Tanya L; Heins, Courtney N; Boughey, Judy C

2016-10-01

CPS + EG staging, which incorporates estrogen receptor (ER) status and tumor grade with pretreatment clinical stage (CS) and post-treatment pathologic stage (PS), has been reported to have better correlation with outcome than classic TNM staging for patients treated with neoadjuvant chemotherapy (NAC). Our goal was to evaluate the performance of CPS + EG staging system in an external cohort treated with NAC. We reviewed patients with stages I-IIIC breast cancer treated with NAC and surgery at our institution between 1988 and 2014. ER status, Nottingham grade, treatment, American Joint Committee on Cancer (AJCC) CS before NAC and PS after NAC, and follow-up data were collected. The discrimination of CPS + EG and pathologic AJCC stage were assessed using area under the curve (AUC) for survival data. A total of 769 patients were analyzed with a median follow-up of 2.6 (range 0.0-19.4) years; 103 patients died of breast cancer. Overall, the 5-year breast cancer cause-specific survival was 81.5 % [95 % confidence interval (CI) 77.6-85.5]. The 5-year, cause-specific survival by CPS + EG score was 93.8 % score 0, 89.9 % score 1, 90.7 % score 2, 84.8 % score 3, 67.7 % score 4, and 43.4 % score 5/6. CPS + EG score was significantly associated with cause-specific survival (p < 0.001) with an AUC of 0.69 (95 % CI 0.62-0.77) at 5 years. This was higher than the AUC of 0.63 (95 % CI 0.56-0.70) for AJCC PS (p = 0.10). This study validates the CPS + EG staging system using Nottingham grade in an external cohort. Addition of tumor biology and treatment response shows promise in improving survival estimates for patients treated with NAC.

Validation and modification of a proposed substaging system for patients with intermediate hepatocellular carcinoma.

PubMed

Wang, Jing-Houng; Kee, Kwong-Ming; Lin, Chih-Yun; Hung, Chao-Hung; Chen, Chien-Hung; Lee, Chuan-Mo; Lu, Sheng-Nan

2015-02-01

Based on up-to-seven criteria and Child-Pugh score, four substages of Barcelona Clinic Liver Cancer (BCLC) intermediate hepatocellular carcinoma (HCC) were proposed. The purpose of this study was to validate and modify this proposal. Between January 2002 and February 2011, newly diagnosed intermediate HCC patients underwent transarterial embolization (TAE) were enrolled. Patients were stratified into four (B1-B4) substages and followed up until death or end of 2012. Patients' survivals and discriminatory ability of substaging systems were compared. Five-hundred and eighty patients were enrolled. There were 56.6%, 33.8%, 7.4%, and 2.2% in substage B1, B2, B3, and B4. The 5-year survival rate was 21.4%, 13.9%, 7.4%, and 7.7% with median survival time of 2.4, 1.3, 0.5, and 0.8 years (P < 0.001). In addition to substage B1-B4, α-fetoprotein (AFP) level was an independent factor associated with survival in multivariate analysis. According to AFP < or > 200 ng/mL, B1 was classified into B1a and B1b, and B2 into B2a and B2b. There were no differences in survivals between B1b and B2a (P = 0.174), and B2b and B3 (P = 0.785). Patients were re-classified into modified (m)B1 (B1a), mB2 (B1b + B2a), mB3 (B2b + B3). The modified substages (mB1-mB3) showed a more desirable substaging system. For BCLC intermediate HCC patients, substages B1-B4 were useful in predicting survival after TAE. However, modified substaging system provided better prognostic prediction. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Validation of serum amyloid α as an independent biomarker for progression-free and overall survival in metastatic renal cell cancer patients.

PubMed

Vermaat, Joost S; Gerritse, Frank L; van der Veldt, Astrid A; Roessingh, Wijnand M; Niers, Tatjana M; Oosting, Sjoukje F; Sleijfer, Stefan; Roodhart, Jeanine M; Beijnen, Jos H; Schellens, Jan H; Gietema, Jourik A; Boven, Epie; Richel, Dick J; Haanen, John B; Voest, Emile E

2012-10-01

We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model. Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs). For training we used 114 interferon-treated mRCC patients (inclusion 2001-2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003-2009). Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect. Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6-8 wk of TKI treatment had no value in predicting treatment outcome. SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Establishment and Validation of RNA-Based Predictive Models for Understanding Survival of Vibrio parahaemolyticus in Oysters Stored at Low Temperatures

PubMed Central

Liao, Chao; Zhao, Yong

2017-01-01

ABSTRACT This study developed RNA-based predictive models describing the survival of Vibrio parahaemolyticus in Eastern oysters (Crassostrea virginica) during storage at 0, 4, and 10°C. Postharvested oysters were inoculated with a cocktail of five V. parahaemolyticus strains and were then stored at 0, 4, and 10°C for 21 or 11 days. A real-time reverse transcription-PCR (RT-PCR) assay targeting expression of the tlh gene was used to evaluate the number of surviving V. parahaemolyticus cells, which was then used to establish primary molecular models (MMs). Before construction of the MMs, consistent expression levels of the tlh gene at 0, 4, and 10°C were confirmed, and this gene was used to monitor the survival of the total V. parahaemolyticus cells. In addition, the tdh and trh genes were used for monitoring the survival of virulent V. parahaemolyticus. Traditional models (TMs) were built based on data collected using a plate counting method. From the MMs, V. parahaemolyticus populations had decreased 0.493, 0.362, and 0.238 log10 CFU/g by the end of storage at 0, 4, and 10°C, respectively. Rates of reduction of V. parahaemolyticus shown in the TMs were 2.109, 1.579, and 0.894 log10 CFU/g for storage at 0, 4, and 10°C, respectively. Bacterial inactivation rates (IRs) estimated with the TMs (−0.245, −0.152, and −0.121 log10 CFU/day, respectively) were higher than those estimated with the MMs (−0.134, −0.0887, and −0.0732 log10 CFU/day, respectively) for storage at 0, 4, and 10°C. Higher viable V. parahaemolyticus numbers were predicted using the MMs than using the TMs. On the basis of this study, RNA-based predictive MMs are the more accurate and reliable models and can prevent false-negative results compared to TMs. IMPORTANCE One important method for validating postharvest techniques and for monitoring the behavior of V. parahaemolyticus is to establish predictive models. Unfortunately, previous predictive models established based on plate counting methods or on DNA-based PCR can underestimate or overestimate the number of surviving cells. This study developed and validated RNA-based molecular predictive models to describe the survival of V. parahaemolyticus in oysters during low-temperature storage (0, 4, and 10°C). The RNA-based predictive models show the advantage of being able to count all of the culturable, nonculturable, and stressed cells. By using primers targeting the tlh gene and pathogenesis-associated genes (tdh and trh), real-time RT-PCR can evaluate the total surviving V. parahaemolyticus population as well as differentiate the pathogenic ones from the total population. Reliable and accurate predictive models are very important for conducting risk assessment and management of pathogens in food. PMID:28087532

Establishment and Validation of RNA-Based Predictive Models for Understanding Survival of Vibrio parahaemolyticus in Oysters Stored at Low Temperatures.

PubMed

Liao, Chao; Zhao, Yong; Wang, Luxin

2017-03-15

This study developed RNA-based predictive models describing the survival of Vibrio parahaemolyticus in Eastern oysters ( Crassostrea virginica ) during storage at 0, 4, and 10°C. Postharvested oysters were inoculated with a cocktail of five V. parahaemolyticus strains and were then stored at 0, 4, and 10°C for 21 or 11 days. A real-time reverse transcription-PCR (RT-PCR) assay targeting expression of the tlh gene was used to evaluate the number of surviving V. parahaemolyticus cells, which was then used to establish primary molecular models (MMs). Before construction of the MMs, consistent expression levels of the tlh gene at 0, 4, and 10°C were confirmed, and this gene was used to monitor the survival of the total V. parahaemolyticus cells. In addition, the tdh and trh genes were used for monitoring the survival of virulent V. parahaemolyticus Traditional models (TMs) were built based on data collected using a plate counting method. From the MMs, V. parahaemolyticus populations had decreased 0.493, 0.362, and 0.238 log 10 CFU/g by the end of storage at 0, 4, and 10°C, respectively. Rates of reduction of V. parahaemolyticus shown in the TMs were 2.109, 1.579, and 0.894 log 10 CFU/g for storage at 0, 4, and 10°C, respectively. Bacterial inactivation rates (IRs) estimated with the TMs (-0.245, -0.152, and -0.121 log 10 CFU/day, respectively) were higher than those estimated with the MMs (-0.134, -0.0887, and -0.0732 log 10 CFU/day, respectively) for storage at 0, 4, and 10°C. Higher viable V. parahaemolyticus numbers were predicted using the MMs than using the TMs. On the basis of this study, RNA-based predictive MMs are the more accurate and reliable models and can prevent false-negative results compared to TMs. IMPORTANCE One important method for validating postharvest techniques and for monitoring the behavior of V. parahaemolyticus is to establish predictive models. Unfortunately, previous predictive models established based on plate counting methods or on DNA-based PCR can underestimate or overestimate the number of surviving cells. This study developed and validated RNA-based molecular predictive models to describe the survival of V. parahaemolyticus in oysters during low-temperature storage (0, 4, and 10°C). The RNA-based predictive models show the advantage of being able to count all of the culturable, nonculturable, and stressed cells. By using primers targeting the tlh gene and pathogenesis-associated genes ( tdh and trh ), real-time RT-PCR can evaluate the total surviving V. parahaemolyticus population as well as differentiate the pathogenic ones from the total population. Reliable and accurate predictive models are very important for conducting risk assessment and management of pathogens in food. Copyright © 2017 American Society for Microbiology.

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

PubMed Central

Genova, Carlo; Mora, Marco; Dal Bello, Maria Giovanna; Vanni, Irene; Alama, Angela; Rijavec, Erika; Biello, Federica; Barletta, Giulia; Merlo, Domenico Franco; Valentino, Alessandro; Ferro, Paola; Ravetti, Gian Luigi; Stigliani, Sara; Vigani, Antonella; Fedeli, Franco; Beer, David G.; Roncella, Silvio; Grossi, Francesco

2017-01-01

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18–8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM. PMID:28978143

Nomograms Predicting Platinum Sensitivity, Progression-Free Survival, and Overall Survival Using Pretreatment Complete Blood Cell Counts in Epithelial Ovarian Cancer

PubMed Central

Paik, E Sun; Sohn, Insuk; Baek, Sun-Young; Shim, Minhee; Choi, Hyun Jin; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Kim, Byoung-Gie; Lee, Yoo-Young; Bae, Duk-Soo

2017-01-01

Purpose This study was conducted to evaluate the prognostic significance of pre-treatment complete blood cell count (CBC), including white blood cell (WBC) differential, in epithelial ovarian cancer (EOC) patients with primary debulking surgery (PDS) and to develop nomograms for platinum sensitivity, progression-free survival (PFS), and overall survival (OS). Materials and Methods We retrospectively reviewed the records of 757 patients with EOC whose primary treatment consisted of surgical debulking and chemotherapy at Samsung Medical Center from 2002 to 2012. We subsequently created nomograms for platinum sensitivity, 3-year PFS, and 5-year OS as prediction models for prognostic variables including age, stage, grade, cancer antigen 125 level, residual disease after PDS, and pre-treatment WBC differential counts. The models were then validated by 10-fold cross-validation (CV). Results In addition to stage and residual disease after PDS, which are known predictors, lymphocyte and monocyte count were found to be significant prognostic factors for platinum-sensitivity, platelet count for PFS, and neutrophil count for OS on multivariate analysis. The area under the curves of platinum sensitivity, 3-year PFS, and 5-year OS calculated by the 10-fold CV procedure were 0.7405, 0.8159, and 0.815, respectively. Conclusion Prognostic factors including pre-treatment CBC were used to develop nomograms for platinum sensitivity, 3-year PFS, and 5-year OS of patients with EOC. These nomograms can be used to better estimate individual outcomes. PMID:27669704

Nomograms Predicting Platinum Sensitivity, Progression-Free Survival, and Overall Survival Using Pretreatment Complete Blood Cell Counts in Epithelial Ovarian Cancer.

PubMed

Paik, E Sun; Sohn, Insuk; Baek, Sun-Young; Shim, Minhee; Choi, Hyun Jin; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Kim, Byoung-Gie; Lee, Yoo-Young; Bae, Duk-Soo

2017-07-01

This study was conducted to evaluate the prognostic significance of pre-treatment complete blood cell count (CBC), including white blood cell (WBC) differential, in epithelial ovarian cancer (EOC) patients with primary debulking surgery (PDS) and to develop nomograms for platinum sensitivity, progression-free survival (PFS), and overall survival (OS). We retrospectively reviewed the records of 757 patients with EOC whose primary treatment consisted of surgical debulking and chemotherapy at Samsung Medical Center from 2002 to 2012. We subsequently created nomograms for platinum sensitivity, 3-year PFS, and 5-year OS as prediction models for prognostic variables including age, stage, grade, cancer antigen 125 level, residual disease after PDS, and pre-treatment WBC differential counts. The models were then validated by 10-fold cross-validation (CV). In addition to stage and residual disease after PDS, which are known predictors, lymphocyte and monocyte count were found to be significant prognostic factors for platinum-sensitivity, platelet count for PFS, and neutrophil count for OS on multivariate analysis. The area under the curves of platinum sensitivity, 3-year PFS, and 5-year OS calculated by the 10-fold CV procedure were 0.7405, 0.8159, and 0.815, respectively. Prognostic factors including pre-treatment CBC were used to develop nomograms for platinum sensitivity, 3-year PFS, and 5-year OS of patients with EOC. These nomograms can be used to better estimate individual outcomes.

Influence of tumor microenvironment on prognosis in colorectal cancer: Tissue architecture-dependent signature of endosialin (TEM-1) and associated proteins

PubMed Central

O'Shannessy, Daniel J.; Somers, Elizabeth B.; Chandrasekaran, Lakshmi K.; Nicolaides, Nicholas C.; Bordeaux, Jennifer; Gustavson, Mark D.

2014-01-01

Tumor survival is influenced by interactions between tumor cells and the stromal microenvironment. One example is Endosialin (Tumor Endothelial Marker-1 (TEM-1) or CD248), which is expressed primarily by cells of mesenchymal origin and some tumor cells. The expression, as a function of architectural masking, of TEM-1 and its pathway-associated proteins was quantified and examined for association with five-year disease-specific survival on a colorectal cancer (CRC) cohort divided into training (n=330) and validation (n=164) sets. Although stromal expression of TEM-1 had prognostic value, a more significant prognostic signature was obtained through linear combination of five compartment-specific expression scores (TEM-1 Stroma, TEM-1 Tumor Vessel, HIF2α Stromal Vessel, Collagen IV Tumor, and Fibronectin Stroma). This resulted in a single continuous risk score (TAPPS: TEM-1 Associated Pathway Prognostic Signature) which was significantly associated with decreased survival on both the training set [HR=1.76 (95%CI: 1.44-2.15); p<0.001] and validation set [HR=1.38 (95%CI: 1.02-1.88); p=0.04]. Importantly, since prognosis is a critical clinical question in Stage II patients, the TAPPS score also significantly predicted survival in the Stage II patient (n=126) cohort [HR=1.75 (95%CI: 1.22-2.52); p=0.002] suggesting the potential of using the TAPPS score to assess overall risk in CRC patients, and specifically in Stage II patients. PMID:24980818

Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers.

PubMed

Ciani, Oriana; Davis, Sarah; Tappenden, Paul; Garside, Ruth; Stein, Ken; Cantrell, Anna; Saad, Everardo D; Buyse, Marc; Taylor, Rod S

2014-07-01

Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers. We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3). A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type. Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.

Predicting survival across chronic interstitial lung disease: the ILD-GAP model.

PubMed

Ryerson, Christopher J; Vittinghoff, Eric; Ley, Brett; Lee, Joyce S; Mooney, Joshua J; Jones, Kirk D; Elicker, Brett M; Wolters, Paul J; Koth, Laura L; King, Talmadge E; Collard, Harold R

2014-04-01

Risk prediction is challenging in chronic interstitial lung disease (ILD) because of heterogeneity in disease-specific and patient-specific variables. Our objective was to determine whether mortality is accurately predicted in patients with chronic ILD using the GAP model, a clinical prediction model based on sex, age, and lung physiology, that was previously validated in patients with idiopathic pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis (n=307), chronic hypersensitivity pneumonitis (n=206), connective tissue disease-associated ILD (n=281), idiopathic nonspecific interstitial pneumonia (n=45), or unclassifiable ILD (n=173) were selected from an ongoing database (N=1,012). Performance of the previously validated GAP model was compared with novel prediction models in each ILD subtype and the combined cohort. Patients with follow-up pulmonary function data were used for longitudinal model validation. The GAP model had good performance in all ILD subtypes (c-index, 74.6 in the combined cohort), which was maintained at all stages of disease severity and during follow-up evaluation. The GAP model had similar performance compared with alternative prediction models. A modified ILD-GAP Index was developed for application across all ILD subtypes to provide disease-specific survival estimates using a single risk prediction model. This was done by adding a disease subtype variable that accounted for better adjusted survival in connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and idiopathic nonspecific interstitial pneumonia. The GAP model accurately predicts risk of death in chronic ILD. The ILD-GAP model accurately predicts mortality in major chronic ILD subtypes and at all stages of disease.

Gene-Expression Signature Predicts Postoperative Recurrence in Stage I Non-Small Cell Lung Cancer Patients

PubMed Central

Lu, Yan; Wang, Liang; Liu, Pengyuan; Yang, Ping; You, Ming

2012-01-01

About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. The purpose of this study is to develop and validate a novel gene-expression signature that can predict tumor recurrence of stage I NSCLC patients. Cox proportional hazards regression analysis was performed to identify recurrence-related genes and a partial Cox regression model was used to generate a gene signature of recurrence in the training dataset −142 stage I lung adenocarcinomas without adjunctive therapy from the Director's Challenge Consortium. Four independent validation datasets, including GSE5843, GSE8894, and two other datasets provided by Mayo Clinic and Washington University, were used to assess the prediction accuracy by calculating the correlation between risk score estimated from gene expression and real recurrence-free survival time and AUC of time-dependent ROC analysis. Pathway-based survival analyses were also performed. 104 probesets correlated with recurrence in the training dataset. They are enriched in cell adhesion, apoptosis and regulation of cell proliferation. A 51-gene expression signature was identified to distinguish patients likely to develop tumor recurrence (Dxy = −0.83, P<1e-16) and this signature was validated in four independent datasets with AUC >85%. Multiple pathways including leukocyte transendothelial migration and cell adhesion were highly correlated with recurrence-free survival. The gene signature is highly predictive of recurrence in stage I NSCLC patients, which has important prognostic and therapeutic implications for the future management of these patients. PMID:22292069

Selection, calibration, and validation of models of tumor growth.

PubMed

Lima, E A B F; Oden, J T; Hormuth, D A; Yankeelov, T E; Almeida, R C

2016-11-01

This paper presents general approaches for addressing some of the most important issues in predictive computational oncology concerned with developing classes of predictive models of tumor growth. First, the process of developing mathematical models of vascular tumors evolving in the complex, heterogeneous, macroenvironment of living tissue; second, the selection of the most plausible models among these classes, given relevant observational data; third, the statistical calibration and validation of models in these classes, and finally, the prediction of key Quantities of Interest (QOIs) relevant to patient survival and the effect of various therapies. The most challenging aspects of this endeavor is that all of these issues often involve confounding uncertainties: in observational data, in model parameters, in model selection, and in the features targeted in the prediction. Our approach can be referred to as "model agnostic" in that no single model is advocated; rather, a general approach that explores powerful mixture-theory representations of tissue behavior while accounting for a range of relevant biological factors is presented, which leads to many potentially predictive models. Then representative classes are identified which provide a starting point for the implementation of OPAL, the Occam Plausibility Algorithm (OPAL) which enables the modeler to select the most plausible models (for given data) and to determine if the model is a valid tool for predicting tumor growth and morphology ( in vivo ). All of these approaches account for uncertainties in the model, the observational data, the model parameters, and the target QOI. We demonstrate these processes by comparing a list of models for tumor growth, including reaction-diffusion models, phase-fields models, and models with and without mechanical deformation effects, for glioma growth measured in murine experiments. Examples are provided that exhibit quite acceptable predictions of tumor growth in laboratory animals while demonstrating successful implementations of OPAL.

Stochastic variation in avian survival rates: Life-history predictions, population consequences, and the potential responses to human perturbations and climate change

USGS Publications Warehouse

Schmutz, Joel A.; Thomson, David L.; Cooch, Evan G.; Conroy, Michael J.

2009-01-01

Stochastic variation in survival rates is expected to decrease long-term population growth rates. This expectation influences both life-history theory and the conservation of species. From this expectation, Pfister (1998) developed the important life-history prediction that natural selection will have minimized variability in those elements of the annual life cycle (such as adult survival rate) with high sensitivity. This prediction has not been rigorously evaluated for bird populations, in part due to statistical difficulties related to variance estimation. I here overcome these difficulties, and in an analysis of 62 populations, I confirm her prediction by showing a negative relationship between the proportional sensitivity (elasticity) of adult survival and the proportional variance (CV) of adult survival. However, several species deviated significantly from this expectation, with more process variance in survival than predicted. For instance, projecting the magnitude of process variance in annual survival for American redstarts (Setophaga ruticilla) for 25 years resulted in a 44% decline in abundance without assuming any change in mean survival rate. For most of these species with high process variance, recent changes in harvest, habitats, or changes in climate patterns are the likely sources of environmental variability causing this variability in survival. Because of climate change, environmental variability is increasing on regional and global scales, which is expected to increase stochasticity in vital rates of species. Increased stochasticity in survival will depress population growth rates, and this result will magnify the conservation challenges we face.

Certification of training

NASA Technical Reports Server (NTRS)

Gibson, Richard S.

1994-01-01

Training has been around as an informal process for countless years. Most higher order animals require some level of training in hunting, social skills, or other survival related skills to continue their existence beyond early infancy. Much of the training is accomplished through imitation, trial and error, and good luck. In some ways the essentials of training in aviation have not deviated from this original formula a great deal. One of the major changes in aviation and other technical areas is that more complex response chains based on a broader base of knowledge are now required. 'To certify' means many things according to the American Heritage dictionary of the English Language. These meanings range from 'to guarantee as meeting a standard' to 'to declare legally insane'. For this discussion, we will use the definition 'an action taken by some authoritative body that essentially guarantees that the instruction meets some defined standard'. In order to make this certification, the responsible body subjects the educational process, training, training device, or simulator to some type of examination to determine its adequacy or validity.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

PubMed Central

Wei, Caimiao; Gould, Rebekah; Yu, Xian; Zhang, Ya; Liu, Mei; Walls, Andrew; Bousamra, Alex; Ramineni, Maheshwari; Sinn, Bruno; Hunt, Kelly; Buchholz, Thomas A.; Valero, Vicente; Buzdar, Aman U.; Yang, Wei; Brewster, Abenaa M.; Moulder, Stacy; Pusztai, Lajos; Hatzis, Christos; Hortobagyi, Gabriel N.

2017-01-01

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)–targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor–negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor–negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated. PMID:28135148

GENOMIC PREDICTOR OF RESPONSE AND SURVIVAL FOLLOWING TAXANE-ANTHRACYCLINE CHEMOTHERAPY FOR INVASIVE BREAST CANCER

PubMed Central

Hatzis, Christos; Pusztai, Lajos; Valero, Vicente; Booser, Daniel J.; Esserman, Laura; Lluch, Ana; Vidaurre, Tatiana; Holmes, Frankie; Souchon, Eduardo; Martin, Miguel; Cotrina, José; Gomez, Henry; Hubbard, Rebekah; Chacón, J. Ignacio; Ferrer-Lozano, Jaime; Dyer, Richard; Buxton, Meredith; Gong, Yun; Wu, Yun; Ibrahim, Nuhad; Andreopoulou, Eleni; Ueno, Naoto T.; Hunt, Kelly; Yang, Wei; Nazario, Arlene; DeMichele, Angela; O’Shaughnessy, Joyce; Hortobagyi, Gabriel N.; Symmans, W. Fraser

2017-01-01

CONTEXT Accurate prediction of who will (or won’t) have high probability of survival benefit from standard treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN Development of different predictive signatures for resistance and response to neoadjuvant chemotherapy (stratified according to estrogen receptor (ER) status) from gene expression microarrays of newly diagnosed breast cancer (310 patients). Then prediction of breast cancer treatment-sensitivity using the combination of signatures for: 1) sensitivity to endocrine therapy, 2) chemo-resistance, and 3) chemo-sensitivity. Independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. SETTING Prospective multicenter study to develop and test genomic predictors for neoadjuvant chemotherapy. PATIENTS Newly diagnosed HER2-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens then endocrine therapy (if hormone receptor-positive). MAIN OUTCOME MEASURES Distant relapse-free survival (DRFS) if predicted treatment-sensitive and absolute risk reduction (ARR, difference in DRFS of the two predicted groups) at median follow-up (3 years), and their 95% confidence intervals (CI). RESULTS Patients in the independent validation cohort (99% clinical Stage II–III) who were predicted to be treatment-sensitive (28% of total) had DRFS of 92% (CI 85–100) and survival benefit compared to others (absolute risk reduction (ARR) 18%; CI 6–28). Predictions were accurate if breast cancer was ER-positive (30% predicted sensitive, DRFS 97%, CI 91–100; ARR 11%, CI 0.1–21) or ER-negative (26% predicted sensitive, DRFS 83%, CI 68–100; ARR 26%, CI 4–28), and were significant in multivariate analysis after adjusting for relevant clinical-pathologic characteristics. Other genomic predictors showed paradoxically worse survival if predicted to be responsive to chemotherapy. CONCLUSION A genomic predictor combining ER status, predicted chemo-resistance, predicted chemo-sensitivity, and predicted endocrine sensitivity accurately identified patients with survival benefit following taxane-anthracycline chemotherapy. PMID:21558518

Validation of Clinical Scoring Systems ART and ABCR after Transarterial Chemoembolization of Hepatocellular Carcinoma.

PubMed

Kloeckner, Roman; Pitton, Michael B; Dueber, Christoph; Schmidtmann, Irene; Galle, Peter R; Koch, Sandra; Wörns, Marcus A; Weinmann, Arndt

2017-01-01

To perform an external validation of the Assessment for Retreatment with Transarterial Chemoembolization (ART) and α-fetoprotein (AFP), Barcelona Clinic Liver Cancer (BCLC), Child-Pugh, and response (ABCR) scores and to compare them in terms of prognostic power. From 2000 to 2015, 871 patients with hepatocellular carcinoma underwent transarterial chemoembolization at a tertiary referral hospital, and 176 met all inclusion and exclusion criteria for both scores and were analyzed. Nineteen percent (n = 34) had BCLC stage A disease and 81% had stage B disease. Thirty-nine patients (22%) presented with elevated AFP levels. Overall survival was calculated. Scores were validated and compared with a Harrell C-index, integrated Brier score (IBS), and prediction error curves. Before the second chemoembolization procedure, 22 patients (12%) showed an increase of 1 point in Child-Pugh score and 51 patients (22%) had an increase of ≥ 2 points. Thirty-one patients (23%) showed a > 25% increase in aspartate aminotransferase level, and 114 (65%) showed a response to treatment. Consequently, 127 patients (72%) had a low ART score and 49 (28%) had a high ART score. One hundred fifty-eight patients (90%) had a low ABCR score, whereas 18 (10%) had a high ABCR score. Low and high ART score groups had median survival durations of 20.8 and 15.3 mo, respectively. Harrell C-indexes were 0.572 and 0.608, and IBSs were 0.135 and 0.128, for ART and ABCR, respectively. For both scores, an increase in Child-Pugh score ≥ 2 points and a radiologic response were significantly associated with survival. Both scores were of limited predictive value, and neither was sufficient to support clear-cut clinical decisions. Further effort is necessary to determine criteria for making valid clinical predictions. Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.

Independent validation of the prognostic capacity of the ISUP prostate cancer grade grouping system for radiation treated patients with long-term follow-up.

PubMed

Spratt, D E; Jackson, W C; Abugharib, A; Tomlins, S A; Dess, R T; Soni, P D; Lee, J Y; Zhao, S G; Cole, A I; Zumsteg, Z S; Sandler, H; Hamstra, D; Hearn, J W; Palapattu, G; Mehra, R; Morgan, T M; Feng, F Y

2016-09-01

There has been a recent proposal to change the grading system of prostate cancer into a five-tier grade grouping system. The prognostic impact of this has been demonstrated in regards only to biochemical recurrence-free survival (bRFS) with short follow-up (3 years). Between 1990 and 2013, 847 consecutive men were treated with definitive external beam radiation therapy at a single academic center. To validate the new grade grouping system, bRFS, distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS) were calculated. Adjusted Kaplan-Meier and multivariable Cox regression analyses were performed to assess the independent impact of the new grade grouping system. Discriminatory analyses were performed to compare the commonly used three-tier Gleason score system (6, 7 and 8-10) to the new system. The median follow-up of our cohort was 88 months. The 5-grade groups independently validated differing risks of bRFS (group 1 as reference; adjusted hazard ratio (aHR) 1.35, 2.16, 1.79 and 3.84 for groups 2-5, respectively). Furthermore, a clear stratification was demonstrated for DMFS (aHR 2.03, 3.18, 3.62 and 13.77 for groups 2-5, respectively) and PCSS (aHR 3.00, 5.32, 6.02 and 39.02 for groups 2-5, respectively). The 5-grade group system had improved prognostic discrimination for all end points compared with the commonly used three-tiered system (that is, Gleason score 6, 7 and 8-10). In a large independent radiotherapy cohort with long-term follow-up, we have validated the bRFS benefit of the proposed five-tier grade grouping system. Furthermore, we have demonstrated that the system is highly prognostic for DMFS and PCSS. Grade group 5 had markedly worse outcomes for all end points, and future work is necessary to improve outcomes in these patients.

Predicting long-term survival after coronary artery bypass graft surgery.

PubMed

Karim, Md N; Reid, Christopher M; Huq, Molla; Brilleman, Samuel L; Cochrane, Andrew; Tran, Lavinia; Billah, Baki

2018-02-01

To develop a model for predicting long-term survival following coronary artery bypass graft surgery. This study included 46 573 patients from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZCTS) registry, who underwent isolated coronary artery bypass graft surgery between 2001 and 2014. Data were randomly split into development (23 282) and validation (23 291) samples. Cox regression models were fitted separately, using the important preoperative variables, for 4 'time intervals' (31-90 days, 91-365 days, 1-3 years and >3 years), with optimal predictors selected using the bootstrap bagging technique. Model performance was assessed both in validation data and in combined data (development and validation samples). Coefficients of all 4 final models were estimated on the combined data adjusting for hospital-level clustering. The Kaplan-Meier mortality rates estimated in the sample were 1.7% at 90 days, 2.8% at 1 year, 4.4% at 2 years and 6.1% at 3 years. Age, peripheral vascular disease, respiratory disease, reduced ejection fraction, renal dysfunction, arrhythmia, diabetes, hypercholesterolaemia, cerebrovascular disease, hypertension, congestive heart failure, steroid use and smoking were included in all 4 models. However, their magnitude of effect varied across the time intervals. Harrell's C-statistics was 0.83, 0.78, 0.75 and 0.74 for 31-90 days, 91-365 days, 1-3 years and >3 years models, respectively. Models showed excellent discrimination and calibration in validation data. Models were developed for predicting long-term survival at 4 time intervals after isolated coronary artery bypass graft surgery. These models can be used in conjunction with the existing 30-day mortality prediction model. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Improving the quality of adult mortality data collected in demographic surveys: validation study of a new siblings' survival questionnaire in Niakhar, Senegal.

PubMed

Helleringer, Stéphane; Pison, Gilles; Masquelier, Bruno; Kanté, Almamy Malick; Douillot, Laetitia; Duthé, Géraldine; Sokhna, Cheikh; Delaunay, Valérie

2014-05-01

In countries with limited vital registration, adult mortality is frequently estimated using siblings' survival histories (SSHs) collected during Demographic and Health Surveys (DHS). These data are affected by reporting errors. We developed a new SSH questionnaire, the siblings' survival calendar (SSC). It incorporates supplementary interviewing techniques to limit omissions of siblings and uses an event history calendar to improve reports of dates and ages. We hypothesized that the SSC would improve the quality of adult mortality data. We conducted a retrospective validation study among the population of the Niakhar Health and Demographic Surveillance System in Senegal. We randomly assigned men and women aged 15-59 y to an interview with either the DHS questionnaire or the SSC. We compared SSHs collected in each group to prospective data on adult mortality collected in Niakhar. The SSC reduced respondents' tendency to round reports of dates and ages to the nearest multiple of five or ten ("heaping"). The SSC also had higher sensitivity in recording adult female deaths: among respondents whose sister(s) had died at an adult age in the past 15 y, 89.6% reported an adult female death during SSC interviews versus 75.6% in DHS interviews (p = 0.027). The specificity of the SSC was similar to that of the DHS questionnaire, i.e., it did not increase the number of false reports of deaths. However, the SSC did not improve the reporting of adult deaths among the brothers of respondents. Study limitations include sample selectivity, limited external validity, and multiple testing. The SSC has the potential to collect more accurate SSHs than the questionnaire used in DHS. Further research is needed to assess the effects of the SSC on estimates of adult mortality rates. Additional validation studies should be conducted in different social and epidemiological settings. Controlled-Trials.com ISRCTN06849961

Serum Gamma-Glutamyl-Transferase Independently Predicts Outcome After Transarterial Chemoembolization of Hepatocellular Carcinoma: External Validation

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

Guiu, Boris, E-mail: boris.guiu@chu-dijon.fr; Deschamps, Frederic; Boulin, Mathieu

Purpose: An Asian study showed that gamma glutamyl transpeptidase (GGT) can predict survival after transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). This study was designed to validate in a European population this biomarker as an independent predictor of outcome after TACE of HCC and to determine a threshold value for clinical use. Methods: In 88 consecutive patients treated by TACE for HCC, the optimal threshold for GGT serum level was determined by a ROC analysis. Endpoints were time-to-treatment failure (TTTF) and overall survival (OS). All multivariate models were internally validated using bootstrapping (90 replications). Results: Median follow-up lasted 373 days,more » and median overall survival was 748 days. The optimal threshold for GGT was 165 U/L (sensitivity: 89.3%; specificity: 56.7%; area under the ROC curve: 0.7515). Median TTTF was shorter when GGT was {>=}165 U/L (281 days vs. 850 days; P < 0.001). GGT {>=}165 U/L (hazard ratio (HR) = 2.06; P = 0.02), WHO PS of 2 (HR = 5.4; P = 0.002), and tumor size (HR = 1.12; P = 0.014) were independently associated with shorter TTTF. Median OS was shorter when GGT was {>=}165 U/L (508 days vs. not reached; P < 0.001). GGT {>=} 165 U/L (HR = 3.05; P = 0.029), WHO PS of 2 (HR = 12.95; P < 0.001), alfa-fetoprotein (HR = 2.9; P = 0.01), and tumor size (HR = 1.096; P = 0.013) were independently associated with shorter OS. The results were confirmed by bootstrapping. Conclusions: Our results provide in a European population the external validation of GGT as an independent predictor of outcome after TACE of HCC. A serum level of GGT {>=} 165 U/L is independently associated with both shorter TTTF and OS.« less

Effect of diet processing method and ingredient substitution on feed characteristics and survival of larval walleye, Sander vitreus

USGS Publications Warehouse

Barrows, F.T.; Lellis, W.A.

2006-01-01

Two methods were developed for the production of larval fish diets. The first method, microextrusion marumerization (MEM), has been tested in laboratory feeding trials for many years and produces particles that are palatable and water stable. The second method, particle-assisted rotational agglomeration (PARA), produced diets that have lower density than diets produced by MEM. Each method was used to produce diets in the 250- to 400- and 400- to 700-??m range and compared with a reference diet (Fry Feed Kyowa* [FFK]) for feeding larval walleye in two experiments. The effect of substituting 4% of the fish meal with freeze-dried artemia fines was also investigated. In the first experiment, 30-d survival was greater (P < 0.05) for fish fed a diet produced by PARA without Artemia (49.1.0%) than for fish fed the same diet produced by MEM (27.6%). The addition of Artemia to a diet produced by MEM did not increase survival of larval walleye. Fish fed the reference diet had 24.4% survival. In the second experiment, there was an effect of both processing method and Artemia supplementation, and an interaction of these effects, on survival. Fish fed a diet produced by PARA without Artemia supplementation had 48.4% survival, and fish fed the same diet produced by MEM had only 19.6% survival. Inclusion of 4% freeze-dried Artemia improved (P < 0.04) survival of fish fed MEM particles but not those fed PARA particles. Fish fed FFK had greater weight gain than fish fed other diets in both experiments. Data indicate that the PARA method of diet processing produces smaller, lower density particles than the MEM process and that diets produced by the PARA process support higher survival of larval walleye with low capital and operating costs. ?? Copyright by the World Aquaculture Society 2006.

Extensions of the Survival Advantage in Memory: Examining the Role of Ancestral Context and Implied Social Isolation

ERIC Educational Resources Information Center

Kostic, Bogdan; McFarlan, Chastity C.; Cleary, Anne M.

2012-01-01

Recent work (e.g., Nairne & Pandeirada, 2010) has shown that words are remembered better when they have been processed for their survival value in a grasslands context than when processed in other contexts. It has been suggested that this is because human memory systems were shaped by evolution specifically to help humans survive. Thus far,…

21 CFR 820.75 - Process validation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Process validation. 820.75 Section 820.75 Food and... QUALITY SYSTEM REGULATION Production and Process Controls § 820.75 Process validation. (a) Where the... validated with a high degree of assurance and approved according to established procedures. The validation...

21 CFR 820.75 - Process validation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Process validation. 820.75 Section 820.75 Food and... QUALITY SYSTEM REGULATION Production and Process Controls § 820.75 Process validation. (a) Where the... validated with a high degree of assurance and approved according to established procedures. The validation...

21 CFR 820.75 - Process validation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Process validation. 820.75 Section 820.75 Food and... QUALITY SYSTEM REGULATION Production and Process Controls § 820.75 Process validation. (a) Where the... validated with a high degree of assurance and approved according to established procedures. The validation...

21 CFR 820.75 - Process validation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Process validation. 820.75 Section 820.75 Food and... QUALITY SYSTEM REGULATION Production and Process Controls § 820.75 Process validation. (a) Where the... validated with a high degree of assurance and approved according to established procedures. The validation...

21 CFR 820.75 - Process validation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Process validation. 820.75 Section 820.75 Food and... QUALITY SYSTEM REGULATION Production and Process Controls § 820.75 Process validation. (a) Where the... validated with a high degree of assurance and approved according to established procedures. The validation...

Bayesian Adaptive Trial Design for a Newly Validated Surrogate Endpoint

PubMed Central

Renfro, Lindsay A.; Carlin, Bradley P.; Sargent, Daniel J.

2011-01-01

Summary The evaluation of surrogate endpoints for primary use in future clinical trials is an increasingly important research area, due to demands for more efficient trials coupled with recent regulatory acceptance of some surrogates as ‘valid.’ However, little consideration has been given to how a trial which utilizes a newly-validated surrogate endpoint as its primary endpoint might be appropriately designed. We propose a novel Bayesian adaptive trial design that allows the new surrogate endpoint to play a dominant role in assessing the effect of an intervention, while remaining realistically cautious about its use. By incorporating multi-trial historical information on the validated relationship between the surrogate and clinical endpoints, then subsequently evaluating accumulating data against this relationship as the new trial progresses, we adaptively guard against an erroneous assessment of treatment based upon a truly invalid surrogate. When the joint outcomes in the new trial seem plausible given similar historical trials, we proceed with the surrogate endpoint as the primary endpoint, and do so adaptively–perhaps stopping the trial for early success or inferiority of the experimental treatment, or for futility. Otherwise, we discard the surrogate and switch adaptive determinations to the original primary endpoint. We use simulation to test the operating characteristics of this new design compared to a standard O’Brien-Fleming approach, as well as the ability of our design to discriminate trustworthy from untrustworthy surrogates in hypothetical future trials. Furthermore, we investigate possible benefits using patient-level data from 18 adjuvant therapy trials in colon cancer, where disease-free survival is considered a newly-validated surrogate endpoint for overall survival. PMID:21838811

Inactivation of Salmonella and Listeria in ground chicken breast meat during thermal processing.

PubMed

Murphy, R Y; Marks, B P; Johnson, E R; Johnson, M G

1999-09-01

Thermal inactivation of six Salmonella spp. and Listeria innocua was evaluated in ground chicken breast and liquid medium. Survival of Salmonella and Listeria was affected by the medium composition. Under the same thermal process condition, significantly more Salmonella and Listeria survived in chicken breast meat than in 0.1% peptone-agar solution. The thermal lethality of six tested Salmonella spp. was additive in chicken meat. Survival of Listeria in chicken meat during thermal processing was not affected by the presence of the six Salmonella spp. Sample size and shape affected the inactivation of Salmonella and Listeria in chicken meat during thermal processing.

Bone marrow vascular endothelial growth factor level per platelet count might be a significant predictor for the treatment outcomes of patients with diffuse large B-cell lymphomas.

PubMed

Kim, Jung Sun; Gang, Ga Won; Lee, Se Ryun; Sung, Hwa Jung; Park, Young; Kim, Dae Sik; Choi, Chul Won; Kim, Byung Soo

2015-10-01

Developing a parameter to predict bone marrow invasion by non-Hodgkin's lymphoma is an important unmet medical need for treatment decisions. This study aimed to confirm the validity of the hypothesis that bone marrow plasma vascular endothelial growth factor level might be correlated with the risk of bone marrow involvement and the prognosis of patients with diffuse large B-cell non-Hodgkin's lymphoma. Forty-nine diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone regimen were enrolled. Vascular endothelial growth factor level was measured with enzyme-linked immunosorbent assay. The validity of bone marrow plasma vascular endothelial growth factor level and bone marrow vascular endothelial growth factor level per platelet count for predicting treatment response and survival after initial rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone combined chemotherapy was assessed. Bone marrow plasma vascular endothelial growth factor level per platelet count was significantly associated with old age (≥ 65 years), poor performance score (≥ 2), high International prognosis index (≥ 3) and bone marrow invasion. The patients with high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) showed a significantly lower complete response rate than the others. On Kaplan-Meier survival curves, the patients with high bone marrow plasma vascular endothelial growth factor levels (≥ 655 pg/ml) or high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) demonstrated a significantly shorter overall survival and progression-free survival than the others. In the patients without bone marrow involvement, bone marrow plasma vascular endothelial growth factor level per platelet count had a significant relationship with overall survival and progression-free survival. Multivariate analysis revealed that the patients without BM invasion showing high level of bone marrow plasma vascular endothelial growth factor per platelet count had significantly shorter progression-free survival and overall survival. Bone marrow plasma vascular endothelial growth factor level per platelet count might be associated with bone marrow invasion by diffuse large B-cell lymphoma and is correlated with clinical outcomes after treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study.

PubMed

Bensimon, Gilbert; Ludolph, Albert; Agid, Yves; Vidailhet, Marie; Payan, Christine; Leigh, P Nigel

2009-01-01

Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40% decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 249-1095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators' assessment of diagnostic probability (point-biserial correlation: MSA r(pb) = 0.93, P < 0.0001; PSP, r(pb) = 0.95, P < 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95% CI) for PSP 0.95 (0.88-0.98) and 0.84 (0.77-0.87); and for MSA 0.96 (0.88-0.99) and 0.91 (0.86-0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan-Meier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P = 0.66 and P = 0.48 by the log-rank test, respectively), or in the population as a whole (P = 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80% power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution.

Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study

PubMed Central

Bensimon, Gilbert; Ludolph, Albert; Agid, Yves; Vidailhet, Marie; Payan, Christine; Leigh, P. Nigel

2009-01-01

Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40% decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 249–1095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators’ assessment of diagnostic probability (point-biserial correlation: MSA rpb = 0.93, P < 0.0001; PSP, rpb = 0.95, P < 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95% CI) for PSP 0.95 (0.88–0.98) and 0.84 (0.77–0.87); and for MSA 0.96 (0.88–0.99) and 0.91 (0.86–0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan–Meier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P = 0.66 and P = 0.48 by the log-rank test, respectively), or in the population as a whole (P = 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80% power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution. PMID:19029129

Scaling and validation of breakaway connection for multi-post ground signs.

DOT National Transportation Integrated Search

2016-11-01

Multi-post ground signs installed adjacent to Florida roadways must be designed for both hurricane wind loading and vehicle : collision loading. With respect to hurricanes, all structural sign components must be designed to survive applicable code-sp...

[Patients' Priorities in the Treatment of Neuroendocrine Tumours: An Analytical Hierarchy Process].

PubMed

Mühlbacher, A C; Juhnke, C; Kaczynski, A

2016-10-01

Background: Neuroendocrine tumours (NET) are relatively rare, usually slow-growing malignant tumours. So far there are no data on the patient preferences/priorities regarding the therapy for NET. This empirical study aimed at the elicitation of patient priorities in the drug treatment of NET. Method: Qualitative patient interviews (N=9) were conducted. To elicit the patient's perspective regarding various treatment aspects of NET a self-administered questionnaire using the Analytical Hierarchy Process (AHP) was developed. The data collection was carried out using paper questionnaires supported by an item response system in a group discussion. To evaluate the patient-relevant outcomes, the eigenvector method was applied. Results: N=24 patients, experts and relatives participated in the AHP survey. In the AHP all respondents had clear priorities for all considered attributes. The attribute "overall survival" was the most significant feature of a drug therapy for all respondents. As in the qualitative interviews, "efficacy attributes" dominated the side effects in the AHP as well. The evaluation of all participants thus showed the attributes "overall survival" (Wglobal:0.418), "progression-free survival" (Wglobal:0.172) and "response to treatment" (Wglobal:0.161) to be most relevant. "Occurrence of abdominal pain" (Wglobal:0.051) was ranked sixth, with "tiredness/fatigue" and "risk of a hypoglycaemia" (Wglobal:0.034) in a shared seventh place. Conclusion: The results thus provide evidence about how much influence a treatment capacity has on therapeutic decisions. Using the AHP major aspects of drug therapy from the perspective of those affected were captured, and positive and negative therapeutic properties could be related against each other. Based on the assessment of the patient's perspective further investigation must elicit patient preferences for NET drug therapy. In the context of a discrete choice experiment or another choice-based method of preference measurement, the results obtained here can be validated and the therapeutic features weighted according to their preferability. © Georg Thieme Verlag KG Stuttgart · New York.

[Lung transplant therapy for suppurative diseases].

PubMed

de Pablo, A; López, S; Ussetti, P; Carreño, M C; Laporta, R; López García-Gallo, C; Ferreiro, M J

2005-05-01

Lung transplantation is a valid therapeutic approach for patients with bronchiectasis. The objective of the present study was to evaluate our experience with bronchiectasis patients and compare the results in patients with cystic fibrosis to results in those with bronchiectasis caused by other processes. We carried out a retrospective study of bronchiectasis patients treated by lung transplantation in order to analyze demographic, functional and microbiological characteristics before and after transplantation, and survival. From 1991 to 2002 lung transplants were performed on 171 patients, 44 of whom had suppurative lung disease (27 had cystic fibrosis and 17 had bronchiectasis caused by other processes). There were no significant differences in the demographic variables between the 2 groups. At transplantation, lung function variables showed severe bronchial obstruction (mean [SD] forced expiratory volume in 1 second of 808 [342] mL and forced vital capacity of 1,390 [611] mL) and respiratory insufficiency (PaO2 at 52 [10] mm Hg and PaCO2 at 48 [9] mm Hg). Only PaO2 was significantly lower in patients with bronchiectasis from causes other than cystic fibrosis. Airway colonization was present in 91% of the patients; Pseudomonas spp germs were detected in 64% of the cases and were multiresistant in 9%. In the early postoperative period germs were isolated in 59% of the cases, half of which involved the same germ as had been isolated before transplantation. One year after lung transplantation, 34% of the patients continued to have bronchial colonization. Survival at 1 year was 79% and at 5 years, 49%, with no significant difference between the patients with cystic fibrosis and those with other suppurative diseases, nor between the patients with and without Pseudomonas colonization. Only 2 patients had died of bacterial pneumonia at 1 month after transplantation. Although airway colonization in patients with suppurative diseases complicates postoperative management, the results in terms of survival are good.

Predictors of outcome after elective endovascular abdominal aortic aneurysm repair and external validation of a risk prediction model.

PubMed

Wisniowski, Brendan; Barnes, Mary; Jenkins, Jason; Boyne, Nicholas; Kruger, Allan; Walker, Philip J

2011-09-01

Endovascular abdominal aortic aneurysm (AAA) repair (EVAR) has been associated with lower operative mortality and morbidity than open surgery but comparable long-term mortality and higher delayed complication and reintervention rates. Attention has therefore been directed to identifying preoperative and operative variables that influence outcomes after EVAR. Risk-prediction models, such as the EVAR Risk Assessment (ERA) model, have also been developed to help surgeons plan EVAR procedures. The aims of this study were (1) to describe outcomes of elective EVAR at the Royal Brisbane and Women's Hospital (RBWH), (2) to identify preoperative and operative variables predictive of outcomes after EVAR, and (3) to externally validate the ERA model. All elective EVAR procedures at the RBWH before July 1, 2009, were reviewed. Descriptive analyses were performed to determine the outcomes. Univariate and multivariate analyses were performed to identify preoperative and operative variables predictive of outcomes after EVAR. Binomial logistic regression analyses were used to externally validate the ERA model. Before July 1, 2009, 197 patients (172 men), who were a mean age of 72.8 years, underwent elective EVAR at the RBWH. Operative mortality was 1.0%. Survival was 81.1% at 3 years and 63.2% at 5 years. Multivariate analysis showed predictors of survival were age (P = .0126), American Society of Anesthesiologists (ASA) score (P = .0180), and chronic obstructive pulmonary disease (P = .0348) at 3 years and age (P = .0103), ASA score (P = .0006), renal failure (P = .0048), and serum creatinine (P = .0022) at 5 years. Aortic branch vessel score was predictive of initial (30-day) type II endoleak (P = .0015). AAA tortuosity was predictive of midterm type I endoleak (P = .0251). Female sex was associated with lower rates of initial clinical success (P = .0406). The ERA model fitted RBWH data well for early death (C statistic = .906), 3-year survival (C statistic = .735), 5-year survival (C statistic = .800), and initial type I endoleak (C statistic = .850). The outcomes of elective EVAR at the RBWH are broadly consistent with those of a nationwide Australian audit and recent randomized trials. Age and ASA score are independent predictors of midterm survival after elective EVAR. The ERA model predicts mortality-related outcomes and initial type I endoleak well for RBWH elective EVAR patients. Copyright © 2011 Society for Vascular Surgery. All rights reserved.

New agreement measures based on survival processes

PubMed Central

Guo, Ying; Li, Ruosha; Peng, Limin; Manatunga, Amita K.

2013-01-01

Summary The need to assess agreement arises in many scenarios in biomedical sciences when measurements were taken by different methods on the same subjects. When the endpoints are survival outcomes, the study of agreement becomes more challenging given the special characteristics of time-to-event data. In this paper, we propose a new framework for assessing agreement based on survival processes that can be viewed as a natural representation of time-to-event outcomes. Our new agreement measure is formulated as the chance-corrected concordance between survival processes. It provides a new perspective for studying the relationship between correlated survival outcomes and offers an appealing interpretation as the agreement between survival times on the absolute distance scale. We provide a multivariate extension of the proposed agreement measure for multiple methods. Furthermore, the new framework enables a natural extension to evaluate time-dependent agreement structure. We develop nonparametric estimation of the proposed new agreement measures. Our estimators are shown to be strongly consistent and asymptotically normal. We evaluate the performance of the proposed estimators through simulation studies and then illustrate the methods using a prostate cancer data example. PMID:23844617

Modeling Stochastic Variability in the Numbers of Surviving Salmonella enterica, Enterohemorrhagic Escherichia coli, and Listeria monocytogenes Cells at the Single-Cell Level in a Desiccated Environment

PubMed Central

Koyama, Kento; Hokunan, Hidekazu; Hasegawa, Mayumi; Kawamura, Shuso

2016-01-01

ABSTRACT Despite effective inactivation procedures, small numbers of bacterial cells may still remain in food samples. The risk that bacteria will survive these procedures has not been estimated precisely because deterministic models cannot be used to describe the uncertain behavior of bacterial populations. We used the Poisson distribution as a representative probability distribution to estimate the variability in bacterial numbers during the inactivation process. Strains of four serotypes of Salmonella enterica, three serotypes of enterohemorrhagic Escherichia coli, and one serotype of Listeria monocytogenes were evaluated for survival. We prepared bacterial cell numbers following a Poisson distribution (indicated by the parameter λ, which was equal to 2) and plated the cells in 96-well microplates, which were stored in a desiccated environment at 10% to 20% relative humidity and at 5, 15, and 25°C. The survival or death of the bacterial cells in each well was confirmed by adding tryptic soy broth as an enrichment culture. Changes in the Poisson distribution parameter during the inactivation process, which represent the variability in the numbers of surviving bacteria, were described by nonlinear regression with an exponential function based on a Weibull distribution. We also examined random changes in the number of surviving bacteria using a random number generator and computer simulations to determine whether the number of surviving bacteria followed a Poisson distribution during the bacterial death process by use of the Poisson process. For small initial cell numbers, more than 80% of the simulated distributions (λ = 2 or 10) followed a Poisson distribution. The results demonstrate that variability in the number of surviving bacteria can be described as a Poisson distribution by use of the model developed by use of the Poisson process. IMPORTANCE We developed a model to enable the quantitative assessment of bacterial survivors of inactivation procedures because the presence of even one bacterium can cause foodborne disease. The results demonstrate that the variability in the numbers of surviving bacteria was described as a Poisson distribution by use of the model developed by use of the Poisson process. Description of the number of surviving bacteria as a probability distribution rather than as the point estimates used in a deterministic approach can provide a more realistic estimation of risk. The probability model should be useful for estimating the quantitative risk of bacterial survival during inactivation. PMID:27940547

Modeling Stochastic Variability in the Numbers of Surviving Salmonella enterica, Enterohemorrhagic Escherichia coli, and Listeria monocytogenes Cells at the Single-Cell Level in a Desiccated Environment.

PubMed

Koyama, Kento; Hokunan, Hidekazu; Hasegawa, Mayumi; Kawamura, Shuso; Koseki, Shigenobu

2017-02-15

Despite effective inactivation procedures, small numbers of bacterial cells may still remain in food samples. The risk that bacteria will survive these procedures has not been estimated precisely because deterministic models cannot be used to describe the uncertain behavior of bacterial populations. We used the Poisson distribution as a representative probability distribution to estimate the variability in bacterial numbers during the inactivation process. Strains of four serotypes of Salmonella enterica, three serotypes of enterohemorrhagic Escherichia coli, and one serotype of Listeria monocytogenes were evaluated for survival. We prepared bacterial cell numbers following a Poisson distribution (indicated by the parameter λ, which was equal to 2) and plated the cells in 96-well microplates, which were stored in a desiccated environment at 10% to 20% relative humidity and at 5, 15, and 25°C. The survival or death of the bacterial cells in each well was confirmed by adding tryptic soy broth as an enrichment culture. Changes in the Poisson distribution parameter during the inactivation process, which represent the variability in the numbers of surviving bacteria, were described by nonlinear regression with an exponential function based on a Weibull distribution. We also examined random changes in the number of surviving bacteria using a random number generator and computer simulations to determine whether the number of surviving bacteria followed a Poisson distribution during the bacterial death process by use of the Poisson process. For small initial cell numbers, more than 80% of the simulated distributions (λ = 2 or 10) followed a Poisson distribution. The results demonstrate that variability in the number of surviving bacteria can be described as a Poisson distribution by use of the model developed by use of the Poisson process. We developed a model to enable the quantitative assessment of bacterial survivors of inactivation procedures because the presence of even one bacterium can cause foodborne disease. The results demonstrate that the variability in the numbers of surviving bacteria was described as a Poisson distribution by use of the model developed by use of the Poisson process. Description of the number of surviving bacteria as a probability distribution rather than as the point estimates used in a deterministic approach can provide a more realistic estimation of risk. The probability model should be useful for estimating the quantitative risk of bacterial survival during inactivation. Copyright © 2017 Koyama et al.

JCDSA: a joint covariate detection tool for survival analysis on tumor expression profiles.

PubMed

Wu, Yiming; Liu, Yanan; Wang, Yueming; Shi, Yan; Zhao, Xudong

2018-05-29

Survival analysis on tumor expression profiles has always been a key issue for subsequent biological experimental validation. It is crucial how to select features which closely correspond to survival time. Furthermore, it is important how to select features which best discriminate between low-risk and high-risk group of patients. Common features derived from the two aspects may provide variable candidates for prognosis of cancer. Based on the provided two-step feature selection strategy, we develop a joint covariate detection tool for survival analysis on tumor expression profiles. Significant features, which are not only consistent with survival time but also associated with the categories of patients with different survival risks, are chosen. Using the miRNA expression data (Level 3) of 548 patients with glioblastoma multiforme (GBM) as an example, miRNA candidates for prognosis of cancer are selected. The reliability of selected miRNAs using this tool is demonstrated by 100 simulations. Furthermore, It is discovered that significant covariates are not directly composed of individually significant variables. Joint covariate detection provides a viewpoint for selecting variables which are not individually but jointly significant. Besides, it helps to select features which are not only consistent with survival time but also associated with prognosis risk. The software is available at http://bio-nefu.com/resource/jcdsa .

76 FR 4360 - Guidance for Industry on Process Validation: General Principles and Practices; Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-25

... elements of process validation for the manufacture of human and animal drug and biological products... process validation for the manufacture of human and animal drug and biological products, including APIs. This guidance describes process validation activities in three stages: In Stage 1, Process Design, the...

Estimating the impact of alcohol consumption on survival for HIV+ individuals

PubMed Central

BRAITHWAITE, R. S.; CONIGLIARO, J.; ROBERTS, M. S.; SHECHTER, S.; SCHAEFER, A.; MCGINNIS, K.; RODRIGUEZ, M. C.; RABENECK, L.; BRYANT, K.; JUSTICE, A. C.

2012-01-01

Alcohol consumption is associated with decreased antiretroviral adherence, and decreased adherence results in poorer outcomes. However the magnitude of alcohol’s impact on survival is unknown. Our objective was to use a calibrated and validated simulation of HIV disease to estimate the impact of alcohol on survival. We incorporated clinical data describing the temporal and dose-response relationships between alcohol consumption and adherence in a large observational cohort (N = 2,702). Individuals were categorized as nondrinkers (no alcohol consumption), hazardous drinkers (consume ≥5 standard drinks on drinking days), and nonhazardous drinkers (consume <5 standard drinks on drinking days). Our results showed that nonhazardous alcohol consumption decreased survival by more than 1 year if the frequency of consumption was once per week or greater, and by 3.3 years (from 21.7 years to 18.4 years) with daily consumption. Hazardous alcohol consumption decreased overall survival by more than 3 years if frequency of consumption was once per week or greater, and by 6.4 years (From 16.1 years to 9.7 years) with daily consumption. Our results suggest that alcohol is an underappreciated yet modifiable risk factor for poor survival among individuals with HIV. PMID:17453583

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma.

PubMed

Arora, Shilpi; Gonzales, Irma M; Hagelstrom, R Tanner; Beaudry, Christian; Choudhary, Ashish; Sima, Chao; Tibes, Raoul; Mousses, Spyro; Azorsa, David O

2010-08-18

Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells. Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.

Brain oscillatory subsequent memory effects differ in power and long-range synchronization between semantic and survival processing.

PubMed

Fellner, Marie-Christin; Bäuml, Karl-Heinz T; Hanslmayr, Simon

2013-10-01

Memory crucially depends on the way information is processed during encoding. Differences in processes during encoding not only lead to differences in memory performance but also rely on different brain networks. Although these assumptions are corroborated by several previous fMRI and ERP studies, little is known about how brain oscillations dissociate between different memory encoding tasks. The present study therefore compared encoding related brain oscillatory activity elicited by two very efficient encoding tasks: a typical deep semantic item feature judgment task and a more elaborative survival encoding task. Subjects were asked to judge words either for survival relevance or for animacy, as indicated by a cue presented prior to the item. This allowed dissociating pre-item activity from item-related activity for both tasks. Replicating prior studies, survival processing led to higher recognition performance than semantic processing. Successful encoding in the semantic condition was reflected by a strong decrease in alpha and beta power, whereas successful encoding in the survival condition was related to increased alpha and beta long-range phase synchrony. Moreover, a pre-item subsequent memory effect in theta power was found which did not vary with encoding condition. These results show that measures of local synchrony (power) and global long range-synchrony (phase synchronization) dissociate between memory encoding processes. Whereas semantic encoding was reflected in decreases in local synchrony, increases in global long range synchrony were related to elaborative survival encoding, presumably reflecting the involvement of a more widespread cortical network in this task. Copyright © 2013 Elsevier Inc. All rights reserved.

Severe postoperative complications adversely affect long-term survival after R1 resection for pancreatic head adenocarcinoma.

PubMed

Petermann, David; Demartines, Nicolas; Schäfer, Markus

2013-08-01

Survival after pancreatic head adenocarcinoma surgery is determined by tumor characteristics, resection margins, and adjuvant chemotherapy. Few studies have analyzed the long-term impact of postoperative morbidity. The aim of the present study was to assess the impact of postoperative complications on long-term survival after pancreaticoduodenectomy for cancer. Of 294 consecutive pancreatectomies performed between January 2000 and July 2011, a total of 101 pancreatic head resections for pancreatic ductal adenocarcinoma were retrospectively analyzed. Postoperative complications were classified on a five-grade validated scale and were correlated with long-term survival. Grade IIIb to IVb complications were defined as severe. Postoperative mortality and morbidity were 5 and 57 %, respectively. Severe postoperative complications occurred in 16 patients (16 %). Median overall survival was 1.4 years. Significant prognostic factors of survival were the N-stage of the tumor (median survival 3.4 years for N0 vs. 1.3 years for N1, p = 0.018) and R status of the resection (median survival 1.6 years for R0 vs. 1.2 years for R1, p = 0.038). Median survival after severe postoperative complications was decreased from 1.9 to 1.2 years (p = 0.06). Median survival for N0 or N1 tumor or after R0 resection was not influenced by the occurrence and severity of complications, but patients with a R1 resection and severe complications showed a worsened median survival of 0.6 vs. 2.0 years without severe complications (p = 0.0005). Postoperative severe morbidity per se had no impact on long-term survival except in patients with R1 tumor resection. These results suggest that severe complications after R1 resection predict poor outcome.

Business Process Reengineering for Quality Improvement.

DTIC Science & Technology

1995-07-01

17 1.7.3. UNDERSTANDING BUSINESS VALUE...44 3.1.1. UNDERSTANDING BUSINESS PROCESS...targets which will promote the survival and growth of the business. 1.7.3. UNDERSTANDING BUSINESS VALUE Many businesses that have survived the test of time

Pyrotechnic Shock Analysis Using Statistical Energy Analysis

DTIC Science & Technology

2015-10-23

SEA subsystems. A couple of validation examples are provided to demonstrate the new approach. KEY WORDS : Peak Ratio, phase perturbation...Ballistic Shock Prediction Models and Techniques for Use in the Crusader Combat Vehicle Program,” 11th Annual US Army Ground Vehicle Survivability

Validation of genetic markers associated with chalkbrood resistance

USDA-ARS?s Scientific Manuscript database

Chalkbrood is one of the major fungal diseases of honey bee brood. Systemic mycoses caused by the fungus, Ascosphaera apis, may significantly reduce brood population, and consequently, colony strength and productivity. Developing genetic marker(s) associated with the enhanced brood survival will be ...

Improved survival with an innovative approach to the treatment of severely burned patients: development of a burn treatment manual.

PubMed

Morisada, S; Nosaka, N; Tsukahara, K; Ugawa, T; Sato, K; Ujike, Y

2015-09-30

The management of severely burned patients remains a major issue worldwide as indicated by the high incidence of permanent debilitating complications and poor survival rates. In April 2012, the Advanced Emergency & Critical Care Medical Center of the Okayama University Hospital began implementing guidelines for severely burned patients, distributed as a standard burn treatment manual. The protocol, developed in-house, was validated by comparing the outcomes of patients with severe extensive burns (SEB) treated before and after implementation of these new guidelines at this institution. The patients included in this study had a burn index (BI) ≥30 or a prognostic burn index (PBI = BI + patient's age) ≥100. The survival rate of the patients with BI ≥30 was 65.2% with the traditional treatment and 100% with the new guidelines. Likewise, the survival rate of the patients with PBI ≥100 was 61.1% with the traditional treatment compared to 100% with the new guidelines. Together, these data demonstrate that the new treatment guidelines dramatically improved the treatment outcome and survival of SEB patients.

A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia

PubMed Central

Luskin, Marlise R.; Gimotty, Phyllis A.; Smith, Catherine; Loren, Alison W.; Figueroa, Maria E.; Harrison, Jenna; Sun, Zhuoxin; Tallman, Martin S.; Paietta, Elisabeth M.; Litzow, Mark R.; Melnick, Ari M.; Levine, Ross L.; Fernandez, Hugo F.; Luger, Selina M.; Master, Stephen R.; Wertheim, Gerald B.W.

2016-01-01

BACKGROUND. Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML. METHODS. We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy. The association of M-score with complete remission (CR) and overall survival (OS) was evaluated. The optimal M-score cut-point for identifying groups with differing survival was used to define a binary M-score classifier. This classifier was validated in an independent cohort of 383 patients from the Eastern Cooperative Oncology Group Trial 1900 (E1900; NCT00049517). RESULTS. A higher mean M-score was associated with death and failure to achieve CR. Multivariable analysis confirmed that a higher M-score was associated with death (P = 0.011) and failure to achieve CR (P = 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. The ability of the M-score to perform as a classifier was confirmed in patients ≤ 60 years with intermediate cytogenetics and patients who achieved CR, as well as in the E1900 validation cohort. CONCLUSION. The M-score represents a valid binary prognostic classifier for patients with de novo AML. The xMELP assay and associated M-score can be used for prognosis and should be further investigated for clinical decision making in AML patients. PMID:27446991

PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer.

PubMed

Wishart, Gordon C; Azzato, Elizabeth M; Greenberg, David C; Rashbass, Jem; Kearins, Olive; Lawrence, Gill; Caldas, Carlos; Pharoah, Paul D P

2010-01-01

The aim of this study was to develop and validate a prognostication model to predict overall and breast cancer specific survival for women treated for early breast cancer in the UK. Using the Eastern Cancer Registration and Information Centre (ECRIC) dataset, information was collated for 5,694 women who had surgery for invasive breast cancer in East Anglia from 1999 to 2003. Breast cancer mortality models for oestrogen receptor (ER) positive and ER negative tumours were derived from these data using Cox proportional hazards, adjusting for prognostic factors and mode of cancer detection (symptomatic versus screen-detected). An external dataset of 5,468 patients from the West Midlands Cancer Intelligence Unit (WMCIU) was used for validation. Differences in overall actual and predicted mortality were <1% at eight years for ECRIC (18.9% vs. 19.0%) and WMCIU (17.5% vs. 18.3%) with area under receiver-operator-characteristic curves (AUC) of 0.81 and 0.79 respectively. Differences in breast cancer specific actual and predicted mortality were <1% at eight years for ECRIC (12.9% vs. 13.5%) and <1.5% at eight years for WMCIU (12.2% vs. 13.6%) with AUC of 0.84 and 0.82 respectively. Model calibration was good for both ER positive and negative models although the ER positive model provided better discrimination (AUC 0.82) than ER negative (AUC 0.75). We have developed a prognostication model for early breast cancer based on UK cancer registry data that predicts breast cancer survival following surgery for invasive breast cancer and includes mode of detection for the first time. The model is well calibrated, provides a high degree of discrimination and has been validated in a second UK patient cohort.

[Prognostic estimation in critical patients. Validation of a new and very simple system of prognostic estimation of survival in an intensive care unit].

PubMed

Abizanda, R; Padron, A; Vidal, B; Mas, S; Belenguer, A; Madero, J; Heras, A

2006-04-01

To make the validation of a new system of prognostic estimation of survival in critical patients (EPEC) seen in a multidisciplinar Intensive care unit (ICU). Prospective analysis of a patient cohort seen in the ICU of a multidisciplinar Intensive Medicine Service of a reference teaching hospital with 19 beds. Four hundred eighty four patients admitted consecutively over 6 months in 2003. Data collection of a basic minimum data set that includes patient identification data (gender, age), reason for admission and their origin, prognostic estimation of survival by EPEC, MPM II 0 and SAPS II (the latter two considered as gold standard). Mortality was evaluated on hospital discharge. EPEC validation was done with analysis of its discriminating capacity (ROC curve), calibration of its prognostic capacity (Hosmer Lemeshow C test), resolution of the 2 x 2 Contingency tables around different probability values (20, 50, 70 and mean value of prognostic estimation). The standardized mortality rate (SMR) for each one of the methods was calculated. Linear regression of the EPEC regarding the MPM II 0 and SAPS II was established and concordance analyses were done (Bland-Altman test) of the prediction of mortality by the three systems. In spite of an apparently good linear correlation, similar accuracy of prediction and discrimination capacity, EPEC is not well-calibrated (no likelihood of death greater than 50%) and the concordance analyses show that more than 10% of the pairs were outside the 95% confidence interval. In spite of its ease of application and calculation and of incorporating delay of admission in ICU as a variable, EPEC does not offer any predictive advantage on MPM II 0 or SAPS II, and its predictions adapt to reality worse.

Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases.

PubMed

Rajput, Ashish B; Turbin, Dmitry A; Cheang, Maggie Cu; Voduc, David K; Leung, Sam; Gelmon, Karen A; Gilks, C Blake; Huntsman, David G

2008-01-01

We have previously demonstrated in a pilot study of 348 invasive breast cancers that mast cell (MC) infiltrates within primary breast cancers are associated with a good prognosis. Our aim was to verify this finding in a larger cohort of invasive breast cancer patients and examine the relationship between the presence of MCs and other clinical and pathological features. Clinically annotated tissue microarrays (TMAs) containing 4,444 cases were constructed and stained with c-Kit (CD-117) using standard immunoperoxidase techniques to identify and quantify MCs. For statistical analysis, we applied a split-sample validation technique. Breast cancer specific survival was analyzed by Kaplan-Meier [KM] method and log rank test was used to compare survival curves. Survival analysis by KM method showed that the presence of stromal MCs was a favourable prognostic factor in the training set (P = 0.001), and the validation set group (P = 0.006). X-tile plot generated to define the optimal number of MCs showed that the presence of any number of stromal MCs predicted good prognosis. Multivariate analysis showed that the MC effect in the training set (Hazard ratio [HR] = 0.804, 95% Confidence interval [CI], 0.653-0.991, P = 0.041) and validation set analysis (HR = 0.846, 95% CI, 0.683-1.049, P = 0.128) was independent of age, tumor grade, tumor size, lymph node, ER and Her2 status. This study concludes that stromal MC infiltration in invasive breast cancer is an independent good prognostic marker and reiterates the critical role of local inflammatory responses in breast cancer progression.

Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases

PubMed Central

Rajput, Ashish B.; Turbin, Dmitry A.; Cheang, Maggie CU; Voduc, David K.; Leung, Sam; Gelmon, Karen A.; Gilks, C. Blake

2007-01-01

Purpose We have previously demonstrated in a pilot study of 348 invasive breast cancers that mast cell (MC) infiltrates within primary breast cancers are associated with a good prognosis. Our aim was to verify this finding in a larger cohort of invasive breast cancer patients and examine the relationship between the presence of MCs and other clinical and pathological features. Experimental design Clinically annotated tissue microarrays (TMAs) containing 4,444 cases were constructed and stained with c-Kit (CD-117) using standard immunoperoxidase techniques to identify and quantify MCs. For statistical analysis, we applied a split-sample validation technique. Breast cancer specific survival was analyzed by Kaplan–Meier [KM] method and log rank test was used to compare survival curves. Results Survival analysis by KM method showed that the presence of stromal MCs was a favourable prognostic factor in the training set (P = 0.001), and the validation set group (P = 0.006). X-tile plot generated to define the optimal number of MCs showed that the presence of any number of stromal MCs predicted good prognosis. Multivariate analysis showed that the MC effect in the training set (Hazard ratio [HR] = 0.804, 95% Confidence interval [CI], 0.653–0.991, P = 0.041) and validation set analysis (HR = 0.846, 95% CI, 0.683–1.049, P = 0.128) was independent of age, tumor grade, tumor size, lymph node, ER and Her2 status. Conclusions This study concludes that stromal MC infiltration in invasive breast cancer is an independent good prognostic marker and reiterates the critical role of local inflammatory responses in breast cancer progression. PMID:17431762

Clinical performance validation of PITX2 DNA methylation as prognostic biomarker in patients with head and neck squamous cell carcinoma.

PubMed

Sailer, Verena; Gevensleben, Heidrun; Dietrich, Joern; Goltz, Diane; Kristiansen, Glen; Bootz, Friedrich; Dietrich, Dimo

2017-01-01

Despite advances in combined modality therapy, outcomes in head and neck squamous cell cancer (HNSCC) remain dismal with five-year overall survival rates of less than 50%. Prognostic biomarkers are urgently needed to identify patients with a high risk of death after initial curative treatment. Methylation status of the paired-like homeodomain transcription factor 2 (PITX2) has recently emerged as a powerful prognostic biomarker in various cancers. In the present study, the clinical performance of PITX2 methylation was validated in a HNSCC cohort by means of an independent analytical platform (Infinium HumanMethylation450 BeadChip, Illumina, Inc.). A total of 528 HNSCC patients from The Cancer Genome Atlas (TCGA) were included in the study. Death was defined as primary endpoint. PITX2 methylation was correlated with overall survival and clinicopathological parameters. PITX2 methylation was significantly associated with sex, tumor site, p16 status, and grade. In univariate Cox proportional hazards analysis, PITX2 hypermethylation analyzed as continuous and dichotomized variable was significantly associated with prolonged overall survival of HNSCC patients (continuous: hazard ratio (HR) = 0.19 [95%CI: 0.04-0.88], p = 0.034; dichotomized: HR = 0.52 [95%CI: 0.33-0.84], p = 0.007). In multivariate Cox analysis including established clinicopathological parameters, PITX2 promoter methylation was confirmed as prognostic factor (HR = 0.28 [95%CI: 0.09-0.84], p = 0.023). Using an independent analytical platform, PITX2 methylation was validated as a prognostic biomarker in HNSCC patients, identifying patients that potentially benefit from intensified surveillance and/or administration of adjuvant/neodjuvant treatment, i.e. immunotherapy.

Evaluation of the proposed International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) staging revisions in thymic well-differentiated neuroendocrine carcinoma patients.

PubMed

Zhao, Yang; Shi, Jianxin; Fan, Limin; Yang, Jun; Hu, Dingzhong; Zhao, Heng

2016-02-01

In 2014, the International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) launched a worldwide Tumor Node Metastasis (TNM) staging proposal for the next edition of thymic tumours. The objective of the current study was to evaluate the proposed new staging system specific to the thymic well-differentiated neuroendocrine carcinoma (TWDNC). From November 2003 to July 2014, 61 consecutive patients were enrolled in this study with pathologically confirmed TWDNC in Shanghai Chest Hospital. Clinical and pathological data were retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier and log-rank tests. Validity evaluation was addressed by Cox proportional hazards regression model, after adjusting for potential confounders and visually assessing the distinction of curves generated based on the staging system of Masaoka-Koga and the proposed TNM ones. Thymic carcinoids made up 4% of total thymic tumours in our institution. The 5-year overall survival (OS) rate and the disease-free survival (DFS) rate were 72 and 41%, respectively. Neither Masaoka-Koga staging system nor the proposed TNM system showed ordered appropriateness visually in survival curves and the prognostic demarcation between stages was poor on both OS and DFS. The IASLC/ITMIG suggested that the TNM and Masaoka-Koga staging systems fail to predict the clinical course of TWDNC patients. Collaborative effort is needed in the future staging validation as ITMIG recommended. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Staying alive: Vibrio cholerae’s cycle of environmental survival, transmission, and dissemination

PubMed Central

Jones, Christopher J.; Yildiz, Fitnat H.

2015-01-01

Infectious diseases kill nearly 9 million people annually. Bacterial pathogens are responsible for a large proportion of these diseases and the bacterial agents of pneumonia, diarrhea, and tuberculosis are leading causes of death and disability worldwide (1). Increasingly, the crucial role of non-host environments in the life cycle of bacterial pathogens is being recognized. Heightened scrutiny has been given to the biological processes impacting pathogen dissemination and survival in the natural environment, as these processes are essential for the transmission of pathogenic bacteria to new hosts. This chapter focuses on the model environmental pathogen, Vibrio cholerae, to describe recent advances in our understanding of how pathogens survive between hosts and highlight the processes necessary to support the cycle of environmental survival, transmission, and dissemination. We describe the physiological and molecular responses of V. cholerae to changing environmental conditions, focusing on its survival in aquatic reservoirs between hosts and its entry and exit from human hosts. PMID:27227302

How Many Batches Are Needed for Process Validation under the New FDA Guidance?

PubMed

Yang, Harry

2013-01-01

The newly updated FDA Guidance for Industry on Process Validation: General Principles and Practices ushers in a life cycle approach to process validation. While the guidance no longer considers the use of traditional three-batch validation appropriate, it does not prescribe the number of validation batches for a prospective validation protocol, nor does it provide specific methods to determine it. This potentially could leave manufacturers in a quandary. In this paper, I develop a Bayesian method to address the issue. By combining process knowledge gained from Stage 1 Process Design (PD) with expected outcomes of Stage 2 Process Performance Qualification (PPQ), the number of validation batches for PPQ is determined to provide a high level of assurance that the process will consistently produce future batches meeting quality standards. Several examples based on simulated data are presented to illustrate the use of the Bayesian method in helping manufacturers make risk-based decisions for Stage 2 PPQ, and they highlight the advantages of the method over traditional Frequentist approaches. The discussions in the paper lend support for a life cycle and risk-based approach to process validation recommended in the new FDA guidance. The newly updated FDA Guidance for Industry on Process Validation: General Principles and Practices ushers in a life cycle approach to process validation. While the guidance no longer considers the use of traditional three-batch validation appropriate, it does not prescribe the number of validation batches for a prospective validation protocol, nor does it provide specific methods to determine it. This potentially could leave manufacturers in a quandary. In this paper, I develop a Bayesian method to address the issue. By combining process knowledge gained from Stage 1 Process Design (PD) with expected outcomes of Stage 2 Process Performance Qualification (PPQ), the number of validation batches for PPQ is determined to provide a high level of assurance that the process will consistently produce future batches meeting quality standards. Several examples based on simulated data are presented to illustrate the use of the Bayesian method in helping manufacturers make risk-based decisions for Stage 2 PPQ, and THEY highlight the advantages of the method over traditional Frequentist approaches. The discussions in the paper lend support for a life cycle and risk-based approach to process validation recommended in the new FDA guidance.

Survival probability of a truncated radial oscillator subject to periodic kicks

NASA Astrophysics Data System (ADS)

Tanabe, Seiichi; Watanabe, Shinichi; Saif, Farhan; Matsuzawa, Michio

2002-03-01

Classical and quantum survival probabilities are compared for a truncated radial oscillator undergoing impulsive interactions with periodic laser pulses represented here as kicks. The system is truncated in the sense that the harmonic potential is made valid only within a finite range; the rest of the space is treated as a perfect absorber. Exploring extended values of the parameters of this model [Phys. Rev. A 63, 052721 (2001)], we supplement discussions on classical and quantum features near resonances. The classical system proves to be quasi-integrable and preserves phase-space area despite the momentum transfered by the kicks, exhibiting simple yet rich phase-space features. A geometrical argument reveals quantum-classical correspondence in the locations of minima in the paired survival probabilities while the ``ionization'' rates differ due to quantum tunneling.

Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials-are we in a new era?

PubMed

Clarke, Jeffrey M; Wang, Xiaofei; Ready, Neal E

2015-12-01

Surrogate endpoints for clinical trials in oncology offer an alternative metric for measuring clinical benefit, allowing for shorter trial duration, smaller patient cohorts, and single arm design. The correlation of surrogate endpoints with overall survival (OS) in therapeutic studies is a central consideration to their validity. The Food and Drug Administration (FDA) recently published an analysis of fourteen clinical trials in advanced non-small cell lung cancer (NSCLC), and discovered a strong association between response rate and progression free survival. Furthermore, a correlation between response rate and OS is demonstrated when analyzing the experimental treatment arm separately, minimizing bias from patient crossover. We also highlight multiple, important considerations when using response as an endpoint in clinical trials involving NSCLC patients.

Survival Processing Enhances Visual Search Efficiency.

PubMed

Cho, Kit W

2018-05-01

Words rated for their survival relevance are remembered better than when rated using other well-known memory mnemonics. This finding, which is known as the survival advantage effect and has been replicated in many studies, suggests that our memory systems are molded by natural selection pressures. In two experiments, the present study used a visual search task to examine whether there is likewise a survival advantage for our visual systems. Participants rated words for their survival relevance or for their pleasantness before locating that object's picture in a search array with 8 or 16 objects. Although there was no difference in search times among the two rating scenarios when set size was 8, survival processing reduced visual search times when set size was 16. These findings reflect a search efficiency effect and suggest that similar to our memory systems, our visual systems are also tuned toward self-preservation.

Complete hazard ranking to analyze right-censored data: An ALS survival study.

PubMed

Huang, Zhengnan; Zhang, Hongjiu; Boss, Jonathan; Goutman, Stephen A; Mukherjee, Bhramar; Dinov, Ivo D; Guan, Yuanfang

2017-12-01

Survival analysis represents an important outcome measure in clinical research and clinical trials; further, survival ranking may offer additional advantages in clinical trials. In this study, we developed GuanRank, a non-parametric ranking-based technique to transform patients' survival data into a linear space of hazard ranks. The transformation enables the utilization of machine learning base-learners including Gaussian process regression, Lasso, and random forest on survival data. The method was submitted to the DREAM Amyotrophic Lateral Sclerosis (ALS) Stratification Challenge. Ranked first place, the model gave more accurate ranking predictions on the PRO-ACT ALS dataset in comparison to Cox proportional hazard model. By utilizing right-censored data in its training process, the method demonstrated its state-of-the-art predictive power in ALS survival ranking. Its feature selection identified multiple important factors, some of which conflicts with previous studies.

Ion Channel Gene Expression in Lung Adenocarcinoma: Potential Role in Prognosis and Diagnosis

PubMed Central

Ko, Jae-Hong; Gu, Wanjun; Lim, Inja; Bang, Hyoweon; Ko, Eun A.; Zhou, Tong

2014-01-01

Ion channels are known to regulate cancer processes at all stages. The roles of ion channels in cancer pathology are extremely diverse. We systematically analyzed the expression patterns of ion channel genes in lung adenocarcinoma. First, we compared the expression of ion channel genes between normal and tumor tissues in patients with lung adenocarcinoma. Thirty-seven ion channel genes were identified as being differentially expressed between the two groups. Next, we investigated the prognostic power of ion channel genes in lung adenocarcinoma. We assigned a risk score to each lung adenocarcinoma patient based on the expression of the differentially expressed ion channel genes. We demonstrated that the risk score effectively predicted overall survival and recurrence-free survival in lung adenocarcinoma. We also found that the risk scores for ever-smokers were higher than those for never-smokers. Multivariate analysis indicated that the risk score was a significant prognostic factor for survival, which is independent of patient age, gender, stage, smoking history, Myc level, and EGFR/KRAS/ALK gene mutation status. Finally, we investigated the difference in ion channel gene expression between the two major subtypes of non-small cell lung cancer: adenocarcinoma and squamous-cell carcinoma. Thirty ion channel genes were identified as being differentially expressed between the two groups. We suggest that ion channel gene expression can be used to improve the subtype classification in non-small cell lung cancer at the molecular level. The findings in this study have been validated in several independent lung cancer cohorts. PMID:24466154

Utility of the Psychosocial Assessment of Candidates for Transplantation in Patients Undergoing Continuous-Flow Left Ventricular Assist Device Implantation.

PubMed

Halkar, Meghana; Nowacki, Amy S; Kendall, Kay; Efeovbokhan, Nephertiti; Gorodeski, Eiran Z; Moazami, Nader; Starling, Randall C; Young, James B; Lee, Sangjin; Tang, W H Wilson

2018-01-01

Psychosocial assessment of patients comprises an important element in the selection process of appropriate candidates for left ventricular assist device (LVAD) implantation. We sought to determine the association of the well-validated psychosocial assessment of candidates for transplantation (PACT) scale to clinical outcomes post-LVAD implantation. The PACT scale was used retrospectively to reconstruct psychosocial profiles of all patients who underwent a continuous-flow LVAD implantation for all indications at our institution between March 2008 and August 2012 (N = 230). Psychosocial elements including social support, psychological health, lifestyle factors, comprehension of the operation, and follow-up were evaluated. The primary outcome was overall survival, and the secondary outcomes were hospital readmission, pump thrombosis, hemolysis, gastrointestinal (GI) bleeding, and LVAD driveline infections. The mean age of patients was 55.3 years, with 83% being male; 58% (N = 135) were bridge to transplant and 42% (N = 95) were destination therapy. Up to 1-year post-LVAD implant, there were no statistical differences among the 5 PACT candidate groups in terms of survival ( P = .79), hospital readmissions ( P = .55), suspected or confirmed pump thrombosis ( P = .31), hemolysis ( P = .43), GI bleeding ( P = .71), or driveline infections ( P = .06). In this single-center retrospective review, post hoc reconstruction of psychosocial profiles using the PACT scale and independent assessment of postimplant outcomes, including survival and adverse events, did not show any association. However, given the small number of patients in the low score PACT groups as well as limited duration of follow-up, further studies are required to elucidate the association.

Identifying cut points for biomarker defined subset effects in clinical trials with survival endpoints.

PubMed

He, Pei

2014-07-01

The advancements in biotechnology and genetics lead to an increasing research interest in personalized medicine, where a patient's genetic profile or biological traits contribute to choosing the most effective treatment for the patient. The process starts with finding a specific biomarker among all possible candidates that can best predict the treatment effect. After a biomarker is chosen, identifying a cut point of the biomarker value that splits the patients into treatment effective and non-effective subgroups becomes an important scientific problem. Numerous methods have been proposed to validate the predictive marker and select the appropriate cut points either prospectively or retrospectively using clinical trial data. In trials with survival outcomes, the current practice applies an interaction testing procedure and chooses the cut point that minimizes the p-values for the tests. Such method assumes independence between the baseline hazard and biomarker value. In reality, however, this assumption is often violated, as the chosen biomarker might also be prognostic in addition to its predictive nature for treatment effect. In this paper we propose a block-wise estimation and a sequential testing approach to identify the cut point in biomarkers that can group the patients into subsets based on their distinct treatment outcomes without assuming independence between the biomarker and baseline hazard. Numerical results based on simulated survival data show that the proposed method could pinpoint accurately the cut points in biomarker values that separate the patient subpopulations into subgroups with distinctive treatment outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

Development and External Validation of a Prognostic Nomogram for Metastatic Uveal Melanoma

PubMed Central

Valpione, Sara; Moser, Justin C.; Parrozzani, Raffaele; Bazzi, Marco; Mansfield, Aaron S.; Mocellin, Simone; Pigozzo, Jacopo; Midena, Edoardo; Markovic, Svetomir N.; Aliberti, Camillo; Campana, Luca G.; Chiarion-Sileni, Vanna

2015-01-01

Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials. PMID:25780931

Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma.

PubMed

Yang, Lin; Xia, Liangping; Wang, Yan; He, Shasha; Chen, Haiyang; Liang, Shaobo; Peng, Peijian; Hong, Shaodong; Chen, Yong

2017-09-06

The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC. A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions. Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group. The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC.

Risk perception and information processing: the development and validation of a questionnaire to assess self-reported information processing.

PubMed

Smerecnik, Chris M R; Mesters, Ilse; Candel, Math J J M; De Vries, Hein; De Vries, Nanne K

2012-01-01

The role of information processing in understanding people's responses to risk information has recently received substantial attention. One limitation of this research concerns the unavailability of a validated questionnaire of information processing. This article presents two studies in which we describe the development and validation of the Information-Processing Questionnaire to meet that need. Study 1 describes the development and initial validation of the questionnaire. Participants were randomized to either a systematic processing or a heuristic processing condition after which they completed a manipulation check and the initial 15-item questionnaire and again two weeks later. The questionnaire was subjected to factor reliability and validity analyses on both measurement times for purposes of cross-validation of the results. A two-factor solution was observed representing a systematic processing and a heuristic processing subscale. The resulting scale showed good reliability and validity, with the systematic condition scoring significantly higher on the systematic subscale and the heuristic processing condition significantly higher on the heuristic subscale. Study 2 sought to further validate the questionnaire in a field study. Results of the second study corresponded with those of Study 1 and provided further evidence of the validity of the Information-Processing Questionnaire. The availability of this information-processing scale will be a valuable asset for future research and may provide researchers with new research opportunities. © 2011 Society for Risk Analysis.

Cost-effective conservation of amphibian ecology and evolution

PubMed Central

Campos, Felipe S.; Lourenço-de-Moraes, Ricardo; Llorente, Gustavo A.; Solé, Mirco

2017-01-01

Habitat loss is the most important threat to species survival, and the efficient selection of priority areas is fundamental for good systematic conservation planning. Using amphibians as a conservation target, we designed an innovative assessment strategy, showing that prioritization models focused on functional, phylogenetic, and taxonomic diversity can include cost-effectiveness–based assessments of land values. We report new key conservation sites within the Brazilian Atlantic Forest hot spot, revealing a congruence of ecological and evolutionary patterns. We suggest payment for ecosystem services through environmental set-asides on private land, establishing potential trade-offs for ecological and evolutionary processes. Our findings introduce additional effective area-based conservation parameters that set new priorities for biodiversity assessment in the Atlantic Forest, validating the usefulness of a novel approach to cost-effectiveness–based assessments of conservation value for other species-rich regions. PMID:28691084

Development and validation of a prognostic nomogram for colorectal cancer after radical resection based on individual patient data from three large-scale phase III trials

PubMed Central

Akiyoshi, Takashi; Maeda, Hiromichi; Kashiwabara, Kosuke; Kanda, Mitsuro; Mayanagi, Shuhei; Aoyama, Toru; Hamada, Chikuma; Sadahiro, Sotaro; Fukunaga, Yosuke; Ueno, Masashi; Sakamoto, Junichi; Saji, Shigetoyo; Yoshikawa, Takaki

2017-01-01

Background Few prediction models have so far been developed and assessed for the prognosis of patients who undergo curative resection for colorectal cancer (CRC). Materials and Methods We prepared a clinical dataset including 5,530 patients who participated in three major randomized controlled trials as a training dataset and 2,263 consecutive patients who were treated at a cancer-specialized hospital as a validation dataset. All subjects underwent radical resection for CRC which was histologically diagnosed to be adenocarcinoma. The main outcomes that were predicted were the overall survival (OS) and disease free survival (DFS). The identification of the variables in this nomogram was based on a Cox regression analysis and the model performance was evaluated by Harrell's c-index. The calibration plot and its slope were also studied. For the external validation assessment, risk group stratification was employed. Results The multivariate Cox model identified variables; sex, age, pathological T and N factor, tumor location, size, lymphnode dissection, postoperative complications and adjuvant chemotherapy. The c-index was 0.72 (95% confidence interval [CI] 0.66-0.77) for the OS and 0.74 (95% CI 0.69-0.78) for the DFS. The proposed stratification in the risk groups demonstrated a significant distinction between the Kaplan–Meier curves for OS and DFS in the external validation dataset. Conclusions We established a clinically reliable nomogram to predict the OS and DFS in patients with CRC using large scale and reliable independent patient data from phase III randomized controlled trials. The external validity was also confirmed on the practical dataset. PMID:29228760

Validation of a Radiosensitivity Molecular Signature in Breast Cancer

PubMed Central

Eschrich, Steven A.; Fulp, William J.; Pawitan, Yudi; Foekens, John A.; Smid, Marcel; Martens, John W. M.; Echevarria, Michelle; Kamath, Vidya; Lee, Ji-Hyun; Harris, Eleanor E.; Bergh, Jonas; Torres-Roca, Javier F.

2014-01-01

Purpose Previously, we developed a radiosensitivity molecular signature (RSI) that was clinically-validated in three independent datasets (rectal, esophageal, head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT) treated breast cancer patients. Experimental Design RSI was tested in two previously published breast cancer datasets. Patients were treated at the Karolinska University Hospital (n=159) and Erasmus Medical Center (n=344). RSI was applied as previously described. Results We tested RSI in RT-treated patients (Karolinska). Patients predicted to be radiosensitive (RS) had an improved 5 yr relapse-free survival when compared with radioresistant (RR) patients (95% vs. 75%, p=0.0212) but there was no difference between RS/RR patients treated without RT (71% vs. 77%, p=0.6744), consistent with RSI being RT-specific (interaction term RSIxRT, p=0.05). Similarly, in the Erasmus dataset RT-treated RS patients had an improved 5-year distant-metastasis-free survival over RR patients (77% vs. 64%, p=0.0409) but no difference was observed in patients treated without RT (RS vs. RR, 80% vs. 81%, p=0.9425). Multivariable analysis showed RSI is the strongest variable in RT-treated patients (Karolinska, HR=5.53, p=0.0987, Erasmus, HR=1.64, p=0.0758) and in backward selection (removal alpha of 0.10) RSI was the only variable remaining in the final model. Finally, RSI is an independent predictor of outcome in RT-treated ER+ patients (Erasmus, multivariable analysis, HR=2.64, p=0.0085). Conclusions RSI is validated in two independent breast cancer datasets totaling 503 patients. Including prior data, RSI is validated in five independent cohorts (621 patients) and represents, to our knowledge, the most extensively validated molecular signature in radiation oncology. PMID:22832933

Genome-Wide Methylation Analyses in Glioblastoma Multiforme

PubMed Central

Lai, Rose K.; Chen, Yanwen; Guan, Xiaowei; Nousome, Darryl; Sharma, Charu; Canoll, Peter; Bruce, Jeffrey; Sloan, Andrew E.; Cortes, Etty; Vonsattel, Jean-Paul; Su, Tao; Delgado-Cruzata, Lissette; Gurvich, Irina; Santella, Regina M.; Ostrom, Quinn; Lee, Annette; Gregersen, Peter; Barnholtz-Sloan, Jill

2014-01-01

Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal. PMID:24586730

Predicting survival of men with recurrent prostate cancer after radical prostatectomy.

PubMed

Dell'Oglio, Paolo; Suardi, Nazareno; Boorjian, Stephen A; Fossati, Nicola; Gandaglia, Giorgio; Tian, Zhe; Moschini, Marco; Capitanio, Umberto; Karakiewicz, Pierre I; Montorsi, Francesco; Karnes, R Jeffrey; Briganti, Alberto

2016-02-01

To develop and externally validate a novel nomogram aimed at predicting cancer-specific mortality (CSM) after biochemical recurrence (BCR) among prostate cancer (PCa) patients treated with radical prostatectomy (RP) with or without adjuvant external beam radiotherapy (aRT) and/or hormonal therapy (aHT). The development cohort included 689 consecutive PCa patients treated with RP between 1987 and 2011 with subsequent BCR, defined as two subsequent prostate-specific antigen values >0.2 ng/ml. Multivariable competing-risks regression analyses tested the predictors of CSM after BCR for the purpose of 5-year CSM nomogram development. Validation (2000 bootstrap resamples) was internally tested. External validation was performed into a population of 6734 PCa patients with BCR after treatment with RP at the Mayo Clinic from 1987 to 2011. The predictive accuracy (PA) was quantified using the receiver operating characteristic-derived area under the curve and the calibration plot method. The 5-year CSM-free survival rate was 83.6% (confidence interval [CI]: 79.6-87.2). In multivariable analyses, pathologic stage T3b or more (hazard ratio [HR]: 7.42; p = 0.008), pathologic Gleason score 8-10 (HR: 2.19; p = 0.003), lymph node invasion (HR: 3.57; p = 0.001), time to BCR (HR: 0.99; p = 0.03) and age at BCR (HR: 1.04; p = 0.04), were each significantly associated with the risk of CSM after BCR. The bootstrap-corrected PA was 87.4% (bootstrap 95% CI: 82.0-91.7%). External validation of our nomogram showed a good PA at 83.2%. We developed and externally validated the first nomogram predicting 5-year CSM applicable to contemporary patients with BCR after RP with or without adjuvant treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sumoylation in p27kip1 via RanBP2 promotes cancer cell growth in cholangiocarcinoma cell line QBC939.

PubMed

Yang, Jun; Liu, Yan; Wang, Bing; Lan, Hongzhen; Liu, Ying; Chen, Fei; Zhang, Ju; Luo, Jian

2017-09-07

Cholangiocarcinoma is one of the deadly disease with poor 5-year survival and poor response to conventional therapies. Previously, we found that p27kip1 nuclear-cytoplasmic translocation confers proliferation potential to cholangiocarcinoma cell line QBC939 and this process is mediated by crm-1. However, no other post-transcriptional regulation was found in this process including sumoylation in cholangiocarcinoma. In this study, we explored the role of sumoylation in the nuclear-cytoplasmic translocation of p27kip1 and its involvement of QBC939 cells' proliferation. First, we identified K73 as the sumoylation site in p27kip1. By utilizing plasmid flag-p27kip1, HA-RanBP2, GST-RanBP2 and His-p27kip1 and immunoprecipitation assay, we validated that p27kip1 can serve as the sumoylation target of RanBP2 in QBC939. Furthermore, we confirmed crm-1's role in promoting nuclear-cytoplasmic translocation of p27kip1 and found that RanBP2's function relies on crm-1. However, K73R mutated p27kip1 can't be identified by crm-1 or RanBP2 in p27kip1 translocation process, suggesting sumoylation of p27kip1 via K73 site is necessary in this process by RanBP2 and crm-1. Phenotypically, the overexpression of either RanBP2 or crm-1 can partially rescue the anti-proliferative effect brought by p27kip1 overexpression in both the MTS and EdU assay. For the first time, we identified and validated the K73 sumoylation site in p27kip1, which is critical to RanBP2 and crm-1 in p27kip1 nuclear-cytoplasmic translocation process. Taken together, targeted inhibition of sumoylation of p27kip1 may serve as a potentially potent therapeutic target in the eradication of cholangiocarcinoma development and relapses.

Survival Impact of Increasing Time to Treatment Initiation for Patients With Head and Neck Cancer in the United States.

PubMed

Murphy, Colin T; Galloway, Thomas J; Handorf, Elizabeth A; Egleston, Brian L; Wang, Lora S; Mehra, Ranee; Flieder, Douglas B; Ridge, John A

2016-01-10

To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival. © 2015 by American Society of Clinical Oncology.

Survival Impact of Increasing Time to Treatment Initiation for Patients With Head and Neck Cancer in the United States

PubMed Central

Murphy, Colin T.; Handorf, Elizabeth A.; Egleston, Brian L.; Wang, Lora S.; Mehra, Ranee; Flieder, Douglas B.; Ridge, John A.

2016-01-01

Purpose To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). Methods Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. Results A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. Conclusion TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival. PMID:26628469

An overview of molecular stress response mechanisms in Escherichia coli contributing to survival of Shiga toxin-producing Escherichia coli during raw milk cheese production.

PubMed

Peng, Silvio; Tasara, Taurai; Hummerjohann, Jörg; Stephan, Roger

2011-05-01

The ability of foodborne pathogens to survive in certain foods mainly depends on stress response mechanisms. Insight into molecular properties enabling pathogenic bacteria to survive in food is valuable for improvement of the control of pathogens during food processing. Raw milk cheeses are a potential source for human infections with Shiga toxin-producing Escherichia coli (STEC). In this review, we focused on the stress response mechanisms important for allowing STEC to survive raw milk cheese production processes. The major components and regulation pathways for general, acid, osmotic, and heat shock stress responses in E. coli and the implications of these responses for the survival of STEC in raw milk cheeses are discussed.

Effective Disengagement: Insecure People Are More Likely to Disengage From an Ongoing Task and Take Effective Action When Facing Danger.

PubMed

Ein-Dor, Tsachi; Perry-Paldi, Adi; Merrin, Jenna; Efrati, Yaniv; Hirschberger, Gilad

2018-04-01

People believe that they can respond effectively to threats, but actually they experience difficulties in disengaging from ongoing tasks and shifting their attention to life-threatening events. We contend that this tendency is especially true for secure people with respect to their worldview and perception of others and not for insecure individuals. In Study 1 (N = 290), we examined individuals' reactions to various threat scenarios. In Study 2 (N = 65), we examined these reactions using a behavioral design high in ecological validity. In Study 3 (N = 78), we examined group-level benefits for the actions of insecure individuals by manipulating asocial behavior in response to an emergency. Study 1 indicated that anxiously attached individuals stayed away from threats and sought help; avoidant people tended to take action by either assessing the risk of the event and/or enacting an asocial action such as fight or flight. Study 2 added ecological validity to these findings, and Study 3 showed that priming asocial behavior responses promoted actions that increased group members' chances of survival. Results validate the central tenets of social defense theory and indicate that actions that are deemed asocial may paradoxically promote the survival of individuals and groups. © 2017 Wiley Periodicals, Inc.

To brood or not to brood: Are marine invertebrates that protect their offspring more resilient to ocean acidification?

NASA Astrophysics Data System (ADS)

Lucey, Noelle Marie; Lombardi, Chiara; Demarchi, Lucia; Schulze, Anja; Gambi, Maria Cristina; Calosi, Piero

2015-07-01

Anthropogenic atmospheric carbon dioxide (CO2) is being absorbed by seawater resulting in increasingly acidic oceans, a process known as ocean acidification (OA). OA is thought to have largely deleterious effects on marine invertebrates, primarily impacting early life stages and consequently, their recruitment and species’ survival. Most research in this field has been limited to short-term, single-species and single-life stage studies, making it difficult to determine which taxa will be evolutionarily successful under OA conditions. We circumvent these limitations by relating the dominance and distribution of the known polychaete worm species living in a naturally acidic seawater vent system to their life history strategies. These data are coupled with breeding experiments, showing all dominant species in this natural system exhibit parental care. Our results provide evidence supporting the idea that long-term survival of marine species in acidic conditions is related to life history strategies where eggs are kept in protected maternal environments (brooders) or where larvae have no free swimming phases (direct developers). Our findings are the first to formally validate the hypothesis that species with life history strategies linked to parental care are more protected in an acidifying ocean compared to their relatives employing broadcast spawning and pelagic larval development.

In serum veritas—in serum sanitas? Cell non-autonomous aging compromises differentiation and survival of mesenchymal stromal cells via the oxidative stress pathway

PubMed Central

Geißler, S; Textor, M; Schmidt-Bleek, K; Klein, O; Thiele, M; Ellinghaus, A; Jacobi, D; Ode, A; Perka, C; Dienelt, A; Klose, J; Kasper, G; Duda, G N; Strube, P

2013-01-01

Even tissues capable of complete regeneration, such as bone, show an age-related reduction in their healing capacity. Here, we hypothesized that this decline is primarily due to cell non-autonomous (extrinsic) aging mediated by the systemic environment. We demonstrate that culture of mesenchymal stromal cells (MSCs) in serum from aged Sprague–Dawley rats negatively affects their survival and differentiation ability. Proteome analysis and further cellular investigations strongly suggest that serum from aged animals not only changes expression of proteins related to mitochondria, unfolded protein binding or involved in stress responses, it also significantly enhances intracellular reactive oxygen species production and leads to the accumulation of oxidatively damaged proteins. Conversely, reduction of oxidative stress levels in vitro markedly improved MSC function. These results were validated in an in vivo model of compromised bone healing, which demonstrated significant increase regeneration in aged animals following oral antioxidant administration. These observations indicate the high impact of extrinsic aging on cellular functions and the process of endogenous (bone) regeneration. Thus, addressing the cell environment by, for example, systemic antioxidant treatment is a promising approach to enhance tissue regeneration and to regain cellular function especially in elderly patients. PMID:24357801

MiR-615 inhibits cell proliferation, migration and invasion by targeting EGFR in human glioblastoma.

PubMed

Ji, Yanwei; Sun, Qingshan; Zhang, Jianbin; Hu, Haoran

2018-05-15

MiR-615 and epidermal growth factor receptor (EGFR) are associated with a number of disease processes and pathogenesis. However, little is known about the mechanisms of miR-615 and EGFR in human glioblastoma multiforme (GBM). Here, we found that down-regulation of miR-615 expression occurred in GBM tissues and cells, and was inversely correlated with overall survival, relapse-free survival, WHO grade as well as EGFR expression. We further determined that miR-615 functions as a tumor suppressor by inhibiting GBM cell proliferation, cell cycle, migration and invasion, and promoting cell apoptosis. In-vivo assay validated the inhibition effect of miR-615 on tumor growth and EGFR expression. Luciferase reporter assays demonstrated that miR-615 targeted the 3'-untranslated region (3'-UTR) of EGFR. Besides, over-expression of EGFR reversed the inhibition effects of miR-615, while silencing of EGFR aggravated these inhibition effects. In conclusions, we identified that miR-615 plays a tumor suppressor role in GBM cell proliferation, migration and invasion by targeting EGFR expression, and miR-615 may act as a novel biomarker for early diagnosis or therapeutic targets of GBM. Copyright © 2018 Elsevier Inc. All rights reserved.

Flow cytometry quality requirements for monitoring of minimal disease in plasma cell myeloma.

PubMed

Oldaker, Teri A; Wallace, Paul K; Barnett, David

2016-01-01

Current therapeutic approaches for plasma cell myeloma (PCM) attain an overall survival of more than 6 years for the majority of newly diagnosed patients. However, PFS and OS are the only accepted FDA clinical endpoints for demonstrating drug efficacy before they can be become frontline therapeutic options. There is, however, recognition that the increasing gap between drug development and approval for mainstream therapeutic use needs to be shortened. As such regulatory bodies such as the FDA are now considering whether biomarker response evaluation, as in measurement of minimal residual disease (MRD) as assessed by flow cytometry (FC), can provide an early, robust prediction of survival and therefore improve the drug approval process. Recently, FC MRD using a standardized eight-color antibody methodology has been shown to have a minimum sensitivity of 0.01% and an upper sensitivity of 0.001%. To ensure that all laboratories using this approach achieve the same levels of sensitivity it is crucially important to have standardized quality management procedures in place. This manuscript accompanies those published in this special issue and describes the minimum that is required for validating and quality monitoring of this highly specific test to ensure any laboratory, irrespective of location, will achieve the expected quality standards required. © 2015 International Clinical Cytometry Society.

Host cell processes that influence the intracellular survival of Legionella pneumophila.

PubMed

Shin, Sunny; Roy, Craig R

2008-06-01

Key to the pathogenesis of intracellular pathogens is their ability to manipulate host cell processes, permitting the establishment of an intracellular replicative niche. In turn, the host cell deploys defence mechanisms that limit intracellular infection. The bacterial pathogen Legionella pneumophila, the aetiological agent of Legionnaire's Disease, has evolved virulence mechanisms that allow it to replicate within protozoa, its natural host. Many of these tactics also enable L. pneumophila's survival and replication inside macrophages within a membrane-bound compartment known as the Legionella-containing vacuole. One of the virulence factors indispensable for L. pneumophila's intracellular survival is a type IV secretion system, which translocates a large repertoire of bacterial effectors into the host cell. These effectors modulate multiple host cell processes and in particular, redirect trafficking of the L. pneumophila phagosome and mediate its conversion into an ER-derived organelle competent for intracellular bacterial replication. In this review, we discuss how L. pneumophila manipulates host cells, as well as host cell processes that either facilitate or impede its intracellular survival.

Evaluating disease management program effectiveness: an introduction to survival analysis.

PubMed

Linden, Ariel; Adams, John L; Roberts, Nancy

2004-01-01

Currently, the most widely used method in the disease management industry for evaluating program effectiveness is the "total population approach." This model is a pretest-posttest design, with the most basic limitation being that without a control group, there may be sources of bias and/or competing extraneous confounding factors that offer plausible rationale explaining the change from baseline. Survival analysis allows for the inclusion of data from censored cases, those subjects who either "survived" the program without experiencing the event (e.g., achievement of target clinical levels, hospitalization) or left the program prematurely, due to disenrollement from the health plan or program, or were lost to follow-up. Additionally, independent variables may be included in the model to help explain the variability in the outcome measure. In order to maximize the potential of this statistical method, validity of the model and research design must be assured. This paper reviews survival analysis as an alternative, and more appropriate, approach to evaluating DM program effectiveness than the current total population approach.

Survival analysis of heart failure patients: A case study.

PubMed

Ahmad, Tanvir; Munir, Assia; Bhatti, Sajjad Haider; Aftab, Muhammad; Raza, Muhammad Ali

2017-01-01

This study was focused on survival analysis of heart failure patients who were admitted to Institute of Cardiology and Allied hospital Faisalabad-Pakistan during April-December (2015). All the patients were aged 40 years or above, having left ventricular systolic dysfunction, belonging to NYHA class III and IV. Cox regression was used to model mortality considering age, ejection fraction, serum creatinine, serum sodium, anemia, platelets, creatinine phosphokinase, blood pressure, gender, diabetes and smoking status as potentially contributing for mortality. Kaplan Meier plot was used to study the general pattern of survival which showed high intensity of mortality in the initial days and then a gradual increase up to the end of study. Martingale residuals were used to assess functional form of variables. Results were validated computing calibration slope and discrimination ability of model via bootstrapping. For graphical prediction of survival probability, a nomogram was constructed. Age, renal dysfunction, blood pressure, ejection fraction and anemia were found as significant risk factors for mortality among heart failure patients.

[Soft tissue sarcoma of the upper extremities. Analysis of factors relevant for prognosis in 160 patients].

PubMed

Lehnhardt, M; Hirche, C; Daigeler, A; Goertz, O; Ring, A; Hirsch, T; Drücke, D; Hauser, J; Steinau, H U

2012-02-01

Soft tissue sarcomas (STS) are a rare entity with reduced prognosis due to their aggressive biology. For an optimal treatment of STS identification of independent prognostic factors is crucial in order to reduce tumor-related mortality and recurrence rates. The surgical oncological concept includes wide excisions with resection safety margins >1 cm which enables acceptable functional results and reduced rates of amputation of the lower extremities. In contrast, individual anatomy of the upper extremities, in particular of the hand, leads to an intentional reduction of resection margins in order to preserve the extremity and its function with the main intention of tumor-free resection margins. In this study, the oncological safety and outcome as well as functional results were validated by a retrospective analysis of survival rate, recurrence rate and potential prognostic factors. A total of 160 patients who had been treated for STS of the upper extremities were retrospectively included. Independent prognostic factors were analyzed (primary versus recurrent tumor, tumor size, resection status, grade of malignancy, additional therapy, localization in the upper extremity). Kaplan-Meier analyses for survival rate and local control were calculated. Further outcome measures were functional results validated by the DASH score and rate of amputation. In 130 patients (81%) wide tumor excision (R0) was performed and in 19 patients (12%) an amputation was necessary. The 5-year overall survival rate was 70% and the 5-year survival rate in primary tumors was 81% whereas in recurrences 55% relapsed locally. The 10-year overall survival rate was 45% and the 5-year recurrence rate was 18% for primary STS and 43% for recurrent STS. Variance analysis revealed primary versus recurrent tumor, tumor size, resection status and grade of malignancy as independent prognostic factors. Analysis of functional results showed a median DASH score of 37 (0-100; 0=contralateral extremity). The 5-year survival and local recurrence rates are comparable to STS wide resections with safety margins >1 cm for the lower extremities and the trunk. Analysis of prognostic factors revealed resection status and the tumor-free resection margins to be the main goals in STS resection of upper extremity.

Effect of telomere length on survival in idiopathic pulmonary fibrosis: an observational study with independent validation

PubMed Central

Stuart, Bridget D.; Lee, Joyce S.; Kozlitina, Julia; Noth, Imre; Devine, Megan S.; Glazer, Craig S.; Torres, Fernando; Kaza, Vaidehi; Girod, Carlos E.; Jones, Kirk D.; Elicker, Brett M.; Ma, Shwu-Fan; Vij, Rekha; Collard, Harold R.; Wolters, Paul J.; Garcia, Christine Kim

2014-01-01

Background Short telomere lengths are found in a subset of idiopathic pulmonary fibrosis (IPF) patients, but their clinical significance is unknown. The aim of this study was to investigate whether patients with various blood leukocyte telomere lengths had different overall survival. Methods Telomere lengths were measured in 370 genomic DNA samples isolated from peripheral blood collected from patients with interstitial lung disease (149 with IPF) at the time of their initial evaluation. Associations of telomere length with transplant-free survival were determined. Findings were validated in two independent IPF cohorts. Findings Patients with IPF had shorter telomere lengths than controls, but similar telomere lengths when compared to patients with other interstitial lung disease diagnoses after adjusting for age, male sex and ethnicity. Telomere length was independently associated with transplant-free survival time for patients with IPF (HR 0·22 [0·08–0·63], P-value = 0·0048), but not for patients with interstitial lung disease diagnoses other than IPF (HR 0·73 [0·16–3·41], P-value = 0·69). The association between telomere length and IPF survival was independent of age, male sex, forced vital capacity or diffusing capacity of carbon monoxide (and was replicated in two independent IPF cohorts (HR 0·11 [0·03–0·39], P-value 0·00066; HR 0·25 [0·07–0·87], P-value = 0·029). Addition of telomere length to clinical prediction models improved the integrative discrimination index, especially for IPF cohorts with milder disease. Interpretation These findings suggest that shorter leukocyte telomere lengths are associated with worse survival in IPF. Additional studies will be needed to determine clinically relevant thresholds for telomere length and how this biomarker may influence future risk stratification of IPF patients. Furthermore, this study offers mechanistic insight as disease progression in certain IPF patients may be related to aberrant signaling from short telomeres. Funding US National Heart, Lung, and Blood Institute; the National Center for Advancing Translational Science, the Harroun Family Foundation and the Nina Ireland Lung Disease Program. PMID:24948432

18F-FDG PET/CT has a high impact on patient management and provides powerful prognostic stratification in the primary staging of esophageal cancer: a prospective study with mature survival data.

PubMed

Barber, Thomas W; Duong, Cuong P; Leong, Trevor; Bressel, Mathias; Drummond, Elizabeth G; Hicks, Rodney J

2012-06-01

The aim of this study is to evaluate the incremental staging information, management impact, and prognostic stratification of PET/CT in the primary staging of esophageal cancer in a cohort of patients with mature survival data. Between July 2002 and June 2005, 139 consecutive patients with newly diagnosed esophageal cancer underwent conventional staging investigations (CSI), followed by PET/CT. Disease stage was classified according to the American Joint Committee on Cancer staging system (6th edition) and grouped as stage I-IIA, stage IIB-III, and stage IV reflecting broad groupings that determine therapeutic choice. Validation of results was performed when PET/CT and CSI stage groups were discordant and in those patients where PET/CT changed management. Management impact was determined by comparing prospectively recorded pre-PET/CT management plans with post-PET/CT management plans. Survival after follow-up of at least 5 y in patients was analyzed using the Kaplan-Meier product limit method and the Cox proportional hazards regression model. PET/CT changed the stage group in 56 of 139 (40%) patients and changed management in 47 of 139 (34%) patients. In 22 patients, therapy was changed from curative to palliative and in 3 from palliative to curative; in 11, treatment modality was changed without a change in treatment intent, and in 11 the delivery of therapy or diagnostic procedure was changed. Of the 47 patients with management change, imaging results could be validated in 31 patients, and PET/CT correctly changed management in 26 (84%) of these. Of the remaining 5 patients, CSI stage was also incorrect in 4 and correct in 1. Median survival was 23 mo. PET/CT stages I-IIA, IIB-III, and IV had a 5-y survival of 40%, 38%, and 6%, respectively. Post-PET/CT stage group and treatment intent were both strongly associated with survival (P < 0.001). PET/CT provides incremental staging information compared with CSI, changes management in one third of patients, and has powerful prognostic stratification in the primary staging of esophageal cancer.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

PubMed

Briceño, Javier; Cruz-Ramírez, Manuel; Prieto, Martín; Navasa, Miguel; Ortiz de Urbina, Jorge; Orti, Rafael; Gómez-Bravo, Miguel-Ángel; Otero, Alejandra; Varo, Evaristo; Tomé, Santiago; Clemente, Gerardo; Bañares, Rafael; Bárcena, Rafael; Cuervas-Mons, Valentín; Solórzano, Guillermo; Vinaixa, Carmen; Rubín, Angel; Colmenero, Jordi; Valdivieso, Andrés; Ciria, Rubén; Hervás-Martínez, César; de la Mata, Manuel

2014-11-01

There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Numerical and experimental study of the thermal degradation process during the atmospheric re-entry of a TiAl6V4 tank

NASA Astrophysics Data System (ADS)

Prévereaud, Y.; Vérant, J.-L.; Balat-Pichelin, M.; Moschetta, J.-M.

2016-05-01

To answer the question of space debris survivability during atmospheric entry ONERA uses its software named MUSIC/FAST. So, the first part of this paper is dedicated to the presentation of the ONERA tool and its validation by comparison with flight data and CFD computations. However, the influence of oxidation on the thermal degradation process and material properties in atmospheric entry conditions is still unknown. A second step is then devoted to the presentation of an experimental campaign investigating TA6V oxidation in atmospheric entry conditions, as the most of the debris found on ground are made of this material. Experiments have been realized using the MESOX facility implemented at the 6 kW solar furnace in PROMES-CNRS laboratory. Finally, an application of MUSIC/FAST is proposed on the atmospheric re-entry of a generic TA6V tank. Aiming at degradation assessment, a sensitive study to initial conditions is conducted. To complete computational analysis regarding degradation process by melting, a numerical analysis of the influence of oxidation on the thermal wall degradation during the tank atmospheric re-entry is presented as well.

Convergent microRNA actions coordinate neocortical development.

PubMed

Barca-Mayo, Olga; De Pietri Tonelli, Davide

2014-08-01

Neocortical development is a complex process that, at the cellular level, involves tight control of self-renewal, cell fate commitment, survival, differentiation and delamination/migration. These processes require, at the molecular level, the precise regulation of intrinsic signaling pathways and extrinsic factors with coordinated action in a spatially and temporally specific manner. Transcriptional regulation plays an important role during corticogenesis; however, microRNAs (miRNAs) are emerging as important post-transcriptional regulators of various aspects of central nervous system development. miRNAs are a class of small, single-stranded noncoding RNA molecules that control the expression of the majority of protein coding genes (i.e., targets). How do different miRNAs achieve precise control of gene networks during neocortical development? Here, we critically review all the miRNA-target interactions validated in vivo, with relevance to the generation and migration of pyramidal-projection glutamatergic neurons, and for the initial formation of cortical layers in the embryonic development of rodent neocortex. In particular, we focus on convergent miRNA actions, which are still a poorly understood layer of complexity in miRNA signaling, but potentially one of the keys to disclosing how miRNAs achieve the precise coordination of complex biological processes such as neocortical development.

Heat inactivation of Salmonella spp. in fresh poultry compost by simulating early phase of composting process.

PubMed

Singh, R; Kim, J; Jiang, X

2012-05-01

The purpose of this study was to determine the effect of moisture on thermal inactivation of Salmonella spp. in poultry litter under optimal composting conditions. Thermal inactivation of Salmonella was studied in fresh poultry compost by simulating early phase of composting process. A mixture of three Salmonella serotypes grown in Tryptic soy broth with rifampin (TSB-R) was inoculated in fresh compost with 40 or 50% moisture at a final concentration of c. 7 log CFU g(-1). The inoculated compost was kept in an environmental chamber which was programmed to rise from room temperature to target composting temperatures in 2 days. In poultry compost with optimal moisture content (50%), Salmonella spp. survived for 96, 72 and 24 h at 50, 55 and 60°C, respectively, as compared with 264, 144 and 72 h at 50, 55 and 60°C, respectively, in compost with suboptimal moisture (40%). Pathogen decline was faster during the come-up time owing to higher ammonia volatilization. Our results demonstrated that Salmonella spp. survived longer in fresh poultry compost with suboptimal moisture of 40% than in compost with optimal moisture of 50% during thermophilic composting. High nitrogen content of the poultry compost is an additional factor contributing to Salmonella inactivation through ammonia volatilization during thermal exposure. This research validated the effectiveness of the current composting guidelines on Salmonella inactivation in fresh poultry compost. Both initial moisture level and ammonia volatilization are important factors affecting microbiological safety and quality of compost product. © 2012 The Authors. Journal of Applied Microbiology © 2012 The Society for Applied Microbiology.

Identification and verification of differentially expressed genes in the caprine hypothalamic-pituitary-gonadal axis that are associated with litter size.

PubMed

Feng, Tao; Cao, Gui-Ling; Chu, Ming-Xing; Di, Ran; Huang, Dong-Wei; Liu, Qiu-Yue; Pan, Zhang-Yuan; Jin, Mei; Zhang, Ying-Jie; Li, Ning

2015-02-01

Litter size is a favorable economic trait for the goat industry, but remains a complex trait controlled by multiple genes in multiple organs. Several genes have been identified that may affect embryo survival, follicular development, and the health of fetuses during pregnancy. Jining Grey goats demonstrate the largest litter size among goat breeds indigenous to China. In order to better understand the genetic basis of this trait, six suppression subtractive hybridization (SSH) cDNA libraries were constructed using pooled mRNAs from hypothalamuses, pituitaries, and ovaries of sexually mature and adult polytocous Jining Grey goats, as testers, versus the pooled corresponding mRNAs of monotocous Liaoning Cashmere goats, as drivers. A total of 1,458 true-positive clones--including 955 known genes and 481 known and 22 unknown expressed sequence tags--were obtained from the SSH libraries by sequencing and alignment. The known genes were categorized into cellular processes and signaling information storage and processing, and metabolism. Three genes (FTH1, GH, and SAA) were selected to validate the SSH results by quantitative real-time PCR; all three were up-regulated in the corresponding tissues in the tester group indicating that these are candidate genes associated with the large litter size of Jining Grey goats. Several other identified genes may affect embryo survival, follicular development, and health during pregnancy. This study provides insights into the mechanistic basis by which the caprine hypothalamic-pituitary-gonadal axis affects reproductive traits and provides a theoretical basis for goat production and breeding. © 2015 Wiley Periodicals, Inc.

Full-scale tank car rollover tests - survivability of top fittings and top fittings protective structures : final report.

DOT National Transportation Integrated Search

2016-05-01

Full-scale rollover crash tests were performed on three non-pressure tank carbodies to validate previous analytical work and : determine the effectiveness of two different types of protective structures in protecting the top fittings. The tests were ...

Prognostic model of survival for typical bronchial carcinoid tumours: analysis of 1109 patients on behalf of the European Association of Thoracic Surgeons (ESTS) Neuroendocrine Tumours Working Group.

PubMed

Filosso, Pier Luigi; Guerrera, Francesco; Evangelista, Andrea; Welter, Stefan; Thomas, Pascal; Casado, Paula Moreno; Rendina, Erino Angelo; Venuta, Federico; Ampollini, Luca; Brunelli, Alessandro; Stella, Franco; Nosotti, Mario; Raveglia, Federico; Larocca, Valentina; Rena, Ottavio; Margaritora, Stefano; Ardissone, Francesco; Travis, William D; Sarkaria, Inderpal; Sagan, Dariusz

2015-09-01

Typical carcinoids (TCs) are uncommon, slow-growing neoplasms, usually with high 5-year survival rates. As these are rare tumours, their management is still based on small clinical observations and no international guidelines exist. Based on the European Society of Thoracic Surgeon Neuroendocrine Tumours Working Group (NET-WG) Database, we evaluated factors that may influence TCs mortality. Using the NET-WG database, an analysis on TC survival was performed. Overall survival (OS) was calculated starting from the date of intervention. Predictors of OS were investigated using the Cox model with shared frailty (accounting for the within-centre correlation). Candidate predictors were: gender, age, smoking habit, tumour location, previous malignancy, Eastern Cooperative Oncology Group (ECOG) performance status (PS), pT, pN, TNM stage and tumour vascular invasion. The final model included predictors with P ≤ 0.15 after a backward selection. Missing data in the evaluated predictors were multiple-imputed and combined estimates were obtained from five imputed data sets. For 58 of 1167 TC patients vital status was unavailable and analyses were therefore performed on 1109 patients from 17 institutions worldwide. During a median follow-up of 50 months, 87 patients died, with a 5-year OS rate of 93.7% (95% confidence interval: 91.7-95.3). Backward selection resulted in a prediction model for mortality containing age, gender, previous malignancies, peripheral tumour, TNM stage and ECOG PS. The final model showed a good discrimination ability with a C-statistic equal to 0.836 (bootstrap optimism-corrected 0.806). We presented and validated a promising prognostic model for TC survival, showing good calibration and discrimination ability. Further analyses are needed and could be focused on an external validation of this model. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

A quantitative comparison of physiologic indicators of cardiopulmonary resuscitation quality: Diastolic blood pressure versus end-tidal carbon dioxide.

PubMed

Morgan, Ryan W; French, Benjamin; Kilbaugh, Todd J; Naim, Maryam Y; Wolfe, Heather; Bratinov, George; Shoap, Wesley; Hsieh, Ting-Chang; Nadkarni, Vinay M; Berg, Robert A; Sutton, Robert M

2016-07-01

The American Heart Association (AHA) recommends monitoring invasive arterial diastolic blood pressure (DBP) and end-tidal carbon dioxide (ETCO2) during cardiopulmonary resuscitation (CPR) when available. In intensive care unit patients, both may be available to the rescuer. The objective of this study was to compare DBP vs. ETCO2 during CPR as predictors of cardiac arrest survival. In two models of cardiac arrest (primary ventricular fibrillation [VF] and asphyxia-associated VF), 3-month old swine received either standard AHA guideline-based CPR or patient-centric, BP-guided CPR. Mean values of DBP and ETCO2 in the final 2min before the first defibrillation attempt were compared using receiver operating characteristic curves (area under curve [AUC] analysis). The optimal DBP cut point to predict survival was derived and subsequently validated in two independent, randomly generated cohorts. Of 60 animals, 37 (61.7%) survived to 45min. DBP was higher in survivors than in non-survivors (40.6±1.8mmHg vs. 25.9±2.4mmHg; p<0.001), while ETCO2 was not different (30.0±1.5mmHg vs. 32.5±1.8mmHg; p=0.30). By AUC analysis, DBP was superior to ETCO2 (0.82 vs. 0.60; p=0.025) in discriminating survivors from non-survivors. The optimal DBP cut point in the derivation cohort was 34.1mmHg. In the validation cohort, this cut point demonstrated a sensitivity of 0.78, specificity of 0.81, positive predictive value of 0.64, and negative predictive value of 0.89 for survival. In both primary and asphyxia-associated VF porcine models of cardiac arrest, DBP discriminates survivors from non-survivors better than ETCO2. Failure to attain a DBP >34mmHg during CPR is highly predictive of non-survival. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

PubMed Central

Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K.; GarcClosas, Montserrat; Heikkilä, Päivi; Saarela, Jani; Beesley, Jonathan; Jamshidi, Maral; Aittomäki, Kristiina; Liu, Jianjun; Raza Ali, H.; Andrulis, Irene L.; Beckmann, Matthias W.; Behrens, Sabine; Blows, Fiona M.; Brenner, Hermann; Chang-Claude, Jenny; Couch, Fergus J.; Czene, Kamila; Fasching, Peter A.; Figueroa, Jonine; Floris, Giuseppe; Glendon, Gord; Guo, Qi; Hall, Per; Hallberg, Emily; Hamann, Ute; Holleczek, Bernd; Hooning, Maartje J.; Hopper, John L.; Jager, Agnes; Kabisch, Maria; Investigators, kConFab/AOCS; Keeman, Renske; Kosma, Veli-Matti; Lambrechts, Diether; Lindblom, Annika; Mannermaa, Arto; Margolin, Sara; Provenzano, Elena; Shah, Mitul; Southey, Melissa C.; Dennis, Joe; Lush, Michael; Michailidou, Kyriaki; Wang, Qin; Bolla, Manjeet K.; Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D.P .; Chenevix-Trench, Georgia; Blomqvist, Carl; Nevanlinna, Heli

2017-01-01

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes. In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 05E010-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 05E010-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines. If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer. PMID:28179588

Prognostic impact of KRAS mutation subtypes in 677 patients with metastatic lung adenocarcinomas

PubMed Central

Yu, Helena A.; Sima, Camelia S.; Shen, Ronglai; Kass, Samantha; Gainor, Justin; Shaw, Alice; Hames, Megan; Iams, Wade; Aston, Jonathan; Lovly, Christine M.; Horn, Leora; Lydon, Christine; Oxnard, Geoffrey R.; Kris, Mark G.; Ladanyi, Marc; Riely, Gregory J.

2015-01-01

Background We previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared to patients with KRAS wild type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer. Methods We reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6 year time period. We evaluated the associations between KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient data set. Results Among 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p=0.99), smoking status (p=0.33) or when comparing specific amino acid substitutions (p=0.20). In our data set, patients with KRAS codon 13 mutant tumors (n=53) had shorter overall survival compared to patients with codon 12 mutant tumors (n=624)( 1.1 vs 1.3 years, respectively, p=0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex and smoking status (HR 1.52 95% CI 1.11-2.08, p=0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 vs 1.1 years respectively, p=0.41). Conclusions Among individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are apparent differences in outcome based on KRAS mutation subtype PMID:25415430

MO-FG-BRA-05: Dosimetric and Radiobiological Validation of Respiratory Gating in Conventional and Hypofractionated Radiotherapy of the Lung: Effect of Dose, Dose Rate, Gating Window and Breathing Pattern

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

Cervino, L; Soultan, D; Pettersson, N

2016-06-15

Purpose: to evaluate the dosimetric and radiobiological consequences from having different gating windows, dose rates, and breathing patterns in gated VMAT lung radiotherapy. Methods: A novel 3D-printed moving phantom with central high and peripheral low tracer uptake regions was 4D FDG-PET/CT-scanned using ideal, patient-specific regular, and irregular breathing patterns. A scan of the stationary phantom was obtained as a reference. Target volumes corresponding to different uptake regions were delineated. Simultaneous integrated boost (SIB) 6 MV VMAT plans were produced for conventional and hypofractionated radiotherapy, using 30–70 and 100% cycle gating scenarios. Prescribed doses were 200 cGy with SIB to 240more » cGy to high uptake volume for conventional, and 800 with SIB to 900 cGy for hypofractionated plans. Dose rates of 600 MU/min (conventional and hypofractionated) and flattening filter free 1400 MU/min (hypofractionated) were used. Ion chamber measurements were performed to verify delivered doses. Vials with A549 cells placed in locations matching ion chamber measurements were irradiated using the same plans to measure clonogenic survival. Differences in survival for the different doses, dose rates, gating windows, and breathing patterns were analyzed. Results: Ion chamber measurements agreed within 3% of the planned dose, for all locations, breathing patterns and gating windows. Cell survival depended on dose alone, and not on gating window, breathing pattern, MU rate, or delivery time. The surviving fraction varied from approximately 40% at 2Gy to 1% for 9 Gy and was within statistical uncertainty relative to that observed for the stationary phantom. Conclusions: Use of gated VMAT in PET-driven SIB radiotherapy was validated using ion chamber measurements and cell survival assays for conventional and hypofractionated radiotherapy.« less

A Quantitative Comparison of Physiologic Indicators of Cardiopulmonary Resuscitation Quality: Diastolic Blood Pressure Versus End-Tidal Carbon Dioxide

PubMed Central

Morgan, Ryan W.; French, Benjamin; Kilbaugh, Todd J.; Naim, Maryam Y.; Wolfe, Heather; Bratinov, George; Shoap, Wesley; Hsieh, Ting-Chang; Nadkarni, Vinay M.; Berg, Robert A.; Sutton, Robert M.

2016-01-01

Aim The American Heart Association (AHA) recommends monitoring invasive arterial diastolic blood pressure (DBP) and end-tidal carbon dioxide (ETCO2) during cardiopulmonary resuscitation (CPR) when available. In intensive care unit patients, both may be available to the rescuer. The objective of this study was to compare DBP versus ETCO2 during CPR as predictors of cardiac arrest survival. Methods In two models of cardiac arrest (primary ventricular fibrillation [VF] and asphyxia-associated VF), 3-month old swine received either standard AHA guideline-based CPR or patient-centric, BP-guided CPR. Mean values of DBP and ETCO2 in the final two minutes before the first defibrillation attempt were compared using receiver operating characteristic curves (area under curve [AUC] analysis). The optimal DBP cut point to predict survival was derived and subsequently validated in two independent, randomly generated cohorts. Results Of 60 animals, 37 (61.7%) survived to 45 minutes. DBP was higher in survivors than in non-survivors (40.6±1.8mmHg vs. 25.9±2.4mmHg; p<0.001), while ETCO2 was not different (30.0±1.5mmHg vs. 32.5±1.8mmHg; p=0.30). By AUC analysis, DBP was superior to ETCO2 (0.82 vs. 0.60; p=0.025) in discriminating survivors from non-survivors. The optimal DBP cut point in the derivation cohort was 34.1mmHg. In the validation cohort, this cut point demonstrated a sensitivity of 0.78, specificity of 0.81, positive predictive value of 0.64, and negative predictive value of 0.89 for survival. Conclusions In both primary and asphyxia-associated VF porcine models of cardiac arrest, DBP discriminates survivors from non-survivors better than ETCO2. Failure to attain a DBP >34mmHg during CPR is highly predictive of non-survival. PMID:27107688

Testing assumptions for unbiased estimation of survival of radiomarked harlequin ducks

USGS Publications Warehouse

Esler, Daniel N.; Mulcahy, Daniel M.; Jarvis, Robert L.

2000-01-01

Unbiased estimates of survival based on individuals outfitted with radiotransmitters require meeting the assumptions that radios do not affect survival, and animals for which the radio signal is lost have the same survival probability as those for which fate is known. In most survival studies, researchers have made these assumptions without testing their validity. We tested these assumptions by comparing interannual recapture rates (and, by inference, survival) between radioed and unradioed adult female harlequin ducks (Histrionicus histrionicus), and for radioed females, between right-censored birds (i.e., those for which the radio signal was lost during the telemetry monitoring period) and birds with known fates. We found that recapture rates of birds equipped with implanted radiotransmitters (21.6 ± 3.0%; x̄ ± SE) were similar to unradioed birds (21.7 ± 8.6%), suggesting that radios did not affect survival. Recapture rates also were similar between right-censored (20.6 ± 5.1%) and known-fate individuals (22.1 ± 3.8%), suggesting that missing birds were not subject to differential mortality. We also determined that capture and handling resulted in short-term loss of body mass for both radioed and unradioed females and that this effect was more pronounced for radioed birds (the difference between groups was 15.4 ± 7.1 g). However, no difference existed in body mass after recapture 1 year later. Our study suggests that implanted radios are an unbiased method for estimating survival of harlequin ducks and likely other species under similar circumstances.

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial

PubMed Central

Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

2015-01-01

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice’s four criteria. The Spearman’s rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice’s second criterion. Being consistent with all Prentice’s criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival. PMID:26219568

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial.

PubMed

Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

2015-07-29

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice's four criteria. The Spearman's rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice's second criterion. Being consistent with all Prentice's criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival.

Cryotherapy for primary treatment of prostate cancer: intermediate term results of a prospective study from a single institution.

PubMed

Rodríguez, S Alvarez; Arias Fúnez, F; Bueno Bravo, C; Rodríguez-Patrón Rodríguez, R; Sanz Mayayo, E; Palacios, V Hevia; Burgos Revilla, F J

2014-01-01

Purpose. Published data about cryotherapy for prostate cancer (PC) treatment are based on case series with a lack of clinical trials and the inexistence of a validated definition of biochemical failure. A prospective study with standardized followup protocol was conducted in our institution. Material and Methods. Prospective study of a series of cases including 108 patients diagnosed with localized PC at clinical stage T1c-T2c treated by primary cryoablation and median followup of 61 months. Criteria of biochemical recurrence were unified according to the American Society for Therapeutic Radiology and Oncology (ASTRO). End points were biochemical progression-free survival (BPFS), cancer-specific survival, and overall survival. Rate of complications was reported. Results. The BPFS for low-, medium-, and high-risk patients was 96.4%, 91.2%, and 62.2%, respectively. Cancer-specific survival was 98.1%. Overall survival reached 94.4%. Complications included incontinence in 5.6%, urinary tract obstruction in 1.9%, urethral sloughing in 5.6%, haematuria in 1.9%, perineal pain in 11.1%, and prostatorectal fistula in 0.9%. Erectile disfunction was found in 98.1%. Conclusions. Cryotherapy is an effective and minimally invasive treatment for primary PC in well-selected cases, with low surgical risk and good results in terms of BPFS, cancer-specific survival, and overall survival.

Cryotherapy for Primary Treatment of Prostate Cancer: Intermediate Term Results of a Prospective Study from a Single Institution

PubMed Central

Rodríguez, S. Alvarez; Arias Fúnez, F.; Bueno Bravo, C.; Rodríguez-Patrón Rodríguez, R.; Sanz Mayayo, E.; Palacios, V. Hevia; Burgos Revilla, F. J.

2014-01-01

Purpose. Published data about cryotherapy for prostate cancer (PC) treatment are based on case series with a lack of clinical trials and the inexistence of a validated definition of biochemical failure. A prospective study with standardized followup protocol was conducted in our institution. Material and Methods. Prospective study of a series of cases including 108 patients diagnosed with localized PC at clinical stage T1c-T2c treated by primary cryoablation and median followup of 61 months. Criteria of biochemical recurrence were unified according to the American Society for Therapeutic Radiology and Oncology (ASTRO). End points were biochemical progression-free survival (BPFS), cancer-specific survival, and overall survival. Rate of complications was reported. Results. The BPFS for low-, medium-, and high-risk patients was 96.4%, 91.2%, and 62.2%, respectively. Cancer-specific survival was 98.1%. Overall survival reached 94.4%. Complications included incontinence in 5.6%, urinary tract obstruction in 1.9%, urethral sloughing in 5.6%, haematuria in 1.9%, perineal pain in 11.1%, and prostatorectal fistula in 0.9%. Erectile disfunction was found in 98.1%. Conclusions. Cryotherapy is an effective and minimally invasive treatment for primary PC in well-selected cases, with low surgical risk and good results in terms of BPFS, cancer-specific survival, and overall survival. PMID:24693437

Survival rates of teeth, implants, and double crown-retained removable dental prostheses: a systematic literature review.

PubMed

Koller, Beatrice; Att, Wael; Strub, Jorg-Rudolf

2011-01-01

The aim of this systematic literature review was to investigate the survival rates of teeth, implants, and double crown-retained removable dental prostheses (RDPs). A systematic review of the literature published from January 1973 through May 2010 was conducted using electronic databases and hand-searching to assess the clinical outcomes of teeth, implants, and double crown-retained RDPs. This review yielded 512 articles, which were narrowed down to 11. The included studies demonstrated tooth survival rates between 60.6% and 95.3% after an observation period of 4 to 10 years. The survival rates of RDPs supported by teeth ranged between 90.0% and 95.1% after 4 and 5.3 years, respectively. The survival rates of implants supporting prostheses in the mandible were between 97% and 100% after an observation period between 3 and 10.4 years. The survival rates of implant-retained RDPs in the mandible ranged between 95% and 100% after 9 and 10.4 years. Teeth and implants supporting prostheses in the maxilla, as well as the RDPs themselves, demonstrated a survival rate of 100% after 3.2 years. The current literature does not provide sufficient information regarding the long-term outcome of double crown-retained RDPs. Further studies based on a higher level of evidence are needed to validate the outcomes of this treatment modality.

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy.

PubMed

Hellwig, Birte; Madjar, Katrin; Edlund, Karolina; Marchan, Rosemarie; Cadenas, Cristina; Heimes, Anne-Sophie; Almstedt, Katrin; Lebrecht, Antje; Sicking, Isabel; Battista, Marco J; Micke, Patrick; Schmidt, Marcus; Hengstler, Jan G; Rahnenführer, Jörg

2016-01-01

In breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery. Affymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer. Ten late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer. Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.

Adult Survivorship of the Dengue Mosquito Aedes aegypti Varies Seasonally in Central Vietnam

PubMed Central

Hugo, Leon E.; Jeffery, Jason A. L.; Trewin, Brendan J.; Wockner, Leesa F.; Thi Yen, Nguyen; Le, Nguyen Hoang; Nghia, Le Trung; Hine, Emma; Ryan, Peter A.; Kay, Brian H.

2014-01-01

The survival characteristics of the mosquito Aedes aegypti affect transmission rates of dengue because transmission requires infected mosquitoes to survive long enough for the virus to infect the salivary glands. Mosquito survival is assumed to be high in tropical, dengue endemic, countries like Vietnam. However, the survival rates of wild populations of mosquitoes are seldom measured due the difficulty of predicting mosquito age. Hon Mieu Island in central Vietnam is the site of a pilot release of Ae. aegypti infected with a strain of Wolbachia pipientis bacteria (wMelPop) that induces virus interference and mosquito life-shortening. We used the most accurate mosquito age grading approach, transcriptional profiling, to establish the survival patterns of the mosquito population from the population age structure. Furthermore, estimations were validated on mosquitoes released into a large semi-field environment consisting of an enclosed house, garden and yard to incorporate natural environmental variability. Mosquito survival was highest during the dry/cool (January-April) and dry/hot (May-August) seasons, when 92 and 64% of Hon Mieu mosquitoes had survived to an age that they were able to transmit dengue (12 d), respectively. This was reduced to 29% during the wet/cool season from September to December. The presence of Ae. aegypti older than 12 d during each season is likely to facilitate the observed continuity of dengue transmission in the region. We provide season specific Ae. aegypti survival models for improved dengue epidemiology and evaluation of mosquito control strategies that aim to reduce mosquito survival to break the dengue transmission cycle. PMID:24551251

Station Set Residual: Event Classification Using Historical Distribution of Observing Stations

NASA Astrophysics Data System (ADS)

Procopio, Mike; Lewis, Jennifer; Young, Chris

2010-05-01

Analysts working at the International Data Centre in support of treaty monitoring through the Comprehensive Nuclear-Test-Ban Treaty Organization spend a significant amount of time reviewing hypothesized seismic events produced by an automatic processing system. When reviewing these events to determine their legitimacy, analysts take a variety of approaches that rely heavily on training and past experience. One method used by analysts to gauge the validity of an event involves examining the set of stations involved in the detection of an event. In particular, leveraging past experience, an analyst can say that an event located in a certain part of the world is expected to be detected by Stations A, B, and C. Implicit in this statement is that such an event would usually not be detected by Stations X, Y, or Z. For some well understood parts of the world, the absence of one or more "expected" stations—or the presence of one or more "unexpected" stations—is correlated with a hypothesized event's legitimacy and to its survival to the event bulletin. The primary objective of this research is to formalize and quantify the difference between the observed set of stations detecting some hypothesized event, versus the expected set of stations historically associated with detecting similar nearby events close in magnitude. This Station Set Residual can be quantified in many ways, some of which are correlated with the analysts' determination of whether or not the event is valid. We propose that this Station Set Residual score can be used to screen out certain classes of "false" events produced by automatic processing with a high degree of confidence, reducing the analyst burden. Moreover, we propose that the visualization of the historically expected distribution of detecting stations can be immediately useful as an analyst aid during their review process.

Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study.

PubMed

Gordon, Jacob A; Buonerba, Carlo; Pond, Gregory; Crona, Daniel; Gillessen, Silke; Lucarelli, Giuseppe; Rossetti, Sabrina; Dorff, Tanya; Artale, Salvatore; Locke, Jennifer A; Bosso, Davide; Milowsky, Matthew Ivan; Witek, Mira Sofie; Battaglia, Michele; Pignata, Sandro; Cherhroudi, Cyrus; Cox, Michael E; De Placido, Pietro; Ribera, Dario; Omlin, Aurelius; Buonocore, Gaetano; Chi, Kim; Kollmannsberger, Christian; Khalaf, Daniel; Facchini, Gaetano; Sonpavde, Guru; De Placido, Sabino; Eigl, Bernhard J; Di Lorenzo, Giuseppe

2018-04-13

Statins may potentiate the effects of anti-hormonal agents for metastatic castration-resistant prostate cancer (mCRPC) through further disruption of essential steroidogenic processes. We investigated the effects of statin use on clinical outcomes in patients with mCRPC receiving abiraterone or enzalutamide. This was a retrospective multicenter study including patients that received abiraterone or enzalutamide for mCRPC. The effect of concurrent statin use on outcomes was evaluated. The associations of statins with early (≤12 weeks) prostate-specific antigen (PSA) declines (> 30%), cancer-specific survival and overall survival (OS) were evaluated after controlling for known prognostic factors. Five hundred and ninety-eight patients treated with second-line abiraterone or enzalutamide after docetaxel for mCRPC were included. A total of 199 men (33.3%) received statins during abiraterone/enzalutamide treatment. Median OS was 20.8 months (95% CI = 18.3-23.2) for patients who received statins, versus 12.9 months (95% CI = 11.4-14.6) for patients who did not receive statins ( P < 0.001). After adjusting for age, alkaline phosphatase, PSA, neutrophil-to-lymphocytes ratio, Charlson comorbidity score, Gleason score, visceral disease, hemoglobin, opiate use and abiraterone versus enzalutamide treatment, the use of statin therapy was associated with a 53% reduction in the overall risk of death (hazard ratio [HR] = 0.47; 95% CI = 0.35-0.63; P < 0.001). Statin use was also associated with a 63% increased odds of a > 30% PSA decline within the first 12 weeks of treatment (OR = 1.63; 95% CI = 1.03-2.60; P = 0.039). In this retrospective cohort, statin use was significantly associated with both prolonged OS and cancer-specific survival and increased early > 30% PSA declines. Prospective validation is warranted.

Neyman, Markov processes and survival analysis.

PubMed

Yang, Grace

2013-07-01

J. Neyman used stochastic processes extensively in his applied work. One example is the Fix and Neyman (F-N) competing risks model (1951) that uses finite homogeneous Markov processes to analyse clinical trials with breast cancer patients. We revisit the F-N model, and compare it with the Kaplan-Meier (K-M) formulation for right censored data. The comparison offers a way to generalize the K-M formulation to include risks of recovery and relapses in the calculation of a patient's survival probability. The generalization is to extend the F-N model to a nonhomogeneous Markov process. Closed-form solutions of the survival probability are available in special cases of the nonhomogeneous processes, like the popular multiple decrement model (including the K-M model) and Chiang's staging model, but these models do not consider recovery and relapses while the F-N model does. An analysis of sero-epidemiology current status data with recurrent events is illustrated. Fix and Neyman used Neyman's RBAN (regular best asymptotic normal) estimates for the risks, and provided a numerical example showing the importance of considering both the survival probability and the length of time of a patient living a normal life in the evaluation of clinical trials. The said extension would result in a complicated model and it is unlikely to find analytical closed-form solutions for survival analysis. With ever increasing computing power, numerical methods offer a viable way of investigating the problem.

A Risk Stratification Model for Lung Cancer Based on Gene Coexpression Network and Deep Learning

PubMed Central

2018-01-01

Risk stratification model for lung cancer with gene expression profile is of great interest. Instead of previous models based on individual prognostic genes, we aimed to develop a novel system-level risk stratification model for lung adenocarcinoma based on gene coexpression network. Using multiple microarray, gene coexpression network analysis was performed to identify survival-related networks. A deep learning based risk stratification model was constructed with representative genes of these networks. The model was validated in two test sets. Survival analysis was performed using the output of the model to evaluate whether it could predict patients' survival independent of clinicopathological variables. Five networks were significantly associated with patients' survival. Considering prognostic significance and representativeness, genes of the two survival-related networks were selected for input of the model. The output of the model was significantly associated with patients' survival in two test sets and training set (p < 0.00001, p < 0.0001 and p = 0.02 for training and test sets 1 and 2, resp.). In multivariate analyses, the model was associated with patients' prognosis independent of other clinicopathological features. Our study presents a new perspective on incorporating gene coexpression networks into the gene expression signature and clinical application of deep learning in genomic data science for prognosis prediction. PMID:29581968

Nitrosourea efficacy in high-grade glioma: a survival gain analysis summarizing 504 cohorts with 24193 patients.

PubMed

Wolff, Johannes E A; Berrak, Su; Koontz Webb, Susannah E; Zhang, Ming

2008-05-01

Even though past studies have suggested efficacy of nitrosourea drugs in patients with high-grade glioma and temozolomide has recently been shown significantly to be beneficial, no conclusive comparisons between these agents have been published. We performed a survival gain analysis of 364 studies describing 24,193 patients with high-grade glioma treated in 504 cohorts, and compared the effects of drugs. The most frequent diagnoses were glioblastoma multiforme (GBM) (72%) and anaplastic astrocytoma (22%). The mean overall survival (mOS) was 14.1 months. The outcome was influenced by several of the known prognostic factors including the histological grade, if the tumors were newly diagnosed or recurrent, the completeness of resection, patients' age, and gender. This information allowed the calculation of a predicted mOS for each cohort based on their prognostic factors independent of treatment. Survival gain to characterize the influence of treatment was subsequently defined and validated as the difference between the observed and the predicted mOS. In 62 CCNU-treated cohorts and 15 ACNU-treated cohorts the survival gain was 5.3 months and 8.9 months (P < 0.0005), respectively. No detectable survival gain for patients treated with various BCNU-containing regimens was found. Conclusion CCNU- and ACNU-containing regimens were superior to BCNU containing regiments.

Global cost of child survival: estimates from country-level validation

PubMed Central

van Ekdom, Liselore; Scherpbier, Robert W; Niessen, Louis W

2011-01-01

Abstract Objective To cross-validate the global cost of scaling up child survival interventions to achieve the fourth Millennium Development Goal (MDG4) as estimated by the World Health Organization (WHO) in 2007 by using the latest country-provided data and new assumptions. Methods After the main cost categories for each country were identified, validation questionnaires were sent to 32 countries with high child mortality. Publicly available estimates for disease incidence, intervention coverage, prices and resources for individual-level and programme-level activities were validated against local data. Nine updates to the 2007 WHO model were generated using revised assumptions. Finally, estimates were extrapolated to 75 countries and combined with cost estimates for immunization and malaria programmes and for programmes for the prevention of mother-to-child transmission of the human immunodeficiency virus (HIV). Findings Twenty-six countries responded. Adjustments were largest for system- and programme-level data and smallest for patient data. Country-level validation caused a 53% increase in original cost estimates (i.e. 9 billion 2004 United States dollars [US$]) for 26 countries owing to revised system and programme assumptions, especially surrounding community health worker costs. The additional effect of updated population figures was small; updated epidemiologic figures increased costs by US$ 4 billion (+15%). New unit prices in the 26 countries that provided data increased estimates by US$ 4.3 billion (+16%). Extrapolation to 75 countries increased the original price estimate by US$ 33 billion (+80%) for 2010–2015. Conclusion Country-level validation had a significant effect on the cost estimate. Price adaptations and programme-related assumptions contributed substantially. An additional 74 billion US$ 2005 (representing a 12% increase in total health expenditure) would be needed between 2010 and 2015. Given resource constraints, countries will need to prioritize health activities within their national resource envelope. PMID:21479091

A New Clinicobiological Scoring System for the Prediction of Infection-Related Mortality and Survival after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Forcina, Alessandra; Rancoita, Paola M V; Marcatti, Magda; Greco, Raffaella; Lupo-Stanghellini, Maria Teresa; Carrabba, Matteo; Marasco, Vincenzo; Di Serio, Clelia; Bernardi, Massimo; Peccatori, Jacopo; Corti, Consuelo; Bondanza, Attilio; Ciceri, Fabio

2017-12-01

Infection-related mortality (IRM) is a substantial component of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). No scores have been developed to predict IRM before transplantation. Pretransplantation clinical and biochemical data were collected from a study cohort of 607 adult patients undergoing allo-HSCT between January 2009 and February 2017. In a training set of 273 patients, multivariate analysis revealed that age >60 years (P = .003), cytomegalovirus host/donor serostatus different from negative/negative (P < .001), pretransplantation IgA level <1.11 g/L (P = .004), and pretransplantation IgM level <.305 g/L (P = .028) were independent predictors of increased IRM. Based on these results, we developed and subsequently validated a 3-tiered weighted prognostic index for IRM in a retrospective set of patients (n = 219) and a prospective set of patients (n = 115). Patients were assigned to 3 different IRM risk classes based on this index score. The score significantly predicted IRM in the training set, retrospective validation set, and prospective validation set (P < .001, .044, and .011, respectively). In the training set, 100-day IRM was 5% for the low-risk group, 11% for the intermediate-riak group, and 16% for the high-risk groups. In the retrospective validation set, the respective 100-day IRM values were 7%, 17%, and 28%, and in the prospective set, they were 0%, 5%, and 7%. This score predicted also overall survival (P < .001 in the training set, P < 041 in the retrospective validation set, and P < .023 in the prospective validation set). Because pretransplantation levels of IgA/IgM can be modulated by the supplementation of enriched immunoglobulins, these results suggest the possibility of prophylactic interventional studies to improve transplantation outcomes. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Validation of the Hong Kong Liver Cancer Staging System in Determining Prognosis of the North American Patients Following Intra-arterial Therapy

PubMed Central

Sohn, Jae Ho; Duran, Rafael; Zhao, Yan; Fleckenstein, Florian; Chapiro, Julius; Sahu, Sonia P.; Schernthaner, Rüdiger E.; Qian, Tianchen; Lee, Howard; Zhao, Li; Hamilton, James; Frangakis, Constantine; Lin, MingDe; Salem, Riad; Geschwind, Jean-Francois

2018-01-01

Background & Aims There is debate over the best way to stage hepatocellular carcinoma (HCC). We attempted to validate the prognostic and clinical utility of the recently developed Hong Kong Liver Cancer (HKLC) staging system, a hepatitis B-based model, and compared data with that from the Barcelona Clinic Liver Cancer (BCLC) staging system in a North American population who underwent intra-arterial therapy (IAT). Methods We performed a retrospective analysis of data from 1009 patients with HCC who underwent intra-arterial therapy from 2000 through 2014. Most patients had hepatitis C or unresectable tumors; all patients underwent IAT, with or without resection, transplantation, and/or systemic chemotherapy. We calculated HCC stage for each patient using 5-stage HKLC (HKLC-5) and 9-stage HKLC (HKLC-9) system classifications, as well as the BCLC system. Survival information was collected up until end of 2014 at which point living or unconfirmed patients were censored. We compared performance of the BCLC, HKLC-5, and HKLC-9 systems in predicting patient outcomes using Kaplan-Meier estimates, calibration plots, c-statistic, Akaike information criterion, and the likelihood ratio test. Results Median overall survival time, calculated from first IAT until date of death or censorship, for the entire cohort (all stages) was 9.8 months. The BCLC and HKLC staging systems predicted patient survival times with significance (P<.001). HKLC-5 and HKLC-9 each demonstrated good calibration. The HKLC-5 system outperformed the BCLC system in predicting patient survival times (HKLC c=0.71, Akaike information criterion=6242; BCLC c=0.64, Akaike information criterion=6320), reducing error in predicting survival time (HKLC reduced error by 14%, BCLC reduced error by 12%), and homogeneity (HKLC χ2=201; P<.001; BCLC χ2=119; P<.001) and monotonicity (HKLC linear trend χ2=193; P<.001; BCLC linear trend χ2=111; P<.001). Small proportions of patients with HCC of stages IV or V, according to the HKLC system, survived for 6 months and 4 months, respectively. Conclusion In a retrospective analysis of patients who underwent IAT for unresectable HCC, we found the HKLC-5 staging system to have the best combination of performances in survival separation, calibration, and discrimination; it consistently outperformed the BCLC system in predicting survival times of patients. The HKLC system identified patients with HCC of stages IV and V who are unlikely to benefit from IAT. PMID:27847278

Validation of the Hong Kong Liver Cancer Staging System in Determining Prognosis of the North American Patients Following Intra-arterial Therapy.

PubMed

Sohn, Jae Ho; Duran, Rafael; Zhao, Yan; Fleckenstein, Florian; Chapiro, Julius; Sahu, Sonia; Schernthaner, Rüdiger E; Qian, Tianchen; Lee, Howard; Zhao, Li; Hamilton, James; Frangakis, Constantine; Lin, MingDe; Salem, Riad; Geschwind, Jean-Francois

2017-05-01

There is debate over the best way to stage hepatocellular carcinoma (HCC). We attempted to validate the prognostic and clinical utility of the recently developed Hong Kong Liver Cancer (HKLC) staging system, a hepatitis B-based model, and compared data with that from the Barcelona Clinic Liver Cancer (BCLC) staging system in a North American population that underwent intra-arterial therapy (IAT). We performed a retrospective analysis of data from 1009 patients with HCC who underwent IAT from 2000 through 2014. Most patients had hepatitis C or unresectable tumors; all patients underwent IAT, with or without resection, transplantation, and/or systemic chemotherapy. We calculated HCC stage for each patient using 5-stage HKLC (HKLC-5) and 9-stage HKLC (HKLC-9) system classifications, and the BCLC system. Survival information was collected up until the end of 2014 at which point living or unconfirmed patients were censored. We compared performance of the BCLC, HKLC-5, and HKLC-9 systems in predicting patient outcomes using Kaplan-Meier estimates, calibration plots, C statistic, Akaike information criterion, and the likelihood ratio test. Median overall survival time, calculated from first IAT until date of death or censorship, for the entire cohort (all stages) was 9.8 months. The BCLC and HKLC staging systems predicted patient survival times with significance (P < .001). HKLC-5 and HKLC-9 each demonstrated good calibration. The HKLC-5 system outperformed the BCLC system in predicting patient survival times (HKLC C = 0.71, Akaike information criterion = 6242; BCLC C = 0.64, Akaike information criterion = 6320), reducing error in predicting survival time (HKLC reduced error by 14%, BCLC reduced error by 12%), and homogeneity (HKLC chi-square = 201, P < .001; BCLC chi-square = 119, P < .001) and monotonicity (HKLC linear trend chi-square = 193, P < .001; BCLC linear trend chi-square = 111, P < .001). Small proportions of patients with HCC of stages IV or V, according to the HKLC system, survived for 6 months and 4 months, respectively. In a retrospective analysis of patients who underwent IAT for unresectable HCC, we found the HKLC-5 staging system to have the best combination of performances in survival separation, calibration, and discrimination; it consistently outperformed the BCLC system in predicting survival times of patients. The HKLC system identified patients with HCC of stages IV and V who are unlikely to benefit from IAT. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Survival As a Quality Metric of Cancer Care: Use of the National Cancer Data Base to Assess Hospital Performance.

PubMed

Shulman, Lawrence N; Palis, Bryan E; McCabe, Ryan; Mallin, Kathy; Loomis, Ashley; Winchester, David; McKellar, Daniel

2018-01-01

Survival is considered an important indicator of the quality of cancer care, but the validity of different methodologies to measure comparative survival rates is less well understood. We explored whether the National Cancer Data Base (NCDB) could serve as a source of unadjusted and risk-adjusted cancer survival data and whether these data could be used as quality indicators for individual hospitals or in the aggregate by hospital type. The NCDB, an aggregate of > 1,500 hospital cancer registries, was queried to analyze unadjusted and risk-adjusted hazards of death for patients with stage III breast cancer (n = 116,787) and stage IIIB or IV non-small-cell lung cancer (n = 252,392). Data were analyzed at the individual hospital level and by hospital type. At the hospital level, after risk adjustment, few hospitals had comparative risk-adjusted survival rates that were statistically better or worse. By hospital type, National Cancer Institute-designated comprehensive cancer centers had risk-adjusted survival ratios that were statistically significantly better than those of academic cancer centers and community hospitals. Using the NCDB as the data source, survival rates for patients with stage III breast cancer and stage IIIB or IV non-small-cell lung cancer were statistically better at National Cancer Institute-designated comprehensive cancer centers when compared with other hospital types. Compared with academic hospitals, risk-adjusted survival was lower in community hospitals. At the individual hospital level, after risk adjustment, few hospitals were shown to have statistically better or worse survival, suggesting that, using NCDB data, survival may not be a good metric to determine relative quality of cancer care at this level.

Etiology and clinical outcome in dogs with aspiration pneumonia: 88 cases (2004-2006).

PubMed

Kogan, David A; Johnson, Lynelle R; Sturges, Beverly K; Jandrey, Karl E; Pollard, Rachel E

2008-12-01

To evaluate the number and types of underlying disorders detected in dogs with aspiration pneumonia and determine the survival rate among affected dogs. Retrospective case series. Animals-88 dogs with aspiration pneumonia. Medical records were reviewed to identify disease processes that could result in aspiration pneumonia. To assess outcome (ie, survival to discharge from the hospital or nonsurvival), dogs were grouped by the type and number of underlying disease processes. Duration of hospitalization and radiographic severity of disease were evaluated with regard to case outcome. As the cause of aspiration pneumonia, a single underlying disorder was identified in 60 of the 88 dogs; 2 or more diseases were identified in the remaining dogs. Esophageal disease (n = 35), vomiting (34), neurologic disorders (24), laryngeal disease (16), and postanesthetic aspiration (12) were identified most commonly. Overall, 68 dogs survived to discharge from the hospital (survival rate, 77%). Survival rates were comparable among dogs regardless of the underlying cause of aspiration pneumonia. Radiographic severity of disease and duration of hospitalization did not influence survival. Among these study dogs, aspiration pneumonia was associated with a high survival rate. The presence of more than 1 underlying disease associated with aspiration pneumonia did not adversely impact survival rate. Interestingly, radiographic severity of disease and duration of hospitalization were not associated with overall survival rate.

Measuring the quality of child health care at first-level facilities.

PubMed

Gouws, Eleanor; Bryce, Jennifer; Pariyo, George; Armstrong Schellenberg, Joanna; Amaral, João; Habicht, Jean-Pierre

2005-08-01

Sound policy and program decisions require timely information based on valid and relevant measures. Recent findings suggest that despite the availability of effective and affordable guidelines for the management of sick children in first-level health facilities in developing countries, the quality and coverage of these services remains low. We report on the development and evaluation of a set of summary indices reflecting the quality of care received by sick children in first-level facilities. The indices were first developed through a consultative process to achieve face validity by involving technical experts and policymakers. The definition of evaluation measures for many public health programs stops at this point. We added a second phase in which standard statistical techniques were used to evaluate the content and construct validity of the indices and their reliability, drawing on data sets from the multi-country evaluation of integrated management of childhood illness (MCE) in Brazil, Tanzania and Uganda. The statistical evaluation identified important conceptual errors in the indices arising from the theory-driven expert review. The experts had combined items into inappropriate indicators resulting in summary indices that were difficult to interpret and had limited validity for program decision making. We propose a revised set of summary indices for the measurement of child health care in developing countries that is supported by both expert and statistical reviews and that led to similar programmatic insights across the three countries. We advocate increased cross-disciplinary research within public health to improve measurement approaches. Child survival policymakers, program planners and implementers can use these tools to improve their monitoring and so increase the health impact of investments in health facility care.

An Integrated Approach Identifies Mediators of Local Recurrence in Head and Neck Squamous Carcinoma.

PubMed

Citron, Francesca; Armenia, Joshua; Franchin, Giovanni; Polesel, Jerry; Talamini, Renato; D'Andrea, Sara; Sulfaro, Sandro; Croce, Carlo M; Klement, William; Otasek, David; Pastrello, Chiara; Tokar, Tomas; Jurisica, Igor; French, Deborah; Bomben, Riccardo; Vaccher, Emanuela; Serraino, Diego; Belletti, Barbara; Vecchione, Andrea; Barzan, Luigi; Baldassarre, Gustavo

2017-07-15

Purpose: Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC. Experimental Design: A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results. Results: Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-gene signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence. Conclusions: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development. Clin Cancer Res; 23(14); 3769-80. ©2017 AACR . ©2017 American Association for Cancer Research.

Habitat suitability and nest survival of white-headed woodpeckers in unburned forests of Oregon

USGS Publications Warehouse

Hollenbeck, Jeff P.; Saab, Victoria A.; Frenzel, Richard W.

2011-01-01

We evaluated habitat suitability and nest survival of breeding white-headed woodpeckers (Picoides albolarvatus) in unburned forests of central Oregon, USA. Daily nest-survival rate was positively related to maximum daily temperature during the nest interval and to density of large-diameter trees surrounding the nest tree. We developed a niche-based habitat suitability model (partitioned Mahalanobis distance) for nesting white-headed woodpeckers using remotely sensed data. Along with low elevation, high density of large trees, and low slope, our habitat suitability model suggested that interspersion–juxtaposition of low- and high-canopy cover ponderosa pine (Pinus ponderosa) patches was important for nest-site suitability. Cross-validation suggested the model performed adequately for management planning at a scale >1 ha. Evaluation of mapped habitat suitability index (HSI) suggested that the maximum predictive gain (HSI = 0.36), where the number of nest locations are maximized in the smallest proportion of the modeled landscape, provided an objective initial threshold for identification of suitable habitat. However, managers can choose the threshold HSI most appropriate for their purposes (e.g., locating regions of low–moderate suitability that have potential for habitat restoration). Consequently, our habitat suitability model may be useful for managing dry coniferous forests for white-headed woodpeckers in central Oregon; however, model validation is necessary before our model could be applied to other locations.

A comparative study of machine learning methods for time-to-event survival data for radiomics risk modelling.

PubMed

Leger, Stefan; Zwanenburg, Alex; Pilz, Karoline; Lohaus, Fabian; Linge, Annett; Zöphel, Klaus; Kotzerke, Jörg; Schreiber, Andreas; Tinhofer, Inge; Budach, Volker; Sak, Ali; Stuschke, Martin; Balermpas, Panagiotis; Rödel, Claus; Ganswindt, Ute; Belka, Claus; Pigorsch, Steffi; Combs, Stephanie E; Mönnich, David; Zips, Daniel; Krause, Mechthild; Baumann, Michael; Troost, Esther G C; Löck, Steffen; Richter, Christian

2017-10-16

Radiomics applies machine learning algorithms to quantitative imaging data to characterise the tumour phenotype and predict clinical outcome. For the development of radiomics risk models, a variety of different algorithms is available and it is not clear which one gives optimal results. Therefore, we assessed the performance of 11 machine learning algorithms combined with 12 feature selection methods by the concordance index (C-Index), to predict loco-regional tumour control (LRC) and overall survival for patients with head and neck squamous cell carcinoma. The considered algorithms are able to deal with continuous time-to-event survival data. Feature selection and model building were performed on a multicentre cohort (213 patients) and validated using an independent cohort (80 patients). We found several combinations of machine learning algorithms and feature selection methods which achieve similar results, e.g. C-Index = 0.71 and BT-COX: C-Index = 0.70 in combination with Spearman feature selection. Using the best performing models, patients were stratified into groups of low and high risk of recurrence. Significant differences in LRC were obtained between both groups on the validation cohort. Based on the presented analysis, we identified a subset of algorithms which should be considered in future radiomics studies to develop stable and clinically relevant predictive models for time-to-event endpoints.

Nomograms for Prediction of Outcome With or Without Adjuvant Radiation Therapy for Patients With Endometrial Cancer: A Pooled Analysis of PORTEC-1 and PORTEC-2 Trials

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

Creutzberg, Carien L., E-mail: c.l.creutzberg@lumc.nl; Stiphout, Ruud G.P.M. van; Nout, Remi A.

Background: Postoperative radiation therapy for stage I endometrial cancer improves locoregional control but is without survival benefit. To facilitate treatment decision support for individual patients, accurate statistical models to predict locoregional relapse (LRR), distant relapse (DR), overall survival (OS), and disease-free survival (DFS) are required. Methods and Materials: Clinical trial data from the randomized Post Operative Radiation Therapy for Endometrial Cancer (PORTEC-1; N=714 patients) and PORTEC-2 (N=427 patients) trials and registered group (grade 3 and deep invasion, n=99) were pooled for analysis (N=1240). For most patients (86%) pathology review data were available; otherwise original pathology data were used. Trial variablesmore » which were clinically relevant and eligible according to data constraints were age, stage, given treatment (pelvic external beam radiation therapy (EBRT), vaginal brachytherapy (VBT), or no adjuvant treatment, FIGO histological grade, depth of invasion, and lymph-vascular invasion (LVSI). Multivariate analyses were based on Cox proportional hazards regression model. Predictors were selected based on a backward elimination scheme. Model results were expressed by the c-index (0.5-1.0; random to perfect prediction). Two validation sets (n=244 and 291 patients) were used. Results: Accuracy of the developed models was good, with training accuracies between 0.71 and 0.78. The nomograms validated well for DR (0.73), DFS (0.69), and OS (0.70), but validation was only fair for LRR (0.59). Ranking of variables as to their predictive power showed that age, tumor grade, and LVSI were highly predictive for all outcomes, and given treatment for LRR and DFS. The nomograms were able to significantly distinguish low- from high-probability patients for these outcomes. Conclusions: The nomograms are internally validated and able to accurately predict long-term outcome for endometrial cancer patients with observation, pelvic EBRT, or VBT after surgery. These models facilitate decision support in daily clinical practice and can be used for patient counseling and shared decision making, selecting patients who benefit most from adjuvant treatment, and generating new hypotheses.« less

Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix.

PubMed

Jesinghaus, Moritz; Strehl, Johanna; Boxberg, Melanie; Brühl, Frido; Wenzel, Adrian; Konukiewitz, Björn; Schlitter, Anna M; Steiger, Katja; Warth, Arne; Schnelzer, Andreas; Kiechle, Marion; Beckmann, Matthias W; Noske, Aurelia; Hartmann, Arndt; Mehlhorn, Grit; Koch, Martin C; Weichert, Wilko

2018-04-01

A novel histopathological grading system based on tumour budding and cell nest size has recently been shown to outperform conventional (WHO-based) grading algorithms in several tumour entities such as lung, oral, and oesophageal squamous cell carcinoma (SCC) in terms of prognostic patient stratification. Here, we tested the prognostic value of this innovative grading approach in two completely independent cohorts of SCC of the uterine cervix. To improve morphology-based grading, we investigated tumour budding activity and cell nest size as well as several other histomorphological factors (e.g., keratinization, nuclear size, mitotic activity) in a test cohort (n = 125) and an independent validation cohort (n = 122) of cervical SCC. All parameters were correlated with clinicopathological factors and patient outcome. Small cell nest size and high tumour budding activity were strongly associated with a dismal patient prognosis (p < 0.001 for overall survival [OS], disease-specific survival, and disease-free survival; test cohort) in both cohorts of cervical SCC. A novel grading algorithm combining these two parameters proved to be a highly effective, stage-independent prognosticator in both cohorts (OS: p < 0.001, test cohort; p = 0.001, validation cohort). In the test cohort, multivariate statistical analysis of the novel grade revealed that the hazard ratio (HR) for OS was 2.3 for G2 and 5.1 for G3 tumours compared to G1 neoplasms (p = 0.010). In the validation cohort, HR for OS was 3.0 for G2 and 7.2 for G3 tumours (p = 0.012). In conclusion, our novel grading algorithm incorporating cell nest size and tumour budding allows strongly prognostic histopathological grading of cervical SCC superior to WHO-based grading. Therefore, our data can be regarded as a cross-organ validation of previous results demonstrated for oesophageal, lung, and oral SCC. We suggest this grading algorithm as an additional morphology-based parameter for the routine diagnostic assessment of this tumour entity. © 2018 The Authors The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.

Improving the Quality of Adult Mortality Data Collected in Demographic Surveys: Validation Study of a New Siblings' Survival Questionnaire in Niakhar, Senegal

PubMed Central

Helleringer, Stéphane; Pison, Gilles; Masquelier, Bruno; Kanté, Almamy Malick; Douillot, Laetitia; Duthé, Géraldine; Sokhna, Cheikh; Delaunay, Valérie

2014-01-01

Background In countries with limited vital registration, adult mortality is frequently estimated using siblings' survival histories (SSHs) collected during Demographic and Health Surveys (DHS). These data are affected by reporting errors. We developed a new SSH questionnaire, the siblings' survival calendar (SSC). It incorporates supplementary interviewing techniques to limit omissions of siblings and uses an event history calendar to improve reports of dates and ages. We hypothesized that the SSC would improve the quality of adult mortality data. Methods and Findings We conducted a retrospective validation study among the population of the Niakhar Health and Demographic Surveillance System in Senegal. We randomly assigned men and women aged 15–59 y to an interview with either the DHS questionnaire or the SSC. We compared SSHs collected in each group to prospective data on adult mortality collected in Niakhar. The SSC reduced respondents' tendency to round reports of dates and ages to the nearest multiple of five or ten (“heaping”). The SSC also had higher sensitivity in recording adult female deaths: among respondents whose sister(s) had died at an adult age in the past 15 y, 89.6% reported an adult female death during SSC interviews versus 75.6% in DHS interviews (p = 0.027). The specificity of the SSC was similar to that of the DHS questionnaire, i.e., it did not increase the number of false reports of deaths. However, the SSC did not improve the reporting of adult deaths among the brothers of respondents. Study limitations include sample selectivity, limited external validity, and multiple testing. Conclusions The SSC has the potential to collect more accurate SSHs than the questionnaire used in DHS. Further research is needed to assess the effects of the SSC on estimates of adult mortality rates. Additional validation studies should be conducted in different social and epidemiological settings. Trial Registration Controlled-Trials.com ISRCTN06849961 Please see later in the article for the Editors' Summary PMID:24866715

Is there a hierarchy of survival reflexes?

PubMed

Macphail, Kieran

2013-10-01

A hierarchy of survival reflexes for prioritising assessment and treatment in patients with pain of insidious onset is hypothesised. The hierarchy asserts that some systems are more vital than others and that the central nervous system (CNS) prioritises systems based on their significance to survival. The hypothesis suggests that dysfunction in more important systems will cause compensation in less important systems. This paper presents studies examining these effects for each system, arguing that each section of the hierarchy may have effects on other systems within the hierarchy. This concept is untested empirically, highly speculative and substantial research is required to validate the suggested hierarchical prioritisation by the CNS. Nonetheless, the hierarchy does provide a theoretical framework to use to exclude contributing systems in patients with pain of insidious onset. Copyright © 2013 Elsevier Ltd. All rights reserved.

Affirmative Action Fallout

ERIC Educational Resources Information Center

Roach, Ronald

2005-01-01

Race-conscious affirmative action in higher education survived a close challenge in 2003 when the U.S. Supreme Court ruled that race was a valid academic admission criteria in the "Grutter v. Bollinger" case. Two years later, a number of "pipeline" programs to help under-represented minorities gain admission to and complete graduate school have…

Development and validation of a Daphnia magna four-day survival and growth test method

EPA Science Inventory

Zooplankton are an important part of the aquatic ecology of all lakes and streams. As a result, numerous methods have been developed to assess the quality of waterbodies using various zooplankton species. Included in these is the freshwater species Daphnia magna. Current test me...

The Effects of Temperature, Photoperiod, and Vernalization on Regrowth and Flowering Competence in Euphorbia Esula (Euphorbiaceae) Crown Buds

USDA-ARS?s Scientific Manuscript database

The herbaceous perennial weed Euphorbia esula (Euphorbiaceae) reproduces by vegetative and sexual means; characteristics that are key to its persistence and survival. In this study, we examined environmental effects on dormancy and flowering under controlled conditions to further validate field obse...

Detection and validation of QTL affecting bacterial cold water disease resistance in rainbow trout using restriction-site associated DNA sequencing

USDA-ARS?s Scientific Manuscript database

Bacterial cold water disease (BCWD) causes significant economic loss in salmonid aquaculture. Using microsatellites genome scan we have previously detected significant and suggestive QTL with major effects on the phenotypic variation of survival following challenge with Flavobacterium psychrophilum...

Civil Defense: An Analysis of Attitudes and Knowledge.

ERIC Educational Resources Information Center

Marko, George Franklin

The study aimed at constructing, validating, and testing two instruments, one of which measured attitude change toward Civil Defense adult education, and one which measured level of knowledge about Civil Defense practices; and evaluating the effectiveness of the Personal and Family Survival (PFS) Course in terms of attitude change and knowledge…

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.

PubMed

Merlini, G; Lousada, I; Ando, Y; Dispenzieri, A; Gertz, M A; Grogan, M; Maurer, M S; Sanchorawala, V; Wechalekar, A; Palladini, G; Comenzo, R L

2016-10-01

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

A modified TNM staging system for non-metastatic colorectal cancer based on nomogram analysis of SEER database.

PubMed

Kong, Xiangxing; Li, Jun; Cai, Yibo; Tian, Yu; Chi, Shengqiang; Tong, Danyang; Hu, Yeting; Yang, Qi; Li, Jingsong; Poston, Graeme; Yuan, Ying; Ding, Kefeng

2018-01-08

To revise the American Joint Committee on Cancer TNM staging system for colorectal cancer (CRC) based on a nomogram analysis of Surveillance, Epidemiology, and End Results (SEER) database, and to prove the rationality of enhancing T stage's weighting in our previously proposed T-plus staging system. Total 115,377 non-metastatic CRC patients from SEER were randomly grouped as training and testing set by ratio 1:1. The Nomo-staging system was established via three nomograms based on 1-year, 2-year and 3-year disease specific survival (DSS) Logistic regression analysis of the training set. The predictive value of Nomo-staging system for the testing set was evaluated by concordance index (c-index), likelihood ratio (L.R.) and Akaike information criteria (AIC) for 1-year, 2-year, 3-year overall survival (OS) and DSS. Kaplan-Meier survival curve was used to valuate discrimination and gradient monotonicity. And an external validation was performed on database from the Second Affiliated Hospital of Zhejiang University (SAHZU). Patients with T1-2 N1 and T1N2a were classified into stage II while T4 N0 patients were classified into stage III in Nomo-staging system. Kaplan-Meier survival curves of OS and DSS in testing set showed Nomo-staging system performed better in discrimination and gradient monotonicity, and the external validation in SAHZU database also showed distinctly better discrimination. The Nomo-staging system showed higher value in L.R. and c-index, and lower value in AIC when predicting OS and DSS in testing set. The Nomo-staging system showed better performance in prognosis prediction and the weight of lymph nodes status in prognosis prediction should be cautiously reconsidered.

Intubation is not a marker for coma after in-hospital cardiac arrest: A retrospective study.

PubMed

Berg, Katherine M; Grossestreuer, Anne V; Uber, Amy; Patel, Parth V; Donnino, Michael W

2017-10-01

In-hospital cardiac arrest (IHCA) strikes over 200,000 people in the United States annually. Targeted temperature management (TTM) is considered beneficial in other settings, but there is no prospective data for IHCA. Recent work on TTM and IHCA found an association between TTM and worse outcome. However, the authors used intubation as a marker for coma to determine eligibility for TTM. The validity of this approach is unexplored. Retrospective, single center study of adult patients with IHCA occurring in an intensive care unit, intubated prior to or during the event, or immediately after ROSC. We evaluated the percentage of patients documented as comatose after arrest, defined as Glasgow Comas Score (GCS) <8 for the primary analysis. We also evaluated the difference in hospital survival in patients with GCS <8 versus ≥8. Two sensitivity analyses using different methods for defining coma using post-ROSC GCS were conducted. 29/102 (28%) intubated patients had a post-ROSC GCS≥8, and 22 (22%) were documented as following commands. Survival in patients with GCS≥8 vs.<8 was 62% (18/29) vs. 37% (27/73) in unadjusted analysis (p=0.02). The adjusted odds ratio for survival to hospital discharge was 3.81 (95%CI: 1.37-10.61, p=0.01). Results were similar in both sensitivity analyses. Intubation prior to or during IHCA was not a valid marker of coma after ROSC. Post-ROSC mental status was associated with hospital survival, and thus could be an important confounder when conducting observational studies on the association of TTM with outcomes in this patient population. Copyright © 2017 Elsevier B.V. All rights reserved.

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis

PubMed Central

Merlini, G; Lousada, I; Ando, Y; Dispenzieri, A; Gertz, M A; Grogan, M; Maurer, M S; Sanchorawala, V; Wechalekar, A; Palladini, G; Comenzo, R L

2016-01-01

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival. PMID:27416985

Empirical study of the dependence of the results of multivariable flexible survival analyses on model selection strategy.

PubMed

Binquet, C; Abrahamowicz, M; Mahboubi, A; Jooste, V; Faivre, J; Bonithon-Kopp, C; Quantin, C

2008-12-30

Flexible survival models, which avoid assumptions about hazards proportionality (PH) or linearity of continuous covariates effects, bring the issues of model selection to a new level of complexity. Each 'candidate covariate' requires inter-dependent decisions regarding (i) its inclusion in the model, and representation of its effects on the log hazard as (ii) either constant over time or time-dependent (TD) and, for continuous covariates, (iii) either loglinear or non-loglinear (NL). Moreover, 'optimal' decisions for one covariate depend on the decisions regarding others. Thus, some efficient model-building strategy is necessary.We carried out an empirical study of the impact of the model selection strategy on the estimates obtained in flexible multivariable survival analyses of prognostic factors for mortality in 273 gastric cancer patients. We used 10 different strategies to select alternative multivariable parametric as well as spline-based models, allowing flexible modeling of non-parametric (TD and/or NL) effects. We employed 5-fold cross-validation to compare the predictive ability of alternative models.All flexible models indicated significant non-linearity and changes over time in the effect of age at diagnosis. Conventional 'parametric' models suggested the lack of period effect, whereas more flexible strategies indicated a significant NL effect. Cross-validation confirmed that flexible models predicted better mortality. The resulting differences in the 'final model' selected by various strategies had also impact on the risk prediction for individual subjects.Overall, our analyses underline (a) the importance of accounting for significant non-parametric effects of covariates and (b) the need for developing accurate model selection strategies for flexible survival analyses. Copyright 2008 John Wiley & Sons, Ltd.

Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis.

PubMed

Reddy, Sreekanth P; Britto, Ramona; Vinnakota, Katyayni; Aparna, Hebbar; Sreepathi, Hari Kishore; Thota, Balaram; Kumari, Arpana; Shilpa, B M; Vrinda, M; Umesh, Srikantha; Samuel, Cini; Shetty, Mitesh; Tandon, Ashwani; Pandey, Paritosh; Hegde, Sridevi; Hegde, A S; Balasubramaniam, Anandh; Chandramouli, B A; Santosh, Vani; Kondaiah, Paturu; Somasundaram, Kumaravel; Rao, M R Satyanarayana

2008-05-15

Current methods of classification of astrocytoma based on histopathologic methods are often subjective and less accurate. Although patients with glioblastoma have grave prognosis, significant variability in patient outcome is observed. Therefore, the aim of this study was to identify glioblastoma diagnostic and prognostic markers through microarray analysis. We carried out transcriptome analysis of 25 diffusely infiltrating astrocytoma samples [WHO grade II--diffuse astrocytoma, grade III--anaplastic astrocytoma, and grade IV--glioblastoma (GBM)] using cDNA microarrays containing 18,981 genes. Several of the markers identified were also validated by real-time reverse transcription quantitative PCR and immunohistochemical analysis on an independent set of tumor samples (n = 100). Survival analysis was carried out for two markers on another independent set of retrospective cases (n = 51). We identified several differentially regulated grade-specific genes. Independent validation by real-time reverse transcription quantitative PCR analysis found growth arrest and DNA-damage-inducible alpha (GADD45alpha) and follistatin-like 1 (FSTL1) to be up-regulated in most GBMs (both primary and secondary), whereas superoxide dismutase 2 and adipocyte enhancer binding protein 1 were up-regulated in the majority of primary GBM. Further, identification of the grade-specific expression of GADD45alpha and FSTL1 by immunohistochemical staining reinforced our findings. Analysis of retrospective GBM cases with known survival data revealed that cytoplasmic overexpression of GADD45alpha conferred better survival while the coexpression of FSTL1 with p53 was associated with poor survival. Our study reveals that GADD45alpha and FSTLI are GBM-specific whereas superoxide dismutase 2 and adipocyte enhancer binding protein 1 are primary GBM-specific diagnostic markers. Whereas GADD45alpha overexpression confers a favorable prognosis, FSTL1 overexpression is a hallmark of poor prognosis in GBM patients.

Predicting functional decline and survival in amyotrophic lateral sclerosis.

PubMed

Ong, Mei-Lyn; Tan, Pei Fang; Holbrook, Joanna D

2017-01-01

Better predictors of amyotrophic lateral sclerosis disease course could enable smaller and more targeted clinical trials. Partially to address this aim, the Prize for Life foundation collected de-identified records from amyotrophic lateral sclerosis sufferers who participated in clinical trials of investigational drugs and made them available to researchers in the PRO-ACT database. In this study, time series data from PRO-ACT subjects were fitted to exponential models. Binary classes for decline in the total score of amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) (fast/slow progression) and survival (high/low death risk) were derived. Data was segregated into training and test sets via cross validation. Learning algorithms were applied to the demographic, clinical and laboratory parameters in the training set to predict ALSFRS-R decline and the derived fast/slow progression and high/low death risk categories. The performance of predictive models was assessed by cross-validation in the test set using Receiver Operator Curves and root mean squared errors. A model created using a boosting algorithm containing the decline in four parameters (weight, alkaline phosphatase, albumin and creatine kinase) post baseline, was able to predict functional decline class (fast or slow) with fair accuracy (AUC = 0.82). However similar approaches to build a predictive model for decline class by baseline subject characteristics were not successful. In contrast, baseline values of total bilirubin, gamma glutamyltransferase, urine specific gravity and ALSFRS-R item score-climbing stairs were sufficient to predict survival class. Using combinations of small numbers of variables it was possible to predict classes of functional decline and survival across the 1-2 year timeframe available in PRO-ACT. These findings may have utility for design of future ALS clinical trials.

Eigentumors for prediction of treatment failure in patients with early-stage breast cancer using dynamic contrast-enhanced MRI: a feasibility study

NASA Astrophysics Data System (ADS)

Chan, H. M.; van der Velden, B. H. M.; E Loo, C.; Gilhuijs, K. G. A.

2017-08-01

We present a radiomics model to discriminate between patients at low risk and those at high risk of treatment failure at long-term follow-up based on eigentumors: principal components computed from volumes encompassing tumors in washin and washout images of pre-treatment dynamic contrast-enhanced (DCE-) MR images. Eigentumors were computed from the images of 563 patients from the MARGINS study. Subsequently, a least absolute shrinkage selection operator (LASSO) selected candidates from the components that contained 90% of the variance of the data. The model for prediction of survival after treatment (median follow-up time 86 months) was based on logistic regression. Receiver operating characteristic (ROC) analysis was applied and area-under-the-curve (AUC) values were computed as measures of training and cross-validated performances. The discriminating potential of the model was confirmed using Kaplan-Meier survival curves and log-rank tests. From the 322 principal components that explained 90% of the variance of the data, the LASSO selected 28 components. The ROC curves of the model yielded AUC values of 0.88, 0.77 and 0.73, for the training, leave-one-out cross-validated and bootstrapped performances, respectively. The bootstrapped Kaplan-Meier survival curves confirmed significant separation for all tumors (P  <  0.0001). Survival analysis on immunohistochemical subgroups shows significant separation for the estrogen-receptor subtype tumors (P  <  0.0001) and the triple-negative subtype tumors (P  =  0.0039), but not for tumors of the HER2 subtype (P  =  0.41). The results of this retrospective study show the potential of early-stage pre-treatment eigentumors for use in prediction of treatment failure of breast cancer.

Analytic considerations and axiomatic approaches to the concept cell death and cell survival functions in biology and cancer treatment.

PubMed

Gkigkitzis, Ioannis; Haranas, Ioannis; Austerlitz, Carlos

2015-01-01

This study contains a discussion on the connection between current mathematical and biological modeling systems in response to the main research need for the development of a new mathematical theory for study of cell survival after medical treatment and cell biological behavior in general. This is a discussion of suggested future research directions and relations with interdisciplinary science. In an effort to establish the foundations for a possible framework that may be adopted to study and analyze the process of cell survival during treatment, we investigate the organic connection among an axiomatic system foundation, a predator-prey rate equation, and information theoretic signal processing. A new set theoretic approach is also introduced through the definition of cell survival units or cell survival units indicating the use of "proper classes" according to the Zermelo-Fraenkel set theory and the axiom of choice, as the mathematics appropriate for the development of biological theory of cell survival.

New Symptom-Based Predictive Tool for Survival at Seven and Thirty Days Developed by Palliative Home Care Teams

PubMed Central

Bescos, Mar; Barcons, Miquel; Torrubia, Pilar; Trujillano, Javier; Requena, Antonio

2014-01-01

Abstract Aim: This study sought to develop models to predict survival at 7 and 30 days based on symptoms detected by palliative home care teams (PHCTs). Materials and methods: This prospective analytic study included a 6-month recruitment period with patient monitoring until death or 180 days after recruitment. The inclusion criteria consisted of age greater than 18 years, advanced cancer, and treatment provided by participating PHCTs between April and July 2009. The study variables included death at 7 or 30 days, survival time, age, gender, place of residence, type of tumor and extension, presence of 11 signs and symptoms measured with a 0–3 Likert scale, functional and cognitive status, and use of a subcutaneous butterfly needle. The statistics applied included a descriptive analysis according to the percentage or mean±standard deviation. For symptom comparison between surviving and nonsurviving patients, the χ2 test was used. Classification and regression tree (CART) methodology was used for model development. An internal validation system (cross-validation with 10 partitions) was used to ensure generalization of the models. The area under the receiver operating characteristics (ROC) curve was calculated (with a 95% confidence interval) to assess the validation of the models. Results: A total of 698 patients were included. The mean age of the patients was 73.7±12 years, and 60.3% were male. The most frequent type of neoplasm was digestive (37.6%). The mean Karnofsky score was 51.8±14, the patients' cognitive status according to the Pfeiffer test was 2.6±4 errors, and 8.3% of patients required a subcutaneous butterfly needle. Each model provided 8 decision rules with a probability assignment range between 2.2% and 99.1%. The model used to predict the probability of death at 7 days included the presence of anorexia and dysphagia and the level of consciousness, and this model produced areas under the curve (AUCs) of 0.88 (0.86–0.90) and 0.81 (0.79–0.83). The model used to predict the probability of death at 30 days included the presence of asthenia and anorexia and the level of consciousness, and this model produced AUCs of 0.78 (0.77–0.80) and 0.77 (0.75–0.79). Conclusion: For patients with advanced cancer treated by PHCTs, the use of classification schemes and decision trees based on specific symptoms can help clinicians predict survival at 7 and 30 days. PMID:24922117

Computer-Aided Diagnosis Systems for Lung Cancer: Challenges and Methodologies

PubMed Central

El-Baz, Ayman; Beache, Garth M.; Gimel'farb, Georgy; Suzuki, Kenji; Okada, Kazunori; Elnakib, Ahmed; Soliman, Ahmed; Abdollahi, Behnoush

2013-01-01

This paper overviews one of the most important, interesting, and challenging problems in oncology, the problem of lung cancer diagnosis. Developing an effective computer-aided diagnosis (CAD) system for lung cancer is of great clinical importance and can increase the patient's chance of survival. For this reason, CAD systems for lung cancer have been investigated in a huge number of research studies. A typical CAD system for lung cancer diagnosis is composed of four main processing steps: segmentation of the lung fields, detection of nodules inside the lung fields, segmentation of the detected nodules, and diagnosis of the nodules as benign or malignant. This paper overviews the current state-of-the-art techniques that have been developed to implement each of these CAD processing steps. For each technique, various aspects of technical issues, implemented methodologies, training and testing databases, and validation methods, as well as achieved performances, are described. In addition, the paper addresses several challenges that researchers face in each implementation step and outlines the strengths and drawbacks of the existing approaches for lung cancer CAD systems. PMID:23431282

Micro ecosystems from feed industry surfaces: a survival and biofilm study of Salmonella versus host resident flora strains.

PubMed

Habimana, Olivier; Møretrø, Trond; Langsrud, Solveig; Vestby, Lene K; Nesse, Live L; Heir, Even

2010-11-02

The presence of Salmonella enterica serovars in feed ingredients, products and processing facilities is a well recognized problem worldwide. In Norwegian feed factories, strict control measures are implemented to avoid establishment and spreading of Salmonella throughout the processing chain. There is limited knowledge on the presence and survival of the resident microflora in feed production plants. Information on interactions between Salmonella and other bacteria in feed production plants and how they affect survival and biofilm formation of Salmonella is also limited. The aim of this study was to identify resident microbiota found in feed production environments, and to compare the survival of resident flora strains and Salmonella to stress factors typically found in feed processing environments. Moreover, the role of dominant resident flora strains in the biofilm development of Salmonella was determined. Surface microflora characterization from two feed productions plants, by means of 16 S rDNA sequencing, revealed a wide diversity of bacteria. Survival, disinfection and biofilm formation experiments were conducted on selected dominant resident flora strains and Salmonella. Results showed higher survival properties by resident flora isolates for desiccation, and disinfection compared to Salmonella isolates. Dual-species biofilms favored Salmonella growth compared to Salmonella in mono-species biofilms, with biovolume increases of 2.8-fold and 3.2-fold in the presence of Staphylococcus and Pseudomonas, respectively. These results offer an overview of the microflora composition found in feed industry processing environments, their survival under relevant stresses and their potential effect on biofilm formation in the presence of Salmonella. Eliminating the establishment of resident flora isolates in feed industry surfaces is therefore of interest for impeding conditions for Salmonella colonization and growth on feed industry surfaces. In-depth investigations are still needed to determine whether resident flora has a definite role in the persistence of Salmonella in feed processing environments.

Review of surface steam sterilization for validation purposes.

PubMed

van Doornmalen, Joost; Kopinga, Klaas

2008-03-01

Sterilization is an essential step in the process of producing sterile medical devices. To guarantee sterility, the process of sterilization must be validated. Because there is no direct way to measure sterility, the techniques applied to validate the sterilization process are based on statistical principles. Steam sterilization is the most frequently applied sterilization method worldwide and can be validated either by indicators (chemical or biological) or physical measurements. The steam sterilization conditions are described in the literature. Starting from these conditions, criteria for the validation of steam sterilization are derived and can be described in terms of physical parameters. Physical validation of steam sterilization appears to be an adequate and efficient validation method that could be considered as an alternative for indicator validation. Moreover, physical validation can be used for effective troubleshooting in steam sterilizing processes.

21 CFR 1271.230 - Process validation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Process validation. 1271.230 Section 1271.230 Food..., AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue Practice § 1271.230 Process validation. (a... validation activities and results must be documented, including the date and signature of the individual(s...

21 CFR 1271.230 - Process validation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Process validation. 1271.230 Section 1271.230 Food..., AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue Practice § 1271.230 Process validation. (a... validation activities and results must be documented, including the date and signature of the individual(s...

21 CFR 1271.230 - Process validation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Process validation. 1271.230 Section 1271.230 Food..., AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue Practice § 1271.230 Process validation. (a... validation activities and results must be documented, including the date and signature of the individual(s...

21 CFR 1271.230 - Process validation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Process validation. 1271.230 Section 1271.230 Food..., AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue Practice § 1271.230 Process validation. (a... validation activities and results must be documented, including the date and signature of the individual(s...

21 CFR 1271.230 - Process validation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Process validation. 1271.230 Section 1271.230 Food..., AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue Practice § 1271.230 Process validation. (a... validation activities and results must be documented, including the date and signature of the individual(s...

Long-term survival with modern therapeutic agents against metastatic melanoma-vemurafenib and ipilimumab in a daily life setting.

PubMed

Lang, B M; Peveling-Oberhag, A; Faidt, D; Hötker, A M; Weyer-Elberich, V; Grabbe, S; Loquai, C

2018-01-31

Despite new therapeutic options, metastatic melanoma remains to be one of the most fatal tumors. With the development of BRAF inhibitors and immune checkpoint inhibitors, overall survival could be prolonged significantly for the first time. Clinical studies implied that even long-term survival is possible with both types of drugs, but predictive markers are so far missing. In this study, we analyzed survival data from patients that received the first-in-class substances vemurafenib and ipilimumab, respectively, during the time period from registration of the drugs until availability of combination treatments. We aimed to evaluate the possibility of long-term survival in a daily life setting and to characterize patients that benefit from these drugs in order to gain insight into predictive attributes. Eighty patients were evaluated who were treated with either vemurafenib (n = 40) or ipilimumab (n = 40), and overall survival was analyzed. Subgroup analysis was performed for patients who were still alive 24 months after induction of therapy (long-term survival). Median overall survival (OS) was 8.0 months for patients treated with vemurafenib and 10.0 months for patients treated with ipilimumab (log-rank P value = 0.689). Long-term survival was achieved in 32.5% of patients (42.3% vemurafenib, 57.7% ipilimumab). Negative predictors of long-term survival in the vemurafenib group were brain and liver metastases, as well as elevated LDH, S100ß and liver enzymes. For ipilimumab, an increase in lymphocytes and eosinophils during course of treatment correlated with long-term survival. Our real-life experience shows that long-term survival is possible with using both therapeutic agents, vemurafenib and ipilimumab. Pattern of metastases and laboratory values might be of interest in decision making for a specific therapeutic approach. Combination of drugs and observational studies in larger patient cohorts are necessary to further validate our findings.

Digital transcriptome profiling of normal and glioblastoma-derived neural stem cells identifies genes associated with patient survival

PubMed Central

2012-01-01

Background Glioblastoma multiforme, the most common type of primary brain tumor in adults, is driven by cells with neural stem (NS) cell characteristics. Using derivation methods developed for NS cells, it is possible to expand tumorigenic stem cells continuously in vitro. Although these glioblastoma-derived neural stem (GNS) cells are highly similar to normal NS cells, they harbor mutations typical of gliomas and initiate authentic tumors following orthotopic xenotransplantation. Here, we analyzed GNS and NS cell transcriptomes to identify gene expression alterations underlying the disease phenotype. Methods Sensitive measurements of gene expression were obtained by high-throughput sequencing of transcript tags (Tag-seq) on adherent GNS cell lines from three glioblastoma cases and two normal NS cell lines. Validation by quantitative real-time PCR was performed on 82 differentially expressed genes across a panel of 16 GNS and 6 NS cell lines. The molecular basis and prognostic relevance of expression differences were investigated by genetic characterization of GNS cells and comparison with public data for 867 glioma biopsies. Results Transcriptome analysis revealed major differences correlated with glioma histological grade, and identified misregulated genes of known significance in glioblastoma as well as novel candidates, including genes associated with other malignancies or glioma-related pathways. This analysis further detected several long non-coding RNAs with expression profiles similar to neighboring genes implicated in cancer. Quantitative PCR validation showed excellent agreement with Tag-seq data (median Pearson r = 0.91) and discerned a gene set robustly distinguishing GNS from NS cells across the 22 lines. These expression alterations include oncogene and tumor suppressor changes not detected by microarray profiling of tumor tissue samples, and facilitated the identification of a GNS expression signature strongly associated with patient survival (P = 1e-6, Cox model). Conclusions These results support the utility of GNS cell cultures as a model system for studying the molecular processes driving glioblastoma and the use of NS cells as reference controls. The association between a GNS expression signature and survival is consistent with the hypothesis that a cancer stem cell component drives tumor growth. We anticipate that analysis of normal and malignant stem cells will be an important complement to large-scale profiling of primary tumors. PMID:23046790

Predictive Genes in Adjacent Normal Tissue Are Preferentially Altered by sCNV during Tumorigenesis in Liver Cancer and May Rate Limiting

PubMed Central

Lamb, John R.; Zhang, Chunsheng; Xie, Tao; Wang, Kai; Zhang, Bin; Hao, Ke; Chudin, Eugene; Fraser, Hunter B.; Millstein, Joshua; Ferguson, Mark; Suver, Christine; Ivanovska, Irena; Scott, Martin; Philippar, Ulrike; Bansal, Dimple; Zhang, Zhan; Burchard, Julja; Smith, Ryan; Greenawalt, Danielle; Cleary, Michele; Derry, Jonathan; Loboda, Andrey; Watters, James; Poon, Ronnie T. P.; Fan, Sheung T.; Yeung, Chun; Lee, Nikki P. Y.; Guinney, Justin; Molony, Cliona; Emilsson, Valur; Buser-Doepner, Carolyn; Zhu, Jun; Friend, Stephen; Mao, Mao; Shaw, Peter M.; Dai, Hongyue; Luk, John M.; Schadt, Eric E.

2011-01-01

Background In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. Methodology/Principal Findings Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types. PMID:21750698

Microbial dynamics in mixed culture biofilms of bacteria surviving sanitation of conveyor belts in salmon-processing plants.

PubMed

Langsrud, S; Moen, B; Møretrø, T; Løype, M; Heir, E

2016-02-01

The microbiota surviving sanitation of salmon-processing conveyor belts was identified and its growth dynamics further investigated in a model mimicking processing surfaces in such plants. A diverse microbiota dominated by Gram-negative bacteria was isolated after regular sanitation in three salmon processing plants. A cocktail of 14 bacterial isolates representing all genera isolated from conveyor belts (Listeria, Pseudomonas, Stenotrophomonas, Brochothrix, Serratia, Acinetobacter, Rhodococcus and Chryseobacterium) formed stable biofilms on steel coupons (12°C, salmon broth) of about 10(9) CFU cm(-2) after 2 days. High-throughput sequencing showed that Listeria monocytogenes represented 0·1-0·01% of the biofilm population and that Pseudomonas spp dominated. Interestingly, both Brochothrix sp. and a Pseudomonas sp. dominated in the surrounding suspension. The microbiota surviving sanitation is dominated by Pseudomonas spp. The background microbiota in biofilms inhibit, but do not eliminate L. monocytogenes. The results highlights that sanitation procedures have to been improved in the salmon-processing industry, as high numbers of a diverse microbiota survived practical sanitation. High-throughput sequencing enables strain level studies of population dynamics in biofilm. © 2015 The Society for Applied Microbiology.

High Myeloperoxidase Positive Cell Infiltration in Colorectal Cancer Is an Independent Favorable Prognostic Factor

PubMed Central

Eppenberger-Castori, Serenella; Zlobec, Inti; Viehl, Carsten T.; Frey, Daniel M.; Nebiker, Christian A.; Rosso, Raffaele; Zuber, Markus; Amicarella, Francesca; Iezzi, Giandomenica; Sconocchia, Giuseppe; Heberer, Michael; Lugli, Alessandro; Tornillo, Luigi; Oertli, Daniel

2013-01-01

Background Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). Methods A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. Results MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO−. Conclusions High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC. PMID:23734221

Low Tumor Infiltrating Mast Cell Density Confers Prognostic Benefit and Reflects Immunoactivation in Colorectal Cancer.

PubMed

Mao, Yihao; Feng, Qingyang; Zheng, Peng; Yang, Liangliang; Zhu, Dexiang; Chang, Wenju; Ji, Meiling; He, Guodong; Xu, Jianmin

2018-06-06

The role of mast cells (MCs) in colorectal cancer (CRC) progression was controversial. Thus, this study was designed to evaluate the prognostic value of MCs as well as their correlation with immune microenvironment. A retrospective cohort of CRC patients of stage I-IV was enrolled in this study. 854 consecutive patients were divided into training set (427 patients) and validation set (427 patients) randomly. The findings were further validated in a GEO cohort, GSE39582 (556 patients). The mast cell density (MCD) was measured by immunohistochemical staining of tryptase or by CIBERSORT algorithm. Low MCD predicted prolonged overall survival (OS) in training and validation set. Moreover, MCD was identified as an independent prognostic indicator in both sets. Better stratification for CRC prognosis can be achieved by building a MCD based nomogram. The prognostic role of MCD was further validated in GSE39582. In addition, MCD predicted improved survival in stage II and III CRC patients receiving adjuvant chemotherapy (ACT). Multiple immune pathways were enriched in low MCD group while cytokines/chemokines promoting anti-tumor immunity were highly expressed in such group. Furthermore, MCD was negatively correlated with CD8+ T cells infiltration. In conclusion, MCD was identified as an independent prognostic factor, as well as a potential biomarker for ACT benefit in stage II and III CRC. Better stratification of CRC prognosis could be achieved by building a MCD based nomogram. Moreover, immunoactivation in low MCD tumors may contributed to improved prognosis. This article is protected by copyright. All rights reserved. © 2018 UICC.

Childhood bereavement: The role of the surviving parent and the continuing bond with the deceased.

PubMed

Karydi, Evangelia

2018-08-01

This study investigated the relationship between the role of the surviving parent in the child's grieving process, the continuing bond with the deceased parent and biopsychosocial functioning and active grief in adulthood. A survey of 135 adults, parentally bereaved in childhood, indicated that the surviving parent's role in facilitating the grieving process promoted a positive continuing bond with the deceased in childhood as well as general functioning in adulthood. The continuing bond with the deceased had a weak association with both better general functioning and relational active grief.

Feasibility of utilizing bioindicators for testing microbial inactivation in sweetpotato purees processed with a continuous-flow microwave system.

PubMed

Brinley, T A; Dock, C N; Truong, V-D; Coronel, P; Kumar, P; Simunovic, J; Sandeep, K P; Cartwright, G D; Swartzel, K R; Jaykus, L-A

2007-06-01

Continuous-flow microwave heating has potential in aseptic processing of various food products, including purees from sweetpotatoes and other vegetables. Establishing the feasibility of a new processing technology for achieving commercial sterility requires evaluating microbial inactivation. This study aimed to assess the feasibility of using commercially available plastic pouches of bioindicators containing spores of Geobacillius stearothermophilus ATCC 7953 and Bacillus subtilis ATCC 35021 for evaluating the degree of microbial inactivation achieved in vegetable purees processed in a continuous-flow microwave heating unit. Sweetpotato puree seeded with the bioindicators was subjected to 3 levels of processing based on the fastest particles: undertarget process (F(0) approximately 0.65), target process (F(0) approximately 2.8), and overtarget process (F(0) approximately 10.10). After initial experiments, we found it was necessary to engineer a setup with 2 removable tubes connected to the continuous-flow microwave system to facilitate the injection of indicators into the unit without interrupting the puree flow. Using this approach, 60% of the indicators injected into the system could be recovered postprocess. Spore survival after processing, as evaluated by use of growth indicator dyes and standard plating methods, verified inactivation of the spores in sweetpotato puree. The log reduction results for B. subtilis were equivalent to the predesigned degrees of sterilization (F(0)). This study presents the first report suggesting that bioindicators such as the flexible, food-grade plastic pouches can be used for microbial validation of commercial sterilization in aseptic processing of foods using a continuous-flow microwave system.

Improving Risk Adjustment for Mortality After Pediatric Cardiac Surgery: The UK PRAiS2 Model.

PubMed

Rogers, Libby; Brown, Katherine L; Franklin, Rodney C; Ambler, Gareth; Anderson, David; Barron, David J; Crowe, Sonya; English, Kate; Stickley, John; Tibby, Shane; Tsang, Victor; Utley, Martin; Witter, Thomas; Pagel, Christina

2017-07-01

Partial Risk Adjustment in Surgery (PRAiS), a risk model for 30-day mortality after children's heart surgery, has been used by the UK National Congenital Heart Disease Audit to report expected risk-adjusted survival since 2013. This study aimed to improve the model by incorporating additional comorbidity and diagnostic information. The model development dataset was all procedures performed between 2009 and 2014 in all UK and Ireland congenital cardiac centers. The outcome measure was death within each 30-day surgical episode. Model development followed an iterative process of clinical discussion and development and assessment of models using logistic regression under 25 × 5 cross-validation. Performance was measured using Akaike information criterion, the area under the receiver-operating characteristic curve (AUC), and calibration. The final model was assessed in an external 2014 to 2015 validation dataset. The development dataset comprised 21,838 30-day surgical episodes, with 539 deaths (mortality, 2.5%). The validation dataset comprised 4,207 episodes, with 97 deaths (mortality, 2.3%). The updated risk model included 15 procedural, 11 diagnostic, and 4 comorbidity groupings, and nonlinear functions of age and weight. Performance under cross-validation was: median AUC of 0.83 (range, 0.82 to 0.83), median calibration slope and intercept of 0.92 (range, 0.64 to 1.25) and -0.23 (range, -1.08 to 0.85) respectively. In the validation dataset, the AUC was 0.86 (95% confidence interval [CI], 0.82 to 0.89), and the calibration slope and intercept were 1.01 (95% CI, 0.83 to 1.18) and 0.11 (95% CI, -0.45 to 0.67), respectively, showing excellent performance. A more sophisticated PRAiS2 risk model for UK use was developed with additional comorbidity and diagnostic information, alongside age and weight as nonlinear variables. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Influence of High-Pressure Processing at Low Temperature and Nisin on Listeria innocua Survival and Sensory Preference of Dry-Cured Cold-Smoked Salmon.

PubMed

Lebow, Noelle K; DesRocher, Lisa D; Younce, Frank L; Zhu, Mei-Jun; Ross, Carolyn F; Smith, Denise M

2017-12-01

Cold-smoked salmon (CSS) production lacks a validated kill step for Listeria monocytogenes. Although Listeria spp. are reduced by nisin or high-pressure processing (HPP), CSS muscle discoloration is often observed after HPP. Effects of nisin and low-temperature HPP on L. innocua survival (nonpathogenic surrogate for L. monocytogenes), spoilage organism growth, color, and sensory preference and peelability of CSS were studied. Cold-smoked sockeye salmon (Oncorhynchus nerka) fillets ± nisin (10 μg/g) were inoculated with a 3-strain L. innocua cocktail, vacuum-packaged, frozen at - 30 °C, and high-pressure processed in an ice slurry within an insulated sleeve. Initial experiments indicated that nisin and HPP for 120 s at 450 MPa (N450) and 600 MPa (N600) were most effective against L. innocua, and thus were selected for further storage studies. L. innocua in N450 and N600-treated CSS was reduced 2.63 ± 0.15 and 3.99 ± 0.34 Log CFU/g, respectively, immediately after HPP. L. innocua and spoilage growth were not observed in HPP-treated CSS during 36 d storage at 4 °C. Low-temperature HPP showed a smaller increase in lightness of CSS compared to ambient-temperature HPP performed in previous studies. Sensory evaluation indicated that overall liking of CSS treated with N450 and N600 were preferred over the control by 61% and 62% of panelists, respectively (P < 0.05). Peelability of sliced CSS was reduced by HPP (P < 0.05). Nisin in combination with low-temperature HPP was effective in controlling L. innocua in CSS while maintaining consumer acceptability. Cold-smoked salmon is a high-risk ready-to-eat product that may be contaminated with L. monocytogenes. Results showed that nisin combined with high-pressure processing at low temperature, reduced the population of Listeria and controlled the spoilage organisms during storage. As an added benefit, high-pressure processing at low temperature may reduce lightening of the salmon flesh, leading to enhanced consumer preference. © 2017 Institute of Food Technologists®.

Terminology and biology of fire scars in selected central hardwoods

Treesearch

Kevin T. Smith; Elaine Kennedy Sutherland

2001-01-01

Dendrochronological analysis of fire scars requires tree survival of fire exposure. Trees survive fire exposure by: (1) avoidance of injury through constitutive protection and (2) induced defense. Induced defenses include (a) compartmentalization processes that resist the spread of injury and infection and (b) closure processes that restore the continuity of the...

Dual-species biofilms formation by Escherichia coli O157:H7 and environmental bacteria isolated from fresh-cut processing plants

USDA-ARS?s Scientific Manuscript database

Biofilm formation is a mechanism adapted by many microorganisms that enhances the survival in stressful environments. In food processing facilities, bacterial strains with strong biofilm forming capacities are more likely to survive the daily cleaning and disinfection. Foodborne bacterial pathogens,...

Effects of polyphosphate additives on the pH of processed chicken exudates and the survival of Campylobacter

USDA-ARS?s Scientific Manuscript database

Campylobacter spp. are nutritionally fastidious organisms that are sensitive to normal atmospheric oxygen levels and lack homologues of common cold shock genes. At first glance these bacteria seem ill equipped to persist within food processing and storage conditions; however, they survive in number...

Survival of foot-and-mouth disease virus in cheese.

PubMed

Blackwell, J H

1976-09-01

Persistence of foot-and-mouth disease virus during the manufacture of Cheddar, Mozzarella, Camembert cheese prepared from milk of cows experimentally infected with the virus was studied. Cheese samples were made on a laboratory scale with commercial lactic acid starter cultures and the microbial protease MARZYME as a coagulant. Milk was heated at different temperatures for different intervals before it was made into cheese. Food-and-mouth disease virus survived the acidic conditions of Cheddar and Camembert cheese processing but not that of Mozzarella. Foot-and-mouth disease virus survived processing but not curing for 30 days in Cheddar cheese preparaed from heated milk. However, the virus survived curing for 60 days but not for 120 days in cheese (pH 5) prepared from unheated milk. Foot-and-mouth disease virus survived in Camembert cheese (pH 5) for 21 days at 2 C but not for 35 days.

Landscape inheritance: Report of Working Group Number 2

NASA Technical Reports Server (NTRS)

Twidale, C. R.

1985-01-01

The conventional wisdom is, or until recently has been, that the earth's scenery is essentially youthful, much of it being of pleistocene age. The validity of this assertion was questioned, surfaces and forms of much greater antiquity being cited from several cratonic regions, and also from the older orogens. Exhumed forms, some of them of great age (one inselberg landscape of Archaean age was noted), are more common and extensive than has previously been supposed. Epigene forms of Mesozoic ate are increasingly being demonstrated from the world's cratons and orogens. Etch features also are more widely eveloped than has been realized. It was recommended that studies of denudation chronology be undertaken, possible in relation to contrasted cratonic regions. The nature and age range of surfaces that make up the shields ought to be analysed, the processes responsible for shaping the surfaces, and, in the case of the ancien epigene forms, the reasons for their survival.

Modeling of Receptor Tyrosine Kinase Signaling: Computational and Experimental Protocols.

PubMed

Fey, Dirk; Aksamitiene, Edita; Kiyatkin, Anatoly; Kholodenko, Boris N

2017-01-01

The advent of systems biology has convincingly demonstrated that the integration of experiments and dynamic modelling is a powerful approach to understand the cellular network biology. Here we present experimental and computational protocols that are necessary for applying this integrative approach to the quantitative studies of receptor tyrosine kinase (RTK) signaling networks. Signaling by RTKs controls multiple cellular processes, including the regulation of cell survival, motility, proliferation, differentiation, glucose metabolism, and apoptosis. We describe methods of model building and training on experimentally obtained quantitative datasets, as well as experimental methods of obtaining quantitative dose-response and temporal dependencies of protein phosphorylation and activities. The presented methods make possible (1) both the fine-grained modeling of complex signaling dynamics and identification of salient, course-grained network structures (such as feedback loops) that bring about intricate dynamics, and (2) experimental validation of dynamic models.

First in line: Prioritizing receipt of Social Security disability benefits based on likelihood of death during adjudication

PubMed Central

Rasch, Elizabeth K.; Huynh, Minh; Ho, Pei-Shu; Heuser, Aaron; Houtenville, Andrew; Chan, Leighton

2014-01-01

Background: Given the complexity of the adjudication process and volume of applications to Social Security Administration’s (SSA) disability programs, many individuals with serious medical conditions die while awaiting an application decision. Limitations of traditional survival methods called for a new empirical approach to identify conditions resulting in rapid mortality. Objective: To identify health conditions associated with significantly higher mortality than a key reference group among applicants for SSA disability programs. Research design: We identified mortality patterns and generated a survival surface for a reference group using conditions already designated for expedited processing. We identified conditions associated with significantly higher mortality than the reference group and prioritized them by the expected likelihood of death during the adjudication process. Subjects: Administrative records of 29 million Social Security disability applicants, who applied for benefits from 1996 – 2007, were analyzed. Measures: We computed survival spells from time of onset of disability to death, and from date of application to death. Survival data were organized by entry cohort. Results: In our sample, we observed that approximately 42,000 applicants died before a decision was made on their disability claims. We identified 24 conditions with survival profiles comparable to the reference group. Applicants with these conditions were not likely to survive adjudication. Conclusions: Our approach facilitates ongoing revision of the conditions SSA designates for expedited awards and has applicability to other programs where survival profiles are a consideration. PMID:25310524

Eye-Tracking as a Tool in Process-Oriented Reading Test Validation

ERIC Educational Resources Information Center

Solheim, Oddny Judith; Uppstad, Per Henning

2011-01-01

The present paper addresses the continuous need for methodological reflection on how to validate inferences made on the basis of test scores. Validation is a process that requires many lines of evidence. In this article we discuss the potential of eye tracking methodology in process-oriented reading test validation. Methodological considerations…

Discovery and validation of a glioblastoma co-expressed gene module

PubMed Central

Dunwoodie, Leland J.; Poehlman, William L.; Ficklin, Stephen P.; Feltus, Frank Alexander

2018-01-01

Tumors exhibit complex patterns of aberrant gene expression. Using a knowledge-independent, noise-reducing gene co-expression network construction software called KINC, we created multiple RNAseq-based gene co-expression networks relevant to brain and glioblastoma biology. In this report, we describe the discovery and validation of a glioblastoma-specific gene module that contains 22 co-expressed genes. The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors. Among the proneural, neural, mesenchymal, and classical glioblastoma subtypes, these genes are most-highly expressed in the mesenchymal subtype. Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype. These genes are of interest to glioblastoma biology and our gene interaction discovery and validation workflow can be used to discover and validate co-expressed gene modules derived from any co-expression network. PMID:29541392

Discovery and validation of a glioblastoma co-expressed gene module.

PubMed

Dunwoodie, Leland J; Poehlman, William L; Ficklin, Stephen P; Feltus, Frank Alexander

2018-02-16

Tumors exhibit complex patterns of aberrant gene expression. Using a knowledge-independent, noise-reducing gene co-expression network construction software called KINC, we created multiple RNAseq-based gene co-expression networks relevant to brain and glioblastoma biology. In this report, we describe the discovery and validation of a glioblastoma-specific gene module that contains 22 co-expressed genes. The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors. Among the proneural, neural, mesenchymal, and classical glioblastoma subtypes, these genes are most-highly expressed in the mesenchymal subtype. Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype. These genes are of interest to glioblastoma biology and our gene interaction discovery and validation workflow can be used to discover and validate co-expressed gene modules derived from any co-expression network.

Adaptive Memory: Survival Processing Enhances Retention

ERIC Educational Resources Information Center

Nairne, James S.; Thompson, Sarah R.; Pandeirada, Josefa N. S.

2007-01-01

The authors investigated the idea that memory systems might have evolved to help us remember fitness-relevant information--specifically, information relevant to survival. In 4 incidental learning experiments, people were asked to rate common nouns for their survival relevance (e.g., in securing food, water, or protection from predators); in…

Review on comparative efficacy of bevacizumab, panitumumab and cetuximab antibody therapy with combination of FOLFOX-4 in KRAS-mutated colorectal cancer patients.

PubMed

Pathak, Surajit; S, Sushmitha; Banerjee, Antara; Marotta, Francesco; Gopinath, Madhumala; Murugesan, Ramachandran; Zhang, Hong; B, Bhavani; Girigoswami, Agnishwar; Sollano, Jose; Sun, Xiao-Feng

2018-01-26

Colorectal cancer, fourth leading form of cancer worldwide and is increasing in alarming rate in the developing countries. Treating colorectal cancer has become a big challenge worldwide and several antibody therapies such as bevacizumab, panitumumab and cetuximab are being used with limited success. Moreover, mutation in KRAS gene which is linked with the colorectal cancer initiation and progression further interferes with the antibody therapies. Considering median progression free survival and overall survival in account, this review focuses to identify the most efficient antibody therapy in combination with chemotherapy (FOLFOX-4) in KRAS mutated colorectal cancer patients. The bevacizumab plus FOLFOX-4 therapy shows about 9.3 months and 8.7 months of progression free survival for KRAS wild and mutant type, respectively. The overall survival is about 34.8 months for wild type whereas for the mutant it is inconclusive for the same therapy. In comparison, panitumumab results in better progression-free survival which is about (9.6 months) and overall survival is about (23.9 months) for the wild type KRAS and the overall survival is about 15.5 months for the mutant KRAS . Cetuximab plus FOLFOX-4 therapy shows about 7.7 months and 5.5 months of progression-free survival for wild type KRAS and mutant type, respectively. Thus, panitumumab shows significant improvement in overall survival rate for wild type KRAS , validating as a cost effective therapeutic for colorectal cancer therapy. This review depicts that panitumumab along with FOLFOX-4 has a higher response in colorectal cancer patients than the either of the two monoclonal antibodies plus FOLFOX-4.

The Diet and Haemodialysis Dyad: Three Eras, Four Open Questions and Four Paradoxes. A Narrative Review, Towards a Personalized, Patient-Centered Approach

PubMed Central

Piccoli, Giorgina Barbara; Moio, Maria Rita; Fois, Antioco; Sofronie, Andreea; Gendrot, Lurlinys; Cabiddu, Gianfranca; D’Alessandro, Claudia; Cupisti, Adamasco

2017-01-01

The history of dialysis and diet can be viewed as a series of battles waged against potential threats to patients’ lives. In the early years of dialysis, potassium was identified as “the killer”, and the lists patients were given of forbidden foods included most plant-derived nourishment. As soon as dialysis became more efficient and survival increased, hyperphosphatemia, was identified as the enemy, generating an even longer list of banned aliments. Conversely, the “third era” finds us combating protein-energy wasting. This review discusses four questions and four paradoxes, regarding the diet-dialysis dyad: are the “magic numbers” of nutritional requirements (calories: 30–35 kcal/kg; proteins > 1.2 g/kg) still valid? Are the guidelines based on the metabolic needs of patients on “conventional” thrice-weekly bicarbonate dialysis applicable to different dialysis schedules, including daily dialysis or haemodiafiltration? The quantity of phosphate and potassium contained in processed and preserved foods may be significantly different from those in untreated foods: what are we eating? Is malnutrition one condition or a combination of conditions? The paradoxes: obesity is associated with higher survival in dialysis, losing weight is associated with mortality, but high BMI is a contraindication for kidney transplantation; it is difficult to limit phosphate intake when a patient is on a high-protein diet, such as the ones usually prescribed on dialysis; low serum albumin is associated with low dialysis efficiency and reduced survival, but on haemodiafiltration, high efficiency is coupled with albumin losses; banning plant derived food may limit consumption of “vascular healthy” food in a vulnerable population. Tailored approaches and agreed practices are needed so that we can identify attainable goals and pursue them in our fragile haemodialysis populations. PMID:28394304

Artificial intelligence: Neural network model as the multidisciplinary team member in clinical decision support to avoid medical mistakes.

PubMed

Buzaev, Igor Vyacheslavovich; Plechev, Vladimir Vyacheslavovich; Nikolaeva, Irina Evgenievna; Galimova, Rezida Maratovna

2016-09-01

The continuous uninterrupted feedback system is the essential part of any well-organized system. We propose aLYNX concept that is a possibility to use an artificial intelligence algorithm or a neural network model in decision-making system so as to avoid possible mistakes and to remind the doctors to review tactics once more in selected cases. aLYNX system includes: registry with significant factors, decisions and results; machine learning process based on this registry data; the use of the machine learning results as the adviser. We show a possibility to build a computer adviser with a neural network model for making a choice between coronary aortic bypass surgery (CABG) and percutaneous coronary intervention (PCI) in order to achieve a higher 5-year survival rate in patients with angina based on the experience of 5107 patients. The neural network was trained by 4679 patients who achieved 5-year survival. Among them, 2390 patients underwent PCI and 2289 CABG. After training, the correlation coefficient ( r ) of the network was 0.74 for training, 0.67 for validation, 0.71 for test and 0.73 for total. Simulation of the neural network function has been performed after training in the two groups of patients with known 5-year outcome. The disagreement rate was significantly higher in the dead patient group than that in the survivor group between neural network model and heart team [16.8% (787/4679) vs. 20.3% (87/428), P  = 0.065)]. The study shows the possibility to build a computer adviser with a neural network model for making a choice between CABG and PCI in order to achieve a higher 5-year survival rate in patients with angina.

[Current Possibilities for Predicting Responses to EGFR Blockade in Metastatic Colorectal Cancer].

PubMed

Němeček, R; Svoboda, M; Slabý, O

2016-01-01

The combination of modern systemic chemotherapy and anti-EGFR monoclonal antibodies improves overall survival and quality of life for patients with metastatic colorecal cancer. By contrast, the addition of anti-EGFR therapy to the treatment regime of resistant patients may lead to worse progression-free survival and overall survival. Therefore, identifying sensitive and resistant patients prior to targeted therapy of metastatic colorecal cancer is a key point during the initial decision making process. Previous research shows that primary resistance to EGFR blockade is in most cases caused by constitutive activation of signaling pathways downstream of EGFR. Of all relevant factors (mutation of KRAS, NRAS, BRAF, and PIK3CA oncogenes, inactivation of tumor suppressors PTEN and TP53, amplification of EGFR and HER2, and expression of epiregulin and amphiregulin, mikroRNA miR-31-3p, and miR-31-5p), only evaluation of KRAS and NRAS mutations has entered routine clinical practice. The role of the other markers still needs to be validated. The ongoing benefit of anti-EGFR therapy could be indicated by specific clinical parameters measured after the initiation of targeted therapy, including early tumor shrinkage, the deepness of the response, or hypomagnesemia. The accuracy of predictive dia-gnostic tools could be also increased by examining a combination of predictive markers using next generation sequencing methods. However, unjustified investigation of many molecular markers should be resisted as this may complicate interpretation of the results, particularly in terms of their specific clinical relevance. The aim of this review is to describe current possibilities with respect to predicting responses to EGFR blockade in the context of the EGFR pathway, and the utilization of such results in routine clinical practice.

Anatomy and Cranial Functional Morphology of the Small-Bodied Dinosaur Fruitadens haagarorum from the Upper Jurassic of the USA

PubMed Central

Butler, Richard J.; Porro, Laura B.; Galton, Peter M.; Chiappe, Luis M.

2012-01-01

Background Heterodontosaurids are an important but enigmatic and poorly understood early radiation of ornithischian dinosaurs. The late-surviving heterodontosaurid Fruitadens haagarorum from the Late Jurassic (early Tithonian) Morrison Formation of the western USA is represented by remains of several small (<1 metre total body length, <1 kg body mass) individuals that include well-preserved but incomplete cranial and postcranial material. Fruitadens is hypothesized to represent one of the smallest known ornithischian dinosaurs. Methodology/Principal Findings We describe the cranial and postcranial anatomy of Fruitadens in detail, providing comparisons to all other known heterodontosaurid taxa. High resolution micro-CT data provides new insights into tooth replacement and the internal anatomy of the tooth-bearing bones. Moreover, we provide a preliminary functional analysis of the skull of late-surviving heterodontosaurids, discuss the implications of Fruitadens for current understanding of heterodontosaurid monophyly, and briefly review the evolution and biogeography of heterodontosaurids. Conclusions/Significance The validity of Fruitadens is supported by multiple unique characters of the dentition and hindlimb as well as a distinct character combination. Fruitadens shares highly distinctive appendicular characters with other heterodontosaurids, strengthening monophyly of the clade on the basis of the postcranium. Mandibular morphology and muscle moment arms suggest that the jaws of late-surviving heterodontosaurids, including Fruitadens, were adapted for rapid biting at large gape angles, contrasting with the jaws of the stratigraphically older Heterodontosaurus, which were better suited for strong jaw adduction at small gapes. The lack of wear facets and plesiomorphic dentition suggest that Fruitadens used orthal jaw movements and employed simple puncture-crushing to process food. In combination with its small body size, these results suggest that Fruitadens was an ecological generalist, consuming select plant material and possibly insects or other invertebrates. PMID:22509242

The formula for survival in resuscitation.

PubMed

Søreide, Eldar; Morrison, Laurie; Hillman, Ken; Monsieurs, Koen; Sunde, Kjetil; Zideman, David; Eisenberg, Mickey; Sterz, Fritz; Nadkarni, Vinay M; Soar, Jasmeet; Nolan, Jerry P

2013-11-01

The International Liaison Committee on Resuscitation (ILCOR) Advisory Statement on Education and Resuscitation in 2003 included a hypothetical formula--'the formula for survival' (FfS)--whereby three interactive factors, guideline quality (science), efficient education of patient caregivers (education) and a well-functioning chain of survival at a local level (local implementation), form multiplicands in determining survival from resuscitation. In May 2006, a symposium was held to discuss the validity of the formula for survival hypothesis and to investigate the influence of each of the multiplicands on survival. This commentary combines the output from this symposium with an updated illustration of the three multiplicands in the FfS using rapid response systems (RRS) for medical science, therapeutic hypothermia (TH) for local implementation, and bystander cardiopulmonary resuscitation (CPR) for educational efficiency. International differences between hospital systems made it difficult to assign a precise value for the multiplicand medical science using RRS as an example. Using bystander CPR as an example for the multiplicand educational efficiency, it was also difficult to provide a precise value, mainly because of differences between compression-only and standard CPR. The local implementation multiplicand (exemplified by therapeutic hypothermia) is probably the easiest to improve, and is likely to have the most immediate improvement in observed survival outcome in most systems of care. Despite the noted weaknesses, we believe that the FfS will be useful as a mental framework when trying to improve resuscitation outcome in communities worldwide. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Modeling time-to-event (survival) data using classification tree analysis.

PubMed

Linden, Ariel; Yarnold, Paul R

2017-12-01

Time to the occurrence of an event is often studied in health research. Survival analysis differs from other designs in that follow-up times for individuals who do not experience the event by the end of the study (called censored) are accounted for in the analysis. Cox regression is the standard method for analysing censored data, but the assumptions required of these models are easily violated. In this paper, we introduce classification tree analysis (CTA) as a flexible alternative for modelling censored data. Classification tree analysis is a "decision-tree"-like classification model that provides parsimonious, transparent (ie, easy to visually display and interpret) decision rules that maximize predictive accuracy, derives exact P values via permutation tests, and evaluates model cross-generalizability. Using empirical data, we identify all statistically valid, reproducible, longitudinally consistent, and cross-generalizable CTA survival models and then compare their predictive accuracy to estimates derived via Cox regression and an unadjusted naïve model. Model performance is assessed using integrated Brier scores and a comparison between estimated survival curves. The Cox regression model best predicts average incidence of the outcome over time, whereas CTA survival models best predict either relatively high, or low, incidence of the outcome over time. Classification tree analysis survival models offer many advantages over Cox regression, such as explicit maximization of predictive accuracy, parsimony, statistical robustness, and transparency. Therefore, researchers interested in accurate prognoses and clear decision rules should consider developing models using the CTA-survival framework. © 2017 John Wiley & Sons, Ltd.

The Role of Structural Models in the Solar Sail Flight Validation Process

NASA Technical Reports Server (NTRS)

Johnston, John D.

2004-01-01

NASA is currently soliciting proposals via the New Millennium Program ST-9 opportunity for a potential Solar Sail Flight Validation (SSFV) experiment to develop and operate in space a deployable solar sail that can be steered and provides measurable acceleration. The approach planned for this experiment is to test and validate models and processes for solar sail design, fabrication, deployment, and flight. These models and processes would then be used to design, fabricate, and operate scaleable solar sails for future space science missions. There are six validation objectives planned for the ST9 SSFV experiment: 1) Validate solar sail design tools and fabrication methods; 2) Validate controlled deployment; 3) Validate in space structural characteristics (focus of poster); 4) Validate solar sail attitude control; 5) Validate solar sail thrust performance; 6) Characterize the sail's electromagnetic interaction with the space environment. This poster presents a top-level assessment of the role of structural models in the validation process for in-space structural characteristics.

Earth Science Enterprise Scientific Data Purchase Project: Verification and Validation

NASA Technical Reports Server (NTRS)

Jenner, Jeff; Policelli, Fritz; Fletcher, Rosea; Holecamp, Kara; Owen, Carolyn; Nicholson, Lamar; Dartez, Deanna

2000-01-01

This paper presents viewgraphs on the Earth Science Enterprise Scientific Data Purchase Project's verification,and validation process. The topics include: 1) What is Verification and Validation? 2) Why Verification and Validation? 3) Background; 4) ESE Data Purchas Validation Process; 5) Data Validation System and Ingest Queue; 6) Shipment Verification; 7) Tracking and Metrics; 8) Validation of Contract Specifications; 9) Earth Watch Data Validation; 10) Validation of Vertical Accuracy; and 11) Results of Vertical Accuracy Assessment.

Development of a numerical pump testing framework.

PubMed

Kaufmann, Tim A S; Gregory, Shaun D; Büsen, Martin R; Tansley, Geoff D; Steinseifer, Ulrich

2014-09-01

It has been shown that left ventricular assist devices (LVADs) increase the survival rate in end-stage heart failure patients. However, there is an ongoing demand for an increased quality of life, fewer adverse events, and more physiological devices. These challenges necessitate new approaches during the design process. In this study, computational fluid dynamics (CFD), lumped parameter (LP) modeling, mock circulatory loops (MCLs), and particle image velocimetry (PIV) are combined to develop a numerical Pump Testing Framework (nPTF) capable of analyzing local flow patterns and the systemic response of LVADs. The nPTF was created by connecting a CFD model of the aortic arch, including an LVAD outflow graft to an LP model of the circulatory system. Based on the same geometry, a three-dimensional silicone model was crafted using rapid prototyping and connected to an MCL. PIV studies of this setup were performed to validate the local flow fields (PIV) and the systemic response (MCL) of the nPTF. After validation, different outflow graft positions were compared using the nPTF. Both the numerical and the experimental setup were able to generate physiological responses by adjusting resistances and systemic compliance, with mean aortic pressures of 72.2-132.6 mm Hg for rotational speeds of 2200-3050 rpm. During LVAD support, an average flow to the distal branches (cerebral and subclavian) of 24% was found in the experiments and the nPTF. The flow fields from PIV and CFD were in good agreement. Numerical and experimental tools were combined to develop and validate the nPTF, which can be used to analyze local flow fields and the systemic response of LVADs during the design process. This allows analysis of physiological control parameters at early development stages and may, therefore, help to improve patient outcomes. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Forgotten but not gone: Retro-cue costs and benefits in a double-cueing paradigm suggest multiple states in visual short-term memory.

PubMed

van Moorselaar, Dirk; Olivers, Christian N L; Theeuwes, Jan; Lamme, Victor A F; Sligte, Ilja G

2015-11-01

Visual short-term memory (VSTM) performance is enhanced when the to-be-tested item is cued after encoding. This so-called retro-cue benefit is typically accompanied by a cost for the noncued items, suggesting that information is lost from VSTM upon presentation of a retrospective cue. Here we assessed whether noncued items can be restored to VSTM when made relevant again by a subsequent second cue. We presented either 1 or 2 consecutive retro-cues (80% valid) during the retention interval of a change-detection task. Relative to no cue, a valid cue increased VSTM capacity by 2 items, while an invalid cue decreased capacity by 2. Importantly, when a second, valid cue followed an invalid cue, capacity regained 2 items, so that performance was back on par. In addition, when the second cue was also invalid, there was no extra loss of information from VSTM, suggesting that those items that survived a first invalid cue, automatically also survived a second. We conclude that these results are in support of a very versatile VSTM system, in which memoranda adopt different representational states depending on whether they are deemed relevant now, in the future, or not at all. We discuss a neural model that is consistent with this conclusion. (c) 2015 APA, all rights reserved).

The influence of printing parameters on cell survival rate and printability in microextrusion-based 3D cell printing technology.

PubMed

Zhao, Yu; Li, Yang; Mao, Shuangshuang; Sun, Wei; Yao, Rui

2015-11-02

Three-dimensional (3D) cell printing technology has provided a versatile methodology to fabricate cell-laden tissue-like constructs and in vitro tissue/pathological models for tissue engineering, drug testing and screening applications. However, it still remains a challenge to print bioinks with high viscoelasticity to achieve long-term stable structure and maintain high cell survival rate after printing at the same time. In this study, we systematically investigated the influence of 3D cell printing parameters, i.e. composition and concentration of bioink, holding temperature and holding time, on the printability and cell survival rate in microextrusion-based 3D cell printing technology. Rheological measurements were utilized to characterize the viscoelasticity of gelatin-based bioinks. Results demonstrated that the bioink viscoelasticity was increased when increasing the bioink concentration, increasing holding time and decreasing holding temperature below gelation temperature. The decline of cell survival rate after 3D cell printing process was observed when increasing the viscoelasticity of the gelatin-based bioinks. However, different process parameter combinations would result in the similar rheological characteristics and thus showed similar cell survival rate after 3D bioprinting process. On the other hand, bioink viscoelasticity should also reach a certain point to ensure good printability and shape fidelity. At last, we proposed a protocol for 3D bioprinting of temperature-sensitive gelatin-based hydrogel bioinks with both high cell survival rate and good printability. This research would be useful for biofabrication researchers to adjust the 3D bioprinting process parameters quickly and as a referable template for designing new bioinks.

[Computerized system validation of clinical researches].

PubMed

Yan, Charles; Chen, Feng; Xia, Jia-lai; Zheng, Qing-shan; Liu, Daniel

2015-11-01

Validation is a documented process that provides a high degree of assurance. The computer system does exactly and consistently what it is designed to do in a controlled manner throughout the life. The validation process begins with the system proposal/requirements definition, and continues application and maintenance until system retirement and retention of the e-records based on regulatory rules. The objective to do so is to clearly specify that each application of information technology fulfills its purpose. The computer system validation (CSV) is essential in clinical studies according to the GCP standard, meeting product's pre-determined attributes of the specifications, quality, safety and traceability. This paper describes how to perform the validation process and determine relevant stakeholders within an organization in the light of validation SOPs. Although a specific accountability in the implementation of the validation process might be outsourced, the ultimate responsibility of the CSV remains on the shoulder of the business process owner-sponsor. In order to show that the compliance of the system validation has been properly attained, it is essential to set up comprehensive validation procedures and maintain adequate documentations as well as training records. Quality of the system validation should be controlled using both QC and QA means.

On the validity of time-dependent AUC estimators.

PubMed

Schmid, Matthias; Kestler, Hans A; Potapov, Sergej

2015-01-01

Recent developments in molecular biology have led to the massive discovery of new marker candidates for the prediction of patient survival. To evaluate the predictive value of these markers, statistical tools for measuring the performance of survival models are needed. We consider estimators of discrimination measures, which are a popular approach to evaluate survival predictions in biomarker studies. Estimators of discrimination measures are usually based on regularity assumptions such as the proportional hazards assumption. Based on two sets of molecular data and a simulation study, we show that violations of the regularity assumptions may lead to over-optimistic estimates of prediction accuracy and may therefore result in biased conclusions regarding the clinical utility of new biomarkers. In particular, we demonstrate that biased medical decision making is possible even if statistical checks indicate that all regularity assumptions are satisfied. © The Author 2013. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression

PubMed Central

2012-01-01

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

Combination vinblastine, prednisolone and toceranib phosphate for treatment of grade II and III mast cell tumours in dogs.

PubMed

Olsen, Jaime A; Thomson, Maurine; O'Connell, Kathleen; Wyatt, Ken

2018-05-24

This retrospective study evaluates the progression-free interval and survival outcomes of 40 canine (Canis familiaris) patients with Patnaik grade II and III mast cell tumours treated with combination vinblastine, prednisolone and toceranib phosphate from 2011 to 2015. Patients were subdivided into three groups; patients who received neoadjuvant therapy for poorly operable lesions, patients who received adjuvant therapy following surgical resection and patients being palliated for gross metastatic disease. Median survival time (MST) for the neoadjuvant group was not reached. Median survival time for the remaining groups was 893 days and 218 days, respectively. This combination demonstrated response in 90% (26/29) patients with measurable disease. The predominant side effects related to this chemotherapy combination were gastrointestinal in origin. Further prospective studies are required to further validate the efficacy of this treatment protocol. © 2018 The Authors Veterinary Medicine and Science Published by John Wiley & Sons Ltd.

Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas.

PubMed

Mo, Qianxing; Nikolos, Fotis; Chen, Fengju; Tramel, Zoe; Lee, Yu-Cheng; Hayashi, Kazukuni; Xiao, Jing; Shen, Jianjun; Chan, Keith Syson

2018-05-01

Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide. Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome. Non-MIBCs (NMIBCs) generally have favorable outcome; however, a portion progress to MIBC. Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas. Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome. The current study extrapolates this conventional wisdom and combines it with molecular profiling. We developed an 18-gene signature that molecularly defines urothelial cellular differentiation, thus classifying MIBCs and NMIBCs into two subgroups: basal and differentiated. We evaluated the prognostic capability of this "tumor differentiation signature" and three other existing gene signatures including the The Cancer Genome Atlas (TCGA; 2707 genes), MD Anderson Cancer Center (MDA; 2252 genes/2697 probes), and University of North Carolina at Chapel Hill (UNC; 47 genes) using five gene expression data sets derived from MIBC and NMIBC patients. All statistical tests were two-sided. The tumor differentiation signature demonstrated consistency and statistical robustness toward stratifying MIBC patients into different overall survival outcomes (TCGA cohort 1, P = .03; MDA discovery, P = .009; MDA validation, P = .01), while the other signatures were not as consistent. In addition, we analyzed the progression (Ta/T1 progressing to ≥T2) probability of NMIBCs. NMIBC patients with a basal tumor differentiation signature associated with worse progression outcome (P = .008). Gene functional term enrichment and gene set enrichment analyses revealed that genes involved in the biologic process of immune response and inflammatory response are among the most elevated within basal bladder cancers, implicating them as candidates for immune checkpoint therapies. These results provide definitive evidence that a biology-prioritizing clustering methodology generates meaningful insights into patient stratification and reveals targetable molecular pathways to impact future therapeutic approach.

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

Code of Federal Regulations, 2011 CFR

2011-01-01

... vaccine. For a valid test, at least 80 percent of the embryos shall survive for 48 hours post-inoculation... requirements prescribed in this section. Any serial found unsatisfactory by a prescribed test shall not be released. (a) Safety tests. (1) The prechallenge part of the potency test prescribed in paragraph (b) of...

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

Code of Federal Regulations, 2010 CFR

2010-01-01

... vaccine. For a valid test, at least 80 percent of the embryos shall survive for 48 hours post-inoculation... requirements prescribed in this section. Any serial found unsatisfactory by a prescribed test shall not be released. (a) Safety tests. (1) The prechallenge part of the potency test prescribed in paragraph (b) of...

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

Code of Federal Regulations, 2012 CFR

2012-01-01

... vaccine. For a valid test, at least 80 percent of the embryos shall survive for 48 hours post-inoculation... requirements prescribed in this section. Any serial found unsatisfactory by a prescribed test shall not be released. (a) Safety tests. (1) The prechallenge part of the potency test prescribed in paragraph (b) of...

Evaluation of habitat suitability models for forest passerines using demographic data

Treesearch

Chadwick D. Rittenhouse; Frank R., III Thompson; William D. Dijak; Joshua J. Millspaugh; Richard L. Clawson

2010-01-01

Habitat suitability is often used as a surrogate for demographic responses (i.e., abundance, survival, fecundity, or population viability) in the application of habitat suitability index (HSI) models. Whether habitat suitability actually relates to demographics, however, has rarely been evaluated. We validated HSI models of breeding habitat suitability for wood thrush...

Validation of a 30-year-old process for the manufacture of L-asparaginase from Erwinia chrysanthemi.

PubMed

Gervais, David; Allison, Nigel; Jennings, Alan; Jones, Shane; Marks, Trevor

2013-04-01

A 30-year-old manufacturing process for the biologic product L-asparaginase from the plant pathogen Erwinia chrysanthemi was rigorously qualified and validated, with a high level of agreement between validation data and the 6-year process database. L-Asparaginase exists in its native state as a tetrameric protein and is used as a chemotherapeutic agent in the treatment regimen for Acute Lymphoblastic Leukaemia (ALL). The manufacturing process involves fermentation of the production organism, extraction and purification of the L-asparaginase to make drug substance (DS), and finally formulation and lyophilisation to generate drug product (DP). The extensive manufacturing experience with the product was used to establish ranges for all process parameters and product quality attributes. The product and in-process intermediates were rigorously characterised, and new assays, such as size-exclusion and reversed-phase UPLC, were developed, validated, and used to analyse several pre-validation batches. Finally, three prospective process validation batches were manufactured and product quality data generated using both the existing and the new analytical methods. These data demonstrated the process to be robust, highly reproducible and consistent, and the validation was successful, contributing to the granting of an FDA product license in November, 2011.

Red blood cells as modulators of T cell growth and survival.

PubMed

Arosa, Fernando A; Pereira, Carlos F; Fonseca, Ana M

2004-01-01

T cell homeostasis is largely controlled by a balance between cell death and survival and anomalies in either process account for a number of diseases linked to excessive or faulty T cell growth. Yet, the influence that cells outside the immunological system have on these processes has only recently received attention. Accumulated evidence indicate that homeostasis of the CD4+ and CD8+ T cell pools is highly dynamic and regulated by signals delivered by cells and molecules present in the different internal microenvironments. The major function of red blood cells (RBC) is generally considered to be oxygen and carbon dioxide transport. In recent years, however, RBC have been implicated in the regulation of basic physiological processes, from vascular contraction and platelet aggregation to T cell growth and survival. Regulation of T cell survival by RBC may influence the response of selected subsets of T cells to internal or external stimuli and may help explaining the immunomodulatory activities of red blood cells. By interfering in the balance between death and survival RBC become potential tools that can be manipulated to improve or reverse pathological situations characterized by anomalies in the control of T cell growth.

Prognostic significance of hemoglobin level in patients with congestive heart failure and normal ejection fraction.

PubMed

Varadarajan, Padmini; Gandhi, Siddharth; Sharma, Sanjay; Umakanthan, Branavan; Pai, Ramdas G

2006-10-01

Previous studies have shown low hemoglobin (Hb) to have an adverse effect on survival in patients with congestive heart failure (CHF) and reduced left ventricular (LV) ejection fraction (EF); but its effect on survival in patients with CHF and normal EF is not known. This study sought to determine whether low Hb has an effect on survival in patients with both CHF and normal EF. Detailed chart reviews were performed by medical residents on 2,246 patients (48% with normal EF) with a discharge diagnosis of CHF in a large tertiary care hospital from 1990 to 1999. The CHF diagnosis was validated using the Framingham criteria. Mortality data were obtained from the National Death Index. Survival analysis was performed using Kaplan-Meier and Cox regression models. By Kaplan-Meier analysis, low Hb (< 12 gm/dl) compared with normal hemoglobin was associated with a lower 5-year survival in patients with CHF and both normal (38 vs. 50%, p = 0.0008) and reduced (35 vs. 48%, p = 0.0009) EF. Using the Cox regression model, low Hb was an independent predictor of mortality after adjusting for age, gender, renal dysfunction, diabetes mellitus, hypertension, and EF in both groups of patients. Low Hb has an independent adverse effect on survival in patients with CHF and both normal and reduced EF in both groups of patients.

Rethinking the advantage of zero-HLA mismatches in unrelated living donor kidney transplantation: implications on kidney paired donation.

PubMed

Casey, Michael Jin; Wen, Xuerong; Rehman, Shehzad; Santos, Alfonso H; Andreoni, Kenneth A

2015-04-01

The OPTN/UNOS Kidney Paired Donation (KPD) Pilot Program allocates priority to zero-HLA mismatches. However, in unrelated living donor kidney transplants (LDKT)-the same donor source in KPD-no study has shown whether zero-HLA mismatches provide any advantage over >0 HLA mismatches. We hypothesize that zero-HLA mismatches among unrelated LDKT do not benefit graft survival. This retrospective SRTR database study analyzed LDKT recipients from 1987 to 2012. Among unrelated LDKT, subjects with zero-HLA mismatches were compared to a 1:1-5 matched (by donor age ±1 year and year of transplantation) control cohort with >0 HLA mismatches. The primary endpoint was death-censored graft survival. Among 32,654 unrelated LDKT recipients, 83 had zero-HLA mismatches and were matched to 407 controls with >0 HLA mismatches. Kaplan-Meier analyses for death-censored graft and patient survival showed no difference between study and control cohorts. In multivariate marginal Cox models, zero-HLA mismatches saw no benefit with death-censored graft survival (HR = 1.46, 95% CI 0.78-2.73) or patient survival (HR = 1.43, 95% CI 0.68-3.01). Our data suggest that in unrelated LDKT, zero-HLA mismatches may not offer any survival advantage. Therefore, particular study of zero-HLA mismatching is needed to validate its place in the OPTN/UNOS KPD Pilot Program allocation algorithm. © 2014 Steunstichting ESOT.

Impact of age on the survival of patients with liver cancer: an analysis of 27,255 patients in the SEER database.

PubMed

Zhang, Wenjie; Sun, Beicheng

2015-01-20

The risk of liver cancer (LC) is regarded as age dependent. However, the influence of age on its prognosis is controversial. The aim of our study was to compare the long-term survival of younger versus older patients with LC. In this retrospective study, we searched Surveillance, Epidemiology, and End-RESULTS (SEER) population-based data and identified 27,255 patients diagnosed with LC between 1988 and 2003. These patients were categorized into younger (45 years and under) and older age (over 45 years of age) groups. Five-year cancer specific survival data was obtained. Kaplan-Meier methods and multivariable Cox regression models were used to analyze long-term survival outcomes and risk factors. There were significant differences between groups with regards to pathologic grading, histologic type, stage, and tumor size (p < 0.001). The 5-year liver cancer specific survival (LCSS) rates in the younger and older age groups were 14.5% and 8.4%, respectively (p < 0.001 by univariate and multivariate analysis). A stratified analysis of age on cancer survival showed only localized and regional stages to be validated as independent predictors, but not for advanced stages. Compared to older patients, younger patients with LC have a higher LCSS after surgery, despite the poorer biological behavior of this carcinoma.

Parametric Model Based On Imputations Techniques for Partly Interval Censored Data

NASA Astrophysics Data System (ADS)

Zyoud, Abdallah; Elfaki, F. A. M.; Hrairi, Meftah

2017-12-01

The term ‘survival analysis’ has been used in a broad sense to describe collection of statistical procedures for data analysis. In this case, outcome variable of interest is time until an event occurs where the time to failure of a specific experimental unit might be censored which can be right, left, interval, and Partly Interval Censored data (PIC). In this paper, analysis of this model was conducted based on parametric Cox model via PIC data. Moreover, several imputation techniques were used, which are: midpoint, left & right point, random, mean, and median. Maximum likelihood estimate was considered to obtain the estimated survival function. These estimations were then compared with the existing model, such as: Turnbull and Cox model based on clinical trial data (breast cancer data), for which it showed the validity of the proposed model. Result of data set indicated that the parametric of Cox model proved to be more superior in terms of estimation of survival functions, likelihood ratio tests, and their P-values. Moreover, based on imputation techniques; the midpoint, random, mean, and median showed better results with respect to the estimation of survival function.

Semiparametric temporal process regression of survival-out-of-hospital.

PubMed

Zhan, Tianyu; Schaubel, Douglas E

2018-05-23

The recurrent/terminal event data structure has undergone considerable methodological development in the last 10-15 years. An example of the data structure that has arisen with increasing frequency involves the recurrent event being hospitalization and the terminal event being death. We consider the response Survival-Out-of-Hospital, defined as a temporal process (indicator function) taking the value 1 when the subject is currently alive and not hospitalized, and 0 otherwise. Survival-Out-of-Hospital is a useful alternative strategy for the analysis of hospitalization/survival in the chronic disease setting, with the response variate representing a refinement to survival time through the incorporation of an objective quality-of-life component. The semiparametric model we consider assumes multiplicative covariate effects and leaves unspecified the baseline probability of being alive-and-out-of-hospital. Using zero-mean estimating equations, the proposed regression parameter estimator can be computed without estimating the unspecified baseline probability process, although baseline probabilities can subsequently be estimated for any time point within the support of the censoring distribution. We demonstrate that the regression parameter estimator is asymptotically normal, and that the baseline probability function estimator converges to a Gaussian process. Simulation studies are performed to show that our estimating procedures have satisfactory finite sample performances. The proposed methods are applied to the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international end-stage renal disease study.

Tinkering with the tinkerer: pollution versus evolution.

PubMed Central

Fox, G A

1995-01-01

Pollutants can act as powerful selective forces by altering genetic variability, its intergenerational transfer, and the size, functional viability, adaptability, and survival of future generations. It is at the level of the cell and the individual that meiosis occurs, that genetic diversity is maintained, and behavior, reproduction, growth, and survival occur and are regulated. It is at this level that evolutionary processes occur and most pollutants exert their toxic effects. Chronic exposure to chemicals contributes to the cumulative stress on individuals and disrupts physiological processes and chemically mediated communication thereby threatening the diversity and long-term survival of sexually reproducing biota. Regional or global effects of pollution on the atmosphere, hydrosphere, and lithosphere have indirectly altered Earth's life-support systems, thereby modifying trace metal balance, reproduction, and incidence of UV-B-induced DNA damage in biota. By altering the competitive ability and survival of species, chemical pollutants potentially threaten evolutionary processes and the biodiversity and function of intercepting ecosystems. PMID:7556031

Experimentally induced anhydrobiosis in the tardigrade Richtersius coronifer: phenotypic factors affecting survival.

PubMed

Jönsson, K Ingemar; Rebecchi, Lorena

2002-11-01

The ability of some animal taxa (e.g., nematodes, rotifers, and tardigrades) to enter an ametabolic (cryptobiotic) state is well known. Nevertheless, the phenotypic factors affecting successful anhydrobiosis have rarely been investigated. We report a laboratory study on the effects of body size, reproductive condition, and energetic condition on anhydrobiotic survival in a population of the eutardigrade Richtersius coronifer. Body size and energetic condition interacted in affecting the probability of survival, while reproductive condition had no effect. Large tardigrades had a lower probability of survival than medium-sized tardigrades and showed a positive response in survival to energetic condition. This suggests that energy constrained the possibility for large tardigrades to enter and to leave anhydrobiosis. As a possible alternative explanation for low survival in the largest specimens we discuss the expression of senescence. In line with the view that processes related to anhydrobiosis are connected with energetic costs we documented a decrease in the size of storage cells over a period of anhydrobiosis, showing for the first time that energy is consumed in the process of anhydrobiosis in tardigrades. Copyright 2002 Wiley-Liss, Inc.

Survival and germination of Mediterranean grassland species after simulated sheep ingestion: ecological correlates with seed traits

NASA Astrophysics Data System (ADS)

Peco, B.; Lopez-Merino, L.; Alvir, M.

2006-09-01

Large amounts of viable seeds from Mediterranean grassland species have been found in herbivore dung; however which species produce seeds that can survive and germinate after ingestion by herbivores is still not well understood. This paper evaluates the importance of seed size, shape and coat impermeability in the endozoochorous dispersal process of 20 abundant species from central Iberian rangelands. Seed survival, germination percentages and germination speed were analysed in controlled experiments on the chewing and gut passage process by inserting seeds in the rumen of fistulated sheep, followed by simulated acid-pepsin digestion. Higher germination percentages in the control than the simulated sheep ingestion treatment were found in 75% of seeds. All species showed lower survival following the treatment, two species had a higher germination speed and five had a lower rate. Large-seeded species generally had higher survival percentages than small-seeded species. Species with impermeable seed coats had higher germination percentages following treatment although no significant differences were noted for either seed survival or germination speed.

Recommendations for elaboration, transcultural adaptation and validation process of tests in Speech, Hearing and Language Pathology.

PubMed

Pernambuco, Leandro; Espelt, Albert; Magalhães, Hipólito Virgílio; Lima, Kenio Costa de

2017-06-08

to present a guide with recommendations for translation, adaptation, elaboration and process of validation of tests in Speech and Language Pathology. the recommendations were based on international guidelines with a focus on the elaboration, translation, cross-cultural adaptation and validation process of tests. the recommendations were grouped into two Charts, one of them with procedures for translation and transcultural adaptation and the other for obtaining evidence of validity, reliability and measures of accuracy of the tests. a guide with norms for the organization and systematization of the process of elaboration, translation, cross-cultural adaptation and validation process of tests in Speech and Language Pathology was created.

Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.

PubMed

Press, Michael F; Sauter, Guido; Buyse, Marc; Bernstein, Leslie; Guzman, Roberta; Santiago, Angela; Villalobos, Ivonne E; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Bee, Valerie; Taupin, Henry; Flom, Kerry J; Tabah-Fisch, Isabelle; Pauletti, Giovanni; Lindsay, Mary-Ann; Riva, Alessandro; Slamon, Dennis J

2011-03-01

Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers. A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined. Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification. In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought.

Alteration of Topoisomerase II–Alpha Gene in Human Breast Cancer: Association With Responsiveness to Anthracycline-Based Chemotherapy

PubMed Central

Press, Michael F.; Sauter, Guido; Buyse, Marc; Bernstein, Leslie; Guzman, Roberta; Santiago, Angela; Villalobos, Ivonne E.; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Bee, Valerie; Taupin, Henry; Flom, Kerry J.; Tabah-Fisch, Isabelle; Pauletti, Giovanni; Lindsay, Mary-Ann; Riva, Alessandro; Slamon, Dennis J.

2011-01-01

Purpose Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers. Methods A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined. Results Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification. Conclusion In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought. PMID:21189395

Validation of the Risk Prediction Models STATE-Score and START-Strategy to Guide TACE Treatment in Patients with Hepatocellular Carcinoma.

PubMed

Mähringer-Kunz, Aline; Kloeckner, Roman; Pitton, Michael B; Düber, Christoph; Schmidtmann, Irene; Galle, Peter R; Koch, Sandra; Weinmann, Arndt

2017-07-01

Several scoring systems that guide patients' treatment regimen for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) have been introduced, but none have gained widespread acceptance in clinical practice. The purpose of this study is to externally validate the Selection for TrAnsarterial chemoembolization TrEatment (STATE)-score and START-strategy [i.e., sequential use of the STATE-score and Assessment for Retreatment with TACE (ART)-score]. From January 2000 to September 2015, 933 patients with HCC underwent TACE at our institution. All variables needed to calculate the STATE-score and implement the START-strategy were determined. STATE comprised serum albumin, up-to-seven criteria, and C-reactive protein (CRP). ART comprised an increase in aspartate aminotransferase, the Child-Pugh score, and a radiological tumor response. Overall survival was calculated, and multivariate analysis performed. In addition, the STATE-score and START-strategy were validated using the Harrell's C-index and integrated Brier score (IBS). The STATE-score was calculated in 228 patients. Low and high STATE-scores corresponded to median survival of 14.3 and 20.2 months, respectively. Harrell's C was 0.558 and IBS 0.133. For the STATE-score, significant predictors of survival were up-to-seven criteria (p = 0.006) and albumin (p = 0.022). CRP values were not predictive (p = 0.367). The ART-score was calculated in 207 patients. Combining the STATE-score and ART-score led to a Harrell's C of 0.580 and IBS of 0.132. The STATE-score was unable to reliably determine the suitability for initial TACE. The START-strategy only slightly improved the predictive ability compared to the ART-score alone. Therefore, neither the STATE-score nor START-strategy alone provides sufficient certainty for clear-cut clinical decisions.

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

PubMed

Suenaga, Mitsukuni; Schirripa, Marta; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Cremolini, Chiara; Antoniotti, Carlotta; Borelli, Beatrice; Mashima, Tetsuo; Okazaki, Satoshi; Berger, Martin D; Miyamoto, Yuji; Gopez, Roel; Barzi, Afsaneh; Lonardi, Sara; Yamaguchi, Toshiharu; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

2018-06-01

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy

PubMed Central

Cardesa-Salzmann, Teresa M.; Colomo, Luis; Gutierrez, Gonzalo; Chan, Wing C.; Weisenburger, Dennis; Climent, Fina; González-Barca, Eva; Mercadal, Santiago; Arenillas, Leonor; Serrano, Sergio; Tubbs, Ray; Delabie, Jan; Gascoyne, Randy D.; Connors, Joseph M; Mate, Jose L.; Rimsza, Lisa; Braziel, Rita; Rosenwald, Andreas; Lenz, Georg; Wright, George; Jaffe, Elaine S.; Staudt, Louis; Jares, Pedro; López-Guillermo, Armando; Campo, Elias

2011-01-01

Background Diffuse large B-cell lymphoma is a clinically and molecularly heterogeneous disease. Gene expression profiling studies have shown that the tumor microenvironment affects survival and that the angiogenesis-related signature is prognostically unfavorable. The contribution of histopathological microvessel density to survival in diffuse large B-cell lymphomas treated with immunochemotherapy remains unknown. The purpose of this study is to assess the prognostic impact of histopathological microvessel density in two independent series of patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Design and Methods One hundred and forty-seven patients from the Leukemia Lymphoma Molecular Profiling Project (training series) and 118 patients from the Catalan Lymphoma-Study group-GELCAB (validation cohort) were included in the study. Microvessels were immunostained with CD31 and quantified with a computerized image analysis system. The stromal scores previously defined in 110 Leukemia Lymphoma Molecular Profiling Project cases were used to analyze correlations with microvessel density data. Results Microvessel density significantly correlated with the stromal score (r=0.3209; P<0.001). Patients with high microvessel density showed significantly poorer overall survival than those with low microvessel density both in the training series (4-year OS 54% vs. 78%; P=0.004) and in the validation cohort (57% vs. 81%; P=0.006). In multivariate analysis, in both groups high microvessel density was a statistically significant unfavorable prognostic factor independent of international prognostic index [training series: international prognostic index (relative risk 2.7; P=0.003); microvessel density (relative risk 1.96; P=0.002); validation cohort: international prognostic index (relative risk 4.74; P<0.001); microvessel density (relative risk 2.4; P=0.016)]. Conclusions These findings highlight the impact of angiogenesis in the outcome of patients with diffuse large B-cell lymphoma and the interest of evaluating antiangiogenic drugs in clinical trials. PMID:21546504

Multi-objective evolutionary algorithms for fuzzy classification in survival prediction.

PubMed

Jiménez, Fernando; Sánchez, Gracia; Juárez, José M

2014-03-01

This paper presents a novel rule-based fuzzy classification methodology for survival/mortality prediction in severe burnt patients. Due to the ethical aspects involved in this medical scenario, physicians tend not to accept a computer-based evaluation unless they understand why and how such a recommendation is given. Therefore, any fuzzy classifier model must be both accurate and interpretable. The proposed methodology is a three-step process: (1) multi-objective constrained optimization of a patient's data set, using Pareto-based elitist multi-objective evolutionary algorithms to maximize accuracy and minimize the complexity (number of rules) of classifiers, subject to interpretability constraints; this step produces a set of alternative (Pareto) classifiers; (2) linguistic labeling, which assigns a linguistic label to each fuzzy set of the classifiers; this step is essential to the interpretability of the classifiers; (3) decision making, whereby a classifier is chosen, if it is satisfactory, according to the preferences of the decision maker. If no classifier is satisfactory for the decision maker, the process starts again in step (1) with a different input parameter set. The performance of three multi-objective evolutionary algorithms, niched pre-selection multi-objective algorithm, elitist Pareto-based multi-objective evolutionary algorithm for diversity reinforcement (ENORA) and the non-dominated sorting genetic algorithm (NSGA-II), was tested using a patient's data set from an intensive care burn unit and a standard machine learning data set from an standard machine learning repository. The results are compared using the hypervolume multi-objective metric. Besides, the results have been compared with other non-evolutionary techniques and validated with a multi-objective cross-validation technique. Our proposal improves the classification rate obtained by other non-evolutionary techniques (decision trees, artificial neural networks, Naive Bayes, and case-based reasoning) obtaining with ENORA a classification rate of 0.9298, specificity of 0.9385, and sensitivity of 0.9364, with 14.2 interpretable fuzzy rules on average. Our proposal improves the accuracy and interpretability of the classifiers, compared with other non-evolutionary techniques. We also conclude that ENORA outperforms niched pre-selection and NSGA-II algorithms. Moreover, given that our multi-objective evolutionary methodology is non-combinational based on real parameter optimization, the time cost is significantly reduced compared with other evolutionary approaches existing in literature based on combinational optimization. Copyright © 2014 Elsevier B.V. All rights reserved.

Investigating the effect of invasion characteristics on onion thrips (Thysanoptera: Thripidae) populations in onions with a temperature-driven process model.

PubMed

Mo, Jianhua; Stevens, Mark; Liu, De Li; Herron, Grant

2009-12-01

A temperature-driven process model was developed to describe the seasonal patterns of populations of onion thrips, Thrips tabaci Lindeman, in onions. The model used daily cohorts (individuals of the same developmental stage and daily age) as the population unit. Stage transitions were modeled as a logistic function of accumulated degree-days to account for variability in development rate among individuals. Daily survival was modeled as a logistic function of daily mean temperature. Parameters for development, survival, and fecundity were estimated from published data. A single invasion event was used to initiate the population process, starting at 1-100 d after onion emergence (DAE) for 10-100 d at the daily rate of 0.001-0.9 adults/plant/d. The model was validated against five observed seasonal patterns of onion thrips populations from two unsprayed sites in the Riverina, New South Wales, Australia, during 2003-2006. Performance of the model was measured by a fit index based on the proportion of variations in observed data explained by the model (R (2)) and the differences in total thrips-days between observed and predicted populations. Satisfactory matching between simulated and observed seasonal patterns was obtained within the ranges of invasion parameters tested. Model best-fit was obtained at invasion starting dates of 6-98 DAE with a daily invasion rate of 0.002-0.2 adults/plant/d and an invasion duration of 30-100 d. Under the best-fit invasion scenarios, the model closely reproduced the observed seasonal patterns, explaining 73-95% of variability in adult and larval densities during population increase periods. The results showed that small invasions of adult thrips followed by a gradual population build-up of thrips within onion crops were sufficient to bring about the observed seasonal patterns of onion thrips populations in onion. Implications of the model on timing of chemical controls are discussed.

Validation of gamma irradiator controls for quality and regulatory compliance

NASA Astrophysics Data System (ADS)

Harding, Rorry B.; Pinteric, Francis J. A.

1995-09-01

Since 1978 the U.S. Food and Drug Administration (FDA) has had both the legal authority and the Current Good Manufacturing Practice (CGMP) regulations in place to require irradiator owners who process medical devices to produce evidence of Irradiation Process Validation. One of the key components of Irradiation Process Validation is the validation of the irradiator controls. However, it is only recently that FDA audits have focused on this component of the process validation. What is Irradiator Control System Validation? What constitutes evidence of control? How do owners obtain evidence? What is the irradiator supplier's role in validation? How does the ISO 9000 Quality Standard relate to the FDA's CGMP requirement for evidence of Control System Validation? This paper presents answers to these questions based on the recent experiences of Nordion's engineering and product management staff who have worked with several US-based irradiator owners. This topic — Validation of Irradiator Controls — is a significant regulatory compliance and operations issue within the irradiator suppliers' and users' community.

A novel challenge test incorporating irradiation (60Co) of compost sub-samples to validate thermal lethality towards pathogenic bacteria.

PubMed

Moore, John E; Watabe, Miyuki; Stewart, Andrew; Cherie Millar, B; Rao, Juluri R

2009-01-01

Maturing compost heaps normally attaining temperatures ranging from 55 to 65 degrees C is generally regarded to conform to recommended biological risks and sanitation standards for composts stipulated by either EU or US-EPA. Composted products derived from animal sources are further required by EU biohazard safety regulatory legislation that such composts either attain 70 degrees C for over 3h during maturation or via treatment at 70 degrees C for 1h before being considered for dispensation on land. The setting of the upper limit of thermal lethality at 70 degrees C/1h for achieving biosecurity of the animal waste composted products (e.g. pelleted fertilizer formulations) is not properly substantiated by specific validation tests, comprising a 'wipe-out' step (usually via autoclaving) followed by inoculation of a prescribed bacterium, exposure to 70 degrees C/1h and the lethality determined. Pelleted formulations of composts are not amenable for wet methods (autoclaving) for wipe-out sterilization step as this is detrimental to the pellet and compromises sample integrity. This study describes a laboratory method involving the employment of ((60)Co) irradiation 'wipe-out' step to: (a) compost sub-samples drawn from compost formulation heaps and (b) pelleted products derived from composted animal products while determining the thermal lethality of a given time/temperature (70 degrees C/1h) treatment process and by challenging the irradiated sample (not just with one bacterium but), out with 10 potential food-poisoning organisms from the bacterial genera (Campylobacter, Escherichia, Listeria, Salmonella, Yersinia) frequently detected in pig and poultry farm wastes. This challenge test on compost sub-samples can be a useful intervention ploy for 'inspection and validation' technique for composters during the compost maturity process, whose attainment of temperatures of 55-65 degrees C is presumed sufficient for attainment of sanitation. Stringent measures are further required by law for composted products arising from rural industrialists producing pelleted fertilizers from re-composted animal agriculture wastes comprising pig slurry solids, poultry litter and spent mushroom compost, which carry residual food-borne pathogens with implications to the food chain including humans. Environmentally, sustainable means of recycling farm wastes require that final composted products are free of pathogens in compliance with environmental safety legislation before their release to the market. This test developed provides a science-based risk characterization tool for sustainably managing environmental safety by 'validating' thermal lethality of a given composting process or their derivatives achieved without compromising the sample integrity or ambiguity attached to microbiological validation involving steam sterilization or autoclaving procedures and helps audit the resurgent bacterial populations from surviving non-pathogenic organisms in the end-products of animal waste compost formulations.

Difference between observed and expected number of involved lymph nodes reflects the metastatic potential of breast cancer independent to intrinsic subtype.

PubMed

Yu, Ke-Da; Jiang, Yi-Zhou; Shao, Zhi-Ming

2015-06-30

Poor prognosis associated with metastasis in breast cancer patients highlights the critical need to develop an effective evaluation model for metastatic potential (MP). We hypothesized that MP could be also indicated by primary tumor size and involved lymph nodes (LNs). The expected number of involved LNs is defined as tumor size (cm) divided by 1.5. The effect of the surrogate for MP (defined as difference between the number of observed and expected involved LNs) on breast cancer-specific survival (BCSS) was investigated in the first cohort from SEER (n = 108,814). Validation was performed in another SEER cohort (n = 50,414) and a third cohort (n = 3,755). MP is an independent predictor for BCSS in the overall population [hazard ratio (HR) for high MP: 2.92; 95% confidence interval (CI): 2.80-3.03] and in subgroups. The effect of surrogate for MP on survival was independent to intrinsic subtype, with adjusted HRs of 3.46 (95%CI, 2.02-5.93), 2.30 (95%CI, 1.64-3.24), 4.05 (95%CI, 2.85-5.76), and 1.45 (95%CI, 1.04-2.03) in luminal-A, luminal-B, triple-negative, and HER2-positive subtypes, respectively. Difference between the observed and expected number of involved LNs serves as an indicator for MP, which is independent to intrinsic subtype and could predict survival. Our findings need further validation.

Variability in Predictions from Online Tools: A Demonstration Using Internet-Based Melanoma Predictors.

PubMed

Zabor, Emily C; Coit, Daniel; Gershenwald, Jeffrey E; McMasters, Kelly M; Michaelson, James S; Stromberg, Arnold J; Panageas, Katherine S

2018-02-22

Prognostic models are increasingly being made available online, where they can be publicly accessed by both patients and clinicians. These online tools are an important resource for patients to better understand their prognosis and for clinicians to make informed decisions about treatment and follow-up. The goal of this analysis was to highlight the possible variability in multiple online prognostic tools in a single disease. To demonstrate the variability in survival predictions across online prognostic tools, we applied a single validation dataset to three online melanoma prognostic tools. Data on melanoma patients treated at Memorial Sloan Kettering Cancer Center between 2000 and 2014 were retrospectively collected. Calibration was assessed using calibration plots and discrimination was assessed using the C-index. In this demonstration project, we found important differences across the three models that led to variability in individual patients' predicted survival across the tools, especially in the lower range of predictions. In a validation test using a single-institution data set, calibration and discrimination varied across the three models. This study underscores the potential variability both within and across online tools, and highlights the importance of using methodological rigor when developing a prognostic model that will be made publicly available online. The results also reinforce that careful development and thoughtful interpretation, including understanding a given tool's limitations, are required in order for online prognostic tools that provide survival predictions to be a useful resource for both patients and clinicians.

Deep-sequencing transcriptome analysis of field-grown Medicago sativa L. crown buds acclimated to freezing stress.

PubMed

Song, Lili; Jiang, Lin; Chen, Yue; Shu, Yongjun; Bai, Yan; Guo, Changhong

2016-09-01

Medicago sativa L. (alfalfa) 'Zhaodong' is an important forage legume that can safely survive in northern China where winter temperatures reach as low as -30 °C. Survival of alfalfa following freezing stress depends on the amount and revival ability of crown buds. In order to investigate the molecular mechanisms of frost tolerance in alfalfa, we used transcriptome sequencing technology and bioinformatics strategies to analyze crown buds of field-grown alfalfa during winter. We statistically identified a total of 5605 differentially expressed genes (DEGs) involved in freezing stress including 1900 upregulated and 3705 downregulated DEGs. We validated 36 candidate DEGs using qPCR to confirm the accuracy of the RNA-seq data. Unlike other recent studies, this study employed alfalfa plants grown in the natural environment. Our results indicate that not only the CBF orthologs but also membrane proteins, hormone signal transduction pathways, and ubiquitin-mediated proteolysis pathways indicate the presence of a special freezing adaptation mechanism in alfalfa. The antioxidant defense system may rapidly confer freezing tolerance to alfalfa. Importantly, biosynthesis of secondary metabolites and phenylalanine metabolism, which is of potential importance in coordinating freezing tolerance with growth and development, were downregulated in subzero temperatures. The adaptive mechanism for frost tolerance is a complex multigenic process that is not well understood. This systematic analysis provided an in-depth view of stress tolerance mechanisms in alfalfa.

IPMP Global Fit - A one-step direct data analysis tool for predictive microbiology.

PubMed

Huang, Lihan

2017-12-04

The objective of this work is to develop and validate a unified optimization algorithm for performing one-step global regression analysis of isothermal growth and survival curves for determination of kinetic parameters in predictive microbiology. The algorithm is incorporated with user-friendly graphical interfaces (GUIs) to develop a data analysis tool, the USDA IPMP-Global Fit. The GUIs are designed to guide the users to easily navigate through the data analysis process and properly select the initial parameters for different combinations of mathematical models. The software is developed for one-step kinetic analysis to directly construct tertiary models by minimizing the global error between the experimental observations and mathematical models. The current version of the software is specifically designed for constructing tertiary models with time and temperature as the independent model parameters in the package. The software is tested with a total of 9 different combinations of primary and secondary models for growth and survival of various microorganisms. The results of data analysis show that this software provides accurate estimates of kinetic parameters. In addition, it can be used to improve the experimental design and data collection for more accurate estimation of kinetic parameters. IPMP-Global Fit can be used in combination with the regular USDA-IPMP for solving the inverse problems and developing tertiary models in predictive microbiology. Published by Elsevier B.V.

Survival probability for a diffusive process on a growing domain

NASA Astrophysics Data System (ADS)

Simpson, Matthew J.; Sharp, Jesse A.; Baker, Ruth E.

2015-04-01

We consider the motion of a diffusive population on a growing domain, 0

Validation of column-based chromatography processes for the purification of proteins. Technical report No. 14.

PubMed

2008-01-01

PDA Technical Report No. 14 has been written to provide current best practices, such as application of risk-based decision making, based in sound science to provide a foundation for the validation of column-based chromatography processes and to expand upon information provided in Technical Report No. 42, Process Validation of Protein Manufacturing. The intent of this technical report is to provide an integrated validation life-cycle approach that begins with the use of process development data for the definition of operational parameters as a basis for validation, confirmation, and/or minor adjustment to these parameters at manufacturing scale during production of conformance batches and maintenance of the validated state throughout the product's life cycle.

TGFBI expression is an independent predictor of survival in adjuvant-treated lung squamous cell carcinoma patients.

PubMed

Pajares, M J; Agorreta, J; Salvo, E; Behrens, C; Wistuba, I I; Montuenga, L M; Pio, R; Rouzaut, A

2014-03-18

Transforming growth factor β-induced protein (TGFBI) is a secreted protein that mediates cell anchoring to the extracellular matrix. This protein is downregulated in lung cancer, and when overexpressed, contributes to apoptotic cell death. Using a small series of stage IV non-small cell lung cancer (NSCLC) patients, we previously suggested the usefulness of TGFBI as a prognostic and predictive factor in chemotherapy-treated late-stage NSCLC. In order to validate and extend these results, we broaden the analysis and studied TGFBI expression in a large series of samples obtained from stage I-IV NSCLC patients. TGFBI expression was assessed by immunohistochemistry in 364 completely resected primary NSCLC samples: 242 adenocarcinomas (ADCs) and 122 squamous cell carcinomas (SCCs). Kaplan-Meier curves, log-rank tests and the Cox proportional hazards model were used to analyse the association between TGFBI expression and survival. High TGFBI levels were associated with longer overall survival (OS, P<0.001) and progression-free survival (PFS, P<0.001) in SCC patients who received adjuvant platinium-based chemotherapy. Moreover, multivariate analysis demonstrated that high TGFBI expression is an independent predictor of better survival in patients (OS: P=0.030 and PFS: P=0.026). TGFBI may be useful for the identification of a subset of NSCLC who may benefit from adjuvant therapy.

A thermal control system for long-term survival of scientific instruments on lunar surface.

PubMed

Ogawa, K; Iijima, Y; Sakatani, N; Otake, H; Tanaka, S

2014-03-01

A thermal control system is being developed for scientific instruments placed on the lunar surface. This thermal control system, Lunar Mission Survival Module (MSM), was designed for scientific instruments that are planned to be operated for over a year in the future Japanese lunar landing mission SELENE-2. For the long-term operations, the lunar surface is a severe environment because the soil (regolith) temperature varies widely from nighttime -200 degC to daytime 100 degC approximately in which space electronics can hardly survive. The MSM has a tent of multi-layered insulators and performs a "regolith mound". Temperature of internal devices is less variable just like in the lunar underground layers. The insulators retain heat in the regolith soil in the daylight, and it can keep the device warm in the night. We conducted the concept design of the lunar survival module, and estimated its potential by a thermal mathematical model on the assumption of using a lunar seismometer designed for SELENE-2. Thermal vacuum tests were also conducted by using a thermal evaluation model in order to estimate the validity of some thermal parameters assumed in the computed thermal model. The numerical and experimental results indicated a sufficient survivability potential of the concept of our thermal control system.

Data Mining of Gene Arrays for Biomarkers of Survival in Ovarian Cancer

PubMed Central

Coveney, Clare; Boocock, David J.; Rees, Robert C.; Deen, Suha; Ball, Graham R.

2015-01-01

The expected five-year survival rate from a stage III ovarian cancer diagnosis is a mere 22%; this applies to the 7000 new cases diagnosed yearly in the UK. Stratification of patients with this heterogeneous disease, based on active molecular pathways, would aid a targeted treatment improving the prognosis for many cases. While hundreds of genes have been associated with ovarian cancer, few have yet been verified by peer research for clinical significance. Here, a meta-analysis approach was applied to two carefully selected gene expression microarray datasets. Artificial neural networks, Cox univariate survival analyses and T-tests identified genes whose expression was consistently and significantly associated with patient survival. The rigor of this experimental design increases confidence in the genes found to be of interest. A list of 56 genes were distilled from a potential 37,000 to be significantly related to survival in both datasets with a FDR of 1.39859 × 10−11, the identities of which both verify genes already implicated with this disease and provide novel genes and pathways to pursue. Further investigation and validation of these may lead to clinical insights and have potential to predict a patient’s response to treatment or be used as a novel target for therapy. PMID:27600227

Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic prostate cancer.

PubMed

Brown, Matthew S; Kim, Grace Hyun J; Chu, Gregory H; Ramakrishna, Bharath; Allen-Auerbach, Martin; Fischer, Cheryce P; Levine, Benjamin; Gupta, Pawan K; Schiepers, Christiaan W; Goldin, Jonathan G

2018-01-01

A clinical validation of the bone scan lesion area (BSLA) as a quantitative imaging biomarker was performed in metastatic castration-resistant prostate cancer (mCRPC). BSLA was computed from whole-body bone scintigraphy at baseline and week 12 posttreatment in a cohort of 198 mCRPC subjects (127 treated and 71 placebo) from a clinical trial involving a different drug from the initial biomarker development. BSLA computation involved automated image normalization, lesion segmentation, and summation of the total area of segmented lesions on bone scan AP and PA views as a measure of tumor burden. As a predictive biomarker, treated subjects with baseline BSLA [Formula: see text] had longer survival than those with higher BSLA ([Formula: see text] and [Formula: see text]). As a surrogate outcome biomarker, subjects were categorized as progressive disease (PD) if the BSLA increased by a prespecified 30% or more from baseline to week 12 and non-PD otherwise. Overall survival rates between PD and non-PD groups were statistically different ([Formula: see text] and [Formula: see text]). Subjects without PD at week 12 had longer survival than subjects with PD: median 398 days versus 280 days. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different prostate cancer drug treatments.

Protocol biopsies in renal transplantation: prognostic value of structural monitoring.

PubMed

Serón, D; Moreso, F

2007-09-01

The natural history of renal allograft damage has been characterized in serial protocol biopsies. The prevalence of subclinical rejection (SCR) is maximal during the first months and it is associated with the progression of interstitial fibrosis/tubular atrophy (IF/TA) and a decreased graft survival. IF/TA rapidly progress during the first months and constitutes an independent predictor of graft survival. IF/TA associated with transplant vasculopathy, SCR, or transplant glomerulopathy implies a poorer prognosis than IF/TA without additional lesions. These observations suggest that protocol biopsies could be considered a surrogate of graft survival. Preliminary data suggest that the predictive value of protocol biopsies is not inferior to acute rejection or renal function. Additionally, protocol biopsies have been employed as a secondary efficacy variable in clinical trials. This strategy has been useful to demonstrate a decrease in the progression of IF/TA in some calcineurin-free regimens. Quantification of renal damage is associated with graft survival suggesting that quantitative parameters might improve the predictive value of protocol biopsies. Validation of protocol biopsies as a surrogate of graft survival is actively pursued, as the utility of classical surrogates of graft outcome such as acute rejection has become less useful because of its decreased prevalence with actual immunosuppression.

Time-resolved metabolomics analysis of individual differences during the early stage of lipopolysaccharide-treated rats.

PubMed

Dai, Die; Gao, Yiqiao; Chen, Jiaqing; Huang, Yin; Zhang, Zunjian; Xu, Fengguo

2016-10-03

Lipopolysaccharide (LPS) can lead to uncontrollable cytokine production and eventually cause fatal sepsis syndrome. Individual toxicity difference of LPS has been widely reported. In our study we observed that two thirds of the rats (24/36) died at a given dose of LPS, while the rest (12/36) survived. Tracking the dynamic metabolic change in survival and non-survival rats in the early stage may reveal new system information to understand the inter-individual variation in response to LPS. As the time-resolved datasets are very complex and no single method can elucidate the problem clearly and comprehensively, the static and dynamic metabolomics methods were employed in combination as cross-validation. Intriguingly, some common results have been observed. Lipids were the main different metabolites between survival and non-survival rats in pre-dose serum and in the early stage of infection with LPS. The LPS treatment led to S-adenosly-methionine and total cysteine individual difference in early stage, and subsequent significant perturbations in energy metabolism and oxidative stress. Furthermore, cytokine profiles were analyzed to identify potential biological associations between cytokines and specific metabolites. Our collective findings may provide some heuristic guidance for elucidating the underlying mechanism of individual difference in LPS-mediated disease.

Effect of salt, smoke compound and temperature on the survival of Listeria monocytogenes in salmon during simulated smoking processes

USDA-ARS?s Scientific Manuscript database

In smoked fish processes, smoking is the only step that is capable of inactivating pathogens, such as Listeria monocytogenes, that contaminate the raw fish. The objectives of this study were to examine and develop a model to describe the survival of L. monocytogenes in salmon as affected by salt, s...

Adaptive Memory: Determining the Proximate Mechanisms Responsible for the Memorial Advantages of Survival Processing

ERIC Educational Resources Information Center

Burns, Daniel J.; Burns, Sarah A.; Hwang, Ana J.

2011-01-01

J. S. Nairne, S. R. Thompson, and J. N. S. Pandeirada (2007) suggested that our memory systems may have evolved to help us remember fitness-relevant information and showed that retention of words rated for their relevance to survival is superior to that of words encoded under other deep processing conditions. The authors present 4 experiments that…

Updated Prognostic Model for Predicting Overall Survival in First-Line Chemotherapy for Patients With Metastatic Castration-Resistant Prostate Cancer

PubMed Central

Halabi, Susan; Lin, Chen-Yen; Kelly, W. Kevin; Fizazi, Karim S.; Moul, Judd W.; Kaplan, Ellen B.; Morris, Michael J.; Small, Eric J.

2014-01-01

Purpose Prognostic models for overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC) are dated and do not reflect significant advances in treatment options available for these patients. This work developed and validated an updated prognostic model to predict OS in patients receiving first-line chemotherapy. Methods Data from a phase III trial of 1,050 patients with mCRPC were used (Cancer and Leukemia Group B CALGB-90401 [Alliance]). The data were randomly split into training and testing sets. A separate phase III trial served as an independent validation set. Adaptive least absolute shrinkage and selection operator selected eight factors prognostic for OS. A predictive score was computed from the regression coefficients and used to classify patients into low- and high-risk groups. The model was assessed for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The model included Eastern Cooperative Oncology Group performance status, disease site, lactate dehydrogenase, opioid analgesic use, albumin, hemoglobin, prostate-specific antigen, and alkaline phosphatase. Median OS values in the high- and low-risk groups, respectively, in the testing set were 17 and 30 months (hazard ratio [HR], 2.2; P < .001); in the validation set they were 14 and 26 months (HR, 2.9; P < .001). The tAUCs were 0.73 (95% CI, 0.70 to 0.73) and 0.76 (95% CI, 0.72 to 0.76) in the testing and validation sets, respectively. Conclusion An updated prognostic model for OS in patients with mCRPC receiving first-line chemotherapy was developed and validated on an external set. This model can be used to predict OS, as well as to better select patients to participate in trials on the basis of their prognosis. PMID:24449231

The non-linear, interactive effects of population density and climate drive the geographical patterns of waterfowl survival

USGS Publications Warehouse

Zhao, Qing; Boomer, G. Scott; Kendall, William L.

2018-01-01

On-going climate change has major impacts on ecological processes and patterns. Understanding the impacts of climate on the geographical patterns of survival can provide insights to how population dynamics respond to climate change and provide important information for the development of appropriate conservation strategies at regional scales. It is challenging to understand the impacts of climate on survival, however, due to the fact that the non-linear relationship between survival and climate can be modified by density-dependent processes. In this study we extended the Brownie model to partition hunting and non-hunting mortalities and linked non-hunting survival to covariates. We applied this model to four decades (1972–2014) of waterfowl band-recovery, breeding population survey, and precipitation and temperature data covering multiple ecological regions to examine the non-linear, interactive effects of population density and climate on waterfowl non-hunting survival at a regional scale. Our results showed that the non-linear effect of temperature on waterfowl non-hunting survival was modified by breeding population density. The concave relationship between non-hunting survival and temperature suggested that the effects of warming on waterfowl survival might be multifaceted. Furthermore, the relationship between non-hunting survival and temperature was stronger when population density was higher, suggesting that high-density populations may be less buffered against warming than low-density populations. Our study revealed distinct relationships between waterfowl non-hunting survival and climate across and within ecological regions, highlighting the importance of considering different conservation strategies according to region-specific population and climate conditions. Our findings and associated novel modelling approach have wide implications in conservation practice.