Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group.

PubMed

Janssens, Geert O; Gandola, Lorenza; Bolle, Stephanie; Mandeville, Henry; Ramos-Albiac, Monica; van Beek, Karen; Benghiat, Helen; Hoeben, Bianca; Morales La Madrid, Andres; Kortmann, Rolf-Dieter; Hargrave, Darren; Menten, Johan; Pecori, Emilia; Biassoni, Veronica; von Bueren, Andre O; van Vuurden, Dannis G; Massimino, Maura; Sturm, Dominik; Peters, Max; Kramm, Christof M

2017-03-01

Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression. At first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; P < .01; 6-12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27-.54; P < .01) and re-irradiation (corrected hazard ratio = .18-.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prototype solar heating and cooling systems

NASA Technical Reports Server (NTRS)

1979-01-01

A combination of monthly progress reports are presented. It contains a summary of activities and progress made from November 1, 1978, to February 28, 1979. The effort calls for the development, manufacture, test, system installation, maintenance, problem resolution, and performance evaluation.

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.

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

PubMed Central

Schuster, Cornelia; Eikesdal, Hans P.; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E.; Akslen, Lars A.; Straume, Oddbjørn

2012-01-01

Background VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. Trial Registration ClinicalTrials.gov NCT00139360. PMID:22719881

Proton Therapy for Reirradiation of Progressive or Recurrent Chordoma

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

McDonald, Mark W., E-mail: mmcdona2@iuhealth.org; Indiana University Health Proton Therapy Center, Bloomington, Indiana; Linton, Okechuckwu R.

2013-12-01

Purpose: To report the results in patients reirradiated with proton therapy for recurrent or progressive chordoma, with or without salvage surgery. Methods and Materials: A retrospective review of 16 consecutive patients treated from 2005 to 2012 was performed. All patients had received at least 1 prior course of radiation therapy to the same area, and all but 1 patient had at least 1 surgical resection for disease before receiving reirradiation. At the time of recurrence or progression, half of the patients underwent additional salvage surgery before receiving reirradiation. The median prior dose of radiation was 75.2 Gy (range, 40-79.2 Gy).more » Six patients had received prior proton therapy, and the remainder had received photon radiation. The median gross tumor volume at the time of reirradiation was 71 cm{sup 3} (range, 0-701 cm{sup 3}). Reirradiation occurred at a median interval of 37 months after prior radiation (range, 12-129 months), and the median dose of reirradiation was 75.6 Gy (relative biological effectiveness [RBE]) (range. 71.2-79.2 Gy [RBE]), given in standard daily fractionation (n=14) or hyperfractionation (n=2). Results: The median follow-up time was 23 months (range, 6-63 months); it was 26 months in patients alive at the last follow-up visit (range, 12-63 months). The 2-year estimate for local control was 85%, overall survival 80%, chordoma-specific survival 88%, and development of distant metastases 20%. Four patients have had local progression: 3 in-field and 1 marginal. Late toxicity included grade 3 bitemporal lobe radionecrosis in 1 patient that improved with hyperbaric oxygen, a grade 4 cerebrospinal fluid leak with meningitis in 1 patient, and a grade 4 ischemic brainstem stroke (out of radiation field) in 1 patient, with subsequent neurologic recovery. Conclusions: Full-dose proton reirradiation provided encouraging initial disease control and overall survival for patients with recurrent or progressive chordoma, although additional toxicities may develop with longer follow-up times.« less

A retrospective study of correlation of morphologic patterns, MIB1 proliferation index, and survival analysis in 134 cases of plasmacytoma.

PubMed

Ghodke, Kiran; Shet, Tanuja; Epari, Sridhar; Sengar, Manju; Menon, Hari; Gujral, Sumeet

2015-06-01

Plasmacytoma classified into solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) is characterized by infiltrate of plasma cells of diverse maturity and by their monoclonal immunoglobulin products. Both SPB and EMP represent different groups of neoplasm in terms of location, tumor progression, and overall survival rate. There is a need for features that indicate likelihood of myeloma in patients with plasmacytoma without other manifestations. This study was an attempt to study the morphologic patterns of plasmacytoma (SPB and EMP), MIB1 proliferation index, and correlation of these with clinicopathologic features and survival of the patients. The study group comprised of 134 cases of plasmacytoma (88 SPB and 46 EMP) over duration of 8 years and were graded as per Bartl's histologic grading system. Commonest site was vertebral body in SPB (36%) and upper aerodigestive tract in EMP (48%). On serum electrophoresis, overall M band was detected in 41% cases. Both SPB and EMP on histology revealed similar morphologic features. MIB1 proliferation index ranged from less than 1% to 80%. It was slightly higher in EMP in comparison with SPB (P value = .002). Seventy percent of cases, which progressed to multiple myeloma (MM) showed MIB1 labeling index more than 10%; however, it was not statistically significant in predicting the disease progression. With the median follow-up of 19 months (range, 1-99 months), 10 SPB had disease progression of which 7 converted to MM, and 3 developed EMP, with a median interval of 21 months (range, 8-75 months) for the development of MM and 3 months (range, 3-9 months) for the progression to EMP. Five-year survival for EMP varied by site, with poorest survival in brain/central nervous system EMP as compared with EMP at other sites. To conclude, grade and MIB1 proliferation index help in predicting aggressive course in plasmacytoma. Copyright © 2015 Elsevier Inc. All rights reserved.

Aberrant expression of copper associated genes after copper accumulation in COMMD1-deficient dogs.

PubMed

Favier, Robert P; Spee, Bart; Fieten, Hille; van den Ingh, Ted S G A M; Schotanus, Baukje A; Brinkhof, Bas; Rothuizen, Jan; Penning, Louis C

2015-01-01

COMMD1-deficient dogs progressively develop copper-induced chronic hepatitis. Since high copper leads to oxidative damage, we measured copper metabolism and oxidative stress related gene products during development of the disease. Five COMMD1-deficient dogs were studied from 6 months of age over a period of five years. Every 6 months blood was analysed and liver biopsies were taken for routine histological evaluation (grading of hepatitis), rubeanic acid copper staining and quantitative copper analysis. Expression of genes involved in copper metabolism (COX17, CCS, ATOX1, MT1A, CP, ATP7A, ATP7B, ) and oxidative stress (SOD1, catalase, GPX1 ) was measured by qPCR. Due to a sudden death of two animals, the remaining three dogs were treated with d-penicillamine from 43 months of age till the end of the study. Presented data for time points 48, 54, and 60 months was descriptive only. A progressive trend from slight to marked hepatitis was observed at histology, which was clearly preceded by an increase in semi-quantitative copper levels starting at 12 months until 42 months of age. During the progression of hepatitis most gene products measured were transiently increased. Most prominent was the rapid increase in the copper binding gene product MT1A mRNA levels. This was followed by a transient increase in ATP7A and ATP7B mRNA levels. In the sequence of events, copper accumulation induced progressive hepatitis followed by a transient increase in gene products associated with intracellular copper trafficking and temporal activation of anti-oxidative stress mechanisms. Copyright © 2014 Elsevier GmbH. All rights reserved.

Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients.

PubMed

Buda-Nowak, Anna; Kucharz, Jakub; Dumnicka, Paulina; Kuzniewski, Marek; Herman, Roman Maria; Zygulska, Aneta L; Kusnierz-Cabala, Beata

2017-04-01

Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in 'good' or 'intermediate' MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan-Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4-36.2 months] versus 9.8 months (6.4-13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly.

Carbon ion radiotherapy performed as re-irradiation using active beam delivery in patients with tumors of the brain, skull base and sacral region.

PubMed

Combs, Stephanie E; Kalbe, Adriana; Nikoghosyan, Anna; Ackermann, Benjamin; Jäkel, Oliver; Haberer, Thomas; Debus, Jürgen

2011-01-01

To asses carbon ion radiation therapy (RT) performed as re-irradiation in 28 patients with recurrent tumors. Twenty-eight patients were treated with carbon ion RT as re-irradiation for recurrent chordoma and chondrosarcoma of the skull base (n=16 and n=2), one chordoma and one chondrosarcoma of the os sacrum, high-risk meningioma (n=3), adenoid-cystic carcinoma (n=4) as well as one SCCHN. All patients were treated using active raster scanning, and treatment planning was performed on CT- and MRI-basis. All patients were followed prospectively during follow-up. In all patients re-irradiation could be applied safely without interruptions. For skull base tumors, local tumor control after re-irradiation was 92% at 24 months and 64% at 36 months. Survival after re-irradiation was 86% at 24 months, and 43% at 60 months. In all three meningiomas treated with C12 for re-irradiation, the tumor recurrence was located within the former RT-field. Two patients developed tumor progression at 6 months, and in one patient the tumor remained stable for 67 months. In patients with head-and-neck tumors, three patients developed local tumor progression at 12, 24 and 29 months after re-irradiation. Median local progression-free survival was 24 months. For sacral tumors, re-irradiation offered palliation with tumor control for 24 and 36 months. Due to the physical characteristics particle therapy offers a new treatment modality in cases with tumor recurrences. With carbon ions, the additional biological benefits may be exploited for long-term tumor control. Further evaluation in a larger patients' cohort will be performed in the future. Copyright © 2010. Published by Elsevier Ireland Ltd.

The Family Development Research Program: A Program for Prenatal, Infant and Early Childhood Enrichment. Progress Report.

ERIC Educational Resources Information Center

Lally, J. Ronald

This progress report on the Family Development Research Program for 108 low-income families, conducted at Syracuse University Children's Center, provides information on a longitudinal comparison instituted when the program children reached 36 months of age. The families of the children were matched to control families on a number of variables.…

Increasing Psychotherapists’ Adoption and Implementation of the Evidence-based Practice of Progress Monitoring

PubMed Central

Persons, Jacqueline B.; Koerner, Kelly; Eidelman, Polina; Thomas, Cannon; Liu, Howard

2015-01-01

Evidence-based practices (EBPs) reach consumers slowly because practitioners are slow to adopt and implement them. We hypothesized that giving psychotherapists a tool + training intervention that was designed to help the therapist integrate the EBP of progress monitoring into his or her usual way of working would be associated with adoption and sustained implementation of the particular progress monitoring tool we trained them to use (the Depression Anxiety Stress Scales on our Online Progress Tracking tool) and would generalize to all types of progress monitoring measures. To test these hypotheses, we developed an online progress monitoring tool and a course that trained psychotherapists to use it, and we assessed progress monitoring behavior in 26 psychotherapists before, during, immediately after, and 12 months after they received the tool and training. Immediately after receiving the tool + training intervention, participants showed statistically significant increases in use of the online tool and of all types of progress monitoring measures. Twelve months later, participants showed sustained use of any type of progress monitoring measure but not the online tool. PMID:26618237

Increasing psychotherapists' adoption and implementation of the evidence-based practice of progress monitoring.

PubMed

Persons, Jacqueline B; Koerner, Kelly; Eidelman, Polina; Thomas, Cannon; Liu, Howard

2016-01-01

Evidence-based practices (EBPs) reach consumers slowly because practitioners are slow to adopt and implement them. We hypothesized that giving psychotherapists a tool + training intervention that was designed to help the therapist integrate the EBP of progress monitoring into his or her usual way of working would be associated with adoption and sustained implementation of the particular progress monitoring tool we trained them to use (the Depression Anxiety Stress Scales on our Online Progress Tracking tool) and would generalize to all types of progress monitoring measures. To test these hypotheses, we developed an online progress monitoring tool and a course that trained psychotherapists to use it, and we assessed progress monitoring behavior in 26 psychotherapists before, during, immediately after, and 12 months after they received the tool and training. Immediately after receiving the tool + training intervention, participants showed statistically significant increases in use of the online tool and of all types of progress monitoring measures. Twelve months later, participants showed sustained use of any type of progress monitoring measure but not the online tool. Copyright © 2015 Elsevier Ltd. All rights reserved.

The development and utility of a novel scale that quantifies the glycemic progression toward type 1 diabetes over 6 months.

PubMed

Sosenko, Jay M; Skyler, Jay S; Beam, Craig A; Boulware, David; Mahon, Jeffrey L; Krischer, Jeffrey P; Greenbaum, Carla J; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Palmer, Jerry P

2015-05-01

We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Spinal Sarcomas

PubMed Central

Balagamwala, Ehsan H.; Angelov, Lilyana; Suh, John H.; Djemil, Toufik; Magnelli, Anthony; Qi, Peng; Zhuang, Tingliang; Godley, Andrew

2016-01-01

Purpose: Despite advancements in local and systemic therapy, metastasis remains common in the natural history of sarcomas. Unfortunately, such metastases are the most significant source of morbidity and mortality in this heterogeneous disease. As a classically radioresistant histology, stereotactic radiosurgery has emerged to control spinal sarcomas and provide palliation. However, there is a lack of data regarding pain relief and relapse following stereotactic radiosurgery. Methods: We queried a retrospective institutional database of patients who underwent spine stereotactic radiosurgery for primary and metastatic sarcomas. The primary outcome was pain relief following stereotactic radiosurgery. Secondary outcomes included progression of pain, radiographic failure, and development of toxicities following treatment. Results: Forty treatment sites were eligible for inclusion; the median prescription dose was 16 Gy in a single fraction. Median time to radiographic failure was 14 months. At 6 and 12 months, radiographic control was 63% and 51%, respectively. Among patients presenting with pain, median time to pain relief was 1 month. Actuarial pain relief at 6 months was 82%. Median time to pain progression was 10 months; at 12 months, actuarial pain progression was 51%. Following multivariate analysis, presence of neurologic deficit at consult (hazard ratio: 2.48, P < .01) and presence of extraspinal bone metastases (hazard ratio: 2.83, P < .01) were associated with pain relief. Greater pain at consult (hazard ratio: 1.92, P < .01), prior radiotherapy (hazard ratio: 4.65, P = .02), and greater number of irradiated vertebral levels were associated with pain progression. Conclusions: Local treatment of spinal sarcomas has remained a challenge for decades, with poor rates of local control and limited pain relief following conventional radiotherapy. In this series, pain relief was achieved in 82% of treatments at 6 months, with half of patients experiencing pain progression by 12 months. Given minimal toxicity and suboptimal pain control at 12 months, dose escalation beyond 16 Gy is warranted. PMID:27074915

On the Horizon: New Standards to Dawn at AASL 2017

ERIC Educational Resources Information Center

Mardis, Marcia A.

2017-01-01

As the sun rises over the horizon each day, we rarely get the opportunity to consider how the new day contributes to the month that forms part of a season that culminates in the year. A year's progress guides and shapes the development of all growing things. Though not necessarily in a tidy twelve-month cycle, while developing the new standards…

miR-21 is associated with fibrosis and right ventricular failure

PubMed Central

Hu, Dong-Qing; Zhao, Mingming; Blay, Eddie; Sandeep, Nefthi; Ong, Sang-Ging; Jung, Gwanghyun; Kooiker, Kristina B.; Coronado, Michael; Fajardo, Giovanni; Bernstein, Daniel

2017-01-01

Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms of congenital heart disease, causing progressive right ventricular (RV) dilation and failure. Little is known of the mechanisms underlying this combination of preload and afterload stressors. We developed a murine model of PI and PS (PI+PS) to identify clinically relevant pathways and biomarkers of disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated RV end-diastolic pressures) at 1 month after generation of PI+PS and progressed to systolic dysfunction (decreased RV shortening) by 3 months. RV fibrosis progressed from 1 month (4.4% ± 0.4%) to 3 months (9.2% ± 1%), along with TGF-β signaling and tissue expression of profibrotic miR-21. Although plasma miR-21 was upregulated with diastolic dysfunction, it was downregulated with the onset of systolic dysfunction), correlating with RV fibrosis. Plasma miR-21 in children with PI+PS followed a similar pattern. A model of combined RV volume and pressure overload recapitulates the evolution of RV failure unique to patients with prior RV outflow tract surgery. This progression was characterized by enhanced TGF-β and miR-21 signaling. miR-21 may serve as a plasma biomarker of RV failure, with decreased expression heralding the need for valve replacement. PMID:28469078

Letrozole in advanced breast cancer: the PO25 trial

PubMed Central

2007-01-01

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n = 453) or tamoxifen 20 mg (n = 454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS. PMID:17333340

Mine or Yours? Development of Sharing in Toddlers in Relation to Ownership Understanding

ERIC Educational Resources Information Center

Brownell, Celia A.; Iesue, Stephanie S.; Nichols, Sara R.; Svetlova, Margarita

2013-01-01

To examine early developments in other-oriented resource sharing, fifty-one 18- and 24-month-old children were administered 6 tasks with toys or food that could be shared with an adult playmate who had none. On each task the playmate communicated her desire for the items in a series of progressively more explicit cues. Twenty-four-month-olds…

High beta and second stability region transport and stability analysis: Technical progress report

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

Hughes, M.H.; Phillips, M.W.

1995-03-01

This report summarizes MHD equilibrium and stability studies carried out at Northrop Grumman`s Advanced Technology and Development Center during the 12 month period starting March 1, 1994. Progress is reported in both ideal and resistive MHD modeling of TFTR plasmas. The development of codes to calculate the significant effects of highly anisotropic pressure distributions is discussed along with results from this model.

Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

PubMed

Robin, Tyler P; Breeze, Robert E; Smith, Derek E; Rusthoven, Chad G; Lewis, Karl D; Gonzalez, Rene; Brill, Amanda; Saiki, Robin; Stuhr, Kelly; Gaspar, Laurie E; Karam, Sana D; Raben, David; Kavanagh, Brian D; Nath, Sameer K; Liu, Arthur K

2018-06-16

Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.

Epoch Analysis of On-Treatment Disability Progression Events over Time in the Tysabri Observational Program (TOP)

PubMed Central

Wiendl, Heinz; Butzkueven, Helmut; Kappos, Ludwig; Trojano, Maria; Pellegrini, Fabio; Paes, Dominic; Zhang, Annie; Belachew, Shibeshih

2016-01-01

Objective To evaluate the effect of natalizumab on disability progression beyond 2 years of treatment in clinical practice. Methods Analyses included the 496 relapsing-remitting multiple sclerosis (RRMS) patients among 5122 patients in the Tysabri Observational Program (TOP) who had completed 4 continuous years of natalizumab treatment and had baseline (study enrollment) and postbaseline Expanded Disability Status Scale (EDSS) assessments. Proportions of patients with 6-month or 12-month confirmed ≥1.0-point EDSS progression relative to baseline were compared in treatment months 1–24 and 25–48. Sensitivity analyses compared progression rates in months 13–24 and 25–36. Results Baseline characteristics appeared similar between the overall TOP population (N = 5122), patients who had completed 4 years of natalizumab treatment (n = 469), and patients eligible to complete 4 years in TOP who had discontinued natalizumab after 2 years of treatment (n = 514). Among 4-year completers, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased between months 1–24 and 25–48 of natalizumab treatment by 42% (from 10.9% to 6.3%; p < 0.01) and 52% (from 9.5% to 4.6%; p < 0.01), respectively. Few patients had 6-month or 12-month confirmed EDSS progression in both epochs (0.6% and 0.2%, respectively). Between months 13–24 and 25–36 of treatment, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased by 60% (from 7.5% to 3.0%; p < 0.01) and 58% (from 6.7% to 2.8%; p < 0.01), respectively. Significant reductions in disability progression events between months 13–24 and 25–36 were also observed in relapse-free patients. Conclusion In this observational study, the disability progression rate decreased further beyond 2 years of natalizumab treatment. Patients who responded well and remained on continuous natalizumab therapy for over 4 years had sustained and potentially enhanced reductions in EDSS progression over time. PMID:26771747

Behavioural characterisation of the alpha-mannosidosis guinea pig.

PubMed

Robinson, A J; Crawley, A C; Auclair, D; Weston, P F; Hirte, C; Hemsley, K M; Hopwood, J J

2008-01-25

alpha-Mannosidosis is a lysosomal storage disorder resulting from a functional deficiency of the lysosomal enzyme alpha-mannosidase. This deficiency results in the accumulation of various oligosaccharides in the lysosomes of affected individuals, causing somatic pathology and progressive neurological degeneration that results in cognitive deficits, ataxia, and other neurological symptoms. We have a naturally occurring guinea pig model of this disease which exhibits a deficiency of lysosomal alpha-mannosidase and has a similar clinical presentation to human alpha-mannosidosis. Various tests were developed in the present study to characterise and quantitate the loss of neurological function in alpha-mannosidosis guinea pigs and to follow closely the progression of the disease. General neurological examinations showed progressive differences in alpha-mannosidosis animals from approximately 1 month of age. Significant differences were observed in hind limb gait width from 2 months of age and significant cognitive (memory and learning) deficits were observed from 3 months of age. Evoked response tests showed an increase in somatosensory P1 peak latency in alpha-mannosidosis guinea pigs from approximately 2 months of age, as well as progressive hearing loss using auditory brainstem evoked responses. The alpha-mannosidosis guinea pig therefore appears to exhibit many of the characteristics of the human disease, and will be useful in evaluating therapies for treatment of central nervous system pathology.

Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis.

PubMed

Rubinstein, Samuel; Cornell, Robert F; Du, Liping; Concepcion, Beatrice; Goodman, Stacey; Harrell, Shelton; Horst, Sara; Lenihan, Daniel; Slosky, David; Fogo, Agnes; Langone, Anthony

2017-09-01

Light chain (AL) amyloidosis frequently involves the kidney, causing significant morbidity and mortality. A pathologic scoring system with prognostic utility has not been developed. We hypothesized that the extent of amyloid deposition and degree of scarring injury on kidney biopsy, could provide prognostic value, and aimed to develop pathologic scoring tools based on these features. This is a case-control study of 39 patients treated for AL amyloidosis with biopsy-proven kidney involvement at a large academic medical center. Our novel scoring tools, composite scarring injury score (CSIS) and amyloid score (AS) were applied to each kidney biopsy. The primary outcome was progression to dialysis-dependent end-stage kidney disease (ESKD) using a 12-month landmark analysis. At 12 months, nine patients had progressed to ESKD. Patients with an AS ≥7.5 had a significantly higher cumulative incidence of ESKD than those with AS <7.5 (p = .04, 95% CI 0.13-0.64). Using a 12-month landmark analysis, AS correlated with progression to ESKD. These data suggest that a kidney biopsy, in addition to providing diagnostic information, can be the basis for a pathologic scoring system with prognostic significance.

Routine Computer Tomography Imaging for the Detection of Recurrences in High-Risk Melanoma Patients.

PubMed

Park, Tristen S; Phan, Giao Q; Yang, James C; Kammula, Udai; Hughes, Marybeth S; Trebska-McGowan, Kasia; Morton, Kathleen E; White, Donald E; Rosenberg, Steven A; Sherry, Richard M

2017-04-01

The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.

Microaneurysm turnover is a predictor of diabetic retinopathy progression.

PubMed

Pappuru, Rajeev K R; Ribeiro, Luísa; Lobo, Conceição; Alves, Dalila; Cunha-Vaz, José

2018-04-26

To analyse retinopathy phenotypes and microaneurysm (MA) turnover in mild non-proliferative diabetic retinopathy (NPDR) as predictors of progression to diabetic central-involved macular oedema (CIMO) in patients with type 2 diabetes mellitus (DM) in two different ethnic populations. 205 patients with type 2 DM and mild NPDR were followed in a prospective observational study for 2 years or until development of CIMO, in two centres from different regions of the world. Ophthalmological examinations, including best-corrected visual acuity (BCVA), fundus photography with RetmarkerDR analysis, and optical coherence tomography (OCT), were performed at baseline and 6 12 and 24 months. 158 eyes/patients reached either the study endpoint, CIMO (24) or performed the last study visit (24-month visit) without developing CIMO (134). From the eyes/patients in analysis, 27 eyes (17.1%) progressed to more advanced ETDRS (Early Treatment Diabetic Retinopathy Study) levels: 6 progressed to mild NPDR (level 35), 15 progressed to moderate NPDR (level 43), 5 progressed to moderately severe NPDR (level 47) and 1 progressed to high risk PDR (level 71). Worsening in ETDRS level is associated with phenotype C (p=0.005). From the 130 eyes/patients with a low MA turnover, 18 (13.8%) eyes/patients had an increase in ETDRS level, and from the 19 eyes/patients with a high MA turnover, 9 (47.4%) had an increase in ETDRS level (p<0.001). Eyes in the initial stages of diabetic retinopathy show different phenotypes with different risks for progression to CIMO. In phenotype C, MA turnover correlates with ETDRS grading worsening and development of CIMO. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience.

PubMed

Figura, Nicholas B; Long, Wendy; Yu, Michael; Robinson, Timothy J; Mokhtari, Sepideh; Etame, Arnold B; Tran, Nam D; Diaz, Roberto; Soliman, Hatem; Han, Heather S; Sahebjam, Solmaz; Forsyth, Peter A; Ahmed, Kamran A

2018-06-01

Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease. A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations. The median age of patients was 48 (range 29-75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan-Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6- and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics. IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients.

Recent progress in tidal modeling

NASA Technical Reports Server (NTRS)

Vial, F.; Forbes, J. M.

1989-01-01

Recent contributions to tidal theory during the last five years are reviewed. Specific areas where recent progress has occurred include: the action of mean wind and dissipation on tides, interactions of other waves with tides, the use of TGCM in tidal studies. Furthermore, attention is put on the nonlinear interaction between semidiurnal and diurnal tides. Finally, more realistic thermal excitation and background wind and temperature models have been developed in the past few years. This has led to new month-to-month numerical simulations of the semidiurnal tide. Some results using these models are presented and compared with ATMAP tidal climatologies.

Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission.

PubMed

Lee, Joyce S-S; Frederiksen, Peter; Kossard, Steven

2008-02-01

A 70-year old Caucasian man with chronic lymphocytic leukaemia developed trichodysplasia spinulosa 2 months after ceasing chemotherapy. Histological features characteristic to this condition include dilated and enlarged hair follicles, hyperplastic hair bulbs, hyperplasia of inner root sheath cells with numerous large, eosinophilic, trichohyaline granules, and hypercornification. Although he was in remission for chronic lymphocytic leukaemia, lesions were slowly progressive 15 months after cessation of chemotherapy. We also describe a painless pull-test where spicules can be easily plucked and assessed microscopically for inner root sheath keratinization, or observed with surface microscopy in a clinic setting.

Examining Teachers' Understanding of the Mathematical Learning Progression through Vertical Articulation during Lesson Study

ERIC Educational Resources Information Center

Suh, Jennifer; Seshaiyer, Padmanabhan

2015-01-01

This study examines elementary- and middle-grade teachers' understanding of the mathematical learning progression as they participated in a 6-month professional learning project. Teachers participated in a professional development project that consisted of a 1-week summer content-focused institute with school-based follow-up Lesson Study cycles in…

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms.

PubMed

Baum, Richard P; Kulkarni, Harshad R; Singh, Aviral; Kaemmerer, Daniel; Mueller, Dirk; Prasad, Vikas; Hommann, Merten; Robiller, Franz C; Niepsch, Karin; Franz, Holger; Jochems, Arthur; Lambin, Philippe; Hörsch, Dieter

2018-03-30

Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. In our center, 2294 patients were screened between 2004 and 2014 by 68 Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90 Yttrium or 177 Lutetium-based PRRT. Progression free survival was determined by 68 Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68 Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms

PubMed Central

Baum, Richard P.; Kulkarni, Harshad R.; Singh, Aviral; Kaemmerer, Daniel; Mueller, Dirk; Prasad, Vikas; Hommann, Merten; Robiller, Franz C.; Niepsch, Karin; Franz, Holger; Jochems, Arthur; Lambin, Philippe; Hörsch, Dieter

2018-01-01

Introduction Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. Methods In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Results Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. Conclusion PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy. PMID:29682195

IT-26IDENTIFICATION OF PSEUDO-PROGRESSION IN NEW DIAGNOSED GLIOBLASTOMA (GBM) IN A RANDOMIZED PHASE 2 OF ICT-107: MRI AND PATHOLOGY CORRELATION

PubMed Central

Phuphanich, Surasak; Yu, John; Bannykh, Serguei; Zhu, Jay-Jiguang

2014-01-01

BACKGROUND: Previously reports of pseudo-progression in patients with brain tumor after therapeutic vaccines in pediatric and adult glioma (Pollack, JCO online on June 2, 2014 and Okada, JCO Jan 20, 2011; 29: 330-336) demonstrated that RANO criteria for tumor progression may not be adequate for immunotherapy trials. Similar observations were also seen in other checkpoint inhibitor in melanoma and NSLSC. METHODS: We identified 2 patients, who developed tumor progression by RANO criteria, underwent surgery following enrollment in a phase 2 randomized ICT-107 (an autologous vaccine consisting of patient dendritic cells pulsed with peptides from AIM-2, TRP-2, HER2/neu, IL-13Ra2, gp100, MAGE1) after radiation and Temozolomide (TMZ). RESULTS: The first case is a 69 years old Chinese male, who underwent 1st surgery of gross total resection right occipital GBM on 10/26/2011. Subsequently he received 19 cycles of TMZ and 9 vaccines/placebo. MRI from 7/2/2013 showed enhancement surrounding surgical cavity. After 2nd surgery, pathology showed only rare residual tumor cells with macrophages and positive CD 8 cells. He continued on this vaccine program and MRI showed more progression with finger-like extension into parietal lobe 4 months later. The 3rd surgery also showed extensive reactive changes with no active tumor cells. For 2nd case, a 62 years old male, who underwent first surgery on 7/11/2011 of right temporal lobe, developed 2 areas of enhancement after 6 cycles of TMZ and 7 vaccines/placebo on 4/18/2012. With 2nd surgery, pathology showed reactive gliosis without active tumor. The subject continued in this trial. CONCLUSION: Pseudo-progression was confirmed by pathology in these 2 patients at 20 and 9 months which were delayed comparing to pseudo-progression observed in patients treated with concurrent XRT/TMZ (3-6 months). Future iRANO criteria development is essential for immunotherapy trials. Accurately identifying and managing such patients is necessary to avoid premature termination of therapy.

Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases.

PubMed

Magnuson, William J; Yeung, Jacky T; Guillod, Paul D; Gettinger, Scott N; Yu, James B; Chiang, Veronica L

2016-06-01

To perform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who developed brain metastases (BM) to evaluate our hypothesis that the use of upfront EGFR-tyrosine kinase inhibitors (TKIs), and deferral of radiation therapy (RT), would result in inferior intracranial progression-free survival but similar overall survival (OS). Of 202 patients diagnosed with EGFR-mutant NSCLC between July 1, 2008, and December 31, 2014, 71 developed BM. Twenty-one patients were excluded owing to prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS) or <6 months' follow-up. Of the remaining 50 patients, 17 received upfront EGFR-TKI followed by SRS or WBRT, 17 WBRT then EGFR-TKI, and 16 SRS followed by EGFR-TKI. Disease-specific-graded prognostic assessment was similar among all 3 groups. The median OS was longer in the upfront RT group compared with the upfront EGFR-TKI group (34.1 vs 19.4 months; P=.01). On subgroup analysis, the SRS group had longer OS than the upfront EGFR-TKI group (58.4 vs 19.4 months; P=.01), but the WBRT group did not (29.9 vs 19.4 months; P=.09). Intracranial progression-free survival was improved in patients receiving upfront RT compared with those receiving upfront EGFR-TKI (37.9 vs 10.6 months; P<.001). The present study suggests that the use of upfront EGFR-TKI, and the deferral of SRS or WBRT, may result in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI with RT at intracranial progression versus upfront RT followed by EGFR-TKI is urgently needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases

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

Magnuson, William J., E-mail: william.magnuson@yale.edu; Yeung, Jacky T.; Guillod, Paul D.

Purpose: To perform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who developed brain metastases (BM) to evaluate our hypothesis that the use of upfront EGFR–tyrosine kinase inhibitors (TKIs), and deferral of radiation therapy (RT), would result in inferior intracranial progression-free survival but similar overall survival (OS). Methods and Materials: Of 202 patients diagnosed with EGFR-mutant NSCLC between July 1, 2008, and December 31, 2014, 71 developed BM. Twenty-one patients were excluded owing to prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS) or <6 months' follow-up. Of themore » remaining 50 patients, 17 received upfront EGFR-TKI followed by SRS or WBRT, 17 WBRT then EGFR-TKI, and 16 SRS followed by EGFR-TKI. Disease-specific-graded prognostic assessment was similar among all 3 groups. Results: The median OS was longer in the upfront RT group compared with the upfront EGFR-TKI group (34.1 vs 19.4 months; P=.01). On subgroup analysis, the SRS group had longer OS than the upfront EGFR-TKI group (58.4 vs 19.4 months; P=.01), but the WBRT group did not (29.9 vs 19.4 months; P=.09). Intracranial progression-free survival was improved in patients receiving upfront RT compared with those receiving upfront EGFR-TKI (37.9 vs 10.6 months; P<.001). Conclusions: The present study suggests that the use of upfront EGFR-TKI, and the deferral of SRS or WBRT, may result in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI with RT at intracranial progression versus upfront RT followed by EGFR-TKI is urgently needed.« less

Impact of accelerated progression to AIDS on public health monitoring of late HIV diagnosis.

PubMed

Sabharwal, Charulata J; Sepkowitz, Kent; Mehta, Reshma; Shepard, Colin; Bodach, Sara; Torian, Lucia; Begier, Elizabeth M

2011-03-01

Some patients develop AIDS within a year of HIV infection ("accelerated progression"). Classifying such cases as late HIV diagnosis may lead to inaccurate evaluation of HIV testing efforts. We sought to determine this group's contribution to overall late diagnosis rates. To identify cases of accelerated progression (development of AIDS within 12 months of a negative HIV test), we reviewed published HIV seroconverter cohort studies and used New York City's (NYC) HIV/AIDS surveillance registry. From the literature review, three seroconverter cohort studies revealed that 1.0-3.6% of participants had accelerated progression to AIDS. Applying this frequency estimate to the number of new infections in NYC (4762) for 2006 calculated by the Centers for Diseases Control and Prevention's incidence formula, we estimated that 3.6-13.0% of 1317 NYC HIV cases who are diagnosed with AIDS within 12 months of HIV diagnosis are accelerated progressors, not persons HIV infected for many years who did not test and present with AIDS (i.e., delayed diagnosis). In addition, our analysis of the 2006 NYC surveillance registry confirmed the occurrence of accelerated progression in a population-based setting; 67 accelerated progressors were reported and 9 (13%) could be confirmed through follow-up medical record review. With increased HIV testing initiatives, the irreducible proportion of AIDS cases with accelerated progression must be considered when interpreting late diagnosis data.

[An assessment tool for analysing the early vocal development of young children with cochlear implant].

PubMed

Lang, S; Leistner, S; Sandrieser, P; Kröger, B J

2009-05-01

Early vocal development of German-speaking cochlear implant recipients has rarely been assessed so far. There-fore the purpose of this study was to describe the early vocal development following successful implantation. A case study was designed to assess the temporal progression of early vocal development in a young cochlear implant recipient who was bilaterally implanted at the age of 8;3 months. Data were collected during one year by recording parent-child interactions on a monthly basis. The first recording was made before the onset of the signal-processors, the 12 following recordings were made during the first year of implant use. The child's vocalizations were classified according to the vocalization categories and developmental levels from the Stark Assessment of Early Vocal Development--Revised (SAEVD-R). This assessment tool was translated into German in this study and used with German-speaking children for the first time. It allows a coding of prelinguistic utterances via auditory perceptual analysis. The results show an overall decrease of early vocalizations and an increase of speech-like vowels and consonants. In the first six months no apparent progress took place; The child produced almost exclusively vocalizations from Levels 1-3. In the second half of the year an increase of canonical utterances (Level 4) and advanced forms (Level 5) was observed. However, vocalizations beyond the canonical babbling phase, especially vocants and closants as well as their combinations, continued to be dominant throughout the first year of implant use. The progress of development of the child investigated in this study is comparable to other children implanted at young age who had also been assessed with the SAEVD-R. In comparison to normal-hearing children, the implanted child's development seemed to progress slightly faster. Interrater- and intrarater-reliability using the SAEVD-R were measured for two independent observers and for a first and second coding procedure and revealed to be acceptable to good. The use of SAEVD-R for an implanted German-speaking child allowed the investigation of prelinguistic vocal development before the onset of words. The fact that early vocalizations remain the dominant form throughout the first year of hearing experience emphasizes the importance of documenting and analysing prelinguistic vocal development in order to monitor progression of speech acquisition.

Induction Gemcitabine and Stereotactic Body Radiotherapy for Locally Advanced Nonmetastatic Pancreas Cancer

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

Mahadevan, Anand, E-mail: amahadev@bidmc.harvard.edu; Miksad, Rebecca; Goldstein, Michael

2011-11-15

Purpose: Stereotactic body radiotherapy (SBRT) has been used successfully to treat patients with locally advanced pancreas cancer. However, many patients develop metastatic disease soon after diagnosis and may receive little benefit from such therapy. We therefore retrospectively analyzed a planned strategy of initial chemotherapy with restaging and then treatment for those patients with no evidence of metastatic progression with SBRT. Methods and Materials: Forty-seven patients received gemcitabine (1,000 mg/m{sup 2} per week for 3 weeks then 1 week off) until tolerance, at least six cycles, or progression. Patients without metastases after two cycles were treated with SBRT (tolerance-based dose ofmore » 24-36 Gy in 3 fractions) between the third and fourth cycles without interrupting the chemotherapy cycles. Results: Eight of the 47 patients (17%) were found to have metastatic disease after two cycles of gemcitabine; the remaining 39 patients received SBRT. The median follow-up for survivors was 21 months (range, 6-36 months). The median overall survival for all patients who received SBRT was 20 months, and the median progression-free survival was 15 months. The local control rate was 85% (33 of 39 patients); and 54% of patients (21 of 39) developed metastases. Late Grade III toxicities such as GI bleeding and obstruction were observed in 9% (3/39) of patients. Conclusion: For patients with locally advanced pancreas cancer, this strategy uses local therapy for those who are most likely to benefit from it and spares those patients with early metastatic progression from treatment. SBRT delivers such local therapy safely with minimal interruption to systemic chemotherapy, thereby potentially improving the outcome in these patients.« less

Progression of diabetic retinopathy severity after treatment with dexamethasone implant: a 24-month cohort study the 'DR-Pro-DEX Study'.

PubMed

Iglicki, Matias; Zur, Dinah; Busch, Catharina; Okada, Mali; Loewenstein, Anat

2018-06-01

Intravitreal anti-vascular endothelial growth factor agents have been shown to reduce diabetic retinopathy (DR) progression; data on the effects of intravitreal corticosteroids on modifying disease severity are limited. This study evaluates the long-term effect of intravitreal dexamethasone implant (DEX) on the severity and progression of non-proliferative DR (NPDR). This was a retrospective cohort study. Sixty eyes from 60 consecutive patients with NPDR and diabetic macular edema (DME) treated with dexamethasone implant (DEX group) and 49 eyes from consecutive 49 patients without DME requiring observation only. Fundus angiography images from baseline and after 24 months were graded by two masked assessors into mild, moderate and severe NPDR and PDR, according to the ETDRS classification. Patients were followed up 1-3 and 4-6 months after each DEX implant. Re-treatment with DEX implant was on a pro re nata basis. Records were reviewed for performance of panretinal photocoagulation. Main outcome was as follows: change of DR ≥ 1 grade and progression to proliferative diabetic retinopathy (PDR). Three eyes (5%) in the DEX group and 43 (87.8%) eyes in the control group progressed to PDR (P < 0.0001). Twenty-five eyes (41.7%) in the DEX group but none in the control group demonstrated an improvement in DR severity (P < 0.0001). This study provides the first long-term evidence that DEX implant has the potential to not only delay progression of DR and PDR development, but may also improve DR severity over 24 months. Better understanding of the effects of corticosteroids will help guide its use in the treatment pathway of DR.

Aversive and non-aversive memory impairment in the mucopolysaccharidosis II mouse model.

PubMed

Azambuja, Amanda Stapenhorst; Correa, Lilian; Gabiatti, Bernardo Pappi; Martins, Giselle Renata; de Oliveira Franco, Álvaro; Ribeiro, Maria Flávia Marques; Baldo, Guilherme

2018-02-01

Hunter syndrome (MPS II, OMIM 309900) is a lysosomal storage disorder due to deficient iduronate sulphatase activity. Patients present multiple cognitive alterations, and the aim of this work was to verify if MPS II mice also present some progressive cognitive alterations. For that, MPS II mice from 2 to 6 months of age were submitted to repeated open field and inhibitory avoidance tests to evaluate memory parameters. MPS II mice presented impaired memory at 6 months evaluated by open field test. They also performed poorly in the inhibitory avoidance test from 4 months. We conclude that MPS II mice develop cognitive alterations as the disease progresses. These tests can be used in the future to study the efficacy of therapeutic approaches in the central nervous system.

Reversibility of Vasalgel™ male contraceptive in a rabbit model.

PubMed

Waller, Donald; Bolick, David; Lissner, Elaine; Premanandan, Christopher; Gamerman, Gary

2017-01-01

Development of a non-hormonal long-acting reversible contraceptive for men could have a significant impact on reducing unintended pregnancies. Vasalgel™ is a high molecular weight polymer consisting of styrene-alt-maleic acid (SMA) dissolved in dimethyl sulfoxide being developed as a reversible male contraceptive device. It forms a hydrogel when implanted into the vasa deferentia, which prevents the passage of sperm. Previous studies in the rabbit have proven its efficacy, durability and rapid onset. This study evaluates the capacity to restore sperm concentrations in ejaculates after a reversal procedure. Sodium bicarbonate was injected into the vasa deferentia after fourteen months of azoospermia following the injection of two device variations (Vasalgel 100 and Vasalgel 80). Semen samples were then collected for six months and sperm characteristics were compared to baseline levels. Samples of vasa deferentia were obtained for histological examination. Spermatozoa were present in all subject ejaculates after the reversal procedure. Sperm concentration and sperm motility were similar to baseline levels after reversal, while sperm forward progression was significantly lower and normal acrosomes were not observed. Forward progression percentages increased linearly during six months of semen collection, however, normal acrosomes were not observed at the conclusion of the study. Histologically, several vasa deferentia were clear of the device and contained an intact epithelial lining. A smaller proportion of tissues contained residual test material. A secondary intraluminal inflammatory response was seen occasionally in the tissues containing residual material. There was no difference between the two device variations for studied parameters. Vasalgel's prevention of sperm transport for 14 months was reversed through an intravasal injection of sodium bicarbonate. Post-reversal sperm concentrations and motility returned to baseline levels during the six-month follow up. Residual material in the vas lumen or compromised epididymal and vas deferens function may be resulting in reduced forward progression and loss of acrosomes during transit through the vas. Reduced forward progression and the lack of normal acrosomes strongly suggest impaired sperm function.

Prelingual auditory-perceptual skills as indicators of initial oral language development in deaf children with cochlear implants.

PubMed

Pianesi, Federica; Scorpecci, Alessandro; Giannantonio, Sara; Micardi, Mariella; Resca, Alessandra; Marsella, Pasquale

2016-03-01

To assess when prelingually deaf children with a cochlear implant (CI) achieve the First Milestone of Oral Language, to study the progression of their prelingual auditory skills in the first year after CI and to investigate a possible correlation between such skills and the timing of initial oral language development. The sample included 44 prelingually deaf children (23 M and 21 F) from the same tertiary care institution, who received unilateral or bilateral cochlear implants. Achievement of the First Milestone of Oral Language (FMOL) was defined as speech comprehension of at least 50 words and speech production of a minimum of 10 words, as established by administration of a validated Italian test for the assessment of initial language competence in infants. Prelingual auditory-perceptual skills were assessed over time by means of a test battery consisting of: the Infant Toddler Meaningful Integration Scale (IT-MAIS); the Infant Listening Progress Profile (ILiP) and the Categories of Auditory Performance (CAP). On average, the 44 children received their CI at 24±9 months and experienced FMOL after 8±4 months of continuous CI use. The IT-MAIS, ILiP and CAP scores increased significantly over time, the greatest improvement occurring between baseline and six months of CI use. On multivariate regression analysis, age at diagnosis and age at CI did not appear to bear correlation with FMOL timing; instead, the only variables contributing to its variance were IT-MAIS and ILiP scores after six months of CI use, accounting for 43% and 55%, respectively. Prelingual auditory skills of implanted children assessed via a test battery six months after CI treatment, can act as indicators of the timing of initial oral language development. Accordingly, the period from CI switch-on to six months can be considered as a window of opportunity for appropriate intervention in children failing to show the expected progression of their auditory skills and who would have higher risk of delayed oral language development. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Urothelial papilloma of the bladder: a review of 34 de novo cases.

PubMed

Magi-Galluzzi, Cristina; Epstein, Jonathan I

2004-12-01

Urothelial papilloma of the bladder is an uncommon entity when using restrictive diagnostic criteria. We retrospectively studied 34 patients who were diagnosed with urothelial papilloma of the bladder using the criteria of the 1998 WHO/ISUP classification system. Six cases were in-house and the remaining 28 were referred from other institutions as consults to one of the authors. In all cases, the diagnosis of papilloma was the first manifestation of urothelial neoplasia. The mean age of the patients at diagnosis was 57.8 years (range, 23-87 years). The male-to-female ratio was 2.4:1 (24 males and 10 females). The tumor size averaged 3.3 mm (range, 1-20 mm; median, 2 mm). Simple papillary fronds were seen in all cases; in 5 cases the additional finding of secondary budding off of small fronds from larger ones was also seen. In all cases, the fronds had a round morphology; yet in 4 cases elongated fronds were also noted. In 5 cases, dilated lymphatics within the fibrovascular fronds were apparent. One case had foamy histiocytes within the fibrovascular stalks. In all cases, the lining consisted of normal-appearing urothelium without hyperplasia, dysplasia, and/or mitotic figures. Some of the distinctive histologic features seen were changes in the umbrella cells: vacuolization (n = 4), prominence with cytologic atypia (n = 2), eosinophilic syncytial morphology (n = 1), apocrine-like morphology (n = 1), and mucinous metaplasia (n = 1). Follow-up was available in 26 cases with a mean follow-up for those without evidence of progression of 28.9 months (range, 3-127 months). Three patients (8.8%) developed recurrent papilloma 4, 15, and 18 months after the initial diagnosis of papilloma; 1 of these patients also showed progression to noninvasive low-grade urothelial carcinoma at the time of recurrence (15 months). Three patients (8.8%) progressed to higher-grade disease: 2 to noninvasive low grade urothelial carcinoma (11 and 15 months after the original diagnosis) and 1 to a papillary urothelial neoplasm of low malignant potential at 104 months and a noninvasive low-grade urothelial carcinoma at 141 months from the initial diagnosis of papilloma. None of the patients demonstrated progression to either lamina propria (T1) or muscularis propria (T2) invasion. Two patients died of unrelated causes. None of the patients died of bladder cancer. Patients with urothelial papillomas have a low incidence of recurrence and rarely progress to develop urothelial carcinoma. It seems reasonable to avoid labeling these patients as having cancer. It remains to be studied whether and when patients with papillomas who have no evidence of recurrence or progression no longer need to be followed.

Depletion of CD4 T Lymphocytes at the time of infection with M. avium subsp. paratuberculosis does not accelerate disease progression

USDA-ARS?s Scientific Manuscript database

A calf model was used to determine if the depletion of CD4 T cells prior to inoculation of Mycobacterium avium subsp. paratuberculosis (Map) would delay development of an immune response to Map and accelerate disease progression. Ileal cannulas were surgically implanted in 5 bull calves at two month...

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

Not Available

A collection of quarterly and monthly reports from Elcam, Inc., covering progress made from January 1, 1978, through September 30, 1978, is presented. Elcam, is developing two solar-heated hot water prototype systems and two heat exchangers. This effort consists of development, manufacture, installation, maintenance, problem resolution, and system evaluation.

Continued EGFR-TKI with concurrent radiotherapy to improve time to progression (TTP) in patients with locally progressive non-small cell lung cancer (NSCLC) after front-line EGFR-TKI treatment.

PubMed

Wang, Y; Li, Y; Xia, L; Niu, K; Chen, X; Lu, D; Kong, R; Chen, Z; Sun, J

2018-03-01

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the optimal treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, most patients developed systemic or local progression due to acquired EGFR-TKI resistance. This retrospective study aimed to evaluate the feasibility of continued EGFR-TKI with concurrent radiotherapy (CTCRT) in patients with local progression after front-line EGFR-TKI treatment. Advanced NSCLC patients with active EGFR mutation who received EGFR-TKI were treated with CTCRT after local progression. Medical data were analyzed for time to progression (TTP), progression-free survival (PFS), tumor response rate, overall survival (OS) and adverse events. A total of 50 irradiated lesions from 44 patients were included. Median TTP and PFS of measurable lesions (n = 31) were both significantly prolonged after local radiotherapy (TTP1 + TTP2 vs. TTP1: 21.7 vs. 16.0 months, P = 0.010; PFS1 + PFS2 vs. PFS1: 21.3 vs. 16.0 months, P = 0.027). For all lesions (n = 50), objective response rate (ORR) and local tumor control rate (LCR) were 54.0 and 84.0%, respectively. Median OS was 26.6 months. There were no serious adverse events before or after radiotherapy. The treatment modality of CTCRT is considerable and effective for EGFR-mutant NSCLC patients even with local failure from front-line EGFR-TKI treatment.

Morphologies of the atria and pulmonary veins in relation to lone atrial fibrillation progression: a dual-source computed tomography scan study.

PubMed

Liu, Xing-Peng; Xu, Xia; Tian, Ying; Tang, Ri-Bo; Yu, Rong-Hui; Long, De-Yong; Sang, Cai-Hua; Jiang, Chen-Xi; Ning, Man; Dong, Jian-Zeng; Ma, Chang-Sheng

2012-11-01

Atrial Remodeling and Lone Atrial Fibrillation. We sought to investigate the role of anatomic remodeling of the atria and pulmonary veins (PVs) in the progression of lone atrial fibrillation (AF) using dual-source computed tomography (DSCT). From 1,308 consecutive patients referred for an index ablation procedure for AF, we prospectively enrolled 29 consecutive patients with recently developed (<3 months) lone persistent AF (PsAF) and 23 consecutive patients with short-lasting (6-12 months) lone PsAF, all of whom had a history of paroxysmal AF (PAF). The control group consisted of 33 patients with lone PAF. On DSCT, the recently developed PsAF group showed more extensive atrial anatomic remodeling than the PAF group as shown by ∼40% higher spot biatrial volume, even though the mean duration of continuous AF was only 6 weeks. In contrast, the DSCT variables in the recently developed PsAF group and the short-lasting PsAF group were comparable, despite the fact that the mean duration of continuous AF in the latter group was 8 months. Series of cross-sectional areas of the ostial 1.5 cm of PV trunks were comparable in the PAF and PsAF groups in all but 3 ostial planes. A higher spot left atrial volume was the only independent factor associated with the progression of lone PAF to PsAF (OR: 1.06, 95% CI: 1.03-1.09, P<0.0001) on logistic regression. Prominent anatomic remodeling of the atria, rather than the PVs, underlies the mechanism of recent progression of lone paroxysmal AF to the persistent variety. © 2012 Wiley Periodicals, Inc.

Simultaneous characterization of metabolic, cardiac, vascular and renal phenotypes of lean and obese SHHF rats.

PubMed

Youcef, Gina; Olivier, Arnaud; L'Huillier, Clément P J; Labat, Carlos; Fay, Renaud; Tabcheh, Lina; Toupance, Simon; Rodriguez-Guéant, Rosa-Maria; Bergerot, Damien; Jaisser, Frédéric; Lacolley, Patrick; Zannad, Faiez; Laurent Vallar; Pizard, Anne

2014-01-01

Individuals with metabolic syndrome (MetS) are prone to develop heart failure (HF). However, the deleterious effects of MetS on the continuum of events leading to cardiac remodeling and subsequently to HF are not fully understood. This study characterized simultaneously MetS and cardiac, vascular and renal phenotypes in aging Spontaneously Hypertensive Heart Failure lean (SHHF(+/?) regrouping (+/+) and (+/cp) rats) and obese (SHHF(cp/cp), "cp" defective mutant allele of the leptin receptor gene) rats. We aimed to refine the milestones and their onset during the progression from MetS to HF in this experimental model. We found that SHHF(cp/cp )but not SHHF(+/?) rats developed dyslipidemia, as early as 1.5 months of age. This early alteration in the lipidic profile was detectable concomitantly to impaired renal function (polyuria, proteinuria but no glycosuria) and reduced carotid distensibility as compared to SHHF(+/?) rats. By 3 months of age SHHFcp/cp animals developed severe obesity associated with dislipidemia and hypertension defining the onset of MetS. From 6 months of age, SHHF(+/?) rats developed concentric left ventricular hypertrophy (LVH) while SHHF(cp/cp) rats developed eccentric LVH apparent from progressive dilation of the LV dimensions. By 14 months of age only SHHF(cp/cp) rats showed significantly higher central systolic blood pressure and a reduced ejection fraction resulting in systolic dysfunction as compared to SHHF(+/?). In summary, the metabolic and hemodynamic mechanisms participating in the faster decline of cardiac functions in SHHF(cp/cp) rats are established long before their physiological consequences are detectable. Our results suggest that the molecular mechanisms triggered within the first three months after birth of SHHF(cp/cp) rats should be targeted preferentially by therapeutic interventions in order to mitigate the later HF development.

Simultaneous Characterization of Metabolic, Cardiac, Vascular and Renal Phenotypes of Lean and Obese SHHF Rats

PubMed Central

Youcef, Gina; Olivier, Arnaud; L'Huillier, Clément P. J.; Labat, Carlos; Fay, Renaud; Tabcheh, Lina; Toupance, Simon; Rodriguez-Guéant, Rosa-Maria; Bergerot, Damien; Jaisser, Frédéric; Lacolley, Patrick; Zannad, Faiez; Laurent Vallar; Pizard, Anne

2014-01-01

Individuals with metabolic syndrome (MetS) are prone to develop heart failure (HF). However, the deleterious effects of MetS on the continuum of events leading to cardiac remodeling and subsequently to HF are not fully understood. This study characterized simultaneously MetS and cardiac, vascular and renal phenotypes in aging Spontaneously Hypertensive Heart Failure lean (SHHF+/? regrouping +/+ and +/cp rats) and obese (SHHFcp/cp, “cp” defective mutant allele of the leptin receptor gene) rats. We aimed to refine the milestones and their onset during the progression from MetS to HF in this experimental model. We found that SHHFcp/cp but not SHHF+/? rats developed dyslipidemia, as early as 1.5 months of age. This early alteration in the lipidic profile was detectable concomitantly to impaired renal function (polyuria, proteinuria but no glycosuria) and reduced carotid distensibility as compared to SHHF+/? rats. By 3 months of age SHHFcp/cp animals developed severe obesity associated with dislipidemia and hypertension defining the onset of MetS. From 6 months of age, SHHF+/? rats developed concentric left ventricular hypertrophy (LVH) while SHHFcp/cp rats developed eccentric LVH apparent from progressive dilation of the LV dimensions. By 14 months of age only SHHFcp/cp rats showed significantly higher central systolic blood pressure and a reduced ejection fraction resulting in systolic dysfunction as compared to SHHF+/?. In summary, the metabolic and hemodynamic mechanisms participating in the faster decline of cardiac functions in SHHFcp/cp rats are established long before their physiological consequences are detectable. Our results suggest that the molecular mechanisms triggered within the first three months after birth of SHHFcp/cp rats should be targeted preferentially by therapeutic interventions in order to mitigate the later HF development. PMID:24831821

Progression of varicella-zoster virus necrotizing retinopathy in an HIV-negative patient with transient immune deviation.

PubMed

Lim, Wee-Kiak; Chee, Soon-Phaik; Nussenblatt, Robert Burton

2005-06-01

To report a case of unilateral varicella-zoster virus (VZV) necrotizing retinopathy that progressed from outer retinitis with features of progressive outer retinal necrosis (PORN) to typical acute retinal necrosis (ARN) in an HIV-negative patient with a transient decrease in CD4 lymphocyte counts and CD4/CD8 ratio. Case report. A 41-year-old Chinese man presenting with blurred vision in the right eye was diagnosed with herpetic necrotizing retinitis without vitritis. Fundus examination revealed retinal arteritis and extensive deep whitish retinal lesions in the mid-periphery with minimal vitritis. Aqueous humor and vitreous PCR were positive for VZV. His CD4 count on presentation was depressed (239 cells/ul) and the CD4/CD8 ratio was low (0.8). The referring ophthalmologist had treated him with prednisolone 60 mg/day. At our institution, when intravenous acyclovir was started and the steroid therapy discontinued, he developed severe vitritis and the deep retinal lesions progressed to full-thickness retinitis typical of ARN. Repeat CD4 count was 512 cells/ul at day 14. In total, he was treated with 14 days of i.v. acyclovir (12 mg/kg 8-hourly) followed by oral valaciclovir 500 mg three times a day for 3 months. Prednisolone 30 mg once daily was restarted and tapered over 3 months. Despite prophylactic argon retinal photocoagulation to the edge of the retinitis, the patient developed a total retinal detachment at 3 months. VZV retinal infection in an HIV-negative patient with transient immune deviation can manifest initially as outer retinitis with features similar to PORN and progress to typical ARN when CD4 counts return to normal.

E4206: AMG 706 and Octreotide in Patients with Low-Grade Neuroendocrine Tumors.

PubMed

Lubner, Sam; Feng, Yang; Mulcahy, Mary; O'Dwyer, Peter; Giang, Guang-Yu; Louis Hinshaw, J; Deming, Dustin; Klein, Leonard; Teitelbaum, Ursina; Payne, Jennifer; Engstrom, Paul; Stella, Philip; Meropol, Neal; Benson, Al

2018-05-31

Rate of progression-free survival at a particular point in time, i.e., a landmark analysis, is a difficult endpoint for a heterogenous malignancy such as neuroendocrine cancer.Landmark analyses can also be complicated by evolution in the standard of care during the conduct of a clinical trial.Improvements in biomarker development would be useful in developing future clinical trials in NET to better tailor individualized therapies and assess for possible efficacy endpoints. Neuroendocrine tumors (NETs) are rare malignancies of the gastrointestinal (GI) tract that are highly vascularized and overexpress vascular-endothelial growth factor (VEGF). Sunitinib has demonstrated efficacy in the pancreatic subset of NET. This study explored the activity of another oral VEGF inhibitor, AMG 706 or motesanib, a multikinase inhibitor that targets receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, KIT, RET, and PDGFR (IC50s = 2, 3, 6, 8, 59, and 84 nM, respectively). This was a single-arm, first-line, phase II study run through the Eastern Cooperative Oncology Group. Patients with low-grade NET (as defined by central confirmation of Ki-67 of 0%-2%) were administered a flat dose of 125 mg per day orally combined with octreotide long acting-repeatable (LAR) for patients who had been on a stable dose. The primary objective was to determine the 4-month progression-free survival (PFS). Forty-four patients were evaluated per protocol. The 4-month PFS was 78.5%. The partial response rate was 13.6% (6/44), stable disease was 54.5% (24/44), 9.1% (4/44) had progressive disease, and 10/44 were not evaluable for response. Common toxicities included fatigue, hypertension, nausea, and headache, and most were grade 1-2. Median PFS was 8.7 months, and overall survival was 27.5 months. Motesanib (AMG 706) demonstrated a 4-month PFS that met the per-protocol definition of efficacy. Fatigue and hypertension were the most common toxicities, and few grade 3-4 toxicities were encountered. The progression-free survival of 8.7 months in all NETs merits further study. The Oncologist 2018. © AlphaMed Press 2018.

Prelinguistic Vocal Development in Young Cochlear Implant Recipients and Typically Developing Infants: Year 1 of Robust Hearing Experience

PubMed Central

Ertmer, David J.; Jung, Jongmin

2012-01-01

This investigation examined the time course and sequence of prelinguistic vocal development during the first year of cochlear implant (CI) experience. Thirteen children who were implanted between 8 and 35 months and 11 typically developing (TD) infants participated in this longitudinal study. Adult–child play interactions were video- and audio-recorded at trimonthly intervals for each group, and child utterances were classified into categories representing progressively more mature productions: Precanonical Vocalizations, Basic Canonical Syllables, and Advanced Form vocalizations. Young CI recipients met the 20% criterion for establishment of the Basic Canonical Syllables and Advanced Forms levels with fewer months of robust hearing experience than the TD infants. Most CI recipients followed the sequence of development predicted by the Stark Assessment of Early Vocal Development—Revised. The relatively rapid progress of the CI children suggests that an earlier period of auditory deprivation did not have negative consequences for prelinguistic vocal development. It also supports the notion that young CI recipients comparatively advanced maturity facilitated expeditious auditory-guided speech development. PMID:21586617

Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.

PubMed Central

Maroulakou, I G; Anver, M; Garrett, L; Green, J E

1994-01-01

A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands. Images PMID:7972041

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models

PubMed Central

Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-01-01

Aim To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Material and Methods Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. Results In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87–97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4–5 months and sites recovered with a high probability (96–98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Conclusion Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. PMID:24888705

Macular Atrophy in Neovascular Age-Related Macular Degeneration with Monthly versus Treat-and-Extend Ranibizumab: Findings from the TREX-AMD Trial.

PubMed

Abdelfattah, Nizar S; Al-Sheikh, Mayss; Pitetta, Sean; Mousa, Ahmed; Sadda, SriniVas R; Wykoff, Charles C

2017-02-01

To compare the enlargement rate of macular atrophy (ERMA) in eyes treated with ranibizumab monthly or using a treat-and-extend (TREX) regimen for neovascular age-related macular degeneration (AMD) or fellow control eyes, as well as analyze risk factors for macular atrophy (MA) development and progression. Eighteen-month, multicenter, randomized, controlled clinical trial. Sixty patients with treatment-naïve neovascular AMD in 1 eye randomized 1:2 to monthly or TREX ranibizumab. Patients' study and fellow eyes were followed for 18 months using spectral-domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF) imaging. The MA was quantified on FAF images using Heidelberg Region Finder software (Heidelberg Engineering, Heidelberg, Germany), with suspected areas of atrophy confirmed by SD OCT and infrared reflectance imaging. For eyes without baseline MA yet developed MA by 18 months, intervening visits were assessed to determine the first visit at which MA appeared to define progression rates. Foveal choroidal thickness (FCT), subretinal hyperreflective material (SHRM), and pigment epithelial detachment (PED), were assessed at baseline to determine whether they influenced MA progression. Mean ERMA at 18 months. Relationship between visual acuity and MA, and the baseline risk factors for ERMA were also assessed. The final analysis cohort included 88 eyes in 3 groups: monthly (n = 19), TREX (n = 30), and control fellow eyes (n = 39). Mean ERMA over 18 months was 0.39±0.67 (monthly), 1.1±1.9 (TREX), and 0.49±1 mm 2 (control, P = 0.12). Mean ERMA per group among the 40.9% (n = 36) of baseline patients with MA was 0.9±1, 1.9±2.2, and 1±1.3 mm 2 , respectively (P = 0.31). The incidence rate of MA in the 3 groups was 40%, 0%, and 8.3%, respectively. Mann-Whitney U test revealed a statistically significant association between baseline FCT (127±46 vs. 155±55 μm, P = 0.01) and SHRM thickness (106±131 vs. 50±85 μm, P = 0.02) on MA. In eyes with no baseline MA, presence of SHRM, SHRM, and PED thickness, and presence of baseline hemorrhage were all significant predictors of new MA development (P = 0.04, 0.01, 0.04, 0.004, 0.01, respectively). Ranibizumab did not show a statistically significant influence on new MA development in eyes with neovascular AMD, whether dosed monthly or per TREX regimen. The FCT, SHRM thickness, and hemorrhage at baseline were all significant predictors of new MA. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Progressive outer retinal necrosis associated with occlusive vasculitis in acquired immunodeficiency syndrome.

PubMed

Tseng, Chien-Chi; Chen, San-Ni; Hwang, Jiunn-Feng; Lin, Chun-Ju; Chen, Huan-Sheng

2015-05-01

A 45-year-old man, a case of acquired immunodeficiency syndrome, received a highly active antiretroviral therapy at the outpatient service for 4 years without regular follow-up. He experienced progressively blurred vision for 6 months and a cutaneous zoster on his back 3 months ago. He was diagnosed with progressive outer retinal necrosis by polymerase chain reaction-restriction fragment length polymorphism using an aqueous humor sample, which revealed an existence of varicella zoster virus. He was given a combination of systemic, intravitreal antiviral and a highly active antiretroviral therapy. Occlusive vasculitis, an unusual finding for progressive outer retinal necrosis, developed in both eyes 1 week after the secondary intravitreal injection. Unfortunately, his vision deteriorated to no light perception in both eyes within 2 weeks. Progressive outer retinal necrosis is characterized clinically as showing minimal or no inflammation in the aqueous and vitreous humors, absence of retinal vasculitis, and patches of yellowish spots located deep in the retina. Physicians should pay attention to this rare case of progressive outer retinal necrosis associated occlusive vasculitis with very poor prognosis in spite of aggressive treatment. Copyright © 2015. Published by Elsevier B.V.

PubMed Central

BENSON, R.; BHASKER, S.; MOHANTI, B.K.

2015-01-01

SUMMARY Juvenile nasopharyngeal angiofibroma (JNA) is a disease of adolescent males characterised by high vascularity with local aggressiveness. This analysis was intended to see the effectiveness of radiation in locally advanced JNA. We included patients treated from 1990-2012. A total of 31 patients met study criteria. Median age was 16 years (range: 12-33 years). Radiation was used for refractory, residual or unresectable locally advanced disease. The median radiation dose was 30 Gy (range: 30-45 Gy). Median follow-up was 36 months (Range: 1-271 months). The median progression-free survival [PFS] was not reached. PFS at 3, 5 and 10 years was 91.7, 70.7 and 70.7% respectively. Three patients progressed at 38, 43 and 58 months after completion of treatment and opted for alternative therapy. One patient developed squamous cell carcinoma of the nasal ale 15 years after radiation. PMID:26019389

Motor development from 4 to 8 months corrected age in infants born at or less than 29 weeks' gestation.

PubMed

Pin, Tamis W; Darrer, Tanya; Eldridge, Bev; Galea, Mary P

2009-09-01

Clinically, preterm infants show motor delay and atypical postures compared with their peers born at term. A longitudinal cohort study was designed to describe the motor development of very preterm infants from 4 to 18 months corrected age (CA). The study was also designed to investigate how the atypical postures observed in early infancy in the preterm infants might be related to their later motor development. Here we report the findings in early motor skills from 4 to 8 months CA. Early motor skills were assessed in 62 preterm infants (32 males, 30 females, mean gestation 26.94wks, SD 1.11) and 53 term infants (32 males, 21 females, mean gestation 39.55wks, SD 1.17) using the Alberta Infant Motor Scale (AIMS). The preterm infants demonstrated different motor behaviours from their term peers, with an uneven progression of motor skills in different positions from 4 to 8 months CA. At 8 months CA, 90%of the term infants were able to sit without arm support, but only 56%of the preterm infants could maintain sitting very briefly without arm support. This uneven progression may have been due to an imbalance between the active flexor and extensor strength and hence inadequate postural control in these positions. The AIMS has also been shown to be a valid assessment tool to demonstrate unique characteristics in movement quality in the preterm population.

Ultrasound findings predict progression to inflammatory arthritis in anti-CCP antibody-positive patients without clinical synovitis.

PubMed

Nam, Jackie L; Hensor, Elizabeth M A; Hunt, Laura; Conaghan, Philip G; Wakefield, Richard J; Emery, Paul

2016-12-01

To determine whether ultrasound can identify anti-cyclic citrullinated peptide (anti-CCP) antibody-positive patients without clinical synovitis (CS) who progress to inflammatory arthritis (IA). In a prospective study, anti-CCP-positive patients without CS underwent ultrasound imaging of 32 joints (wrists, metacarpophalangeal joints, proximal interphalangeal joints and metatarsophalangeal joints (MTPs)) and were monitored for the development of IA. Associations between baseline ultrasound findings (grey scale (GS), power Doppler (PD) and erosions) and (1) progression to IA and (2) development of CS within an individual joint were measured. Consecutive anti-CCP-positive patients (n=136; mean age 51 years, 100 women) were followed up for median of 18.3 months (range 0.1-79.6). At baseline 96% had GS, 30% had PD and 21% had one or more erosions. IA developed in 57 patients (42%) after median of 8.6 months (range 0.1-52.4). Ultrasound abnormalities (GS ≥2, PD ≥1 or erosion ≥1) were found in 86% at baseline compared with 67% of non-progressors (χ 2 =6.3, p=0.012). Progression to IA was significantly higher in those with ultrasound findings in any joint (excluding MTPs for GS) (GS ≥2: 55% vs 24%, HR (95% CI) 2.3 (1.0 to 4.9), p=0.038; PD ≥2: 75% vs 32%, 3.7 (2.0 to 6.9), p<0.001 and erosion ≥1: 71% vs 34%, 2.9 (1.7 to 5.1), p<0.001). Furthermore, progression occurred earlier with PD ≥2 (median 7.1 vs 52.4 months) and erosion ≥1 (15.4 vs 46.5). At the individual joint level, the trend for progression to CS was more significant for GS and PD (GS ≥2: 26% vs 3%, 9.4 (5.1 to 17.5), p<0.001; PD ≥2: 55% vs 4%, 31.3 (15.6 to 62.9), p<0.001). Ultrasound features of joint inflammation may be detected in anti-CCP-positive patients without CS. Ultrasound findings predict progression (and rate of progression) to IA, with the risk of progression highest in those with PD signal. NCT02012764; Results. 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/.

Dr. John H. Hopps Jr. Research Scholars Program

DTIC Science & Technology

2014-10-20

Program staff, alumni and existing participants. Over the course of the last five months, SageFox has successfully obtained IRB approval for all...and awards. Progress made in development of the HoppsNet system included design and implementation of a relational database in MySQL , development of

Progressive outer retinal necrosis presenting as cherry red spot.

PubMed

Yiu, Glenn; Young, Lucy H

2012-10-01

To report a case of progressive outer retinal necrosis (PORN) presenting as a cherry red spot. Case report. A 53-year-old woman with recently diagnosed HIV and varicella-zoster virus (VZV) aseptic meningitis developed rapid sequential vision loss in both eyes over 2 months. Her exam showed a "cherry red spot" in both maculae with peripheral atrophy and pigmentary changes, consistent with PORN. Due to her late presentation and the rapid progression of her condition, she quickly developed end-stage vision loss in both eyes. PORN should be considered within the differential diagnosis of a "cherry red spot." Immune-deficient patients with a history of herpetic infection who present with visual loss warrant prompt ophthalmological evaluation.

Clinical analysis by next-generation sequencing for NSCLC patients with MET amplification resistant to osimertinib.

PubMed

Wang, Yubo; Li, Li; Han, Rui; Jiao, Lin; Zheng, Jie; He, Yong

2018-04-01

The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated. This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification. We performed capture-based sequencing on longitudinal plasma and tissue samples obtained before osimertinib treatment and after resistance development from lung adenocarcinoma patients to investigate the underlying resistance mechanism. We also investigated the correlation of MET amplification and patient prognosis after osimertinib resistance using Kaplan-Meier analysis. Paired biopsies before osimertinib treatment and after the resistance development revealed underlying resistance mechanisms. In addition, a cohort of 13 patients who developed disease progression after osimertinib resistance was investigated. Patients with MET amplification after osimertinib resistance commonly had inferior median progression-free survival (mPFS) than patients without MET amplification appearance or increase (3.5 months vs. 9.9 months, p = .117). Patients in MET amplification group also displayed poor median overall survival (mOS) compared to MET amplification negative group (15.6 months vs. 30.7 months, p = .885). Furthermore, combinatorial treatment of first/third-generation EGFR-TKI and crizotinib was efficaciously administrated into two patients with newly acquired MET amplification after osimertinib resistance. Partial responses were achieved by them, both clinically and radiographically. We investigated the osimertinib resistance mechanism in a small cohort of lung adenocarcinoma patients, and demonstrated MET amplification was correlated with inferior PFS/OS after osimertinib treatment. Moreover, we reported the first clinical evidence of efficacy generated by combination of first-generation EGFR-TKI icotinib and crizotinib after the resistance to osimertinib. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

The RenTg mice: a powerful tool to study renin-dependent chronic kidney disease.

PubMed

Huby, Anne-Cecile; Kavvadas, Panagiotis; Alfieri, Carlo; Abed, Ahmed; Toubas, Julie; Rastaldi, Maria-Pia; Dussaule, Jean-Claude; Chatziantoniou, Christos; Chadjichristos, Christos E

2012-01-01

Several studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD. We used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFβ family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation. The RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease.

Developmental Progression of Looking and Reaching Performance on the A-not-B Task

PubMed Central

Cuevas, Kimberly; Bell, Martha Ann

2013-01-01

From a neuropsychological perspective, the cognitive skills of working memory, inhibition, and attention and the maturation of the frontal lobe are requisites for successful A-not-B performance on both the looking and reaching versions of the task. This study used a longitudinal design to examine the developmental progression of infants’ performance on the looking and reaching versions of the A-not-B task. Twenty infants were tested on both versions of the task once a month from 5 to 10 months of age. Infants had higher object permanence scores on the looking version of the task from 5 to 8 months, with comparable performance across response modalities at 9 and 10 months. The same pattern of performance was found on nonreversal (A) trials: Infants performed better on looking trials from 5 to 7 months and they performed equally on both response trials from 8 to 10 months. Overall, infants performed better on looking reversal (B) trials than reaching reversal trials. These data suggest that performance differences between response modalities early in development can be attributed to major differences in the maturation of brain circuitry associated with the actual task response. PMID:20822245

Ceroid-lipofuscinosis in border collie dogs.

PubMed

Taylor, R M; Farrow, B R

1988-01-01

Five Border Collie dogs with ceroid-lipofuscinosis developed progressive neurological disease between 18 and 22 months of age. These dogs had behavioural abnormalities, gait and visual deficits and became progressively demented. All dogs examined had common ancestors. Light microscopic examination of tissues demonstrated extensive accumulation of granular, sudan black-staining autofluorescent material in the cytoplasm of neurones, retinal ganglion cells and some visceral cells. At ultrastructural examination inclusions of variable morphology were observed.

Rapidly progressive idiopathic lenticular astigmatism.

PubMed

Tint, Naing L; Jayaswal, Rakesh; Masood, Imran; Maharajan, V Senthil

2007-02-01

A myopic 43-year-old woman with early nuclear sclerotic cataract developed more than 11.0 diopters (D) of astigmatism over a 6-month period. This was found to be lenticular in origin. Phacoemulsification with intraocular lens implantation was performed, resulting in residual astigmatism of 0.75 D. To our knowledge, this is the first case of rapidly progressive lenticular astigmatism in an otherwise healthy eye with early nuclear sclerotic cataract.

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design.

PubMed

Peeters, Frederique E C M; van Mourik, Manouk J W; Meex, Steven J R; Bucerius, Jan; Schalla, Simon M; Gerretsen, Suzanne C; Mihl, Casper; Dweck, Marc R; Schurgers, Leon J; Wildberger, Joachim E; Crijns, Harry J G M; Kietselaer, Bas L J H

2018-03-21

BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild-moderate CAVS will be included in the study, and baseline 18 F-sodiumfluoride ( 18 F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second 18 F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR 18 F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT).

Chemosaturation with Percutaneous Hepatic Perfusion for Unresectable Isolated Hepatic Metastases from Sarcoma

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

Deneve, Jeremiah L., E-mail: Jeremiah.Deneve@Moffitt.org; Choi, Junsung; Gonzalez, Ricardo J.

Purpose: Treatment of patients with unresectable liver metastases is challenging. Regional therapies to the liver have been developed that maximize treatment of the localized disease process without systemic toxic adverse effects. We discuss the procedural aspects of liver chemosaturation with percutaneous hepatic perfusion (CS-PHP). Methods: We present as an illustration of this technique a case report of the treatment of unresectable metastatic leiomyosarcoma of the liver. Results: A randomized phase III trial for unresectable liver metastases from melanoma was recently completed comparing CS-PHP with melphalan vs. best alternative care (BAC). When compared with BAC, CS-PHP was associated with a significantmore » improvement in hepatic progression-free survival (8.0 months CS-PHP vs. 1.6 months BAC, p < 0.0001) and overall progression-free survival (6.7 months CS-PHP vs. 1.6 months BAC, p < 0.0001), respectively. On the basis of these results, and given our experience as one of the treating institutions for this phase III trial, we appealed for compassionate use of CS-PHP in a patient with isolated bilobar unresectable hepatic metastases from leiomyosarcoma. Four target lesions were identified and monitored to assess treatment response. A total of 4 CS-PHP procedures were performed, with a 25 % reduction in size of the largest lesion observed and 16 month hepatic progression-free survival. Toxicity was mild (neutropenia) and manageable on an outpatient basis. Conclusion: CS-PHP offers several advantages for unresectable hepatic sarcoma metastases. CS-PHP is minimally invasive and repeatable, and it has a predictable and manageable systemic toxicity profile. For appropriately selected patients, CS-PHP can delay tumor progression and could potentially improve survival.« less

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort

PubMed Central

Zang, R Y; Harter, P; Chi, D S; Sehouli, J; Jiang, R; Tropé, C G; Ayhan, A; Cormio, G; Xing, Y; Wollschlaeger, K M; Braicu, E I; Rabbitt, C A; Oksefjell, H; Tian, W J; Fotopoulou, C; Pfisterer, J; du Bois, A; Berek, J S

2011-01-01

Background: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. Methods: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. Results: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1–1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (⩽23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. Conclusion: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer. PMID:21878937

An Empirical Comparison of Formulas Evaluating Early Intervention Program Impact on Development.

ERIC Educational Resources Information Center

Rosenberg, Steven A.; And Others

1987-01-01

The study evaluated developmental progress in three groups of infants (9-30 months) presenting Down syndrome (n=28), mild disability (n=16), or moderate/severe disabilities (n=16). To evaluate intervention impact, formulas that measure rate of development and change in rate of development were computed. Findings indicated rate change formulas were…

A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis.

PubMed Central

Lai, M; Hodgson, T; Gawne-Cain, M; Webb, S; MacManus, D; McDonald, W I; Thompson, A J; Miller, D H

1996-01-01

Long TR and gadolinium enhanced spin echo brain MRI was performed weekly for three months in three patients with relapsing-remitting or secondary progressive multiple sclerosis. During the study, 38 new enhancing lesions were seen; 11 showed enhancement for less than four weeks, and two enhanced on only one scan. All 16 new lesions seen on long TR scans showed initial enhancement. When only every fourth (monthly) scan was analysed, a total of 33 new enhancing lesions were seen. Subject to confirmation in a larger cohort, the results suggest: (a) that blood brain barrier leakage is an invariable event in new lesion development in relapsing-remitting and secondary progressive multiple sclerosis; (b) the small increase in sensitivity of weekly scanning does not justify its use in preference to monthly scanning when monitoring treatments. Images PMID:8609517

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models.

PubMed

Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-09-01

To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87-97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4-5 months and sites recovered with a high probability (96-98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. © 2014 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

Research into the development of a knowledge acquisition taxonomy

NASA Technical Reports Server (NTRS)

Fink, Pamela K.

1991-01-01

Monthly progress reports for September 1990 to January 1991 are given. Topics that are briefly covered include problem solving and learning taxonomies, knowledge acquisition techniques, software design, air traffic control, and space shuttle flight control.

Heterogeneity-based, multiple mechanisms in the resistance to osimertinib (AZD9291): A case report.

PubMed

Liu, Yutao; Hao, Xuezhi; Hu, Xingsheng; Li, Junling; Wang, Yan; Wang, Hongyu; Xing, Puyuan; Li, Weihua; Ying, Jianming; Han, Xiaohong; Shi, Yuankai

2018-04-01

Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism. Our findings revealed the underlying multiple and heterogeneous mechanisms in resistance to osimertinib, suggesting combination strategies should be considered post-osimertinib progression. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Optical fiber sensors and signal processing for intelligent structure monitoring

NASA Technical Reports Server (NTRS)

Rogowski, Robert; Claus, R. O.; Lindner, D. K.; Thomas, Daniel; Cox, Dave

1988-01-01

The analytic and experimental performance of optical fiber sensors for the control of vibration of large aerospace and other structures are investigated. In particular, model domain optical fiber sensor systems, are being studied due to their apparent potential as distributed, low mass sensors of vibration over appropriate ranges of both low frequency and low amplitude displacements. Progress during the past three months is outlined. Progress since September is divided into work in the areas of experimental hardware development, analytical analysis, control design and sensor development. During the next six months, tests of a prototype closed-loop control system for a beam are planned which will demonstrate the solution of several optical fiber instrumentation device problems, the performance of the control system theory which incorporates the model of the modal domain sensor, and the potential for distributed control which this sensor approach offers.

Atypical immunologic response in a patient with CRIM-negative Pompe disease

PubMed Central

Abbott, Mary-Alice; Prater, Sean N.; Banugaria, Suhrad G.; Richards, Susan M.; Young, Sarah P.; Rosenberg, Amy S.; Kishnani, Priya S.

2013-01-01

We report the clinical course of a patient with severe infantile onset Pompe disease [cross-reactive immunologic material (CRIM) negative, R854X/R854X] who was diagnosed prenatally and received standard dosing of alglucosidase alfa (Myozyme®) enzyme replacement therapy (ERT) from day 10 of life until she passed away at the age of 3 years 9 months. In the immediate neonatal period there was cardiomegaly on chest X-ray, cardiac hypertrophy by echocardiogram, and development of a wide complex tachycardia. CRIM negative (CN) status was suspected based on her family history, and the available data at the time indicated that CN patients had limited survival even with ERT. However, given the opportunity for very early treatment, the treating provider and family elected to initiate treatment with ERT, without immune modulation. By 9 months of age echocardiogram was normal. Early motor development was within normal limits but by 2 years of age her developmental progress had slowed. She seroconverted by the 4th month of ERT, and anti-rhGAA antibody titers peaked at 25,600 in the 27th month. Immunomodulatory therapy was considered but declined by family. She acquired Influenza A at 2 years 6 months, which led to a prolonged hospitalization with invasive respiratory support, and placement of tracheostomy and gastrostomy tube. Her developmental progress ceased, and she died suddenly at home from a presumed cardiac event at age 3 years 9 months. The poor outcomes observed in CN patients have been attributed to the development of high sustained antibody titers. Although this CN patient’s anti-rhGAA response was elevated and sustained, it is unlike any of the 3 patterns that have been previously described: high titer CN, high titer CRIM positive (HTCP), and low titer CP (LTCP) patients. This patient’s clinical course, with achievement of 24 months of motor gains, 30 months of ventilator-free survival and 45 month survival, is like that of only a fraction of ERT treated CN patients, yet it is identical to other reported CN patients in its relentless progression and early fatality. The immunologic response (moderate sustained antibody titers) described here has not been previously reported and may have played a role in the overall pattern of developmental decline. In light of proposed universal newborn screening for Pompe disease, there is an urgent need for improved understanding of the interplay between immunologic responses to the only available treatment, ERT, and the relentless nature of this disease in CN patients. PMID:21889385

The potential of composite cognitive scores for tracking progression in Huntington's disease.

PubMed

Jones, Rebecca; Stout, Julie C; Labuschagne, Izelle; Say, Miranda; Justo, Damian; Coleman, Allison; Dumas, Eve M; Hart, Ellen; Owen, Gail; Durr, Alexandra; Leavitt, Blair R; Roos, Raymund; O'Regan, Alison; Langbehn, Doug; Tabrizi, Sarah J; Frost, Chris

2014-01-01

Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.

Postdischarge growth and development in a predominantly Hispanic, very low birth weight population.

PubMed

Powers, George C; Ramamurthy, Rajam; Schoolfield, John; Matula, Kathleen

2008-12-01

The goals were to assess postdischarge growth and developmental progress of very low birth weight (birth weight: <1500 g) premature infants in a predominantly Hispanic population and to identify predictors for neurodevelopmental impairment at 3 years of age. A cohort of 135 very low birth weight infants (gestational age: 23 to 35 weeks) were monitored to 3 years of age. Maternal and neonatal characteristics, anthropometric z scores, and developmental performance (using corrected age until 24 months) were analyzed collectively and according to gestational age groups. Specific criteria for failure to thrive and microcephaly were used. A characteristic pattern of poor weight gain in the first 12 months was followed by accelerated weight gain starting at 18 months, whereas head growth decreased at 18 months, with recovery beginning at 30 months of age. Infants born at gestational age of or=27 weeks achieved catch-up growth by 30 months of age. Mean developmental scores also decreased in infancy, with improvements in motor development emerging at 18 months and cognitive skills at 30 months. Growth z scores, particularly for head growth, correlated with developmental scores. Infants born at gestational age of

Development of Choroidal Neovascularization in rats with Advanced Intense Cyclic Light-induced Retinal Degeneration

PubMed Central

Albert, Daniel M.; Neekhra, Aneesh; Wang, Shoujian; Darjatmoko, Soesiawati R.; Sorenson, Christine M.; Dubielzig, Richard R.; Sheibani, Nader

2010-01-01

Objective To study the progressive changes of intense cyclic light-induced retinal degeneration and determine whether it results in choroidal neovascularization (CNV). Methods Albino rats were exposed to 12 h of 3000 lux cyclic light for 1, 3, or 6 months. Prior to euthanization, fundus examination, fundus photographs, fluorescein and indocyanine green angiography, and Optical Coherence Tomography (OCT) evaluations were performed. Light exposed animals were euthanized after 1, 3, or 6 months for histopathological evaluation. Retinas were examined for the presence of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine modified proteins by immunofluorescence staining. Results Chronic intense cyclic light exposure resulted in retinal degeneration with loss of the outer segments of photoreceptors and approximately two-thirds of the outer nuclear layer (ONL) and development of sub-retinal pigment epithelium (RPE) neovascularization after 1 month. Almost the entire ONL was absent with the presence of CNV, which penetrated Bruch’s membrane and extended into the outer retina after 3 months. Absence of the ONL, multiple foci of CNV, RPE fibrous metaplasia, and connective tissue bands containing blood vessels extending into the retina were observed after 6 months. All intense light exposed animals showed an increased presence of HNE and nitrotyrosine staining. OCT and angiographic studies confirmed retinal thinning and leakiness of the newly fromed blood vessels. Conclusions Our results suggest albino rats develop progressive stages of retinal degeneration and CNV after chronic intense cyclic light exposure allowing the detailed study of the pathogenesis and treatment of age-related macular degeneration. PMID:20142545

Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial.

PubMed

O'Leary, Daniel H; Reuwer, Anne Q; Nissen, Steven E; Després, Jean-Pierre; Deanfield, John E; Brown, Michael W; Zhou, Rong; Zabbatino, Salvatore M; Job, Bernard; Kastelein, John J P; Visseren, Frank L J

2011-07-01

The aim of this trial was to determine whether obese patients benefit from treatment with rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese. A prospective, double-blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intima-media Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intima-media thickness from baseline to month 30 was 0.010 ± 0.095 mm in the rimonabant group and 0.012 ± 0.091 mm in the placebo group (p=0.67). The annualised change was an increase of 0.005 ± 0.042 mm for the rimonabant-treated group and 0.007 ± 0.043 mm for the placebo-treated group (p=0.45). There was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intima-media thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome. Clinical trial registration information clinicaltrials.gov Identifier: NCT00228176.

Restrictive allograft syndrome after lung transplantation: new radiological insights.

PubMed

Dubbeldam, Adriana; Barthels, Caroline; Coolen, Johan; Verschakelen, Johny A; Verleden, Stijn E; Vos, Robin; Verleden, Geert M; De Wever, Walter

2017-07-01

To describe the CT changes in patients with restrictive allograft syndrome (RAS) after lung transplantation, before and after clinical diagnosis. This retrospective study included 22 patients with clinical diagnosis of RAS. Diagnosis was based on a combination of forced expiratory volume (FEV1) decline (≥20 %) and total lung capacity (TLC) decline (≥10 %). All available CT scans after transplantation were analyzed for the appearance and evolution of lung abnormalities. In 14 patients, non-regressing nodules and reticulations predominantly affecting the upper lobes developed an average of 13.9 months prior to the diagnosis of RAS. Median graft survival after onset of non-regressing abnormalities was 33.5 months, with most patients in follow-up (9/14). In eight patients, a sudden appearance of diffuse consolidations mainly affecting both upper and lower lobes was seen an average of 2.8 months prior to the diagnosis of RAS. Median graft survival was 6.4 months after first onset of non-regressing abnormalities, with graft loss in most patients (6/8). RAS has been previously described as a homogenous group. However, our study shows two different groups of RAS-patients: one with slow progression and one with fast progression. The two groups show different onset and progression patterns of CT abnormalities. • RAS is the newest discovered form of chronic lung allograft dysfunction (CLAD). • RAS is not a homogenous group, as survival varies greatly between patients. • In this study, we see two different CT onset and progression patterns. • These two different CT patterns also correlate with a different survival rate.

Progressive lenticular astigmatism in the clear lens.

PubMed

Tatham, Andrew; Prydal, Jeremy

2008-03-01

We describe a case of progressive lenticular astigmatism in a 53-year-old man with a clear lens. The patient acquired 5 diopters of lenticular astigmatism in his right eye over an 18-month period. The visual acuity was reduced to 6/60. Following phacoemulsification and intraocular lens implantation, the uncorrected visual acuity was 6/5. Progressive astigmatism is usually corneal in origin and in an otherwise healthy eye, significant lenticular astigmatism is rare. When lenticular astigmatism occurs, it is usually associated with a cortical cataract; however, astigmatism may precede the development of a clinically visible cataract.

Subacute sclerosing panencephalitis presenting as rapidly progressive young-onset dementia.

PubMed

Chakor, Rahul Tryambak; Santosh, Nandanavana Subbareddy

2013-07-01

Onset of dementia before 65 years of age is termed as young-onset dementia (YOD). Very little literature exists regarding the clinical features and diagnoses of dementia in younger individuals. We present a case series of four patients of age 10 to 23 years with severe dementia within 18 months of clinical onset (rapidly progressive dementia). Three patients had generalised periodic complexes typical of subacute sclerosing panencephalitis (SSPE) on electroencephalogram (EEG). All patients had elevated cerebrospinal fluid (CSF) IgG measles antibodies. Our case series highlights that SSPE is an important cause of rapidly progressive YOD in developing countries like India.

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

Oh, Dongryul; Ahn, Yong Chan, E-mail: ycahn.ahn@samsung.com; Kim, Seok Jin

Purpose: To evaluate the effectiveness of concurrent chemoradiation therapy (CCRT) with 40 Gy followed by consolidation chemotherapy for localized extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type. Methods and Materials: From August 2004 to August 2012, 62 patients with newly diagnosed stage IE to IIE ENKTL underwent CCRT followed by consolidation chemotherapy. The median RT dose was 40 Gy. Cisplatin, 30 mg/m{sup 2}, was administered weekly during the RT course. Responders to CCRT were encouraged to undergo consolidation chemotherapy. Three different consolidation chemotherapy regimens were used consecutively: VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone); VIDL (etoposide, ifosfamide, and dexamethasone followed by intramuscular injection ofmore » L-asparaginase); and MIDLE (methotrexate, etoposide, ifosfamide, mesna, and L-asparaginase). Results: The median follow-up period was 49 months (range 8-112). After completion of CCRT, 56 patients (90.3%) had a complete response, 4 (6.4%) had a partial response, 1 (1.6%) had stable disease, and 1 patient (1.6%) had progressive disease (PD). Consolidation chemotherapy was recommended to 61 patients, after excluding the patient with PD, but was actually delivered to 58. Of these 58 patients, 56 (96.5%) had a complete response and 2 (3.5%) had PD. During the follow-up period, 17 patients (including 3 with PD) experienced progression. The median interval to progression was 11 months (range 1-61). Local failure developed in 6 patients, of whom, 2 had developed progression outside the RT field. For all patients, the 3-year overall survival, progression-free survival, and local control rates were 83.1%, 77.1%, and 92.4%, respectively. Grade ≥3 nonhematologic toxicity developed in only 3 patients (4.8%). Conclusions: Excellent clinical outcomes were achieved using CCRT with 40 Gy followed by consolidation chemotherapy. Additional investigation, however, is warranted to confirm our findings.« less

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation.

PubMed

Jaramillo, A; Smith, M A; Phelan, D; Sundaresan, S; Trulock, E P; Lynch, J P; Cooper, J D; Patterson, G A; Mohanakumar, T

1999-04-27

Development of anti-HLA antibodies after lung transplantation (LT) is thought to play an important role in the etiology of bronchiolitis obliterans syndrome (BOS). However, a cause-effect relationship between anti-HLA antibodies and BOS has not been established. This study was conducted to determine the temporal relationship between the development of anti-HLA antibodies and BOS after LT, and to determine the antigenic specificity of the antibodies developed in BOS patients. Sera from 15 BOS+ LT patients and 12 BOS- LT patients were obtained before LT and collected again at 6, 12, 24, 36, and 48 months after LT. Anti-HLA antibodies were detected by the PRA-STAT ELISA system and by complement-dependent cytotoxicity assays. Anti-HLA reactivity was further characterized by flow cytometry and absorption/elution with human platelets. When analyzed by ELISA, 10 of 15 BOS+ patients developed anti-HLA antibodies, whereas 0 of 12 BOS- patients developed anti-HLA antibodies (P<0.001). When analyzed by complement-dependent cytotoxicity, only 2 of 15 BOS+ patients developed anti-HLA antibodies and 1 of 12 BOS- patients developed anti-HLA antibodies (P = 0.99). There was a significant difference of 20.1 months between the time of anti-HLA antibody detection and the time of BOS diagnosis (P = 0.005). A progressive decrease in pulmonary function correlated with a progressive increase in the anti-HLA reactivity 36 months after LT. The anti-HLA reactivity was directed to one of the donor HLA class I antigens and to other unrelated HLA class I antigens. No anti-HLA reactivity was found against HLA class II molecules. Our study indicates that anti-HLA class I antibodies play an important role in the pathogenesis of BOS and that monitoring of anti-HLA class I antibody development by a highly sensitive assay such as the PRA-STAT ELISA after LT can provide an early identification of an important subset of LT patients with an increased risk of developing BOS.

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor

PubMed Central

Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice

2016-01-01

Purpose To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. Patients and methods ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Results Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. Conclusion ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted. PMID:27801670

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor.

PubMed

Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

2016-11-15

To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted.

Terrestrial Planet Finder Interferometer: Architecture, Mission Design and Technology Development

NASA Technical Reports Server (NTRS)

Henry, Curt; Lay, Oliver; Aung, MiMi; Gunter, Steven M.; Dubovitsky, Serge; Blackwood, Gary

2004-01-01

This overview paper is a progress report about the system design and technology development of two interferometer concepts studied for the Terrestrial Planet Finder (TPF) project. The two concepts are a structurally-connected interferometer (SCI) intended to fulfill minimum TPF science goals and a formation-flying interferometer (FFI) intended to fulfill full science goals. Described are major trades, analyses, and technology experiments completed. Near term plans are also described. This paper covers progress since August 2003 and serves as an update to a paper presented at that month's SPIE conference, 'Techniques and Instrumentation for Detection of Exoplanets.

Identification of age-dependent motor and neuropsychological behavioural abnormalities in a mouse model of Mucopolysaccharidosis Type II

PubMed Central

Gleitz, Hélène F. E.; O’Leary, Claire; Holley, Rebecca J.

2017-01-01

Severe mucopolysaccharidosis type II (MPS II) is a progressive lysosomal storage disease caused by mutations in the IDS gene, leading to a deficiency in the iduronate-2-sulfatase enzyme that is involved in heparan sulphate and dermatan sulphate catabolism. In constitutive form, MPS II is a multi-system disease characterised by progressive neurocognitive decline, severe skeletal abnormalities and hepatosplenomegaly. Although enzyme replacement therapy has been approved for treatment of peripheral organs, no therapy effectively treats the cognitive symptoms of the disease and novel therapies are in development to remediate this. Therapeutic efficacy and subsequent validation can be assessed using a variety of outcome measures that are translatable to clinical practice, such as behavioural measures. We sought to consolidate current knowledge of the cognitive, skeletal and motor abnormalities present in the MPS II mouse model by performing time course behavioural examinations of working memory, anxiety, activity levels, sociability and coordination and balance, up to 8 months of age. Cognitive decline associated with alterations in spatial working memory is detectable at 8 months of age in MPS II mice using spontaneous alternation, together with an altered response to novel environments and anxiolytic behaviour in the open-field. Coordination and balance on the accelerating rotarod were also significantly worse at 8 months, and may be associated with skeletal changes seen in MPS II mice. We demonstrate that the progressive nature of MPS II disease is also seen in the mouse model, and that cognitive and motor differences are detectable at 8 months of age using spontaneous alternation, the accelerating rotarod and the open-field tests. This study establishes neurological, motor and skeletal measures for use in pre-clinical studies to develop therapeutic approaches in MPS II. PMID:28207863

CD30 As a Target for the Treatment of Cutaneous T-Cell Lymphoma.

PubMed

Prince, H Miles

2015-11-10

A 72-year-man presented with a 7-month history of progressive patches and plaques over the trunk and limbs. A skin biopsy confirmed mycosis fungoides (MF). After staging investigations, he was considered to have T2N0M0B0 (stage Ib) disease and began ultraviolet (UV) B phototherapy. Despite initial response, his disease progressed after 4 months, with enlarging patches and plaques but without nodal involvement. As second-line therapy, he received interferon alfa-2b (IFN--2b) 2.7 MU daily, which he tolerated well. He again experienced initial partial response (PR), but by 18 months, he had experienced tumor progression, with patches, plaques, and multiple tumors over the body (up to 3 cm; Fig 1). Biopsy of a neck tumor demonstrated tumor-stage MF,with no evidence of large-cell transformation. Approximately 30% of lymphocytes strongly expressed CD30. CD25 was negative. He began treatment with oral methotrexate 20mg per week, which he tolerated well, and achieved a PR lasting 7 months before multiple plaque and tumor lesions recurred, along with the development of inguinal lymphadenopthy. Biopsy of the skin lesions confirmed the same disease, and [18F]fluorodeoxyglucose–positron emission tomography demonstrated avidity in inguinal and internal iliac nodes, with lymphadenopathy measuring up to 3.5 cm. He has been referred for consideration of further systemic therapy.

Education Matters, March 2010

ERIC Educational Resources Information Center

Beckner, Gary, Ed.

2010-01-01

"Education Matters" is the monthly newsletter of the Association of American Educators (AAE), an organization dedicated to advancing the American teaching profession through personal growth, professional development, teacher advocacy and protection. This issue of the newsletter includes: (1) The War on Progress: Why the National…

CXCL12 chemokine genotypes as predictive biomarkers of ovarian cancer outcome.

PubMed

Coelho, Ana; Pereira, Deolinda; Nogal, Ana; Pinto, Daniela; Catarino, Raquel; Araújo, António; Medeiros, Rui

2009-01-01

Ovarian cancer is an aggressive disease with high mortality. The CXCL12 chemokine has been associated with the development of this neoplasia. The aim of this study was to evaluate the genetic influence of the CXCL12-3'A polymorphism as a prognostic/predictive factor in ovarian cancer patients treated with platinum/paclitaxel chemotherapy. The mean survival rates for early stages (I/II) of the disease were statistically different according to patient genotype (96 months for GG and 57 months for A carrier genotypes; p=0.017). The mean progression-free interval was statistically lower in patients with early stages (I/II) of the tumour carrying the A allele (55 months) than in those carrying the GG genotype (91 months; P=0.009). The CXCL12-3'A polymorphism leads to a poorer response to chemotherapy with cisplatin/paclitaxel, and diminishes the mean survival rate and the progression-free interval in patients with ovarian cancer. CXCL12-3'A may therefore serve as an important predictive biomarker for the determination of outcome in ovarian cancer.

Towards optimizing the sequence of bevacizumab and nitrosoureas in recurrent malignant glioma.

PubMed

Wiestler, Benedikt; Radbruch, Alexander; Osswald, Matthias; Combs, Stephanie E; Jungk, Christine; Winkler, Frank; Bendszus, Martin; Unterberg, Andreas; Platten, Michael; Wick, Wolfgang; Wick, Antje

2014-03-01

Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p = 0.03). Survival times were similar for patients with grade III (n = 9) and grade IV (n = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs.

The time course of neurolinguistic and neuropsychological symptoms in three cases of logopenic primary progressive aphasia.

PubMed

Etcheverry, Louise; Seidel, Barbara; Grande, Marion; Schulte, Stephanie; Pieperhoff, Peter; Südmeyer, Martin; Minnerop, Martina; Binkofski, Ferdinand; Huber, Walter; Grodzinsky, Yosef; Amunts, Katrin; Heim, Stefan

2012-06-01

Primary progressive aphasia (PPA) is a rare clinical dementia syndrome affecting predominantly language abilities. Word-finding difficulties and comprehension deficits despite relatively preserved cognitive functions are characteristic symptoms during the first two years, and distinguish PPA from other dementia types like Alzheimer's disease. However, the dynamics of changes in language and non-linguistic abilities are not well understood. Most studies on progression used cross-sectional designs, which provide only limited insight into the course of the disease. Here we report the results of a longitudinal study in three cases of logopenic PPA over a period of 18 months, with exemplary longitudinal data from one patient even over 46 months. A comprehensive battery of neurolinguistic and neuropsychological tests was applied four times at intervals of six months. Over this period, deterioration of verbal abilities such as picture naming, story retelling, and semantic word recall was found, and the individual decline was quantified and compared between the three patients. Furthermore, decrease in non-verbal skills such as divided attention and increasing apraxia was observed in all three patients. In addition, inter-subject variability in the progression with different focuses was observed, with one patient developing a non-fluent PPA variant. The longitudinal, multivariate investigation of logopenic PPA thus provides novel insights into the progressive deterioration of verbal as well as non-verbal abilities. These deficits may further interact and thus form a multi-causal basis for the patients' problems in every-day life which need to be considered when planning individually targeted intervention in PPA. Copyright © 2012 Elsevier Ltd. All rights reserved.

Representation of the equatorial stratospheric quasi-biennial oscillation in EOF phase space. [EOF (empirical orthogonal function)

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

Wallace, J.M.; Panetta, R.L.; Estberg, J.

1993-06-15

A 35-year record of monthly mean zonal wind data for the equatorial stratosphere is represented in terms of a vector (radius and phase angle) in a two-dimensional phase space defined by the normalized expansion coefficients of the two leading empirical orthogonal functions (EOFs) of the vertical structure. The tip of the vector completes one nearly circular loop during each cycle of the quasi-biennial oscillation (QBO). Hence, its position and rate of progress along the orbit of the point provide a measure of the instantaneous amplitude and rate of phase progression of the QBO. Although the phase of the QBO bearsmore » little if any relation to calendar month, the rate of phase progression is strongly modulated by the first and second harmonics of the annual cycle, with a primary maximum in April/May, in agreement with previous studies based on the descent rates of easterly and westerly regimes. A simple linear prediction model is developed for the rate of phase progression, based on the phase of the QBO and the phase of the annual cycle. The model is capable of hindcasting the phase of the QBO to within a specified degree of accuracy approximately 50% longer than a default scheme based on the mean observed rate of phase progression of the QBO (1 cycle per 28.1 months). If the seasonal dependence is ignored, the prediction equation corresponds to the [open quotes]circle map,[close quotes] for which an extensive literature exists in dynamical systems theory. 17 refs., 14 figs., 2 tabs.« less

[Rapidly progressive puberty in a patient with mosaic Turner syndrome: a case report and literature review].

PubMed

Liang, Y; Wei, H; Yu, X; Huang, W; Luo, X P

2017-02-02

Objective: To explore the clinical characteristics of diagnosis and treatment in patients with Turner syndrome and rapidly progressive puberty. Method: A rare case of rapidly progressive puberty in Turner syndrome with a mosaic karyotype of 45, X/46, X, del(X)(p21)(80%/20%)was diagnosed at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in January. 2015. Clinical characteristics and the related literature were reviewed. Original papers on precocious puberty or rapidly progressive puberty in Turner syndrome, published until Apr. 2016 were retrieved at PubMed and CNKI databases by the use of the key words "Turner syndrome" , "precocious puberty" and "rapidly progressive puberty" . Result: The patient was born at term with birth weight of 2 450 g and was diagnosed with SGA at 3 years of age for the first evaluating of growth and development. Then recombined human growth hormone (rhGH )was given at 4 years of age due to short stature (height<3 percentile) and low growth velocity(<5.0 cm/year) as well. However, rhGH treatment was discontinued after 9 months because of economic burdens. Breast development was noted at 9 years and 3 months. The patient was followed up at 3 months intervals. Physical examination revealed a Tanner stage Ⅲ breast development at 10.33 years , the bone age was 11.6 years. Then, gonadotropin-releasing hormone analogs treatment was added to slow pubertal progression and to preserve maximum adult height. The growth rate decreased with therapy from 7.5 cm/year to 4.4 cm/year. The patient was reevaluated, and the chromosome analysis of peripheral blood revealed a mosaic karyotype 45, X/46, X, del(X)(p21)(80%/ 20%). To date, only 10 cases have been reported in the literature. Six of them showing mosaic TS, three karyotypes with structural abnormality of short arm of X chromosome, one with the karyotype 45, X. Conclusion: It is the first time that rapidly progressive puberty in a 45, X/46, X, del(X)(p21) mosaic Turner syndrome is reported. Although short stature and ovarian dysgenesis are common in TS, precocious puberty may occur in TS, which is liable to cause delayed diagnosis and misdiagnosis. Careful examination is recommended for patients with unusual growth pattern, even though girls have normal height in accord with standard growth curve or spontaneous puberty. Evaluation for TS and subsequent investigation should be prompted.

Changes in retinal venular oxygen saturation predict activity of proliferative diabetic retinopathy 3 months after panretinal photocoagulation.

PubMed

Torp, Thomas Lee; Kawasaki, Ryo; Wong, Tien Yin; Peto, Tunde; Grauslund, Jakob

2018-03-01

Proliferative diabetic retinopathy (PDR) is a severe blinding condition. We investigated whether retinal metabolism, measured by retinal oximetry, may predict PDR activity after panretinal laser photocoagulation (PRP). We performed a prospective, interventional, clinical study of patients with treatment-naive PDR. Wide-field fluorescein angiography (OPTOS, Optomap) and global and focal retinal oximetry (Oxymap T1) were performed at baseline (BL), and 3 months (3M) after PRP. Angiographic findings were used to divide patients according to progression or non-progression of PDR after PRP. We evaluated differences in global and focal retinal oxygen saturation between patients with and without progression of PDR after PRP treatment. We included 45 eyes of 37 patients (median age and duration of diabetes were 51.6 and 20 years). Eyes with progression of PDR developed a higher retinal venous oxygen saturation than eyes with non-progression at 3M (global: +5.9% (95% CI -1.5 to 12.9), focal: +5.4%, (95% CI -4.1 to 14.8)). Likewise, progression of PDR was associated with a lower arteriovenular (AV) oxygen difference between BL and 3M (global: -6.1%, (95% CI -13.4 to -1.4), focal: -4.5% (95% CI -12.1 to 3.2)). In a multiple logistic regression model, increment in global retinal venular oxygen saturation (OR 1.30 per 1%-point increment, p=0.017) and decrement in AV oxygen saturation difference (OR 0.72 per 1%-point increment, p=0.016) at 3M independently predicted progression of PDR. Development of higher retinal venular and lower AV global oxygen saturation independently predicts progression of PDR despite standard PRP and might be a potential non-invasive marker of angiogenic disease activity. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

System integration of marketable subsystems

NASA Technical Reports Server (NTRS)

1978-01-01

These monthly reports, covering the period February 1978 through June 1978, describe the progress made in the major areas of the program. The areas covered are: systems integration of marketable subsystems; development, design, and building of site data acquisition subsystems; development and operation of the central data processing system; operation of the MSFC Solar Test Facility; and systems analysis.

A Model Program for Teenage Youth: First Year Evaluation of Knowledge Development.

ERIC Educational Resources Information Center

Pooley, Richard C.

Progress in the second 6 months of a program development model for learning disabled (LD) and emotionally disturbed (ED) adolescents is reported. The program is designed to teach ED and LD children necessary work skills so that they can become productive members of society. Three methods are under investigation: (1) use of audio/visual resources…

Human Papilloma Virus in Melanoma Biopsy Specimens and Its Relation to Melanoma Progression

PubMed Central

Dréau, Didier; Culberson, Cathy; Wyatt, Sharon; Holder, Walter D.

2000-01-01

Objectives To evaluate melanoma biopsy specimens for human papilloma virus (HPV) and determine the relation between the presence of HPV, in vitro growth, and clinical progression of melanoma in the patients from whom the biopsy specimens were derived. Summary Background Data Ultraviolet radiation from sun exposure appears to be the primary causal agent in the development of cutaneous melanoma. However, other agents, including HPV, as observed in different epithelial carcinomas, may also play a role in melanoma development and progression. Methods Twelve melanoma biopsy specimens obtained from 12 patients with AJCC stage III and IV melanoma were stained with antibodies against gp-100 (HMB-45) and S-100 protein to confirm melanoma diagnosis and with a polyclonal HPV antibody. After mechanical dissociation, the melanoma specimen cells’ ability to grow in vitro was assessed. Patients were evaluated for melanoma progression with physical examination, complete blood count, and liver function tests every 3 months and a chest radiograph every 6 months. Results All biopsy specimens were positive for S-100, and nine (75%) were positive for gp-100. Seven of 12 (58%) were positive for HPV by immunohistochemistry. In vitro, none of the HPV-negative tumor cells grew from the tumor biopsies, whereas five of seven (71%) of the HPV-positive melanoma tumor cells grew very well. All patients with HPV-positive tumor cells had recurrences and died of melanoma progression, whereas four of five (80%) patients with HPV-negative tumor cells remained alive and without melanoma recurrence. Conclusions The presence of HPV was found in 58% of the biopsy specimens obtained from patients with stage III and IV melanoma and correlated with rapid melanoma progression. HPV may serve as a cofactor in the development of melanoma and may modulate a more aggressive phenotype in HPV-containing melanoma cells. PMID:10767787

Dietary broccoli protects against fatty liver development but not against progression of liver cancer in mice pretreated with diethylnitrosamine

PubMed Central

Chen, Yung-Ju; Myracle, Angela D.; Wallig, Matthew A.; Jeffery, Elizabeth H.

2016-01-01

Western-style high fat, high sugar diets are associated with non-alcoholic fatty liver disease (NAFLD) and increased liver cancer risk. Sulforaphane from broccoli may protect against these. Previously we initiated broccoli feeding to mice prior to exposure to the hepatocarcinogen diethylnitrosamine (DEN), and saw protection against NAFLD and liver cancer. Here we administered DEN to unweaned mice, initiating broccoli feeding two weeks later, to determine if broccoli protects against cancer progression. Specifically, male 15-day-old C57BL/6J mice were given DEN and placed on a Western or Western+10%Broccoli diet from the age of 4 weeks through 7 months. Dietary broccoli decreased hepatic triacylglycerols, NAFLD, liver damage and tumour necrosis factor by month 5 without changing body weight or relative liver weight, but did not slow carcinogenesis, seen in 100% of mice. We conclude that broccoli, a good source of sulforaphane, slows progression of hepatic lipidosis, but not tumourigenesis in this robust model. PMID:27672403

Prevention of Posttraumatic Contractures with Ketotifen (PERK)

DTIC Science & Technology

2016-10-01

the Peer Reviewed Orthopaedic Research Program (PRORP) Clinical Trial Award (CTA), W81XWH-16-PRORP-CTA, was submitted. Database development and Pre...and Safety Months Identify database and partner – Clinical Research Unit 1-2 Completed Develop Case Report Forms, consent forms 6-12 Case...report forms completed, consent forms pending – 80% completed Develop database and multicenter submission process 12-18 In progress, 30% completed

Accelerated development of object permanence in Down's syndrome infants.

PubMed

Pasnak, C F; Pasnak, R

1987-01-01

Six infants with Down's syndrome, aged 3-19 months, were taught to solve object permanence problems. The instruction took place in the infants' homes and in a child development centre, and was conducted both by parents and by a child psychologist. Object permanence tasks ranging over stages 3-6 of the sensorimotor period of intelligence were utilized in the intervention, which lasted for up to 8 months. The infants were able to progress rather rapidly on these tasks. When the instruction was terminated most had mastered multiple visible displacements, which index the fifth stage of sensorimotor intelligence.

Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

PubMed

Jung, Jae-Joon; Razavian, Mahmoud; Kim, Hye-Yeong; Ye, Yunpeng; Golestani, Reza; Toczek, Jakub; Zhang, Jiasheng; Sadeghi, Mehran M

2016-09-13

Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Currently, there is no non-invasive medical therapy for CAVD. Matrix metalloproteinases (MMPs) are upregulated in CAVD and play a role in its pathogenesis. Here, we evaluated the effect of doxycycline, a nonselective MMP inhibitor on CAVD progression in the mouse. Apolipoprotein (apo)E(-/-) mice (n = 20) were fed a Western diet (WD) to induce CAVD. After 3 months, half of the animals was treated with doxycycline, while the others continued WD alone. After 6 months, we evaluated the effect of doxycycline on CAVD progression by echocardiography, MMP-targeted micro single photon emission computed tomography (SPECT)/computed tomography (CT), and tissue analysis. Despite therapeutic blood levels, doxycycline had no significant effect on MMP activation, aortic valve leaflet separation or flow velocity. This lack of effect on in vivo images was confirmed on tissue analysis which showed a similar level of aortic valve gelatinase activity, and inflammation between the two groups of animals. In conclusion, doxycycline (100 mg/kg/day) had no effect on CAVD progression in apoE(-/-) mice with early disease. Studies with more potent and specific inhibitors are needed to establish any potential role of MMP inhibition in CAVD development and progression.

Recurrence Patterns and Second Primary Lung Cancers After Stereotactic Body Radiation Therapy for Early-Stage Non-Small-Cell Lung Cancer: Implications for Surveillance.

PubMed

Spratt, Daniel E; Wu, Abraham J; Adeseye, Victoria; Din, Shaun U; Shaikh, Fauzia; Woo, Kaitlin M; Zhang, Zhigang; Foster, Amanda; Rosenzweig, Kenneth E; Gewanter, Richard; Huang, James; Rimner, Andreas

2016-05-01

Patients treated with stereotactic body radiation therapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) are subject to locoregional and distant recurrence, as well as the formation of second primary lung cancers (SPLCs). The optimal surveillance regimen for patients treated with SBRT for early-stage NSCLC remains unclear; we therefore investigated the posttreatment recurrence patterns and development of SPLCs. Three hundred sixty-six patients with pathologically proven inoperable early-stage NSCLC treated with SBRT between 2006 and 2013 were assessed. Patients underwent a computed tomographic (CT) scan of the chest every 3 months during years 1 and 2, every 6 months during years 3 and 4, and annually thereafter. Competing risk analysis was used for all time-to-event analyses. With a median follow-up of 23 months, the 2-year cumulative incidence of local, nodal, and distant treatment failures were 12.2%, 16.1%, and 15.5%, respectively. In patients with disease progression after SBRT (n = 108), 84% (n = 91) of cases occurred within the first 2 years. Five percent (n = 19) of patients experienced SPLCs. The median time to development of an SPLC was 16.5 months (range, 6.5-71.1 months), with 33% (n = 6) of these patients experiencing SPLCs after 2 years. None of the never smokers, but 4% of former tobacco smokers and 15% of current tobacco smokers, experienced an SPLC (P = .005). Close monitoring with routine CT scans within the first 2 years after SBRT is effective in detecting early disease progression. In contrast, the risk for the development of an SPLC remains elevated beyond 2 years, particularly in former and current smokers. Copyright © 2015 Elsevier Inc. All rights reserved.

Novel fluorescence in situ hybridization-based definition of bacille Calmette-Guérin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies.

PubMed

Kamat, Ashish M; Willis, Daniel L; Dickstein, Rian J; Anderson, Rooselvelt; Nogueras-González, Graciela; Katz, Ruth L; Wu, Xifeng; Barton Grossman, H; Dinney, Colin P

2016-05-01

To present a molecular definition of bacille Calmette-Guérin (BCG) failure that incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident, which can be used to enhance trial designs for patients with non-muscle-invasive bladder cancer. We used data from 143 patients who were followed prospectively for 2 years during intravesical BCG therapy, during which time FISH assays were collected and correlated to clinical outcomes. Of the 95 patients with no evidence of tumour at 3-month cystoscopy, 23 developed tumour recurrence and 17 developed disease progression by 2 years. Patients with a positive FISH test at both 6 weeks and 3 months were more likely to develop tumour recurrence (17/37 patients [46%] and 16/28 patients [57%], respectively) than patients with a negative FISH test (6/58 patients [10%] and 3/39 patients [8%], respectively; both P < 0.001). Using hazard ratios for recurrence with positive 6-week and 3-month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3-month cystoscopy and positive FISH result could be considered to have 'molecular BCG failure' and could be enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy. Patients with positive early FISH and negative 3-month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression. This definition is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.

Longitudinal telomere shortening and early Alzheimer's disease progression in adults with down syndrome.

PubMed

Jenkins, Edmund C; Marchi, Elaine J; Velinov, Milen T; Ye, Lingling; Krinsky-McHale, Sharon J; Zigman, Warren B; Schupf, Nicole; Silverman, Wayne P

2017-12-01

Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome. © 2017 Wiley Periodicals, Inc.

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

PubMed

Hacker, Mallory L; DeLong, Mahlon R; Turchan, Maxim; Heusinkveld, Lauren E; Ostrem, Jill L; Molinari, Anna L; Currie, Amanda D; Konrad, Peter E; Davis, Thomas L; Phibbs, Fenna T; Hedera, Peter; Cannard, Kevin R; Drye, Lea T; Sternberg, Alice L; Shade, David M; Tonascia, James; Charles, David

2018-06-29

To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT ( p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy ( p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT ( p = 0.001). These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor. © 2018 American Academy of Neurology.

Profiles of Vocal Development in Young Cochlear Implant Recipients

PubMed Central

Ertmer, David J.; Young, Nancy M.; Nathani, Suneeti

2012-01-01

The aim of this study was to examine prelinguistic vocal development in very young cochlear implant recipients. A prospective longitudinal research design was used to observe the sequence and time-course of vocal development in seven children who were implanted between 10 and 36 months of age. Speech samples were collected twice before implant activation and on a monthly basis thereafter for up to 2 years. Children’s vocalizations were classified according to the levels of the Stark Assessment of Early Vocal Development- Revised (SAEVD-R; Nathani, Ertmer, & Stark, in press). The main findings were (a) six of seven children made advancements in vocal development after implantation, (b) children implanted between 12 and 36 months progressed through SAEVD-R levels in the predicted sequence whereas a child implanted at a younger age showed a different sequence, (c) milestones in vocal development were often achieved with fewer months of hearing experience than observed in typically developing infants and appeared to be influenced by age at implantation, and (d) in general, children implanted at younger ages completed vocal development at younger chronological ages than those implanted later in life. Clinical indicators of benefit from implant use were also identified. PMID:17463237

Airborne Oceanographic Lidar (AOL) (Global Carbon Cycle)

NASA Technical Reports Server (NTRS)

2003-01-01

This bimonthly contractor progress report covers the operation, maintenance and data management of the Airborne Oceanographic Lidar and the Airborne Topographic Mapper. Monthly activities included: mission planning, sensor operation and calibration, data processing, data analysis, network development and maintenance and instrument maintenance engineering and fabrication.

75 FR 45124 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-02

... to obtain a copy of the information collection plans, call the SAMHSA Reports Clearance Officer on... clinicians and supervisors, implementation calls and monthly progress reports, and topical workgroups that... evaluate the implementation, expansion, and sustainability of adolescent substance use services developed...

Effect of atorvastatin on progression of sensorineural hearing loss and tinnitus in the elderly: results of a prospective, randomized, double-blind clinical trial.

PubMed

Olzowy, Bernhard; Canis, Martin; Hempel, John-Martin; Mazurek, Birgit; Suckfüll, Markus

2007-06-01

To test whether the 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitor atorvastatin can slow down the progression of presbycusis. Fifty patients 60- to 75-years-old with presbycusis and moderately elevated serum cholesterol. In a double-blind design, patients were randomly assigned to treatment with either atorvastatin (40 mg/d orally) or placebo. Pure-tone audiometry and tinnitus evaluation at enrolment and after 7 and 13 months. Development of hearing thresholds after 7 and 13 months showed no significant differences between the groups. Tinnitus score continuously improved in the atorvastatin group (34.8 at 7 and 27.6 at 13 mo), whereas it slightly deteriorated in the placebo group (24.8 at 7 and 26.8 at 13 mo). The effect on tinnitus was a tendency without statistic significance (p = 0.0833). Atorvastatin had no effect on the development of hearing thresholds, but resulted in a trend toward a relief of tinnitus.

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

PubMed

Antonia, Scott J; Villegas, Augusto; Daniel, Davey; Vicente, David; Murakami, Shuji; Hui, Rina; Yokoi, Takashi; Chiappori, Alberto; Lee, Ki H; de Wit, Maike; Cho, Byoung C; Bourhaba, Maryam; Quantin, Xavier; Tokito, Takaaki; Mekhail, Tarek; Planchard, David; Kim, Young-Chul; Karapetis, Christos S; Hiret, Sandrine; Ostoros, Gyula; Kubota, Kaoru; Gray, Jhanelle E; Paz-Ares, Luis; de Castro Carpeño, Javier; Wadsworth, Catherine; Melillo, Giovanni; Jiang, Haiyi; Huang, Yifan; Dennis, Phillip A; Özgüroğlu, Mustafa

2017-11-16

Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

Sequencing of Local Therapy Affects the Pattern of Treatment Failure and Survival in Children With Atypical Teratoid Rhabdoid Tumors of the Central Nervous System

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

Pai Panandiker, Atmaram S., E-mail: atmaram.pai-panandiker@stjude.org; Merchant, Thomas E.; Beltran, Chris

Purpose: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). Methods and Materials: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. Results: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolledmore » into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% {+-} 9%; progression-free survival was 33.2% {+-} 10%; and OS was 53.5% {+-} 10%. Children receiving delayed RT ({>=}1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. Conclusions: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.« less

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.

PubMed

Fizazi, Karim; Tran, NamPhuong; Fein, Luis; Matsubara, Nobuaki; Rodriguez-Antolin, Alfredo; Alekseev, Boris Y; Özgüroğlu, Mustafa; Ye, Dingwei; Feyerabend, Susan; Protheroe, Andrew; De Porre, Peter; Kheoh, Thian; Park, Youn C; Todd, Mary B; Chi, Kim N

2017-07-27

Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).

POEMS syndrome with Guillan-Barre syndrome-like acute onset: a case report and review of neurological progression in 30 cases.

PubMed

Isose, S; Misawa, S; Kanai, K; Shibuya, K; Sekiguchi, Y; Nasu, S; Fujimaki, Y; Noto, Y; Nakaseko, C; Kuwabara, S

2011-06-01

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare cause of demyelinating neuropathy with monoclonal plasma cell proliferation, and POEMS neuropathy is usually chronically progressive. Herein, the authors report a 34-year-old woman with POEMS syndrome presenting as acute polyneuropathy. Within 2 weeks of disease onset, she became unable to walk with electrodiagnostic features of demyelination and was initially diagnosed as having Guillan-Barré syndrome. Other systemic features (oedema and skin changes) developed later, and an elevated serum level of vascular endothelial growth factor led to the diagnosis of POEMS syndrome. She received high-dose chemotherapy with autologous peripheral blood stem cell transplantation, resulting in good recovery. The authors also reviewed patterns and speed of progression of neuropathy in the 30 patients with POEMS syndrome; 22 (73%) of them were unable to walk independently with the median period of 9.5 months from POEMS onset (range 0.5-51 months). Whereas the speed of neuropathy progression varies considerably among patients, some POEMS patients can show acute or subacute polyneuropathy. The early diagnosis and treatment could result in rapid improvement as shown in the present patient.

Vemurafenib for BRAF V600 mutated advanced melanoma: results of treatment beyond progression.

PubMed

Scholtens, A; Geukes Foppen, M H; Blank, C U; van Thienen, J V; van Tinteren, H; Haanen, J B

2015-03-01

Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAF V600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (BRAFi TBP). In this retrospective study, we analysed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirty-five patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. Median overall survival beyond documented progression was found to be 5.2months versus 1.4months (95% confidence interval (CI): 3.8-7.4 versus 0.6-3.4; Log-Rank p=0.002) in favour of BRAFi TBP. In the multivariate survival analysis, stopping treatment at disease progression was significantly associated with shorter survival (hazard ratio: 1.92; 95% CI: 1.04-3.55; p=0.04). Our results suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients, who prior to progression responded to vemurafenib. Copyright © 2015 Elsevier Ltd. All rights reserved.

Progress on linking gender and sustainable energy

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

Farhar, B.

2000-04-05

The field of gender and energy has been identified as critical in global sustainable energy development and is increasingly important to decision makers. The theme of women and energy was of significance at the 1998 World Renewable Energy Congress in Florence, Italy. This paper traces further developments in this field by summarizing selected programmatic initiatives, meetings, and publications over the past 18 months.

Children’s development of intonation during the first year of cochlear implant experience

PubMed Central

Snow, David P.; Ertmer, David J.

2012-01-01

This article describes the longitudinal development of intonation in 18 deaf children who received cochlear implants (CIs) before the age of three years and 12 infants with typical development (TD) who served as controls. At the time their implants were activated, the children with CIs ranged in age from 9 to 36 months. Cross-group comparisons were made when the children had equivalent amounts of robust hearing experience but different chronological ages. This paper reports the results for the 6-month period ending 9 months after activation of the child’s device for children with CIs, and the 6-month period ending at 12 months of age for TD infants. The findings were compared to a model of early intonation development in children with normal hearing. The results indicated that all groups progressed through 1 or more of the stages predicted by the normative model. At the end of the study period, however, children who had received a cochlear implant later than 24 months reached a more mature stage of intonation development than younger CI-recipients. Moreover, the older CI group reached the same stage of development as the TD infants who had 3 additional months of language listening experience. The findings suggest that the developmental advantage which older children had previously demonstrated shortly after activation of their CIs is maintained throughout most or all of the first year of cochlear implant use. PMID:21728834

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma.

PubMed

Kim, George P; Mahoney, Michelle R; Szydlo, Daniel; Mok, Tony S K; Marshke, Robert; Holen, Kyle; Picus, Joel; Boyer, Michael; Pitot, Henry C; Rubin, Joseph; Philip, Philip A; Nowak, Anna; Wright, John J; Erlichman, Charles

2012-02-01

Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma

PubMed Central

Kim, George P.; Mahoney, Michelle R.; Szydlo, Daniel; Mok, Tony S. K.; Marshke, Robert; Holen, Kyle; Picus, Joel; Boyer, Michael; Pitot, Henry C.; Rubin, Joseph; Philip, Philip A.; Nowak, Anna; Wright, John J.; Erlichman, Charles

2013-01-01

Summary Background and Rationale Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitinproteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1–12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib. PMID:20839030

Grant Application Development, Submission, Review, & Award

Cancer.gov

This infographic shows the National Cancer Institute general timeline progression through Grant Application Development, Submission, Review, and Award Infographic. In the first month, Applicant prepares and submits Grant Application to Grants.gov in response to FOA. In month two, The Center for Scientific Review (CSR) assigns applications that fall under the category of R01s, etc. to a Scientific Review Group (SRG) or the CSR assigns applications that fall under the category of Program Projects and Center Grants to NCI Division of Extramural Activities (DEA). Months four through five: First-level review by Scientific Review Group (SRG) for Scientific Merit: SRG assigns Impact Scores. Month five Summary Sstatements are prepared and are available to NCI Program staff and applicants. Month six, second-level review by National Cancer Advisory board (NCAB) for NCI Funding determination begins. NCAB makes recommendation to NCI Director, NCI develops funding plan, Applications selected for Funding, “Paylists” forwarded to Office of Grant Administration (OGA). Month ten, Award Negotiations and Issuance: Award issued, Award received by Institution, and Investigator begins work. www.cancer.gov Icons made by Freepik from http://www.flaticon.com is licensed by CC BY3.0

Identifying a therapeutic window in acute and subacute inflammatory sensory neuronopathies.

PubMed

Antoine, Jean-Christophe; Robert-Varvat, Florence; Maisonobe, Thierry; Créange, Alain; Franques, Jérôme; Mathis, Stéphane; Delmont, Emilien; Kuntzer, Thierry; Lefaucheur, Jean-Pascal; Pouget, Jean; Viala, Karine; Desnuelle, Claude; Echaniz-Laguna, Andoni; Rotolo, Francesco; Camdessanché, Jean-Philippe

2016-02-15

Patients with inflammatory sensory neuronopathy (SNN) may benefit from immunomodulatory or immunosuppressant treatments if administered timely. Knowing the temporal profile of neuronal loss in dorsal root ganglia will help to ascertain whether a final diagnosis may be reached before the occurrence of irreversible neuronal injuries. Thus, we addressed the evolution of neuronal loss in SNN by using sensory nerve action potentials (SNAPs) as a surrogate marker of neuron degeneration. Eighty-six patients with acute/subacute inflammatory SNN (paraneoplastic, associated with dysimmune diseases, or idiopathic) were retrospectively studied. The monthly SNAP reduction was determined and normalized with the lower limit of normal. Disability progression was expressed by the modified Rankin score and correlated with SNAP reduction. The monthly SNAP reduction was similar in the four limbs although the median nerve was less severely affected. The monthly SNAP reduction was very severe within the first two months of evolution, began to slow down after seven months, and stabilized after ten months. It was tightly correlated with disability progression. Kaplan-Meier analysis showed that the median time until matching the diagnostic criteria of SNN was 8.5 months. Within this period, 42% of nerves remained excitable. Developing treatment aiming at the stabilization of SNN is possible within the first 8 months of evolution. An improvement of the disease is possible if patients are treated within two months, which needs an early referral to an expert center and ENMG testing of the radial and ulnar nerves, which are most sensitive to changes. Copyright © 2015 Elsevier B.V. All rights reserved.

Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

PubMed

Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske; Géczi, Lajos; Hotte, Sebastien J; Mainwaring, Paul N; Saad, Fred; Souza, Ciro; Tay, Miah H; Garrido, José M Tello; Galli, Luca; Londhe, Anil; De Porre, Peter; Goon, Betty; Lee, Emma; McGowan, Tracy; Naini, Vahid; Todd, Mary B; Molina, Arturo; George, Daniel J

2014-10-01

In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8). No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes. Janssen Research & Development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Observational Prospective Natural History of Patients with Sanfilippo Syndrome Type B.

PubMed

Whitley, Chester B; Cleary, Maureen; Eugen Mengel, Karl; Harmatz, Paul; Shapiro, Elsa; Nestrasil, Igor; Haslett, Patrick; Whiteman, David; Alexanderian, David

2018-06-01

To evaluate the natural course of disease progression in patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB), identify potential end points for future therapy trials, and characterize biomarkers related to the disease. A prospective, multicenter study was conducted. Baseline, 6-month, and 12-month assessments included neurodevelopmental status (Bayley Scales of Infant Development, Third edition), adaptive status (Vineland Adaptive Behavior Scales, Second Edition), volumetric brain magnetic resonance imaging, cerebrospinal fluid heparan sulfate, and urine glycosaminoglycan (GAG) measurements. Nineteen patients aged 1.6-31.7 years were enrolled. Over 12 months, cognition, adaptive behavior, and cortical gray matter volume (GMV) declined in most patients. For patients diagnosed at <6 years, although there was no overall mean change over 12 months, there were 10%-48%, 3%-66%, and 1%-14% decreases in cognitive development quotient score, Vineland Adaptive Behavior Scales, Second Edition development quotient score, and cortical GMV in 8/12, 9/11, and 10/11 patients, respectively. Mean urine GAG and cerebrospinal fluid heparan sulfate levels were stable, but patients diagnosed at <6 years (n = 14) had higher levels than those ≥6 years at diagnosis (n = 4), which was likely associated with age as they also were generally younger. Cognition, adaptive behavior, and cortical GMV measures sensitively tracked deterioration in patients with mucopolysaccharidosis type IIIB aged ≤8.6 years. Biomarkers may have prognostic value, but their sensitivity to disease progression requires further investigation. These findings should help evaluate enzyme replacement and gene therapy agents for this rare, devastating, neurodegenerative disease. ClinicalTrials.gov: NCT01509768. Copyright © 2018 Elsevier Inc. All rights reserved.

A Radiographic Comparison of Progressive and Conventional Loading on Crestal Bone Loss and Density in Single Dental Implants: A Randomized Controlled Trial Study

PubMed Central

Ghoveizi, Rahab; Alikhasi, Marzieh; Siadat, Mohammad-Reza; Siadat, Hakimeh; Sorouri, Majid

2013-01-01

Objective: Crestal bone loss is a biological complication in implant dentistry. The aim of this study was to compare the effect of progressive and conventional loading on crestal bone height and bone density around single osseointegrated implants in the posterior maxilla by a longitudinal radiographic assessment technique. Materials and Methods: Twenty micro thread implants were placed in 10 patients (two implants per patient). One of the two implants in each patient was assigned to progressive and the other to conventional loading groups. Eight weeks after surgery, conventional implants were restored with a metal ceramic crown and the progressive group underwent a progressive loading protocol. The progressive loading group took different temporary acrylic crowns at 2, 4 and 6 months. After eight months, acrylic crowns were replaced with a metal ceramic crown. Computer radiography of both progressive and conventional implants was taken at 2, 4, 6, and 12 months. Image analysis was performed to measure the height of crestal bone loss and bone density. Results: The mean values of crestal bone loss at month 12 were 0.11 (0.19) mm for progressively and 0.36 (0.36) mm for conventionally loaded implants, with a statistically significant difference (P < 0.05) using Wilcoxon sign rank. Progressively loaded group showed a trend for higher bone density gain compared to the conventionally loaded group, but when tested with repeated measure ANOVA, the differences were not statistically significant (P > 0.05). Conclusion: The progressive group showed less crestal bone loss in single osseointegrated implant than the conventional group. Bone density around progressively loaded implants showed increase in crestal, middle and apical areas. PMID:23724215

Chronology of KSC and KSC-related events for 1985

NASA Technical Reports Server (NTRS)

Nail, Ken, Jr.; Liston, Elaine

1986-01-01

A chronology of developments and events at the Kennedy Space Center (KSC) in 1985 documents the KSC role in NASA's progress. The chronology serves as a reference source for historians and other researchers. Arrangement is by day and month. Individual articles are attributed to published sources.

Monitoring of allograft vasculopathy by intravascular ultrasound one month and one year after heart transplantation: A single center study.

PubMed

Bedanova, Helena; Orban, Marek; Tretina, Martin; Fila, Petr; Horvath, Vladimir; Krejci, Jan; Nemec, Petr

2016-03-01

The aim of this trial was to use intravascular ultrasound (IVUS) to determine whether cardiac allograft vasculopathy (CAV) starts progressing during the first year after heart transplantation (HTx). We retrospectively analyzed 51 patients (11 women) who received heart transplants in our center between January 2010 and September 2013 and underwent coronary angiography as well as IVUS examination one month and one year after HTx. Patients with proven calcification and fibrotic plates in the IVUS examination one month after HTx constituted a group with defined donor-transmitted atherosclerosis (DTA). In patients without DTA, measurements of maximal intimal thickening (MIT) were made in two predetermined locations. Eight of the 51 patients had DTA, while 43 did not. These were divided based on maximal intimal thickness (MIT) into a group with MIT < 0.5 mm (27) and MIT ≥ 0.5 mm (16). No patient with MIT < 0.5 mm developed allograft vasculopathy within one year after HTx. CAV developed in three patients (P = 0.045) out of the 16 patients with MIT ≥ 0.5. In patients with DTA, a statistically significant deterioration in percent area stenosis (PAS) occurred in both artery sections (P = 0.01). Our trial showed that CAV progresses during the first year after HTx significantly more frequently in patients with DTA and MIT ≥ 0.5 mm. It is essential in these patients to implement an IVUS control examination one year after transplantation. The results can lead to a change in treatment strategy to prevent further progress of the disease.

Mine or Yours? Development of Sharing in Toddlers in Relation to Ownership Understanding

PubMed Central

Brownell, Celia A.; Iesue, Stephanie S.; Nichols, Sara R.; Svetlova, Margarita

2012-01-01

To examine early developments in other-oriented resource sharing, fifty-one 18- and 24-month-old children were administered six tasks with toys or food that could be shared with an adult playmate who had none. On each task the playmate communicated her desire for the items in a series of progressively more explicit cues. Twenty-four-month-olds shared frequently and spontaneously. Eighteen-month-olds shared when given multiple opportunities and when the partner provided enough communicative support. Younger children engaged in self-focused and hypothesis-testing behavior in lieu of sharing more often than did older children. Ownership understanding, separately assessed, was positively associated with sharing and negatively associated with non-sharing behavior, independent of age and language ability. PMID:23145536

Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.

PubMed

Garske-Román, Ulrike; Sandström, Mattias; Fröss Baron, Katarzyna; Lundin, Lars; Hellman, Per; Welin, Staffan; Johansson, Silvia; Khan, Tanweera; Lundqvist, Hans; Eriksson, Barbro; Sundin, Anders; Granberg, Dan

2018-06-01

Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome. The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177 Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%). In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity. Dosimetry-based therapy with 177 Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Economic impact of disease progression in follicular non-Hodgkin lymphoma

PubMed Central

Beveridge, Roy; Satram-Hoang, Sacha; Sail, Kavita; Darragh, Joseph; Chen, Clara; Forsyth, Michael; Reyes, Carolina

2011-01-01

Using a retrospective claims database, we estimated the economic costs of progression among patients with follicular non-Hodgkin lymphoma (f-NHL) treated in an outpatient community-based setting. Patients with f-NHL who received care between 1 July 2006 and 31 December 2009 were categorized into two cohorts based on whether they experienced progressive disease (PD) or not. Costs per patient per month (PPPM) were compared between patients with PD versus non-PD. Follow-up time was censored at the last entry for disease status or 6 months after the date of remission/stable disease or progression. Of the 1002 patients with f-NHL identified, 268 progressed and 734 did not. The mean overall costs PPPM over the 6-month follow-up period were significantly higher for patients with PD versus non-PD ($3527 vs. $860; difference = $2667; p < 0.001). This cost difference persisted within all resource categories evaluated. Results of this study indicate that therapies which delay progression for patients with f-NHL may result in potential cost savings. PMID:21745172

Identifying high frequency signals in the daily swath mascon solutions from GRACE

NASA Astrophysics Data System (ADS)

Save, H.

2016-12-01

The Gravity Recovery and Climate Experiment (GRACE) mission has provided us with unique information about the total water column in the Earth system over the past 14 years. The GRACE project provides a monthly mean time-variable gravity solution. There has been significant progress in the community over the years to develop shorter time-window gravity solutions. The daily swath mascon solutions, which are under development at the Center for Space Research (CSR), are computed using daily GRACE observation data. This paper discusses the development and the progress of this product. This paper summarizes the analysis of these solutions with special emphasis on identifying the higher frequency natural processes observed by GRACE using these daily swath mascon solutions.

The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse.

PubMed

Bolivar, Valerie J; Scott Ganus, J; Messer, Anne

2002-05-24

The motor neuron degeneration (mnd) mouse, which has widespread abnormal accumulating lipoprotein and neuronal degeneration, has a mutation in CLN8, the gene for human progressive epilepsy with mental retardation (EPMR). EPMR is one of the neuronal ceroid lipofuscinoses (NCLs), a group of neurological disorders characterized by autofluorescent lipopigment accumulation, blindness, seizures, motor deterioration, and dementia. The human phenotype of EPMR suggests that, in addition to the motor symptoms previously categorized, various types of progressive behavioral abnormalities would be expected in mnd mice. We have therefore examined exploratory behavior, fear conditioning, and aggression in 2-3 month and 4-5 month old male mnd mice and age-matched C57BL/6 (B6) controls. The mnd mice displayed increased activity with decreased habituation in the activity monitor, poor contextual and cued memory, and heightened aggression relative to B6 controls. These behavioral deficits were most prominent at 4-5 months of age, which is prior to the onset of gross motor symptoms at 6 months. Our results provide a link from the mutation via pathology to a quantifiable multidimensional behavioral phenotype of this naturally occurring mouse model of NCL.

Eribulin mesylate (halichondrin B Analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a two-cohort, phase II study

PubMed Central

Hensley, Martee L.; Kravetz, Sara; Jia, Xiaoyu; Iasonos, Alexia; Tew, William; Pereira, Lauren; Sabbatini, Paul; Whalen, Christin; Aghajanian, Carol A.; Zarwan, Corinne; Berlin, Suzanne

2011-01-01

Background Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. We sought to assess the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer. Methods Patients with recurrent measurable epithelial ovarian cancer, ≤2 prior cytotoxic regimens, and adequate organ function were enrolled into two separate cohorts: 1) Platinum resistant (progression-free interval from last platinum-based therapy <6 months); and 2) Platinum sensitive (progression-free interval from last platinum-based therapy ≥6 months). Treatment: Eribulin 1.4 mg/m2 over 15 minutes by vein on days 1 and 8, every 21 days. Efficacy was determined by objective response by computed tomography. Results Platinum-resistant cohort: Thirty-seven patients enrolled. Thirty-six patients were evaluable for response and toxicity. Two patients achieved partial response (PR, 5.5%). Sixteen (44%) had a best response of stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.4–2.8 months). Platinum-sensitive cohort: Thirty-seven patients enrolled, and all were evaluable for response. Seven patients achieved partial response (PR, 19%). Median progression-free survival was 4.1 months (95% confidence interval, 2.8–5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% in platinum-resistant patients; 54% in platinum-sensitive patients). Conclusions Eribulin achieved objective response in 5.5% of women with platinum-resistant recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. Median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group. PMID:21935916

One year outcomes of a mentoring scheme for female academics: a pilot study at the Institute of Psychiatry, King's College London

PubMed Central

2011-01-01

Background The professional development of under-represented faculty may be enhanced by mentorship, but we understand very little about the mechanisms by which mentoring brings about change. Our study posed the research question, what are the mechanisms by which mentoring may support professional development in under-represented groups? The study aims to: (i) to pilot a mentoring scheme for female academics; (ii) to compare various health-related and attitudinal measures in mentees at baseline, 6 months, and 1 year into the mentoring relationship and, (iii) to compare pre-mentoring expectations to outcomes at 6 months and 1 year follow-up for mentees and mentors. Methods Female academic mentees were matched 1:1 or 2:1 with more senior academic mentors. Online surveys were conducted to compare health-related and attitudinal measures and expectations of mentoring at baseline with outcomes at 6 months and 1 year using paired t-tests and McNemar's test for matched cohort data. Results N = 46 mentoring pairs, 44 (96%) mentees completed the pre-mentoring survey, 37 (80%) at 6 months and 30 (65%) at 1 year. Job-related well-being (anxiety-contentment), self-esteem and self-efficacy all improved significantly and work-family conflict diminished at 1 year. Highest expectations were career progression (39; 89%), increased confidence (38; 87%), development of networking skills (33; 75%), better time-management (29; 66%) and better work-life balance (28; 64%). For mentees, expectations at baseline were higher than perceived achievements at 6 months or 1 year follow-up. For mentors (N = 39), 36 (92%) completed the pre-mentoring survey, 32 (82%) at 6 months and 28 (72%) at 1 year. Mentors' highest expectations were of satisfaction in seeing people progress (26; 69%), seeing junior staff develop and grow (19; 53%), helping solve problems (18; 50%), helping women advance their careers (18; 50%) and helping remove career obstacles (13; 36%). Overall, gains at 6 months and 1 year exceeded pre-mentoring expectations. Conclusions This uncontrolled pilot study suggests that mentoring can improve aspects of job-related well-being, self-esteem and self-efficacy over 6 months, with further improvements seen after 1 year for female academics. Work-family conflict can also diminish. Despite these gains, mentees' prior expectations were shown to be unrealistically high, but mentors' expectations were exceeded. PMID:21473749

One year outcomes of a mentoring scheme for female academics: a pilot study at the Institute of Psychiatry, King's College London.

PubMed

Dutta, Rina; Hawkes, Sarah L; Kuipers, Elizabeth; Guest, David; Fear, Nicola T; Iversen, Amy C

2011-04-07

The professional development of under-represented faculty may be enhanced by mentorship, but we understand very little about the mechanisms by which mentoring brings about change. Our study posed the research question, what are the mechanisms by which mentoring may support professional development in under-represented groups? The study aims to: (i) to pilot a mentoring scheme for female academics; (ii) to compare various health-related and attitudinal measures in mentees at baseline, 6 months, and 1 year into the mentoring relationship and, (iii) to compare pre-mentoring expectations to outcomes at 6 months and 1 year follow-up for mentees and mentors. Female academic mentees were matched 1:1 or 2:1 with more senior academic mentors. Online surveys were conducted to compare health-related and attitudinal measures and expectations of mentoring at baseline with outcomes at 6 months and 1 year using paired t-tests and McNemar's test for matched cohort data. N = 46 mentoring pairs, 44 (96%) mentees completed the pre-mentoring survey, 37 (80%) at 6 months and 30 (65%) at 1 year. Job-related well-being (anxiety-contentment), self-esteem and self-efficacy all improved significantly and work-family conflict diminished at 1 year. Highest expectations were career progression (39; 89%), increased confidence (38; 87%), development of networking skills (33; 75%), better time-management (29; 66%) and better work-life balance (28; 64%). For mentees, expectations at baseline were higher than perceived achievements at 6 months or 1 year follow-up. For mentors (N = 39), 36 (92%) completed the pre-mentoring survey, 32 (82%) at 6 months and 28 (72%) at 1 year. Mentors' highest expectations were of satisfaction in seeing people progress (26; 69%), seeing junior staff develop and grow (19; 53%), helping solve problems (18; 50%), helping women advance their careers (18; 50%) and helping remove career obstacles (13; 36%). Overall, gains at 6 months and 1 year exceeded pre-mentoring expectations. This uncontrolled pilot study suggests that mentoring can improve aspects of job-related well-being, self-esteem and self-efficacy over 6 months, with further improvements seen after 1 year for female academics. Work-family conflict can also diminish. Despite these gains, mentees' prior expectations were shown to be unrealistically high, but mentors' expectations were exceeded.

Next Generation Attenuation Relationships for the Eastern United States (NGA-East)

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

Mahin, Stephen; Bozorgnia, Yousef

2016-04-11

This is a progress report to DOE for project Next Generation Attenuation for Central & Eastern US (NGA-East).This progress report consists of numerous monthly progress segments starting June 1, 2010 until December 31, 2015. Please note: the December 2015 progress report was issued in January 2016 due to the final university financial reporting at the end of this project. For each month, there is a technical progress list, and an update on the financial progress of the project. As you know, this project is jointly funded by the DOE, US Nuclear Regulatory Commission (NRC) and Electric Power Research Institute (EPRI).more » Thus, each segment includes financial progress for these three funding agencies.« less

Impact of Lifestyle and Metformin Interventions on the Risk of Progression to Diabetes and Regression to Normal Glucose Regulation in Overweight or Obese People With Impaired Glucose Regulation.

PubMed

Herman, William H; Pan, Qing; Edelstein, Sharon L; Mather, Kieren J; Perreault, Leigh; Barrett-Connor, Elizabeth; Dabelea, Dana M; Horton, Edward; Kahn, Steven E; Knowler, William C; Lorenzo, Carlos; Pi-Sunyer, Xavier; Venditti, Elizabeth; Ye, Wen

2017-12-01

Both lifestyle and metformin interventions can delay or prevent progression to type 2 diabetes mellitus (DM) in people with impaired glucose regulation, but there is considerable interindividual variation in the likelihood of receiving benefit. Understanding an individual's 3-year risk of progressing to DM and regressing to normal glucose regulation (NGR) might facilitate benefit-based tailored treatment. We used the values of 19 clinical variables measured at the Diabetes Prevention Program (DPP) baseline evaluation and Cox proportional hazards models to assess the 3-year risk of progression to DM and regression to NGR separately for DPP lifestyle, metformin, and placebo participants who were adherent to the interventions. Lifestyle participants who lost ≥5% of their initial body weight at 6 months and metformin and placebo participants who reported taking ≥80% of their prescribed medication at the 6-month follow-up were defined as adherent. Eleven of 19 clinical variables measured at baseline predicted progression to DM, and 6 of 19 predicted regression to NGR. Compared with adherent placebo participants at lowest risk of developing diabetes, participants at lowest risk of developing diabetes who adhered to a lifestyle intervention had an 8% absolute risk reduction (ARR) of developing diabetes and a 35% greater absolute likelihood of reverting to NGR. Participants at lowest risk of developing diabetes who adhered to a metformin intervention had no reduction in their risk of developing diabetes and a 17% greater absolute likelihood of reverting to NGR. Participants at highest risk of developing DM who adhered to a lifestyle intervention had a 39% ARR of developing diabetes and a 24% greater absolute likelihood of reverting to NGR, whereas those who adhered to the metformin intervention had a 25% ARR of developing diabetes and an 11% greater absolute likelihood of reverting to NGR. Unlike our previous analyses that sought to explain population risk, these analyses evaluate individual risk. The models can be used by overweight and obese adults with fasting hyperglycemia and impaired glucose tolerance to facilitate personalized decision-making by allowing them to explicitly weigh the benefits and feasibility of the lifestyle and metformin interventions. © 2017 by the American Diabetes Association.

A Serum Circulating miRNA Signature for Short-Term Risk of Progression to Active Tuberculosis Among Household Contacts.

PubMed

Duffy, Fergal J; Thompson, Ethan; Downing, Katrina; Suliman, Sara; Mayanja-Kizza, Harriet; Boom, W Henry; Thiel, Bonnie; Weiner Iii, January; Kaufmann, Stefan H E; Dover, Drew; Tabb, David L; Dockrell, Hazel M; Ottenhoff, Tom H M; Tromp, Gerard; Scriba, Thomas J; Zak, Daniel E; Walzl, Gerhard

2018-01-01

Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors < 6 Mo to active TB and ROC AUC 0.66, up to 24 Mo to active TB], and complements the predictions of a previous cellular mRNA-based signature of TB risk.

Beginning to Talk Like an Adult: Increases in Speech-like Utterances in Young Cochlear Implant Recipients and Toddlers with Normal Hearing

PubMed Central

Ertmer, David J.; Jung, Jongmin; Kloiber, Diana True

2013-01-01

Background Speech-like utterances containing rapidly combined consonants and vowels eventually dominate the prelinguistic and early word productions of toddlers who are developing typically (TD). It seems reasonable to expect a similar phenomenon in young cochlear implants (CI) recipients. This study sought to determine the number of months of robust hearing experience needed to achieve a majority of speech-like utterances in both of these groups. Methods Speech samples were recorded at 3-month intervals during the first 2 years of CI experience, and between 6- and 24 months of age in TD children. Speech-like utterances were operationally defined as those belonging to the Basic Canonical Syllables (BCS) or Advanced Forms (AF) levels of the Consolidated Stark Assessment of Early Vocal Development-Revised. Results On average, the CI group achieved a majority of speech- like utterances after 12 months, and the TD group after 18 months of robust hearing experience. The CI group produced greater percentages of speech-like utterances at each interval until 24-months, when both groups approximated 80%. Conclusion Auditory deprivation did not limit progress in vocal development as young CI recipients showed more-rapid-than-typical speech development during the first 2 years of device use. Implications for the Infraphonological model of speech development are considered. PMID:23813203

The development of intonation in young children with cochlear implants: A preliminary study of the influence of age at implantation and length of implant experience

PubMed Central

Snow, David; Ertmer, David

2010-01-01

This study describes the development of emerging intonation in six children who had received a cochlear implant (CI) before the age of three years. At the time their implant was activated, the children ranged in age from 11 to 37 months. Spontaneous longitudinal speech samples were recorded from 30-minute sessions in which the child interacted with his or her mother. Data were collected 2 months before activation of each child's CI and at monthly intervals after activation for 6 months. The findings were compared to the typical pattern of early intonation development in children with normal hearing (NH). The results suggested that young CI recipients progress through stages similar to those observed in children with NH. However, the intonation development of children with a CI reflects a marked interaction between chronological age at implantation and amount of CI experience. That is, after 2 months of CI-assisted hearing experience, the older children demonstrated a later stage of intonation development than younger children. These preliminary results support the idea that children acquire some foundations or prerequisites of intonation production through maturation, as measured by chronological age, even without robust auditory experience. PMID:20882119

IL-33 and soluble ST2 levels as novel predictors for remission and progression of carotid plaque in early rheumatoid arthritis: A prospective study.

PubMed

Shen, Jiayun; Shang, Qing; Wong, Chun-Kwok; Li, Edmund K; Wang, Shang; Li, Rui-Jie; Lee, Ka-Lai; Leung, Ying-Ying; Ying, King-Yee; Yim, Cheuk-Wan; Kun, Emily W; Leung, Moon-Ho; Li, Martin; Li, Tena K; Zhu, Tracy Y; Yu, Shui-Lian; Kuan, Woon-Pang; Yu, Cheuk-Man; Tam, Lai-Shan

2015-08-01

To study the association between the baseline IL-33 and soluble ST2 (sST2) levels with disease remission and progression of carotid atherosclerosis in early rheumatoid arthritis (ERA) patients. A total of 98 ERA patients were enrolled. Disease activity and the presence of carotid plaque were evaluated at baseline and 12 months later. Plasma IL-33 and sST2 levels were determined using enzyme-linked immunosorbent assay kits. Baseline IL-33 and sST2 levels were associated with inflammatory markers and cardiovascular (CV) risk factors. Overall, 44(45%), 18(18%), and 21(21%) patients achieved remission based on 28-joint disease activity score (DAS28), Boolean, and simplified disease activity score (SDAI) criteria at 12 months, respectively. Patients with detectable IL-33 at baseline were less likely to achieve DAS28 (P = 0.010) and SDAI remission (P = 0.021), while a lower baseline sST2 level was able to predict DAS28, Boolean, and SDAI remission (P = 0.005, 0.001, and <0.001, respectively). Using multivariate analysis, a lower baseline sST2 level independently predict Boolean (OR = 0.789; P = 0.005) and SDAI remission (0.812; P = 0.008). Regarding carotid atherosclerosis, 9/98(9.2%) patients had plaque progression at 12 months. Baseline IL-33 was detectable in 8/9(89%) and 42/83(51%) of patients with and without plaque progression respectively (P = 0.029). Baseline detectable IL-33 was an independent predictor for plaque progression after adjusting for traditional CV risk factors (P = 0.017). Lower baseline sST2 levels independently predict disease remission and baseline detectable IL-33 independently predicts carotid plaque progression in ERA patients. This study suggests that inflammation induced by the IL-33/ST2 axis may play a significant role in the development of cardiovascular disease in RA. Copyright © 2015 Elsevier Inc. All rights reserved.

Combined vemurafenib and fotemustine in patients with BRAF V600 melanoma progressing on vemurafenib.

PubMed

Queirolo, Paola; Spagnolo, Francesco; Picasso, Virginia; Spano, Laura; Tanda, Enrica; Fontana, Valeria; Giorello, Laura; Merlo, Domenico Franco; Simeone, Ester; Grimaldi, Antonio Maria; Curvietto, Marcello; Del Vecchio, Michele; Bruzzi, Paolo; Ascierto, Paolo Antonio

2018-02-23

BRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor. In this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS. Thirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients.This trial is registered with ClinicalTrials.gov number NCT01983124. The combination of vemurafenib plus fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients.

Fuel Processor Development for a Soldier-Portable Fuel Cell System

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

Palo, Daniel R.; Holladay, Jamie D.; Rozmiarek, Robert T.

2002-01-01

Battelle is currently developing a soldier-portable power system for the U.S. Army that will continuously provide 15 W (25 W peak) of base load electric power for weeks or months using a micro technology-based fuel processor. The fuel processing train consists of a combustor, two vaporizers, and a steam-reforming reactor. This paper describes the concept and experimental progress to date.

[Association between time of permanence at early education program (Estancias Infantiles) and developmental level for children in situation of poverty].

PubMed

Rizzoli-Córdoba, Antonio; Vargas-Carrillo, Laura Ibernia; Vásquez-Ríos, Jorge Rodrigo; Reyes-Morales, Hortensia; Villasís-Keever, Miguel Ángel; O'Shea-Cuevas, Gabriel; Aceves-Villagrán, Daniel; Muñoz-Hernández, Onofre; García-Aranda, José Alberto

Early education program (EEP) was created to support parents with 1 to 3 year olds living in poverty situation in Mexico, and includes education and child daycare for 8h five days per week. The objective of this study was to evaluate the association between length of stay in EEP and the level of development in children. Cross sectional, population-based study conducted in two Mexican states. All children aged between 12 to 48 months enrolled in EEP from November 2014 to January 2015 were included. Child Development Evaluation (CDE) test was used to screen early development in every child. Normal early development prevalence odds ratio (OR) was calculated adjusted by gender, impairment and state, using as a reference those children with less than 30 days in the program. The study included 3,387 children from 177 EEP nurseries, from which 53% were male; age by group was divided in 12-24 months (22.3%), 25-36 months (37.6%) and 37-42 months (40.1%). Normal development adjusted OR by age was 1.9 (CI95%: 1.30-2.78) for 6-11 months, 2.36 (CI95%: 1.60-3.50) for 12-17 months, 2.78 (CI95%: 1.65-4.65) for 18-23 months and 3.46 (CI95%: 2.13-5.60) for >24 months. By area of development, a greater probability of having a normal result for language and social areas was observed after 6 months in the program, and for motor (both gross and fine) and knowledge areas after 12 months. The length of the stay in the EEP after 6 months significantly and progressively increases the probability of normal development regardless of gender and age. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition.

PubMed

Kutryb-Zajac, Barbara; Mateuszuk, Lukasz; Zukowska, Paulina; Jasztal, Agnieszka; Zabielska, Magdalena A; Toczek, Marta; Jablonska, Patrycja; Zakrzewska, Agnieszka; Sitek, Barbara; Rogowski, Jan; Lango, Romuald; Slominska, Ewa M; Chlopicki, Stefan; Smolenski, Ryszard T

2016-11-01

Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis. Vascular activities of ecto-nucleoside triphosphate diphosphohydrolase 1, ecto-5'-nucleotidase, and ecto-adenosine deaminase (eADA) were measured in aortas of apolipoprotein E-/- low density lipoprotein receptor (ApoE-/-LDLR-/-) and wild-type mice as well as in human aortas. Plaques were analysed in the entire aorta, aortic root, and brachiocephalic artery by Oil-Red O and Orcein Martius Scarlet Blue staining and vascular accumulation of macrophages. The cellular location of ecto-enzymes was analysed by immunofluorescence. The effect of eADA inhibition on atherosclerosis progression was studied by a 2-month deoxycoformycin treatment of ApoE-/-LDLR-/- mice. The vascular eADA activity prominently increased in ApoE-/-LDLR-/- mice when compared with wild type already at the age of 1 month and progressed along atherosclerosis development, reaching a 10-fold difference at 10 months. The activity of eADA correlated with atherosclerotic changes in human aortas. High abundance of eADA in atherosclerotic vessels originated from activated endothelial cells and macrophages. There were no changes in ecto-nucleoside triphosphate diphosphohydrolase 1 activity, whereas ecto-5'-nucleotidase was moderately decreased in ApoE-/-LDLR-/- mice. Deoxycoformycin treatment attenuated plaque development in aortic root and brachiocephalic artery of ApoE-/-LDLR-/- mice, suppressed vascular inflammation and improved endothelial function. This study highlights the importance of extracellular nucleotides and adenosine metabolism in the atherosclerotic vessel in both experimental and clinical setting. The increased eADA activity marks an early stage of atherosclerosis, contributes to its progression and could represent a novel target for therapy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

Assessment of collaborative problem solving skills in Undergraduate Medical Students at Ziauddin College of Medicine, Karachi

PubMed Central

Mughal, Arsalan Manzoor; Shaikh, Sirajul Haque

2018-01-01

Objective: Collaborative Problem Solving Empirical Progressions from the Assessment and Teaching of 21st Century Skills (ATC21S) framework were used to determine the level of collaborative problem solving skills (CPS) in first, second and third year MBBS students at Ziauddin College of Medicine during Problem-Based Learning (PBL) sessions. Variations based on gender and roles were studied. Methods: It is an analytical comparative cross-sectional study in which seven PBL groups were selected per year by non-probability convenient sampling. Data was collected using the Collaborative Problem Solving Five Strands Empirical Progressions by the primary investigator through observation of the students during PBL sessions. Duration of study was six months. Results: We found that in our students, development of social dimension skills is facilitated to a greater extent than the development of cognitive dimension skills through the process of PBL. These skills are generally better developed in the leader compared to the scribe and members in a group. They are also more developed in females compared to males. Modification in them is also observed as the year's progress. Conclusion: Although PBLs facilitate development of CPS skills' progression however in our curriculum, PBLs mainly focus on social skills development and have less emphasis on cognitive skill development. Thus, hybrid instructional strategies with components from TBL and mentorship are recommended for better development of CPS skills. PMID:29643904

Assessment of collaborative problem solving skills in Undergraduate Medical Students at Ziauddin College of Medicine, Karachi.

PubMed

Mughal, Arsalan Manzoor; Shaikh, Sirajul Haque

2018-01-01

Collaborative Problem Solving Empirical Progressions from the Assessment and Teaching of 21st Century Skills (ATC21S) framework were used to determine the level of collaborative problem solving skills (CPS) in first, second and third year MBBS students at Ziauddin College of Medicine during Problem-Based Learning (PBL) sessions. Variations based on gender and roles were studied. It is an analytical comparative cross-sectional study in which seven PBL groups were selected per year by non-probability convenient sampling. Data was collected using the Collaborative Problem Solving Five Strands Empirical Progressions by the primary investigator through observation of the students during PBL sessions. Duration of study was six months. We found that in our students, development of social dimension skills is facilitated to a greater extent than the development of cognitive dimension skills through the process of PBL. These skills are generally better developed in the leader compared to the scribe and members in a group. They are also more developed in females compared to males. Modification in them is also observed as the year's progress. Although PBLs facilitate development of CPS skills' progression however in our curriculum, PBLs mainly focus on social skills development and have less emphasis on cognitive skill development. Thus, hybrid instructional strategies with components from TBL and mentorship are recommended for better development of CPS skills.

Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma.

PubMed

Kaseb, Ahmed O; Morris, Jeffrey S; Iwasaki, Michiko; Al-Shamsi, Humaid O; Raghav, Kanwal Pratap Singh; Girard, Lauren; Cheung, Sheree; Nguyen, Van; Elsayes, Khaled M; Xiao, Lianchun; Abdel-Wahab, Reham; Shalaby, Ahmed S; Hassan, Manal; Hassabo, Hesham M; Wolff, Robert A; Yao, James C

2016-01-01

Clinicaltrials.gov #NCT01180959. Early clinical studies of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) have a tolerable toxicity and a promising clinical outcome. We evaluated the efficacy and tolerability of this combination as a second-line therapy for HCC refractory to sorafenib. For this single-arm, Phase II study, we recruited patients with Child-Pugh class A or B liver disease, Eastern Cooperative Oncology Group performance status 0-2, and advanced HCC that was not amenable to surgical or regional therapies and treatment with sorafenib had failed (disease progressed or patient could not tolerate sorafenib). Patients received 10 mg/kg intravenous bevacizumab every 14 days and 150 mg oral erlotinib daily for 28-day cycles until progression. Tumor response was evaluated every two cycles using Response Evaluation Criteria in Solid Tumors. The primary end point was the 16-week progression-free survival rate. Secondary end points included time to progression and overall survival. A total of 44 patients were enrolled and had a median follow-up time of 33.8 months (95% confidence interval [CI]: 23.5 months - not defined). The 16-week progression-free survival rate was 43% (95% CI: 28%-59%), median time to progression was 3.9 months (95% CI: 2.0-8.3 months), and median overall survival duration was 9.9 months (95% CI: 8.3-15.5 months). Grade 3-4 adverse events included fatigue (13%), acne (11%), diarrhea (9%), anemia (7%), and upper gastrointestinal hemorrhage (7%). Bevacizumab plus erlotinib was tolerable and showed a signal of survival benefit in the second-line setting for patients with advanced HCC. Because standard-of-care options are lacking in this setting, further studies to identify predictors of response to this regimen are warranted.

Predictive Value of Early Tumor Shrinkage and Density Reduction of Lung Metastases in Patients With Metastatic Colorectal Cancer Treated With Regorafenib.

PubMed

Vanwynsberghe, Hannes; Verbeke, Xander; Coolen, Johan; Van Cutsem, Eric

2017-12-01

The benefit of regorafenib in colorectal cancer is not very pronounced. At present, there is lack of predictive biological or radiological markers. We studied if density reduction or small changes in size of lung metastases could be a predictive marker. We retrospectively measured density in size of lung metastases of all patients included in the CORRECT and CONSIGN trials at our center. Contrast-enhanced CT scan at baseline and at week 8 were compared. Data of progressive-free survival and overall survival were collected from the CORRECT and CONSIGN trials. A significant difference in progressive-free survival was seen in 3 groups: response or stable disease in size (5.36 vs. 3.96 months), response in density (6.03 vs. 2.72 months), and response in corrected density (6.14 vs. 3.08 months). No difference was seen for response in size versus stable disease or progressive disease in size. For overall survival, a difference was observed in the same 3 groups: response or stable disease in size (9.89 vs. 6.44 months), response in density (9.59 vs. 7.04 months), and response in corrected density (9.09 vs. 7.16 months). No difference was seen for response in size versus stable disease or progressive disease in size. Density reduction in lung metastases might be a good predictive parameter to predict outcome for regorafenib. Early tumor progression might be a negative predictive factor. If further validated, density reduction and early tumor progression might be useful to ameliorate the cost-benefit of regorafenib. Copyright © 2017 Elsevier Inc. All rights reserved.

Outcomes in Lung Cancer: 9-Year Experience From a Tertiary Cancer Center in India

PubMed Central

Murali, Aditya Navile; Ganesan, Trivadi S.; Rajendranath, Rejiv; Ganesan, Prasanth; Selvaluxmy, Ganesarajah; Swaminathan, Rajaraman; Sundersingh, Shirley; Krishnamurthy, Arvind; Sagar, Tenali Gnana

2017-01-01

Purpose Lung cancer is the most common cause of cancer mortality in the world. There are limited studies on survival outcomes of lung cancer in developing countries such as India. This study analyzed the outcomes of patients with lung cancer who underwent treatment at Cancer Institute (WIA), Chennai, India, between 2006 and 2015 to determine survival outcomes and identify prognostic factors. Patients and Methods In all, 678 patients with lung cancer underwent treatment. Median age was 58 years, and 91% of patients had non–small-cell lung cancer (NSCLC). Testing for epidermal growth factor receptor mutation was performed in 132 of 347 patients and 61 (46%) were positive. Results Median progression-free survival was 6.9 months and overall survival (OS) was 7.6 months for patients with NSCLC. Median progression-free survival was 6 months and OS was 7.2 months for patients with small-cell lung cancer. On multivariable analysis, the factors found to be significantly associated with inferior OS in NSCLC included nonadenocarcinoma histology, performance status more than 2, and stage. In small-cell lung cancer, younger age and earlier stage at presentation showed significantly better survival. Conclusion Our study highlights the challenges faced in treating lung cancer in India. Although median survival in advanced-stage lung cancer is still poor, strategies such as personalized medicine and use of second-line and maintenance chemotherapy may significantly improve the survival in patients with advanced-stage lung cancer in developing countries. PMID:29094084

MONTHLY PROGRESS REPORT ON THE FEASIBILITY AND DESIGN STUDY FOR COLLECTIVE PROTECTION EQUIPMENT FOR THE AN/MSG-4 SYSTEM. PHASEIA. Technical Report, April 15 to May 30, 1962 (1st Report). Financial Report, April 15 to May 30, 1962 (1st Report). GSG Report No. 1663.00/54

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

Glaser, J.

1962-06-19

Initial efforts devoted to development of layout drawings of the protective equipment from which detailed fabrication drawings are to be established are reported. Collective protection equipment design progress is reported on 400- and 800-cfm filter units and on protective entrances for shelters and vehicles. (J.R.D.)

Progression of brain atrophy in PSP and CBS over 6 months and 1 year.

PubMed

Dutt, Shubir; Binney, Richard J; Heuer, Hilary W; Luong, Phi; Attygalle, Suneth; Bhatt, Priyanka; Marx, Gabe A; Elofson, Jonathan; Tartaglia, Maria C; Litvan, Irene; McGinnis, Scott M; Dickerson, Bradford C; Kornak, John; Waltzman, Dana; Voltarelli, Lisa; Schuff, Norbert; Rabinovici, Gil D; Kramer, Joel H; Jack, Clifford R; Miller, Bruce L; Rosen, Howard J; Boxer, Adam L

2016-11-08

To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects. © 2016 American Academy of Neurology.

Progressive Pathological Changes in Neurochemical Profile of the Hippocampus and Early Changes in the Olfactory Bulbs of Tau Transgenic Mice (rTg4510).

PubMed

Kim, Jieun; Choi, In-Young; Duff, Karen E; Lee, Phil

2017-06-01

Tauopathies such as Alzheimer's disease and frontotemporal lobe degeneration (FTLD-tau) dementia, characterized by pathologic aggregation of the microtubule-associated tau protein and formation of neurofibrillary tangles, have been linked to neurodegeneration and cognitive decline. The early detection of cerebral abnormalities and the identification of biological contributors to the continuous pathologic processes of neurodegeneration in tauopathies critically hinge on sensitive and reliable measures of biomarkers in the living brain. In this study, we measured alterations in a number of key neurochemicals associated with tauopathy-induced neurodegeneration in the hippocampus and the olfactory bulbs of a transgenic mouse model of FTLD-tauopathy, line rTg4510, using in vivo 1 H magnetic resonance spectroscopy at 9.4 T. The rTg4510 line develops tauopathy at a young age (4-5 months), reaching a severe stage by 8-12 months of age. Longitudinal measurement of neurochemical concentrations in the hippocampus of mice from 5 to 12 months of age showed significant progressive changes with distinctive disease staging patterns including N-acetylaspartate, myo-inositol, γ-aminobutyric acid, glutathione and glutamine. The accompanying hippocampal volume loss measured using magnetic resonance imaging showed significant correlation (p < 0.01) with neurochemical measurements. Neurochemical alterations in the olfactory bulbs were more pronounced than those in the hippocampus in rTg4510 mice. These results demonstrate progressive neuropathology in the mouse model and provide potential biomarkers of early neuropathological events and effective noninvasive monitoring of the disease progression and treatment efficacy, which can be easily translated to clinical studies.

Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis

PubMed Central

Johung, Kimberly L.; Yeh, Norman; Desai, Neil B.; Williams, Terence M.; Lautenschlaeger, Tim; Arvold, Nils D.; Ning, Matthew S.; Attia, Albert; Lovly, Christine M.; Goldberg, Sarah; Beal, Kathryn; Yu, James B.; Kavanagh, Brian D.; Chiang, Veronica L.; Camidge, D. Ross

2016-01-01

Purpose We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non–small-cell lung cancer (NSCLC) and brain metastasis. Patients and Methods A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. Results Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). Conclusion Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease. PMID:26438117

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience

PubMed Central

Vici, Patrizia; Pizzuti, Laura; Michelotti, Andrea; Sperduti, Isabella; Natoli, Clara; Mentuccia, Lucia; Lauro, Luigi Di; Sergi, Domenico; Marchetti, Paolo; Santini, Daniele; Magnolfi, Emanuela; Iezzi, Laura; Moscetti, Luca; Fabbri, Agnese; Cassano, Alessandra; Grassadonia, Antonino; Omarini, Claudia; Piacentini, Federico; Botticelli, Andrea; Bertolini, Ilaria; Scinto, Angelo Fedele; Zampa, Germano; Mauri, Maria; D’Onofrio, Loretta; Sini, Valentina; Barba, Maddalena; Maugeri-Saccà, Marcello; Rossi, Ernesto; Landucci, Elisabetta; Tomao, Silverio; Alberti, Antonio Maria; Giotta, Francesco; Ficorella, Corrado; Adamo, Vincenzo; Russo, Antonio; Lorusso, Vito; Cannita, Katia; Barni, Sandro; Laudadio, Lucio; Greco, Filippo; Garrone, Ornella; Giulia, Marina Della; Marolla, Paolo; Sanguineti, Giuseppe; Cocco, Barbara Di; Ciliberto, Gennaro; Maria, Ruggero De; Gamucci, Teresa

2017-01-01

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order. PMID:28915642

Continuous passive motion and its effects on knee flexion after total knee arthroplasty in patients with knee osteoarthritis.

PubMed

Liao, Chun-De; Huang, Yi-Ching; Lin, Li-Fong; Chiu, Yen-Shuo; Tsai, Jui-Chen; Chen, Chun-Lung; Liou, Tsan-Hon

2016-08-01

This study evaluated the effects of continuous passive motion (CPM) on accelerated flexion after total knee arthroplasty (TKA) and whether CPM application measures (i.e. initial angle and daily increment) are associated with functional outcomes. A retrospective investigation was conducted at the rehabilitation centre of a university-based teaching hospital. Patients who received CPM therapy immediately after TKA surgery were categorized into rapid-, normal-, and slow-progress groups according to their response to CPM during their acute inpatient stay. Knee pain, passive knee flexion, and knee function-measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-were assessed preoperatively at discharge and at 3- and 6-month outpatient follow-up visits. A total of 354 patients were followed for 6 months after inpatient-stay discharge. The patients in the rapid-progress group (n = 119) exhibited significantly greater knee flexions than those in the slow-progress group did (n = 103) at the 3-month follow-up [mean difference (MD) = 10.3°, 95 % confidence interval (CI) 4.3°-16.3°, p < 0.001] and 6-month follow-up (MD = 10.9°, 95 % CI 6.3°-15.6°, p < 0.001). Significant WOMAC score differences between the rapid- and slow-progress groups were observed at the 3-month follow-up (MD = 7.2, 95 % CI 5.4-9.1, p < 0.001) and 6-month follow-up (MD = 16.1, 95 % CI 13.4-18.7, p < 0.001). CPM initial angles and rapid progress significantly predicted short- and long-term outcomes in knee flexion and WOMAC scores (p < 0.001). When CPM is used, early application with initial high flexion and rapid progress benefits knee function up to 6 months after TKA. II.

Analysis of serum immune markers in seropositive and seronegative rheumatoid arthritis and in high-risk seropositive arthralgia patients.

PubMed

Chalan, Paulina; Bijzet, Johan; van den Berg, Anke; Kluiver, Joost; Kroesen, Bart-Jan; Boots, Annemieke M H; Brouwer, Elisabeth

2016-05-18

Presence of autoantibodies precedes development of seropositive rheumatoid arthritis (SP RA) and seropositive arthralgia patients (SAP) are at risk of developing RA. The aims of the study are to identify additional serum immune markers discriminating between SP and seronegative (SN) RA, and markers identifying high-risk SAP. Sera from SAP (n = 27), SP RA (n = 22), SN RA (n = 11) and healthy controls (n = 20) were analyzed using the Human Cytokine 25-Plex Panel. Selected markers were validated in independent cohorts of SP RA (n = 35) and SN RA (n = 12) patients. Eleven of 27 SAP developed RA within 8 months (median follow-up time, range 1-32 months), and their baseline serum markers were compared to 16 non-progressing SAP. SAP and SP RA patients showed a marked overlap in their systemic immune profiles, while SN RA showed a distinct immune profile. Three of 4 markers discriminating between SP and SN RA (IL-1β, IL-15 and Eotaxin, but not CCL5) were similarly modulated in independent cohorts. SAP progressing to RA showed trends for increases in IL-5, MIP-1β, IL-1RA and IL-12 compared to non-progressing SAP. ROC analysis showed that serum IL-5 most accurately discriminated between the two SAP groups (AUC > 0.8), suggesting that baseline IL-5 levels may aid the identification of high-risk SAP.

Crevicular Fluid Biomarkers and Periodontal Disease Progression

PubMed Central

Oh, Min; Braun, Thomas M.; Ramseier, Christoph A.; Sugai, Jim V.; Giannobile, William V.

2014-01-01

Aim Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). Materials and Methods 100 individuals participated in a 12-month longitudinal investigation and categorized into 4 groups according to their periodontal status. GCF, clinical parameters, and saliva were collected bi-monthly. Sub-gingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6-months, patients received periodontal therapy and continued participation from 6-12 months. GCF samples were analyzed by ELISA for MMP-8, MMP-9, OPG, CRP and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p=0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Results Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61,86). Conclusions Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). PMID:24303954

Thermal ablation of intrahepatic cholangiocarcinoma: Safety, efficacy, and factors affecting local tumor progression.

PubMed

Takahashi, Edwin A; Kinsman, Kristin A; Schmit, Grant D; Atwell, Thomas D; Schmitz, John J; Welch, Brian T; Callstrom, Matthew R; Geske, Jennifer R; Kurup, A Nicholas

2018-06-04

To evaluate the safety and oncologic efficacy of percutaneous thermal ablation of intrahepatic cholangiocarcinoma (ICC) and identify risk factors for local tumor progression (LTP). Retrospective review of an institutional tumor ablation registry demonstrated that 20 patients (9 males, 11 females; mean age 62.5 ± 15.8 years) with 50 ICCs (mean size 1.8 ± 1.3 cm) were treated with percutaneous radiofrequency ablation (RFA) or microwave ablation (MWA) between 2006 and 2015. Thirty-eight of the treated ICCs (76%) were metastases that developed after surgical resection of the primary tumor. Patient demographics, procedure technical parameters, and clinical outcomes were reviewed. A Cox proportional hazards model was used to examine the risk of LTP by ablation modality. Survival analyses were performed using the Kaplan-Meier method. Mean imaging follow-up time was 41.5 ± 42.7 months. Forty-four (88%) ICCs were treated with RFA, and 6 (12%) with MWA. Eleven (22%) cases of LTP developed in 5 (25%) patients. The median time to LTP among these 11 tumors was 7.1 months (range, 2.3-22.9 months). Risk of LTP was not significantly different for ICCs treated with MWA compared to RFA (HR 2.72; 95% CI 0.58-12.84; p = 03.21). Median disease-free survival was 8.2 months (1.1-70.4 months), and median overall survival was 23.6 months (7.4-122.5 months). No major complication occurred. Percutaneous thermal ablation is a safe and effective treatment for patients with ICCs and may be particularly valuable in unresectable patients, or those who have already undergone hepatic surgery. Tumor size and ablation modality were not associated with LTP, whereas primary tumors and superficially located tumors were more likely to subsequently recur.

Distal acquired demyelinating symmetric polyneuropathy progressing to classic chronic inflammatory demyelinating polyneuropathy and response to fludarabine and cyclophosphamide.

PubMed

Leitch, Megan M; Sherman, William H; Brannagan, Thomas H

2013-02-01

Distal acquired demyelinating symmetric polyneuropathy (DADS) is proposed as a distinct entity from classic chronic inflammatory demyelinating polyneuropathy (CIDP). We report a 58-year-old woman with DADS that progressed to a severe case of classic CIDP. She had distal numbness and paresthesias, minimal distal weakness and impaired vibratory sensation. She had anti-MAG antibodies, negative Western blot, and lacked a monoclonal gammopathy. There were prolonged distal motor latencies. She remained stable for 6 years until developing proximal and distal weakness. Nerve conduction studies showed multiple conduction blocks. She developed quadriparesis despite first-line treatment for CIDP. She was started on cyclophosphamide and fludarabine. Twenty-five months after receiving chemotherapy, she had only mild signs of neuropathy off all immunotherapy. DADS may progress to classic CIDP and is unlikely to be a separate disorder. Fludarabine and cyclophosphamide may be effective for refractory CIDP. Copyright © 2012 Wiley Periodicals, Inc.

Mass Transportation in Massachusetts : demonstration project progress report no. 5 - tentative conclusions

DOT National Transportation Integrated Search

1963-11-22

This fifth progress report is submitted twelve months after the initiation of the first MTC-HHFA experiment, and ten months after the start of the large Boston and Maine Railroad. Because of the urgent need to present comprehensive analyses in some d...

Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients.

PubMed

Conry, Robert M; Rodriguez, Michael G; Pressey, Joseph G

2016-01-01

Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression. In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18-20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA. Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.

Prospective study of natural history of deep vein thrombosis: early predictors of poor late outcomes.

PubMed

van Rij, André M; Hill, Gerry; Krysa, Jo; Dutton, Samantha; Dickson, Riordon; Christie, Ross; Smillie, Judi; Jiang, Ping; Solomon, Clive

2013-10-01

A proportion of patients with deep vein thrombosis (DVT) will develop postthrombotic syndrome (PTS). Currently, the only clearly identified risk factors for developing PTS are recurrent ipsilateral DVT and extensive proximal disease. The aim of the study was to assess the natural history of DVT and identify early predictors of poor clinical outcome at 5 years. Patients with suspected acute DVT in the lower limb were assessed prospectively. All patients with a confirmed DVT were asked to participate in this study. Within 7-10 days after diagnosis of DVT, patients underwent a further review, involving clinical, ultrasound, and air plethysmography assessment of both lower limbs. Patients were reassessed at regular intervals for 5 years. One hundred twenty-two limbs in 114 patients were included in this study. Thrombus regression occurred in two phases, with a rapid regression between 10 days and 3 months, and a more gradual regression thereafter. Reflux developed as thrombus regression occurred. Segmental reflux progressed to axial deep reflux and continued to deteriorate in a significant proportion of patients with iliofemoral-popliteal-calf DVT throughout the 5-year study period. Similarly, venous filling index became progressively more abnormal, in this group, over the course of the study. Four risk factors for PTS were identified as best predictors: extensive clot load on presentation; <50% clot regression at 6 months; venous filling index >2.5 mL/sec; and abnormal outflow rate (<0.6). Patients with three or more of these risk factors had a significant risk of developing PTS with sensitivity 100%, specificity 83%, and positive predictive value 67%. Patients scoring 2 or less did not have PTS at 5 years with a negative predictive value of 100%. This is the first study to show that venous assessment at 6 months post-DVT can predict PTS at 5 years. Those who will not develop PTS can be reassured of this at 6 months. Copyright © 2013 Elsevier Inc. All rights reserved.

Low-Dose Radiotherapy in Indolent Lymphoma

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

Rossier, Christine; Schick, Ulrike; Miralbell, Raymond

Purpose: To assess the response rate, duration of response, and overall survival after low-dose involved-field radiotherapy in patients with recurrent low-grade lymphoma or chronic lymphocytic leukemia (CLL). Methods and Materials: Forty-three (24 women, 19 men) consecutive patients with indolent lymphoma or CLL were treated with a total dose of 4 Gy (2 x 2 Gy) using 6- 18-MV photons. The median age was 73 years (range, 39-88). Radiotherapy was given either after (n = 32; 75%) or before (n = 11; 25%) chemotherapy. The median time from diagnosis was 48 months (range, 1-249). The median follow-up period was 20 monthsmore » (range, 1-56). Results: The overall response rate was 90%. Twelve patients (28%) had a complete response, 15 (35%) had a partial response, 11 (26%) had stable disease, and 5 (11%) had progressive disease. The median overall survival for patients with a positive response (complete response/partial response/stable disease) was 41 months; for patients with progressive disease it was 6 months (p = 0.001). The median time to in-field progression was 21 months (range, 0-24), and the median time to out-field progression was 8 months (range, 0-40). The 3-year in-field control was 92% in patients with complete response (median was not reached). The median time to in-field progression was 9 months (range, 0.5-24) in patients with partial response and 6 months (range, 0.6-6) in those with stable disease (p < 0.05). Younger age, positive response to radiotherapy, and no previous chemotherapy were the best factors influencing the outcome. Conclusions: Low-dose involved-field radiotherapy is an effective treatment in the management of patients with recurrent low-grade lymphoma or CLL.« less

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study

PubMed Central

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Background Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. Patients and methods This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Results Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63–7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Conclusion Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects. PMID:29075129

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study.

PubMed

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63-7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects.

Angiosarcoma after breast-conserving therapy: long-term outcomes with hyperfractionated radiotherapy.

PubMed

Palta, Manisha; Morris, Christopher G; Grobmyer, Stephen R; Copeland, Edward M; Mendenhall, Nancy P

2010-04-15

With breast-conserving therapy (BCT) as the standard of care for patients with noninvasive and early stage invasive breast cancer, a small incidence of post-BCT angiosarcoma has emerged. The majority of therapeutic interventions have been unsuccessful. To the authors' knowledge, there is no consensus in the medical literature to date regarding the treatment of this malignancy. The current study was conducted to report the long-term outcomes of a novel approach using hyperfractionated and accelerated radiotherapy (HART) for angiosarcoma developing after BCT. The authors retrospectively reviewed the outcomes of 14 patients treated with HART with or without surgery at the University of Florida between November 1997 and March 2006 for angiosarcoma that developed after BCT. At the time of last follow-up, 9 patients had remained continuously without evidence of disease for a median of 61 months after HART (range, 36-127 months). Five patients had further manifestations of angiosarcoma after HART at a median of 1 month (range, 1-28 months): 3 with progressive pulmonary and/or mediastinal disease that was likely present before HART and 2 with local or regional disease extension. Progression-free survival rates for the 14 patients at 2 years and 5 years were 71% and 64%, respectively. The overall and cause-specific survival rates were both 86% at 2 years and 5 years. To the best of the authors' knowledge, HART with or without subsequent surgery, as documented in the current series, is the first approach to provide a high rate of local control, disease-free survival, and overall survival after the development of post-BCT angiosarcoma. The authors believe the success noted with this approach is related to both the hyperfractionation and acceleration of the RT. (c) 2010 American Cancer Society.

Analysis of Patients With Oligometastases Undergoing Two or More Curative-Intent Stereotactic Radiotherapy Courses

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

Milano, Michael T.; Philip, Abraham; Okunieff, Paul

2009-03-01

Purpose: A subset of patients treated with curative-intent stereotactic radiotherapy (RT) for limited metastases (defined as five lesions or fewer) develop local failure and/or a small number of new lesions. We hypothesized that these patients would remain amenable to curative-intent treatment with additional RT courses. Methods and Materials: Of 121 prospective patients with five lesions or fewer treated with stereotactic RT, 32 underwent additional RT courses for local failure (n = 9) and/or new lesions (n = 29). Ten patients underwent three or more courses of RT. Results: The treated local failures developed a median of 20 months after RTmore » completion. For the new oligometastases, the interval between the first and second RT course was 1-71 months (median, 8). Of the 32 patients undergoing multiple courses of curative-intent RT, the 2-year overall survival and progression-free survival rate was 65% and 54%, respectively. The corresponding 4-year rates were 33% and 28%. Compared with the 89 patients who underwent one RT course, these patients experienced a trend toward improved overall survival (median, 32 vs. 21 months, p = 0.13) and significantly greater progression-free survival (median, 28 vs. 9 months, p = 0.008). Conclusion: The results of our study have shown that patients fare well with respect to survival and disease control with aggressive RT for limited metastases, even after local failure and/or the development of new metastases. Although patients amenable to multiple courses of curative-intent RT are arguably selected for more indolent disease, our hypothesis-generating analysis supports the notion of aggressively treating limited metastases, which, in some patients, might be curable and/or represent a chronic disease state.« less

Serum thyrotrophin at baseline predicts the natural course of subclinical hyperthyroidism.

PubMed

Das, G; Ojewuyi, T A; Baglioni, P; Geen, J; Premawardhana, L D; Okosieme, O E

2012-07-01

Optimal therapeutic strategies for subclinical hyperthyroidism are undecided. Overt disease develops in a minority of cases, but the risk factors for progression remain unclear. We examined whether a baseline thyrotrophin (TSH) predicted progression to overt hyperthyroidism in asymptomatic individuals with subclinical hyperthyroidism. This was a retrospective study of 323 patients with subclinical hyperthyroidism seen in our institution from 2003 to 2010 (mean age 71 years, males 26·9%, females 73·1%, mean follow-up duration 32 months, range 6-93 months). Serum TSH and free thyroxine (FT4) were documented at baseline and during follow-up. After excluding individuals with nonthyroid causes of low TSH, patients were grouped according to initial TSH as: TSH 0·10-0·39 mU/l (grade I) and TSH < 0·10 mU/l (grade II). Only 38 patients (11·8%) developed overt hyperthyroidism with annual progression rates of 0·6-3·7%. Most patients reverted to normal thyroid status (31·6%) or remained subclinically hyperthyroid (56·7%). Progression to frank hyperthyroidism was higher in grade II than in grade I patients (20·3% vs 6·8%, P < 0·001, Chi square test). Kaplan-Meier curves showed faster progression rates in grade II than grade I (P < 0·001, log rank test). In stepwise multivariate Cox regression analysis, TSH < 0·1 mU/l was associated with overt hyperthyroidism (hazard ratio 3·4, confidence interval 1·6-7·0), whereas age, gender, FT4 and aetiological diagnosis were not associated with hyperthyroidism. Thyrotrophin predicts overt hyperthyroidism in asymptomatic individuals with subclinical hyperthyroidism. Patients with TSH < 0·10 mU/l have a higher risk of progressing to hyperthyroidism than those with TSH 0·10-0·39 mU/l. © 2012 Blackwell Publishing Ltd.

Liver proteomics in progressive alcoholic steatosis

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

Fernando, Harshica; Wiktorowicz, John E.; Soman, Kizhake V.

2013-02-01

Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber–DeCarli diet daily for 1 and 3 months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3 months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved inmore » alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3 months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (− 1.6) at 1 month and up regulation of aldehyde dehydrogenase (2.1) at 3 months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1 month) while peroxiredoxin-1 was down regulated (− 1.5) at late fatty liver stage (3 months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified D-dopachrome tautomerase (− 1.7, at 3 months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum. -- Graphical abstract: The figure shows the Hierarchial cluster analysis of differentially expressed protein spots obtained after ethanol feeding for 1 (1–3) and 3 (4–6) months. C and E represent pair-fed control and ethanol-fed rats, respectively. Highlights: ► Proteins related to ethanol-induced steatosis and mild steatohepatitis are identified. ► ADH1C and ALDH2 involved in alcohol metabolism are differentially expressed at 1 and 3 months. ► Discovery proteomics identified a group of proteins to serve as potential biomarkers. ► Using nonparametric analysis DDT is identified as a possible marker for liver damage.« less

Outcome prediction in plasmacytoma of bone: a risk model utilizing bone marrow flow cytometry and light-chain analysis.

PubMed

Hill, Quentin A; Rawstron, Andy C; de Tute, Ruth M; Owen, Roger G

2014-08-21

The purpose of this study was to use multiparameter flow cytometry to detect occult marrow disease (OMD) in patients with solitary plasmacytoma of bone and assess its value in predicting outcome. Aberrant phenotype plasma cells were demonstrable in 34 of 50 (68%) patients and comprised a median of 0.52% of bone marrow leukocytes. With a median follow-up of 3.7 years, 28 of 50 patients have progressed with a median time to progression (TTP) of 18 months. Progression was documented in 72% of patients with OMD vs 12.5% without (median TTP, 26 months vs not reached; P = .003). Monoclonal urinary light chains (ULC) were similarly predictive of outcome because progression was documented in 91% vs 44% without (median TTP, 16 vs 82 months; P < .001). By using both parameters, it was possible to define patients with an excellent outcome (lacking both OMD and ULC, 7.7% progression) and high-risk patients (OMD and/or ULC, 75% progression; P = .001). Trials of systemic therapy are warranted in high-risk patients. © 2014 by The American Society of Hematology.

Cyclophosphamide's addition in relapsed/refractory multiple myeloma patients with biochemical progression during lenalidomide-dexamethasone treatment.

PubMed

Cesini, Laura; Siniscalchi, Agostina; Grammatico, Sara; Andriani, Alessandro; Fiorini, Alessia; De Rosa, Luca; Za, Tommaso; Rago, Angela; Caravita, Tommaso; Petrucci, Maria Teresa

2018-05-02

The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

PubMed

Davis, I D; Long, A; Yip, S; Espinoza, D; Thompson, J F; Kichenadasse, G; Harrison, M; Lowenthal, R M; Pavlakis, N; Azad, A; Kannourakis, G; Steer, C; Goldstein, D; Shapiro, J; Harvie, R; Jovanovic, L; Hudson, A L; Nelson, C C; Stockler, M R; Martin, A

2015-06-01

We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. We recruited 55 eligible participants from September 2010 to August 2012. mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. ACTRN12609000643279. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Subsequent development of fibroatheromas with inflamed fibrous caps can be predicted by intracoronary near infrared spectroscopy.

PubMed

Patel, Dhavalkumar; Hamamdzic, Damir; Llano, Raul; Patel, Daivesh; Cheng, Lan; Fenning, Robert S; Bannan, Khalid; Wilensky, Robert L

2013-02-01

To prospectively evaluate whether the development of fibroatheromas exhibiting features of potential instability can be detected and predicted by serial invasive imaging. Multivessel intravascular ultrasound and near infrared spectroscopy (NIRS) were performed in diabetic/hypercholesterolemic pigs 3, 6, and 9 months after induction. Animals were euthanized at 9 months and histological/immunohistochemical evaluation of the arteries was performed (n=304 arterial segments). Intravascular ultrasound demonstrated, over time, a progressive increase in plaque + media and necrotic core areas and positive vascular remodeling. By histology, NIRS+ lesions were significantly more likely to be a high-risk fibroatheroma (P=0.0001) containing larger plaque (P<0.0001) and necrotic core areas (P<0.0019) and thinner fibrous caps (P=0.04). NIRS + fibroatheromas possessed a greater concentration of inflammatory cells demonstrating protease activity (P=0.006), and proliferating (P=0.016), and apoptotic cells (P=0.04) within the fibrous cap. Eighty-eight percent of NIRS+ lesions at 3 and 6 months subsequently developed into a fibroatheroma at 9 months (P<0.01). By multivariate analysis NIRS positivity at 6 months predicted the subsequent presence of a fibroatheroma at 9 months (P=0.005; odds ratio, 2.71). The future development of inflamed fibroatheromas with thinner fibrous caps, greater plaque, and necrotic core areas, and posessing characteristics of increased plaque instability were detected by intravascular ultrasound/NIRS imaging.

Stability in Young Infants' Discrimination of Optic Flow

ERIC Educational Resources Information Center

Gilmore, Rick O.; Baker, Thomas J.; Grobman, K. H.

2004-01-01

Although considerable progress has been made in understanding how adults perceive their direction of self-motion, or heading, from optic flow, little is known about how these perceptual processes develop in infants. In 3 experiments, the authors explored how well 3- to 6-month-old infants could discriminate between optic flow patterns that…

Cats with diabetes mellitus have diastolic dysfunction in the absence of structural heart disease.

PubMed

Pereira, N J; Novo Matos, J; Baron Toaldo, M; Bartoszuk, U; Summerfield, N; Riederer, A; Reusch, C; Glaus, T M

2017-07-01

Diabetes mellitus (DM) can result in cardiovascular dysfunction and heart failure characterized by diastolic dysfunction with or without the presence of systolic dysfunction in people and laboratory animals. The objective of this prospective study was to determine if cats with newly diagnosed DM had myocardial dysfunction and, if present, whether it would progress if appropriate antidiabetic therapy was commenced. Thirty-two diabetic cats were enrolled and received baseline echocardiographic examination; of these, 15 cats were re-examined after 6 months. Ten healthy age- and weight-matched cats served as controls. Diabetic cats at diagnosis showed decreased diastolic, but not systolic function, when compared to healthy controls, with lower mitral inflow E wave (E) and E/E' than controls. After 6 months, E and E/IVRT' decreased further in diabetic cats compared to the baseline evaluation. After excluding cats whose DM was in remission at 6 months, insulin-dependent diabetic cats had lower E, E/A and E' than controls. When classifying diastolic function according to E/A and E'/A', there was shift towards impaired relaxation patterns at 6 months. All insulin-dependent diabetic cats at 6 months had abnormal diastolic function. These results indicate that DM has similar effects on diastolic function in feline and human diabetics. The dysfunction seemed to progress rather than to normalize after 6 months, despite antidiabetic therapy. In cats with pre-existing heart disease, the development of DM could represent an important additional health risk. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cued recall measure predicts the progression of gray matter atrophy in patients with amnesic mild cognitive impairment.

PubMed

Koric, Lejla; Ranjeva, Jean-Philippe; Felician, Olivier; Guye, Maxime; de Anna, Francesca; Soulier, Elisabeth; Didic, Mira; Ceccaldi, Mathieu

2013-01-01

Amnesic mild cognitive impairment (aMCI) is a heterogeneous syndrome that could be subdivided into distinct neuropsychological variants. To investigate relationships between the neuropsychological profile of memory impairment at baseline and the neuroimaging pattern of grey matter (GM) loss over 18 months, we performed a prospective volumetric brain study on 31 aMCI patients and 29 matched controls. All subjects were tested at baseline using a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for the assessment of verbal declarative memory. Over 18 months, patients with impaired free recall but normal total recall (high index of cueing) on the FCSRT developed subcortical and frontal GM loss, while patients with impaired free and total recall (low index of cueing) developed GM atrophy within the left anterior and lateral temporal lobe. In summary, cued recall deficits are associated with a progression of atrophy that closely parallels the spatiotemporal distribution of neurofibrillary degeneration in early Alzheimer's disease (AD), indicating possible AD pathological changes. © 2013 S. Karger AG, Basel.

Nurse-assisted education and exercise decrease the prevalence and morbidity of lymphedema following breast cancer surgery.

PubMed

Sisman, H; Sahin, B; Duman, B B; Tanriverdi, G

2012-01-01

To evaluate an educational and exercise program for the prevention and progression of post-mastectomy lymphedema of the arm and shoulder. Fifty-five patients who had undergone mastectomy and axillary lymph node dissection between June 2009 and January 2010 were included in this study. The patients were informed by a trainer nurse about the precautions they should take to prevent the development of lymphedema. The patients were also trained for the appropriate exercises and were given written educational material prepared by the investigators. Among the participants, 96.4% underwent modified radical mastectomy (MRM) and 3.6% breast-conserving (BCS) surgery. The mean postoperative follow-up period was 9.87 ± 17.55 months. The degree of lymphedema was found lower, even within 6 months, in the patients that exercised as compared to the patients that did not (p<0.05). The results indicate that the risk of development and progression of mastectomy-related lymphedema was reduced with education and exercise provided by trained nurses at an early stage.

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study.

PubMed

von Minckwitz, Gunter; du Bois, Andreas; Schmidt, Marcus; Maass, Nicolai; Cufer, Tanja; de Jongh, Felix E; Maartense, Eduard; Zielinski, Christoph; Kaufmann, Manfred; Bauer, Wolfgang; Baumann, Klaus H; Clemens, Michael R; Duerr, Ralph; Uleer, Christoph; Andersson, Michael; Stein, Robert C; Nekljudova, Valentina; Loibl, Sibylle

2009-04-20

Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project

PubMed Central

Carson, Kenneth R.; Evens, Andrew M.; Richey, Elizabeth A.; Habermann, Thomas M.; Focosi, Daniele; Seymour, John F.; Laubach, Jacob; Bawn, Susie D.; Gordon, Leo I.; Winter, Jane N.; Furman, Richard R.; Vose, Julie M.; Zelenetz, Andrew D.; Mamtani, Ronac; Raisch, Dennis W.; Dorshimer, Gary W.; Rosen, Steven T.; Muro, Kenji; Gottardi-Littell, Numa R.; Talley, Robert L.; Sartor, Oliver; Green, David; Major, Eugene O.

2009-01-01

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons. PMID:19264918

Treatment carryover impacts on effectiveness of intraocular pressure lowering agents, estimated by a discrete event simulation model.

PubMed

Denis, P; Le Pen, C; Umuhire, D; Berdeaux, G

2008-01-01

To compare the effectiveness of two treatment sequences, latanoprost-latanoprost timolol fixed combination (L-LT) versus travoprost-travoprost timolol fixed combination (T-TT), in the treatment of open-angle glaucoma (OAG) or ocular hypertension (OHT). A discrete event simulation (DES) model was constructed. Patients with either OAG or OHT were treated first-line with a prostaglandin, either latanoprost or travoprost. In case of treatment failure, patients were switched to the specific prostaglandin-timolol sequence LT or TT. Failure was defined as intraocular pressure higher than or equal to 18 mmHg at two visits. Time to failure was estimated from two randomized clinical trials. Log-rank tests were computed. Linear functions after log-log transformation were used to model time to failure. The time horizon of the model was 60 months. Outcomes included treatment failure and disease progression. Sensitivity analyses were performed. Latanoprost treatment resulted in more treatment failures than travoprost (p<0.01), and LT more than TT (p<0.01). At 60 months, the probability of starting a third treatment line was 39.2% with L-LT versus 29.9% with T-TT. On average, L-LT patients developed 0.55 new visual field defects versus 0.48 for T-TT patients. The probability of no disease progression at 60 months was 61.4% with L-LT and 65.5% with T-TT. Based on randomized clinical trial results and using a DES model, the T-TT sequence was more effective at avoiding starting a third line treatment than the L-LT sequence. T-TT treated patients developed less glaucoma progression.

Prospective Randomized Trial Comparing Efficacy of Topical Loteprednol Etabonate 0.5% Versus Cyclosporine-A 0.05% for Treatment of Dry Eye Syndrome Following Hematopoietic Stem Cell Transplantation.

PubMed

Boynton, Grace E; Raoof, Duna; Niziol, Leslie M; Hussain, Munira; Mian, Shahzad I

2015-07-01

To evaluate the safety and efficacy of topical loteprednol etabonate (LE) 0.5% compared with cyclosporine A (CsA) 0.05% for the prophylaxis and treatment of dry eye syndrome (DES) after hematopoietic stem cell transplantation (HSCT). Seventy-five patients were randomized to LE (n = 76 eyes of 38 patients) or CsA (n = 74 eyes of 37 patients) pre-HSCT. Lissamine green and fluorescein staining, tear break-up time, tear osmolarity (Osm), Schirmer score (Sch), intraocular pressure, visual acuity, and Ocular Surface Disease Index were assessed pre-HSCT, 3, 6, 9, and 12 months post-HSCT. There were no differences in DES incidence (P = 0.22; log-rank test) or progression (P = 0.41; log-rank test) between the 2 treatment arms during the course of the study. Among eyes with no DES at enrollment, the Kaplan-Meier analysis yielded a 90% rate of DES development in cyclosporine-treated eyes and a 79% rate of DES development in LE-treated eyes by 12 months post-HSCT. The Kaplan-Meier analysis of eyes with DES at enrollment demonstrated a 38% rate of disease progression among cyclosporine-treated eyes and a 26% rate of disease progression among loteprednol-treated eyes by 12 months. No patient in either group had an elevation of 10 mm Hg or greater from baseline at any study visit, and no patients had their treatment discontinued for elevation in intraocular pressure. Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT.

Cytopathology and coagulopathy associated with viral erythrocytic necrosis in chum salmon

USGS Publications Warehouse

MacMillian, John R.; Mulcahy, D.; Landolt, M.L.

1989-01-01

The 8-month cytopathologic progression of viral erythrocytic necrosis (VEN) disease in chum salmon Oncorhynchus keta is described. Single to multiple acidophilic, cytoplasmic viral inclusion bodies developed first in mature erythrocytes and then, within 1–2 months, all morphologically identifiable hemopoietic cell types contained VEN inclusions. Cytologic analysis indicated that multinucleate giant erythroblasts, ineffective erythropoiesis, and abnormal erythroid cell maturation occurred. A significant increase in blood coagulation time occurred concomitantly. This severe and chronic blood dyscrasia accounts for some of the pathophysiologic sequelae previously observed.

Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

PubMed

Suliman, Sara; Thompson, Ethan; Sutherland, Jayne; Weiner Rd, January; Ota, Martin O C; Shankar, Smitha; Penn-Nicholson, Adam; Thiel, Bonnie; Erasmus, Mzwandile; Maertzdorf, Jeroen; Duffy, Fergal J; Hill, Philip C; Hughes, E Jane; Stanley, Kim; Downing, Katrina; Fisher, Michelle L; Valvo, Joe; Parida, Shreemanta K; van der Spuy, Gian; Tromp, Gerard; Adetifa, Ifedayo M O; Donkor, Simon; Howe, Rawleigh; Mayanja-Kizza, Harriet; Boom, W Henry; Dockrell, Hazel; Ottenhoff, Tom H M; Hatherill, Mark; Aderem, Alan; Hanekom, Willem A; Scriba, Thomas J; Kaufmann, Stefan He; Zak, Daniel E; Walzl, Gerhard

2018-04-06

Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. We investigated biosignatures with predictive ability for incident tuberculosis. In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non-progressors, who remained healthy during 24 months of follow-up, were investigated. A four-transcript signature (RISK4), derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, C1QC/TRAV27, that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs.

Career progress in online and blended learning environments.

PubMed

DeRosier, Melissa; Kameny, Rebecca; Holler, Wendy; Davis, Naomi Ornstein; Maschauer, Emily

2013-03-01

The authors examined the career achievement of early- and mid-career researchers in social, behavioral, and mental health who participated in a career-development conference. Trainees participated in a career-development conference either through attending a live conference supplemented with an online version of the conference (Combined: N=46) or through the online version of the conference alone (Web-Only: N=60). An objective measure tracked the trainees' publications, involvement in research projects, honors and grant awards, collaborations, and scientific presentations before and 9 months after participation in the career-development conference. Statistical analysis showed that trainees improved for each category measured, with no significant differences across the Combined and Web-Only groups. The strongest variable affecting improvement was Time, and the most significant time effect was seen in the production of presentations and publications. A significant Gender difference was present, with women showing greater total career progress than men. Career-development conferences can support career growth for trainees. Online training provides a cost-effective and time-efficient alternative to in-person methods, while still enhancing key markers of career progress.

Early childhood growth and cognitive outcomes: Findings from the MAL-ED study.

PubMed

Scharf, Rebecca J; Rogawski, Elizabeth T; Murray-Kolb, Laura E; Maphula, Angelina; Svensen, Erling; Tofail, Fahmida; Rasheed, Muneera; Abreu, Claudia; Vasquez, Angel Orbe; Shrestha, Rita; Pendergast, Laura; Mduma, Estomih; Koshy, Beena; Conaway, Mark R; Platts-Mills, James A; Guerrant, Richard L; DeBoer, Mark D

2018-02-02

Although many studies around the world hope to measure or improve developmental progress in children to promote community flourishing and productivity, growth is sometimes used as a surrogate because cognitive skills are more difficult to measure. Our objective was to assess how childhood measures of anthropometry correlate with measures of child development in low-income settings with high prevalence of poor nutrition and enteric disease, to inform studies considering growth outcomes in the absence of direct child developmental skill assessment. Children from the MAL-ED study were followed from birth to 24 months of age in field sites in 8 low- and middle-income countries across 3 continents. Monthly weight, length, and head circumference measurements were performed. At 24 months, the Bayley Scales of Infant and Toddler Development was administered. We correlated cognitive measures at 24 months with anthropometric measurements from birth to 2 years comparing 3 constructs: absolute attained monthly measures, summative difference in measures from the mean growth curve, and rate of change in measures. Growth faltering at multiple time periods is related to Bayley cognitive outcomes at 24 months. Birthweight, overall growth by 18-24 months, and rate of growth in the 6- to 18-month period were most associated with 24-month developmental scores. In this study, head circumference measurements, compared with length, was more closely linked to cognitive scores at 24 months. Notably, all studies between growth and cognitive outcomes exhibited low r 2 values (0.001-0.049). Anthropometric measures, particularly head circumference, were related to cognitive development, although explaining a low percent of variance. When feasible, direct measures of child development may be more useful. © 2018 John Wiley & Sons Ltd.

Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy.

PubMed

Ding, Zhi-Ming; Xiao, Yue; Wu, Xikun; Zou, Haixia; Yang, Shurong; Shen, Yiyun; Xu, Juehua; Workman, Heather C; Usborne, Amy L; Hua, Haiqing

2018-01-01

Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) enzyme activities, CK18 (cytokeratin-18), PIIINP (N-terminal propeptide of type III collagen), and TIMP-1 (tissue inhibitor of metalloproteinase-1). Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva), or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte degeneration, and mildly decreased liver fibrosis, but exhibited no effect on hepatic steatosis/macrovesicular vacuolation. In conclusion, we found the progression of NASH hepatic steatosis/macrovesicular vacuolation, and inflammation eventually lead to hepatocyte death and fibrosis. Life style change and current pharmacotherapies in development may be effective in treating NASH, but their effects on NASH-induced fibrosis may be mild. Since fibrosis is known to be an independent risk for decompensated cirrhosis, cardiovascular events, and mortality, our study suggests that effective anti-fibrosis therapy should be an essential component of the combined pharmacotherapy for advanced NASH.

Radiotherapy in the treatment of solitary plasmacytoma.

PubMed

Jyothirmayi, R; Gangadharan, V P; Nair, M K; Rajan, B

1997-05-01

Solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) are rare. High local control rates are reported with radiotherapy, although the optimal dose and extent of radiotherapy portals remains controversial. Between 1983 and 1993, 30 patients with solitary plasmacytoma were seen at the Regional Cancer Centre, Trivandrum, India. 23 patients had SPB and seven EMP. The mean age was 52 years and the male to female ratio 3.2:1. Diagnosis of SPB was confirmed by biopsy in 16 patients and tumour excision in seven. 20 patients received megavoltage radiotherapy to the bone lesion with limited margins, and one received chemotherapy. Two patients who underwent complete tumour excision received no further treatment. All seven patients with EMP received megavoltage radiotherapy, four following biopsy and three after tumour excision. Local control was achieved in all patients with SPB. Nine progressed to multiple myeloma and one developed a solitary plasmacytoma in another bone. Six patients with EMP achieved local control. Three later progressed to multiple myeloma and one had local relapse. Median time to relapse was 28 months in SPB and 30 months in EMP. 5-year overall survival rates were 82% and 57% for patients with SPB and EMP, respectively. The corresponding progression free survival rates were 55% and 50%, respectively. Age, sex, site of tumour, serum M protein and haemoglobin levels did not significantly influence progression free survival. The extent of surgery, radiotherapy dose or time to relapse were not significant prognostic factors. Radiotherapy appears to be an effective modality of treatment of solitary plasmacytoma. No dose-response relationship is observed, and high local control rates are achieved with limited portals. Progression to multiple myeloma is the commonest pattern of failure, although no prognostic factors for progression are identified. The role of chemotherapy in preventing disease progression needs further evaluation.

Subcutaneous interferon β-1a three times weekly and the natural evolution of gadolinium-enhancing lesions into chronic black holes in relapsing and progressive multiple sclerosis: Analysis of PRISMS and SPECTRIMS trials.

PubMed

Traboulsee, A; Li, Dkb; Tam, R; Zhao, G; Riddehough, A; Fang, J; Dangond, F; Kappos, L

2017-01-01

Evolution of gadolinium-enhancing lesions into chronic black holes (CBH) may be reduced by interferon (IFN) therapy. The objective of this paper is to assess the effect of IFN β-1a and placebo on CBH evolution and disability in patients with relapsing-remitting multiple sclerosis (RRMS), as well as CBH evolution in patients with secondary progressive multiple sclerosis (SPMS). A post hoc, exploratory analysis of patients with RRMS and SPMS with monthly MRI scans (months -1 to 9) from two separate placebo-controlled clinical trials of IFN β-1a was conducted. In RRMS patients, the risk of ≥1 evolved CBH was lower for IFN β-1a versus placebo (odds ratio 0.42; p  = 0.024); volume of newly evolved CBH was numerically reduced. A numerically higher proportion of patients with ≥1 evolving CBH vs no evolving CBH had confirmed three-month disability progression (four-year rate 55.8% vs 43.1%, respectively). Proportion of lesions evolving into CBH (patient level: 34.7% vs 12.6%, p  < 0.0001; lesion level: 28.8% vs 11.0%, p  < 0.0001) and evolved CBH volume (median 33.5 mm 3 (Quartile 1, 0.0; Quartile 3, 173.4) vs 0.0 mm 3 (0.0; 52.4); p  = 0.0008) was higher for SPMS than RRMS patients treated with IFN β-1a. In RRMS, IFN β-1a significantly decreased the proportion of new T1 Gd+ lesions evolving into CBH and the risk of developing a CBH. In patients with SPMS, more lesions develop to CBH, indicating reduced repair capacity, and the natural history of lesion development appears to be unaffected by IFN β-1a treatment.

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 6 2014-10-01 2014-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 6 2013-10-01 2013-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 6 2012-10-01 2012-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

Morphine hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.

PubMed

Lotfipour, Shahrdad; Smith, Maree T

2018-01-01

Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post-STZ. Administration of dietary l-arginine (NO precursor) at 1 g/d to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9 weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary l-arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ-diabetic rats. © 2017 John Wiley & Sons Australia, Ltd.

Auditory skills, language development, and adaptive behavior of children with cochlear implants and additional disabilities

PubMed Central

Beer, Jessica; Harris, Michael S.; Kronenberger, William G.; Holt, Rachael Frush; Pisoni, David B.

2012-01-01

Objective The objective of this study was to evaluate the development of functional auditory skills, language, and adaptive behavior in deaf children with cochlear implants (CI) who also have additional disabilities (AD). Design A two-group, pre-test versus post-test design was used. Study sample Comparisons were made between 23 children with CIs and ADs, and an age-matched comparison group of 23 children with CIs without ADs (No-AD). Assessments were obtained pre-CI and within 12 months post-CI. Results All but two deaf children with ADs improved in auditory skills using the IT-MAIS. Most deaf children in the AD group made progress in receptive but not expressive language using the Preschool Language Scale, but their language quotients were lower than the No-AD group. Five of eight children with ADs made progress in daily living skills and socialization skills; two made progress in motor skills. Children with ADs who did not make progress in language, did show progress in adaptive behavior. Conclusions Children with deafness and ADs made progress in functional auditory skills, receptive language, and adaptive behavior. Expanded assessment that includes adaptive functioning and multi-center collaboration is recommended to best determine benefits of implantation in areas of expected growth in this clinical population. PMID:22509948

A Case Study Assessing the Auditory and Speech Development of Four Children Implanted with Cochlear Implants by the Chronological Age of 12 Months

PubMed Central

2013-01-01

Children with severe hearing loss most likely receive the greatest benefit from a cochlear implant (CI) when implanted at less than 2 years of age. Children with a hearing loss may also benefit greater from binaural sensory stimulation. Four children who received their first CI under 12 months of age were included in this study. Effects on auditory development were determined using the German LittlEARS Auditory Questionnaire, closed- and open-set monosyllabic word tests, aided free-field, the Mainzer and Göttinger speech discrimination tests, Monosyllabic-Trochee-Polysyllabic (MTP), and Listening Progress Profile (LiP). Speech production and grammar development were evaluated using a German language speech development test (SETK), reception of grammar test (TROG-D) and active vocabulary test (AWST-R). The data showed that children implanted under 12 months of age reached open-set monosyllabic word discrimination at an age of 24 months. LiP results improved over time, and children recognized 100% of words in the MTP test after 12 months. All children performed as well as or better than their hearing peers in speech production and grammar development. SETK showed that the speech development of these children was in general age appropriate. The data suggests that early hearing loss intervention benefits speech and language development and supports the trend towards early cochlear implantation. Furthermore, the data emphasizes the potential benefits associated with bilateral implantation. PMID:23509653

A case study assessing the auditory and speech development of four children implanted with cochlear implants by the chronological age of 12 months.

PubMed

May-Mederake, Birgit; Shehata-Dieler, Wafaa

2013-01-01

Children with severe hearing loss most likely receive the greatest benefit from a cochlear implant (CI) when implanted at less than 2 years of age. Children with a hearing loss may also benefit greater from binaural sensory stimulation. Four children who received their first CI under 12 months of age were included in this study. Effects on auditory development were determined using the German LittlEARS Auditory Questionnaire, closed- and open-set monosyllabic word tests, aided free-field, the Mainzer and Göttinger speech discrimination tests, Monosyllabic-Trochee-Polysyllabic (MTP), and Listening Progress Profile (LiP). Speech production and grammar development were evaluated using a German language speech development test (SETK), reception of grammar test (TROG-D) and active vocabulary test (AWST-R). The data showed that children implanted under 12 months of age reached open-set monosyllabic word discrimination at an age of 24 months. LiP results improved over time, and children recognized 100% of words in the MTP test after 12 months. All children performed as well as or better than their hearing peers in speech production and grammar development. SETK showed that the speech development of these children was in general age appropriate. The data suggests that early hearing loss intervention benefits speech and language development and supports the trend towards early cochlear implantation. Furthermore, the data emphasizes the potential benefits associated with bilateral implantation.

Crevicular fluid biomarkers and periodontal disease progression.

PubMed

Kinney, Janet S; Morelli, Thiago; Oh, Min; Braun, Thomas M; Ramseier, Christoph A; Sugai, Jim V; Giannobile, William V

2014-02-01

Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). In this study, 100 individuals participated in a 12-month longitudinal investigation and were categorized into four groups according to their periodontal status. GCF, clinical parameters and saliva were collected bi-monthly. Subgingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6 months, patients received periodontal therapy and continued participation from 6 to 12 months. GCF samples were analysed by ELISA for MMP-8, MMP-9, Osteoprotegerin, C-reactive Protein and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p = 0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61, 86). Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

PubMed

Sedel, Frédéric; Papeix, Caroline; Bellanger, Agnès; Touitou, Valérie; Lebrun-Frenay, Christine; Galanaud, Damien; Gout, Olivier; Lyon-Caen, Olivier; Tourbah, Ayman

2015-03-01

No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Task 10 - technology development integration. Semi-annual report, April 1--September 30, 1996

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

Hendrikson, J.G.; Daly, D.J.

1997-05-01

The Energy and Environmental Research Center (EERC), in conjunction with the Waste Policy Institute (WPI), will identify and integrate new technologies to meet site-specific environmental management (EM) requirements at contaminated sites appropriate to U.S. Department of Energy (DOE) interests. This paper briefly reports overall progress for three activities: technology management, project management, and technology integration. Work performed over the reporting period has focused on providing logistical and administrative support. In addition, six monthly WPI reports to the EERC are included as appendices. The WPI reports contained detailed information for progress in each activity.

A study of methods to predict and measure the transmission of sound through the walls of light aircraft

NASA Technical Reports Server (NTRS)

Bernhard, R. J.; Bolton, J. S.

1988-01-01

The objectives are: measurement of dynamic properties of acoustical foams and incorporation of these properties in models governing three-dimensional wave propagation in foams; tests to measure sound transmission paths in the HP137 Jetstream 3; and formulation of a finite element energy model. In addition, the effort to develop a numerical/empirical noise source identification technique was completed. The investigation of a design optimization technique for active noise control was also completed. Monthly progress reports which detail the progress made toward each of the objectives are summarized.

Longitudinal changes in serum catecholamines, dopamine, serotonin, ACTH and cortisol in pregnant Spanish mares.

PubMed

Marcilla, María; Muñoz, Ana; Satué, Katy

2017-12-01

Systemic physiological changes required for placental and fetal development during pregnancy are associated with an activation of the sympathetic nervous system (SNS) and the hypothalamus-pituitary-adrenal axis (HPA) in women, but this fact has not been investigated in mares. Venous blood samples were taken monthly from 31 successful Spanish mares during the 11months of pregnancy. During the first 4months of pregnancy, adrenaline (AD), dopamine (DOPA) and ACTH increases, whereas 5-hydroxitryptamine (5-HT) decreased, and noradrenaline (NAD) and cortisol (CORT) did not change. Serum NAD increased at 8th month, 5-HT at 5th, 7th months, and DOPA increased progressively between the 5th and 8th months and CORT concentrations peak at 5th month. During the three last months of pregnancy, NAD, 5-TH and DOPA decreased, particularly at the 11th month. These results confirmed an activation of the SNS and the HPA axis in pregnant mares during successful pregnancies. The next step would be to elucidate whether these changes also appear in unsuccessful pregnancies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters

PubMed Central

2011-01-01

Background Diagnosis of primary HIV infection (PHI) has important clinical and public health implications. HAART initiation at this stage remains controversial. Methods Our objective was to identify predictors of disease progression among Argentinean seroconverters during the first year of infection, within a multicentre registry of PHI-patients diagnosed between 1997 and 2008. Cox regression was used to analyze predictors of progression (LT-CD4 < 350 cells/mm3, B, C events or death) at 12 months among untreated patients. Results Among 134 subjects, 74% presented with acute retroviral syndrome (ARS). Seven opportunistic infections (one death), nine B events, and 10 non-AIDS defining serious events were observed. Among the 92 untreated patients, 24 (26%) progressed at 12 months versus three (7%) in the treated group (p = 0.01). The 12-month progression rate among untreated patients with ARS was 34% (95% CI 22.5-46.3) versus 13% (95% CI 1.1-24.7) in asymptomatic patients (p = 0.04). In univariate analysis, ARS, baseline LT-CD4 < 350 cells/mm3, and baseline and six-month viral load (VL) > 100,000 copies/mL were associated with progression. In multivariate analysis, only ARS and baseline VL > 100,000 copies/mL remained independently associated; HR: 8.44 (95% CI 0.97-73.42) and 9.44 (95% CI 1.38-64.68), respectively. Conclusions In Argentina, PHI is associated with significant morbidity. HAART should be considered in PHI patients with ARS and high baseline VL to prevent disease progression. PMID:21831310

Rett syndrome

PubMed Central

Sitholey, Prabhat; Agarwal, Vivek; Srivastava, Rohit

2005-01-01

Rett syndrome is a rare, progressive, neurodevelopmental disorder that has been reported only in the girl child. We describe the case of a 6.9-year-old girl with Rett syndrome. She had normal development till the age of 2 years. However, over the next 4–5 months, she lost her acquired, purposeful hand skills; expressive and receptive language; and reciprocal social interaction; and gradually developed a broad-based gait and typical midline stereotyped hand movements (mouthing, rubbing). PMID:20711295

SIBLING CONCORDANCE FOR CLINICAL FEATURES OF DUCHENNE AND BECKER MUSCULAR DYSTROPHIES

PubMed Central

PETTYGROVE, SYDNEY; LU, ZHENQIANG; ANDREWS, JENNIFER G.; MEANEY, F. JOHN; SHEEHAN, DANIEL W.; PRICE, ELINORA T.; FOX, DEBORAH J.; PANDYA, SHREE; OUYANG, LIJING; APKON, SUSAN D.; POWIS, ZOE; CUNNIFF, CHRISTOPHER

2015-01-01

Introduction The correlation of markers of disease severity among brothers with Duchenne or Becker muscular dystrophy has implications for clinical guidance and clinical trials. Methods Sibling pairs with Duchenne or Becker muscular dystrophy (n = 60) were compared for ages when they reached clinical milestones of disease progression, including ceased ambulation, scoliosis of ≥ 20°, and development of cardiomyopathy. Results The median age at which younger brothers reached each milestone, compared with their older brothers ranged from 25 months younger for development of cardiomyopathy to 2 months older for ceased ambulation. For each additional month of ambulation by the older brother, the hazard of ceased ambulation by the younger brother decreased by 4%. Conclusions The ages when siblings reach clinical milestones of disease vary widely between siblings. However, the time to ceased ambulation for older brothers predicts the time to ceased ambulation for their younger brothers. PMID:24030636

How Toddlers Acquire and Transfer Tool Knowledge: Developmental Changes and the Role of Executive Functions.

PubMed

Pauen, Sabina; Bechtel-Kuehne, Sabrina

2016-07-01

This report investigates tool learning and its relations to executive functions (EFs) in toddlers. In Study 1 (N = 93), 18-, 20-, 22-, and 24-month-old children learned equally well to choose a correct tool from observation, whereas performance based on feedback improved with age. Knowledge transfer showed significant progress after 22 months of age: Older children ignored irrelevant features more easily and adjusted their behavior more flexibly. Study 2 (N = 62) revealed that spontaneous transfer in 22- to 24-month-olds was related to set-shifting skills and response inhibition. Flexible adaptation to feedback correlated with working-memory capacity. These findings suggest that toddlerhood is a highly dynamic phase of tool learning and that EFs are related to transfer performance at this age. © 2016 The Authors. Child Development © 2016 Society for Research in Child Development, Inc.

Novel Lean Type 2 Diabetic Rat Model Using Gestational Low Protein Programming

PubMed Central

BLESSON, Chellakkan S.; SCHUTT, Amy K.; BALAKRISHNAN, Meena P.; PAUTLER, Robia G.; PEDERSEN, Steen E.; SARKAR, Poonam; GONZALES, Daniel; ZHU, Gang; MARINI, Juan C.; CHACKO, Shaji K.; YALLAMPALLI, Uma; YALLAMPALLI, Chandra

2016-01-01

Background Type 2 diabetes in lean individuals is not well studied and up to 26% of diabetes occurs in these individuals. Although the cause is not well understood, it has been primarily attributed to nutritional issues during early development. Objective Our objective was to develop a lean type 2 diabetes model using gestational low protein programming. Study Design Pregnant rats were fed control (20% protein) or isocaloric low protein (6%) diet from gestational day 4 until delivery. Standard diet was given to dams after delivery and to pups after weaning. Glucose tolerance test was done at 2, 4 and 6 months of age. Magnetic resonance imaging of body fat for the females was done at 4 months. Rats were sacrificed at 4 months and 8 months of age and their peri-gonadal, peri-renal, inguinal and brown fat were weighed and expressed relative to their body weight. Euglycemic-hyperinsulinemic clamp was done around 6 months of age. Results Male and female offspring exposed to a low protein diet during gestation developed glucose intolerance and insulin resistance. Further, glucose intolerance progressed with increasing age and occurred earlier and was more severe in females when compared to males. Euglycemic hyperinsulinemic clamp showed whole body insulin resistance in both sexes, with females demonstrating increased insulin resistance compared to males. Low protein females showed a 4.5-fold increase in insulin resistance while males showed a 2.5-fold increase when compared to their respective controls. Data from magnetic resonance imaging on female offspring showed no difference in the subcutaneous, inguinal and visceral fat content. We were able to validate this observation by sacrificing the rats at 4 and 8 months and measuring total body fat content. This showed no differences in body fat content between control and LP offspring in both males and females. Additionally, diabetic rats had a similar body mass index to that of the controls. Conclusion LP gestational programming produces a progressively worsening type 2 diabetes model in rats with a lean phenotype without obesity. PMID:26874300

Exfoliative cutaneous lupus erythematosus in German shorthaired pointer dogs: disease development, progression and evaluation of three immunomodulatory drugs (ciclosporin, hydroxychloroquine, and adalimumab) in a controlled environment

PubMed Central

Mauldin, Elizabeth A.; Morris, Daniel O.; Brown, Dorothy C.; Casal, Margret L.

2011-01-01

Six German shorthaired pointer dogs (two females, four males) with exfoliative cutaneous lupus erythematosus (ECLE) were studied in a controlled setting until disease progression necessitated euthanasia. During investigations into the heredity of disease, five dogs received immunomodulatory drugs to alleviate clinical signs (lameness, erythema, scaling, erosions/ulcers). One dog served as a control and received only baths and oral fatty acids. Four dogs received ciclosporin (5–10 mg/kg once daily) for 4.5 months to 2 years. Ciclosporin decreased erythema and arthralgia, but did not halt worsening of lesions. Three dogs received hydroxychloroquine (5–10 mg/kg once daily) for 8 weeks, 7 months, and 9 months, respectively, with no side effects. Hydroxychloroquine appeared to slow clinical progression in two dogs on extended treatment and normalized globulin levels in all three dogs while receiving the drug. Four dogs, including the control dog, were euthanized between 1 and 4.5 years of age. Two remaining male dogs received a tumour necrosis factor (TNF)-α antagonist, adalimumab, at 0.5 mg/kg every 2 weeks for 8 weeks then weekly for 8 weeks. Serum TNF-α levels were not significantly altered nor were quantifiable changes seen in skin lesions or lameness. Subsequently, the dogs were maintained on hydroxychloroquine for another year. This is the first study to evaluate the use of a TNF-α inhibitor for canine lupus and the first to address the safety of long-term administration of hydroxychloroquine, albeit in a small number of dogs. The study documents the progression of ECLE and generally poor response to therapy. PMID:20374572

Progression and effect of cognitive-behavioral changes in patients with amyotrophic lateral sclerosis.

PubMed

Bock, Meredith; Duong, Y-Nhy; Kim, Anthony; Allen, Isabel; Murphy, Jennifer; Lomen-Hoerth, Catherine

2017-12-01

To prospectively evaluate the progression of cognitive-behavioral function in amyotrophic lateral sclerosis (ALS) and examine the association of cognitive-behavioral deficits with disease progression, patient quality of life (QOL), and caregiver burden. We evaluated cognitive-behavioral function using the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen at enrollment and after 7 months in a cohort of patients with ALS. Paired t tests were used to evaluate the change in the 2 assessments. Linear regression and Kruskal-Wallis tests were applied to investigate how initial cognitive or behavioral status related to outcomes. The mean test-retest interval was 6.8 months (SD 1.6). Cognitive status of the study population (n = 49) overall did not change over the study period ( p = 0.06) despite progression of motor weakness ( p < 0.001), though small subsets of the sample demonstrate cognitive change. Patients initially classified as behaviorally normal showed increased behavioral problems over time ( t = -2.8, p = 0.009). Decline in cognitive (β = -1.3, p = 0.03) and behavioral (β = -0.76, p = 0.002) status predicted increasing caregiver burden. Behavioral abnormalities predicted decline in forced vital capacity and ALS Functional Rating Scale-Revised score ( p = 0.008, 0.012) in the study population and patient QOL in the most severely affected group ( t = 4.3, p = 0.003). Cognitive-behavioral change is a key aspect of disease heterogeneity in ALS. Executive function in ALS overall remains stable over 7 months as detected by an administered screening tool. However, patients may develop caregiver-reported behavioral symptoms in that time period. Screening for caregiver-reported symptoms has a particular utility in predicting future clinical decline, increased caregiver burden, and worsening patient QOL.

Salvage Stereotactic Body Radiotherapy for Isolated Lymph Node Recurrent Prostate Cancer: Single Institution Series of 94 Consecutive Patients and 124 Lymph Nodes.

PubMed

Jereczek-Fossa, Barbara Alicja; Fanetti, Giuseppe; Fodor, Cristiana; Ciardo, Delia; Santoro, Luigi; Francia, Claudia Maria; Muto, Matteo; Surgo, Alessia; Zerini, Dario; Marvaso, Giulia; Timon, Giorgia; Romanelli, Paola; Rondi, Elena; Comi, Stefania; Cattani, Federica; Golino, Federica; Mazza, Stefano; Matei, Deliu Victor; Ferro, Matteo; Musi, Gennaro; Nolè, Franco; de Cobelli, Ottavio; Ost, Piet; Orecchia, Roberto

2017-08-01

The purpose of the study was to evaluate the prostate serum antigen (PSA) response, local control, progression-free survival (PFS), and toxicity of stereotactic body radiotherapy (SBRT) for lymph node (LN) oligorecurrent prostate cancer. Between May 2012 and October 2015, 124 lesions were treated in 94 patients with a median dose of 24 Gy in 3 fractions. Seventy patients were treated for a single lesion and 25 for > 1 lesion. In 34 patients androgen deprivation (AD) was combined with SBRT. We evaluated biochemical response according to PSA level every 3 months after SBRT: a 3-month PSA decrease from pre-SBRT PSA of more than 10% identified responder patients. In case of PSA level increase, imaging was performed to evaluate clinical progression. Toxicity was assessed every 6 to 9 months after SBRT. Median follow-up was 18.5 months. In 13 patients (14%) Grade 1 to 2 toxicity was reported without any Grade 3 to 4 toxicity. Biochemical response, stabilization, and progression were observed in 64 (68%), 10 (11%), and 20 (21%) of 94 evaluable patients. Clinical progression was observed in 31 patients (33%) after a median time of 8.1 months. In-field progression occurred in 12 lesions (9.7%). Two-year local control and PFS rates were 84% and 30%, respectively. Age older than 75 years correlated with better biochemical response rate. Age older than 75 years, concomitant AD administered up to 12 months, and pelvic LN involvement correlated with longer PFS. SBRT is safe and offers good in-field control. At 2 years after SBRT, 1 of 3 patients is progression-free. Further investigation is warranted to identify patients who benefit most from SBRT and to define the optimal combination with AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

PubMed

de Castroneves, Luciana Audi; Negrão, Marcelo Vailati; de Freitas, Ricardo Miguel Costa; Papadia, Carla; Lima, José Viana; Fukushima, Julia T; Simão, Eduardo Furquim; Kulcsar, Marco Aurélio Vamondes; Tavares, Marcos Roberto; Jorge, Alexander Augusto de Lima; de Castro, Gilberto; Hoff, Paulo Marcelo; Hoff, Ana Oliveira

2016-03-01

Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.

Exercise Improves Cognition in Parkinson’s Disease: the PRET-PD Randomized Clinical Trial

PubMed Central

David, Fabian J.; Robichaud, Julie A.; Leurgans, Sue E.; Poon, Cynthia; Kohrt, Wendy M.; Goldman, Jennifer G.; Comella, Cynthia L.; Vaillancourt, David E.; Corcos, Daniel M.

2015-01-01

Background This paper reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes which were gathered as part of the Progressive Resistance Exercise Training in Parkinson’s disease randomized controlled trial. Methods This study was a prospective, parallel-group, single-center trial. Fifty-one non-demented patients with mild-to-moderate Parkinson’s disease were randomly assigned either to modified Fitness Counts or to Progressive Resistance Exercise, and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention. Results Eighteen patients in modified Fitness Counts and 20 patients in Progressive Resistance Exercise completed the trial. At 12 and at 24 months no differences between groups were observed. At 12 months, relative to baseline, modified Fitness Counts improved on the Digit Span (estimated change, 0.3; Inter-Quartile Range, 0, 0.7; p=0.04) and Stroop (0.3; 0, 0.6; p=0.04), and Progressive Resistance Exercise improved only on the Digit Span (0.7; 0.3, 1; p<0.01). At 24 months, relative to baseline, modified Fitness Counts improved on the Digit Span (0.7; 0.3, 1.7; p<0.01) and Stroop (0.3; 0.1, 0.5; p=0.03), while Progressive Resistance Exercise improved on the Digit Span (0.5; 0.2, 0.8; p<0.01), Stroop (0.2; −0.1, 0.6; p=0.048), and Brief Test of Attention (0.3; 0, 0.8; p=0.048). No neurologic or cognitive adverse events were seen. Conclusions This study provides Class IV level of evidence that 24 months of Progressive Resistance Exercise or modified Fitness Counts may improve attention and working memory in non-demented patients with mild-to-moderate Parkinson’s disease. PMID:26148003

HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

PubMed

Ahmed, Nabil; Brawley, Vita; Hegde, Meenakshi; Bielamowicz, Kevin; Kalra, Mamta; Landi, Daniel; Robertson, Catherine; Gray, Tara L; Diouf, Oumar; Wakefield, Amanda; Ghazi, Alexia; Gerken, Claudia; Yi, Zhongzhen; Ashoori, Aidin; Wu, Meng-Fen; Liu, Hao; Rooney, Cliona; Dotti, Gianpietro; Gee, Adrian; Su, Jack; Kew, Yvonne; Baskin, David; Zhang, Yi Jonathan; New, Pamela; Grilley, Bambi; Stojakovic, Milica; Hicks, John; Powell, Suzanne Z; Brenner, Malcolm K; Heslop, Helen E; Grossman, Robert; Wels, Winfried S; Gottschalk, Stephen

2017-08-01

Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. A total of 17 patients (8 females and 9 males; 10 patients ≥18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 106/m2 to 1 × 108/m2) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis. Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.

Liver transplant patients have a similar risk of progression as sporadic patients with branch duct intraductal papillary mucinous neoplasms

PubMed Central

Lennon, Anne Marie; Victor, David; Zaheer, Atif; Ostovaneh, Mohammad Reza; Jeh, Jessica; Law, Joanna K.; Rezaee, Neda; Molin, Marco Dal; Ahn, Young Joon; Wu, Wenchuan; Khashab, Mouen A.; Girotra, Mohit; Ahuja, Nita; Makary, Martin A.; Weiss, Matthew J.; Hirose, Kenzo; Goggins, Michael; Hruban, Ralph H.; Cameron, Andrew; Wolfgang, Christopher L.; Singh, Vikesh K.; Gurakar, Ahmet

2015-01-01

Background Intraductal papillary mucinous neoplasms (IPMNs) have malignant potential, and can progress from low- to high-grade dysplasia to invasive adenocarcinoma. The management of patients with IPMNs is dependent on their risk of malignant progression, with surgical resection recommended for patients with branch duct-IPMN (BD-IPMN) who develop high-risk features. There is increasing evidence that liver transplant patients are at increased risk of extra-hepatic malignancy. However there are few data regarding the risk of progression of BD-IPMNs in liver transplant recipients. The aim of this study was to determine if liver transplant recipients with BD-IPMNs are at higher risk of developing high-risk features than patients with BD-IPMNs who did not receive a transplant. Methods Consecutive patients who underwent a liver transplant with BD-IPMNs were included. Patients with BD-IPMNs with no history of immunosuppression were used as controls. Progression of the BD-IPMNs was defined as development of a high-risk feature (jaundice, dilated main pancreatic duct, mural nodule, cytology suspicious or diagnostic for malignancy, cyst diameter ≥3cm). Results Twenty three liver transplant patients with BD-IPMN were compared with 274 control patients. The median length of follow-up was 53.7 and 24 months in liver transplant and control groups respectively. Four (17.4%) liver transplant patients and 45 (16.4%) controls developed high-risk features (p=0.99). In multivariate analysis, progression of BD-IPMNs was associated with age at diagnosis but not with liver transplantation. Conclusion There was no statistically significant difference in the risk of developing high-risk features between the liver transplant and control groups. PMID:25155689

Educational Progress Profiles of Cochlear Implant Children.

ERIC Educational Resources Information Center

Dawson, Sarah A.

This study examined the educational development of 22 children (ages 2 to 10), under the supervision of the Cochlear Implant Team of the Medical College of Virginia, who had received implants as a result of deafness (in most cases prelingual and congenital) from 6 months to 3 years prior to the study. Data included a review of the children's case…

The Developmental Progression of Understanding of Mind during a Hiding Game

ERIC Educational Resources Information Center

Nelson, P. Brooke; Adamson, Lauren B.; Bakeman, Roger

2012-01-01

In this longitudinal study, 52 typically developing preschoolers engaged in a hiding game with their mothers when children were 42-, 54-, and 66-months old. Children's understanding of mind, positive affect, and engagement with the task were rated, and mothers' utterances were coded for role and content. Analyses confirmed that some facets of…

A Teenager Revisits Her Father's Death during Childhood: A Study in Resilience and Healthy Mourning

ERIC Educational Resources Information Center

Hurd, Russell C.

2004-01-01

"Debbie," 14, was 8 when her father died. During 4 interviews over 3 months, Debbie described the impact of his death as she progressed from childhood to adolescence. Themes drawn from her experience were related to theories of development, bereavement, and resilience. Triangulating interviews with her mother and brother established validity.…

The Campbell Collaboration Crime and Justice Group: Early Development and Progress

ERIC Educational Resources Information Center

Petrosino, Anthony; Farrington, David P.; Sherman, Lawrence W.

2003-01-01

The Campbell Collaboration Crime and Justice Group was inaugurated in 2000 to prepare, update, and disseminate systematic reviews on what works to reduce crime or improve justice. After providing a brief description of a systematic review and the origins of the Campbell Collaboration, this paper provides an overview of the first 36 months of the…

Development of a Rabbit Model of Radiation-Induced Sciatic Nerve Injury: In Vivo Evaluation Using T2 Relaxation Time Measurements.

PubMed

Wan, Qi; Zeng, Qian; Li, Xinchun; Sun, Chongpeng; Zhou, Jiaxuan; Zou, Qiao; Deng, Yingshi; Niu, Daoli

2015-01-01

To develop a rabbit model of radiation-induced sciatic nerve injury (RISNI), using computed tomography (CT)-guided stereotactic radiosurgery, and assess the value of T2 measurements of injured nerves. Twenty New Zealand rabbits were randomly divided into A (n = 5) and B (n = 15) groups. Group A rabbits underwent CT and magnetic resonance scan and were then killed for comparison of images and anatomy of sciatic nerves. One side of the sciatic nerve of group B rabbits received irradiation doses of 35, 50, or 70 Gy (n = 5 per group). Magnetic resonance imaging and functional assessments were performed before irradiation and 1, 2, 3, and 4 months thereafter. The thigh section of the sciatic nerve outside the pelvis could be observed by CT and magnetic resonance imaging. T2 values of the irradiated nerve of the 35-Gy group increased gradually, peaking at 4 months; T2 values of the 50-Gy group increased faster, peaking at 3 months. Significant differences between the 35-Gy and control groups were found at 3 and 4 months, and between the 50-Gy and control groups at 2, 3, and 4 months. Functional scores of the 50-Gy group declined progressively, whereas the 35-Gy group scores reached a low point at 3 months posttreatment and then recovered. Functional scores of the irradiated limbs demonstrated a negative correlation with T2 values (r = -0.591 and -0.595, P < 0.05). Electron microscopy revealed progressive deformation and degeneration of the irradiated nerve in the 35- and 50-Gy groups, which were more severe in the 50-Gy group. A rabbit RISNI model can be produced using the midthigh segment of the sciatic nerve and single-fraction doses of 35 and 50 Gy. Although T2 values are useful for monitoring RISNI, they may not be sensitive enough to evaluate its severity.

The Effects of 6 Months of Progressive High Effort Resistance Training Methods upon Strength, Body Composition, Function, and Wellbeing of Elderly Adults.

PubMed

Steele, James; Raubold, Kristin; Kemmler, Wolfgang; Fisher, James; Gentil, Paulo; Giessing, Jürgen

2017-01-01

The present study examined the progressive implementation of a high effort resistance training (RT) approach in older adults over 6 months and through a 6-month follow-up on strength, body composition, function, and wellbeing of older adults. Twenty-three older adults (aged 61 to 80 years) completed a 6-month supervised RT intervention applying progressive introduction of higher effort set end points. After completion of the intervention participants could choose to continue performing RT unsupervised until 6-month follow-up. Strength, body composition, function, and wellbeing all significantly improved over the intervention. Over the follow-up, body composition changes reverted to baseline values, strength was reduced though it remained significantly higher than baseline, and wellbeing outcomes were mostly maintained. Comparisons over the follow-up between those who did and those who did not continue with RT revealed no significant differences for changes in any outcome measure. Supervised RT employing progressive application of high effort set end points is well tolerated and effective in improving strength, body composition, function, and wellbeing in older adults. However, whether participants continued, or did not, with RT unsupervised at follow-up had no effect on outcomes perhaps due to reduced effort employed during unsupervised RT.

EVALUATION OF PATCHY ATROPHY SECONDARY TO HIGH MYOPIA BY SEMIAUTOMATED SOFTWARE FOR FUNDUS AUTOFLUORESCENCE ANALYSIS.

PubMed

Miere, Alexandra; Capuano, Vittorio; Serra, Rita; Jung, Camille; Souied, Eric; Querques, Giuseppe

2017-05-31

To evaluate the progression of patchy atrophy in high myopia using semiautomated software for fundus autofluorescence (FAF) analysis. The medical records and multimodal imaging of 21 consecutive highly myopic patients with macular chorioretinal patchy atrophy (PA) were retrospectively analyzed. All patients underwent repeated fundus autofluorescence and spectral domain optical coherence tomography over at least 12 months. Color fundus photography was also performed in a subset of patients. Total atrophy area was measured on FAF images using Region Finder semiautomated software embedded in Spectralis (Heidelberg Engineering, Heidelberg, Germany) at baseline and during follow-up visits. Region Finder was compared with manually measured PA on FAF images. Twenty-two eyes of 21 patients (14 women, 7 men; mean age 62.8 + 13.0 years, range 32-84 years) were included. Mean PA area using Region Finder was 2.77 ± 2.91 SD mm at baseline, 3.12 ± 2.68 mm at Month 6, 3.43 ± 2.68 mm at Month 12, and 3.73 ± 2.74 mm at Month 18 (overall P < 0.005); this accounts for PA progression rate of 0.821 mm/year. Atrophy progression was significantly greater among eyes with larger PA compared with smaller baseline PA at Months 6, 12, and 18. There was no statistically significant difference between semiautomated Region Finder PA area and manually measured PA area on FAF images. Fundus autofluorescence analysis by Region Finder semiautomated software provides accurate measurements of lesion area and allows us to quantify the progression of PA in high myopia. In our series, PA enlarged significantly over at least 12 months, and its progression seemed to be related to the lesion size at baseline.

Abiraterone and increased survival in metastatic prostate cancer.

PubMed

de Bono, Johann S; Logothetis, Christopher J; Molina, Arturo; Fizazi, Karim; North, Scott; Chu, Luis; Chi, Kim N; Jones, Robert J; Goodman, Oscar B; Saad, Fred; Staffurth, John N; Mainwaring, Paul; Harland, Stephen; Flaig, Thomas W; Hutson, Thomas E; Cheng, Tina; Patterson, Helen; Hainsworth, John D; Ryan, Charles J; Sternberg, Cora N; Ellard, Susan L; Fléchon, Aude; Saleh, Mansoor; Scholz, Mark; Efstathiou, Eleni; Zivi, Andrea; Bianchini, Diletta; Loriot, Yohann; Chieffo, Nicole; Kheoh, Thian; Haqq, Christopher M; Scher, Howard I

2011-05-26

Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).

PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

PubMed

Hammerer, Peter; Al-Batran, Salah-Eddin; Windemuth-Kieselbach, Christine; Keller, Martin; Hofheinz, Ralf-Dieter

2018-03-01

To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel. Men with mCRPC receiving cabazitaxel (25 mg/m 2 , every 3 weeks) plus oral prednis(ol)one (10 mg/day) were enrolled in the non-interventional, prospective QoLiTime study. Main outcome measures were progression-free survival and overall survival, in all patients and in those who showed a ≥ 50 or a ≥ 30% decrease in PSA relative to baseline after four cycles of cabazitaxel, as well as quality-of-life parameters. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P < 0.0001). Overall survival (50% cut-off) was 23.3 months in responders and 16.0 months in non-responders (P = 0.068); corresponding data at the 30% cut-off are 21.7 and 16.0 months (P = 0.057). Overall, 55.4% of men experienced ≥ 1 adverse event, 59.6% of whom had a serious adverse event. PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

Whole lung lavage: the salvage therapy for pulmonary alveolar proteinosis.

PubMed

Indira, K S Kumari; Rajesh, V; Darsana, V; Ranjit, U; John, Jiju; Vengadakrishnaraj, S P; Dharmadhikari, Shubhada Amol

2007-01-01

A 53-year-old school teacher presented with progressive exertional breathlessness and dry cough of three months duration. His diagnosis was confirmed as pulmonary alveolar proteinosis on open lung biopsy. In about three months, the disease progressed to life threatening respiratory failure. He was subjected to whole lung lavage (WLL) as a salvage therapy. The technical details of WLL performed on this patient are described. At six months follow up, he was clinically and functionally stable and leading a near normal life.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

PubMed

Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars; Dyrby, Tim B; Romme Christensen, Jeppe; Ammitzbøll, Cecilie; Madsen, Camilla Gøbel; Garde, Ellen; Lyksborg, Mark; Andersen, Birgit; Hyldstrup, Lars; Sørensen, Per Soelberg; Siebner, Hartwig R; Sellebjerg, Finn

2016-06-01

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. © The Author(s), 2015.

Risk factors for sensorineural hearing loss in children.

PubMed

Núñez-Batalla, Faustino; Trinidad-Ramos, Germán; Sequí-Canet, José Miguel; Alzina De Aguilar, Valentín; Jáudenes-Casaubón, Carmen

2012-01-01

In the last decade, tremendous progress has been made very rapidly in the development of Early Hearing Detection and Intervention (EHDI) systems as a major public health initiative. The percentage of infants screened annually in Spain has increased significantly since the EHDI systems have expanded to all autonomic regions. Historically, high risk indicators have been used for the identification of infants who should receive audiological evaluation but who live in geographic locations where universal hearing screening is not yet available, to help identify infants who pass neonatal screening but are at risk of developing delayed-onset hearing loss and to identify infants who may have passed neonatal screening but have mild forms of permanent hearing loss. In this review, the standard risk factors for hearing loss are analysed and the risk factors known to be associated with late onset or progressive hearing loss are identified. The recommendation for infants with a risk factor that may be considered as low risk is to perform at least one audiology assessment by 24-30 months. In contrast, for an infant with risk factors known to be associated with late onset or progressive hearing loss (such as cytomegalovirus infection or family history), early and more frequent assessment is appropriate. All infants should have an objective standardised screening of global development with a validated assessment tool at 9, 18 and 24-30 months of age or at any time if the health care professional or the family is concerned. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Progression of recurrent acute and chronic pancreatitis: A short-term follow up study from a southern Indian centre.

PubMed

Kamath, M Ganesh; Pai, C Ganesh; Kamath, Asha

2016-11-01

Little data exist on the progression of recurrent acute (RAP) and chronic pancreatitis (CP) from regions from where the entity of tropical chronic pancreatitis was originally described. The study aimed to follow up patients with RAP and CP seen at a southern Indian centre for progression of disease over time. Prospectively enrolled patients with RAP and CP were followed up, and the alcoholic and idiopathic subgroups were assessed for progression of structural and functional changes in the organ. One hundred and forty patients (RAP = 44; 31.4 %, CP = 96; 68.5 %) were followed up over a median 12.2 (interquartile range 12.0-16.8) months. The cause was alcohol in 31 (22.1 %) and not evident in 109 (77.8 %). The disease progressed from RAP to CP in 7 (15.9 %), 6 (16.2 %) out of 37 in the idiopathic and 1 (14.2 %; p = 1.00) out of 7 in the alcoholic subgroups. Three (42.8 %) and 1 (14.2 %) developed steatorrhea and diabetes mellitus (DM), respectively, and 2 (4.5 %) developed calcification. Established CP progressed in 19 (19.7 %), 1 (1.0 %), 5 (5.2 %), 2 (2.0 %) and 11 (11.4 %) newly developed DM, steatorrhea, calcification and duct dilation during follow up. Among the idiopathic and alcoholic CP, disease progression was seen in 15 (20.8 %) out of 72 and 4 (16.6 %) out of 24 respectively. Idiopathic RAP and CP progressed during the short-term follow up. This is similar to other etiological forms of pancreatitis, as described from elsewhere in the world.

Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

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

Gan, Gregory N., E-mail: gregory.gan@ucdenver.edu; Weickhardt, Andrew J.; Scheier, Benjamin

Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progressionmore » meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.« less

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

Vogl, Thomas J., E-mail: t.vogl@em.uni-frankfurt.de; Koch, Silvia A., E-mail: silvia.koch@web.de; Lotz, Gösta, E-mail: goesta.lotz@kgu.de

PurposePercutaneous isolated hepatic perfusion (PIHP) with Melphalan has been developed as a treatment for patients with isolated hepatic metastases of uveal melanoma. We discuss patient outcome and safety in a retrospective multi-centre study.Materials and MethodsBetween 2012 and 2016 18 patients with un-resectable isolated hepatic metastases of uveal melanoma received single or repeated PIHP with Melphalan (n = 35) at seven sites. Progression-free time, overall survival time (OS) and tumour response by means of RECIST 1.1 criteria were evaluated. Peri- and post-procedural adverse events (AE) were registered. Patients’ life quality was assessed using four-point scale questionnaires.ResultsOf 18 patients, initial PIHP treatment resulted inmore » partial response (PR) in eight, stable disease (SD) in seven and progressive disease (PD) in three cases. Nine patients underwent second PIHP with PR in eight cases and PD in one case. Six patients were evaluated after third PIHP with PR in five patients and SD in one patient. Two patients received fourth PIHP with PD in both cases. Median OS was 9.6 months (range 1.6–41.0 months). Median progression-free survival time was 12.4 months (range 0.9–41.0 months) with 1-year survival of 44%. Most common post-procedural AE grade 3 and 4 were temporary leukopenia (n = 11) and thrombocytopenia (n = 8). Patients’ self-assessments showed good ratings for overall health and quality of life with only slight changes after PIHP, and a high degree of satisfaction with PIHP treatment.ConclusionPIHP with Melphalan proved to be a relatively safe, minimal-invasive and repeatable treatment for patients with non-resectable hepatic metastases of uveal melanoma.« less

Total lymphoid irradiation for multiple sclerosis

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

Devereux, C.K.; Vidaver, R.; Hafstein, M.P.

1988-01-01

Although chemical immunosuppression has been shown to benefit patients with chronic progressive multiple sclerosis (MS), it appears that chemotherapy has an appreciable oncogenic potential in patients with multiple sclerosis. Accordingly, we developed a modified total lymphoid irradiation (TLI) regimen designed to reduce toxicity and applied it to a randomized double blind trial of TLI or sham irradiation in MS. Standard TLI regimens were modified to reduce dose to 1,980 rad, lowering the superior mantle margin to midway between the thyroid cartilage and angle of the mandible (to avert xerostomia) and the lower margin of the mantle field to the inferiormore » margin of L1 (to reduce gastrointestinal toxicity by dividing abdominal radiation between mantle and inverted Y), limiting spinal cord dose to 1,000 rad by custom-made spine blocks in the mantle and upper 2 cm of inverted Y fields, and also protecting the left kidney even if part of the spleen were shielded. Clinical efficacy was documented by the less frequent functional scale deterioration of 20 TLI treated patients with chronic progressive MS compared to to 20 sham-irradiated progressive MS patients after 12 months (16% versus 55%, p less than 0.03), 18 months (28% versus 63%, p less than 0.03), and 24 months (44% versus 74%, N.S.). Therapeutic benefit during 3 years follow-up was related to the reduction in lymphocyte count 3 months post-irradiation (p less than 0.02). Toxicity was generally mild and transient, with no instance of xerostomia, pericarditis, herpes zoster, or need to terminate treatment in TLI patients. However, menopause was induced in 2 patients and staphylococcal pneumonia in one.« less

Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer.

PubMed Central

Nicholson, S.; Halcrow, P.; Sainsbury, J. R.; Angus, B.; Chambers, P.; Farndon, J. R.; Harris, A. L.

1988-01-01

We have used primary endocrine therapy for 61 elderly women with operable breast cancer (median age 77 years). Eleven patients (18%) had complete and 24 (39%) partial tumour regression, 12 (20%) had stable disease for a minimum of six months and 14 (23%) no response. Salvage surgery was undertaken in the 14 with no response and 8/9 with progressive disease following initial response, thus samples were available from relapse patients only. Assays for EGFr (two point radioreceptor assay) and oestrogen receptors (ER) (dextran coated charcoal method and an immunohistochemical method) were performed on 20/22 patients. Ten of these 20 tumours were EGFr+ (greater than 10 fmol mg-1 binding) and 9/13 patients progressing within six months had EGFr+ tumours. 15/22 were available for ER evaluation and there was no such association with ER status. EGFr status was also associated with early recurrence after surgery and death in the endocrine failure group (P less than 0.005 and P less than 0.05 respectively). Of a control population of 33 patients (median age 72 years) treated by primary surgery, only 6 were EGFr+. In this group early relapse was predicted by EGFr status, but not by ER status (median disease free survival for EGFr+ patients 15 months, and for EGFr- patients 40 months, P less than 0.01, logrank test). There was a significantly higher proportion of EGFr+ tumours in the endocrine failure group compared with the control population (P less than 0.001). EGFr status is a marker for rapid early progression on primary endocrine therapy and the development of non-excisional methods of EGFr analysis would allow better directed therapeutic decisions. PMID:3224082

Regorafenib-induced hypothyroidism and cancer-related fatigue: is there a potential link?

PubMed

Pani, Fabiana; Massidda, Matteo; Pusceddu, Valeria; Puzzoni, Marco; Massa, Elena; Madeddu, Clelia; Scartozzi, Mario; Mariotti, Stefano

2017-07-01

Thyroid dysfunction has been reported during Regorafenib (Reg) administration, but no detailed study is presently available. Prospective, observational cohort study. Patients with documented metastatic colorectal cancer and progression of disease during or within 3 months after the last standard therapy, with no evidence and history of previous thyroid disease were enrolled. Twenty-five consecutive patients were evaluated before and 8-50 weeks after initiating Reg therapy by monthly clinical, ultrasound and laboratory (thyrotropin (TSH), free thyroxine (fT4), antithyroglobulin (TgAb) and antithyroid peroxidase (TPOAb)) evaluation. Thirteen/25 patients (52%) became hypothyroid (TSH: 12.5 ± 4.01 IU/L, range: 4.6-22.0) within 5 months of therapy. TPOAb became detectable (99-155 IU/mL) in 2/25 (8%) patients. Thyroid volume progressively decreased (from 8.6  ±  2.2 mL to 4.9 ± 2.4 mL after 5 months of Reg therapy, P  < 0.0001). The progression-free survival (PFS) was longer in patients developing hypothyroidism (43 weeks) than in those remaining euthyroid (17 weeks, P  < 0.01). Fatigue (the most common general serious Reg adverse event) was associated with hypothyroidism severity and reversed after levothyroxine therapy (L-T4). Reg rapidly causes hypothyroidism in about 50% of patients and in a minority of them also triggers thyroid autoimmunity. Reg-induced hypothyroidism was strictly related to fatigue, easily reversed by L-T4 administration and associated to longer survival. These results suggest that prompt recognition of hypothyroidism in patients with severe fatigue may prevent unnecessary Reg dose reduction or withdrawal. © 2017 European Society of Endocrinology.

The natural history of skin-limited Langerhans cell histiocytosis: a single-institution experience.

PubMed

Ehrhardt, Matthew J; Humphrey, Stephen R; Kelly, Michael E; Chiu, Yvonne E; Galbraith, Sheila S

2014-11-01

Prior reports of Langerhans cell histiocytosis (LCH) suggest that isolated skin involvement is rare and often progresses to systemic disease. More rapid access to pediatric subspecialty care has likely led to more frequent representation of this condition. The purpose of this study is to characterize the natural history of skin-limited LCH in an era of increased access to pediatric subspecialty care. A retrospective chart review was performed on all patients newly diagnosed with LCH between 2001 and 2012 at the Children's Hospital of Wisconsin. Extensive review of laboratory, physical examination, and imaging reports was performed and data collected for patients with biopsy-proven skin LCH. Sixteen individuals with skin-limited LCH were identified. The median age at onset of skin eruption was birth (range, birth to 6 mo), and median duration of follow-up was 19.5 months (range, 2 wk to 10 y) from diagnosis. One patient (6%) developed pituitary disease and 1 patient (6%) had refractory skin involvement. All others experienced complete resolution. For patients without progressive or refractory disease, resolution of skin findings occurred within 7 months from onset. Progression of skin-limited to multisystem LCH likely may be less frequent than previously described.

Component Identification and Item Difficulty of Raven's Matrices Items.

ERIC Educational Resources Information Center

Green, Kathy E.; Kluever, Raymond C.

Item components that might contribute to the difficulty of items on the Raven Colored Progressive Matrices (CPM) and the Standard Progressive Matrices (SPM) were studied. Subjects providing responses to CPM items were 269 children aged 2 years 9 months to 11 years 8 months, most of whom were referred for testing as potentially gifted. A second…

In vivo measurements of tooth wear over 12 months.

PubMed

Rodriguez, J M; Austin, R S; Bartlett, D W

2012-01-01

The aim of this study was to measure the progression of tooth wear in a cohort of 63 patients, 43 males and 20 females with a mean age of 39.1 years. Recruitment followed referral from general practice to Guy's Hospital for advice/management of tooth wear. Addition silicone impressions were taken at 6-month intervals for a total of 12 months; impressions were subsequently poured in type IV gypsum. Casts were scanned using a non-contacting laser profilometer and then superimposed using Geomagic® Qualify 11. Wear was measured in μm by tooth per time interval. A questionnaire highlighting dietary, parafunctional and gastric risk factors was obtained from each participant. Clustered multiple regression analysis was used to determine the relationship between tooth wear progression and risk factors. Maximum follow-up times were 6 months for 63 participants and 12 months for 30 participants. The measurement error was 15 μm. At the tooth level, 72.2% of 1,078 teeth wore <15 μm over a 6-month period. At the subject level, 77.7% of 63 participants showed median wear <15 μm over a 6-month period. There was a statistical trend towards tooth wear progression being associated with gastric risk factors (p < 0.05). The lower molars and the upper anterior teeth were the most commonly affected teeth; the lower molars and the upper central incisors were the most severely affected teeth. Tooth wear progression was slow in this cohort, suggesting that tooth wear may be cyclical and inactive in the majority of participants. Copyright © 2011 S. Karger AG, Basel.

Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib.

PubMed

Watanabe, Satomi; Hayashi, Hidetoshi; Okamoto, Kunio; Fujiwara, Kimiko; Hasegawa, Yoshikazu; Kaneda, Hiroyasu; Tanaka, Kaoru; Takeda, Masayuki; Nakagawa, Kazuhiko

2016-11-01

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Development of global cortical networks in early infancy.

PubMed

Homae, Fumitaka; Watanabe, Hama; Otobe, Takayuki; Nakano, Tamami; Go, Tohshin; Konishi, Yukuo; Taga, Gentaro

2010-04-07

Human cognition and behaviors are subserved by global networks of neural mechanisms. Although the organization of the brain is a subject of interest, the process of development of global cortical networks in early infancy has not yet been clarified. In the present study, we explored developmental changes in these networks from several days to 6 months after birth by examining spontaneous fluctuations in brain activity, using multichannel near-infrared spectroscopy. We set up 94 measurement channels over the frontal, temporal, parietal, and occipital regions of the infant brain. The obtained signals showed complex time-series properties, which were characterized as 1/f fluctuations. To reveal the functional connectivity of the cortical networks, we calculated the temporal correlations of continuous signals between all the pairs of measurement channels. We found that the cortical network organization showed regional dependency and dynamic changes in the course of development. In the temporal, parietal, and occipital regions, connectivity increased between homologous regions in the two hemispheres and within hemispheres; in the frontal regions, it decreased progressively. Frontoposterior connectivity changed to a "U-shaped" pattern within 6 months: it decreases from the neonatal period to the age of 3 months and increases from the age of 3 months to the age of 6 months. We applied cluster analyses to the correlation coefficients and showed that the bilateral organization of the networks begins to emerge during the first 3 months of life. Our findings suggest that these developing networks, which form multiple clusters, are precursors of the functional cerebral architecture.

Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.

PubMed

Cella, D; Traina, S; Li, T; Johnson, K; Ho, K F; Molina, A; Shore, N D

2018-02-01

Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P < 0.0001). In multivariate models, all except pain intensity remained associated with OS. Pain intensity, PWB and FWB improvements remained associated with rPFS. In COU-AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression. © The Author 2017. 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.

Low-dose ultraviolet exposure early in development can lead to widespread melanoma in the opossum model.

PubMed

Robinson, E S; Hubbard, G B; Colon, G; Vandeberg, J L

1998-08-01

Suckling young of opossums (Monodelphis domestica) were exposed to ultraviolet radiation (UVR, predominantly UVB: 290-320 nm) in part to determine an optimal protocol for induction and progression of melanoma in this species. In all, 620 litters were introduced to one of seven protocols. The lowest dose (175 J/m2) administered three times a week for almost three weeks led to the highest incidence of melanotic lesions with melanoma potential (8.1%) among young (5-month-old) adults. Among 101 much older animals (> 17 months at necropsy), 43% showed metastatic melanoma to the lymph nodes and almost one-third of these had progressed to widespread dissemination. Three of the latter animals, from a total of 13 obtained so far, were selected for detailed histological examination of disseminated disease. At necropsy, all three showed widespread metastases beyond the lymph nodes to the spleen, lungs, and other distant sites. Histological changes typical of malignant melanoma included junctional activity, mitotic figures, and nerve and vessel invasion. This novel finding leads us to conclude that UVR can act as a complete carcinogen for progression to widely disseminated disease and that exposure of sucklings can lead, in old age, to widespread metastatic melanoma in this model. The results are thus not inconsistent with the view that, in humans, early exposure to sunlight might act as an initiating factor in a later progression to malignant melanoma.

Serum Tryptase Monitoring in Indolent Systemic Mastocytosis: Association with Disease Features and Patient Outcome

PubMed Central

Matito, Almudena; Morgado, José Mario; Álvarez-Twose, Iván; Laura Sánchez-Muñoz; Pedreira, Carlos Eduardo; Jara-Acevedo, María; Teodosio, Cristina; Sánchez-López, Paula; Fernández-Núñez, Elisa; Moreno-Borque, Ricardo; García-Montero, Andrés; Orfao, Alberto; Escribano, Luis

2013-01-01

Background Serum baseline tryptase (sBT) is a minor diagnostic criterion for systemic mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. Methods In total 74 adult ISM patients who were followed for ≥48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. Results Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). Conclusions Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values. PMID:24155887

Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome.

PubMed

Matito, Almudena; Morgado, José Mario; Álvarez-Twose, Iván; Sánchez-Muñoz, Laura; Pedreira, Carlos Eduardo; Jara-Acevedo, María; Teodosio, Cristina; Sánchez-López, Paula; Fernández-Núñez, Elisa; Moreno-Borque, Ricardo; García-Montero, Andrés; Orfao, Alberto; Escribano, Luis

2013-01-01

Serum baseline tryptase (sBT) is a minor diagnostic criterion for systemic mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. In total 74 adult ISM patients who were followed for ≥48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values.

Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate.

PubMed

Polski, Jacek M; Galambos, Csaba; Gale, Gordon B; Dunphy, Cherie H; Evans, H Lance; Batanian, Jacqueline R

2002-01-01

We report a case of transient myeloproliferative disorder (TMD) in a neonate without features of Down syndrome (DS) with clonal karyotype evolution, after apparent spontaneous resolution of TMD, but eventually progressing to acute megakaryoblastic leukemia (AMKL). The patient had petechiae, thrombocytopenia, and blastemia. Trisomy 21 with a satellited Y chromosome (Yqs) was found in proliferating blasts. A stimulated peripheral blood culture confirmed the constitutional origin of the Yqs, but did not reveal the presence of any trisomic 21 cell. By the age of 3 months, clonal chromosome evolution in the form of an interstitial deletion of the long-arm of chromosome 13 [del(13)(q13q31)] was detected along with trisomy 21 in unstimulated bone marrow cultures. However, remission was achieved without treatment at the age of 4 months. Trisomy 21 and del(13)(q13q31) were not identified in either cytogenetics or fluorescence in situ hybridization studies at that time. The child was asymptomatic until the age of 20 months when anemia and thrombocytopenia prompted a bone marrow biopsy, revealing changes consistent with AMKL. The remission proceeded by clonal karyotype evolution in a neonate with TMD demonstrates that clonal karyotype evolution does not indicate an immediately progressive disease. However, the development of AMKL after TMD in this case illustrates the increased risk for leukemia in TMD cases, even without DS. The gradual clonal evolution of the blasts in our patient suggests that "multiple hits" oncogenesis applies to TMD progression to acute leukemia.

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate.

PubMed

Kamp, Kimberly; Gumz, Brenda; Feelders, Richard A; Kwekkeboom, Dik J; Kaltsas, Gregory; Costa, Frederico P; de Herder, Wouter W

2013-12-01

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study.

PubMed

Yao, James C; Pavel, Marianne; Lombard-Bohas, Catherine; Van Cutsem, Eric; Voi, Maurizio; Brandt, Ulrike; He, Wei; Chen, David; Capdevila, Jaume; de Vries, Elisabeth G E; Tomassetti, Paola; Hobday, Timothy; Pommier, Rodney; Öberg, Kjell

2016-11-10

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.

PubMed

Ou, Sai-Hong Ignatius; Ahn, Jin Seok; De Petris, Luigi; Govindan, Ramaswamy; Yang, James Chih-Hsin; Hughes, Brett; Lena, Hervé; Moro-Sibilot, Denis; Bearz, Alessandra; Ramirez, Santiago Viteri; Mekhail, Tarek; Spira, Alexander; Bordogna, Walter; Balas, Bogdana; Morcos, Peter N; Monnet, Annabelle; Zeaiter, Ali; Kim, Dong-Wan

2016-03-01

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases. © 2015 by American Society of Clinical Oncology.

Progressive proliferative and dysplastic typhlocolitis in aging syrian hamsters naturally infected with Helicobacter spp.: a spontaneous model of inflammatory bowel disease.

PubMed

Nambiar, P R; Kirchain, S M; Courmier, K; Xu, S; Taylor, N S; Theve, E J; Patterson, M M; Fox, J G

2006-01-01

Helicobacter spp. have been implicated in a variety of gastrointestinal tract diseases, including peptic ulcer disease, gastric cancer, and inflammatory bowel disease (IBD), in humans and animals. Although most models of IBD are experimentally induced, spontaneous or natural models of IBD are rare. Herein, we describe a long-term study of chronic, progressive lesions that develop in the distal portion of the large bowel of unmanipulated Syrian hamsters naturally infected with Helicobacter spp. Twenty-four Syrian hamsters of three age groups (group A, 1 month [n = 4], group B, 7-12 months [n = 12], group C, 18-24 months [n = 12]), underwent complete postmortem examination. Results of microbial isolation and polymerase chain reaction and restriction fragment length polymorphism analyses confirmed the presence of Helicobacter spp. infection in the distal portion of the large bowel of all animals. Additionally, confounding pathogens, such as Clostridium difficile, Lawsonia intracellularis, and Giardia spp. that can cause proliferative enteritis, were absent in the hamsters of this study. Histopathologic scores for inflammation (P < 0.01), hyperplasia (P < 0.01), and dysplasia (P < 0.05) were significantly higher in the ileocecocolic (ICC) junction of animals in group C, relative to group A. Dysplastic lesions of various grades were detected in 5 of 11 hamsters in group C. Interestingly, the segment of the bowel that is usually colonized by Helicobacter spp. in hamsters had the most severe lesions. One hamster of group C developed a malignant fibrous histiocytoma, whereas another hamster developed a round cell sarcoma originating from the ICC junction. Thus, lesions in the distal portion of the large bowel of aging hamsters naturally colonized with Helicobacter spp. warrants developing the hamster as an animal model of IBD and potentially IBD-related cancer.

Simulating the role of visual selective attention during the development of perceptual completion

PubMed Central

Schlesinger, Matthew; Amso, Dima; Johnson, Scott P.

2014-01-01

We recently proposed a multi-channel, image-filtering model for simulating the development of visual selective attention in young infants (Schlesinger, Amso & Johnson, 2007). The model not only captures the performance of 3-month-olds on a visual search task, but also implicates two cortical regions that may play a role in the development of visual selective attention. In the current simulation study, we used the same model to simulate 3-month-olds’ performance on a second measure, the perceptual unity task. Two parameters in the model – corresponding to areas in the occipital and parietal cortices – were systematically varied while the gaze patterns produced by the model were recorded and subsequently analyzed. Three key findings emerged from the simulation study. First, the model successfully replicated the performance of 3-month-olds on the unity perception task. Second, the model also helps to explain the improved performance of 2-month-olds when the size of the occluder in the unity perception task is reduced. Third, in contrast to our previous simulation results, variation in only one of the two cortical regions simulated (i.e. recurrent activity in posterior parietal cortex) resulted in a performance pattern that matched 3-month-olds. These findings provide additional support for our hypothesis that the development of perceptual completion in early infancy is promoted by progressive improvements in visual selective attention and oculomotor skill. PMID:23106728

Simulating the role of visual selective attention during the development of perceptual completion.

PubMed

Schlesinger, Matthew; Amso, Dima; Johnson, Scott P

2012-11-01

We recently proposed a multi-channel, image-filtering model for simulating the development of visual selective attention in young infants (Schlesinger, Amso & Johnson, 2007). The model not only captures the performance of 3-month-olds on a visual search task, but also implicates two cortical regions that may play a role in the development of visual selective attention. In the current simulation study, we used the same model to simulate 3-month-olds' performance on a second measure, the perceptual unity task. Two parameters in the model - corresponding to areas in the occipital and parietal cortices - were systematically varied while the gaze patterns produced by the model were recorded and subsequently analyzed. Three key findings emerged from the simulation study. First, the model successfully replicated the performance of 3-month-olds on the unity perception task. Second, the model also helps to explain the improved performance of 2-month-olds when the size of the occluder in the unity perception task is reduced. Third, in contrast to our previous simulation results, variation in only one of the two cortical regions simulated (i.e. recurrent activity in posterior parietal cortex) resulted in a performance pattern that matched 3-month-olds. These findings provide additional support for our hypothesis that the development of perceptual completion in early infancy is promoted by progressive improvements in visual selective attention and oculomotor skill. © 2012 Blackwell Publishing Ltd.

Postoperative Treatment of Primary Glioblastoma Multiforme With Radiation and Concomitant Temozolomide in Elderly Patients

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

Combs, Stephanie E.; Wagner, Johanna; Bischof, Marc

2008-03-15

Purpose: To evaluate efficacy and toxicity in elderly patients with glioblastoma multiforme (GBM) treated with postoperative radiochemotherapy with temozolomide (TMZ). Patients and Methods: Forty-three patients aged 65 years or older were treated with postoperative with radiochemotherapy using TMZ for primary GBM. Median age at primary diagnosis was 67 years; 14 patients were female, 29 were male. A complete surgical resection was performed in 12 patients, subtotal resection in 17 patients, and biopsy only in 14 patients. Radiotherapy was applied with a median dose of 60 Gy, in a median fractionation of 5 x 2 Gy/wk. Thirty-five patients received concomitant TMZmore » at 50 mg/m{sup 2}, and in 8 patients 75 mg/m{sup 2} of TMZ was applied. Adjuvant cycles of TMZ were prescribed in 5 patients only. Results: Median overall survival was 11 months in all patients; the actuarial overall survival rate was 48% at 1 year and 8% at 2 years. Median overall survival was 18 months after complete resection, 16 months after subtotal resection, and 6 months after biopsy only. Median progression-free survival was 4 months; the actuarial progression-free survival rate was 41% at 6 months and 18% at 12 months. Radiochemotherapy was well tolerated in most patients and could be completed without interruption in 38 of 43 patients. Four patients developed hematologic side effects greater than Common Terminology Criteria Grade 2, which led to early discontinuation of TMZ in 1 patient. Conclusions: Radiochemotherapy is safe and effective in a subgroup of elderly patients with GBM and should be considered in patients without major comorbidities.« less

Active surveillance for low-risk prostate cancer in Austria: the online registry of the Qualitätspartnerschaft Urologie (QuapU).

PubMed

Eredics, Klaus; Dorfinger, Karl; Kramer, Gero; Ponholzer, Anton; Madersbacher, Stephan

2017-06-01

Active surveillance (AS) is a well-recognized strategy to reduce the risk of overtreatment in men with low-risk prostate cancer. No data on this approach are available from Austria. The Qualitätspartnerschaft Urologie (QuapU) developed an online database for patients managed with AS in Austria. Principal inclusion/exclusion criteria corresponded to those of the S3 prostate cancer guideline of German urologists: prostate-specific antigen (PSA) <10 ng/ml, Gleason score <7 (maximum 20% of biopsies being positive). Control visits were scheduled at 3‑month intervals, control biopsies were scheduled at 12 and 36 months. To date 131 patients have been entered into this data base. Mean patient age is 64 years, 6% were younger than 50 years, two thirds of patients were aged 50-70 years and 25% were older than 70 years. Mean PSA value was 5.9 ng/ml (PSA 0-4 ng/ml: 15%; PSA >4-10 ng/ml: 85%). The prostate volume averaged 39 ml. The mean time under AS was 17.5 months (<12 months: 60%; >12 months: 40%). The AS adherence at 12 months was 85% and at 24 months 76%. To date, a total of 23 patients (17.6%) stopped AS. The most frequent reasons for discontinuing AS were patient wish for active treatment (43.5%) and PSA progression (30.4%). A histological progression was rarely seen (6.1%) and the control biopsy rate was low (19.8%). This study is the first description of AS in Austria and documents the feasibility of an online registry for AS. The data confirm the international experience with this approach with acceptable adherence rates.

The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: outcomes of a drug and disease model.

PubMed

Holz, Frank G; Korobelnik, Jean-François; Lanzetta, Paolo; Mitchell, Paul; Schmidt-Erfurth, Ursula; Wolf, Sebastian; Markabi, Sabri; Schmidli, Heinz; Weichselberger, Andreas

2010-01-01

Differences in treatment responses to ranibizumab injections observed within trials involving monthly (MARINA and ANCHOR studies) and quarterly (PIER study) treatment suggest that an individualized treatment regimen may be effective in neovascular age-related macular degeneration. In the present study, a drug and disease model was used to evaluate the impact of an individualized, flexible treatment regimen on disease progression. For visual acuity (VA), a model was developed on the 12-month data from ANCHOR, MARINA, and PIER. Data from untreated patients were used to model patient-specific disease progression in terms of VA loss. Data from treated patients from the period after the three initial injections were used to model the effect of predicted ranibizumab vitreous concentration on VA loss. The model was checked by comparing simulations of VA outcomes after monthly and quarterly injections during this period with trial data. A flexible VA-guided regimen (after the three initial injections) in which treatment is initiated by loss of >5 letters from best previously observed VA scores was simulated. Simulated monthly and quarterly VA-guided regimens showed good agreement with trial data. Simulation of VA-driven individualized treatment suggests that this regimen, on average, sustains the initial gains in VA seen in clinical trials at month 3. The model predicted that, on average, to maintain initial VA gains, an estimated 5.1 ranibizumab injections are needed during the 9 months after the three initial monthly injections, which amounts to a total of 8.1 injections during the first year. A flexible, individualized VA-guided regimen after the three initial injections may sustain vision improvement with ranibizumab and could improve cost-effectiveness and convenience and reduce drug administration-associated risks.

Monitoring Progress in Vocal Development in Young Cochlear Implant Recipients: Relationships between Speech Samples and Scores from the Conditioned Assessment of Speech Production (CASP)

PubMed Central

Ertmer, David J.; Jung, Jongmin

2012-01-01

Background Evidence of auditory-guided speech development can be heard as the prelinguistic vocalizations of young cochlear implant recipients become increasingly complex, phonetically diverse, and speech-like. In research settings, these changes are most often documented by collecting and analyzing speech samples. Sampling, however, may be too time-consuming and impractical for widespread use in clinical settings. The Conditioned Assessment of Speech Production (CASP; Ertmer & Stoel-Gammon, 2008) is an easily administered and time-efficient alternative to speech sample analysis. The current investigation examined the concurrent validity of the CASP and data obtained from speech samples recorded at the same intervals. Methods Nineteen deaf children who received CIs before their third birthdays participated in the study. Speech samples and CASP scores were gathered at 6, 12, 18, and 24 months post-activation. Correlation analyses were conducted to assess the concurrent validity of CASP scores and data from samples. Results CASP scores showed strong concurrent validity with scores from speech samples gathered across all recording sessions (6 – 24 months). Conclusions The CASP was found to be a valid, reliable, and time-efficient tool for assessing progress in vocal development during young CI recipient’s first 2 years of device experience. PMID:22628109

Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma.

PubMed

Shah, Manish A; Ramanathan, Ramesh K; Ilson, David H; Levnor, Alissa; D'Adamo, David; O'Reilly, Eileen; Tse, Archie; Trocola, Robin; Schwartz, Lawrence; Capanu, Marinela; Schwartz, Gary K; Kelsen, David P

2006-11-20

Bevacizumab improves survival in several solid tumor malignancies when combined with chemotherapy. We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma. Forty-seven patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m2, and cisplatin 30 mg/m2 on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival. Patient characteristics were as follows: median age 59 years (range, 25 to 75); Karnofsky performance status 90% (70% to 100%); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95% CI, 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65% (95% CI, 46% to 80%). Median survival was 12.3 months (95% CI, 11.3 to 17.2 months). We observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28% incidence of grade 3 hypertension, two patients with a gastric perforation and one patient with a near perforation (6%), and one patient with a myocardial infarction (2%). Grade 3 to 4 thromboembolic events occurred in 25% of patients. Although the primary tumor was unresected in 40 patients, we observed only one patient with a significant upper gastrointestinal bleed. Bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and overall survival are encouraging, with TTP improved over historical controls by 75%. Further development of bevacizumab in gastric and GEJ cancers is warranted.

Infant Ependymoma in a 10-Year AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) Experience With Omitted or Deferred Radiotherapy

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

Massimino, Maura, E-mail: maura.massimino@istitutotumori.mi.it; Gandola, Lorenza; Barra, Salvina

Purpose: The protocols of the 1990s omitted or delayed irradiation, using upfront chemotherapy to spare the youngest children with ependymoma the sequelae of radiotherapy (RT). We treated 41 children under the age of 3 years with intracranial ependymoma between 1994 and 2003. Patients and Methods: After surgery, chemotherapy was given as follows: regimen I with four blocks of vincristine, high-dose methotrexate 5 g/m{sup 2}, and cyclophosphamide 1.5 g/m{sup 2} alternating with cisplatin 90 mg/m{sup 2} plus VP16 450 mg/m{sup 2} for 14 months; subsequently, regimen II was used: VEC (VCR, VP16 300 mg/m{sup 2}, and cyclophosphamide 3 g/m{sup 2}) formore » 6 months. Radiotherapy was planned for residual tumor after the completion of chemotherapy or for progression. Results: We treated 23 boys and 18 girls who were a median 22 months old; 14 were given regimen I, 27 were given regimen II; 22 underwent complete resection, 19 had residual tumor. Ependymoma was Grade 2 in 25 patients and Grade 3 in 16; tumors were infratentorial in 37 patients and supratentorial in 4. One child had intracranial metastases; 29 had progressed locally after a median 9 months. Event-free survival was 26% at 3 and 5 years and 23% at 8 years. One child died of sepsis, and another developed a glioblastoma 72 months after RT. Progression-free survival was 27% at 3, 5, and 8 years, and overall survival was 48%, 37%, and 28% at 3, 5, and 8 years, respectively. Of the 13 survivors, 6 never received RT; their intellectual outcome did not differ significantly in those children than in those without RT. Conclusions: Our results confirm poor rates of event-free survival and overall survival for up-front chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT.« less

Low Prostate Concentration of Lycopene Is Associated with Development of Prostate Cancer in Patients with High-Grade Prostatic Intraepithelial Neoplasia

PubMed Central

Mariani, Simone; Lionetto, Luana; Cavallari, Michele; Tubaro, Andrea; Rasio, Debora; De Nunzio, Cosimo; Hong, Gena M.; Borro, Marina; Simmaco, Maurizio

2014-01-01

Prostate cancer (PC) is a frequent male malignancy and represents the second most diagnosed cancer in men. Since pre-cancerous lesions, i.e., the high-grade prostatic intraepithelial neoplasia (HGPIN), can be detected years before progression to PC, early diagnosis and chemoprevention are targeted strategies to reduce PC rates. Animal studies have shown that lycopene, a carotenoid contained in tomatoes, is a promising candidate for the chemoprevention of PC. However, its efficacy in humans remains controversial. The present study aimed to investigate the relevance of plasma and prostate concentration of lycopene after a lycopene-enriched diet in patients diagnosed with HGPIN. Thirty-two patients diagnosed with HGPIN were administered a lycopene-enriched diet (20–25 mg/day of lycopene; through 30 g/day of triple concentrated tomato paste) for 6 months. A 6-month follow-up prostate biopsy assessed progression to PC. Patients were classified into three groups according to the histopathological features of the 6-month follow-up biopsy results: prostatitis; HGPIN and PC. PSA and plasma lycopene levels were measured before and after the dietary lycopene supplementation. Prostatic lycopene concentration was only assessed after the supplementation diet. Only prostatic lycopene concentration showed significant differences between the three groups (p = 0.03). Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PC at 6-month follow-up biopsy (p = 0.003). We observed no overall benefits from a 6-month lycopene supplementation, as the rate of HGPIN progression to PC in our population (9/32, 28%) was similar to rates reported in the literature. Baseline PSA levels also showed no significant changes after a lycopene-enriched diet. Our findings point to prostatic lycopene concentration as a promising biomarker of PC. Further prospective longitudinal studies are needed to assess the prognostic role of prostatic lycopene in PC. PMID:24451130

RandomForest4Life: a Random Forest for predicting ALS disease progression.

PubMed

Hothorn, Torsten; Jung, Hans H

2014-09-01

We describe a method for predicting disease progression in amyotrophic lateral sclerosis (ALS) patients. The method was developed as a submission to the DREAM Phil Bowen ALS Prediction Prize4Life Challenge of summer 2012. Based on repeated patient examinations over a three- month period, we used a random forest algorithm to predict future disease progression. The procedure was set up and internally evaluated using data from 1197 ALS patients. External validation by an expert jury was based on undisclosed information of an additional 625 patients; all patient data were obtained from the PRO-ACT database. In terms of prediction accuracy, the approach described here ranked third best. Our interpretation of the prediction model confirmed previous reports suggesting that past disease progression is a strong predictor of future disease progression measured on the ALS functional rating scale (ALSFRS). We also found that larger variability in initial ALSFRS scores is linked to faster future disease progression. The results reported here furthermore suggested that approaches taking the multidimensionality of the ALSFRS into account promise some potential for improved ALS disease prediction.

Progressive behavioral changes in rats after exposure to low levels of ionizing radiation in utero

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

Norton, S.; Kimler, B.F.; Mullenix, P.J.

1991-03-01

The deleterious effects of ionizing radiation on the developing brain may be not only prolonged but progressive. Fetuses were exposed to 0.75 Gy of ionizing radiation on gestational day 15 through whole body exposure of the pregnant rat. Three behavioral tests (gait analysis, continuous corridor activity and photographic analysis of sequences of behavioral acts) were performed at 1 and 3 months, postnatally. Body weight and thickness of the cerebral cortex of irradiated rats were 10-15 percent below controls throughout the period of study. Behavior in all tests was more affected at 3 months than at 1 month of age. Gaitmore » of control rats, as measured by the angle of advanced of hind feet, widened about 20 percent for males and 40 percent for females from 1 to 3 months, as expected, while, in irradiated rats, the angle widened only about 10 percent. Continuous corridor activity increased less than 10 percent in controls and about 35 percent in irradiated rats over the same period. In photographic analysis of behavior, controls increased their time spent standing by about 50 percent in males and 20 percent in females from 1 to 3 months of age. Irradiated males increased time standing only about 10 percent and irradiated females decreased about 30 percent over the same period. The data obtained in these experiments support other evidence that some behavioral alterations from perinatal exposure to radiation become more marked with maturation.« less

The natural history of HIV infection in intravenous drug users: risk of disease progression in a cohort of seroconverters.

PubMed

Rezza, G; Lazzarin, A; Angarano, G; Sinicco, A; Pristerà, R; Ortona, L; Barbanera, M; Gafà, S; Tirelli, U; Salassa, B

1989-02-01

A multicentre cohort study was carried out to estimate the incidence of AIDS and HIV-related conditions in newly infected intravenous drug users (IVDU). The enrollment criteria included the identification of the seroconversion time. Two hundred and five subjects entered the study, and were followed for a mean of 26 months. Twelve subjects developed clinical AIDS over a 4-year period. The actuarial incidence of AIDS estimated by Kaplan-Meier survival technique was 17.8% by 4 years since seroconversion. The risk of developing AIDS increased significantly after 24 months from seroconversion. Relatively small figures accounted for the lack of statistical association between the risk factors investigated and the disease status.

Systemic treatment in advanced biliary cancers: A multicenter Australian analysis and review.

PubMed

Brungs, Daniel; Aghmesheh, Morteza; Sjoquist, Katrin; Goldstein, David

2017-10-01

While first-line palliative chemotherapy (CT1) improves survival and quality of life in advanced biliary cancer (ABC), there is no randomized evidence to support second-line chemotherapy (CT2) in ABC. We aim to explore to role of CT2 in ABC. We performed a retrospective review of all patients who received one or more lines of chemotherapy for ABC at four Australian cancer centers between 2008 and 2011. A Cox proportional hazard model was developed to determine the impact of clinicopathologic variables on overall survival (OS) from time of progression on CT1. We identified 73 patients who received palliative chemotherapy for ABC. Twenty-five patients (34%) received two or more lines of chemotherapy. Patients with a preserved performance status on progression on first-line chemotherapy (CT1) were more likely to receive second-line chemotherapy (CT2) (P < 0.001). Disease control rate with CT2 was 36%, and mean progression-free survival was 3.2 months (95% confidence interval 1.5-4.9 months). The following variables were significant in the univariate analysis of OS from time of progression on CT1: lines of chemotherapy (P = 0.0001), Eastern Cooperative Oncology Group performance status at progression on CT1 (P < 0.0001) and disease control with CT1 (P = 0.027). Lines of chemotherapy received and performance status remained significant in the multivariate analysis for OS from progression on CT1. Second-line chemotherapy is feasible in a subset of patients with ABC. Even after accounting for confounding variables, CT2 appears to increase OS in ABC, although we are unable to exclude other unmeasured factors such as tumor biology. These findings warrant further evaluation with prospective trials. © 2016 John Wiley & Sons Australia, Ltd.

Dental Pulp Revascularization of Necrotic Permanent Teeth with Immature Apices.

PubMed

El Ashiry, Eman A; Farsi, Najat M; Abuzeid, Sawsan T; El Ashiry, Mohamed M; Bahammam, Hammam A

The treatment of immature necrotic teeth with apical periodontitis presents challenges in endodontic and pediatric dentistry. Revascularization is a recent treatment for such cases as an alternative to conventional apexification. The purpose is to examine the effect of a pulpal revascularization procedure on immature necrotic teeth with apical periodontitis. Twenty patients were enrolled for pulp revascularization procedure by root canal disinfection using a triple antibiotic mixture for 1-2 weeks, followed by creating a blood clot, sealing the root canal orifice using white mineral trioxide aggregate and a coronal seal of composite resin. Patients were recalled periodically for up to 24 months. During follow-up, all patients were asymptomatic. Three cases of chronic apical periodontitis showed clinical disappearance of the sinus tract 2 weeks after treatment. Radiography revealed progressive periapical radiolucency resolution within the first 12 months. Within 12-24 months, the treated teeth showed progressive increases in dentinal wall thickness, root length and continued root development. Clinical and radiographic evidence showed successful revascularization treatments of immature necrotic permanent teeth with apical periodontitis. More studies are necessary to understand the underlying mechanisms and to perform histopathology of the pulp space contents after revascularization procedures.

Development of manufacturing processes: improved technology for ceramic engine components. Monthly report, August 1977

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

Craig, D.F.; Taylor, A.J.; Weber, G.W.

Progress is described in a research program to develop advanced tooling concepts, processing techniques, and related technology for the economical high-volume manufacture of ceramic engine components. Because of the success of the initial fabrication effort for hot pressing fully dense ceramic turbine blades to shape and/or contour, the effort has been extended to include the fabrication of more complex shapes and the evaluation of alternative pressure-assisted, high-temperature, consolidation methods.

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL

PubMed Central

Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

2017-01-01

Background: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Methods: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Results: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26–2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Conclusions: Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression. PMID:28117385

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

PubMed

Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

2017-06-01

Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

COSMIC monthly progress report

NASA Technical Reports Server (NTRS)

1994-01-01

Activities of the Computer Software Management and Information Center (COSMIC) are summarized for the month of January 1994. Tables showing the current inventory of programs available from COSMIC are presented and program processing and evaluation activities are discussed. Marketing and customer service activities in this period are presented as is the progress report of NASTRAN maintenance and support. Tables of disseminations and budget summary conclude the report.

Auditory, speech and language development in young children with cochlear implants compared with children with normal hearing.

PubMed

Schramm, Bianka; Bohnert, Andrea; Keilmann, Annerose

2010-07-01

This study had two aims: (1) to document the auditory and lexical development of children who are deaf and received the first cochlear implant (CI) by the age of 16 months and the second CI by the age of 31 months and (2) to compare these children's results with those of children with normal hearing (NH). This longitudinal study included five children with NH and five with sensorineural deafness. All children of the second group were observed for 36 months after the first fitting of the device (cochlear implant). The auditory development of the CI group was documented every 3 months up to the age of two years in hearing age and chronological age and for the NH group in chronological age. The language development of each NH child was assessed at 12, 18, 24 and 36 months of chronological age. Children with CIs were examined at the same age intervals at chronological and hearing age. In both groups, children showed individual patterns of auditory and language development. The children with CIs developed differently in the amount of receptive and expressive vocabulary compared with the NH control group. Three children in the CI group needed almost 6 months to make gains in speech development that were consistent with what would be expected for their chronological age. Overall, the receptive and expressive development in all children of the implanted group increased with their hearing age. These results indicate that early identification and early implantation is advisable to give children with sensorineural hearing loss a realistic chance to develop satisfactory expressive and receptive vocabulary and also to develop stable phonological, morphological and syntactical skills for school life. On the basis of these longitudinal data, we will be able to develop new diagnostic tools that enable clinicians to assess child's progress in hearing and speech development. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Resistance to vemurafenib can be reversible after treatment interruption: a case report of a metastatic melanoma patient.

PubMed

Mackiewicz-Wysocka, Małgorzata; Krokowicz, Lukasz; Kocur, Jacek; Mackiewicz, Jacek

2014-12-01

About 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist.Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial.

Resistance to Vemurafenib Can Be Reversible After Treatment Interruption

PubMed Central

Mackiewicz-Wysocka, Małgorzata; Krokowicz, Łukasz; Kocur, Jacek; Mackiewicz, Jacek

2014-01-01

Abstract About 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist. Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial. PMID:25501056

Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

PubMed

Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O; Marks, Harold; Flanigan, Kevin M; Moore, Steven A

2015-03-01

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2- metastatic breast cancer.

PubMed

Forsythe, Anna; Chandiwana, David; Barth, Janina; Thabane, Marroon; Baeck, Johan; Tremblay, Gabriel

2018-01-01

Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2- MBC. A systematic literature review of RCTs in HR+, HER2- MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson's product-moment correlation and Spearman's rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P =0.000; Spearman =0.650, P =0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R 2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R 2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5-6 months of incremental PFS/TTP. We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2- MBC.

Installing the Communities that Care Prevention System: Implementation Progress and Fidelity in a Randomized Controlled Trial

ERIC Educational Resources Information Center

Quinby, Rose K.; Hanson, Koren; Brooke-Weiss, Blair; Arthur, Michael W.; Hawkins, J. David; Fagan, Abigail A.

2008-01-01

This article describes the degree to which high fidelity implementation of the Communities That Care (CTC) prevention operating system was reached during the first 18 months of intervention in 12 communities in the Community Youth Development Study, a 5-year group randomized controlled trial designed to test the efficacy of the CTC system. CTC…

Knowledge Elicitation and Techniques of Representing Nurse Practitioner Knowledge Use: Establishing Capability and Social Integration within Busy Nursing Contexts.

ERIC Educational Resources Information Center

Fessey, Christine

The progression of qualified surgical nurses toward capable proficiency was examined in an ethnographic study during which 25 nurses, including 4 who transferred to other wards, were observed to determine whether social mediation affects the process of proficiency development. The nurses were observed for 18 months. Data were also gathered through…

Summer Matters: Advocating for Summer Learning That Can Weather Political Seasons

ERIC Educational Resources Information Center

McQuade, Aaron

2015-01-01

Research has shown that an idle summer is not just boring; it can cost a student as much as two to three months of educational progress. Summer is critical to each child's development, both mind and body. Any meaningful attempts to get at America's equity divide and the consequent gap in opportunities for kids must include summer education as a…

Conceptual abilities of children with mild intellectual disability: analysis of wisconsin card sorting test performance.

PubMed

Gligorović, Milica; Buha, Nataša

2013-06-01

The ability to generate and flexibly change concepts is of great importance for the development of academic and adaptive skills. This paper analyses the conceptual reasoning ability of children with mild intellectual disability (MID) by their achievements on the Wisconsin Card Sorting Test (WCST). The sample consisted of 95 children with MID aged between 10 years and 13 years 11 months. The following variables from the WCST were analysed: number of categories completed, initial conceptualisation, total number of errors, non-perseverative errors, perseverative errors, number of perseverative responses, and failures to maintain set. The observed WCST predictive variables account for 79% of the variability in the number of categories completed (p < .000). The total number of errors was the most significant predictor of performance on the WCST. We can conclude that there is a significant progress of conceptual abilities between the age of 13 years to 13 years 11 months, compared to other assessed age groups. The results of our research suggests that the development of mental set flexibility is the basis of progress in conceptual abilities, thus intervention programs should offer specially designed activities that vary in their attentional demands, content, conceptual patterns, and actions required.

Heart rate variability in idiopathic dilated cardiomyopathy: relation to disease severity and prognosis.

PubMed Central

Yi, G.; Goldman, J. H.; Keeling, P. J.; Reardon, M.; McKenna, W. J.; Malik, M.

1997-01-01

OBJECTIVE: To assess the clinical importance of heart rate variability (HRV) in patients with idiopathic dilated cardiomyopathy (DCM). PATIENTS AND METHODS: Time domain analysis of 24 hour HRV was performed in 64 patients with DCM, 19 of their relatives with left ventricular enlargement (possible early DCM), and 33 healthy control subjects. RESULTS: Measures of HRV were reduced in patients with DCM compared with controls (P < 0.05). HRV parameters were similar in relatives and controls. Measures of HRV were lower in DCM patients in whom progressive heart failure developed (n = 28) than in those who remained clinically stable (n = 36) during a follow up of 24 (20) months (P = 0.0001). Reduced HRV was associated with NYHA functional class, left ventricular end diastolic dimension, reduced left ventricular ejection fraction, and peak exercise oxygen consumption (P < 0.05) in all patients. DCM patients with standard deviation of normal to normal RR intervals calculated over the 24 hour period (SDNN) < 50 ms had a significantly lower survival rate free of progressive heart failure than those with SDNN > 50 ms (P = 0.0002, at 12 months; P = 0.0001, during overall follow up). Stepwise multiple regression analysis showed that SDNN < 50 ms identified, independently of other clinical variables, patients who were at increased risk of developing progressive heart failure (P = 0.0004). CONCLUSIONS: HRV is reduced in patients with DCM and related to disease severity. HRV is clinically useful as an early non-invasive marker of DCM deterioration. PMID:9068391

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax.

PubMed

Anderson, Mary Ann; Tam, Constantine; Lew, Thomas E; Juneja, Surender; Juneja, Manu; Westerman, David; Wall, Meaghan; Lade, Stephen; Gorelik, Alexandra; Huang, David C S; Seymour, John F; Roberts, Andrew W

2017-06-22

The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) ( P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not ( P = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy. © 2017 by The American Society of Hematology.

Knee Injuries Are Associated with Accelerated Knee Osteoarthritis Progression: Data from the Osteoarthritis Initiative

PubMed Central

Driban, Jeffrey B.; Eaton, Charles B.; Lo, Grace H.; Ward, Robert J.; Lu, Bing; McAlindon, Timothy E.

2014-01-01

Objective We aimed to evaluate if a recent knee injury was associated with accelerated knee osteoarthritis (KOA) progression. Methods In the Osteoarthritis Initiative (OAI) we studied participants free of KOA on their baseline radiographs (Kellgren-Lawrence [KL]<2). We compared three groups: 1) individuals with accelerated progression of KOA: defined as having at least one knee that progressed to end-stage KOA (KL Grade 3 or 4) within 48 months, 2) common KOA progression: at least one knee increased in radiographic scoring within 48 months (excluding those defined as accelerated KOA), and 3) no KOA: no change in KL grade in either knee. At baseline, participants were asked if their knees had ever been injured and at each annual visit they were asked about injuries during the prior 12 months. We used multinomial logistic regressions to determine if a new knee injury was associated with the outcome of accelerated KOA or common KOA progression after adjusting for age, sex, body mass index, static knee malalignment, and systolic blood pressure. Results A knee injury during the total observation period was associated with accelerated KOA progression (n=54, odds ratio [OR]=3.14) but not common KOA progression (n=187, OR=1.08). Furthermore, a more recent knee injury (within a year of the outcome) was associated with accelerated (OR=8.46) and common KOA progression (OR=3.12). Conclusion Recent knee injuries are associated with accelerated KOA. Most concerning is that certain injuries may be associated with a rapid cascade towards joint failure in less than one year. PMID:24782446

Candida albicans osteomyelitis of the spine: progressive clinical and radiological features and surgical management in three cases.

PubMed

Khazim, Rabi M; Debnath, Ujjwal K; Fares, Youssef

2006-09-01

Candida albicans vertebral osteomyelitis is rare. Three cases are presented. Without antifungal treatment, they developed spinal collapse and neurological deterioration within 3-6 months from the onset of symptoms. There was a delay of 4.5 and 7.5 months between the onset of symptoms and surgery. All patients were managed with surgical debridement and reconstruction and 12-week fluconazole treatment. The neurological deficits resolved completely. The infection has not recurred clinically or radiologically at 5-6 years follow-up. Although rare, Candida should be suspected as a causative pathogen in cases of spinal osteomyelitis. Without treatment the disease is progressive. As soon as osteomyelitis is suspected, investigations with MRI and percutaneous biopsy should be performed followed by medical therapy. This may prevent the need for surgery. However, if vertebral collapse and spinal cord compression occurs, surgical debridement, fusion and stabilisation combined with antifungal medications can successfully eradicate the infection and resolve the neurological deficits.

Candida albicans osteomyelitis of the spine: progressive clinical and radiological features and surgical management in three cases

PubMed Central

Debnath, Ujjwal K; Fares, Youssef

2006-01-01

Candida albicans vertebral osteomyelitis is rare. Three cases are presented. Without antifungal treatment, they developed spinal collapse and neurological deterioration within 3–6 months from the onset of symptoms. There was a delay of 4.5 and 7.5 months between the onset of symptoms and surgery. All patients were managed with surgical debridement and reconstruction and 12-week fluconazole treatment. The neurological deficits resolved completely. The infection has not recurred clinically or radiologically at 5–6 years follow-up. Although rare, Candida should be suspected as a causative pathogen in cases of spinal osteomyelitis. Without treatment the disease is progressive. As soon as osteomyelitis is suspected, investigations with MRI and percutaneous biopsy should be performed followed by medical therapy. This may prevent the need for surgery. However, if vertebral collapse and spinal cord compression occurs, surgical debridement, fusion and stabilisation combined with antifungal medications can successfully eradicate the infection and resolve the neurological deficits. PMID:16429290

Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.

PubMed

Pelzer, Uwe; Blanc, Jean-Frédéric; Melisi, Davide; Cubillo, Antonio; Von Hoff, Daniel D; Wang-Gillam, Andrea; Chen, Li-Tzong; Siveke, Jens T; Wan, Yin; Solem, Caitlyn T; Botteman, Marc F; Yang, Yoojung; de Jong, Floris A; Hubner, Richard A

2017-05-09

In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

The progress of family health nursing in remote and rural Scotland.

PubMed

Macduff, Colin

2005-12-01

Since 2001 the World Health Organization Europe's family health nurse (FHN) role has been developing in remote and rural areas of Scotland. In 2003, an independent evaluation identified a need for facilitation of the FHN role and family-health orientated approaches with local primary health care teams. The Scottish Executive Health Department appointed three part-time, regionally-based family health practice development facilitators (FHPDFs) in December 2003 to work over an 18-month period. This article presents findings from a small study which sought these FHPDFs' judgements on individual FHN autonomy and supportive colleague action at 24 sites where FHNs were practising. These judgements reveal a picture of mixed progress that is consistent with findings from other related research. This collective overview is presented in the form of a new typology and the resultant implications for future development of family health nursing are discussed.

Diagnosis and treatment of clinically amyopathic dermatomyositis (CADM): a case series and literature review.

PubMed

Gil, Bornstein; Merav, Lidar; Pnina, Langevitz; Chagai, Grossman

2016-08-01

The objective of this study was to report the clinical course of a cohort of patients with clinically amyopathic dermatomyositis (CADM) in correlation to the presence or absence of anti-melanoma differentiation-associated gene 5 (MDA-5) antibody. Five patients with CADM presented to our rheumatology unit between September 1, 2011 and March 31, 2014. We hereby present their clinical course, laboratory findings, imaging modalities, functional tests, and treatments regimens. Our cohort included five patients, with a mean age of 41.8 ± 17.7. Three patients, all anti-MDA-5 antibody positive, developed rapidly progressive interstitial lung disease (ILD) within 4.3 ± 4.5 months of presentation. Two of these patients succumbed to their disease within 30 months of diagnosis despite intensive immunosuppressive therapy. The third anti-MDA-5-positive patient with ILD is still stable, 20 months from disease onset, on massive combination therapy. One patient developed CADM associated with the anti-p155/140 antibody, a year after completing chemotherapy for non-seminomatous germ cell tumor. He presented with a benign clinical course with no evidence of ILD and no recurrence of malignancy after 20 months of follow-up. The fifth patient in our cohort, who is anti-MDA-5 negative and has no evidence of malignancy, also enjoys a benign clinical course. The presence of anti-MDA-5 antibodies in CADM patients is associated with rapidly progressive ILD and a poor prognosis. The serologic profile of patients with CADM should be routinely evaluated and integrated with clinical data in the management of these patients.

Regulation of the isozymes of protein kinase C in the surviving rat myocardium after myocardial infarction: distinct modulation for PKC-alpha and for PKC-delta.

PubMed

Simonis, Gregor; Honold, Jörg; Schwarz, Kerstin; Braun, Martin U; Strasser, Ruth H

2002-05-01

The goal of this study was to clarify the regulation of the isozymes of protein kinase C (PKC) in the process of remodeling after myocardial infarction. An in vivo model of regional myocardial infarction induced by ligation of the left anterior coronary artery in rats was used. Hemodynamic parameters and the heart and lung weights were determined 1 week and 1, 2 and 3 months after operation. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, PKC activity (ELISA) and the expression of its major isozymes, PKC-alpha, PKC-delta and PKC-epsilon (Westernblot analysis) were determined. As early as one week after myocardial infarction, heart weight and left ventricular enddiastolic pressures were significantly increased. Lung weights increased after 2 - 3 months, indicating progressive pulmonary congestion. The activity of PKC was significantly increased about 1.8-fold after 1 week, decreasing progressively in the later time course. Whereas the expression of PKC-epsilon did not change, PKC-alpha was increased after 1 month (157%) and then returned to baseline values. In contrast, PKC-delta expression was significantly augmented after 2 and 3 months of myocardial infarction (187%). These data demonstrate for the first time that in the remodeling heart after myocardial infarction, a subtype-selective regulation of the PKC isozymes occurs: The upregulation of PKC-alpha coincides with the development of hypertrophy, whereas the extensive upregulation of PKC-delta outlasts the process of developing hypertrophy and persists in the failing heart. The trigger mechanisms for this newly characterized process remains to be elucidated.

Using a Learning Coach to Develop Family Medicine Residents' Goal-Setting and Reflection Skills

PubMed Central

George, Paul; Reis, Shmuel; Dobson, Margaret; Nothnagle, Melissa

2013-01-01

Background Self-directed learning (SDL) skills, such as self-reflection and goal setting, facilitate learning throughout a physician's career. Yet, residents do not often formally engage in these activities during residency. Intervention To develop resident SDL skills, we created a learning coach role for a junior faculty member to meet with second-year residents monthly to set learning goals and promote reflection. Methods The study was conducted from 2008–2010 at the Brown Family Medicine Residency in Pawtucket, Rhode Island. During individual monthly meetings with the learning coach, residents entered their learning goals and reflections into an electronic portfolio. A mixed-methods evaluation, including coach's ratings of goal setting and reflection, coach's meeting notes, portfolio entries, and resident interviews, was used to assess progress in residents' SDL abilities. Results Coach ratings of 25 residents' goal-setting ability increased from a mean of 1.9 to 4.6 (P < .001); ratings of reflective capacity increased from a mean of 2.0 to 4.7 (P < .001) during each year. Resident portfolio entries showed a range of domains for goal setting and reflection. Resident interviews demonstrated progressive independence in setting goals and appreciation of the value of reflection for personal development. Conclusions Introducing a learning coach, use of a portfolio, and providing protected time for self-reflected learning allowed residents to develop SDL skills at their own pace. The learning coach model may be applicable to other residency programs in developing resident lifelong learning skills. PMID:24404275

Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: A randomized controlled open-label trial

PubMed Central

Adenis, A.; Blay, J.-Y.; Bui-Nguyen, B.; Bouché, O.; Bertucci, F.; Isambert, N.; Bompas, E.; Chaigneau, L.; Domont, J.; Ray-Coquard, I.; Blésius, A.; Van Tine, B. A.; Bulusu, V. R.; Dubreuil, P.; Mansfield, C. D.; Acin, Y.; Moussy, A.; Hermine, O.; Le Cesne, A.

2014-01-01

Background Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance. Patients and methods Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI. Results Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09–0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16–0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6–2.2, P = 0.833). Conclusions Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit–risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted. PMID:25122671

Evaluation of baseline structural factors for predicting glaucomatous visual-field progression using optical coherence tomography, scanning laser polarimetry and confocal scanning laser ophthalmoscopy.

PubMed

Sehi, M; Bhardwaj, N; Chung, Y S; Greenfield, D S

2012-12-01

The objective of this study is to assess whether baseline optic nerve head (ONH) topography and retinal nerve fiber layer thickness (RNFLT) are predictive of glaucomatous visual-field progression in glaucoma suspect (GS) and glaucomatous eyes, and to calculate the level of risk associated with each of these parameters. Participants with ≥28 months of follow-up were recruited from the longitudinal Advanced Imaging for Glaucoma Study. All eyes underwent standard automated perimetry (SAP), confocal scanning laser ophthalmoscopy (CSLO), time-domain optical coherence tomography (TDOCT), and scanning laser polarimetry using enhanced corneal compensation (SLPECC) every 6 months. Visual-field progression was assessed using pointwise linear-regression analysis of SAP sensitivity values (progressor) and defined as significant sensitivity loss of >1 dB/year at ≥2 adjacent test locations in the same hemifield at P<0.01. Cox proportional hazard ratios (HR) were calculated to determine the predictive ability of baseline ONH and RNFL parameters for SAP progression using univariate and multivariate models. Seventy-three eyes of 73 patients (43 GS and 30 glaucoma, mean age 63.2±9.5 years) were enrolled (mean follow-up 51.5±11.3 months). Four of 43 GS (9.3%) and 6 of 30 (20%) glaucomatous eyes demonstrated progression. Mean time to progression was 50.8±11.4 months. Using multivariate models, abnormal CSLO temporal-inferior Moorfields classification (HR=3.76, 95% confidence interval (CI): 1.02-6.80, P=0.04), SLPECC inferior RNFLT (per -1 μm, HR=1.38, 95% CI: 1.02-2.2, P=0.02), and TDOCT inferior RNFLT (per -1 μm, HR=1.11, 95% CI: 1.04-1.2, P=0.001) had significant HRs for SAP progression. Abnormal baseline ONH topography and reduced inferior RNFL are predictive of SAP progression in GS and glaucomatous eyes.

Evaluation of baseline structural factors for predicting glaucomatous visual-field progression using optical coherence tomography, scanning laser polarimetry and confocal scanning laser ophthalmoscopy

PubMed Central

Sehi, M; Bhardwaj, N; Chung, Y S; Greenfield, D S

2012-01-01

Purpose The objective of this study is to assess whether baseline optic nerve head (ONH) topography and retinal nerve fiber layer thickness (RNFLT) are predictive of glaucomatous visual-field progression in glaucoma suspect (GS) and glaucomatous eyes, and to calculate the level of risk associated with each of these parameters. Methods Participants with ≥28 months of follow-up were recruited from the longitudinal Advanced Imaging for Glaucoma Study. All eyes underwent standard automated perimetry (SAP), confocal scanning laser ophthalmoscopy (CSLO), time-domain optical coherence tomography (TDOCT), and scanning laser polarimetry using enhanced corneal compensation (SLPECC) every 6 months. Visual-field progression was assessed using pointwise linear-regression analysis of SAP sensitivity values (progressor) and defined as significant sensitivity loss of >1 dB/year at ≥2 adjacent test locations in the same hemifield at P<0.01. Cox proportional hazard ratios (HR) were calculated to determine the predictive ability of baseline ONH and RNFL parameters for SAP progression using univariate and multivariate models. Results Seventy-three eyes of 73 patients (43 GS and 30 glaucoma, mean age 63.2±9.5 years) were enrolled (mean follow-up 51.5±11.3 months). Four of 43 GS (9.3%) and 6 of 30 (20%) glaucomatous eyes demonstrated progression. Mean time to progression was 50.8±11.4 months. Using multivariate models, abnormal CSLO temporal-inferior Moorfields classification (HR=3.76, 95% confidence interval (CI): 1.02–6.80, P=0.04), SLPECC inferior RNFLT (per −1 μm, HR=1.38, 95% CI: 1.02–2.2, P=0.02), and TDOCT inferior RNFLT (per −1 μm, HR=1.11, 95% CI: 1.04–1.2, P=0.001) had significant HRs for SAP progression. Conclusion Abnormal baseline ONH topography and reduced inferior RNFL are predictive of SAP progression in GS and glaucomatous eyes. PMID:23060026

Progressive Occlusion of Small Saccular Aneurysms Incompletely Occluded After Stent-Assisted Coil Embolization : Analysis of Related Factors and Long-Term Outcomes.

PubMed

Lim, Jeong Wook; Lee, Jeongjun; Cho, Young Dae

2017-08-08

Incompletely occluded aneurysms after coil embolization are subject to recanalization but occasionally progress to a totally occluded state. Deployed stents may actually promote thrombosis of coiled aneurysms. We evaluated outcomes of small aneurysms (<10 mm) wherein saccular filling with contrast medium was evident after stent-assisted coiling, assessing factors implicated in subsequent progressive occlusion. Between September 2012 and June 2016, a total of 463 intracranial aneurysms were treated by stent-assisted coil embolization. Of these, 132 small saccular aneurysms displayed saccular filling with contrast medium in the immediate aftermath of coiling. Progressive thrombosis was defined as complete aneurysmal occlusion at the 6‑month follow-up point. Rates of progressive occlusion and factors predisposing to this were analyzed via binary logistic regression. In 101 (76.5%) of the 132 intracranial aneurysms, complete occlusion was observed in follow-up imaging studies at 6 months. Binary logistic regression analysis indicated that progressive occlusion was linked to smaller neck diameter (odds ratio [OR] = 1.533; p = 0.003), hyperlipidemia (OR = 3.329; p = 0.036) and stent type (p = 0.031). The LVIS stent is especially susceptible to progressive thrombosis, more so than Neuroform (OR = 0.098; p = 0.008) or Enterprise (OR = 0.317; p = 0.098) stents. In 57 instances of progressive thrombosis, followed for ≥12 months (mean 25.0 ± 10.7 months), 56 (98.2%) were stable, with minor recanalization noted once (1.8%) and no major recanalization. Aneurysms associated with smaller diameter necks, hyperlipidemic states and LVIS stent deployment may be inclined to possible thrombosis, if occlusion immediately after stent-assisted coil embolization is incomplete. In such instances, excellent long-term durability is anticipated.

Survival after failure of first-line chemotherapy in advanced gastric cancer patients: differences between Japan and the rest of the world.

PubMed

Takashima, Atsuo; Iizumi, Sakura; Boku, Narikazu

2017-07-01

In this review, we focus on post-progression survival after first-line chemotherapy of advanced gastric cancer, and particularly the differences between Japan and the rest of the world. We reviewed 15 recent phase III trials of which 4 were solely recruited from Japanese and 11 from rest of the world. The patient characteristics age, performance status, previous gastrectomy and the number of metastatic sites were similar in Japan and rest of the world. However, the diffuse histological type was more common in Japan. While overall survival was longer in Japan (10.5-14.1 vs. 7.9-12.2 months), progression-free survival tended to be shorter in Japan (3.6-6.0 vs. 3.1-7.4 months). Post-progression survival calculated as the difference between median overall survival and progression-free survival was clearly longer in Japan (6.9-8.6 vs. 2.4-6.2 months). The proportion of patients receiving second-line chemotherapy (%2nd-CX) was quite different in Japan and rest of the world (69-85% vs. 11-59%). Correlations between %2nd-CX and post-progression survival were strong (Spearman's rank correlation coefficient; ρ = 0.86, P < 0.001). Correlations between %2nd-CX and ratio of post-progression survival to total overall survival were also strong (ρ = 0.84, P < 0.001). Because a survival benefit of second-CX was documented in several phase III trials, it can be concluded that higher %2nd-CX partly contributed to extended post-progression survival. However, considering that second-CX increased survival only by ~1.5 months at median, other factors such as third-line chemotherapy may have some influences to prolonged post-progression survival. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Recurrent endometrial carcinoma: prognosis for patients with recurrence within 6 to 12 months is worse relative to those relapsing at 12 months or later.

PubMed

Miyake, Takahito; Ueda, Yutaka; Egawa-Takata, Tomomi; Matsuzaki, Shinya; Yokoyama, Takuhei; Miyoshi, Yukari; Kimura, Toshihiro; Yoshino, Kiyoshi; Fujita, Masami; Yamasaki, Masato; Enomoto, Takayuki; Kimura, Tadashi

2011-06-01

We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs). We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC). Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months). Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy. Copyright © 2011 Mosby, Inc. All rights reserved.

78 FR 26215 - Jewish American Heritage Month, 2013

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-03

... American Heritage Month, 2013 By the President of the United States of America A Proclamation In his second... American shores. We take this month to celebrate the progress that followed, and the bright future that... May 2013 as Jewish American Heritage Month. I call upon all Americans to visit www.JewishHeritageMonth...

Monitoring Indicators of Scholarly Language: A Progress-Monitoring Instrument for Measuring Narrative Discourse Skills

ERIC Educational Resources Information Center

Gillam, Sandra Laing; Gillam, Ronald B.; Fargo, Jamison D.; Olszewski, Abbie; Segura, Hugo

2017-01-01

The purpose of this study was to assess the basic psychometric properties of a progress-monitoring tool designed to measure narrative discourse skills in school-age children with language impairments (LI). A sample of 109 children with LI between the ages of 5 years 7 months and 9 years 9 months completed the "Test of Narrative Language"…

Progress Monitoring in Reading: Comparison of Weekly, Bimonthly, and Monthly Assessments for Students at Risk for Reading Difficulties in Grades 2-4

ERIC Educational Resources Information Center

January, Stacy-Ann A.; Van Norman, Ethan R.; Christ, Theodore J.; Ardoin, Scott P.; Eckert, Tanya L.; White, Mary Jane

2018-01-01

The present study examined the utility of two progress monitoring assessment schedules (bimonthly and monthly) as alternatives to monitoring once weekly with curriculum-based measurement in reading (CBM-R). General education students (N = 93) in Grades 2-4 who were at risk for reading difficulties but not yet receiving special education services…

Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis.

PubMed

Fogarty, Emer; Schmitz, Susanne; Tubridy, Niall; Walsh, Cathal; Barry, Michael

2016-09-01

Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis (RRMS). However it is unclear how the magnitude of treatment efficacy varies across all currently available therapies. To perform a systematic review and network meta-analysis to evaluate the comparative efficacy of available therapies in reducing relapses and disability progression in RRMS. A systematic review identified 28 randomised, placebo-controlled and direct comparative trials. A network meta-analysis was conducted within a Bayesian framework to estimate comparative annualised relapse rates (ARR) and risks of disability progression (defined by both a 3-month, and 6-month confirmation interval). Potential sources of treatment-effect modification from study-level covariates and baseline risk were evaluated through meta-regression methods. The Surface Under the Cumulative RAnking curve (SUCRA) method was used to provide a ranking of treatments for each outcome. The magnitude of ARR reduction varied between 15-36% for all interferon-beta products, glatiramer acetate and teriflunomide, and from 50 to 69% for alemtuzumab, dimethyl fumarate, fingolimod and natalizumab. The risk of disability progression (3-month) was reduced by 19-28% with interferon-beta products, glatiramer acetate, fingolimod and teriflunomide, by 38-45% for pegylated interferon-beta, dimethyl fumarate and natalizumab and by 68% with alemtuzumab. Broadly similar estimates for the risk of disability progression (6-month), with the exception of interferon-beta-1b 250mcg which was much more efficacious based on this definition. Alemtuzumab and natalizumab had the highest SUCRA scores (97% and 95% respectively) for ARR, while ranking for disability progression varied depending on the definition of the outcome. Interferon-beta-1b 250mcg ranked among the most efficacious treatments for disability progression confirmed after six months (92%) and among the least efficacious when the outcome was confirmed after three months (30%). No significant modification of relative treatment effects was identified from study-level covariates or baseline risk. Compared with placebo, clear reductions in ARR with disease-modifying therapies were accompanied by more uncertain changes in disability progression. The magnitude of the reduction and the uncertainty associated with treatment effects varied between DMTs. While natalizumab and alemtuzumab demonstrated consistently high ranking across outcomes, with older interferon-beta and glatiramer acetate products ranking lowest, variation in disability progression definitions lead to variation in the relative ranking of treatments. Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS. Copyright © 2016 Elsevier B.V. All rights reserved.

Progressive Hearing Impairment in Children with Congenital Cytomegalovirus Infection.

ERIC Educational Resources Information Center

Dahle, Arthur J.; And Others

1979-01-01

Audiological assessment of 86 children (mean age 38 months at last evaluation time) with congenital cytomegalovirus infection revealed progressive hearing loss in four of 12 Ss with sensorineural hearing impairments. Case descriptions documented the progression of the hearing loss. (Author)

NASA's Nuclear Thermal Propulsion Project

NASA Technical Reports Server (NTRS)

Houts, Mike; Mitchell, Sonny; Kim, Tony; Borowski, Stan; Power, Kevin; Scott, John; Belvin, Anthony; Clement, Steve

2015-01-01

HEOMD's (Human Exploration and Operations Mission Directorate) AES (Advanced Exploration Systems) Nuclear Thermal Propulsion (NTP) project is making significant progress. First of four FY 2015 milestones achieved this month. Safety is the highest priority for NTP (as with other space systems). After safety comes affordability. No centralized capability for developing, qualifying, and utilizing an NTP system. Will require a strong, closely integrated team. Tremendous potential benefits from NTP and other space fission systems. No fundamental reason these systems cannot be developed and utilized in a safe, affordable fashion.

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PubMed

Desjardins, Annick; Quinn, Jennifer A; Vredenburgh, James J; Sathornsumetee, Sith; Friedman, Allan H; Herndon, James E; McLendon, Roger E; Provenzale, James M; Rich, Jeremy N; Sampson, John H; Gururangan, Sridharan; Dowell, Jeannette M; Salvado, August; Friedman, Henry S; Reardon, David A

2007-05-01

Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases

PubMed Central

Owen, Dawn; Laack, Nadia N.; Mayo, Charles S.; Garces, Yolanda I.; Park, Sean S.; Bauer, Heather J.; Nelson, Kathryn; Miller, Robert W.; Brown, Paul D.; Olivier, Kenneth R.

2015-01-01

Purpose Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases. Methods and Materials Between 2008 and 2012, 74 subjects with oligometastatic non-spine bony metastases of varying histologies were treated at the Mayo Clinic with SBRT. A total of 85 non-spine bony sites were treated. Median local control, overall survival, and progression-free survival were described. Acute toxicity (defined as toxicity <90 days) and late toxicity (defined as toxicity ≥90 days) were reported and graded as per standardized Common Toxicity Criteria for Adverse Events 4.0 criteria. Results The median age of patients treated was 60 years. The most common histology was prostate cancer (31%) and most patients had fewer than 3 sites of disease at the time of simulation (64%). Most of the non-spine bony sites lay within the pelvis (65%). Dose and fractionation varied but the most common prescription was 24 Gy/1 fraction. Local recurrence occurred in 7 patients with a median time to failure of 2.8 months. Local control was 91.8% at 1 year. With a median follow-up of 7.6 months, median SBRT specific overall survival and progression-free survival were 9.3 months and 9.7 months, respectively. Eighteen patients developed acute toxicity (mostly grade 1 and 2 fatigue and acute pain flare); 9 patients developed grade 1–2 late toxicities. Two patients developed pathologic fractures but both were asymptomatic. There were no late grade 3 or 4 toxicities. Conclusions Stereotactic body radiation therapy is a feasible and tolerable treatment for non-spine bony metastases. Longer follow-up will be needed to accurately determine late effects. PMID:24890360

Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases.

PubMed

Owen, Dawn; Laack, Nadia N; Mayo, Charles S; Garces, Yolanda I; Park, Sean S; Bauer, Heather J; Nelson, Kathryn; Miller, Robert W; Brown, Paul D; Olivier, Kenneth R

2014-01-01

Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases. Between 2008 and 2012, 74 subjects with oligometastatic non-spine bony metastases of varying histologies were treated at the Mayo Clinic with SBRT. A total of 85 non-spine bony sites were treated. Median local control, overall survival, and progression-free survival were described. Acute toxicity (defined as toxicity <90 days) and late toxicity (defined as toxicity ≥90 days) were reported and graded as per standardized Common Toxicity Criteria for Adverse Events 4.0 criteria. The median age of patients treated was 60 years. The most common histology was prostate cancer (31%) and most patients had fewer than 3 sites of disease at the time of simulation (64%). Most of the non-spine bony sites lay within the pelvis (65%). Dose and fractionation varied but the most common prescription was 24 Gy/1 fraction. Local recurrence occurred in 7 patients with a median time to failure of 2.8 months. Local control was 91.8% at 1 year. With a median follow-up of 7.6 months, median SBRT specific overall survival and progression-free survival were 9.3 months and 9.7 months, respectively. Eighteen patients developed acute toxicity (mostly grade 1 and 2 fatigue and acute pain flare); 9 patients developed grade 1-2 late toxicities. Two patients developed pathologic fractures but both were asymptomatic. There were no late grade 3 or 4 toxicities. Stereotactic body radiation therapy is a feasible and tolerable treatment for non-spine bony metastases. Longer follow-up will be needed to accurately determine late effects. Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Glenohumeral arthritis after Latarjet procedure: Progression and it's clinical significance.

PubMed

Kee, Young Moon; Kim, Hwan Jin; Kim, Jung Youn; Rhee, Yong Girl

2017-09-01

The risk factors of glenohumeral arthritis after the Latarjet procedure remain relatively unexplored. The purposes of this study are to evaluate the clinical significance of glenohumeral arthritis after the Latarjet procedure, and to investigate risk factors associated with arthritis progression. We evaluated 110 patients (110 shoulders) who underwent the Latarjet procedure for recurrent anterior shoulder instability. Patients had a mean age of 23.8 years (range, 14-52 years) at the time of the operation, and the mean duration of follow-up was 31 months (range, 24-111 months). At the last follow-up, the mean Visual Analog Scale (VAS), Rowe and University of California at Los Angeles (UCLA) scores significantly improved from 3.1, 36.5 and 23.6 points preoperatively to 1.6, 87.6 and 32.6 points (all P < 0.05, respectively). The postoperative rate of recurrence was 5.4%. Among the 14 shoulders with preoperative arthritis, 8 (57.1%) showed progression of arthritis at the last follow up. New occurrence or progression of arthritis after the Latarjet procedure was in 20 shoulders (18.2%). At the final, overall prevalence of arthritis was 23.6% (26 shoulders). The non-arthritis group showed significantly better functional outcomes (VAS score: 0.9, Rowe Score: 89.3, UCLA score: 33.5) than the arthritis group (2.1, 84.9, 29.2; all P < 0.05, respectively). Preoperative generalized laxity and lateral overhang were associated with glenohumeral arthritis progression after surgery. (all P < 0.05, retrospectively). The Latarjet procedure yielded satisfactory functional outcomes with low recurrent rate at mid-term follow-up. Development or progression of arthritis was observed in 18.2% of patients, postoperatively. Glenohumeral arthritis after the Latarjet procedure had an adverse effect on clinical outcome. Generalized laxity and lateral overhang should be considered as risk factors of progression to glenohumeral arthritis after the Latarjet procedure. Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

PubMed Central

Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P

2018-01-01

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. PMID:29306872

Risk of contralateral avascular necrosis (AVN) after total hip arthroplasty (THA) for non-traumatic AVN.

PubMed

Goker, Berna; Block, Joel A

2006-01-01

The risk of developing bilateral disease progressing to total hip arthroplasty (THA) among patients who undergo unilateral THA for non-traumatic avascular necrosis (AVN) remains poorly understood. An analysis of the time-course to contralateral THA, as well as the effects of underlying AVN risk factors, is presented. Forty-seven consecutive patients who underwent THA for AVN were evaluated. Peri-operative and annual post-operative antero-posterior pelvis radiographs were examined for evidence of contralateral involvement. Patient age, weight, height, underlying AVN risk factor(s), date of onset of contralateral hip pain if occurred, and date of contralateral THA if performed, were recorded. Bone scan, computerized tomography and magnetic resonance imaging data were utilized when available. Twenty-one patients (46.6%) underwent contralateral THA for AVN within a median of 9 months after the initial THA (range 0-93, interquartile range 28.5 months). The median follow-up for patients without contralateral THA was 75 months (range 3-109, interquartile range 69 months). Thirty-four patients had radiographic findings of contralateral AVN at study entry; 25 were symptomatic bilaterally at entry and 7 developed contralateral symptoms within a mean time of 12 months (median 10 months, interquartile range 12 months). None of the 13 patients who were free of radiographic evidence of contralateral AVN at study entry developed evidence of AVN during the follow-up. AVN associated with glucocorticoid use was more likely to manifest as bilateral disease than either idiopathic AVN or ethanol-associated AVN (P=0.02 and P=0.03 respectively). Radiographically-evident AVN in the contralateral hip at THA is unlikely to remain asymptomatic for a prolonged period of time. Conversely, asymptomatic contralateral hips without radiographic evidence of AVN are unlikely to develop clinically significant AVN.

Polymer Infiltration Studies

NASA Technical Reports Server (NTRS)

Marchello, Joseph M.

1993-01-01

Significant progress has been made on the preparation of carbon fiber composites using advanced polymer resins during the past three months. Current and ongoing research activities reported herein include: (1) Prepregger Hot Sled Operation; (2) Ribbonizing Powder-Impregnated Towpreg; (3) Textile Composites from Powder-Coated Towpreg: Role of Bulk Factor; and (4) Powder Curtain Prepreg Process. During the coming months research will be directed toward further development of the new powder curtain prepregging method and on ways to customize dry powder towpreg for textile and robotic applications in aircraft part fabrication. Studies of multi-tow powder prepregging and ribbon preparation will be conducted in conjunction with continued development of prepegging technology and the various aspects of composite part fabrication using customized towpreg. Also, work will continue on the analysis of the new solution prepegger.

A Discrepancy in Comprehension and Production in Early Language Development in ASD: Is it Clinically Relevant?

PubMed

Davidson, Meghan M; Ellis Weismer, Susan

2017-07-01

This study examined the extent to which a discrepant comprehension-production profile (i.e., relatively more delayed comprehension than production) is characteristic of the early language phenotype in autism spectrum disorders (ASD) and tracked the developmental progression of the profile. Our findings indicated that a discrepant comprehension-production profile distinguished toddlers (30 months) with ASD from late talkers without ASD (91% sensitivity, 100% specificity) in groups that were comparable on expressive language, age, and socioeconomic status. Longitudinal data for children with ASD revealed that the discrepant profile steadily decreased from 30 to 44 months until there was no significant comprehension-production difference at 66 months. In conclusion, results suggest that lower comprehension than production may be an age-specific marker of toddlers with ASD.

Daily tadalafil for the chronic phase of stuttering priapism: a case report.

PubMed

Massenio, Paolo; D'Altilia, Nicola; Sanguedolce, Francesca; Carrieri, Giuseppe; Cormio, Luigi

2018-05-31

Recurrent (stuttering) ischemic priapism is a challenging clinical condition. Frequent recurrences result in frequent hospital admissions whereas treatment with a shunting procedure often results in erectile dysfunction. A 22-year-old man with stuttering idiopathic priapism developed erectile dysfunction (IIEF-5 score 12) following a Winter's shunt; he was given tadalafil, 5 mg/daily, for 6 months. This treatment resulted in progressive restoration of erectile function in the 6 months following the shunt as well as in preventing recurrence of priapic episodes over a 24-month follow-up. This is the first report in literature of chronic treatment of stuttering priapism with a phosphodiesterase-5 inhibitor being able not only to prevent recurrent priapic episodes but also to restore erectile function following a Winter's shunt.

Some dissociating factors in the analysis of structural and functional progressive damage in open-angle glaucoma.

PubMed

Hudson, C J W; Kim, L S; Hancock, S A; Cunliffe, I A; Wild, J M

2007-05-01

To identify the presence, and origin, of any "dissociating factors" inherent to the techniques for evaluating progression that mask the relationship between structural and functional progression in open-angle glaucoma (OAG). 23 patients (14 with OAG and 9 with ocular hypertension (OHT)) who had received serial Heidelberg Retina Tomograph (HRT II) and Humphrey Field Analyser (HFA) examinations for >or=5 years (mean 78.4 months (SD 9.5), range 60-101 months) were identified. Evidence of progressive disease was retrospectively evaluated in one eye of each patient using the Topographic Change Analysis (TCA) and Glaucoma Progression Analysis (GPA) for the HRT II and HFA, respectively. Six patients were stable by both techniques; four exhibited both structural and functional progression; seven exhibited structural progression, only, and six showed functional progression, only. Three types of dissociating factors were identified. TCA failed to identify progressive structural damage in the presence of advanced optic nerve head damage. GPA failed to identify progressive functional damage at stimulus locations, with sensitivities exhibiting test-retest variability beyond the maximum stimulus luminance of the perimeter, and where a perimetric learning effect was apparent. The three dissociating factors accounted for nine of the 13 patients who exhibited a lack of concordance between structural and functional progressive damage.

A multicentre phase III randomised controlled single-masked clinical trial evaluating the clinical efficacy and safety of light-masks at preventing dark-adaptation in the treatment of early diabetic macular oedema (CLEOPATRA): study protocol for a randomised controlled trial.

PubMed

Sivaprasad, Sobha; Arden, Geoffrey; Prevost, A Toby; Crosby-Nwaobi, Roxanne; Holmes, Helen; Kelly, Joanna; Murphy, Caroline; Rubin, Gary; Vasconcelos, Joanna; Hykin, Philip

2014-11-22

This study will evaluate hypoxia, as a novel concept in the pathogenesis of diabetic macular oedema (DMO). As the oxygen demand of the eye is maximum during dark-adaptation, we hypothesize that wearing light-masks during sleep will cause regression and prevent the development and progression of DMO. The study protocol comprises both an efficacy and mechanistic evaluation to test this hypothesis. This is a phase III randomised controlled single-masked multicentre clinical trial to test the clinical efficacy of light-masks at preventing dark-adaptation in the treatment of non-central DMO. Three hundred patients with non-centre-involving DMO in at least one eye will be randomised 1:1 to light-masks and control masks (with no light) to be used during sleep at night for a period of 24 months. The primary outcome is regression of non-central oedema by assessing change in the zone of maximal retinal thickness at baseline on optical coherence tomography (SD-OCT). Secondary outcomes will evaluate the prevention of development and progression of DMO by assessing changes in retinal thickness in different regions of the macula, macular volume, refracted visual acuity and level of retinopathy. Safety parameters will include sleep disturbance. Adverse events and measures of compliance will be assessed over 24 months. Participants recruited to the mechanistic sub-study will have additional retinal oximetry, multifocal electroretinography (ERG) and microperimetry to evaluate the role of hypoxia by assessing and comparing changes induced by supplemental oxygen and the light-masks at 12 months. The outcomes of this study will provide insight into the pathogenesis of DMO and provide evidence on whether a simple, non-invasive device in the form of a light-mask can help prevent the progression to centre-involving DMO and visual impairment in people with diabetes.

Silent Corticotroph Adenomas After Stereotactic Radiosurgery: A Case–Control Study

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

Xu, Zhiyuan; Ellis, Scott; Lee, Cheng-Chia

Purpose: To investigate the safety and effectiveness of stereotactic radiosurgery (SRS) in patients with a silent corticotroph adenoma (SCA) compared with patients with other subtypes of non–adrenocorticotropic hormone staining nonfunctioning pituitary adenoma (NFA). Methods and Materials: The clinical features and outcomes of 104 NFA patients treated with SRS in our center between September 1994 and August 2012 were evaluated. Among them, 34 consecutive patients with a confirmatory SCA were identified. A control group of 70 patients with other subtypes of NFA were selected for review based on comparable baseline features, including sex, age at the time of SRS, tumor size, marginmore » radiation dose to the tumor, and duration of follow-up. Results: The median follow-up after SRS was 56 months (range, 6-200 months). No patients with an SCA developed Cushing disease during the follow-up. Tumor control was achieved in 21 of 34 patients (62%) in the SCA group, compared with 65 of 70 patients (93%) in the NFA group. The median progression-free survival (PFS) was 58 months in the SCA group. The actuarial PFS was 73%, 46%, and 31% in the SCA group and was 94%, 87%, and 87% in the NFA group at 3, 5, and 8 years, respectively. Silent corticotroph adenomas treated with a dose of ≥17 Gy exhibited improved PFS. New-onset loss of pituitary function developed in 10 patients (29%) in the SCA group, whereas it occurred in 18 patients (26%) in the NFA group. Eight patients (24%) in the SCA group experienced worsening of a visual field deficit or visual acuity attributed to the tumor progression, as did 6 patients (9%) in the NFA group. Conclusion: Silent corticotroph adenomas exhibited a more aggressive course with a higher progression rate than other subtypes of NFAs. Stereotactic radiosurgery is an important adjuvant treatment for control of tumor growth. Increased radiation dose may lead to improved tumor control in SCA patients.« less

The Emergence of Tool Use during the Second Year of Life

ERIC Educational Resources Information Center

Rat-Fischer, Lauriane; O'Regan, J. Kevin; Fagard, Jacqueline

2012-01-01

Despite a growing interest in the question of tool-use development in infants, no study so far has systematically investigated how learning to use a tool to retrieve an out-of-reach object progresses with age. This was the first aim of this study, in which 60 infants, aged 14, 16, 18, 20, and 22 months, were presented with an attractive toy and a…

Solar-B Mission Extreme Ultraviolet (EUV) Imaging Spectrometer (EIS) Instrument Components

NASA Technical Reports Server (NTRS)

Doschek, George A.

2002-01-01

This Monthly Progress Report covers the reporting period August 2002 of the Detailed Design and Development through Launch plus Thirty Days, Phase C/D, for selected components and subsystems of the Extreme ultraviolet Imaging Spectrometer (EIS) instrument, hereafter referred to as EIS Instrument Components. This document contains the program status through the reporting period and forecasts the status for the upcoming reporting period.

SOLAR-B Mission Extreme Ultraviolet (EUV) Imaging Spectrometer (EIS) Instrument Components

NASA Technical Reports Server (NTRS)

Doschek, George A.

2001-01-01

This Monthly Progress Report covers the reporting period through June 2001, Phase C/D, Detailed Design and Development Through Launch Plus Thirty Days, for selected components and subsystems of the Extreme ultraviolet Imaging Spectrometer (EIS) instrument, hereafter referred to as EIS Instrument Components. This document contains the program status through the reporting period and forecasts the status for the upcoming reporting period.

SOLAR-B Mission Extreme Ultraviolet (EUV) Imaging Spectrometer (EIS) Instrument Components

NASA Technical Reports Server (NTRS)

Doschek, George A.

2001-01-01

This Monthly Progress Report covers the reporting period July 2001 of the Detailed Design and Development through Launch plus Thirty Days, Phase C/D, for selected components and subsystems of the Extreme Ultraviolet Imaging Spectrometer (EIS) instrument, hereafter referred to as EIS Instrument Components. This document contains the program status through the reporting period and forecasts the status for the upcoming reporting period.

Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: a single institutional experience.

PubMed

Leone, Francesco; Gatti, Marco; Massucco, Paolo; Colombi, Federica; Sperti, Elisa; Campanella, Delia; Regge, Daniele; Gabriele, Pietro; Capussotti, Lorenzo; Aglietta, Massimo

2013-01-15

Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol. Patients first received induction gemcitabine and oxaliplatin (GEMOX) (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)). Patients without disease progression then received gemcitabine twice weekly (50 mg/m(2) daily) concurrent with radiotherapy (50.4 grays) and were re-evaluated for resectability. Thirty-nine patients (15 with borderline resectable disease and 24 with unresectable disease) entered the study. The treatment was well tolerated. Disease control was obtained in 29 of 39 patients. Two patients progressed after GEMOX, and 7 progressed after CRT. After a median follow-up of 13 months, the median progression-free survival (PFS) was 10.2 months. The median PFS of patients with borderline resectable and unresectable disease was 16.6 and 9.1 months, respectively (P = .056). For the whole group, the median overall survival (OS) was 16.7 months (27.8 months for patients with borderline resectable disease, 13.3 for patients with unresectable disease; P = .045). Eleven patients (9 with borderline resectable disease and 2 with unresectable disease at diagnosis) underwent successful resection. Patients who underwent resection had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively). The median OS among resected and nonresected patients was 31.5 months and 12.3 months, respectively (P < .001). The current results indicated that induction GEMOX followed by CRT is feasible in patients with LAPC. Both those with borderline resectable disease and those with unresectable disease received clinical benefit, a chance to obtain resectability, and improved survival. The authors concluded that this protocol warrants further evaluation. Copyright © 2012 American Cancer Society.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

PubMed

Tourbah, Ayman; Lebrun-Frenay, Christine; Edan, Gilles; Clanet, Michel; Papeix, Caroline; Vukusic, Sandra; De Sèze, Jerome; Debouverie, Marc; Gout, Olivier; Clavelou, Pierre; Defer, Gilles; Laplaud, David-Axel; Moreau, Thibault; Labauge, Pierre; Brochet, Bruno; Sedel, Frédéric; Pelletier, Jean

2016-11-01

Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated. © The Author(s), 2016.

Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies.

PubMed

Baker, Peter R; Nanduri, Priyaanka; Gottlieb, Peter A; Yu, Liping; Klingensmith, Georgeanna J; Eisenbarth, George S; Barker, Jennifer M

2012-05-01

Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD). Progression to AD can take months to years, and early detection of metabolic decompensation may prevent morbidity and mortality. To define optimal methods of predicting progression to overt AD (defined by subnormal peak cortisol response to Cosyntropin) in 21OH-AA+ individuals. Individuals were screened for 21OH-AA at the Barbara Davis Center from 1993 to 2011. Subjects positive for 21OH-AA (n = 87) were tested, and the majority prospectively followed for the development of Addison's disease, including seven diagnosed with AD upon 21OH-AA discovery (discovered), seven who progressed to AD (progressors) and 73 nonprogressors. Plasma renin activity (PRA), ACTH, baseline cortisol, peak cortisol and 21OH-AA were measured at various time points relative to diagnosis of AD or last AD-free follow-up. Compared with nonprogressors, in the time period 2 months-2 years prior to the onset of AD, progressors were significantly more likely to have elevated ACTH (11-22 pM, P < 1E-4), with no significant differences in mean PRA (P = 0·07) or baseline cortisol (P = 0·08), and significant but less distinct differences seen with 21OH-AA levels (P < 1E-4) and poststimulation cortisol levels (P = 6E-3). Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol, in the 2 months-2 years preceding the onset of AD. © 2012 Blackwell Publishing Ltd.

Corneal collagen crosslinking for corneal ectasia of post-LASIK: one-year results

PubMed Central

Li, Gang; Fan, Zheng-Jun; Peng, Xiu-Jun

2012-01-01

AIM To evaluate the efficacy and safety of corneal collagen crosslinking (CXL) to prevent the progression of post-laser in situ keratomileusis (LASIK) corneal ectasia. METHODS In a prospective, nonrandomized, single-centre study, CXL was performed in 20 eyes of 11 patients who had LASIK for myopic astigmatism and subsequently developed keratectasia.The procedure included instillation of 0.1% riboflavin-20% dextrane solution 30 minutes before UVA irradiation and every 5 minutes for an additional 30 minutes during irradiation. The eyes were evaluated preoperatively and at 1-, 3-, 6-, and 12-month intervals. The complete ophthalmologic examination comprised uncorrected visual acuity, best spectacle-corrected visual acuity, endothelial cell count, ultrasound pachymetry, corneal topography, and in vivo confocal microscopy. RESULTS CXL appeared to stabilise or partially reverse the progression of post-LASIK corneal ectasia without apparent complication in our cohort. UCVA and BCVA improvements were statistically significant(P<0.05) beyond 12 months after surgery (improvement of 0.07 and 0.13 logMAR at 1 year, respectively). Mean baseline flattest meridian keratometry and mean steepest meridian keratometry reduction (improvement of 2.00 and 1.50 diopters(D), respectively) were statistically significant (P<0.05) at 12 months postoperatively. At 1 year after CXL, mean endothelial cell count did not deteriorate. Mean thinnest cornea pachymetry increased significantly. CONCLUSION The results of the study showed a long-term stability of post-LASIK corneal ectasia after crosslinking without relevant side effects. It seems to be a safe and promising procedure to stop the progression of post-LASIK keratectasia, thereby avoiding or delaying keratoplasty. PMID:22762048

Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer.

PubMed

Maemura, Kosei; Mataki, Yuko; Kurahara, Hiroshi; Kawasaki, Yota; Iino, Satoshi; Sakoda, Masahiko; Ueno, Shinichi; Arimura, Takeshi; Higashi, Ryutaro; Yoshiura, Takashi; Shinchi, Hiroyuki; Natsugoe, Shoji

We compared the clinical outcomes of proton beam radiotherapy (PBRT) and those of conventional chemoradiotherapy via hyper-fractionated acceleration radiotherapy (HART) after induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). Twenty-five consecutive patients with LAPC received induction chemotherapy comprising gemcitabine and S-1 before radiotherapy. Of these, 15 and 10 were enrolled in the HART and PBRT groups, respectively. Moderate hematological toxicities were observed only in the HART group, whereas two patients in the PBRT group developed duodenal ulcers. All patients underwent scheduled radiotherapy, with overall disease control rates of 93% and 80% in the HART and PBRT groups, respectively. Local progression was observed in 60% and 40% of patients in the HART and PBRT groups, respectively. However, there was no statistical significance between the two groups regarding the median time to progression (15.4 months in both) and the median overall survival (23.4 v.s. 22.3 months). PBRT was feasible and tolerable, and scheduled protocols could be completed with careful attention to gastrointestinal ulcers. Despite the lower incidence of local recurrence, PBRT did not yield obvious progression control and survival benefits relative to conventional chemoradiotherapy. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

COMPASS: A computational model to predict changes in MMSE scores 24-months after initial assessment of Alzheimer's disease.

PubMed

Zhu, Fan; Panwar, Bharat; Dodge, Hiroko H; Li, Hongdong; Hampstead, Benjamin M; Albin, Roger L; Paulson, Henry L; Guan, Yuanfang

2016-10-05

We present COMPASS, a COmputational Model to Predict the development of Alzheimer's diSease Spectrum, to model Alzheimer's disease (AD) progression. This was the best-performing method in recent crowdsourcing benchmark study, DREAM Alzheimer's Disease Big Data challenge to predict changes in Mini-Mental State Examination (MMSE) scores over 24-months using standardized data. In the present study, we conducted three additional analyses beyond the DREAM challenge question to improve the clinical contribution of our approach, including: (1) adding pre-validated baseline cognitive composite scores of ADNI-MEM and ADNI-EF, (2) identifying subjects with significant declines in MMSE scores, and (3) incorporating SNPs of top 10 genes connected to APOE identified from functional-relationship network. For (1) above, we significantly improved predictive accuracy, especially for the Mild Cognitive Impairment (MCI) group. For (2), we achieved an area under ROC of 0.814 in predicting significant MMSE decline: our model has 100% precision at 5% recall, and 91% accuracy at 10% recall. For (3), "genetic only" model has Pearson's correlation of 0.15 to predict progression in the MCI group. Even though addition of this limited genetic model to COMPASS did not improve prediction of progression of MCI group, the predictive ability of SNP information extended beyond well-known APOE allele.

Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab).

PubMed

Tam, Constantine S; O'Brien, Susan; Plunkett, William; Wierda, William; Ferrajoli, Alessandra; Wang, Xuemei; Do, Kim-Anh; Cortes, Jorge; Khouri, Issa; Kantarjian, Hagop; Lerner, Susan; Keating, Michael J

2014-11-13

Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care. © 2014 by The American Society of Hematology.

Demonstration of an advanced solar garden with a water ceiling. Six-month technical progress report, July 1-December 31, 1979

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

Maes, R.; Riseng, C.; Thomas, G.

1980-02-01

A history of the solar garden with the addition of the transparent water ceiling and a statement of the overall goals of the program are presented. It then details the objectives of the water ceiling grant. The rationale of the transparent water ceiling is developed and its implementation in the solar garden is described. The experimental procedures for evaluating the water ceiling as an integral part of an ongoing garden agricultural experiment are discussed. The results of the first six months of the program and the future activities of the next period are presented.

Undifferentiated carcinoma of the pituitary gland: A case report and review of the literature.

PubMed

Lee, Hsun-Hwa; Hung, Shih-Han; Tseng, Te-Ming; Lin, Yun-Ho; Cheng, Ju-Chuan

2014-03-01

Primary pituitary gland cancer is extremely rare. The current study presents the case of a patient diagnosed with pituitary cancer three months after completing surgery and post-operative chemoradiotherapy for hypopharyngeal cancer. In this report we discuss 57-year-old patient who presented with diplopia and ptosis four months following the completion of treatment for hypopharyngeal cancer. A poorly-differentiated pituitary carcinoma was located. Despite aggressive treatment and surgical excision with postoperative chemoradiotherapy, the disease progressed rapidly and the patient succumbed due to multiple metastases and organ failure. This case report indicates a possible correlation between irradiation and the development of pituitary cancer.

Scaling of theory-of-mind tasks.

PubMed

Wellman, Henry M; Liu, David

2004-01-01

Two studies address the sequence of understandings evident in preschoolers' developing theory of mind. The first, preliminary study provides a meta-analysis of research comparing different types of mental state understandings (e.g., desires vs. beliefs, ignorance vs. false belief). The second, primary study tests a theory-of-mind scale for preschoolers. In this study 75 children (aged 2 years, 11 months to 6 years, 6 months) were tested on 7 tasks tapping different aspects of understanding persons' mental states. Responses formed a consistent developmental progression, where for most children if they passed a later item they passed all earlier items as well, as confirmed by Guttman and Rasch measurement model analyses.

Vitamin E-coated polysulfone membrane improved red blood cell antioxidant status in hemodialysis patients.

PubMed

Bargnoux, Anne-Sophie; Cristol, Jean-Paul; Jaussent, Isabelle; Chalabi, Lotfi; Bories, Pierre; Dion, Jean-Jacques; Henri, Patrick; Delage, Martine; Dupuy, Anne-Marie; Badiou, Stéphanie; Canaud, Bernard; Morena, Marion

2013-01-01

Oxidative stress has emerged as a strong pathogenic cofactor implicated in the development of long-term complications in hemodialysis (HD) patients, such as anemia, and as a major component of the malnutrition inflammation complex syndrome. This prospective multicenter study aimed at evaluating the short-term effects of the new vitamin E (vitE)-coated polysulfone (PS) membrane (VitabranE) on biocompatibility performances and anemia in HD patients. After a 3-month washout period with a high-flux synthetic dialyzer, 43 HD patients were switched to a vitE-PS dialyzer. Sampling was performed at baseline (corresponding to the end of the washout period) and after 1, 2 and 3 months of treatment. Oxidative stress status, as well as inflammatory parameters, was investigated at the end of each study period. Hemoglobin levels and administered doses of recombinant human erythropoietin or epoetin (EPO) were available in each center. The use of vitE-coated membranes for 3 months was not associated with any change in inflammatory parameters. By contrast, vitE-PS dialyzer resulted in a progressive increase in red blood cell (RBC) vitE concentration and in RBC superoxide dismutase activity. A concomitant progressive significant decrease in advanced oxidation protein product concentration at 2 months was observed, suggesting a preventive effect on oxidative stress. Finally, a significant decrease of the erythropoietin resistance index was obtained after 3 months of treatment. Use of the vitE-PS membrane during a short period improves erythrocyte antioxidant defense mechanisms and seems to lead to a reduction in EPO requirements in HD patients.

Cyclic neutropenia with a novel gene mutation presenting with a necrotizing soft tissue infection and severe sepsis: case report.

PubMed

Boo, Yoon Jung; Nam, Myung Hyun; Lee, Eun Hee; Lee, Kuang Chul

2015-04-02

Cyclic neutropenia is a rare disease. We report a 31-month-old girl with congenital cyclic neutropenia with a novel mutation in the ELANE gene who developed an acute necrotizing soft-tissue infection on her left axillary legion. A 31-month-old girl was admitted to our pediatric emergency room because of a necrotizing soft tissue infection of the left axillary area. The infection progressed rapidly and resulted in septic shock. Despite a medical treatment and surgical debridement, the sepsis was not controlled, and severe inflammation developed. After applying of negative-pressure wound therapy, her clinical symptoms improved. Finally, she was diagnosed with cyclic neutropenia with a novel genetic mutation. One month after admission, she was discharged with a completely recovered wound and no need for skin grafting. Both adequate medical treatment and effective control of the source of infection are critically important to reduce morbidity in such complex cases of necrotizing fasciitis as appeared in an immunocompromised pediatric patient.

Vemurafenib beyond progression in a patient with metastatic melanoma: a case report.

PubMed

Grimaldi, Antonio M; Simeone, Ester; Palla, Marco; Festino, Lucia; Caracò, Corrado; Mozzillo, Nicola; Petrillo, Antonella; Muto, Paolo; Ascierto, Paolo A

2015-04-01

The prognosis of metastatic melanoma has changed markedly in recent years because of the advent of newer targeted therapies such as BRAF inhibitors. However, the response to BRAF inhibitor therapy is frequently nondurable in patients with advanced melanoma. Novel approaches are thus needed to overcome resistance to these agents and to improve the management of advanced melanoma patients after disease progression. Here, we present the case of a 44-year-old man diagnosed with advanced melanoma in July 2010, harboring a BRAF mutation. Melanoma progressed during first-line chemotherapy with dacarbazine, but showed significant benefit after the initiation of vemurafenib on August 2011. Six months later, the patient experienced disease progression in left-obturator lymphadenopathy; still, anti-BRAF treatment was continued together with stereotactic radiotherapy, and was interrupted only shortly for intestinal occlusion secondary to melanoma metastasis of the bowel. When his conditions were stable, after 1 month of vemurafenib treatment discontinuation, anti-BRAF therapy was reinitiated, with a positive outcome. Vemurafenib treatment was definitively discontinued for disease progression in the brain, peritoneum, lymph node, intestine, and skin in March 2013, after about 20 months from initiation, and the patient died a few weeks later. The clinical case presented here shows that treatment beyond progression with vemurafenib can yield a survival benefit in melanoma patients whose disease progresses in a few sites, which can be treated with locoregional therapies. This clinical strategy needs further validation in prospective clinical trials.

Liver recurrence in endometrial cancer: a multi-institutional analysis of factors predictive of postrecurrence survival.

PubMed

Toptas, Tayfun; Karalok, Alper; Ureyen, Isin; Tasci, Tolga; Erol, Onur; Bozkurt, Selen; Tulunay, Gokhan; Simsek, Tayup; Turan, Taner

2016-10-01

Predictive factors for survival following liver metastasis in endometrial cancer (EC) have not been studied to date. It is expected that patients who initially presented with liver metastasis or developed liver metastasis as the subsequent metastatic site of progressive disease are likely to have poor outcomes. However, patients developing liver metastasis as the first site of recurrence may have a chance of benefiting from the salvage therapies. Therefore, we aimed to determine factors influencing postrecurrence survival in EC patients who developed liver metastasis as the first site of recurrence. Patients with EC who underwent primary surgery at three centers between 1993 and 2013 were reviewed. Liver recurrence was defined as documentation of parenchymal liver metastasis either by radiologically or biopsy, after a disease-free interval of ≥3 months. Patients with liver metastasis at presentation, or liver metastasis as the subsequent metastatic site of progressive disease were excluded. Forty-six patients were identified. Median time to liver recurrence was 12 months, with 91.3 % of recurrences detected within 3 years. Most patients (73.9 %) had liver recurrence concomitant with extra-hepatic disease. Median survival after the diagnosis of liver recurrence was 9 months. While in univariate analysis, time to liver recurrence (p < 0.001) and presence of concomitant extra-hepatic metastasis (p = 0.048) were potential predictors of survival, multivariate analysis revealed that time to liver recurrence (p < 0.001) was the only independent predictor. This criterion may be used as a marker for stratifying patients into different prognostic risk groups and for selection of patients for salvage therapies.

Assessment of tumor response to chemoradiotherapy and predicting prognosis in patients with head and neck squamous cell carcinoma by PERCIST.

PubMed

Katsuura, Takayuki; Kitajima, Kazuhiro; Fujiwara, Masayuki; Terada, Tomonori; Uwa, Nobuhiro; Noguchi, Kazuma; Doi, Hiroshi; Tamaki, Yukihisa; Yoshida, Rika; Tsuchitani, Tatsuya; Fujita, Masahiro; Yamakado, Koichiro

2018-06-01

To evaluate therapeutic response to chemoradiotherapy and prediction of recurrence and death in patients with head and neck squamous cell carcinoma (HNSCC) using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Forty-two patients (mean 63.4, range 20-79 years) with nasopharyngeal (n = 10), oropharyngeal (n = 13), hypopharyngeal (n = 11), or laryngeal (n = 8) cancer underwent fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) before and approximately 3 months (mean 95.0, range 70-119 days) after undergoing concurrent chemoradiotherapy. The effect of PERCIST regarding progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods. Complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease shown by PERCIST were seen in 30 (71.4%), 9 (21.4%), 3 (7.1%), and 0 patients, respectively. Fourteen (33.3%) developed recurrent disease (median follow-up 27.2, range 8.7-123.1 months) and 9 (21.4%) died (median follow-up 43.6, range 9.6-132.6 months). Furthermore, 4 (13.3%) of 30 patients with CMR developed recurrence, while 7 (77.8%) of 9 with PMR and all 3 (100%) with SMD developed recurrence. Two (6.7%) of 30 patients with CMR, 4 (44.4%) of 9 with PMR, and all 3 (100%) with SMD died. Patients who achieved CMR showed significantly longer PFS and OS as compared to those who did not (PMR and SMD) (both, p < 0.0001). PERCIST is useful for evaluating therapeutic response to chemoradiotherapy and predicting recurrence and death in HNSCC patients.

Meniscal Extrusion Progresses Shortly after the Medial Meniscus Posterior Root Tear.

PubMed

Furumatsu, Takayuki; Kodama, Yuya; Kamatsuki, Yusuke; Hino, Tomohito; Okazaki, Yoshiki; Ozaki, Toshifumi

2017-12-01

Medial meniscus posterior root tears (MMPRT) induce medial meniscus extrusion (MME). However, the time-dependent extent of MME in patients suffering from the MMPRT remains unclear. This study evaluated the extent of MME after painful popping events that occurred at the onset of the MMPRT. Thirty-five patients who had an episode of posteromedial painful popping were investigated. All the patients were diagnosed as having an MMPRT by magnetic resonance imaging (MRI) within 12 months after painful popping. Medial meniscus body width (MMBW), absolute MME, and relative MME (100×absolute MME/MMBW) were assessed among three groups divided according to the time after painful popping events: early period (〈1 month), subacute period (1-3 months), and chronic period (4-12 months). In the early period, absolute and relative MMEs were 3.0 mm and 32.7%, respectively. Absolute MME increased up to 4.2 mm and 5.8 mm during the subacute and chronic periods, respectively. Relative MME also progressed to 49.2% and 60.3% in the subacute and chronic periods, respectively. This study demonstrated that absolute and relative MMEs increased progressively within the short period after the onset of symptomatic MMPRT. Our results suggest that early diagnosis of an MMPRT may be important to prevent progression of MME following the MMPRT.

The Complex Interaction between Home Environment, Socioeconomic Status, Maternal IQ and Early Child Neurocognitive Development: A Multivariate Analysis of Data Collected in a Newborn Cohort Study.

PubMed

Ronfani, Luca; Vecchi Brumatti, Liza; Mariuz, Marika; Tognin, Veronica; Bin, Maura; Ferluga, Valentina; Knowles, Alessandra; Montico, Marcella; Barbone, Fabio

2015-01-01

The relative role of socioeconomic status (SES), home environment and maternal intelligence, as factors affecting child cognitive development in early childhood is still unclear. The aim of this study is to analyze the association of SES, home environment and maternal IQ with child neurodevelopment at 18 months. The data were collected prospectively in the PHIME study, a newborn cohort study carried out in Italy between 2007 and 2010. Maternal nonverbal abilities (IQ) were evaluated using the Standard Progressive Matrices, a version of the Raven's Progressive Matrices; a direct evaluation of the home environment was carried out with the AIRE instrument, designed using the HOME (Home Observation for Measurement of the Environment) model; the socioeconomic characteristics were evaluated using the SES index which takes into account parents occupation, type of employment, educational level, homeownership. The study outcome was child neurodevelopment evaluated at 18 months, with the Bayley Scales of Infant and Toddler Development Third Edition (BSID III). Linear regression analyses and mediation analyses were carried out to evaluate the association between the three exposures, and the scaled scores of the three main scales of BSID III (cognitive, language and motor scale), with adjustment for a wide range of potential explanatory variables. Data from 502 mother-child pairs were analyzed. Mediation analysis showed a relationship between SES and maternal IQ, with a complete mediation effect of home environment in affecting cognitive and language domains. A direct significant effect of maternal IQ on the BSID III motor development scale and the mediation effect of home environment were found. Our results show that home environment was the variable with greater influence on neurodevelopment at 18 months. The observation of how parents and children interact in the home context is crucial to adequately evaluate early child development.

7-year follow-up after stereotactic ablative radiotherapy for patients with stage I non-small cell lung cancer: Results of a phase 2 clinical trial.

PubMed

Sun, Bing; Brooks, Eric D; Komaki, Ritsuko U; Liao, Zhongxing; Jeter, Melenda D; McAleer, Mary F; Allen, Pamela K; Balter, Peter A; Welsh, James D; O'Reilly, Michael S; Gomez, Daniel; Hahn, Stephen M; Roth, Jack A; Mehran, Reza J; Heymach, John V; Chang, Joe Y

2017-08-15

The authors evaluated the efficacy, patterns of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for patients with medically inoperable, clinical stage I non-small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years of follow-up. Clinical staging was performed according to the seventh edition of the American Joint Committee on Cancer TNM staging system. Eligible patients with histologically confirmed NSCLC of clinical stage I as determined using positron emission tomography staging were treated with SABR (50 grays in 4 fractions). The primary endpoint was progression-free survival. Patients were followed with computed tomography and/or positron emission tomography/computed tomography every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually thereafter. A total of 65 patients were eligible for analysis. The median age of the patients was 71 years, and the median follow-up was 7.2 years. A total of 18 patients (27.7%) developed disease recurrence at a median of 14.5 months (range, 4.3-71.5 months) after SABR. Estimated incidences of local, regional, and distant disease recurrence using competing risk analysis were 8.1%, 10.9%, and 11.0%, respectively, at 5 years and 8.1%, 13.6%, and 13.8%, respectively, at 7 years. A second primary lung carcinoma developed in 12 patients (18.5%) at a median of 35 months (range, 5-67 months) after SABR. Estimated 5-year and 7-year progression-free survival rates were 49.5% and 38.2%, respectively; the corresponding overall survival rates were 55.7% and 47.5%, respectively. Three patients (4.6%) experienced grade 3 treatment-related adverse events. No patients developed grade 4 or 5 adverse events (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). With long-term follow-up, the results of the current prospective study demonstrated outstanding local control and low toxicity after SABR in patients with clinical stage I NSCLC. Regional disease recurrence and distant metastases were the dominant manifestations of failure. Surveillance for second primary lung carcinoma is recommended. Cancer 2017;123:3031-39. © 2017 American Cancer Society. © 2017 American Cancer Society.

Swollen joint count in psoriatic arthritis is associated with progressive radiological damage in hands and feet.

PubMed

Simon, P; Pfoehler, C; Bergner, R; Schreiber, M; Pfreundschuh, M; Assmann, G

2012-01-01

Psoriatic arthritis (PsA) may progress to joint damage. Determining clinical predictors of joint damage assessed by radiography is important. The aim of this study was to determine clinical factors as possible predictors for radiological damage in hands and feet of PsA patients with a 12-month follow-up. We conducted a retrospective study on 53 PsA patients who were taking disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF)-alpha-blockers at a fixed dosage. The patients were observed in 118 follow-up visits (intervals of 12 months ± 3 months), according to a clinical and radiological protocol which included the documentation of the number of swollen and tender joints in hands and feet, the applied therapy, psoriasis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and global health assessment. Outcome was defined as radiographic damage of hands and feet (Ratingen score). For the statistical analysis the Chi-Square test for 2x2 crosstables (with Fisher's correction, as required) was used. Progressive radiological damage was more frequent among patients with an increasing swollen joint count (8 of 26 visits; 30.8%) than among those with a stable or decreased number of swollen joints (5 of 89 visits; 5.6%; p=0.001). The analysis of the patients stratified into the different treatment modalities resulted in a significant higher rate of radiological progress (20.8%) in patients on DMARD therapy compared with TNF-alpha blocking agents (0%) (p=0.009). During a 12-month follow-up of PsA patients, an increasing number of swollen joints heralds progression of radiological damage. TNF-alpha-blocker therapy appears to be superior to DMARDs in the protection from radiological progress.

Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.

PubMed

Dudnik, Elizabeth; Siegal, Tali; Zach, Leor; Allen, Aaron M; Flex, Dov; Yust-Katz, Shlomit; Limon, Dror; Hirsch, Fred R; Peled, Nir

2016-04-01

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred. Copyright © 2015 Elsevier Ltd. All rights reserved.

Histological Development of Male Reproductive Organs in Microminipigs.

PubMed

Kangawa, Akihisa; Otake, Masayoshi; Enya, Satoko; Yoshida, Toshinori; Shibata, Masatoshi

2016-12-01

Microminipigs are becoming increasingly attractive alternatives for various experimental applications, such as general toxicology studies, owing to their manageable size. However, there are limited studies on the male reproductive organs of microminipigs, particularly on the histological aspects of sexual maturity. To clarify the development of male reproductive organs, 35 male microminipigs, aged 0 to 12 months, were used in this study. Histological and histomorphological evaluation was performed based on spermatogenic development, measurement of tubular structure in testes and epididymides, and histological progress of accessory glands. In addition, spontaneous testicular changes were quantitatively assessed. Histologically, male microminipigs sexually matured around 4.5 months of age, when spermatogenesis in testes and structural development in genital organs were completed. Spontaneous testicular changes occurred in all the animals investigated. Multinucleated giant cell was most commonly observed, followed by hypospermatogenesis and tubular atrophy/hypoplasia. However, the number of affected tubules was less than 1% in testes after 4.5 months of age, suggesting that the influence of these changes on evaluation of toxicity studies may be minimal. It is preferable to use sexually mature animals in toxicology studies; therefore, the information obtained by the present study will be helpful for future toxicity evaluations in microminipigs.

The role of knee alignment in disease progression and functional decline in knee osteoarthritis.

PubMed

Sharma, L; Song, J; Felson, D T; Cahue, S; Shamiyeh, E; Dunlop, D D

2001-07-11

Knee osteoarthritis (OA) is a leading cause of disability in older persons. Few risk factors for disease progression or functional decline have been identified. Hip-knee-ankle alignment influences load distribution at the knee; varus and valgus alignment increase medial and lateral load, respectively. To test the hypotheses that (1) varus alignment increases risk of medial knee OA progression during the subsequent 18 months, (2) valgus alignment increases risk of subsequent lateral knee OA progression, (3) greater severity of malalignment is associated with greater subsequent loss of joint space, and (4) greater burden of malalignment is associated with greater subsequent decline in physical function. Prospective longitudinal cohort study conducted March 1997 to March 2000 at an academic medical center in Chicago, Ill. A total of 237 persons recruited from the community with primary knee OA, defined by presence of definite tibiofemoral osteophytes and at least some difficulty with knee-requiring activity; 230 (97%) completed the study. Progression of OA, defined as a 1-grade increase in severity of joint space narrowing on semiflexed, fluoroscopically confirmed knee radiographs; change in narrowest joint space width; and change in physical function between baseline and 18 months, compared by knee alignment at baseline. Varus alignment at baseline was associated with a 4-fold increase in the odds of medial progression, adjusting for age, sex, and body mass index (adjusted odds ratio [OR], 4.09; 95% confidence interval [CI], 2.20-7.62). Valgus alignment at baseline was associated with a nearly 5-fold increase in the odds of lateral progression (adjusted OR, 4.89; 95% CI, 2.13-11.20). Severity of varus correlated with greater medial joint space loss during the subsequent 18 months (R = 0.52; 95% CI, 0.40-0.62 in dominant knees), and severity of valgus correlated with greater subsequent lateral joint space loss (R = 0.35; 95% CI, 0.21-0.47 in dominant knees). Having alignment of more than 5 degrees (in either direction) in both knees at baseline was associated with significantly greater functional deterioration during the 18 months than having alignment of 5 degrees or less in both knees, after adjusting for age, sex, body mass index, and pain. This is, to our knowledge, the first demonstration that in primary knee OA varus alignment increases risk of medial OA progression, that valgus alignment increases risk of lateral OA progression, that burden of malalignment predicts decline in physical function, and that these effects can be detected after as little as 18 months of observation.

Frequency of Evidence-Based Screening for Retinopathy in Type 1 Diabetes.

PubMed

Nathan, David M; Bebu, Ionut; Hainsworth, Dean; Klein, Ronald; Tamborlane, William; Lorenzi, Gayle; Gubitosi-Klug, Rose; Lachin, John M

2017-04-20

In patients who have had type 1 diabetes for 5 years, current recommendations regarding screening for diabetic retinopathy include annual dilated retinal examinations to detect proliferative retinopathy or clinically significant macular edema, both of which require timely intervention to preserve vision. During 30 years of the Diabetes Control and Complications Trial (DCCT) and its longitudinal follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, retinal photography was performed at intervals of 6 months to 4 years. We used retinal photographs from the DCCT/EDIC study to develop a rational screening frequency for retinopathy. Markov modeling was used to determine the likelihood of progression to proliferative diabetic retinopathy or clinically significant macular edema in patients with various initial retinopathy levels (no retinopathy or mild, moderate, or severe nonproliferative diabetic retinopathy). The models included recognized risk factors for progression of retinopathy. Overall, the probability of progression to proliferative diabetic retinopathy or clinically significant macular edema was limited to approximately 5% between retinal screening examinations at 4 years among patients who had no retinopathy, 3 years among those with mild retinopathy, 6 months among those with moderate retinopathy, and 3 months among those with severe nonproliferative diabetic retinopathy. The risk of progression was also closely related to mean glycated hemoglobin levels. The risk of progression from no retinopathy to proliferative diabetic retinopathy or clinically significant macular edema was 1.0% over 5 years among patients with a glycated hemoglobin level of 6%, as compared with 4.3% over 3 years among patients with a glycated hemoglobin level of 10%. Over a 20-year period, the frequency of eye examinations was 58% lower with our practical, evidence-based schedule than with routine annual examinations, which resulted in substantial cost savings. Our model for establishing an individualized schedule for retinopathy screening on the basis of the patient's current state of retinopathy and glycated hemoglobin level reduced the frequency of eye examinations without delaying the diagnosis of clinically significant disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815 .).

Complete surgical resection combined with aggressive adjuvant chemotherapy and bone marrow transplantation prolongs survival in children with advanced neuroblastoma.

PubMed

Chamberlain, R S; Quinones, R; Dinndorf, P; Movassaghi, N; Goodstein, M; Newman, K

1995-03-01

A multi-modality approach combining surgery with aggressive chemotherapy and radiation is used to treat advanced neuroblastoma. Despite this treatment, children with advanced disease have a 20% 2-year survival rate. Controversy has developed regarding the efficacy of combining aggressive chemotherapy with repeated surgical intervention aimed at providing a complete surgical resection (CSR) of the primary tumor and metastatic sites. Several prospective and retrospective studies have provided conflicting reports regarding the benefit of this approach on overall survival. Therefore, we evaluated the efficacy of CSR versus partial surgical resection (PSR) using a strategy combining surgery with aggressive chemotherapy, radiation, and bone marrow transplantation (BMT) for stage IV neuroblastoma. A retrospective study was performed with review of the medical records of 52 consecutive children with neuroblastoma treated between 1985 and 1993. Twenty-eight of these 52 children presented with advanced disease, 24 of which had sufficient data to allow for analysis. All children were managed with protocols designed by the Children's Cancer Group (CCG). Statistical analysis was performed using Student's t test, chi 2 test, and Kaplan-Meier survival curves. Mean survival (35.1 months) and progression-free survival (29.1 months) for the CSR children was statistically superior to that of the PSR children (20.36 and 16.5 months, p = 0.04 and 0.04, respectively). Similar significance was demonstrated using life table analysis of mean and progression-free survival of these two groups (p = 0.05 and < 0.01, respectively). One-, 2-, and 3-year survival rates for the CSR versus the PSR group were 100%, 80%, and 40% versus 77%, 38%, and 15%, respectively. An analysis of the BMT group compared with those children treated with aggressive conventional therapy showed improvement in mean and progression-free survival. Aggressive surgical resection aimed at removing all gross disease is warranted for stage IV neuroblastoma. CSR is associated with prolonged mean and progression-free survival. BMT prolongs mean and progression-free survival in children with stage IV disease. These results suggest that CSR and BMT offer increased potential for long-term remission in children with advanced neuroblastoma.

Early versus late Gamma Knife radiosurgery following transsphenoidal surgery for nonfunctioning pituitary macroadenomas: a multicenter matched-cohort study.

PubMed

Pomeraniec, I Jonathan; Kano, Hideyuki; Xu, Zhiyuan; Nguyen, Brandon; Siddiqui, Zaid A; Silva, Danilo; Sharma, Mayur; Radwan, Hesham; Cohen, Jonathan A; Dallapiazza, Robert F; Iorio-Morin, Christian; Wolf, Amparo; Jane, John A; Grills, Inga S; Mathieu, David; Kondziolka, Douglas; Lee, Cheng-Chia; Wu, Chih-Chun; Cifarelli, Christopher P; Chytka, Tomas; Barnett, Gene H; Lunsford, L Dade; Sheehan, Jason P

2017-10-27

OBJECTIVE Gamma Knife radiosurgery (GKRS) is frequently used to treat residual or recurrent nonfunctioning pituitary macroadenomas. There is no consensus as to whether GKRS should be used early after surgery or if radiosurgery should be withheld until there is evidence of imaging-defined progression of tumor. Given the high incidence of adenoma progression after subtotal resection over time, the present study intended to evaluate the effect of timing of radiosurgery on outcome. METHODS This is a multicenter retrospective review of patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery followed by GKRS from 1987 to 2015 at 9 institutions affiliated with the International Gamma Knife Research Foundation. Patients were matched by adenoma and radiosurgical parameters and stratified based on the interval between last resection and radiosurgery. Operative results, imaging data, and clinical outcomes were compared across groups following early (≤ 6 months after resection) or late (> 6 months after resection) radiosurgery. RESULTS After matching, 222 patients met the authors' study criteria (from an initial collection of 496 patients) and were grouped based on early (n = 111) or late (n = 111) GKRS following transsphenoidal surgery. There was a greater risk of tumor progression after GKRS (p = 0.013) and residual tumor (p = 0.038) in the late radiosurgical group over a median imaging follow-up period of 68.5 months. No significant difference in the occurrence of post-GKRS endocrinopathy was observed (p = 0.68). Thirty percent of patients without endocrinopathy in the early cohort developed new endocrinopathies during the follow-up period versus 27% in the late cohort (p = 0.84). Fourteen percent of the patients in the early group and 25% of the patients in the late group experienced the resolution of endocrine dysfunction after original presentation (p = 0.32). CONCLUSIONS In this study, early GKRS was associated with a lower risk of radiological progression of subtotally resected nonfunctioning pituitary macroadenomas compared with expectant management followed by late radiosurgery. Delaying radiosurgery may increase patient risk for long-term adenoma progression. The timing of radiosurgery does not appear to significantly affect the rate of delayed endocrinopathy.

Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training: abrupt transition to exercise-induced amenorrhea.

PubMed

Williams, N I; Caston-Balderrama, A L; Helmreich, D L; Parfitt, D B; Nosbisch, C; Cameron, J L

2001-06-01

Cross-sectional studies of exercise-induced reproductive dysfunction have documented a high proportion of menstrual cycle disturbances in women involved in strenuous exercise training. However, longitudinal studies have been needed to examine individual susceptibility to exercise-induced reproductive dysfunction and to elucidate the progression of changes in reproductive function that occur with strenuous exercise training. Using the female cynomolgus monkey (Macaca fascicularis), we documented changes in menstrual cyclicity and patterns of LH, FSH, estradiol, and progesterone secretion as the animals developed exercise-induced amenorrhea. As monkeys gradually increased running to 12.3 +/- 0.9 km/day, body weight did not change significantly although food intake remained constant. The time spent training until amenorrhea developed varied widely among animals (7-24 months; mean = 14.3 +/- 2.2 months) and was not correlated with initial body weight, training distance, or food intake. Consistent changes in function of the reproductive axis occurred abruptly, one to two menstrual cycles before the development of amenorrhea. These included significant declines in plasma reproductive hormone concentrations, an increase in follicular phase length, and a decrease in luteal phase progesterone secretion. These data document a high level of interindividual variability in the development of exercise-induced reproductive dysfunction, delineate the progression of changes in reproductive hormone secretion that occur with exercise training, and illustrate an abrupt transition from normal cyclicity to an amenorrheic state in exercising individuals, that is not necessarily associated with weight loss.

An assessment of early mandibular growth.

PubMed

Hutchinson, E F; L'Abbé, E N; Oettlé, A C

2012-04-10

Quantification of skeletal data has been shown to be an effective and reliable method of demonstrating variation in human growth as well as for monitoring and interpreting growth. In South Africa as well as internationally, few researchers have assessed mandibular growth in late fetal period and early childhood and therefore standards for growth and age determination in these groups are limited. The purpose of this study was to evaluate growth in the mandible from the period of 31 gestational weeks to 36 months postnatal. A total of 74 mandibles were used. Dried mandibles were sourced from the Raymond A. Dart Collection (University of Witwatersrand), and cadaveric remains were obtained from the Universities of Pretoria and the Witwatersrand. The sample was divided into four groups; 31-40 gestational weeks (group 1), 0-11 months (group 2), 12-24 months (group 3), and 25-36 months (group 4). Twenty-one osteological landmarks were digitized using a MicroScribe G2. Ten standard measurements were created and included: the maximum length of mandible, mandibular body length and width, mandibular notch width and depth, mental foramen to inferior border of mandible, mandibular basilar widths bigonial and biantegonial, bigonial width of mental foramen and mental angle. Data were analyzed using PAST statistical software and Morphologika2 v2.5. Statistically significant differences were noted in the linear measurements for all group comparisons except between groups 3 and 4. The mandible morphologically changed from a round, smooth contour anteriorly to adopt a more sharp and narrow adult shape. A progressive increase in the depth and definition of the mandibular arch was also noted. In conclusion, the mandible initially grows to accommodate the developing tongue (up to 11 months), progressive dental eruption and mastication from 12 to 36 months. Mastication is associated with muscle mass development; this would necessitate an increase in the dimensions of the mandibular notch and associated muscle attachment sites. These findings might be valuable in the estimation of age in unidentified individuals and to monitor prenatal growth of the mandible for the early diagnosis of conditions associated with stunted mandibular growth. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A group randomized controlled trial integrating obesity prevention and control for postpartum adolescents in a home visiting program.

PubMed

Haire-Joshu, Debra L; Schwarz, Cynthia D; Peskoe, Sarah B; Budd, Elizabeth L; Brownson, Ross C; Joshu, Corinne E

2015-06-26

Adolescence represents a critical period for the development of overweight that tracks into adulthood. This risk is significantly heightened for adolescents that become pregnant, many of whom experience postpartum weight retention. The aim of this study was to evaluate Balance Adolescent Lifestyle Activities and Nutrition Choices for Energy (BALANCE), a multicomponent obesity prevention intervention targeting postpartum adolescents participating in a national home visiting child development-parent education program. A group randomized, nested cohort design was used with 1325 adolescents, 694 intervention and 490 control, (mean age = 17.8 years, 52 % underrepresented minorities) located across 30 states. Participatory methods were used to integrate lifestyle behavior change strategies within standard parent education practice. Content targeted replacement of high-risk obesogenic patterns (e.g. sweetened drink and high fat snack consumption, sedentary activity) with positive behaviors (e.g. water intake, fruit and vegetables, increased walking). Parent educators delivered BALANCE through home visits, school based classroom-group meetings, and website activities. Control adolescents received standard child development information. Phase I included baseline to posttest (12 months); Phase II included baseline to follow-up (24 months). When compared to the control group, BALANCE adolescents who were ≥12 weeks postpartum were 89 % more likely (p = 0.02) to maintain a normal BMI or improve an overweight/obese BMI by 12 months; this change was not sustained at 24 months. When compared to the control group, BALANCE adolescents significantly improved fruit and vegetable intake (p = .03). In stratified analyses, water intake improved among younger BALANCE teens (p = .001) and overweight/obese BALANCE teens (p = .05) when compared to control counterparts. There were no significant differences between groups in sweetened drink and snack consumption or walking. Prevention of postpartum weight retention yields immediate health benefits for the adolescent mother and may prevent the early development or progression of maternal obesity, which contributes to the intergenerational transmission of obesity to her offspring. Implementing BALANCE through a national home visiting organization may hold promise for promoting positive lifestyle behaviors associated with interruption of the progression of maternal obesity. Clinical Trials Registry NCT01617486 .

Successful treatment of Dandy-Walker syndrome by endoscopic third ventriculostomy in a 6-month-old girl with progressive hydrocephalus: a case report and literature review.

PubMed

Hu, Chih-Fen; Fan, Hueng-Chuen; Chang, Cheng-Fu; Wang, Chih-Chien; Chen, Shyi-Jou

2011-02-01

Dandy-Walker syndrome (DWS) is a congenital brain malformation involving the cerebellum and fourth ventricle. We report a 6-month-old girl with DWS presenting an initially normal ventricular system and mild cyst-like lesion over the posterior fossa as assessed by postnatal brain sonography. However, symptoms and signs of increased intracranial cerebral pressure in terms of frequent vomiting and tense anterior fontanel developed, and these were associated with mild hypotonia and poor neck support, and upward-gaze palsy at the age of 6 months. Magnetic resonance imaging revealed a huge cystic lesion of the fourth ventricle, which filled the posterior fossa and ventricular dilatation. The tentorium was progressively displaced upward by the cyst. A nearly complete agenesis of the cerebellar vermis was also confirmed. After a successful endoscopic third ventriculostomy, a series of brain magnetic resonance imaging scans, taken during a follow-up survey, showed normal lateral and third ventricles. Consequently, symptoms of intracranial cerebral pressure resolved, and a developmental milestone was achieved. In conclusion, DWS can be confirmed postpartum, and endoscopic third ventriculostomy was found to be a preferential operative procedure for DWS with hydrocephalus. It may be effective for patients younger than 1 year. Copyright © 2011. Published by Elsevier B.V.

Functional Deficits Precede Structural Lesions in Mice With High-Fat Diet–Induced Diabetic Retinopathy

PubMed Central

Rajagopal, Rithwick; Bligard, Gregory W.; Zhang, Sheng; Yin, Li; Lukasiewicz, Peter

2016-01-01

Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet–induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat–fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat–fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat–fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease. PMID:26740595

Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

PubMed

Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

2013-02-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

PubMed Central

Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

2013-01-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma

PubMed Central

Iwamoto, F M.; Abrey, L E.; Beal, K; Gutin, P H.; Rosenblum, M K.; Reuter, V E.; DeAngelis, L M.; Lassman, A B.

2009-01-01

Background: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically. Methods: We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease. Results: There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%. Conclusions: Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control. GLOSSARY CA9 = carbonic anhydrase 9; CI = confidence interval; FDG = [18F]fluorodeoxyglucose; FLAIR = fluid-attenuation inversion recovery; GBM = glioblastoma; HIF-1 α = hypoxia-inducible factor 1α; KPS = Karnofsky performance status; MR = magnetic resonance; OS = overall survival; PFS = progression-free survival; TMZ = temozolomide; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor. PMID:19822869

The effect of progressive hearing loss on the morphology of endbulbs of Held and bushy cells.

PubMed

Connelly, Catherine J; Ryugo, David K; Muniak, Michael A

2017-01-01

Studies of congenital and early-onset deafness have demonstrated that an absence of peripheral sound-evoked activity in the auditory nerve causes pathological changes in central auditory structures. The aim of this study was to establish whether progressive acquired hearing loss could lead to similar brain changes that would degrade the precision of signal transmission. We used complementary physiologic hearing tests and microscopic techniques to study the combined effect of both magnitude and duration of hearing loss on one of the first auditory synapses in the brain, the endbulb of Held (EB), along with its bushy cell (BC) target in the anteroventral cochlear nucleus. We compared two hearing mouse strains (CBA/Ca and heterozygous shaker-2 +/- ) against a model of early-onset progressive hearing loss (DBA/2) and a model of congenital deafness (homozygous shaker-2 -/- ), examining each strain at 1, 3, and 6 months of age. Furthermore, we employed a frequency model of the mouse cochlear nucleus to constrain our analyses to regions most likely to exhibit graded changes in hearing function with time. No significant differences in the gross morphology of EB or BC structure were observed in 1-month-old animals, indicating uninterrupted development. However, in animals with hearing loss, both EBs and BCs exhibited a graded reduction in size that paralleled the hearing loss, with the most severe pathology seen in deaf 6-month-old shaker-2 -/- mice. Ultrastructural pathologies associated with hearing loss were less dramatic: minor changes were observed in terminal size but mitochondrial fraction and postsynaptic densities remained relatively stable. These results indicate that acquired progressive hearing loss can have consequences on auditory brain structure, with prolonged loss leading to greater pathologies. Our findings suggest a role for early intervention with assistive devices in order to mitigate long-term pathology and loss of function. Copyright © 2016 Elsevier B.V. All rights reserved.

Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV 16/18) prophylactic HPV vaccines.

PubMed

Syrjänen, K

2011-01-01

Recent data indicate that persistent HR-HPV infections represent a significantly increased risk of developing incident high-grade CIN and cervical cancer. Accordingly, 6-month (6M+) or 12-month (12M+) type-specific persistence of HR-HPV have been proposed as powerful surrogates of progressive disease. Because of substantial practical impact in future HPV vaccine trials using non-HPV 16/18 vaccines, studies on HR-HPV persistence as a surrogate endpoint of progressive CIN have been subject to a comprehensive meta-analyses recently. The present communication was solicited to bring this important and timely topic to the awareness of the readers, in a format consisting of a review of the recent literature, supplemented with the author's own experience from different studies. Based on a large number of relevant studies, there remains little doubt that persistence of HR-HPV for 6+ or 12+ months is associated with a significantly increased risk of developing incident high-grade CIN. However, some data also disclosed several important issues that need to be carefully considered and/or adequately resolved before adopting 6M+ or 12M+ HR-HPV persistence as a surrogate of progressive disease. These include i) definitions of HPV persistence, ii) HPV detection techniques and iii) testing intervals and iv) length of follow-up, as well as v) diagnosis of the surrogate endpoints, and vi) other study characteristics, including vii) the type of reference category used in calculating the risk estimates. All these issues are critically discussed in the present communication. Of major impact seems to be the reference category used to calculate these risk estimates, as evident from the NIS-LAMS cohort. Taken together, it is suggested that in all future studies using the 6M+ or 12M+ HR-HPV persistence as a surrogate endpoint of progressive disease, a "gold standard" should be used in calculating the risk estimates. In addition to deciding, 1) whether to use 6M+ or 12M+ persistence criteria, and 2) cytological, histological or combined surrogate endpoints (SIL, CIN1, CIN2, CIN/SIL), one should 3) use exclusively the HPV negative reference group in calculating the risk estimates for viral persistence endpoints. This is supported by the data from the recent meta-analysis as well as from the author's combined NIS-LAMS cohort, both implicating that the most consistent association to progressive disease is obtained when women with persistent HR-HPV are compared with HPV-negative women. It is the conviction of this author that the two other reference categories (HPV transient and HPV mixed outcome) are far too heterogeneous and subject to potential misclassifications to give consistent and reproducible risk estimates for HR-HPV persistence as a surrogate endpoint of progressive CIN.

Disorders of childhood growth and development: precocious puberty.

PubMed

Chauhan, Alia; Grissom, Maureen

2013-07-01

Precocious puberty is defined as pubertal development that begins at an earlier age than expected; most US pediatric endocrinology subspecialists use cutoff ages of 8 years for girls and 9 years for boys. Early activation and maturation of the hypothalamic-pituitary-gonadal axis leads to hormonal changes, physical signs of puberty, and acceleration of linear growth. Factors affecting puberty include race/ethnicity, obesity, and endocrine disruptors. The 2 forms of precocious puberty are central (gonadotropin-dependent precocious puberty) and peripheral (gonadotropin-independent precocious puberty). Most cases of the former have no identifiable etiology, whereas the latter is caused by increased secretion of sex hormones by the gonads or adrenal glands. It is important to differentiate progressive from nonprogressive precocious puberty to avoid unnecessary treatment for the latter; if diagnosis is uncertain, the child should be reassessed within several months. Evaluation begins with a detailed history and physical examination followed by an x-ray for bone age; in precocious puberty, bone age is greater than chronologic age. If indicated, additional serum testing (basal luteinizing hormone) and imaging studies should be obtained. Patients should be referred to a pediatric endocrinology subspecialist for treatment. It is essential to manage underlying etiologies. Gonadotropin-releasing hormone agonists should be considered only for children with progressive central precocious puberty to prevent short stature. For children with apparent nonprogressive precocious puberty, follow-up every 3 to 6 months between ages 6 and 7 years is recommended to assess for progression. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Progressive Susac syndrome with bilateral visual loss and disability.

PubMed

Entezari, Morteza; Karimi, Saeed; Feizi, Mohammadali

2016-09-01

Susac syndrome (SS) is a rare retinal-cochlear-cerebral disease with an unclear etiology. A 35-year-old man presented with sudden painless vision loss in the right eye and 2 months later in the left eye with hemiparesis, behavioral changes, and hearing loss. Ophthalmic examinations revealed multiple branch retinal artery occlusions (BRAOs) in both eyes. Brain magnetic resonance imaging showed inflammatory changes with multiple "punched-out" lesions in the corpus callosum which confirmed the diagnosis of SS. Despite intravenous and oral corticosteroid therapy, the disease progressed with the development of new BRAOs, low vision in both eyes, and disability. Prompt diagnosis and early treatment may save the vision and even patient's life.

ENGAGE: A Game Based Learning and Problem Solving Framework

DTIC Science & Technology

2012-07-13

Gamification Summit 2012  Mensa Colloquium 2012.2: Social and Video Games  Seattle Science Festival  TED Salon Vancouver : http...From - To) 6/1/2012 – 6/30/2012 4. TITLE AND SUBTITLE ENGAGE: A Game Based Learning and Problem Solving Framework 5a. CONTRACT NUMBER N/A 5b...Popović ENGAGE: A Game Based Learning and Problem Solving Framework (Task 1 Month 4) Progress, Status and Management Report Monthly Progress

76 FR 25519 - National Foster Care Month, 2011

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-05

... Foster Care Month, 2011 By the President of the United States A Proclamation Progress in America can be... where they can feel secure and thrive. During National Foster Care Month, we renew our commitment to... possible for children when they cannot remain in their own homes. During National Foster Care Month, we...

NI-60RECURRENT PATTERNS OF BEVACIZUMAB MONOTHERAPY FOR RECURRENT PRIMARY GLIOBLASTOMA AND PERSPECTIVES ON BEVACIZUMAB-BASED THERAPIES

PubMed Central

Nagane, Motoo; Kobayashi, Keiichi; Saito, Kuniaki; Shiokawa, Yoshiaki

2014-01-01

BACKGROUND. Prognosis of patients with recurrent glioblastoma (GBM) remains dismal, their median overall survival (mOS) ranging from 7 to 10 months. Currently, bevacizumab (BEV), a monoclonal antibody against VEGF, has been widely used since it prolonged progression-free survival (PFS) accompanied with symptom relief in BEV trials. However, improvement of OS seems modest at most, and issues regarding short survival after BEV failure, invasive relapse, and difficulty in determining true progression remain unsolved. Here we examined the patterns of radiological BEV failure in relationship with survival of several post-treatment periods. METHODS. Twenty-five patients with primary GBM who were treated with BEV monotherapy at recurrence in Kyorin University hospital since August 2009 were included in this study. Mean age was 53 yo, 13 males/12 females, median KPS was 60 (30-100), and mOS from the initial surgery was 23.2 months. MRI patterns at BEV progression were determined using modified classification by Nowosielsky et al. (Neurology 2014) as follows: 1) T2-diffuse, 2) cT1-flare up, 3) Primary non-responders, 4) T2-circumscribed, and 5) Remote metastasis. RESULTS. mPFS and mOS of BEV monotherapy were 3.4 and 7.6 months, respectively, and post-BEV mOS was 4.7 months. Frequency and BEV-PFS/post-BEV OS were 1) 20%, 3.8/0.8 months; 2) 40%, 3.4/7.1 months, 3) 24%, 0.9/3.3 months, 4) 8%, 3.7/3.9 months, 5) 8%, 2.0/4.2 months. The cT1-flare up recurrent pattern was found most frequently with relatively better survivals, whereas the T2-diffuse recurrence included fatal brain stem invasion in two cases, resulting in poorer prognosis. CONCLUSIONS. BEV monotherapy showed limited survival benefit and the clinical course after BEV failure may differ by patterns of relapse. Although RANO criteria have been a standard method to determine progression, measurement of T2/FLAIR hyperintensity remains critically controversial. Efforts to improve BEV-based therapy for recurrent GBM including longitudinal and combined chemotherapy will be also discussed.

Validation of a preclinical model of diethylnitrosamine-induced hepatic neoplasia in Yucatan miniature pigs

PubMed Central

Mitchell, Jennifer; Tinkey, Peggy T.; Avritscher, Rony; Van Pelt, Carolyn; Eskandari, Ghazaleh; George, Suraj Konnath; Xiao, Lianchun; Cressman, Erik; Morris, Jeffrey S.; Rashid, Asif; Kaseb, Ahmed O.; Amin, Hesham M.; Uthamanthil, Rajesh

2016-01-01

Objective The purpose of this study was to reduce time to tumor onset in a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) swine model via partial liver embolization (PLE) and to characterize the model for use in translational research. Methods Eight Yucatan miniature pigs were injected intraperitoneally with either saline (n=2) or DEN (n=6) solution weekly for 12 weeks. Three of the DEN-treated pigs underwent PLE. Animals underwent periodic radiological evaluation, liver biopsy, and blood sampling, and full necropsy was performed at study termination (~29 months). Results All DEN-treated pigs developed hepatic adenoma and HCC. PLE accelerated the time to adenoma development but not to HCC development. Biomarker analysis results showed that IGF1 levels decreased in all DEN-treated pigs, as functional liver capacity decreased with progression of HCC. VEGF and IL-6 levels were positively correlated with disease progression. Immunohistochemical probing of HCC tissues demonstrated the expression of several important survival-promoting proteins. Conclusion To our knowledge, we are the first to demonstrate accelerated development of hepatic neoplasia in Yucatan miniature pigs. Our HCC swine model closely mimics the human condition (i.e., progressive disease stages and expression of relevant molecular markers) and is a viable translational model. PMID:27305144

Clinical features and disease progression of L-2-hydroxyglutaric aciduria in 27 Staffordshire bull terriers.

PubMed

Shea, A; De Risio, L; Carruthers, H; Ekiri, A; Beltran, E

2016-11-26

To describe the development of clinical signs (CS) and outcome of L-2-hydroxyglutaric aciduria (L-2-HGA), owners of 119 Staffordshire bull terriers positive for the known L-2-hydroxyglutarate dehydrogenase autosomal-recessive mutations were requested to complete a questionnaire regarding their pet's CS. Questionnaires were returned for 27 dogs, all with neurological abnormalities-not all questions were answered in all cases. The mean age of CS onset was 12 months (range 2.5-60). Gait dysfunction was reported in 26/26 dogs, with stiffness of all four limbs the most common (24/26) and earliest recognised abnormality. Kyphosis (19/26), body and/or head tremors (19/26) and hypermetria (15/26) were frequent. Behavioural changes were present in 24/27 dogs; most commonly staring into space (21/24), signs of dementia (17/24) and loss of training (15/24). Eighteen dogs demonstrated paroxysmal seizure-like/dyskinetic episodes. Nineteen (70 per cent) dogs were alive at a mean survival time of 76.6 months (12-170) after onset of CS. L-2-HGA was the cause of euthanasia in six dogs. Euthanasia occurred at a mean survival time of 44 months (8.5-93) after onset of CS, with 2/8 dogs euthanased within 12 months. L-2-HGA is considered a progressive neurological disease; however, CS can be successfully managed with affected dogs potentially living a normal lifespan. British Veterinary Association.

Vitamin D levels are associated with gross motor function in amyotrophic lateral sclerosis.

PubMed

Paganoni, Sabrina; Macklin, Eric A; Karam, Chafic; Yu, Hong; Gonterman, Fernando; Fetterman, K Ashley; Cudkowicz, Merit; Berry, James; Wills, Anne-Marie

2017-10-01

The objective of this study was to determine whether serum vitamin D [25(OH)D] levels are associated with disease progression in amyotrophic lateral sclerosis (ALS). 25(OH)D was measured in subjects enrolled in a multicenter study for validation of ALS biomarkers. Baseline 25(OH)D levels were correlated with baseline ALSFRS-R scores. Average 25(OH)D levels from baseline and month 6 visits (seasonally asynchronous) were used to predict subsequent rate of change in ALSFRS-R from month 6 to month 18. Most subjects had either insufficient or deficient 25(OH)D levels. Lower 25(OH)D was associated with lower ALSFRS-R gross motor scores, but not lower ALSFRS-R total scores at baseline. Levels of 25(OH)D were not predictive of disease progression over the next 12 months. 25(OH)D was associated with baseline gross motor ALSFRS-R scores but did not predict the rate of disease progression. Vitamin D levels may reflect poor mobility in patients with ALS. Muscle Nerve, 2017 Muscle Nerve 56: 726-731, 2017. © 2017 Wiley Periodicals, Inc.

Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

PubMed

Hulin, Alexia; Moore, Vicky; James, Jeanne M; Yutzey, Katherine E

2017-01-01

Myxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/β-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/β-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined. To investigate the role of Wnt/β-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/β-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/β-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/β-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/β-catenin signalling in the development of MVD. Altogether, these data indicate that Axin2 limits Wnt/β-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/β-catenin signalling resulting from loss of Axin2 leads to progressive MVD. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

PubMed Central

Rogers, Justin T.; Liu, Chia-Chen; Zhao, Na; Wang, Jian; Putzke, Travis; Yang, Longyu; Shinohara, Mitsuru; Fryer, John D.; Kanekiyo, Takahisa; Bu, Guojun

2017-01-01

Aging is accompanied by increased neuroinflammation, synaptic dysfunction and cognitive deficits both in rodents and humans, yet the onset and progression of these deficits throughout the life span remain unknown. These aging-related deficits affect the quality of life and present challenges to our aging society. Here, we defined age-dependent and progressive impairments of synaptic and cognitive functions and showed that reducing astrocyte-related neuroinflammation through anti-inflammatory drug treatment in aged mice reverses these events. By comparing young (3 months), middle-aged (18 months), aged (24 months) and advanced-aged wild-type mice (30 months), we found that the levels of an astrocytic marker, GFAP, progressively increased after 18 months of age, which preceded the decreases of the synaptic marker PSD-95. Hippocampal long-term potentiation (LTP) was also suppressed in an age-dependent manner, where significant deficits were observed after 24 months of age. Fear conditioning tests demonstrated that associative memory in the context and cued conditions was decreased starting at the ages of 18 and 30 months, respectively. When the mice were tested on hidden platform water maze, spatial learning memory was significantly impaired after 24 months of age. Importantly, subacute treatment with the anti-inflammatory drug ibuprofen suppressed astrocyte activation, and restored synaptic plasticity and memory function in advanced-aged mice. These results support the critical contribution of aging-related inflammatory responses to hippocampal-dependent cognitive function and synaptic plasticity, in particular during advanced aging. Our findings provide strong evidence that suppression of neuroinflammation could be a promising treatment strategy to preserve cognition during aging. PMID:28254590

[New hosts and vectors for genome cloning]. Progress report

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

Not Available

The main goal of our project remains the development of new bacterial hosts and vectors for the stable propagation of human DNA clones in E. coli. During the past six months of our current budget period, we have (1) continued to develop new hosts that permit the stable maintenance of unstable features of human DNA, and (2) developed a series of vectors for (a) cloning large DNA inserts, (b) assessing the frequency of human sequences that are lethal to the growth of E. coli, and (c) assessing the stability of human sequences cloned in M13 for large-scale sequencing projects.

Fine mapping for Weaver Syndrome in the Brown Swiss breed with the identification of possible casual mutations across NRCAM, PNPLA8, and CTTNBP2 and Developement of a diagnostic SNP haplotype

USDA-ARS?s Scientific Manuscript database

Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) is a recessive neurological disease that has been observed in the Brown Swiss cattle breed since the 1970’s in North America and Europe. Bilateral hind leg weakness and ataxia appear in afflicted animals at 6 to 18 months of age,...

Space Shuttle propulsion parameter estimation using optimal estimation techniques

NASA Technical Reports Server (NTRS)

1983-01-01

This fourth monthly progress report again contains corrections and additions to the previously submitted reports. The additions include a simplified SRB model that is directly incorporated into the estimation algorithm and provides the required partial derivatives. The resulting partial derivatives are analytical rather than numerical as would be the case using the SOBER routines. The filter and smoother routine developments have continued. These routines are being checked out.

Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience

PubMed Central

2012-01-01

Background Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment. Methods We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease) lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment. Results Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed-based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively. Conclusions In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression. PMID:22943698

40 CFR 35.1650-6 - Reports.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Reports. (a) States with Phase 1 projects shall submit semi-annual progress reports (original and one copy... in the next six months. (b) Phase 2. States with Phase 2 projects shall submit progress reports... Phase 2 project progress reports shall be determined by the size and complexity of the project, and...

40 CFR 35.1650-6 - Reports.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Reports. (a) States with Phase 1 projects shall submit semi-annual progress reports (original and one copy... in the next six months. (b) Phase 2. States with Phase 2 projects shall submit progress reports... Phase 2 project progress reports shall be determined by the size and complexity of the project, and...

Progression into Engineering. Building Bridges between Education, Training and Employment.

ERIC Educational Resources Information Center

Evans, Karen; And Others

This publication reports findings of a 12-month study of progression opportunities in engineering education and training, a study which explored ways of bridging the gap between skills and knowledge acquired through basic training and prevocational education and those required for progression to higher levels of occupational training and…

Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy.

PubMed

Krishnan, Sunil; Rana, Vishal; Janjan, Nora A; Varadhachary, Gauri R; Abbruzzese, James L; Das, Prajnan; Delclos, Marc E; Gould, Morris S; Evans, Douglas B; Wolff, Robert A; Crane, Christopher H

2007-07-01

The current study was conducted to determine whether there were differences in outcome for patients with unresectable locally advanced pancreatic cancer (LAPC) who received treatment with chemoradiation therapy (CR) versus induction chemotherapy followed by CR (CCR). Between December 1993 and July 2005, 323 consecutive patients with LAPC were treated at the authors' institution with radiotherapy and concurrent gemcitabine or fluoropyrimidine chemotherapy. Two hundred forty-seven patients received CR as initial treatment, and 76 patients received a median of 2.5 months of gemcitabine-based induction chemotherapy prior to CR. Most patients received a radiation dose of 30 grays in 10 fractions (85%) concurrently with infusional 5-fluorouracil (41%), gemcitabine (39%), or capecitabine (20%). The median follow-up was 5.5 months (range, 1-63 months). For all patients, the median overall survival (OS) and progression-free survival (PFS) were 9 months and 5 months, respectively, and the 2-year estimated OS and PFS rates were 9% and 5%, respectively. The median OS and PFS were 8.5 months and 4.2 months, respectively, in the CR group and 11.9 months and 6.4 months, respectively, in the CCR group (both P < .001). The median times to local and distant progression were 6.0 months and 5.6 months, respectively, in the CR group and 8.9 and 9.5 months, respectively, in the CCR group (P = .003 and P = .007, respectively). There was no significant difference in the patterns of failure with the use of induction chemotherapy. The results from this analysis indicated that, by excluding patients with rapid distant progression, induction chemotherapy may select patients with LAPC for optimal benefit from consolidative CR. The authors believe that this strategy of enriching the population of patients who receive a locoregional treatment modality merits prospective randomized evaluation. Copyright (c) 2007 American Cancer Society.

The impact of pre-intervention rate of kidney function change on the assessment of CKD progression.

PubMed

Fassett, Robert G; Geraghty, Dominic P; Coombes, Jeff S

2014-10-01

Without a run-in phase, chronic kidney disease (CKD) patients enrolled in clinical trials may not be identified as having progressive disease. The aim of this analysis was to quantify the effects of a run-in phase on kidney function outcome in CKD patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial. The LORD trial assessed the effects of atorvastatin on the rate of change in the estimated glomerular filtration rate (eGFR) and included patients with serum creatinine 120 μmol/l. In this post hoc analysis, we assessed eGFR change during the 12-month period prior to enrolment, the 3-month run-in phase and the first 12-month period of the trial. Eighty of the original 132 patients (where retrospective data were available) were included. The rate of eGFR change during each period was compared. Overall kidney function decreased during the 12 months prior to enrolment by (mean, SD) 0.39 ± 0.98 ml/min/1.73 m(2)/month, improved during the 3-month run-in phase by 0.48 ± 2.90 ml/min/1.73 m(2)/month and decreased during the first 12 months of the trial by 0.15 ± 0.57 ml/min/1.73 m(2)/month. However, only 39 % of patients had declining eGFR during the 12 months prior, 19 % in the 3-month run-in and 42 % during the first 12-month study phase. Most patients (>60 %) entering this clinical trial had stable or improving kidney function. Enrolment was associated with further improved kidney function, which may have been due to 'regression to the mean' or to the Hawthorne effect. Investigators should include a run-in period to establish the presence of eGFR decline to use as an inclusion criterion in clinical trials assessing this measure of CKD progression.

Comorbid Mild Cognitive Impairment and Depressive Symptoms Predict Future Dementia in Community Older Adults: A 24-Month Follow-Up Longitudinal Study.

PubMed

Makizako, Hyuma; Shimada, Hiroyuki; Doi, Takehiko; Tsutsumimoto, Kota; Hotta, Ryo; Nakakubo, Sho; Makino, Keitaro; Suzuki, Takao

2016-10-18

Older adults with mild cognitive impairment (MCI) are non-demented, but demonstrate cognitive dysfunction, and have significantly higher risk of progressing to dementia. A better understanding of more sensitive risk factors, such as combination of cognitive and psychological status, for progression of MCI to dementia may be crucial for prevention of development of dementia. To examine MCI, depressive symptoms, and comorbid MCI and depressive symptoms as risk factors for development of dementia. A total of 3,663 community-dwelling older people were included in this prospective longitudinal study. MCI was determined by age- and education-adjusted objective cognitive impairment using computerized comprehensive cognitive measures including memory, attention/executive function, and processing speed. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) and defined by a GDS score of 6 or more. During the 24-month follow-up period, 72 participants (2.0%) developed dementia. Baseline MCI was significantly associated with an increased risk of incident dementia (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.8-5.5) but depressive symptoms were not (2.0; 1.0-4.2) after adjusting for age, sex, education, prescribed medications, and walking speed. Participants with comorbid MCI and depressive symptoms at baseline had a higher risk of developing dementia (HR, 4.8; 2.3-10.5). Although MCI and depressive symptoms may be associated with increased risk for incident dementia independently, comorbid MCI and depressive symptoms have a significantly greater impact on dementia development among community-dwelling older adults.

Plasma D-dimer as a predictor of the progression of abdominal aortic aneurysm.

PubMed

Vele, E; Kurtcehajic, A; Zerem, E; Maskovic, J; Alibegovic, E; Hujdurovic, A

2016-11-01

Essentials D-dimer could provide important information about abdominal aortic aneurysm (AAA) progression. The greatest diameter of the infrarenal aorta and the value of plasma D-dimer were determined. AAA progression is correlated with increasing plasma D-dimer levels. The increasing value of plasma D-dimer could be a predictor of aneurysm progression. Background The natural course of abdominal aortic aneurysm (AAA) is mostly asymptomatic and unpredictable. D-dimer could provide potentially important information about subsequent AAA progression. Objectives The aims of this study were to establish the relationship between the progression of an abdominal aortic aneurysm (AAA) and plasma D-dimer concentration over a 12-month period and determine the value of plasma D-dimer in patients with sub-aneurysmal aortic dilatation. Patients/Methods This was a prospective observational study that involved 33 patients with an AAA, 30 patients with sub-aneurysmal aortic dilatation and 30 control subjects. The greatest diameter of the infrarenal aorta, which was assessed by ultrasound, and the value of plasma D-dimer were determined for all subjects at baseline assessment, as well as after 12 months for those with an AAA. Results A positive correlation was found between the diameter of an AAA and plasma D-dimer concentration at the baseline and the control measurement stages. There was a strong positive correlation between AAA progression and increasing plasma D-dimer concentration over a 12-month period. Among patients with sub-aneurysmal aortic dilatation (n = 30), the value of plasma D-dimer was higher compared with matched controls (n = 30). Conclusions There is a strongly positive correlation between AAA progression and increasing plasma D-dimer concentration. The value of plasma D-dimer is higher in patients with sub-aneurysmal aortic dilatation than in control subjects. © 2016 International Society on Thrombosis and Haemostasis.

Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein.

PubMed

Fleming, Sheila M; Salcedo, Jonathan; Fernagut, Pierre-Olivier; Rockenstein, Edward; Masliah, Eliezer; Levine, Michael S; Chesselet, Marie-Françoise

2004-10-20

Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.

Crossfit training changes brain-derived neurotrophic factor and irisin levels at rest, after wingate and progressive tests, and improves aerobic capacity and body composition of young physically active men and women.

PubMed

Murawska-Cialowicz, E; Wojna, J; Zuwala-Jagiello, J

2015-12-01

Brain-derived neurotrophic factor (BDNF) is a protein that stimulates processes of neurogenesis, the survival of neurons and microglia, stimulates neuroplasticity, and takes part in the differentiation of cells developed in the hippocampus. BDNF is also released from skeletal muscles during exercise and can facilitate cross-talk between the nervous and muscular system. Irisin, the exercise hormone, is also released from skeletal muscles and is involved in oxidation processes in the organism. It is a vital issue from the point of view of prophylaxis and treatment through exercise of age-related diseases (e.g. senile dementia), obesity, type-2 diabetes. The aim of the study was to assess the changes in BDNF and irisin levels in young people after a 3-month CrossFit training program. At baseline and after the training, levels of BDNF and irisin were assayed before and after Wingate and progressive tests. Physical performance, body mass and composition, and muscle circumferences were also measured. There were noted: an improvement in aerobic capacity, an increase in VO2max, a reduction in adipose tissue percentage in women and an increase in LBM in all subjects. After CrossFit training the resting BDNF level increased significantly in all subjects while the resting level of irisin decreased in women, without changes in men. The resting level of BDNF at baseline was higher in men than in women. At baseline we observed an increased level of BDNF in women after Wingate and progressive tests, but in men only after the progressive test. After 3 months of CrossFit training the level of BDNF increased in all subjects, and also was higher in men than in women. In women we did not observe significant differences after both tests in comparison to rest. After the training BDNF was lower in men after Wingate and progressive tests than at rest. At baseline irisin level decreased in women after the Wingate and progressive tests. Changes in men were not observed after both tests. There were no differences in irisin levels between the baseline and 3 months after the training after Wingate and progressive tests. A beneficial influence of CrossFit training on the subjects' body composition, anaerobic capacity and cardiovascular fitness as well as an increase in BDNF makes it possible to assume that this type of training could have a very high application value, especially in a therapeutic process leading to improving a patient's wellbeing.

{sup 18}F-Fluorodeoxyglucose/Positron Emission Tomography Predicts Patterns of Failure After Definitive Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

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

Ohri, Nitin, E-mail: ohri.nitin@gmail.com; Bodner, William R.; Halmos, Balazs

Background: We previously reported that pretreatment positron emission tomography (PET) identifies lesions at high risk for progression after concurrent chemoradiation therapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). Here we validate those findings and generate tumor control probability (TCP) models. Methods: We identified patients treated with definitive, concurrent CRT for locally advanced NSCLC who underwent staging {sup 18}F-fluorodeoxyglucose/PET/computed tomography. Visible hypermetabolic lesions (primary tumors and lymph nodes) were delineated on each patient's pretreatment PET scan. Posttreatment imaging was reviewed to identify locations of disease progression. Competing risks analyses were performed to examine metabolic tumor volume (MTV) and radiation therapymore » dose as predictors of local disease progression. TCP modeling was performed to describe the likelihood of local disease control as a function of lesion size. Results: Eighty-nine patients with 259 hypermetabolic lesions (83 primary tumors and 176 regional lymph nodes) met the inclusion criteria. Twenty-eight patients were included in our previous report, and the remaining 61 constituted our validation cohort. The median follow-up time was 22.7 months for living patients. In 20 patients, the first site of progression was a primary tumor or lymph node treated with radiation therapy. The median time to progression for those patients was 11.5 months. Data from our validation cohort confirmed that lesion MTV predicts local progression, with a 30-month cumulative incidence rate of 23% for lesions above 25 cc compared with 4% for lesions below 25 cc (P=.008). We found no evidence that radiation therapy dose was associated with local progression risk. TCP modeling yielded predicted 30-month local control rates of 98% for a 1-cc lesion, 94% for a 10-cc lesion, and 74% for a 50-cc lesion. Conclusion: Pretreatment FDG-PET identifies lesions at risk for progression after CRT for locally advanced NSCLC. Strategies to improve local control should be tested on high-risk lesions, and treatment deintensification for low-risk lesions should be explored.« less

Pathological characteristics of spine metastases treated with high-dose single-fraction stereotactic radiosurgery.

PubMed

Katsoulakis, Evangelia; Laufer, Ilya; Bilsky, Mark; Agaram, Narasimhan P; Lovelock, Michael; Yamada, Yoshiya

2017-01-01

OBJECTIVE Spine radiosurgery is increasingly being used to treat spinal metastases. As patients are living longer because of the increasing efficacy of systemic agents, appropriate follow-up and posttreatment management for these patients is critical. Tumor progression after spine radiosurgery is rare; however, vertebral compression fractures are recognized as a more common posttreatment effect. The use of radiographic imaging alone posttreatment may makeit difficult to distinguish tumor progression from postradiation changes such as fibrosis. This is the largest series from a prospective database in which the authors examine histopathology of samples obtained from patients who underwent surgical intervention for presumed tumor progression or mechanical pain secondary to compression fracture. The majority of patients had tumor ablation and resulting fibrosis rather than tumor progression. The aim of this study was to evaluate tumor histopathology and characteristics of patients who underwent pathological sampling because of radiographic tumor progression, fibrosis, or collapsed vertebrae after receiving high-dose single-fraction stereotactic radiosurgery. METHODS Between January 2005 and January 2014, a total of 582 patients were treated with linear accelerator-based single-fraction (18-24 Gy) stereotactic radiosurgery. The authors retrospectively identified 30 patients (5.1%) who underwent surgical intervention for 32 lesions with vertebral cement augmentation for either mechanical pain or instability secondary to vertebral compression fracture (n = 17) or instrumentation (n = 15) for radiographic tumor progression. Radiation and surgical treatment, histopathology, and long-term outcomes were reviewed. Survival and time to recurrence were calculated using the Kaplan-Meier method. RESULTS The mean age at the time of radiosurgery was 59 years (range 36-80 years). The initial pathological diagnoses were obtained for all patients and primarily included radioresistant tumor types, including renal cell carcinoma in 7 (22%), melanoma in 6 (19%), lung carcinoma in 4 (12%), and sarcoma in 3 (9%). The median time to surgical intervention was 24.7 months (range 1.6-50.8 months). The median follow-up and overall survival for all patients were 42.5 months and 41 months (overall survival range 7-86 months), respectively. The majority of assessed lesions showed no evidence of tumor on pathological review (25 of 32, 78%), while a minority of lesions revealed residual tumor (7 of 32, 22%). The median survival for patients after tumor recurrence was 5 months (range 2-70 months). CONCLUSIONS High-dose single-fraction radiosurgery is tumor ablative in the majority of instances. In a minority of cases, tumor persists and salvage treatments should be considered.

Pathological characteristics of spine metastases treated with high-dose single-fraction stereotactic radiosurgery

PubMed Central

Katsoulakis, Evangelia; Laufer, Ilya; Bilsky, Mark; Agaram, Narasimhan P.; Lovelock, Michael; Yamada, Yoshiya

2017-01-01

OBJECTIVE Spine radiosurgery is increasingly being used to treat spinal metastases. As patients are living longer because of the increasing efficacy of systemic agents, appropriate follow-up and posttreatment management for these patients is critical. Tumor progression after spine radiosurgery is rare; however, vertebral compression fractures are recognized as a more common posttreatment effect. The use of radiographic imaging alone posttreatment may make it difficult to distinguish tumor progression from postradiation changes such as fibrosis. This is the largest series from a prospective database in which the authors examine histopathology of samples obtained from patients who underwent surgical intervention for presumed tumor progression or mechanical pain secondary to compression fracture. The majority of patients had tumor ablation and resulting fibrosis rather than tumor progression. The aim of this study was to evaluate tumor histopathology and characteristics of patients who underwent pathological sampling because of radiographic tumor progression, fibrosis, or collapsed vertebrae after receiving high-dose single-fraction stereotactic radiosurgery. METHODS Between January 2005 and January 2014, a total of 582 patients were treated with linear accelerator–based single-fraction (18–24 Gy) stereotactic radiosurgery. The authors retrospectively identified 30 patients (5.1%) who underwent surgical intervention for 32 lesions with vertebral cement augmentation for either mechanical pain or instability secondary to vertebral compression fracture (n = 17) or instrumentation (n = 15) for radiographic tumor progression. Radiation and surgical treatment, histopathology, and long-term outcomes were reviewed. Survival and time to recurrence were calculated using the Kaplan-Meier method. RESULTS The mean age at the time of radiosurgery was 59 years (range 36–80 years). The initial pathological diagnoses were obtained for all patients and primarily included radioresistant tumor types, including renal cell carcinoma in 7 (22%), melanoma in 6 (19%), lung carcinoma in 4 (12%), and sarcoma in 3 (9%). The median time to surgical intervention was 24.7 months (range 1.6–50.8 months). The median follow-up and overall survival for all patients were 42.5 months and 41 months (overall survival range 7–86 months), respectively. The majority of assessed lesions showed no evidence of tumor on pathological review (25 of 32, 78%), while a minority of lesions revealed residual tumor (7 of 32, 22%). The median survival for patients after tumor recurrence was 5 months (range 2–70 months). CONCLUSIONS High-dose single-fraction radiosurgery is tumor ablative in the majority of instances. In a minority of cases, tumor persists and salvage treatments should be considered. PMID:28041326

Reliability of chronic allograft nephropathy diagnosis in sequential protocol biopsies.

PubMed

Serón, Daniel; Moreso, Francesc; Fulladosa, Xavier; Hueso, Miguel; Carrera, Marta; Grinyó, Josep M

2002-02-01

Chronic allograft nephropathy (CAN) progresses rapidly during the first few months and slowly thereafter. Although the presence of CAN in protocol renal biopsies is a predictor of outcome, the reliability of this diagnosis according to Banff criteria has not been characterized. Renal lesions were evaluated according to the Banff criteria in sequential protocol biopsies performed at 4 and 14 months in 310 biopsies obtained from 155 patients. CAN progressed from 40 to 53% (P=0.001) while serum creatinine remained stable (146 +/- 44 vs. 147 +/- 48 micromol/L, P=NS). Graft survival in patients with and without CAN in the first biopsy was 74 versus 91% (P < 0.05), and in the second biopsy 75 versus 94% (P < 0.05). In 54 patients (35%) no CAN was present in both biopsies, 39 (25%) showed progression to CAN, 19 (12%) showed regression of CAN, and 43 (28%) showed CAN in both biopsies. Graft survival was: 100%, 81.6%, 82.6% and 69.4%, respectively (P < 0.01). Assuming that CAN does not regress and sampling error is normally distributed, we estimated that 25% of biopsies cannot be properly classified. The increase in the incidence of CAN between the 4th and 14th month is lower than the proportion of misclassified biopsies. Thus, monitoring the progression of CAN by means of two sequential biopsies at 4 and 14 months is inaccurate. We suggest that progression of scarring be monitored by means of a donor and a protocol biopsy performed during the first year evaluated with a quantitative approach.

Iron deficiency anemia: adverse effects on infant psychomotor development.

PubMed

Walter, T; De Andraca, I; Chadud, P; Perales, C G

1989-07-01

In a double-blind, placebo-control prospective cohort study of 196 infants from birth to 15 months of age, assessment was made at 12 months of age of the relationship between iron status and psychomotor development, the effect of a short-term (10-day) trial of oral iron vs placebo, and the effect of long-term (3 months) oral iron therapy. Development was assessed with the mental and psychomotor indices and the infant behavior record of the Bayley Scales of Infant Development in 39 anemic, 30 control, and 127 nonanemic iron-deficient children. Anemic infants had significantly lower Mental and Psychomotor Developmental Index scores than control infants or nonanemic iron-deficient infants (one-way analysis of variance, P less than .0001). Control infants and nonanemic iron-deficient infants performed comparably. No difference was noted between the effect of oral administration of iron or placebo after 10 days or after 3 months of iron therapy. Among anemic infants a hemoglobin concentration less than 10.5 g/dL and duration of anemia of greater than 3 months were correlated with significantly lower motor and mental scores (P less than .05). Anemic infants failed specifically in language capabilities and body balance-coordination skills when compared with controls. These results, in a design in which intervening variables were closely controlled, suggest that when iron deficiency progresses to anemia, but not before, adverse influences in the performance of developmental tests appear and persist for at least 3 months despite correction of anemia with iron therapy. If these impairments prove to be long standing, prevention of iron deficiency anemia in early infancy becomes the only way to avoid them.

Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors

PubMed Central

Hobday, Timothy J.; Qin, Rui; Reidy-Lagunes, Diane; Moore, Malcolm J.; Strosberg, Jonathan; Kaubisch, Andreas; Shah, Manisha; Kindler, Hedy Lee; Lenz, Heinz-Josef; Chen, Helen; Erlichman, Charles

2015-01-01

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted. PMID:25488966

Crack-cocaine use accelerates HIV disease progression in a cohort of HIV-positive drug users.

PubMed

Baum, Marianna K; Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, Bryan; Campa, Adriana

2009-01-01

HIV infection is prevalent among substance abusers. The effects of specific illicit drugs on HIV disease progression have not been established. We evaluated the relationship between substances of abuse and HIV disease progression in a cohort of HIV-1-positive active drug users. A prospective, 30-month, longitudinal study was conducted on 222 HIV-1 seropositive drug users in Miami, FL. History of illicit drug, alcohol, and medication use, CD4+ cell count, and viral load were performed every 6 months. Crack-cocaine users were 2.14 times [95% confidence interval (CI): 1.08 to 4.25, P = 0.029] more likely to present a decline of CD4 to

Risk factors for progression to invasive carcinoma in patients with borderline ovarian tumors.

PubMed

Song, Taejong; Lee, Yoo-Young; Choi, Chel Hun; Kim, Tae-Joong; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

2014-09-01

The aim of this study was to identify risk factors for progression to invasive carcinoma in patients with borderline ovarian tumors (BOTs). We performed a retrospective review of all patients treated and followed for BOTs between 1996 and 2011. Multivariate Cox proportional hazards model analysis was performed to identify independent risk factors for progression to invasive carcinoma. A total of 364 patients were identified. During the median follow-up of 53.8 months, 31 patients (8.5%) developed recurrent disease: 12 (3.3%) had recurrent disease with progression to invasive carcinoma, and 19 (5.2%) had recurrent disease with borderline histology. Disease-related deaths (7/364; 1.7%) were observed only in patients with progression to invasive carcinoma. The multivariate analysis showed that independent risk factors for progression to invasive carcinoma were advanced disease stage (hazard ratio [HR], 5.59; P = 0.005), age 65 years or older (HR, 5.13; P = 0.037), and the presence of microinvasion (HR, 3.71; P = 0.047). These 3 factors were also independently related to overall survival. Although patients with BOTs have an excellent prognosis, the risk of progression to invasive carcinoma and thereby death remains. Therefore, physicians should pay closer attention to BOT patients with these risk factors (ie, advanced disease stage, old age, and microinvasion), and more careful surveillance for progression to invasive carcinoma is needed.

Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study.

PubMed

Jaisamrarn, Unnop; Castellsagué, Xavier; Garland, Suzanne M; Naud, Paulo; Palmroth, Johanna; Del Rosario-Raymundo, Maria Rowena; Wheeler, Cosette M; Salmerón, Jorge; Chow, Song-Nan; Apter, Dan; Teixeira, Julio C; Skinner, S Rachel; Hedrick, James; Szarewski, Anne; Romanowski, Barbara; Aoki, Fred Y; Schwarz, Tino F; Poppe, Willy A J; Bosch, F Xavier; de Carvalho, Newton S; Germar, Maria Julieta; Peters, Klaus; Paavonen, Jorma; Bozonnat, Marie-Cecile; Descamps, Dominique; Struyf, Frank; Dubin, Gary O; Rosillon, Dominique; Baril, Laurence

2013-01-01

The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.

Natural History of Progression of HPV Infection to Cervical Lesion or Clearance: Analysis of the Control Arm of the Large, Randomised PATRICIA Study

PubMed Central

Jaisamrarn, Unnop; Castellsagué, Xavier; Garland, Suzanne M.; Naud, Paulo; Palmroth, Johanna; Del Rosario-Raymundo, Maria Rowena; Wheeler, Cosette M.; Salmerón, Jorge; Chow, Song-Nan; Apter, Dan; Teixeira, Julio C.; Skinner, S. Rachel; Hedrick, James; Szarewski, Anne; Romanowski, Barbara; Aoki, Fred Y.; Schwarz, Tino F.; Poppe, Willy A. J.; Bosch, F. Xavier; de Carvalho, Newton S.; Germar, Maria Julieta; Peters, Klaus; Paavonen, Jorma; Bozonnat, Marie-Cecile; Descamps, Dominique; Struyf, Frank; Dubin, Gary O.; Rosillon, Dominique; Baril, Laurence

2013-01-01

Background The control arm of PATRICIA (PApillomaTRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. Methods and Findings Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 womenwith 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. Conclusions Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance. PMID:24260180

Pilot interaction with automated airborne decision making systems

NASA Technical Reports Server (NTRS)

Rouse, W. B.; Hammer, J. M.; Mitchell, C. M.; Morris, N. M.; Lewis, C. M.; Yoon, W. C.

1985-01-01

Progress was made in the three following areas. In the rule-based modeling area, two papers related to identification and significane testing of rule-based models were presented. In the area of operator aiding, research focused on aiding operators in novel failure situations; a discrete control modeling approach to aiding PLANT operators was developed; and a set of guidelines were developed for implementing automation. In the area of flight simulator hardware and software, the hardware will be completed within two months and initial simulation software will then be integrated and tested.

Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein

PubMed Central

Ardoin, Stacy P; Schanberg, Laura Eve; Sandborg, Christy I; Barnhart, Huiman X; Evans, Greg W; Yow, Eric; Mieszkalski, Kelly L; Ilowite, Norman T; Eberhard, Anne; Imundo, Lisa F; Kimura, Yuki; Levy, Deborah; von Scheven, Emily; Silverman, Earl; Bowyer, Suzanne L; Punaro, L; Singer, Nora G; Sherry, David D; McCurdy, Deborah K; Klein-Gitelman, Marissa; Wallace, Carol; Silver, Richard M; Wagner-Weiner, Linda; Higgins, Gloria C; Brunner, Hermine I; Jung, Lawrence; Soep, Jennifer B; Reed, Ann M; Thompson, Susan D

2014-01-01

Objective Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy. Methods Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. Results Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures. Conclusions Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. ClinicalTrials.gov identifier NCT00065806. PMID:23436914

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.

PubMed

Choueiri, Toni K; Escudier, Bernard; Powles, Thomas; Mainwaring, Paul N; Rini, Brian I; Donskov, Frede; Hammers, Hans; Hutson, Thomas E; Lee, Jae-Lyun; Peltola, Katriina; Roth, Bruce J; Bjarnason, Georg A; Géczi, Lajos; Keam, Bhumsuk; Maroto, Pablo; Heng, Daniel Y C; Schmidinger, Manuela; Kantoff, Philip W; Borgman-Hagey, Anne; Hessel, Colin; Scheffold, Christian; Schwab, Gisela M; Tannir, Nizar M; Motzer, Robert J

2015-11-05

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Exploration of risk factors predicting outcomes for primary T1 high-grade bladder cancer and validation of the Spanish Urological Club for Oncological Treatment scoring model: Long-term follow-up experience at a single institute.

PubMed

Miyake, Makito; Gotoh, Daisuke; Shimada, Keiji; Tatsumi, Yoshihiro; Nakai, Yasushi; Anai, Satoshi; Torimoto, Kazumasa; Aoki, Katsuya; Tanaka, Nobumichi; Konishi, Noboru; Fujimoto, Kiyohide

2015-06-01

To determine the prognostic factors of primary T1 high-grade bladder cancer and to validate the Spanish Urological Club for Oncological Treatment model in Japanese patients with T1 high-grade bladder cancer treated at a single institution. Records of 106 patients with T1 high-grade bladder cancer treated from 1998 to 2013 were retrospectively reviewed. Variables included various clinicopathological parameters, including lymphovascular invasion and tumor growth pattern at the invasion front. Recurrence-free survival and progression-free survival were analyzed. Multivariate Cox proportional regression analysis was used to verify the prognostic significance of the variables. Scores for recurrence and progression were calculated using the Spanish Urological Club for Oncological Treatment model. Of 106 patients, 44 (42%) had recurrence and 16 (15%) developed progression after a median (interquartile range) follow-up period of 54 months (range 32-81 months). Non-papillary shape was the only independent predictor for recurrence, while broad-based tumor stalk and infiltrative tumor growth pattern at the invasion front were determined to be independent predictors for progression. Stratification of patients according to the number of progression risk factors yielded hazard ratios of 10.1 and 13.1 in patients having one and two risks, respectively, compared with those without any risks. The Spanish Urological Club for Oncological Treatment model successfully stratified our patients with a trend toward different probabilities of recurrence and progression. The results of the present study might be helpful for counseling certain patients towards intensive treatment, such as radical cystectomy and/or platinum-based systemic chemotherapy. In addition, the Spanish Urological Club for Oncological Treatment model might be applicable to Japanese patients with T1 high-grade bladder cancer. © 2015 The Japanese Urological Association.

A phase 2 study of vatalanib in metastatic melanoma patients.

PubMed

Cook, Natalie; Basu, Bristi; Biswas, Swethajit; Kareclas, Paula; Mann, Colette; Palmer, Cheryl; Thomas, Anne; Nicholson, Steve; Morgan, Bruno; Lomas, David; Sirohi, Bhawna; Mander, Adrian P; Middleton, Mark; Corrie, Pippa G

2010-10-01

A phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma. Adults with pathologically confirmed metastatic melanoma, WHO Performance status 0-2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Fleming's single stage design. Tumour control rate (CR+PR+SD) was 35% at 16 weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8 months (95% CI 1.8-3.7 months) and median overall survival was 6.5 months (95% CI 3.9-10.2 months). Vatalanib stabilised disease in a proportion of patients, although overall survival was disappointing. Copyright © 2010 Elsevier Ltd. All rights reserved.

Menogaril in the treatment of relapsed multiple myeloma. A phase II trial of the Cancer Center of Wake Forest University.

PubMed

Cruz, J M; Case, L D; Dalton, H B; Ramseur, W L; Richards, F; Jackson, D V; Muss, H B; Zekan, P J; Brodkin, R A; Brown, R C

1992-04-01

Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m2 intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.

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

Janssens, Geert O.R.J.; Gidding, Corrie E.M.; Lindert, Erik J. van

Purpose: Most children with a diffuse intrinsic brainstem glioma will die within 1 year after diagnosis. To reduce patient burden, we investigated the feasibility of a radical hypofractionation radiotherapy schedule, given over 3 weeks, as an alternative to the standard regimen (30 fractions over 6 weeks). Methods and Materials: Nine children, ages 3-13, were treated by 13 fractions of 3 Gy (n = 8) or 6 fractions of 5.5 Gy (n = 1) given over 3 weeks. All patients had symptoms for {<=}3 months and {>=}2 signs of the neurologic triad (long tract signs, ataxia, cranial nerve deficit). Bilateral involvementmore » of the pons (n = 8), encasement of the basilar artery (n = 7) and extension into the cerebellar peduncle (n = 6) was visible on magnetic resonance imaging. Results: Symptom improvement occurred in all patients within 2 weeks after start of radiotherapy. At a mean follow-up time of 15 months, 7 patients have died. Median time to progression and overall survival was 4.9 and 8.6 months, respectively. Median time to death after progression was 3.6 months. No Grade 3 or 4 toxicity was observed. In a recently published review of clinical trials, median time to progression, overall survival, and time between progression and death ranged from 5.0-8.8, 7.0-16, and 1.0-4.5 months, respectively, with more aggressive regimens. Conclusion: This radical hypofractionation radiotherapy regimen for children with diffuse intrinsic brainstem glioma is feasible and associated with no Grade 3 or 4 toxicities. With a minimal overall treatment time, it offers quick symptom relief and outcome results within the range of published data.« less

Glioblastoma Recurrence Patterns After Radiation Therapy With Regard to the Subventricular Zone

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

Adeberg, Sebastian, E-mail: Sebastian.adeberg@med.uni-heidelberg; König, Laila; Bostel, Tilman

Purpose: We evaluated the influence of tumor location and tumor spread in primary glioblastoma (GBM), with respect to the subventricular zone (SVZ), on recurrence behavior, progression-free survival (PFS), and overall survival (OS). Methods and Materials: 607 patients (376 male and 231 female) with a median age of 61.3 years (range, 3.0-87.9 years) and primary GBM treated with radiation therapy (RT) from 2004 to 2012 at a single institution were included in this retrospective study. Preoperative images and follow-up examination results were assessed to evaluate tumor location. Tumors were classified according to the tumor location in relation to the SVZ. Results: The medianmore » PFS of the study population was 5.2 months (range, 1-91 months), and the median OS was 13.8 months (range, 1-102 months). Kaplan-Meier analysis showed that tumor location in close proximity to the SVZ was associated with a significant decline in PFS and OS (4.8 and 12.3 months, respectively; each P<.001). Furthermore, in cases where tumors were involved with the SVZ, distant cerebral progression (43.8%; P=.005) and multifocal progression (39.8%; P=.008) were more common. Interestingly, opening of the ventricle during the previous surgery showed no impact on PFS and OS. Conclusion: GBM in close proximity to the SVZ was associated with decreased survival and had a higher risk of multifocal or distant progression. Ventricle opening during surgery had no effect on survival rates.« less

The three-dimensional feto-maternal vascular interrelationship during early bovine placental development: a scanning electron microscopical study

PubMed Central

PFARRER, CHRISTIANE; EBERT, BRIGITTE; MIGLINO, MARIA ANGELICA; KLISCH, KARL; LEISER, RUDOLF

2001-01-01

Both the fetal and maternal microvasculature of bovine placentomes was examined by scanning electron microscopy of vascular casts. So far the development of the vascular architecture of the bovine placentome in early gestation has only been studied 2-dimensionally due to technical difficulties arising from the fragility of the early placental blood vessels. Repeated experiments led to the selection of the microvascular corrosion casts presented here. The vasculature of the maternal compartment is supplied by large caruncular stalk or spiral arteries, which release short maternal stem arteries. In the 3rd month of gestation, these arteries branch into several arterioles at their base, thus providing the vascular framework for the lower part of the septal walls of the primary crypts. In the 4th month, due to progressive longitudinal growth of the stem arteries, branching into arterioles occurs not only at the base, but over the whole length of the stem arteries. These arterioles supply the capillary complexes of the septa which resemble the major part of the septal vasculature and face the secondary crypts. Further indentation results in the formation of tertiary crypt capillary complexes, encircling the earlier secondary unit. From the 6th month of gestation the architecture resembles the fully developed maternal placenta with stem arteries running directly to the fetal side to branch into 4 to 6 arterioles, which turn back to enter secondary and tertiary septa. Maternal venules, collecting the blood from the capillary bed of secondary and tertiary septa, converge onto stem veins leaving the caruncle via branches of the uterine vein. The fetal part of the placentome is supplied by the cotyledonary arteries, which branch into fetal stem arteries that are the tributary to single villous trees. Over their whole course towards the maternal side, these give off arterioles entering secondary villi. The tertiary or terminal villous vasculature consists of capillaries, which are organised in serial capillary loops. This system is progressively elaborated in the course of gestation. In the 4th month there are only finger-like loops, whereas from the 6th month large fan-like structures can be observed. In early gestation the maternal and fetal blood vessels meet predominantly in a countercurrent fashion, changing to the less efficient crosscurrent exchange when the tertiary unit develops. These results indicate the development of a highly elaborated fetomaternal villous-crypt exchange system, already established in the 1st half of gestation, thus meeting the increasing needs of the fetus. PMID:11430698

Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases.

PubMed

Koutsilieris, Michael; Mitsiades, Constantine S; Bogdanos, John; Dimopoulos, Theodoros; Karamanolakis, Dimitrios; Milathianakis, Constantine; Tsintavis, Athanassios

2004-07-01

Androgen ablation-refractory prostate cancer patients (stage D3) develop painful bone metastases and limited responsiveness to conventional therapies, hence the lack of universally accepted "gold standard" treatment for this poor prognosis clinical setting. We tested the safety and efficacy in stage D3 patients of the combination hormonal therapy, which combines administration of somatostatin analog and dexamethasone with standard androgen ablation monotherapy (luteinizing-hormone releasing-hormone analog or orchiectomy). Thirty eight patients with stage D3 prostate cancer (mean age 71.8 +/- 5.9 years) continued receiving androgen ablation therapy in combination with oral dexamethasone (4 mg daily for the 1st month of treatment, tapered down to 1 mg daily by the 4th month, with 1 mg daily maintenance dose thereafter) and somatostatin analog (20 mg octreotide i.m. injections every 28 days). Twenty-three of 38 patients (60.5%) receiving this combination regimen had partial responses [PR, >/=50% prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease, and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of patients, their serum PSA levels decreased with treatment but did not return to their respective baselines until the end of follow-up (or death from non-prostate cancer-related causes). The median time-to-return to baseline PSA was 12 months (95% CI, 7-17 months), median progression-free survival was 7 months (95% CI, 4.5-9.5 months), median overall survival was 14 months (95% CI, 10.7-17.4 months), and median prostate cancer-specific overall survival (defined as time from onset of combination therapy until prostate cancer-related death) was 16.0 months (95% CI, 11.9-20.1 months). All patients reported significant and durable improvement of bone pain and performance status (for a median duration of 14 months; 95% CI, 9-19 months), without major treatment-related side effects. We observed a statistically significant (P < 0.01) reduction in serum insulin-like growth factor-1 levels at response to the combination therapy. T levels remained suppressed within castration levels at baseline and throughout therapy, including relapse. The combination therapy of dexamethasone plus somatostatin analog and standard androgen ablation manipulation produces objective clinical responses and symptomatic improvement in androgen ablation-refractory refractory prostate cancer patients.

Still a role for surgery as first-line therapy of splenic marginal zone lymphoma? Results of a prospective observational study.

PubMed

Pata, Giacomo; Bartoli, Michele; Damiani, Enrico; Solari, Stefano; Anastasia, Antonella; Pagani, Chiara; Tucci, Alessandra

2017-05-01

Assessment of hematologic improvement, survival and peri-operative morbidity after first-line splenectomy for splenic marginal zone lymphoma (SMZL). Forty-three patients undergoing open splenectomy were prospectively analyzed. Perioperative clinical course, overall and progression-free survival (OS-PFS) were evaluated. Risk factors analyzed were gender, age, ASA-grade, ECOG performance status, presence of B-symptoms, body mass index, steroidal treatment, serum albumin concentration, IIL-score, operative time, spleen size and weight. The median follow-up was 31 months (IQR 15-76; range 24-154). Anemia and thrombocytopenia resolved in 80% of patients at 6 months; in 60% at 2 years. The 5-year and 10-year PFS were 35% and 13% respectively, with a median of 35 months (shorter in patients with ECOG performance status ≥2 and B-symptoms). Nineteen cases (44.2%) had a progression of disease within 2 years. Of these, 14 (32.6%) received adjuvant chemotherapy (mainly R-FC or R-CVP). Progression was attributed to high-grade B lymphoma in 7 (16.3%) patients. The median time between diagnosis and progression to aggressive lymphoma was 25.5 months (range 18.8-81.8). The median time to next treatment was 83.5 months (95% CI 49-118). The 5-year and 10-year OS were 75% and 53% respectively. Mortality was due to disease progression and histological transformation in high-grade B lymphoma in 50% of cases, myelodisplastic syndrome in 15%, recurrence of hemolytic anemia in 15%, Hodgkin lymphoma in 7% and to infections (mainly pulmonary) in the remaining 13% of cases. Post-operative morbidity was 2.3% (1 patient with grade-3 complication). Overall grade ≥2 complication rate was 32.5% (mainly hemorrhagic and pulmonary complications). Spleen weight was the only independent risk factor for morbidity. Mortality was nil. Splenectomy is safe and effective as regards cytopenia resolution and OS, although disease progression is frequently observed at follow-up. Such results are strictly linked to accurate pre- and post-operative clinical management and optimal anesthesiologic approach. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Participation in the workforce after a traumatic brain injury: a matter of control.

PubMed

Johansson, Annica E M; Haugstad, Tor; Berg, Marie; Johansson, Ulla

2016-01-01

This study sought to explore individual experience in developing a mastery of daily activities and roles after a traumatic brain injury (TBI) with the objective of returning to work. Eight 30-60-year-old men, employed at the time of injury, were each interviewed three times over a 6-month period. Ten to 21 months after the injuries, four participants had returned to work at least part time. Grounded theory was adapted for analyses. A single core category emerged: a desire for control: focusing on high-priority issues. Still, 2 years after injury, the participants were uncertain about their abilities with respect to what was expected of them at work. They felt they would do better as time progressed. The participants' uncertainty about their efficacy cast doubt on their beliefs in improving their skills, balancing daily activities and work. They wondered about the sustainability of their health and efficacy at work. Wanting to control their own improvement, the participants asked for counselling in strategies and techniques to help with their progress. This issue could be taken into account in follow-up rehabilitation programmes. Additionally, the workplace might be the ideal context in which to develop the structures and routines necessary to master life in general. Two years after injury, the participants remained uncertain about their abilities with respect to what was expected of them at work. The participants felt they would do better as time progressed. The participants, wanting to control their own improvement, sought counselling to help sort out their priorities and found it could contribute to help with their progress in finding a suitable balance between daily activities and work. A consequence of our main finding, in a multidisciplinary context, is that counselling in structures and routines with respect to work-related tasks should be considered to be an integral part of any rehabilitation programme after TBI.

Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy.

PubMed

Chung, Yoo-Ri; Park, Sung Wook; Choi, Shin-Young; Kim, Seung Woo; Moon, Ka Young; Kim, Jeong Hun; Lee, Kihwang

2017-01-07

To investigate the effects of dyslipidemia and statin therapy on progression of diabetic retinopathy and diabetic macular edema in patients with type 2 diabetes. The medical records of 110 patients with type 2 diabetes (70 statin users and 40 non-users) were retrospectively reviewed. The two outcome measures were progression of diabetic retinopathy by two or more steps on the early treatment diabetic retinopathy study scale and diabetic macular edema based on optical coherence tomography. Serum lipid profiles were analyzed from 6 months prior to diagnosis of diabetic macular edema. Diabetic retinopathy progressed in 23% of statin users and 18% of non-users (p = 0.506), but diabetic macular edema was present in 23% of statin users and 48% of non-users (p = 0.008). Statins reduced low-density lipoprotein cholesterol levels in patients with and without diabetic macular edema (p = 0.043 and p = 0.031, respectively). Among statin users, patients with diabetic macular edema had higher levels of triglycerides (p = 0.004) and lower levels of high-density lipoprotein cholesterol (p = 0.033) than those without diabetic macular edema. Logistic regression analysis showed that statin use significantly lowered the risk of diabetic macular edema [odds ratio (OR): 0.33, 95% confidence interval (CI) 0.12-0.91, p = 0.032]. Hypertriglyceridemia at 6 months prior to development of macular edema was significantly associated with central retinal thickness (OR: 1.52; 95% CI 1.14-2.02, p = 0.005). Lipid lowering therapy with statins protected against the development of diabetic macular edema and progression of diabetic retinopathy in patients with type 2 diabetes. Hypertriglyceridemia could be used as a surrogate marker for diabetic macular edema.

Motor trajectories from 4 to 18 months corrected age in infants born at less than 30 weeks of gestation.

PubMed

Pin, Tamis W; Eldridge, Bev; Galea, Mary P

2010-09-01

Preterm infants are recognised as developing at a significantly slower rate than their full-term peers and with different movement quality. This study aimed to describe the longitudinal gross motor trajectories of these infants in the first 18 months of (corrected) age and investigate factors associated with gross motor development. A longitudinal study was conducted with convenience samples of 58 preterm infants born < or = 29 weeks of gestation and 52 control full-term infants in Australia. The infants were assessed at 4, 8, 12 and 18 months of (corrected) age using the Alberta Infant Motor Scale (AIMS). Forty-six preterm and 48 control infants completed all four assessments. The preterm group scored significantly lower on various sub-scores at all age levels. Almost half of the preterm infants demonstrated less progression in the sit sub-scale from 4 to 8 months (corrected) age, possibly due to an imbalance between flexor and extensor strength in the trunk. At 12 and 18 months of (corrected) age, lack of rotation and fluency in their movements were evident in some preterm infants. Presence of intra-ventricular haemorrhage and chronic lung disease were associated with poor motor performance at 4 months and use of postnatal steroids was associated with poor motor performance at 4, 8 and 18 months of corrected age. The imbalance between flexor and extensor muscle strength in preterm infants had a stronger impact on motor development than usually expected. The AIMS appears to be a sensitive assessment tool to demonstrate the unique movement characteristics in this preterm cohort. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

A New Flow-Diverter (the FloWise): In-Vivo Evaluation in an Elastase-Induced Rabbit Aneurysm Model.

PubMed

Kim, Byung Moon; Kim, Dong Joon; Kim, Dong Ik

2016-01-01

We aimed to evaluate the efficacy and safety of a newly developed, partially retrievable flow-diverter (the FloWise) in an elastase-induced rabbit aneurysm model. We developed a partially retrievable flow diverter composed of 48 strands of Nitinol and platinum wire. The FloWise is compatible with any microcatheter of 0.027-inch inner diameter, and is retrievable up to 70% deployment. The efficacy and safety of the FloWise were evaluated in the elastase-induced rabbit aneurysm model. The rate of technical success (full coverage of aneurysm neck) and assessment of aneurysm occlusion and stent patency was conducted by angiograms and histologic examinations at the 1-month, 3-month, and 6-month follow-up. The patency of small arterial branches (intercostal or lumbar arteries) covered by the FloWise were also assessed in the 5 subjects. We attempted FloWise insertion in a total of 32 aneurysm models. FloWise placement was successful in 31 subjects (96.9%). Two stents (6.2%) were occluded at the 3-month follow-up, but there was no evidence of in-stent stenosis in other subjects. All stented aneurysms showed progressive occlusion: grade I (complete aneurysm occlusion) in 44.4% and grade II (aneurysm occlusion > 90%) in 55.6% at 1 month; grade I in 90% and II in 10% at 3 months; and grade I in 90% and II in 10% at 6 months. All small arterial branches covered by the FloWise remained patent. A newly developed, partially retrievable flow-diverter seems to be a safe and effective tool of aneurysm occlusion, as evaluated in the rabbit aneurysm model.

Progressive outer retinal necrosis syndrome in the course of systemic lupus erythematosus.

PubMed

Turno-Kręcicka, A; Tomczyk-Socha, M; Zimny, A

2016-12-01

Progressive outer retinal necrosis syndrome (PORN) is a severe clinical variant of necrotizing herpetic chorioretinitis, which occurs almost exclusively in patients with advanced acquired immunodeficiency syndrome (AIDS). To date, only a few cases of PORN have been reported in patients, mostly among those who were immunocompromised. To our knowledge, only one case of PORN in a patient with systemic lupus erythematosus (SLE) has been described. We report the case of a 44-year old HIV-negative patient with lupus nephritis, whom was being treated by mycophenolate mophetil (MMF), arechin and prednisone. After 14 months of MMF therapy, the patient revealed PORN symptoms; and several months later, the patient developed Type B primary central nervous system lymphoma (PCNSL). PORN is usually compared to acute retinal necrosis (ARN) syndrome, because of having the same causative agent: varicella zoster virus (VZV). There are also some similarities in clinical findings. Our observation supports the hypothesis that PORN symptoms in HIV-negative patients can be an intermediate form between ARN and PORN, and can vary according to the patient's immune status. © The Author(s) 2016.

Fulminant Subacute Sclerosing Panencephalitis Presenting with Acute Ataxia and Hemiparesis in a 15-Year-Old Boy

PubMed Central

Yada, Praveen; Uppin, Megha S.; Jabeen, Shaik Afshan; Cherian, Ajith; Kanikannan, Meena Angamuthu; Borgohain, Rupam; Challa, Sundaram

2014-01-01

Background Subacute sclerosing panencephalitis (SSPE) is a delayed and fatal manifestation of measles infection. Fulminant SSPE is a rare presentation in which the disease progresses to death over a period of 6 months. The clinical features are atypical and can be misleading. Case Report We report herein a teenage boy who presented with acute-onset gait ataxia followed by right hemiparesis that evolved over 1 month, with left-hemispheric, delta-range slowing on the electroencephalogram (EEG). Magnetic resonance imaging disclosed multiple white-matter hyperintensities, suggesting a diagnosis of acute disseminated encephalomyelitis. He received intravenous steroids, and within 4 days of hospital admission he developed unilateral slow myoclonic jerks. Repeat EEG revealed Rademecker complexes, pathognomonic of SSPE, and an elevated titer of IgG antimeasles antibodies was detected in his cerebrospinal fluid. The disease progressed rapidly and the patient succumbed within 15 days of hospitalization. The diagnosis of SSPE was confirmed by autopsy. Conclusions This case illustrates the difficulty of recognizing fulminant SSPE when it manifests with asymmetric clinical and EEG abnormalities. PMID:25324886

Sleep Problems are Associated with Development and Progression of Lower Urinary Tract Symptoms: Results from REDUCE.

PubMed

Branche, Brandee L; Howard, Lauren E; Moreira, Daniel M; Roehrborn, Claus; Castro-Santamaria, Ramiro; Andriole, Gerald L; Hopp, Martin L; Freedland, Stephen J

2018-02-01

Although lower urinary tract symptoms and sleep problems often develop together, to our knowledge it is unknown whether sleep disturbances are linked to lower urinary tract symptoms development and progression. As measured by the 6-item MOS-Sleep (Medical Outcomes Study Sleep Scale) survey we examined the relationship between sleep problems, and the development and progression of lower urinary tract symptoms in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study. REDUCE was a randomized trial testing prostate cancer chemoprevention with dutasteride in men with prostate specific antigen 2.5 to 10 ng/ml and a negative biopsy. At baseline men completed MOS-Sleep and a scaled average was used to calculate the sleep score. Men were followed for 4 years and I-PSS (International Prostate Symptom Score) was completed at baseline and every 6 months. Asymptomatic men had I-PSS less than 8 while symptomatic men had I-PSS 8 or greater. In the placebo arm of 2,588 men not receiving α-blockers or 5α-reductase inhibitors at baseline we tested the association between sleep problems and lower urinary tract symptom development and progression using Cox models. During followup lower urinary tract symptoms developed in 209 of 1,452 asymptomatic men (14%) and 580 of 1,136 (51%) with lower urinary tract symptoms demonstrated progression. On multivariable analysis higher sleep scores were suggestively associated with increased lower urinary tract symptoms in asymptomatic men (quartile 4 vs 1 HR 1.41, 95% CI 0.92-2.17, p = 0.12) and with lower urinary tract symptom progression in symptomatic men (per 10 points of sleep score HR 1.06, 95% CI 1.01-1.12, p = 0.029). Among men with lower urinary tract symptoms worse sleep scores were associated with the progression of lower urinary tract symptoms and among asymptomatic men worse sleep scores were suggestively associated with the development of lower urinary tract symptoms. If confirmed, these data suggest that sleep problems may precede such symptoms. Whether treating sleep problems would improve lower urinary tract symptoms requires further testing. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2018-05-11

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

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion

PubMed Central

Mir, Tahreem A.; Kherani, Saleema; Hafiz, Gulnar; Scott, Adrienne W.; Zimmer-Galler, Ingrid; Wenick, Adam S.; Solomon, Sharon; Han, Ian; Poon, David; He, Lingmin; Shah, Syed Mahmood; Brady, Christopher J.; Meyerle, Catherine; Sodhi, Akrit; Linz, Marguerite O.; Sophie, Raafay; Campochiaro, Peter A.

2017-01-01

Purpose To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab (RBZ) Design Secondary outcome measure in randomized double-masked controlled clinical trial Subjects Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO) Methods Subjects were randomized to 0.5mg or 2.0mg RBZ every month for 6 months and then re-randomized to pro re nata (prn) groups RBZ+scatter photocoagulation (laser) or RBZ alone for an additional 30 months. Main Outcome Measures Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5mg versus 2.0mg RBZ, during monthly injections versus prn RBZ, and in patients treated with prn RBZ versus prn RBZ+laser. Results In RVO patients given monthly injections of 0.5mg or 2.0mg RBZ for 6 months there was no significant difference in the percentage who showed reduction or increase in area of RNP. However, regardless of dose, during the 6 month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared to subsequent time periods of prn RBZ treatment. After the 6 month period of monthly injections, BRVO, but not CRVO patients randomized to prn RBZ+laser showed significantly less progression of RNP compared to patients treated with prn RBZ. Conclusions Regardless of dose of ranibizumab (0.5mg or 2.0mg), monthly injections promote improvement and reduce progression of RNP compared to prn injections. Addition of scatter photocoagulation to prn RBZ may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO. PMID:26712560

Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

PubMed

Blancas, I; Fontanillas, M; Conde, V; Lao, J; Martínez, E; Sotelo, M J; Jaen, A; Bayo, J L; Carabantes, F; Illarramendi, J J; Gordon, M M; Cruz, J; García-Palomo, A; Mendiola, C; Pérez-Ruiz, E; Bofill, J S; Baena-Cañada, J M; Jáñez, N M; Esquerdo, G; Ruiz-Borrego, M

2018-07-01

This study aimed to describe the efficacy of fulvestrant 500 mg in postmenopausal women with estrogen receptor (ER)-positive advanced/metastatic breast cancer who had disease progression after receiving anti-estrogen therapy in clinical practice, getting real-world data. Multicenter, retrospective, observational study conducted in Spain. Postmenopausal women with locally advanced/metastatic ER-positive breast cancer who received treatment with fulvestrant 500 mg after progression with a previous anti-estrogen therapy were eligible. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), clinical benefit rate (CBR), duration of clinical benefit (DoCB), and safety profile. A total of 263 women were evaluated (median age, 65.8 years). At a median follow-up of 21.5 months, median PFS and OS were 10.6 and 43.2 months, respectively. PFS according to 1st, 2nd, 3rd, and ≥ 4th lines were 11.5, 10.6, 9.9, and 8.5 months, respectively (p = 0.0245). PFS in patients with visceral involvement was 10 months vs 10.6 months in patients without visceral involvement (p = 0.6604), 9.6 months in patients with high Ki67 vs 10 months in patients with low Ki67 (p = 0.7224), and 10.2 months in HER2+ patients vs 10.3 months in HER2- patients (p = 0.6809). The CBR was 56.5% and the DoCB was 18.4 months. The most frequently adverse events were injection site pain (10.3%) and musculoskeletal disorders (7.6%). Fulvestrant 500 mg administered in clinical practice was shown to be effective (PFS, 10.6 months; CBR, 56.5%) and well tolerated, in accordance with previous trials.

Experimental approaches for the treatment of malignant gliomas

PubMed Central

Arko, Leopold; Katsyv, Igor; Park, Grace E.; Luan, William Patrick; Park, John K.

2010-01-01

Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review. PMID:20546782

Cost and Schedule Analytical Techniques Development

NASA Technical Reports Server (NTRS)

1996-01-01

This Final Report summarizes the activities performed by Science Applications International Corporation (SAIC) for the base contract year from December 1, 1994 through November 30, 1995. The Final Report is in compliance with Paragraph 5 of Section F of the contract. This CSATD contract provides technical services and products to the NASA Marshall Space Flight Center's (MSFC) Engineering Cost Office (PP03) and the Program Plans and Requirements Office (PP02). Detailed Monthly Progress Reports were submitted to MSFC in accordance with the contract's Statement of Work Section IV "Reporting and Documentation". These reports spelled out each month's specific work accomplishments, deliverables submitted, major meetings held, and other pertinent information. This Final Report will summarize these activities at a higher level.

Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

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

Moussazadeh, Nelson; Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York; Lis, Eric

Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included diseasemore » progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen treated levels (36.1%) in 12 patients demonstrated progressive vertebral body collapse or endplate fractures at a median of 25.7 months (range 11.6-76.0), of which 5 (14%) became symptomatic and subsequently required percutaneous cement augmentation or surgery. Conclusions: In the longest-term series to date, high-dose single-fraction spinal SRS retained an excellent safety profile among long-term survivors (>5 years)« less

A Fully Automated Diabetes Prevention Program, Alive-PD: Program Design and Randomized Controlled Trial Protocol

PubMed Central

Azar, Kristen MJ; Block, Torin J; Romanelli, Robert J; Carpenter, Heather; Hopkins, Donald; Palaniappan, Latha; Block, Clifford H

2015-01-01

Background In the United States, 86 million adults have pre-diabetes. Evidence-based interventions that are both cost effective and widely scalable are needed to prevent diabetes. Objective Our goal was to develop a fully automated diabetes prevention program and determine its effectiveness in a randomized controlled trial. Methods Subjects with verified pre-diabetes were recruited to participate in a trial of the effectiveness of Alive-PD, a newly developed, 1-year, fully automated behavior change program delivered by email and Web. The program involves weekly tailored goal-setting, team-based and individual challenges, gamification, and other opportunities for interaction. An accompanying mobile phone app supports goal-setting and activity planning. For the trial, participants were randomized by computer algorithm to start the program immediately or after a 6-month delay. The primary outcome measures are change in HbA1c and fasting glucose from baseline to 6 months. The secondary outcome measures are change in HbA1c, glucose, lipids, body mass index (BMI), weight, waist circumference, and blood pressure at 3, 6, 9, and 12 months. Randomization and delivery of the intervention are independent of clinic staff, who are blinded to treatment assignment. Outcomes will be evaluated for the intention-to-treat and per-protocol populations. Results A total of 340 subjects with pre-diabetes were randomized to the intervention (n=164) or delayed-entry control group (n=176). Baseline characteristics were as follows: mean age 55 (SD 8.9); mean BMI 31.1 (SD 4.3); male 68.5%; mean fasting glucose 109.9 (SD 8.4) mg/dL; and mean HbA1c 5.6 (SD 0.3)%. Data collection and analysis are in progress. We hypothesize that participants in the intervention group will achieve statistically significant reductions in fasting glucose and HbA1c as compared to the control group at 6 months post baseline. Conclusions The randomized trial will provide rigorous evidence regarding the efficacy of this Web- and Internet-based program in reducing or preventing progression of glycemic markers and indirectly in preventing progression to diabetes. Trial Registration ClinicalTrials.gov NCT01479062; http://clinicaltrials.gov/show/NCT01479062 (Archived by WebCite at http://www.webcitation.org/6U8ODy1vo). PMID:25608692

Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome.

PubMed

Prosnitz, Aaron R; Leopold, Jane; Irons, Mira; Jenkins, Kathy; Roberts, Amy E

2017-07-01

To describe a group of children with co-incident pulmonary vein stenosis and Smith-Lemli-Opitz syndrome and to generate hypotheses as to the shared pathogenesis of these disorders. Retrospective case series. Five subjects in a pulmonary vein stenosis cohort of 170 subjects were diagnosed with Smith-Lemli-Opitz syndrome soon after birth. All five cases were diagnosed with Smith-Lemli-Opitz syndrome within 6 weeks of life, with no family history of either disorder. All cases had pathologically elevated 7-dehydrocholesterol levels and two of the five cases had previously reported pathogenic 7-dehydrocholesterol reductase mutations. Smith-Lemli-Opitz syndrome severity scores ranged from mild to classical (2-7). Gestational age at birth ranged from 35 to 39 weeks. Four of the cases were male by karyotype. Pulmonary vein stenosis was diagnosed in all cases within 2 months of life, earlier than most published cohorts. All cases progressed to bilateral disease and three cases developed atresia of at least one vein. Despite catheter and surgical interventions, all subjects' pulmonary vein stenosis rapidly recurred and progressed. Three of the subjects died, at 2 months, 3 months, and 11 months. Survival at 16 months after diagnosis was 43%. Patients with pulmonary vein stenosis who have a suggestive syndromic presentation should be screened for Smith-Lemli-Opitz syndrome with easily obtainable serum sterol tests. Echocardiograms should be obtained in all newly diagnosed patients with Smith-Lemli-Opitz syndrome, with a low threshold for repeating the study if new respiratory symptoms of uncertain etiology arise. Further studies into the pathophysiology of pulmonary vein stenosis should consider the role of cholesterol-based signaling pathways in the promotion of intimal proliferation. © 2017 Wiley Periodicals, Inc.

Corneal Collagen Crosslinking Combined with Phototherapeutic Keratectomy and Photorefractive Keratectomy for Corneal Ectasia after Laser in situ Keratomileusis.

PubMed

Zhu, Wei; Han, Yunfei; Cui, Changxia; Xu, Wenwen; Wang, Xuan; Dou, Xiaoxiao; Xu, Linlin; Xu, Yanyun; Mu, Guoying

2018-01-01

The aim of this study was to analyze the effects of corneal crosslinking (CXL) combined with phototherapeutic keratectomy (PTK) and photorefractive keratectomy (PRK) in halting the progression and improving the visual function of corneal ectasia after laser in situ keratomileusis (LASIK). PTK-PRK-CXL was performed on 14 eyes of 14 patients who developed corneal ectasia after LASIK. The visual acuity, spherical refraction and cylinder, corneal topography indices, thinnest corneal thickness (TCT), and endothelial cell count were evaluated at baseline and at 1, 3, 6, and 12 months postoperatively. The mean uncorrected visual acuity improved significantly from 0.64 ± 0.36 logMAR preoperatively to 0.19 ± 0.12 logMAR at 12 months of follow-up (p < 0.001), while the mean best corrected visual acuity improved from 0.21 ± 0.14 logMAR at baseline to 0.04 ± 0.10 logMAR at 12 months postoperatively (p < 0.001). A significant decrease was observed in Kmax and Kmean values from 52.51 ± 6.74 and 43.55 ± 3.37 D at baseline to 45.72 ± 5.18 (p < 0.001) and 40.60 ± 3.05 D (p < 0.001) at the 1-year follow-up. The mean TCT decreased significantly from 419.07 ± 36.56 µm before treatment to 320.93 ± 39.78 µm at 12 months of follow-up (p < 0.001), and there was no significant endothelial cell loss (p > 0.05) beyond 6 months after treatment. PTK-PRK-CXL is a promising procedure to halt the progression of post-LASIK keratectasia with significant visual quality improvement. © 2018 S. Karger AG, Basel.

Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group.

PubMed

Eichenauer, Dennis A; Plütschow, Annette; Fuchs, Michael; von Tresckow, Bastian; Böll, Boris; Behringer, Karolin; Diehl, Volker; Eich, Hans Theodor; Borchmann, Peter; Engert, Andreas

2015-09-10

The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group. The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009. The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL. Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population. © 2015 by American Society of Clinical Oncology.

Infant feeding in relation to islet autoimmunity and type 1 diabetes in genetically susceptible children: the MIDIA Study.

PubMed

Lund-Blix, Nicolai A; Stene, Lars C; Rasmussen, Trond; Torjesen, Peter A; Andersen, Lene F; Rønningen, Kjersti S

2015-02-01

We aimed to study the association of breast-feeding duration and age at the introduction of solid foods with the risk of islet autoimmunity and type 1 diabetes in genetically susceptible children. Newborns were recruited from the Norwegian general population during 2001-2007. After genetic screening of nearly 50,000 newborns, 908 children with the high-risk HLA genotype were followed up with blood samples and questionnaires at age 3, 6, 9, and 12 months and then annually. Complete infant diet data were available for 726 children. Any breast-feeding for 12 months or longer predicted a decreased risk of developing type 1 diabetes compared with any breast-feeding for less than 12 months before and after adjusting for having a first-degree relative with type 1 diabetes, vitamin D supplementation, maternal education, sex, and delivery type (hazard ratio 0.37 [95% CI 0.15-0.93]). Any breast-feeding for 12 months or longer was not associated with islet autoimmunity but predicted a lower risk of progression from islet autoimmunity to type 1 diabetes (hazard ratio 0.35 [95% CI 0.13-0.94]). Duration of full breast-feeding was not significantly associated with the risk of islet autoimmunity or type 1 diabetes nor was age at introduction of solid foods or breast-feeding at the time of introduction of any solid foods. These results suggest that breast-feeding for 12 months or longer predict a lower risk of progression from islet autoimmunity to type 1 diabetes among genetically predisposed children. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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

Hata, Masaharu, E-mail: mhata@syd.odn.ne.j; Omura, Motoko; Koike, Izumi

Purpose: Extramammary Paget's disease (EMPD) is a relatively rare malignancy that usually arises in the genital areas. Wide surgical excision remains the standard and most reliable curative treatment of EMPD. However, surgery is sometimes not possible, because many patients are elderly, and complete excision can be difficult owing to the tumor location. We, therefore, performed a review to determine the role of radiotherapy (RT) for EMPD. Methods and Materials: A total of 22 patients with EMPD in their external genitalia (4 men and 18 women, age 52-94 years at RT) underwent RT with curative intent. Nine patients had regional lymphmore » node metastases. A total dose of 45-70.2 Gy (median, 60) was delivered to the pelvis, including the tumors, in 25-39 fractions (median, 33). Results: In all but 3 patients, the irradiated tumors were controlled during a follow-up period of 8-133 months (median, 42). Of the 22 patients, 13 developed recurrences, including local progression within the radiation field in 3 and lymph node and/or distant metastases outside the radiation field in 10, at 3-43 months after treatment. The 2- and 5-year local progression-free rates were 91% and 84%, respectively. Of the 22 patients, 7 patients had died at 33-73 months after RT. The cause of death was tumor progression in 4, infectious pneumonia in 2, and renal failure in 1 patient. The overall and cause-specific survival rates were 100% for both at 2 years and 53% and 73% at 5 years, respectively. No therapy-related Grade 3 or greater toxicity was observed. Conclusions: RT is safe and effective for patients with EMPD. It appears to contribute to prolonged survival as a result of good tumor control.« less

Left ventricular remodeling leads to heart failure in mice with cardiac-specific overexpression of VEGF-B167: echocardiography and magnetic resonance imaging study.

PubMed

Lottonen-Raikaslehto, Line; Rissanen, Riina; Gurzeler, Erika; Merentie, Mari; Huusko, Jenni; Schneider, Jurgen E; Liimatainen, Timo; Ylä-Herttuala, Seppo

2017-03-01

Cardiac-specific overexpression of vascular endothelial growth factor (VEGF)-B 167 is known to induce left ventricular hypertrophy due to altered lipid metabolism, in which ceramides accumulate to the heart and cause mitochondrial damage. The aim of this study was to evaluate and compare different imaging methods to find the most sensitive way to diagnose at early stage the progressive left ventricular remodeling leading to heart failure. Echocardiography and cardiovascular magnetic resonance imaging were compared for imaging the hearts of transgenic mice with cardiac-specific overexpression of VEGF-B 167 and wild-type mice from 5 to 14 months of age at several time points. Disease progression was verified by molecular biology methods and histology. We showed that left ventricular remodeling is already ongoing at the age of 5 months in transgenic mice leading to heart failure by the age of 14 months. Measurements from echocardiography and cardiovascular magnetic resonance imaging revealed similar changes in cardiac structure and function in the transgenic mice. Changes in histology, gene expressions, and electrocardiography supported the progression of left ventricular hypertrophy. Longitudinal relaxation time in rotating frame (T 1 ρ ) in cardiovascular magnetic resonance imaging could be suitable for detecting severe fibrosis in the heart. We conclude that cardiac-specific overexpression of VEGF-B 167 leads to left ventricular remodeling at early age and is a suitable model to study heart failure development with different imaging methods. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Transgenic mice overexpressing tyrosine-to-cysteine mutant human alpha-synuclein: a progressive neurodegenerative model of diffuse Lewy body disease.

PubMed

Zhou, Wenbo; Milder, Julie B; Freed, Curt R

2008-04-11

Abnormal aggregation of human alpha-synuclein in Lewy bodies and Lewy neurites is a pathological hallmark of Parkinson disease and dementia with Lewy bodies. Studies have shown that oxidation and nitration of alpha-synuclein lead to the formation of stable dimers and oligomers through dityrosine cross-linking. Previously we have reported that tyrosine-to-cysteine mutations, particularly at the tyrosine 39 residue (Y39C), significantly enhanced alpha-synuclein fibril formation and neurotoxicity. In the current study, we have generated transgenic mice expressing the Y39C mutant human alpha-synuclein gene controlled by the mouse Thy1 promoter. Mutant human alpha-synuclein was widely expressed in transgenic mouse brain, resulting in 150% overexpression relative to endogenous mouse alpha-synuclein. At age 9-12 months, transgenic mice began to display motor dysfunction in rotarod testing. Older animals aged 15-18 months showed progressive accumulation of human alpha-synuclein oligomers, associated with worse motor function and cognitive impairment in the Morris water maze. By age 21-24 months, alpha-synuclein aggregates were further increased, accompanied by severe behavioral deficits. At this age, transgenic mice developed neuropathology, such as Lewy body-like alpha-synuclein and ubiquitin-positive inclusions, phosphorylation at Ser(129) of human alpha-synuclein, and increased apoptotic cell death. In summary, Y39C human alpha-synuclein transgenic mice show age-dependent, progressive neuronal degeneration with motor and cognitive deficits similar to diffuse Lewy body disease. The time course of alpha-synuclein oligomer accumulation coincided with behavioral and pathological changes, indicating that these oligomers may initiate protein aggregation, disrupt cellular function, and eventually lead to neuronal death.

Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial.

PubMed

Bines, J; Dienstmann, R; Obadia, R M; Branco, L G P; Quintella, D C; Castro, T M; Camacho, P G; Soares, F A; Costa, M E F

2014-04-01

As novel treatments carry substantial price tags and are mostly cost-prohibitive in low- and middle-income countries, there is an urgent need to develop alternatives, such as off-patent drugs. Megestrol acetate (MA) has a longstanding history in the treatment of breast cancer, but recently it is being used less often due to the advent of newer agents. This two-stage phase II trial evaluated the antitumor activity and toxicity of MA in postmenopausal women with hormone-sensitive advanced breast cancer who had experienced disease progression on a third-generation nonsteroidal aromatase inhibitor (NSAI). Eligible patients had metastatic breast cancer treated with a NSAI with at least 6-month progression-free survival (PFS), or relapse after ≥1 year on adjuvant NSAI. Patients received MA at a single daily oral dose of 160 mg. Primary end point was clinical benefit rate (CBR). Forty-eight patients were enrolled. The CBR was 40% [95% confidence interval (CI) 25% to 55%], and the median duration of clinical benefit was 10.0 (95% CI 8.0-14.2) months. The median PFS was 3.9 (95% CI 3.0-4.8) months. The most common grade 3 adverse events were anemia (2%), dyspnea (2%), fatigue (2%), musculoskeletal pain (4%), deep vein thrombosis (10%), and weight gain (2%). This is the first study to prospectively evaluate the efficacy and safety of MA in postmenopausal women with hormone-sensitive disease progressing on a NSAI. MA has demonstrated activity and acceptable tolerability in this setting, and therefore remains a reasonable treatment option in a cost-sensitive environment. These results also provide the background for further evaluation of progestins in the treatment of breast cancer. local trial number, related to the approval by the IRB: CEP 108/06.

Development of salivary cortisol circadian rhythm in preterm infants.

PubMed

Ivars, Katrin; Nelson, Nina; Theodorsson, Annette; Theodorsson, Elvar; Ström, Jakob O; Mörelius, Evalotte

2017-01-01

To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the first year of life. This prospective, longitudinal study included 51 preterm infants. 130 healthy full-term infants served as controls. Monthly salivary cortisol levels were obtained in the morning (07:30-09:30), at noon (10:00-12:00), and in the evening (19:30-21:30), beginning at gestational age week 28-32 and continuing until twelve months corrected age. Behavioral regularity was studied using the Baby Behavior Questionnaire. A salivary cortisol circadian rhythm was established by one month corrected age and persisted throughout the first year. The preterm infants showed a cortisol pattern increasingly more alike the full-term infants as the first year progressed. The preterm infants increase in behavioral regularity with age but no correlation was found between the development of salivary cortisol circadian rhythm and the development of behavior regularity. The time to establish salivary cortisol circadian rhythm differed between preterm and full-term infants according to postnatal age (p = 0.001) and was dependent on gestational age. Monthly salivary cortisol levels for preterm infants from birth until twelve months are presented. Additional findings were that topical corticosteroid medication was associated with higher concentrations of salivary cortisol (p = 0.02) and establishment of salivary cortisol circadian rhythm occurred later in infants treated with topical corticosteroid medication (p = 0.02). Salivary cortisol circadian rhythm is established by one month corrected age in preterm infants. Establishment of salivary cortisol circadian rhythm is related to gestational age rather than to postnatal age. Salivary cortisol circadian rhythm development is not related to behavioral regularity.

Lack of commensal flora in H. pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia

PubMed Central

Lofgren, Jennifer L.; Whary, Mark T.; Ge, Zhongming; Muthupalani, Sureshkumar; Taylor, Nancy S.; Mobley, Melissa; Potter, Amanda; Varro, Andrea; Eibach, Daniel; Suerbaum, Sebastian; Wang, Timothy C.; Fox, James G.

2010-01-01

Background & Aims Transgenic, insulin–gastrin (INS–GAS) mice have high circulating levels of gastrin. On a FVB/N background, these mice develop spontaneous atrophic gastritis and gastrointestinal intraepithelial neoplasia (GIN) with 80% prevalence 6 months after Helicobacter pylori infection. GIN is associated with gastric atrophy and achlorhydria, predisposing mice to non-helicobacter microbiota overgrowth. We determined if germ-free INS–GAS mice spontaneously develop GIN and if H. pylori accelerates GIN in gnotobiotic INS–GAS mice. Methods We compared gastric lesions and levels of mRNA, serum inflammatory mediators, antibodies, and gastrin among germ-free and H. pylori-monoinfected INS-GAS mice. Microbiota composition of specific pathogen-free (SPF) INS-GAS mice was quantified by pyro-sequencing. Results Germ-free INS-GAS mice had mild hypergastrinemia but did not develop significant gastric lesions until they were 9 months old; they did not develop GIN through 13 months. H. pylori monoassociation caused progressive gastritis, epithelial defects, oxyntic gland atrophy, marked foveolar hyperplasia and dysplasia, and strong serum and tissue proinflammatory immune responses (particularly in male mice) between 5 and 11 months post infection (P<0.05, compared with germ-free controls). Only 2 of 26 female, whereas 8 of 18 male, H. pylori-infected INS-GAS mice developed low- to high-grade GIN by 11 months post infection. Stomachs of H. pylori-infected SPF male mice had significant reductions in Bacteroidetes and significant increases in Firmicutes. Conclusions Gastric lesions take 13 months longer to develop in germ-free INS–GAS mice than male SPF INS-GAS mice. H. pylori-monoassociation accelerated gastritis and GIN but caused less-severe gastric lesions and delayed onset of GIN compared to H. pylori-infected INS-GAS mice with complex gastric microbiota. Changes of gastric microbiota composition might promote GIN in the achlorhydric stomachs of SPF mice. PMID:20950613

Utility of Leflunomide in the Treatment of Drug Resistant Cytomegalovirus Retinitis.

PubMed

Rifkin, Lana M; Minkus, Caroline L; Pursell, Kenneth; Jumroendararasame, Chaisiri; Goldstein, Debra A

2017-02-01

To describe leflunomide use in the treatment of drug resistant cytomegalovirus retinitis. Leflunomide has been shown to be effective in the treatment of systemic CMV viremia. Retrospective chart review of patients with CMV retinitis treated with leflunomide. Two HIV-negative organ transplant recipients with UL 97 mutation resistant-genotype CMV were identified. Patient 1 developed CMV viremia post-kidney transplant and subsequently bilateral CMV retinitis. Retinitis progressed, despite intravitreal injection of ganciclovir and foscarnet, and IV foscarnet and oral valganciclovir. Retinitis control was achieved with the addition of oral leflunomide. Disease remained inactive for 22 months. Patient 2 developed CMV retinitis after lung transplant. Disease progressed despite intravitreal foscarnet injections and oral valganciclovir. Control of retinitis was achieved with addition of oral leflunomide, allowing cessation of intravitreal therapy. Disease remained inactive until his death. Leflunomide may be considered as a treatment option for resistant CMV retinitis.

[Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new leukodystrophy].

PubMed

Vázquez-López, M; Ruiz-Martín, Y; de Castro-Castro, P; Garzo-Fernández, C; Martín-del Valle, F; Márquez-de la Plata, L

To report one patient with slowly progressive encephalopathy, ataxia, central hypomyelination, hypodontia and hypogonadotropic hypogonadism, the 4H syndrome. This clinical picture has been described recently and there are only four patients reported previously. A girl with a previously normal early psychomotor development, presented a slowly progressive deterioration since 15 months of age. Now, she is 14 years old, and has a severe cerebellar ataxia, with tremor and dysmetria. She can't neither walk nor remain standing alone. She has lost the sphincter control and has an immature expressive language. She has no puberal development and definitive hypodontia of upper central incisors. The brain magnetic resonance imaging shows a diffuse hypomyelination, that is confirmed with diffusion and spectroscopy studies. The hypomyelinating leukoencephalopathies are disorders with abnormally low amount of myelin. The diagnosis is difficult in most of the patients. The hypomyelinating leukoencephalopathies include classic disorders and new leukoencephalopathies, described in the past few years.

Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment

PubMed Central

Nobel, Yael R.; Cox, Laura M.; Kirigin, Francis F.; Bokulich, Nicholas A.; Yamanishi, Shingo; Teitler, Isabel; Chung, Jennifer; Sohn, Jiho; Barber, Cecily M.; Goldfarb, David S.; Raju, Kartik; Abubucker, Sahar; Zhou, Yanjiao; Ruiz, Victoria E.; Li, Huilin; Mitreva, Makedonka; Alekseyenko, Alexander V.; Weinstock, George M.; Sodergren, Erica; Blaser, Martin J.

2015-01-01

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment. PMID:26123276

Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment.

PubMed

Nobel, Yael R; Cox, Laura M; Kirigin, Francis F; Bokulich, Nicholas A; Yamanishi, Shingo; Teitler, Isabel; Chung, Jennifer; Sohn, Jiho; Barber, Cecily M; Goldfarb, David S; Raju, Kartik; Abubucker, Sahar; Zhou, Yanjiao; Ruiz, Victoria E; Li, Huilin; Mitreva, Makedonka; Alekseyenko, Alexander V; Weinstock, George M; Sodergren, Erica; Blaser, Martin J

2015-06-30

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

Etiology of Ibrutinib Discontinuation and Outcomes in Chronic Lymphocytic Leukemia Patients

PubMed Central

Maddocks, Kami J.; Ruppert, Amy S.; Lozanski, Gerard; Heerema, Nyla A.; Zhao, Weiqiang; Abruzzo, Lynne; Lozanski, Arletta; Davis, Melanie; Gordon, Amber; Smith, Lisa L.; Mantel, Rose; Jones, Jeffrey A.; Flynn, Joseph M.; Jaglowski, Samantha M.; Andritsos, Leslie A.; Awan, Farrukh; Blum, Kristie A.; Grever, Michael R.; Johnson, Amy J.; Byrd, John C.; Woyach, Jennifer A.

2015-01-01

Importance The Bruton’s Tyrosine Kinase inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuation from this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up. Objective To determine features associated with discontinuation of ibrutinib and outcomes. Design 308 patients participating in four sequential trials of ibrutinib were included. These trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014. Setting The Ohio State University Comprehensive Cancer Center Participants Patients with CLL enrolled on 4 sequential clinical trials. Main Outcome Measure Patients were evaluated for time to discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued due to progression, targeted deep sequencing was performed in samples at baseline and relapse. Results With a median follow-up of 20 months, 232 patients remain on therapy, 31 have discontinued because of progression, and 45 have discontinued for other reasons. Disease progression includes Richter’s transformation or progressive CLL. Richter’s appeared to occur early and CLL progressions later (cumulative incidence at 12 months: 4.5% (95% CI: 2.0% to 7.0%) and 0.3% (95% CI: 0% to 1.0%), respectively). Median survival following Richter’s transformation was 3.5 months (95% CI: 0.3–6.0), and 17.6 months (95% CI: 4.7-not reached) following CLL progression. Sequencing on peripheral blood from 8 patients with Richter’s transformation revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCγ2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCγ2 mutations in all. These mutations were not identified pre-treatment in any patient. Conclusions and Relevance This single institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with Richter’s transformation. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCγ2 with progression and clearly show that CLL progressions are associated with these mutations, while Richter’s transformation is likely not. PMID:26182309

Steady state acetabular cartilage wear after bipolar hemiarthroplasty: a case series of 10 patients with radiostereometric analysis.

PubMed

Tsukanaka, Masako; Støen, Ragnhild Ø; Figved, Wender; Frihagen, Frede; Nordsletten, Lars; Röhrl, Stephan M

2017-03-31

Cartilage wear is a concern after hemiarthroplasty. The precise pattern of the progression of wear has not been evaluated. We previously reported the application of radiostereonetric analysis (RSA) for the measurement of cartilage wear in patients. The purpose of this study was to report the amount and the orientation of the steady state wear of cartilage between 1 and 3 years after bipolar hemiarthroplasty. 22 patients with a bipolar hemiarthroplasty for displaced femoral neck fracture were included. 10 patients completed the mean follow up of 37 months. The cartilage wear was evaluated by calculating the migration of the bipolar head in reference to the markers in the acetabulum using RSA. The mean age of the patients at the final follow-up was 80 (range 67-91) years. The 3-D migration was -0.02 mm (SD 0.30) between 1 and 3 years. The migration in each direction was 0.03 mm (SD 0.49) in medial, 0.03 mm (SD 0.14) in proximal and 0.11 mm (SD 0.29) in posterior directions. 2 patients showed migration of more than 0.2 mm. The large initial migration seen in some patients up to 1 year did not progress further. Total wear after 37 months was 0.43 mm (SD 0.17). Cartilage wear progressed slowly in 2 of 10 patients from 1 to 3 years. No pelvic penetration was seen. We believe that RSA will give a basic knowledge about the development and the progression of cartilage wear after hemiarthroplasty.

Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy.

PubMed

Kyrychenko, Sergii; Poláková, Eva; Kang, Chifei; Pocsai, Krisztina; Ullrich, Nina D; Niggli, Ernst; Shirokova, Natalia

2013-03-15

Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca(2+) homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca(2+) release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca(2+) responses to mechanical stress and 'hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca(2+) sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca(2+) load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca(2+) signals and corrected changes in ECC, Ca(2+) load, and leak. Our findings suggest that increased RyR Ca(2+) sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.

Efficacy of icotinib in lung squamous-cell cancer: A real-world experience from single institution.

PubMed

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-12-01

Squamous cell carcinoma is a less common type of nonsmall cell lung cancer (NSCLC) which associates with a poor clinical prognosis and lacks specific therapy. This study aimed to evaluate the efficacy and safety of icotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has proven to be effective in EGFR-mutated NSCLC, in patients with lung squamous-cell cancer. Retrospective analysis was conducted in patients who had advanced lung squamous-cell cancer confirmed by cytology or histology. Patients were treated orally with icotinib (125 mg, three times daily) until event of unacceptable toxicity, disease progression or death. The primary endpoint was overall survival. The secondary endpoints were progression-free survival, overall response rate and disease control rate. Between January 2014 and May 2016, 20 patients were enrolled and evaluated for the efficacy and safety of icotinib. Overall, the median overall survival and progression-free survival were 9.93 months (95% confidence interval (CI): 3.46-16.40) and 3.0 months (95% CI: 0.00-8.35), respectively. The overall response rate and disease control rate were 20% and 70%, respectively. For treatment-naive patients (n = 11), the overall survival and progression-free survival were 9.93 months (95% CI: 0.00-23.49) and 6.27 months (95% CI: 0.00-12.61); the response rate and disease control rate were 27.3% and 54.5%, respectively. The overall survival and progression-free survival of patients treated with second- or multiple-line icotinib treatment (n = 9) were 6.5 months (95% CI: 0.80-12.20) and 1.2 months (95% CI: 1.10-1.30). A total of 11 patients experienced at least one treatment-related adverse event, most of which were mild to moderate. The most common manifestations were rash (n = 6, 30%) followed by diarrhea (n = 2, 10%). Icotinib has demonstrated a favorable efficacy and safety profile in patients with advanced lung squamous-cell cancer. © 2017 John Wiley & Sons Australia, Ltd.

Hanford Works monthly report, December 1950

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

Prout, G.R.

1951-01-22

This is a progress report of the production reactors on the Hanford Reservation for the month of December 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, April 1952

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

Prout, G.R.

1952-05-20

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, August 1950

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

Prout, G.R.

1950-09-18

This is a progress report of the production reactors on the Hanford Reservation for the month of August 1950. This report takes each division (e.g. manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, May 1951

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

Prout, G.R.

1951-06-21

This is a progress report of the production reactors on the Hanford Reservation for the month of May 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, December 1951

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

Prout, G.R.

1952-01-22

This is a progress report of the production reactors on the Hanford Reservation for the month of December 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, March 1951

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

Prout, G.R.

1951-04-20

This is a progress report of the production reactors on the Hanford Reservation for the month of March 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, July 1951

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

Prout, G.R.

This is a progress report of the production reactors on the Hanford Reservation for the month of July 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, March 1952

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

Prout, G.R.

1952-04-18

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, July 1952

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

Prout, G.R.

1952-08-15

This is a progress report of the production reactors on the Hanford Reservation for the month of July 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford works monthly report, September 1951

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

Prout, G.R.

This is a progress report of the production reactors on the Hanford Reservation for the month of September 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, January 1952

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

Prout, G.R.

This is a progress report of the production reactors on the Hanford Reservation for the month of January 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, August 1951

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

Not Available

1951-09-24

This is a progress report of the production reactors on the Hanford Reservation for the month of August 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, July 1950

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

Prout, G.R.

1950-08-18

This is a progress report of the production reactors on the Hanford Reservation for the month of July 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, November 1951

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

Prout, G.R.

1951-12-21

This is a progress report of the production reactors on the Hanford Reservation for the month of November 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, October 1950

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

Prout, G.R.

1950-11-20

This is a progress report of the production reactors on the Hanford Reservation for the month of October 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, September 1950

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

Prout, G.R.

1950-10-20

This is a progress report of the production reactors on the Hanford Reservation for the month of September 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, November 1950

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

Prout, G.R.

1950-12-20

This is a progress report of the production reactors on the Hanford Reservation for the month of November 1950. This report takes each division (e.g. manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Common Progress Monitoring Omissions: Planning and Practice. Progress Monitoring Brief #1

ERIC Educational Resources Information Center

National Center on Response to Intervention, 2013

2013-01-01

Progress monitoring, one of the essential components of Response to Intervention (RTI), is characterized by repeated measurement of academic performance that is conducted at least monthly. The process may be used to assess students' academic performance over time, to quantify student rates of improvement or responsiveness to instruction, and to…

Common Progress Monitoring Omissions: Reporting Information to Parents. Progress Monitoring Brief #4

ERIC Educational Resources Information Center

National Center on Response to Intervention, 2013

2013-01-01

Progress monitoring, one of the essential components of Response to Intervention (RTI), is characterized by repeated measurement of academic performance that is conducted at least monthly. The process may be used to assess students' academic performance over time, to quantify student rates of improvement or responsiveness to instruction, and to…

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

PubMed

Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P

2018-04-01

Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy

PubMed Central

Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Cloughesy, Timothy F

2018-01-01

Abstract Background Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Methods Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Results Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Conclusions Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. Clinical Trials Registration Number NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288) PMID:29016998

Local food supplementation and psychosocial stimulation improve linear growth and cognitive development among Indonesian infants aged 6 to 9 months.

PubMed

Helmizar, Helmizar; Jalal, Fasli; Lipoeto, Nur Indrawati; Achadi, Endang L

2017-01-01

To evaluate the effect of culturally-relevant food supplementation and psychosocial stimulation on infant growth and development. A community-based randomized controlled trial was conducted in 40 clusters from 5 selected villages in Tanah Datar District of West Sumatera, Indonesia. We assessed 355 infants aged 6 to 9 months at the beginning of the study. The infants were divided into 4 groups: 1) Food Supplementation (FS); 2) Psychosocial Stimulation (PS); 3) Food Supplementation and Psychosocial Stimulation (FS+PS); and 4) Control Group (CG). The formula food supplement was comprised of a variety of local food sources (local MP-ASI) and adjusted for the local habits. The quality of psychosocial stimulation was assessed with the Infant HOME inventory method. Progress at 6 months was assessed by anthropometry and the Bayley scores of cognition, language and motor function. There were improvements in linear growth, cognitive and motor development of children in the FS (p<0.05) and the FS+PS (p<0.01) groups compared to the CG. After six months of intervention, mean length increased to 6.86±2.08 cm and 6.66±2.41 cm for FS and FS+PS respectively (p<0.05). With the combination of food supplementation and psychosocial stimulation (FS+PS), cognitive development increased to 21.4±12.2 points (effect size 0.56) (p<0.01) and motor development increased to 20.7±18.4 points (effect size 0.50) (p<0.001). Combined intervention with local food supplementation and psychosocial stimulation improved infant growth, cognitive and motor development.

EARLY POSTPARTUM PARENTAL PREOCCUPATION AND POSITIVE PARENTING THOUGHTS: RELATIONSHIP WITH PARENT-INFANT INTERACTION.

PubMed

Kim, Pilyoung; Mayes, Linda; Feldman, Ruth; Leckman, James F; Swain, James E

2013-01-01

Parenting behaviors and parent-infant emotional bonding during the early postpartum months play a critical role in infant development. However, the nature and progression of parental thoughts and their relationship with interactive behaviors have received less research. The current study investigated the trajectory of parental thoughts and behaviors among primiparous mothers ( n = 18) and fathers ( n = 15) and multiparous mothers ( n = 13) and fathers ( n = 13), which were measured at the first and third postpartum month. At the third postpartum month, the relationship between parental thoughts and parental interactive behaviors also was tested. Mothers and fathers showed high levels of preoccupations and caregiving thoughts during the first postpartum month that significantly declined by the third postpartum month. In contrast, positive thoughts about parenting and the infant increased over the same time interval. Mothers presented higher levels of preoccupations and positive thoughts than did fathers, and first-time parents reported more intense preoccupations than did experienced parents. Although maternal sensitivity was inversely related to maternal anxious thoughts, paternal sensitivity was predicted by higher levels of anxious as well as caregiving and positive thoughts.

Treatment of advanced Hodgkin's disease with B-CAVE following MOPP failure.

PubMed

Porzig, K J; Portlock, C S; Robertson, A; Rosenberg, S A

1978-05-01

Between March 1973, and December 1976, 22 patients who developed disease progression during or after MOPP therapy were treated with a new combination, B-CAVe (Bleomycin 5 mg/m2 iv days 1, 28, 35; CCNU 100 mg/m2 po day 1; adriamycin 60 mg/m2 iv day 1; and vinblastine 5 mg/m2 iv day 1). Objective responses were achieved in 17 of 22 patients (77%) and 11 of 22 responses were complete (50%). The actuarial survival for all patients is 16.4 months. For complete responders the median is 24 months with 2 complete responders dead without evidence of Hodgkin's Disease. Median relapse free survival for complete responders has not been reached at 35+ months while that for partial responders is 14 months. Significant adriamycin cardiotoxicity was encountered in two patients. There were no life threatening bacterial infections during B-CAVe. Two patients died of Pneumocystis carinii several months after cessation of therapy. B-CAVe is effective in the therapy of advanced Hodgkin's disease after MOPP failure, and this regimen is comparable to other previously reported MOPP salvage combinations.

Chorea in Late-Infantile Neuronal Ceroid Lipofuscinosis: An Atypical Presentation.

PubMed

Saini, Arushi Gahlot; Sankhyan, Naveen; Singhi, Pratibha

2016-07-01

Classic late-infantile neuronal ceroid lipofuscinosis is characterized by progressive intellectual and motor deterioration, seizures, vision loss, and early death. Prominent chorea is an atypical feature and is rarely described in children. A four-year-old girl with seizures followed by a year-long progressive cognitive decline and a three month history of intermittent chorea leading to rapid motor deterioration. The onset of illness was marked by seizures occurring as generalized tonic-clonic seizures and myoclonic jerks. There was gradual regression of cognitive milestones with increasing forgetfulness and impaired quality and content of speech. Nine months later, she developed chorea. These movements were associated with clumsiness, incoordination, and progressive loss of motor milestones. She was unable to perform manual tasks or maintain antigravity posture resulting in unsteadiness and frequent falls. The movements were aggravated by action or excitement and were absent in sleep. Magnetic resonance imaging depicted diffuse cerebral and cerebellar atrophy. Sequencing analysis of TPP1 gene showed a novel, homozygous, splice site mutation c.89+1G>A which resulted in nil enzyme activity and a severe phenotype with onset of disease symptoms at an early age of three years. The presence of chorea in late-infantile neuronal ceroid lipofuscinoses is atypical but does not exclude the diagnosis of late-infantile neuronal ceroid lipofuscinoses, especially in children with psychomotor regression, seizures and diffuse brain atrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma.

PubMed

Kil, P J M; Goldschmidt, H M J; Wieggers, B J A; Kariakine, O B; Studer, U E; Whelan, P; Hetherington, J; de Reijke, Th M; Hoekstra, J W; Collette, L

2003-01-01

To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to clinical progression. Finally to compare TPS with prostate-specific antigen (PSA) measurements in terms of prognostic impact in patients with metastatic prostatic carcinoma. TPS and PSA measurements were performed before start of and monthly during intermittent MAB in 68 patients participating in EORTC protocol 30954. Both TPS and PSA were measured in serum. Fifty-six patients from eight centers were included in the final analysis because at least three TPS values were available. TPS and PSA values were correlated with clinical course of the disease. Median follow-up was 21.3 months. Three patient groups were defined on clinical grounds: (a) clinically progressive disease (n=18); (b) clinically stable disease (n=33); and (c) patients who did not reach a predefined nadir PSA value following 9 months of treatment (n=5). Pretreatment TPS was significantly higher in the clinically progressive patients than in the other patient groups (p=0.0041). When grouping patients according to their pretreatment TPS values (cut-off value of 100 U/l) the pretreatment TPS value (>100 U/l) proved to be a statistically significant prognostic factor with respect to time to progression: elevated TPS was associated with a 3.8 increased risk for progressive disease (p=0.0055). Pretreatment PSA (>100 ng/ml) was of no prognostic value for time to progression. In five patients increase of TPS coincided with or preceded clinical progression during treatment, whereas PSA remained normal. Additional value of pretreatment TPS measurements in metastatic prostate cancer patients is found in defining the patients with rapid clinical progression. Following MAB an increase in TPS signifies clinical progression even if PSA is found to remain normal.

Tolerance of aged Fischer 344 rats against chlordecone-amplified carbon tetrachloride toxicity.

PubMed

Murali, B; Korrapati, M C; Warbritton, Alan; Latendresse, John R; Mehendale, Harihara M

2004-06-01

We have investigated the effects of chlordecone 1(CD)+CCl4 combination in adult (3 months), middle aged (14 months), and old aged (24 months) male Fischer 344 (F344) rats. After a non-toxic dietary regimen of CD (10 ppm) or normal powdered diet for 15 days, rats received a single non-toxic dose of CCl4 (100 microl/kg, i.p., 1:4 in corn oil) or corn oil (500 microl/kg, i.p.) alone on day 16. Liver injury was assessed by plasma ALT, AST, and histopathology during a time course of 0-96 h. Liver tissue repair was measured by [3H-CH3]-thymidine (3H-T) incorporation into hepatic nuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Hepatomicrosomal CYP2E1 protein, enzyme activity, and covalent binding of 14CCl4-derived radiolabel were measured in normal and CD fed rats. Exposure to CCl4 alone caused modest liver injury only in 14- and 24-month-old rats but neither progression of injury nor mortality. The CD+CCl4 combination led to 100% mortality in 3-month-old rats by 72 h, whereas none of the 14- and 24-month-old rats died. Both 3- and 14-month-old rats exposed to CD+Cl4 had identical liver injury up to 36 h indicating that bioactivation-mediated CCl4 injury was the same in the two age groups. Thereafter, liver injury escalated only in 3-month-old while it declined in 14-month-old rats. In 24-month-old rats initial liver injury at 6 h was similar to the 3- and 14-month-old rats and thereafter did not develop to the level of the other two age groups, recovering from injury by 96 h as in the 14-month-old rats. Neither hepatomicrosomal CYP2E1 protein nor the associated p-nitrophenol hydroxylase activity or covalent binding of 14CCl4-derived radiolabel to liver tissue differed between the age groups or diet regimens 2 h after the administration of 14CCl4. Compensatory liver tissue repair (3H-T, PCNA) was prompt and robust soon after CCl4 liver injury in the 14- and 24-month-old rats. In stark contrast, in the 3-month-old rats it failed allowing unabated progression of liver injury. These findings suggest that stimulation of early onset and robust liver tissue repair rescue the 14- and 24-month-old F344 rats from the lethal effect of the CD+CCl4 combination.

Gas-turbine critical research and advanced technology support project

NASA Technical Reports Server (NTRS)

Clark, J. S.; Lowell, C. E.; Niedzwiecki, R. W.; Nainiger, J. J.

1979-01-01

The technical progress made during the first 15 months of a planned 40-month project to provide a critical-technology data base for utility gas-turbine systems capable of burning coal-derived fuels is summarized. Tasks were included in the following areas: (1) combustion, to study the combustion of coal-derived fuels and conversion of fuel-bound nitrogen to NOx; (2) materials, to understand and prevent hot corrosion; and (3) system studies, to integrate and guide the other technologies. Significant progress was made.

[Lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement].

PubMed

Caliez, J; Monnet, I; Pujals, A; Rousseau-Bussac, G; Jabot, L; Boudjemaa, A; Leroy, K; Chouaid, C

2017-05-01

Among patients with non-small-cell lung cancer, coexistence of EGFR mutation and ALK rearrangement is rare. We describe the clinical features of two patients with this double anomaly. A 62-year-old Caucasian non-smoking woman was diagnosed with cT4N0M0 lung adenocarcinoma. Initial biopsy showed EGFR mutation and ALK rearrangement. She received cisplatin-gemcitabine, followed by 17 months of gemcitabine. Owing to progression, she received erlotinib for 14 months, then paclitaxel for 6 months and finally crizotinib. A partial response was achieved and maintained for 24 months. A 45-year-old Caucasian woman, light smoker, was diagnosed with cT2N3M0 lung adenocarcinoma. Only EGFR mutation was found on initial analysis. She underwent treatment with cisplatin-gemcitabine and thoracic radiotherapy. Progression occurred after 8 months and afatinbib was started. Eight months later, progression was observed with a neoplasic pleural effusion in which tumor cells expressing ALK rearrangement were found. A new FISH analysis was performed on the initial tumor but did not find this rearrangement. Despite a third line of crizotinib, the patient died one month later. The literature shows 45 other cases of these two abnormalities, observed either from the start or during follow-up. EGFR's TKI were almost always given before ALK's TKI. Therapeutic strategy needs to be clarified in cases of double alteration. With regard to the second patient, appearance of ALK rearrangement may constitute a resistance mechanism to EGFR's TKI. Copyright © 2016 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Hanford Atomic Products Operation monthly report, April 1954

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

McCune, F.K.

1954-05-21

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1954. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Atomic Products Operation monthly report, March 1953

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

McCune, F.K.

1953-04-22

This is a progress report of the production reactors on the Hanford Reservation for the month of March 1953. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

78 FR 26223 - National Physical Fitness and Sports Month, 2013

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-03

... Physical Fitness and Sports Month, 2013 By the President of the United States of America A Proclamation... life. During National Physical Fitness and Sports Month, we celebrate that progress and keep striving... at work. Through Let's Move! and the President's Council on Fitness, Sports, and Nutrition, we...

Hanford Atomic Products Operation monthly report, April 1953

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

McCune, F.K.

1953-05-20

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Atomic Products Operation monthly report, January 1954

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

McCune, F.K.

1954-02-25

This is a progress report of the production reactors on the Hanford Reservation for the month of January 1954. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes the accomplishments and employee relations for that month.

A case of rectal carcinoma with skin and bone marrow metastasis with concurrent extensive visceral involvement; unusual and dismal co-incidence.

PubMed

Arslan, Cagatay; Sen, Cenk Ahmet; Ortac, Ragip

2015-06-01

Novel systemic therapies and modern surgical and ablative approaches have improved the survival rates for the patients with metastatic colorectal cancer. However, there are still patients with poor prognosis and underlying mechanisms that could not be defined clearly. Metastatic colorectal cancer patients with skin metastasis have a poor prognosis. A 45-year-old man, who presented with large bowel obstruction, was diagnosed with metastatic rectal adenocarcinoma. Unresectable liver metastases were found at diagnosis. FOLFOX plus bevacizumab treatment was started, but the patient developed bowel obstruction after the third cycle. Therefore, ileostomy was performed. Multiple skin, lung, liver and bone metastases appeared during that time. Bone marrow biopsy demonstrated diffuse infiltration by adenocarcinoma cells. Even though partial remission was achieved after 4 cycles of FOLFIRI-cetuximab, the disease progressed after the 8th cycle. The patient lost his life due to disease progression 8 months after the diagnosis. Bone marrow and skin are unusual sites of metastasis for colorectal carcinoma. Metastases in bone marrow and skin develop at later stages of metastatic disease. This patient lived only 4 months after the development of skin and bone marrow metastases. Skin and bone marrow metastases may be the harbingers of short survival. Biopsy of metastatic sites is crucial for diagnosis and detailed molecular analysis. Molecular pathway alterations underlying worse disease course may be found, and hence probable targets for drug improvement may be indicated.

Gene expression suggests spontaneously hypertensive rats may have altered metabolism and reduced hypoxic tolerance.

PubMed

Ritz, Marie-Françoise; Grond-Ginsbach, Caspar; Engelter, Stefan; Lyrer, Philippe

2012-02-01

Cerebral small vessel disease (SVD) is an important cause of stroke, cognitive decline and vascular dementia (VaD). It is associated with diffuse white matter abnormalities and small deep cerebral ischemic infarcts. The molecular mechanisms involved in the development and progression of SVD are unclear. As hypertension is a major risk factor for developing SVD, Spontaneously Hypertensive Rats (SHR) are considered an appropriate experimental model for SVD. Prior work suggested an imbalance between the number of blood microvessels and astrocytes at the level of the neurovascular unit in 2-month-old SHR, leading to neuronal hypoxia in the brain of 9-month-old animals. To identify genes and pathways involved in the development of SVD, we compared the gene expression profile in the cortex of 2 and 9-month-old of SHR with age-matched normotensive Wistar Kyoto (WKY) rats using microarray-based technology. The results revealed significant differences in expression of genes involved in energy and lipid metabolisms, mitochondrial functions, oxidative stress and ischemic responses between both groups. These results strongly suggest that SHR suffer from chronic hypoxia, and therefore are unable to tolerate ischemia-like conditions, and are more vulnerable to high-energy needs than WKY. This molecular analysis gives new insights about pathways accounting for the development of SVD.

Choroid Plexus Papilloma Expansion Over 7 Years in Aicardi Syndrome

PubMed Central

Frye, Richard E.; Polling, Jon S.; Ma, Louis C. K.

2008-01-01

Choroid plexus papillomas have been reported in Aicardi syndrome. Management of these tumors is controversial because their natural progression in Aicardi syndrome has only been rarely documented. This report describes the progression of such a tumor over 7 years in a girl with Aicardi syndrome. A magnetic resonance imaging study at 2 months of age demonstrated a right ventricular mass that was consistent with a unilateral choroid plexus papilloma. The mass enlarged over the next 7 years without causing any clinically apparent symptoms, ventricular enlargement, hydrocephalus, or mass effect. The tumor was removed without change in behavior or development. The know cases of Aicardi syndrome associated with choroid plexus papillomas are reviewed. The heterogeneous nature of this lesion is highlighted. PMID:17621535

A Preliminary Study of the Effects of a Multitheory-Driven Intervention in Adults With Prediabetes Mellitus.

PubMed

Tsai, Fu-Mian; Lin, Chiu-Chu; Lin, Huey-Shyan; Liu, Yi

2018-06-01

Prediabetes mellitus (pre-DM) is an important predictive indicator of Type 2 diabetes. A person with pre-DM is eight times more likely to develop diabetes than a person without pre-DM. Prior research suggests that proactive interventions may delay the progression of this disease and reduce the rate of disease development. The purposes of this preliminary study were to develop a multitheory-driven lifestyle intervention protocol for adults with pre-DM and to evaluate its feasibility and impacts on knowledge regarding pre-DM, dietary behaviors, and physical activity (primary outcomes) as well as to describe the disease progression indicators (secondary outcomes). A single-group, longitudinal study design was used. Thirty-nine participants were included in the analysis. A generalized estimating equation model was used to determine the trends in changes in the outcomes. All of the participants underwent testing at baseline (T0) and at 3 (T1), 6 (T2), and 12 (T3) months after the 4-week lifestyle intervention. There were significantly increasing trends for each study parameter (Pre-DM Knowledge Assessment Form-12, p < .01; Dietary Behavior Scale, p < .01) and significantly positive changes in body weight (p < .01), body mass index (p < .01), fasting glucose level (p < .01), and glycated hemoglobin level (p < .01) over the 12-month study period. This study supports the feasibility of the developed multitheory-driven lifestyle intervention protocol and suggests that its application may improve the effectiveness of diabetes prevention programs in clinical settings. Further randomized controlled trials are needed.

Prognostic Value of [18F]-Fluoromethylcholine Positron Emission Tomography/Computed Tomography Before Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer.

PubMed

Cysouw, Matthijs; Bouman-Wammes, Esther; Hoekstra, Otto; van den Eertwegh, Alfons; Piet, Maartje; van Moorselaar, Jeroen; Boellaard, Ronald; Dahele, Max; Oprea-Lager, Daniela

2018-06-01

To investigate the predictive value of [ 18 F]-fluoromethylcholine positron emission tomography/computed tomography (PET/CT)-derived parameters on progression-free survival (PFS) in oligometastatic prostate cancer patients treated with stereotactic body radiation therapy (SBRT). In [ 18 F]-fluoromethylcholine PET/CT scans of 40 consecutive patients with ≤4 metachronous metastases treated with SBRT we retrospectively measured the number of metastases, standardized uptake values (SUV mean , SUV max , SUV peak ), metabolically active tumor volume (MATV), and total lesion choline uptake. Partial-volume correction was applied using the iterative deconvolution Lucy-Richardson algorithm. Thirty-seven lymph node and 13 bone metastases were treated with SBRT. Thirty-three patients (82.5%) had 1 lesion, 4 (10%) had 2 lesions, and 3 (7.5%) had 3 lesions. After a median follow-up of 32.6 months (interquartile range, 35.5 months), the median PFS was 11.5 months (95% confidence interval 8.4-14.6 months). Having more than a single metastasis was a significant prognostic factor (hazard ratio 2.74; P = .03), and there was a trend in risk of progression for large MATV (hazard ratio 1.86; P = .10). No SUV or total lesion choline uptake was significantly predictive for PFS, regardless of partial-volume correction. All PET semiquantitative parameters were significantly correlated with each other (P ≤ .013). The number of choline-avid metastases was a significant prognostic factor for progression after [ 18 F]-fluormethylcholine PET/CT-guided SBRT for recurrent oligometastatic prostate cancer, and there seemed to be a trend in risk of progression for patients with large MATVs. The lesional level of [ 18 F]-fluoromethylcholine uptake was not prognostic for progression. Copyright © 2018 Elsevier Inc. All rights reserved.

Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study.

PubMed

Ferrucci, Pier F; Minchella, Ida; Mosconi, Massimo; Gandini, Sara; Verrecchia, Francesco; Cocorocchio, Emilia; Passoni, Claudia; Pari, Chiara; Testori, Alessandro; Coco, Paola; Munzone, Elisabetta

2015-06-01

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

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

Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki

Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effectmore » of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.« less

Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression.

PubMed

Puzanov, Igor; Amaravadi, Ravi K; McArthur, Grant A; Flaherty, Keith T; Chapman, Paul B; Sosman, Jeffrey A; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B; Lin, Paul S; Kim, Kevin B

2015-07-01

Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported. Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾ 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. Copyright © 2015 Elsevier Ltd. All rights reserved.

A PHASE II TRIAL OF THALIDOMIDE IN PATIENTS WITH REFRACTORY ENDOMETRIAL CANCER AND CORRELATION WITH ANGIOGENESIS BIOMARKERS: A GYNECOLOGIC ONCOLOGY GROUP STUDY

PubMed Central

McMeekin, D. Scott; Sill, Michael W.; Benbrook, Doris; Darcy, Kathleen M.; Stearns-Kurosawa, Deborah J.; Eaton, Lynne; Yamada, S. Diane

2007-01-01

Objectives A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of thalidomide in persistent or recurrent endometrial cancer refractory to cytotoxic chemotherapy, and to correlate angiogenesis biomarker expression with clinical outcome. Methods Consenting patients were treated until progression or intolerable toxicity with an oral starting dose of 200 mg thalidomide/day that was to increase by 200 mg every 2 weeks to a target dose of 1000 mg/day. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), and soluble endothelial protein C receptor (sEPCR) were analyzed by ELISA in pre and post-treatment specimens. Results Twenty-four of 27 patients enrolled in the study were eligible, of whom 2 reached the target dose, 8 progressed before achieving the target dose and 14 refused or had toxicity that prohibited escalation. Two patients (8.3%) remained progression-free ≥ 6 months. There were 3 (12.5%) with partial responses, 2 (8.3%) with stable disease, 15 (62.5%) with increasing disease, and 4 (16.7%) who were inevaluable for response. Median progression-free survival and overall survival were 1.7 months and 6.3 months, respectively. No grade 4 toxicities were observed. Common grade 3 toxicities included hematologic (n=3), cardiovascular (n=3), constitutional (n=3), and neurologic (n=4). Thalidomide did not decrease VEGF or bFGF levels but reduced sEPCR levels in serum. Elevated plasma vascular endothelial growth factor levels were associated with increased risk of progression and death. Conclusions Thalidomide demonstrated limited ability to delay progression (as measured by PFS at 6 months), produce objective responses or reduce angiogenic marker levels in chemotherapy refractory endometrial cancer. VEGF level appears to be prognostically significant in such patients, independent of thalidomide treatment. PMID:17306350

Vegetarian low-protein diets supplemented with keto analogues: a niche for the few or an option for many?

PubMed

Piccoli, Giorgina B; Ferraresi, Martina; Deagostini, Maria C; Vigotti, Federica Neve; Consiglio, Valentina; Scognamiglio, Stefania; Moro, Irene; Clari, Roberta; Fassio, Federica; Biolcati, Marilisa; Porpiglia, Francesco

2013-09-01

Low-protein diets are often mentioned but seldom used to slow chronic kidney disease (CKD) progression. The aim of the study was to investigate the potential for implementation of a simplified low-protein diet supplemented with alpha-keto analogues (LPD-KA) as part of the routine work-up in CKD patients. In an implementation study (December 2007-November 2011), all patients with CKD Stages IV-V not on dialysis, rapidly progressive Stage III and/or refractory proteinuria, were offered either a simplified LPD-KA, or commercially available low-protein food. LPD-KA consisted of proteins 0.6 g/kg/day, supplementation with Ketosteril 1 pill/10 Kg, 1-3 free-choice meals/week and a simplified schema based on 'allowed' and 'forbidden' foods. 'Success' was defined as at least 6 months on LPD-KA. Progression was defined as reduction in glomerular filtration rate (GFR)[(Chronic Kidney Disease Epidemiology Collaboration) formula CKD-EPI] in patients with at least 6 months of follow-up. Of about 2500 patients referred (8% CKD Stages IV-V), 139 started LPD-KA; median age (70 years) and prevalence of comorbidity (79%) were in line with the dialysis population. Start of dialysis was the main reason for discontinuation (40 cases, unplanned in 7); clinical reasons were recorded in 7, personal preference in 14 and improvement and death in 8 each. The low gross mortality (4% per year) and the progression rate (from -8 to 0 mL/min/year at 6 months) are reassuring concerning safety. None of the baseline conditions, including age, educational level, comorbidity or kidney function, discriminated the patients who followed the diet for at least 6 months. Our data suggest a wider offer of LPD-KA to patients with severe and progressive CKD. The promising results in terms of mortality and progression need confirmation with different study designs.

Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

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

Vainshtein, Jeffrey M., E-mail: jvainsh@med.umich.edu; Schipper, Matthew; Zalupski, Mark M.

2013-05-01

Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factorsmore » on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.« less

Characterization of Retinal Disease Progression in a 1-Year Longitudinal Study of Eyes With Mild Nonproliferative Retinopathy in Diabetes Type 2.

PubMed

Ribeiro, Luisa; Bandello, Francesco; Tejerina, Amparo Navea; Vujosevic, Stela; Varano, Monica; Egan, Catherine; Sivaprasad, Sobha; Menon, Geeta; Massin, Pascale; Verbraak, Frank D; Lund-Andersen, Henrik; Martinez, Jose P; Jürgens, Ignasi; Smets, Erica; Coriat, Caroline; Wiedemann, Peter; Ágoas, Victor; Querques, Giuseppe; Holz, Frank G; Nunes, Sandrina; Neves, Catarina; Cunha-Vaz, José

2015-08-01

To identify eyes of patients with diabetes type 2 that show progression of retinal disease within a 1-year period using noninvasive techniques. Three hundred seventy-four type 2 diabetic patients with mild nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study [ETDRS] level 20 or 35) were included in a 12-month prospective observational study to identify retinopathy progression. Four visits were scheduled at 0, 3, 6, and 12 months. Microaneurysm (MA) activity using the RetmarkerDR and retinal thickness using spectral-domain optical coherence tomography (SD-OCT) were assessed by a central reading center at all visits and ETDRS severity level in the first and last visits. Three hundred thirty-one eyes/patients completed the study. Microaneurysm formation rate greater than or equal to 2 was present in 68.1% of the eyes and MA turnover greater than or equal to 6 in 54.0% at month 6. Higher MA turnover values were registered in eyes that showed progression in ETDRS severity level (P < 0.03). There were also significant correlations between increased microaneurysm activity and increases in retinal thickness. Spectral-domain OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Progression of retinal thickening was registered in eyes that had either subclinical or clinical macular edema at baseline. Changes in MA activity measured with RetmarkerDR and in central retinal thickness in eyes with mild nonproliferative diabetic retinopathy and diabetes type 2 are able to identify eyes at risk of progression. These eyes/patients should be selected for inclusion in future clinical trials of drugs targeted to prevent diabetic retinopathy progression to vision-threatening complications. (ClinicalTrials.gov number, NCT01145599.)

The role of early magnetic resonance imaging in predicting survival on bevacizumab for recurrent glioblastoma: Results from a prospective clinical trial (CABARET).

PubMed

Field, Kathryn M; Phal, Pramit M; Fitt, Greg; Goh, Christine; Nowak, Anna K; Rosenthal, Mark A; Simes, John; Barnes, Elizabeth H; Sawkins, Kate; Cher, Lawrence M; Hovey, Elizabeth J; Wheeler, Helen

2017-09-15

Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma; however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival. Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard. For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values < .001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease; the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors. In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017;123:3576-82. © 2017 American Cancer Society. © 2017 American Cancer Society.

Disease progression of acute pancreatitis in pediatric patients.

PubMed

Hao, Fabao; Guo, Hongjie; Luo, Qianfu; Guo, Chunbao

2016-05-15

Approximately 10% of patients with acute pancreatitis (AP) progress to chronic pancreatitis. Little is known about the factors that affect recurrence of pancreatitis after an initial episode. We retrospectively investigated patients with AP, focusing on their outcomes and the predictors for disease progression. Between July 2003 and June 2015, we retrospectively enrolled first-time AP patients with medical records on disease etiology, severity (according to the Atlanta classifications), and recurrence of AP. Independent predictors of recurrent AP (RAP) and chronic pancreatitis were identified using the logistic regression model. Of the total 159 patients, 45 (28.3%) developed RAP, including two episodes of RAP in 19 patients, and 9 (5.7%) developed chronic pancreatitis. The median duration from the time of AP to the onset of RAP was 5.6 ± 2.3 months. RAP patients were identified as more common among patients with idiopathic first-time AP. The presence of severe ascites, pancreatic necrosis, and systemic complications was independent predictors of RAP in pediatric patients. Experiencing over two RAP episodes was the predictor for developing chronic pancreatitis. No influence of age or number of AP episodes was found on the occurrence of abdominal pain, pain severity, and the prevalence of any pain. Severity of first-time AP and idiopathic first-time AP are related to RAP. Recurrence increases risk for progression to chronic pancreatitis. The risk of recurrence increased with increasing numbers of AP episodes. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma.

PubMed

Noh, Jae Myoung; Lee, Eonju; Ahn, Yong Chan; Oh, Dongryul; Kim, Yoon-Duck; Woo, Kyung In; Ko, Young-Hyeh; Kim, Seokhwi

2016-09-13

Retrospective analyses were done on 19 lacrimal adenoid cystic carcinoma (ACC) patients who underwent curative treatment between 1997 and 2013. Nine patients (47.4%) had T1-2 disease and ten (52.6%) had T4 disease. Surgical procedures were globe-preserving tumor resection in 11 patients (57.9%), incisional biopsy in five (26.3%), and orbital exenteration was undertaken in three (15.8%). Residual tumor burdens were R0/1 in 12 patients (63.2%) and R2 in seven (36.8%). Radiation therapy (RT) was recommended to all patients, and 16 (84.2%) completed RT (median 60 Gy). After median follow-up of 57.5 months, seven (36.8%) developed progression and three (15.8%) died. Local recurrence occurred in four patients (21.1%), distant metastasis in one (5.3%), and combined local recurrence and distant metastasis in two (10.5%). Progression-free survival and overall survival rates at 5-years were 64.5% and 82.6%, respectively. Among 12 patients following R0/1 resection, two (16.7%) developed local recurrence and none died, while among seven following R2 resection, five (71.4%) developed progression and three (42.9%) died. RT following R0/R1 resection could reduce progression. Globe-preserving surgery and RT seemed optimal strategy for T1-2 disease. Careful attention should to be paid to minimize residual tumor burden at surgery and effort for safe radiation dose escalation would be desired.

Erythropoietic bone marrow in the pigeon: Development of its distribution and volume during growth and pneumatization of bones

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

Schepelmann, K.

1990-01-01

During postnatal development of the pigeon, a large portion of the skeleton becomes pneumatized, displacing the hemopoietic bone marrow. The consequences of pneumatization on distribution and quantity of bone marrow as well as the availability of other sites for hemopoiesis have been investigated. Hemopoietic marrow of differently aged pigeons divided into five groups from 1 week posthatching (p.h.) up to 6 months p.h. was labeled with Fe-59 and examined by serial whole-body sections. Autoradiography and morphometry as well as scintillation counts of single bones and organs were also carried out. No sign of a reactivation of embryonic sites of erythropoiesismore » was found. Bone marrow weight and its proportion of whole-body weight increased during the first 4 weeks p.h. from 0.54% to 2.44% and decreased in the following months to about 1.0%. The developing bone marrow showed a progressive distribution during the first months of life, eventually being distributed proportionally over the entire skeleton, except for the skull. At the age of 6 months p.h. bone marrow had been displaced, its volume decreasing in correlation to increasing pneumaticity and conversion to fatty marrow. This generates the characteristic pattern of bone marrow distribution in adult pigeons, which shows hemopoietic bone marrow in ulna, radius, femur, tibiotarsus, scapula, furcula, and the caudal vertebrae.« less

Prophylactic cranial irradiation in small cell lung cancer: a single institution experience.

PubMed

Naidoo, J; Kehoe, M; Sasiadek, W; Hacking, D; Calvert, P

2014-03-01

Prophylactic cranial irradiation (PCI) is used to prevent the development of brain metastases in small cell lung carcinoma. PCI confers an overall survival (OS) benefit in both limited and extensive stage disease. We analyze the incidence of symptomatic brain metastases, progression-free survival (PFS) and OS in a cohort of patients who received PCI, in a 5-year period. A retrospective review of all patients who had received PCI between 2006 and 2011 at the Whitfield Clinic was completed. Patient- and disease-related characteristics, the number of patients who developed brain metastases, PFS and OS data were collected. 24 patients were identified. 14 (58.3 %) patients were male, 10 (41.7 %) were female, with a mean age of 62.5 years (range 31-78). All patients were smokers. 12 (50 %) patients had limited stage small cell lung cancer (SCLC), 12 (50 %) had extensive stage disease. 2 (8.2 %) patients developed brain metastases post PCI (p = 0.478.) The median PFS for limited stage SCLC was 13 months (range 3-20) and 10 months (range 5-18) for extensive stage SCLC. Median OS was 15 months (range 4-29) in limited stage SCLC, and 11 months (range 5-29) in extensive stage SCLC. Our study demonstrated a low incidence of symptomatic brain metastases and favourable median PFS and OS in the patients that received PCI, when compared to published phase III data.

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

PubMed

Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

2011-01-01

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

Conjugal amyotrophic lateral sclerosis: a case report from Scotland.

PubMed

Fernandes, P M; Macleod, M R; Bateman, A; Abrahams, S; Pal, S

2017-03-29

Conjugal amyotrophic lateral sclerosis is rare, with significant effects on psychological and care needs. We report a case of conjugal amyotrophic lateral sclerosis disease from central Scotland. This case is particularly unusual as both patients were diagnosed within an 18-month period and experienced the disease simultaneously, with similar symptomatology and progression. Patient A was a 71-year-old man who presented with unilateral arm weakness and wasting. Patient B was a 68-year-old woman who presented with unilateral shoulder and elbow weakness. Diagnosis of amyotrophic lateral sclerosis was made within a few months of presentation in both cases, based on typical clinical symptomatology together with supportive neurophysiological testing. Interventions included enteral feeding and non-invasive ventilation. The time period between symptom onset and death was 5 years for Patient A and 3.5 years for Patient B. This case illustrates two main points: the care issues surrounding cases of conjugal neurological disease, and the psychological issues in these patients. There are significant care issues arising when co-habiting couples both develop severe functionally limiting neurological diseases at the same time. The more slowly progressive nature of Patient A's disease may be at least partially explained by the support he was able to receive from Patient B before she developed symptoms. Secondly, there are important psychological effects of living with someone with the same - but more advanced - progressive and incurable neurological disease. Thus, Patient B was reluctant to have certain interventions that she had observed being given to her husband. Lastly, no plausible shared environmental risk factors were identified, implying that the co-occurrence of ALS in this couple was a random association.

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

Jalali, Rakesh, E-mail: rjalali@tmc.gov.i; Raut, Nirmal; Arora, Brijesh

Purpose: To present outcome data in a prospective study of radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ) in children with diffuse intrinsic pontine gliomas (DIPGs). Methods and Materials: Pediatric patients with newly diagnosed DIPGs were prospectively treated with focal RT to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m{sup 2}, Days 1-42). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m{sup 2}, Days 1-5) was given every 28 days to a maximum of 12 cycles. Response was evaluated clinically and radiologically with magnetic resonance imaging and positron emission tomographymore » scans. Results: Between March 2005 and November 2006, 20 children (mean age, 8.3 years) were accrued. Eighteen patients have died from disease progression, one patient is alive with progressive disease, and one patient is alive with stable disease. Median overall survival and progression-free survival were 9.15 months and 6.9 months, respectively. Grade III/IV toxicity during the concurrent RT-TMZ phase included thrombocytopenia in 3 patients, leucopenia in 2, and vomiting in 7. Transient Grade II skin toxicity developed in the irradiated fields in 18 patients. During the adjuvant TMZ phase, Grade III/IV leucopenia developed in 2 patients and Grade IV thrombocytopenia in 1 patient. Patients with magnetic resonance imaging diagnosis of a high-grade tumor had worse survival than those with a low-grade tumor (p = 0.001). Patients with neurologic improvement after RT-TMZ had significantly better survival than those who did not (p = 0.048). Conclusions: TMZ with RT has not yielded any improvement in the outcome of DIPG compared with RT alone. Further clinical trials should explore novel treatment modalities.« less

Examining a progressive model of self-stigma and its impact on people with serious mental illness.

PubMed

Corrigan, Patrick W; Rafacz, Jennifer; Rüsch, Nicolas

2011-10-30

The self-esteem of some people with serious psychiatric disorders may be hurt by internalizing stereotypes about mental illness. A progressive model of self-stigma yields four stages leading to diminished self-esteem and hope: being aware of associated stereotypes, agreeing with them, applying the stereotypes to one's self, and suffering lower self-esteem. We expect to find associations between proximal stages - awareness and agreement - to be greater than between more distal stages: awareness and harm. The model was tested on 85 people with schizophrenia or other serious mental illnesses who completed measures representing the four stages of self-stigma, another independently-developed instrument representing self-stigma, proxies of harm (lowered self-esteem and hopelessness), and depression. These measures were also repeated at 6-month follow-up. Results were mixed but some evidence supported the progressive nature of self-stigma. Most importantly, separate stages of the progressive model were significantly associated with lowered self-esteem and hope. Implications of the model for stigma change are discussed. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Progressive valgus angulation of the ankle secondary to loss of fibular congruity treated with medial tibial hemiepiphysiodesis and fibular reconstruction.

PubMed

Lesiak, Alex C; Esposito, Paul W

2014-06-01

The fibula is an important stabilizer of the lateral ankle. Discontinuity of the fibular shaft can lead to progressive pain and shortening of the fibula, ultimately causing loss of lateral support to the ankle. Two children, who sustained segmental bone loss of the shaft of the fibula, developed progressive symptomatic valgus of the ankle with widening of the mortice and lateral subluxation of the talus. Both patients were treated with fibular plating and grafting with tricalcium sulfate with acute reconstitution of fibular length. Distal medial tibial hemiepiphysiodesis was simultaneously performed. One patient required revision plating and grafting 14 months after the index surgery because of plate failure. The valgus angulation and the widened medial mortice were corrected in the ankles of both patients, who returned to full activities. The patients were followed to maturity; the correction has been maintained, and they remain asymptomatic. The technique used in these cases can correct valgus angulation secondary to loss of fibular congruity rather than only halting progression of the deformity.

Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.

PubMed

Ramasubramanian, Aparna; Kytasty, Christina; Meadows, Anna T; Shields, Jerry A; Leahey, Ann; Shields, Carol L

2013-10-01

To report on the frequency of cysts and tumors of the pineal gland in patients with retinoblastoma. Observational retrospective case control study. Institutional. study population: Four hundred eight patients treated for retinoblastoma from January 2000 to January 2012 at Wills Eye Institute, Philadelphia, Pennsylvania, USA. Magnetic resonance imaging (MRI) features of the pineal gland were evaluated in all patients with retinoblastoma. Characteristics of patients with pineal cysts and pineoblastoma were reviewed. Comparison of frequency of pineal gland cyst and pineoblastoma in children managed with systemic chemoreduction vs other methods. Of 408 patients, treatment included systemic chemoreduction in 252 (62%) and nonchemoreduction methods in 156 (38%). Overall, 34 patients (8%) manifested pineal gland cyst and 4 (1%) showed pineoblastoma. Of all 408 patients, comparison (chemoreduction vs nonchemoreduction) revealed pineal cyst (20/252 vs 14/156, P = .7) and pineoblastoma (1/252 vs 3/156, P = .1). The pineal cyst (n = 34) (mean diameter 4 mm) was asymptomatic (n = 34), followed conservatively (n = 34), and with minimal enlargement (n = 2, 9%) but without progression to pineoblastoma. The cyst was found in 22 germline and 12 nongermline patients (P = .15). Among the 4 patients with pineoblastoma, all had germline mutation and 2 had family history of retinoblastoma. Among all patients with family history of retinoblastoma (n = 45), 2 (4%) developed pineoblastoma. The pineoblastoma was asymptomatic in 2 patients and symptomatic with vomiting and headache in 2 patients. The mean interval from date of retinoblastoma detection to pineal cyst was 2 months (median 2, range 0-8 months) and to pineoblastoma was 27 months (median 28, range 7-46 months). Management included aggressive chemotherapy and radiotherapy, with 2 survivors. Pineal gland cyst was incidentally detected in 8% of retinoblastoma patients, causing no symptoms, and without progression to pineoblastoma. Pineoblastoma was detected in 1% of patients and fewer patients who received systemic chemotherapy developed pineoblastoma, possibly indicating a systemic protective effect. Copyright © 2013 Elsevier Inc. All rights reserved.

Health and Safety Research Division progress report, October 1, 1988--March 31, 1990

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

Not Available

1990-09-01

The Health and Safety Research Division (HASRD) of the Oak Ridge National Laboratory (ORNL) continues to maintain an outstanding program of basic and applied research displaying a high level of creativity and achievement as documented by awards, publications, professional service, and successful completion of variety of projects. Our focus is on human health and the scientific basis for measurement and assessment of health-related impacts of energy technologies. It is our custom to publish a division progress report every 18 months that summarizes our programmatic progress and other measures of achievement over the reporting period. Since it is not feasible tomore » summarize in detail all of our work over the period covered by this report (October 1, 1988, to March 30, 1990), we intend this document to point the way to the expensive open literature that documents our findings. During the reporting period the Division continued to maintain strong programs in its traditional areas of R D, but also achieved noteworthy progress in other areas. Much of the Division's work on site characterization, development of new field instruments, compilation of data bases, and methodology development fits into this initiative. Other new work in tunneling microscopy in support of DOE's Human Genome Program and the comprehensive R D work related to surface-enhanced Raman spectroscopy have attained new and exciting results. These examples of our progress and numerous other activities are highlighted in this report.« less