tbuckley/cabot-search huggingface dataset:
Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities
Authors: Christina S. Baik, Eric H. Rubin, Patrick M. Forde, Janice M. Mehnert, Deborah Collyar, Marcus O. Butler, Erica L. Dixon, Laura Q.M. Chow
Journal: Clinical Cancer Research (2017)

Abstract Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials. Clin Cancer Res; 23(17); 4992–5002. ©2017 AACR. See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
Adult Bone Marrow Cell Therapy for Ischemic Heart Disease
Authors: Muhammad R. Afzal, Anweshan Samanta, Zubair I. Shah, Vinodh Jeevanantham, Ahmed Abdel-Latif, Ewa K. Zuba-Surma, Buddhadeb Dawn
Journal: Circulation Research (2015)

Rationale: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. Objective: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. Methods and Results: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91–3.92; P &lt;0.00001), reduced infarct size (−2.25%; 95% confidence interval, −3.55 to −0.95; P =0.0007) and LV end-systolic volume (−6.37 mL; 95% confidence interval, −8.95 to −3.80; P &lt;0.00001), and tended to reduce LV end-diastolic volume (−2.26 mL; 95% confidence interval, −4.59 to 0.07; P =0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (&lt;48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. Conclusions: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.
“Standard Care” in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials
Authors: Rachel F. Dear, Kevin McGeechan, Megan B. Barnet, Alexandra L. Barratt, Martin H.N. Tattersall
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov. Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor–negative disease were less likely consistent), and recruitment in ≥4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation.
Double pathology in a woman with worsening dysphagia
Authors: Pazhanivel Mohan, Kuppusamy Senthamizh Selvan
Journal: BMJ (2017)

A 58 year old woman had intermittent difficulty swallowing solids for several years. She gave a history of large oral pills getting stuck in the throat. She noticed worsening dysphagia over two months, and it was now persistent and progressive so that she could take only liquids. She had lost weight and on examination was thin and pale. Laboratory tests showed low haemoglobin and iron deficiency. An oesophagogram was taken to evaluate the dysphagia (fig 1 …
Longitudinal Fluorescence in Situ Hybridization at Primary Diagnosis and Relapse Reveals Clonal Evolution after Autologous Stem Cell Transplantation in Multiple Myeloma
Authors: Maximilian Merz, Thomas Hielscher, Anja Seckinger, Dirk Hose, Uta Bertsch, Kai Neben, Marc S Raab, Igor Blau, Hans Walter Lindemann, Ingo GH Schmidt-Wolf, Christof Scheid, Mathias Haenel, Katja Weisel, Hartmut Goldschmidt, Anna Jauch, Jens Hillengass
Journal: Blood (2016)
Segmental yttrium-90 radioembolization versus chemoembolization for localized hepatocellular carcinoma.
Authors: Siddharth A Padia, Guy E Johnson, Kathryn Jors Horton, Sharon Kwan, Sandeep Vaidya, Christopher R Ingraham, Wayne L Monsky, Karim Valji, Matthew J Kogut, Raymond Sze Yeung, James O Park, Renuka Bhattacharya, Iris Liou, William Proctor Harris
Journal: Journal of Clinical Oncology (2016)

4084 Background: Transarterial chemoembolization (TACE) remains the standard of care for localized, surgically unresectable hepatocellular carcinoma (HCC). However, yttrium-90 radioembolization (Y90) may yield high response rates when delivered to a single segment in ablative-level radiation doses. This study compared Y90 to TACE for localized HCC, with assessments of toxicity, tumor response, and survival. Methods: Over a 6-year period, 178 patients underwent treatment for 235 tumors with either Y90 or TACE performed to a single hepatic Couinaud segment. Under IRB approval, patient and tumor characteristics were tabulated. TACE was performed utilizing doxorubicin; Y90 was delivered using an ablative-level dosing strategy. Toxicity, index tumor and overall response based on modified RECIST criteria, and overall survival were compared. Results: 101 patients underwent segmental Y90 for 132 tumors. 77 patients underwent segmental TACE for 103 tumors. Age, gender, etiology of liver disease, degree of cirrhosis (Child-Pugh A 60%, B 34%, C 6%), and tumor stage (BCLC A 34%, B 17%, C 42%, D 7%) were similar between the groups. Y90 patients had higher rates of portal venous invasion or infiltrative tumor compared to TACE patients (18% v 1%, p<0.001; 23% v 9%, p=0.004, respectively). TACE trended towards higher rates of bilirubin toxicity (p=0.06). Toxicities (≥ grade 3) were otherwise similar. Y90 demonstrated higher complete response rates for both the index tumor and overall compared to TACE, with longer times to local tumor progression. Survival was similar between the two groups. Conclusions: When performed in a segmental, ablative-level dose strategy, Y90 demonstrates higher complete tumor response rates and local tumor control when compared to TACE, with similar toxicity profiles. Despite a greater proportion of patients with high-risk tumor characteristics in the Y90 group, similar overall survival was achieved. Category Y90 TACE P-value Index tumor response (%) CR 90 73 <0.001 PR 7 19 SD 2 5 PD 1 3 Overall response (%) CR 83 58 <0.001 PR 12 26 SD 2 8 PD 3 8 Local tumor progression (%) 6 months 2 3 0.992 1 year 4 15 0.040 Overall survival (%) 6 months 98 99 0.680 1 year 92 92 0.585 2 years 84 77 0.454
‘二重’ペプチジルオリゴヌクレオチド複合体:RNAの触媒開裂における立体配座柔軟性の役割【Powered by NICT】
Authors: Staroseletz Yaroslav, Williams Aled, K Burusco Kepa, Alibay Irfan, V Vlassov Valentin, A Zenkova Marina, V Bichenkova Elena
Journal: Biomaterials (2017)
ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma
Authors: Abibatou Ndoye, Anna Budina-Kolomets, Curtis H. Kugel, Marie R. Webster, Amanpreet Kaur, Reeti Behera, Vito W. Rebecca, Ling Li, Patricia A. Brafford, Qin Liu, Y.N. Vashisht Gopal, Michael A. Davies, Gordon B. Mills, Xiaowei Xu, Hong Wu, Meenhard Herlyn, Michael C. Nicastri, Jeffrey D. Winkler, Maria S. Soengas, Ravi K. Amaravadi, Maureen E. Murphy, Ashani T. Weeraratna
Journal: Cancer Research (2017)

Abstract Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873–85. ©2017 AACR.
Human Immunodeficiency Virus Preexposure Prophylaxis for Adolescent Men
Authors: Renata Arrington-Sanders
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Abstract 452: Effect of Exercise Training on Sleep Quality and Quality of Life in Post Myocardial Infarction Patients
Authors: Jayati Vohra, Kushal Madan, Manish Sharma, J.P.S Sawhney
Journal: Circulation Research (2016)

Objectives: To study the effect of four weeks of aerobic exercise training, on sleep quality and quality of life parameters like anxiety, depression and physical functioning in Post Myocardial Infarction (MI) patients. Methods: ST elevated MI patients (n=21, &lt;65years age) were voluntarily divided into 2 groups, control group (n=11) and exercising group (n=10). The patients in experimental group followed an exercise program of 3 sessions per week for 4 weeks. The subjective quality of life, anxiety and depression levels were assessed by the SF 36 questionnaire and Hospital Anxiety &amp; Depression Scale (HAD scale) and the sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI). Poor sleep quality and short sleep duration was defined as PSQI &gt; 5 and total sleep time &lt;6hrs. respectively. After 4 weeks of the program the questionnaires were repeated for all 21 patients. Wilcoxon rank order test and Student T test were used. P&lt;0.05 was considered statistically significant Results: Intergroup analysis showed statically significant reduction in anxiety score (9vs0.5) and depression score (3vs0) in exercise group as compared to control group respectively. As compared to control group, exercise group also showed statistically significant improvement in the quality of life parameter score [physical functioning (750vs1000), role functioning physical (0vs400) &amp; emotional (0vs300), energy level (215vs400), emotional well-being (400vs500), social functioning (120vs200), general health (230vs462.5) &amp; health changes (50vs100)]. Intra group analysis also showed significant changes only in exercise group. After 4 weeks of exercise training, PSQI score improved in the experimental group from 9.5±4.11 to 1.13±0.35 (p=0.00029) indicating better sleep quality and duration. While it remained comparable to the baseline values in the control group i.e. from 9.9±4.70 to 10.33±3.87 (p value= 0.514). Conclusion: Four weeks of exercise program improves the quality &amp; duration of sleep and quality of life in MI patients after 2 weeks of index event.
All GP referrals should be subject to clinical peer review, says NHS England
Authors: Anne Gulland
Journal: BMJ (2017)

GPs will be expected to discuss with other GP colleagues their decision to refer any new patients to hospital, as part of a push by NHS England to curb inappropriate referrals to secondary care.

Guidance issued by NHS England to clinical commissioning groups (CCGs) in May stated that all areas of the country should have a system in place from September 2017 to ensure that all new GP referrals are subject to clinical peer review.

A spokesman for NHS England told The BMJ that around half of CCGs already had a peer review process in place and that it was up to the other half to follow suit. NHS England emphasised that any system should not be “established …
Microsatellite instability in pancreatic cancer.
Authors: Jennifer Marie Eatrides, Domenico Coppola, Sameer Al Diffalha, Richard D. Kim, Gregory M. Springett, Amit Mahipal
Journal: Journal of Clinical Oncology (2016)

e15753 Background: Microsatellite instability (MSI) is a feature of cancers related to defective mismatch repair protein functions and has been well characterized in colorectal cancer (CRC). In CRC, high levels of MSI have been found to predict a better overall prognosis and increased benefit of immune based therapies. Pancreatic cancer has few systemic treatment options available and is highly resistant to chemotherapy and radiation. Immune based therapies have had great success in many cancers, however they have shown little clinical benefit in pancreatic cancer. Few studies have evaluated the prevalence of MSI in pancreatic cancer and none have characterized MSI high (MSI-H) versus stable (MSI-S) patients. We aim to explore the incidence and clinical impact of MSI in pancreatic cancer, as it may predict a subset of patients who will respond to immunotherapy. Methods: 109 pancreatic cancer biopsies were identified at a single institution between 2006-2012. Tissue microarray (TMA) blocks were prepared using 1mm tissue cores and evaluated with immunohistochemistry (IHC) using antibodies against MLH1, MSH2, MSH6, and PMS2. TMAs were evaluated by 2 pathologists and scored on a scale of 0-5, with 0 indicating loss of mismatch repair (MSI-H), and others considered MSI-S. Characteristics of patients were collected and Kaplan Meier curves were used to determine median overall survival (OS). Results: 24 (22%) pancreatic biopsies were MSI-H with a deficit of MLH1, PMS2, MSH2 or MSH6, based on TMA. MSI-H patient characteristics: median age 65 yrs, 42% male, 29% stage I, 25% stage II, 42% stage III, 4% stage IV at diagnosis. MSI-S patient characteristics: median age 67 yrs, 45% male, 19% stage I, 53% stage II, 25% stage III, 4% stage IV at diagnosis. 48.6% were treated with surgery alone, 44% were treated with a combination of surgery, radiation and chemotherapy. Although not statistically significant, median OS was 21.5 months in MSI-H patients and 20.0 months in MSI-S patients (p= 0.68). Conclusions: We report incidence of MSI-H pancreatic cancer of 22% primarily in surgically resected patients using IHC on TMA samples. MSI in pancreatic cancer remains poorly characterized. Further investigation is warranted to determine whether MSI predicts response to immunotherapy as it has in CRC.
核酸捕捉マイクロファイバメッシュは外傷誘発性炎症と血栓症を阻害する【Powered by NICT】
Authors: Lee Jaewoo, G Jackman Jennifer, Kwun Jean, Manook Miriam, Moreno Angelo, A Elster Eric, D Kirk Allan, W Leong Kam, A Sullenger Bruce
Journal: Biomaterials (2017)
IMAAGEN trial safety and efficacy update: Effect of abiraterone acetate and low-dose prednisone on prostate-specific antigen and radiographic disease progression in patients with nonmetastatic castration-resistant prostate cancer.
Authors: Charles J. Ryan, E. David Crawford, Neal D. Shore, Willie Underwood, Mary-Ellen Taplin, Anil Londhe, Peter St. John Francis, Jennifer Phillips, Tracy McGowan, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2016)

5061 Background: IMAAGEN is a phase 2, multicenter study evaluating abiraterone acetate (AA) 1000 mg plus prednisone 5 mg (AA+P5) for the treatment of patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). The primary endpoint was proportion of patients with ≥ 50% decrease in prostate-specific antigen (PSA) levels after 6 treatment cycles. Herein, we report updated results on secondary endpoints and safety from the IMAAGEN study (database cutoff: Oct. 2015). Methods: All enrolled pts had high-risk nmCRPC: PSA ≥ 10ng/mL or PSA doubling time ≤ 10 months at screening. Pts received AA+P5 daily; treatment cycles were 28 days. Secondary endpoints included time to PSA progression, time to radiographic progressive disease, and safety. Results: At the time of database cutoff, 44 (33.6%) of the 131 enrolled pts remained on study treatment, and Kaplan-Meier estimate of median follow-up was 40.0 months. Mean age was 72 (48-90) years. Median time to PSA progression was 28.7 months (95% CI 21.2, 38.2). With 31 confirmed progression events, the median time to radiographic progressive disease was not reached; however, in a sensitivity analysis including 15 additional unconfirmed progressions that led to initiation of new therapy, the median time to radiographic progressive disease was 41.4 months (95% CI 27.6, NE). 96.2% of pts had an adverse event (AE) (61.1% had a Grade ≥ 3 AE) and 43.5% had a serious AE (SAE) (41.2% had a Grade ≥ 3 SAE). 15.3% of pts had AEs resulting in study treatment discontinuation. Seven pts had AEs resulting in death. Conclusions: Treatment of high-risk nmCRPC patients with AA+P5 resulted in a median time to PSA progression of 28.7 months and a median time to radiographic progressive disease of 41.4 months. The safety profile of AA+P5 reported in this update is consistent with the safety profile from previously reported studies of AA 1000 mg in combination with either 5 or 10 mg prednisone. Clinical trial information: NCT01314118.
ヒト全血と混合培養した場合の生体材料は内皮細胞活性化を誘発する【Powered by NICT】
Authors: Herklotz Manuela, Hanke Jasmin, Haensel Stefanie, Drichel Juliane, Marx Monique, F Maitz Manfred, Werner Carsten
Journal: Biomaterials (2016)