tbuckley/cabot-search huggingface dataset:
Apalutamide (APA) or enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (CRPC): A systematic review and network meta-analysis of randomized clinical trials (RCTs).
Authors: Irbaz Bin Riaz, Sandipan Bhattacharjee, Saad Malik, Thanh P. Ho, Qurat Ul Ain Riaz Sipra, Muhammad Zain Farooq, Safi U. Khan, M. Hassan Murad, Manish Kohli
Journal: Journal of Clinical Oncology (2019)

263 Background: In non-metastatic CRPC with short PSA doubling time, APA or ENZA with ADT have shown to slow development of metastasis. We performed an indirect comparison of APA and ENZA clinical effectiveness (efficacy and side effects) using network meta-analysis. Methods: A search of Medline, Embase, Cochrane Library, and Cochrane Central Register of Controlled Trials was performed to identify relevant RCTs. Collected data included hazard ratio (HR) and confidence interval (CI) for primary outcome of median time to metastasis free survival (MFS) and secondary outcomes of median time to overall survival (OS), PSA progression, initiation of cytotoxic therapy and number of adverse events (AE) in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. We used a fixed effects model using Bayesian approach to generate pooled estimates. Results: Two randomized trials (n=2608) were analyzed. SPARTAN trial compared APA plus ADT to ADT alone and PROSPER compared ENZA plus ADT to ADT alone. Risk of bias was low. There were no statistically significant differences between APA and ENZA in MFS, OS, median time to PSA progression and initiation of cytotoxic therapy. The MFS endpoint hazard ratio (HR) was 0.97 (95% CI 0.73-1.28) for comparing the two drugs. APA had fewer reports of hypertension (HR 0.54, 95% CI 0.31–0.91) compared to enzalutamide. However, no significant differences were observed in other AEs including grade 3 or higher AE, serious AE, AE leading to death or trial discontinuation. Common AEs (nausea, diarrhea, fall, dizziness, arthralgia, weight loss) and AEs of special interests (mental impairment disorders, seizures) were also comparable between APA and ENZA. Conclusions: In non-metastatic CRPC with short PSA doubling time, APA and ENZA showed similar time to metastasis free survival. APA was associated with lower incidence of hypertension than ENZA; otherwise, side effect profile was similar. Given similar efficacy and risk profile demonstrated in this study, clinical decision making should depend on other factors such as cost and availability.
The presence of virus significantly associates with chronic rhinosinusitis disease severity
Authors: Rachel K. Goggin, Catherine A. Bennett, Seweryn Bialasiewicz, Rajan S. Vediappan, Sarah Vreugde, Peter‐John Wormald, Alkis J. Psaltis
Journal: Allergy (2019)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Genomic and clinical determinants of recurrence in localized clear cell renal cell carcinoma (ccRCC).
Authors: Ziad Bakouny, Sarah Abou Alaiwi, Amin Nassar, Ronan Flippot, Pier Vitale Nuzzo, Dominick Bossé, Xiao X. Wei, Bradley Alexander McGregor, Lauren Christine Harshman, Sabina Signoretti, David J. Kwiatkowski, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2019)

664 Background: Multiple clinical risk scores and gene expression models have predicted recurrence in localized ccRCC. However, few studies explored genomic alterations (GA) predicting recurrence. Methods: We assessed genomic and clinical correlates of disease-free survival (DFS) in surgically treated localized ccRCC using a targeted next generation sequencing (NGS) platform (Oncopanel/PROFILE) and publicly available NGS and clinical data from TCGA. Univariable and stepwise multivariable Cox regression models (stratified by database) were performed. Results: 478 patients (123 patients from our institution and 355 patients from TCGA) were included. 150 (31.4%) patients experienced a DFS event (recurrence or death) and 94 (19.7%) died at 3.1 years (yrs) of median follow-up. Median DFS was 6.3 (5.4-7.2) yrs and the 5-yr overall survival rate was 70.8% (64.9-76.7). On multivariable analysis, 4 clinical factors and mutations in 3 genes were significantly associated with recurrence (Table). Conclusions: Our study suggests that PTEN, BAP1 and KDM5C GA may improve on clinical factors for prediction of localized ccRCC recurrence. Further work is needed to determine if these GA could improve existing validated risk models. [Table: see text]
Abstract P311: Testosterone Therapy and Risk of Venous Thromboembolism Among Men Without Hypogonadism
Authors: Rob F Walker, Neil A Zakai, Richard F MacLehose, Logan T Cowan, Alvaro Alonso, Pamela L Lutsey
Journal: Circulation (2019)

Introduction: Testosterone therapy (TT) prescriptions among men increased over 300% from 2001 to 2013 because of relaxed TT prescription guidelines for common symptoms (such as low libido and fat redistribution) associated with natural declines in testosterone as age increases. After concern about possible adverse cardiovascular effects from TT prompted a FDA warning in 2014, prescriptions of TT initially decreased and then plateaued. TT is often prescribed without clear clinical indication of a true hypogonadism diagnosis. TT may increase VTE risk through hematocrit levels which affect blood viscosity and platelet accumulation for up to 6 months. Previous studies regarding the association between TT and VTE are both limited and unclear. Objective: Using a case-crossover design, we assessed whether TT exposure increases the short-term risk of VTE. We also evaluated whether the association differed by age group. Methods: The case-crossover study included men diagnosed with VTE identified using validated algorithms from 2012 to 2016 in the U.S. MarketScan Commercial and Medicare Supplemental administrative database. After excluding participants with cancer and those with hypogonadism (for which TT is clinically indicated), we identified 36,251 male VTE patients with at least 1 year of follow-up prior to their diagnosis and evaluated whether they had a prescription for TT preceding their first VTE (0-6 months, ‘case period’ and 6-12 months ‘control period’). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) of TT in the case period relative to the control period, after adjusting for number of hospitalizations per period. Associations were also evaluated separately in VTE patients &lt;65 vs. 65+ years old. Results: Overall, 754 out of the 36,251 patients (2.1%) had at least 1 TT prescription during the 12 months prior to their VTE event. Of these, 588 were aged less than 65 years (78.0%) and 166 were aged 65+ years. Overall, use of TT did not vary substantially in the case period compared to the control period (OR: 1.19; 95% CI: 0.86, 1.64). However, the point estimate was slightly elevated for TT use (vs. no TT use) among men under 65 years old (OR: 1.31; 0.91, 1.89). For men aged 65+ the OR was 0.85 (95% CI: 0.42, 1.69). Conclusions: Overall TT was not associated with greater risk of VTE among this population of men without hypogonadism. However, when stratified by age sub-group there was some suggestion of a higher association of TT in younger men. This analysis suggests that TT overall is not a strong risk factor for VTE; however further studies are needed to determine if supraphysiologic TT doses especially those associated with polycythemia could increase VTE risk.
A phase II trial of everolimus (E) and bevacizumab (B) in advanced non-clear cell renal cell cancer (ncRCC) to show efficacy in patients (pts) with papillary features.
Authors: Martin Henner Voss, Yingbei Chen, Joshua Chaim, Devyn Taylor Coskey, Kaitlin Woo, Almedina Redzematovic, Patricia Wang, William Lee, Sujata Patil, Ana M. Molina, James Hsieh, Robert Motzer, Darren Richard Feldman
Journal: Journal of Clinical Oncology (2015)

4522 Background: VEGF- and mTOR-directed therapies achieve inferior outcomes in pts with advanced ncRCC compared to clear cell RCC. Limited benefit from monotherapy supports study of combination regimens, prompting this phase II trial of E + B in pts with metastatic ncRCC. Methods: Treatment-naïve pts received concurrent E + B at standard doses until disease progression or intolerance to therapy. The primary endpoint was 6 month (mo) progression-free survival (PFS) with a planned sample size of 34 pts. Correlative analyses included ultra-deep next generation sequencing (NGS) from tumor and germline across 341 genes of interest. Results: 34 pts are evaluable (median follow-up 13.6 mo). The most common histologic subtype was unclassified RCC (URCC, n=23), the majority of which had papillary growth as a major component (n=14). 60% of pts achieved 6mo PFS; PFS varied significantly by histology (p<0.001). Objective response rates (ORR) were high in pts with significant papillary (7 of 18 pts) or chromophobe (2 of 5 pts) elements. Presence of a major papillary component was associated with treatment benefit across the entire cohort (table), particularly in pts with URCC, where this feature correlated with ORR (43 vs. 11%), median PFS (12.9 vs. 1.9 mo) and median OS (23.2 vs. 9.3 mo) (logrank p<0.001). NGS, performed on 33 cases, provides insight into the molecular background of disease phenotypes (e.g. frequent loss of chromosome 1p in tumors with papillary elements) and of treatment response (e.g. clonal convergence of activating alterations within the PI3K/mTOR pathway). Conclusions: Promising activity of E + B was seen in specific subtypes of ncRCC, particularly those with papillary features, justifying further study in a more defined population. The correlative analysis presented provides insight into the molecular basis of histologic phenotypes and response. Clinical trial information: NCT01399918. n ORR (%) Median PFS, mo (95% CI) Median OS, mo (95% CI) Full cohort 34 29 11.0 (3.8 – NR) 17.3 (14.6 – NR) Cases with major papillary component 18 39 12.9(10.9 – NR) 19.7 (16.7 – NR) Cases without major papillary component 16 19 1.9 (1.6 – NR) 10.3 (7.9 – NR) CI: confidence interval; NR: not reached.
The Veterans Health Administration Precision Oncology Program for Advanced Prostate Cancer Patients: Expanding tumor NGS opportunities to a broader patient population.
Authors: Alexandra Sokolova, Heather H. Cheng, Bradley J Hintze, Michael J. Kelley, Neil L Spector, Jill Duffy, Julie Ann Lynch, Matthew Rettig, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2019)

193 Background: Progress in understanding molecular changes in advanced prostate cancer has led to promising precision oncology opportunities; to date, most have been concentrated at tertiary research centers and urban centers and unequally available to patients. The VHA is the largest integrated healthcare system in the U.S. and provides medical care to &gt;6 million veterans (~40% living in rural areas). The VHA has implemented a system-wide National Precision Oncology Program (NPOP) to offer tumor NGS testing to veterans with cancer. Methods: VHA patients with advanced stage cancers were offered targeted NGS gene panels (Personalis ACE Extended Cancer Panel; PGDx CancerSELECT/PlasmaSELECT) as part of clinical care. Annotated sequence data is collected by NPOP. We report preliminary findings of the participating veterans with prostate cancer. Results: 372 veterans from 81 sites underwent NGS sequencing of their prostate tumors (n=311) or cfDNA (n=61). Tumors from 165 (44%) were found to have mutations (allelic ratio ≥5%) in 47 genes. Of 372, 62 harbored mutations in TP53 (17%), 9 in NOTCH1 (2%), 16 in PTEN (4%), 16 in AR (4%), 13 in ATM (4%), 11 in BRCA2 (3%), 2 in MSH2 (0.5%), 1 in NBN (0.3%), and 1 in PALB2 (0.3%). 7 men (1.8%) had adequate tumor, but no identifiable somatic mutations. NPOP findings were compared to the existing databases SU2C/PCF (of metastatic biopsies in metastatic castration resistant disease) and TCGA (of primary tumors in localized disease), see table. Findings will be updated at presentation. Conclusions: The VA NPOP has been successfully implemented, and prostate tumors from veterans were found to carry potentially actionable mutations, including BRCA2 and ATM, for which there are precision treatment trials. The program will be expanded and will facilitate more diverse and equitable distribution of access to precision oncology diagnostics and therapeutic opportunities, in alignment with the Cancer Moonshot Initiative. (e.g. VA-ABCD clinicaltrials.gov; NCT02985021). [Table: see text]
Mechanisms of gastrointestinal allergic disorders
Authors: Nurit P. Azouz, Marc E. Rothenberg
Journal: Journal of Clinical Investigation (2019)

Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen-driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.
Guidelines in the context of medical ethics
Authors: Laura J Waters, Simon Collins, Marta Boffito
Journal: BMJ (2019)

We fully support patient choice but question the wisdom of “walking away” from guidelines based solely on patient preference.1 All treatment decisions should be considered in the context of all four pillars of medical ethics: beneficence, non-maleficence, autonomy, and justice.2

Using examples from our field of sexual health and HIV we can apply “is this what my …
Prevention of corticosteroid induced osteoporosis
Authors: P. Lips
Journal: BMJ (1999)

Corticosteroid induced osteoporosis has presented a challenge to clinicians for many years. Bone loss during corticosteroid treatment is mediated by inhibition of gonadal and adrenal steroid production, leading to hypogonadism and a direct negative effect on calcium absorption and osteoblast function.1 Epidemiological data suggest that corticosteroid treatment doubles the risk of fractures of the hip and distal radius and at least quadruples the risk of vertebral fracture. How can this damage be limited?

Corticosteroids are widely used, especially for rheumatoid arthritis, polymyalgia rheumatica, and chronic obstructive pulmonary disease. A cross sectional study in Nottinghamshire in over 65 000 patients showed that 0.5% were taking oral corticosteroids.2 Most were aged 60-80 years and the mean dose was 8 mg/day, with a median duration of treatment of three years. Only 14% of these patients had received preventive treatment for osteoporosis. If these data are extrapolated to the whole population, over 250 000 people in the United Kingdom are taking oral corticosteroids.

Monitoring bone loss has become easy now that bone mineral density can be measured with dual energy x ray absorptiometry. Nevertheless, many patients taking long term corticosteroids are not referred for bone mineral density …
Common challenges faced by health delivery systems in the integration of personalized medicine into clinical practice.
Authors: Amjaad Al-Hussain, Daryl Pritchard
Journal: Journal of Clinical Oncology (2015)

e17520 Background: Personalized medicine diagnostic tools identify biological markers, often genetic, that allow providers to develop targeted treatment plans to provide the right treatment at the right dose to the right patient at the right time.But in order to integrate personalized medicine into oncology care, various challenges must be overcome. This study’s objective is to identify and prioritize common barriers to the use of personalized medicine tools by oncology care centers, and to distinguish between challenges faced by academic health centers vs. community health systems. Methods: We convened representatives from oncology care delivery organizations with established personalized medicine programs, including 13 academic health centers and 10 community health systems. We polled the group regarding concerns and challenges to implementing personalized medicine programs, and conducted semi-structured interviews with senior executives to distinguish between challenges faced by community hospitals and those faced by academic health centers. We used the framework approach of qualitative research for thematic analyses. Results: Health care providers identified five key categories of challenges: Appropriate workforce education and awareness, systems infrastructure, data management, ethical, legal and societal issues, and recognition of the value of personalized medical technologies. We developed a comprehensive list of challenges within these five categories. While most of the challenges within these categories were shared by both academic health centers and community health systems, the scope and magnitude of challenges related to education and awareness and systems infrastructure were perceived differently. Conclusions: Health care delivery organizations with personalized medicine programs encounter many common challenges. The scope and magnitude of these challenges often differ between academic health centers and community health care systems. These organizations and those that are considering new personalized medicine programs can benefit from shared perspectives and experiences related to systemic challenges.
Abstract 035: Comparative Effectiveness of Long-term Lifestyle and Pharmacological Interventions for Primary Prevention of Type 2 Diabetes: a Network Meta-analysis of Randomized Controlled Trials
Authors: Huilin Tang, Jin Xia, Keming Yang, Yiqing Song
Journal: Circulation (2019)

Background: Lifestyle modification and some pharmacological interventions have been proven effective in preventing type 2 diabetes (T2D) in previous primary prevention trials. However, there is controversy regarding their comparative effectiveness because of the lack of head-to-head trials for all possible comparisons among different interventions. Network meta-analysis enables us to simultaneously evaluate the relative effectiveness among all interventions by synthesizing both direct evidence from head-to-head trials and indirect evidence through more than one common comparator while maintaining randomization. Objective: We performed a network meta-analysis of randomized controlled trials (RCTs) to directly and indirectly compare lifestyle modification and five commonly prescribed medications (insulin sensitizers, insulin secretagogues, alpha-glucosidase inhibitors, weight-loss drugs, and renin-angiotensin system blockade), and to rank their relative effectiveness for primary prevention of T2D among adults with prediabetes at enrollment. Methods: We systematically searched PubMed, Embase, and CENTRAL from inception to October 2018 and identified long-term RCTs (follow-up ≥ 1year) that evaluated the interventions for T2D prevention in adults with prediabetes (e.g. impaired fasting glucose and impaired glucose tolerance). A network meta-analysis using the frequentist approaches was conducted to calculate the summary odds ratio (OR) and 95% confidence interval (CI) for each active intervention in comparison with controls (i.e. usual care alone or with placebo or control pills) and rank the effectiveness of these interventions by the surface under the cumulative ranking curve probabilities. Results: Thirty-three RCTs involving 54,910 individuals with prediabetes and 13,189 diabetic cases were included. Network meta-analysis showed that lifestyle modification (OR, 0.53; 95% CI, 0.42 to 0.66), insulin sensitizers (0.44; 0.31 to 0.62), alpha-glucosidase inhibitors (0.60; 0.42 to 0.87), and weight-loss drugs (0.39; 0.23 to 0.66) were significantly associated with decreased risk of incident T2D as compared with the controls. Neither insulin secretagogues (0.80; 0.51 to 1.26) nor renin-angiotensin system blockade (0.93; 0.62 to 1.38) were significantly associated with lower risk of developing T2D. Ranking of these interventions revealed weight-loss drugs being the optimal intervention for preventing T2D (89.5%), followed by insulin sensitizers (84.1%), lifestyle modification (66.7%), and alpha-glucosidase inhibitors (54.4%). Conclusions: Among the four interventions (lifestyle modification, insulin sensitizers, alpha-glucosidase inhibitors, and weight-loss drugs) which showed significant benefits on the primary prevention of T2D, weight-loss drugs seem to be the most effective.
Abstract P158: Depression After Cardiac Transplantation From 2012 to 2018 in a Reference Hospital in Recife: A Transversal Study
Authors: Evandro C Brito, Ângela M Arcoverde, Isabela A Martins, Bárbara Cubits, Clarissa O Alves, Verônica S Monteiro, Rodrigo M Carneiro, Fernando A Figueira
Journal: Circulation (2019)

Introduction: Cardiac transplantation represents a treatment opportunity for cardiovascular diseases that are refractory to traditional methods. For the procedure’s success, the individual needs to be collaborative and remain surrounded by restrictions and intensive care even after its performance. Thus, the emotional burden that surrounds the process contributes to depression after the surgery. The impact of depression on one’s quality of life has been subject of research all over the world, but its value is not completely clarified after a heart transplantation. Objective: To estimate the occurrence of symptoms of depression in 50 patients who underwent cardiac transplantation at the Institute of Integral Medicine Professor Fernando Figueira between 2012 and 2018. Hypothesis: Depression was a frenquent event after cardiac transplatation in the sample of this study. Methods: A cross-sectional observational study using questionnaires adapted, translated and validated in Brazil, the Medical Outcomes Study 36- Item Short-Form Health Survey (SF-36) for quality of life assessment and the Beck II Depression Inventory (BDI-II), for evaluation of depression symptoms. The collection was performed at the Cardiac Transplant Outpatient Clinic of the referred hospital, through individual interviews. The data collected was entered in the program Microsoft Excel version 2010 and the Statistical Package for the Social Sciences - SPSS 13.0 Software for Windows was used. All tests were applied with 95% confidence. This study is based on Resolution 466/2012 of the National Health Council. This research was approved in the Ethics Committee of the Institute of Integral Medicine Professor Fernando Figueira with CAAE n°66851517.7.0000.5201. Results: The sample consisted of 50 patients, 76% male (38 of 50), mean age of 47.76 years and 48% (24 of 50) had low education level. Data obtained by the application of BDI-II (n = 50) presented a mean of 13.36, median of 13.00, standard deviation of 12.76. Of the sample, 70% (35 of 50) were considered to have symptoms of depression, reaching scores with more than 9 points, the difference of genres being of little statistical significance. Among the variables related to the symptoms of depression, only the need for anxiolytic after transplantation was statistically relevant. In the comparison of the SF-36 with the 35 symptomatic patients for depression, of their eight scales only limitation by physical aspects and emotional aspects were not statistically relevant. Conclusion: The symptoms of depression could be verified in the sample with a significant impact on quality of life, when associated with functional capacity, pain, general health, vitality, social aspects and mental health. Patients who underwent heart transplantation should receive multidisciplinary care in order to minimize their vulnerabilities.