tbuckley/cabot-search huggingface dataset:
Genetic risk assessment for hereditary RCC: Report from the consensus panel meeting.
Authors: Michael Daneshvar, Neil Mendhiratta, Ramaprasad Srinivasan, Eric Jonasch, Mark Wayne Ball, Adam R Metwali, James Brugarolas, Eric A. Singer, Katherine Nathanson, Phillip M. Pierorazio, Ronald S Boris, Antonio Finelli, Sumanta K. Pal, A. Ari Hakimi, Alexander Kutikov, Othon Iliopoulos, W. Marston Linehan, Brian M. Shuch, Gennady Bratslavsky
Journal: Journal of Clinical Oncology (2020)

615 Background: While many genes are now known to be associated with hereditary kidney cancer syndromes, there is a paucity of guidelines or uniform consensus on genetic testing for these patients. An expert panel was organized to assess who, what, when and how patients should be evaluated and what testing should be initiated. Methods: A national, multidisciplinary, panel of experts in urology, medical oncology, clinical geneticists, genetic counselors and patient advocates with background and knowledge in hereditary syndromic kidney cancer convened in person in September 2019. A renal cell carcinoma (RCC) genetic risk assessment questionnaire consisting of 52 questions was compiled prior to the meeting using modified Delphi methodology. The questions were then discussed and reviewed with uniform consensus defined as a minimum of 85% agreement in accordance with the National Comprehensive Cancer Network criteria. Results: The panel consisted of twenty-six attendees represented by urologists (43%), medical oncologist (23%), genetic counselors (13%), clinical geneticists (7%), and patient advocates (3%). The questionnaire consisted of fifty-five statements focusing on who, what, when and how genetic testing should be performed in a patient suspected of hereditary RCC syndrome. A &gt;85% agreement was reached on 30/52 statements with 18/25 (72%) achieving consensus addressing “who”, 2/6 (33%) achieving consensus in “what’ category, 2/7 (29%) in ‘when’ and 4/6 (67%) on how. The questions with least consensus were found in the “what/when?” category with only 4/13 questions with minimum 85% agreement. Specific areas of debate included an age cutoff for prompting a genetic risk assessment as well as need for familial testing in patients with variants of unknown significance. Conclusions: Despite experience of the panel in management of hereditary RCC, the consensus was reached only on 66% of genetic testing. While many issues will need to be discussed further, those statements with consensus may be used to guide physicians and patients on who, what, when and how genetic RCC risk assessment should be performed.
Automatic labeling of cortical sulci using patch- or CNN-based segmentation techniques combined with bottom-up geometric constraints
Authors: Léonie Borne, Denis Rivière, Martial Mancip, Jean-François Mangin
Journal: Medical Image Analysis (2020)

The extreme variability of the folding pattern of the human cortex makes the recognition of cortical sulci, both automatic and manual, particularly challenging. Reliable identification of the human cortical sulci in its entirety, is extremely difficult and is practiced by only a few experts. Moreover, these sulci correspond to more than a hundred different structures, which makes manual labeling long and fastidious and therefore limits access to large labeled databases to train machine learning. Here, we seek to improve the current model proposed in the Morphologist toolbox, a widely used sulcus recognition toolbox included in the BrainVISA package. Two novel approaches are proposed: patch-based multi-atlas segmentation (MAS) techniques and convolutional neural network (CNN)-based approaches. Both are currently applied for anatomical segmentations because they embed much better representations of inter-subject variability than approaches based on a single template atlas. However, these methods typically focus on voxel-wise labeling, disregarding certain geometrical and topological properties of interest for sulcus morphometry. Therefore, we propose to refine these approaches with domain specific bottom-up geometric constraints provided by the Morphologist toolbox. These constraints are utilized to provide a single sulcus label to each topologically elementary fold, the building blocks of the pattern recognition problem. To eliminate the shortcomings associated with the Morphologist's pre-segmentation into elementary folds, we complement this regularization scheme using a top-down perspective which triggers an additional cleavage of the elementary folds when required. All the newly proposed models outperform the current Morphologist model, the most efficient being a CNN U-Net-based approach which carries out sulcus recognition within a few seconds.
A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk.
Authors: Toni K. Choueiri, Laurence Albiges, Thomas Powles, Christian Scheffold, Fong Wang, Robert J. Motzer
Journal: Journal of Clinical Oncology (2020)

TPS5102 Background: Cabozantinib (C) inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab (N) and as part of a triplet combination with N and the CTLA-4 inhibitor ipilimumab (I) in patients (pts) with advanced renal cell carcinoma (aRCC) (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219 .
Private Equity Acquisitions of Physician Medical Groups Across Specialties, 2013-2016
Authors: Jane M. Zhu, Lynn M. Hua, Daniel Polsky
Journal: JAMA (2020)

Acquisition of physician practices by private equity firms has accelerated, 1,2 with unknown implications for care delivery and patient outcomes.However, available data are limited to single specialties or come from industry reports or opinion articles.A dearth of evidence and the use of nondisclosure agreements at early stages of negotiation have constrained the ability to evaluate this phenomenon empirically. 3In this study, we describe physician group practices acquired in 2013-2016 across specialties.Methods | We identified US physician group practice acquisitions by private equity firms using the Irving Levin Associates Health Care M&A data set, 4 which includes manually collected and verified transactional information on a broad set of health care mergers and acquisitions.We excluded practices bought by entities not classified as private equity firms at the time of acquisition.We verified practice names, locations, specialties, and group practice status via Google searches.We linked acquisitions to the SK&A data set, a commercial data set of verified physician-and practice-level characteristics (eg, specialty, credentials, practice ownership, size, and locations) for US office-based practices.
Improving quality of health-related quality of life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate cancer (mPC).
Authors: Di Maria Jiang, Bryan Wong, Alicia K. Morgans, Christopher Sweeney, Karim Fizazi, Kim N. Chi, Thomas Powles, Nathan Perlis, Girish S. Kulkarni, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2020)

58 Background: HRQOL data are increasingly used to guide patient care and health policy. However, their utility can be compromised by inadequate quality of HRQOL reporting (QHR). We aimed to evaluate QHR in phase III RCTs of mPC. Methods: A systematic review following PRISMA guidelines identified published manuscripts of phase III RCTs of mPC assessing systemic therapies (excluding androgen deprivation therapy and bone targeting agents) between 1990 - 2019. Supplements, references and companion publications were reviewed. QHR was independently quantified using the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (MSC, range 0-11) by 2 investigators. QHR is “probably robust” if MSC score is ≥8 and all 3 mandatory items (baseline compliance, missing data, and psychometric properties) are reported; “limited” if score is 5-7; and “very limited” if score is ≤4. Results: HRQOL was the primary (11%), secondary (61%), explorative (21%), and unspecified (7%) endpoint in 57/76 (75%) RCTs, and reported in 46/57 (81%). Primary HRQOL endpoints were pain palliation only. MSC scores ranged 2 – 11. QHR was mostly limited (Table). Most RCTs did not report mode of administration (82%), rationale for selected instrument (65%), or missing data (59%). Other common limitations were: unreported baseline compliance (35%), lack of culturally validated measure (33%), clinical significance not discussed (33%), no hypotheses stated (28%), and inadequate coverage of HRQOL domains (26%). QHR has improved since 2015, with the median MSC score reaching 8 (Table). Conclusions: QHR has improved considerably over time, with many recent phase III RCTs in mPC reporting “probably robust” HRQOL data. Within existing resource constraints however, nonreporting and methodologic deficiencies still remain. The use of standard checklists may further enhance QHR and promote high quality HRQOL research.[Table: see text]
Health-related quality of life (HRQoL) patient-reported outcomes (PROs) and survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Lorente David, Rebeca Lozano, Guillermo de Velasco, Nuria Romero-Laorden, Elena Castro, Miguel Rodrigo-Aliaga, Angel L. Sanchez, Carlos Di Capua, Alfredo Sanchez-Hernandez, David Olmos
Journal: Journal of Clinical Oncology (2020)

53 Background: HRQoL is a relevant endpoint in trials in advanced prostate cancer. An association between HRQoL and OS has been reported. The Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a validated HRQoL PRO in mCRPC. Methods: We evaluated the association between FACT-P and OS in the COU-301 and COU-302 trials (abiraterone vs placebo in mCRPC pts). FACT-P scores, sub-scores (physical (PWB), emotional (EWB), functional (FWB), social (SWB) well-being, prostate cancer subscale (PCS) FACT-G and the Trial Outcome Index (TOI) were calculated. A decrease in 3 (PWB, EWB, SWB, FWB, PCS), 9 (FACT-G, TOI) or 10 (FACT-Total) points after 3 cycles was considered clinically relevant. The association between FACT-P and OS was evaluated with Kaplan-Meier, Cox-regression models and c-indices. Results: 2,177 pts (COU-301: 1,121 /COU-302: 1,056) had valid baseline (BL) FACT-P scores. Mean BL score was 106.6 (COU-301) and 122.3 (COU-302). BL total scores were associated with OS in both COU-AA-301 (p&lt;0.001) and COU-302 (p&lt;0.001), independent of treatment. All FACT-P sub-scores except SWB were associated with OS (Table). A decrease in FACTP scores was associated with decreased OS in COU-301 (19.6 vs 14.2m; HR: 1.8; p&lt;0.001) and COU-302 (34.4 vs 27.7m; HR: 1.3; p=0.009) datasets. Conclusions: BL FACTP scores (except SWB subscale) are significantly associated with outcome. Early declines in HRQoL can be observed and are associated with worse outcome. Prospective evaluation of the significance of changes in HRQoL is needed. YODA Project 2018-3745.[Table: see text]
Impact of age in advanced renal cell carcinoma treated with immune checkpoint inhibitors.
Authors: Alberto Carretero-González, David Lora, Lucía Carril Ajuria, Maria Cruz Martin Soberón, Daniel Castellano, Guillermo de Velasco
Journal: Journal of Clinical Oncology (2020)

702 Background: Immune checkpoint inhibitors (ICIs) are beneficial in a subset of metastatic renal cell carcinoma (mRCC) patients. Elderly patients are usually under-represented in pivotal trials. Importantly, aging has been pointed as a potential detrimental factor for the benefit with ICIs as a consequence of the “immunosenescence” which could decrease the efficacy of these treatments. Methods: We assessed the potential role of aging according to Cochrane Collaboration's Guidelines. Search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care (SoC) in mRCC patients was performed. Trials must have included subgroup analysis evaluating the selected outcome (overall survival-OS-) in different subsets of patients according to age. Additionally, a retrospective series of mRCC patients treated with ICIs from our institution was also reviewed to assess the impact of age. Results: A total of 3415 patients (4 studies) were included in the meta-analysis (ICIs arm: 1709 patients; SoC arm: 1706 patients). Altogether, OS results favored ICIs. Older patients (aged more than 75 years-old) seem to present a less clear benefit with ICIs compared to SoC in comparison with younger patients (aged up to 75 years-old; p-value for difference between subgroups: 0.006) (Table). No differences between subgroups were found when considering 65 years-old as the borderline (p-value: 0.179). A similar trend was found in our series, with a numerically better median OS in patients younger than 65 years-old compared to those older than 65 years-old (31,6 vs. 23,6 months); the effect of age on outcomes was maintained along all International Metastatic RCC Database Consortium (IMDC) score subgroups. Conclusions: Elderly patients with mRCC, particularly older than 75 years-old, could benefit to a lesser extent compared to younger counterparts from receiving ICIs.[Table: see text]
Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake
Authors: Victoria Meslier, Manolo Laiola, Henrik Munch Roager, Francesca De Filippis, Hugo Roume, Benoit Quinquis, Rosalba Giacco, Ilario Mennella, Rosalia Ferracane, Nicolas Pons, Edoardo Pasolli, Angela Rivellese, Lars Ove Dragsted, Paola Vitaglione, Stanislav Dusko Ehrlich, Danilo Ercolini
Journal: Gut (2020)

Objectives This study aimed to explore the effects of an isocaloric Mediterranean diet (MD) intervention on metabolic health, gut microbiome and systemic metabolome in subjects with lifestyle risk factors for metabolic disease. Design Eighty-two healthy overweight and obese subjects with a habitually low intake of fruit and vegetables and a sedentary lifestyle participated in a parallel 8-week randomised controlled trial. Forty-three participants consumed an MD tailored to their habitual energy intakes (MedD), and 39 maintained their regular diets (ConD). Dietary adherence, metabolic parameters, gut microbiome and systemic metabolome were monitored over the study period. Results Increased MD adherence in the MedD group successfully reprogrammed subjects’ intake of fibre and animal proteins. Compliance was confirmed by lowered levels of carnitine in plasma and urine. Significant reductions in plasma cholesterol (primary outcome) and faecal bile acids occurred in the MedD compared with the ConD group. Shotgun metagenomics showed gut microbiome changes that reflected individual MD adherence and increase in gene richness in participants who reduced systemic inflammation over the intervention. The MD intervention led to increased levels of the fibre-degrading Faecalibacterium prausnitzii and of genes for microbial carbohydrate degradation linked to butyrate metabolism. The dietary changes in the MedD group led to increased urinary urolithins, faecal bile acid degradation and insulin sensitivity that co-varied with specific microbial taxa. Conclusion Switching subjects to an MD while maintaining their energy intake reduced their blood cholesterol and caused multiple changes in their microbiome and metabolome that are relevant in future strategies for the improvement of metabolic health.
Overall survival using radium-223 (Ra223) in metastatic castrate-resistant prostate cancer (mCRPC) patients with and without DNA damage repair (DDR) defects.
Authors: Maarten J. van der Doelen, Pedro Isaacsson Velho, Peter H.J. Slootbeek, Samhita Pamidimarri Naga, Maren Bormann, Sjoerd van Helvert, Leonie I. Kroeze, Inge M. van Oort, Winald R. Gerritsen, Emmanuel S. Antonarakis, Niven Mehra
Journal: Journal of Clinical Oncology (2020)

121 Background: Ra223 is a therapeutic option for mCRPC patients (pts) with symptomatic bone metastases. DDR-defective prostate cancers, specifically those with homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This study assessed presence or absence of DDR alterations in mCRPC pts treated with Ra223, investigating the effect on efficacy and overall survival (OS). Methods: All pts included were treated with Ra223 and had genomic results from a comprehensive next-generation sequencing panel of DDR genes that directly or indirectly led to HRD, from primary or metastatic tissue. Exclusion criteria were prior platinum-based chemotherapy or treatment with poly-ADP ribose polymerase inhibitors (PARPi). Pts were grouped by presence (DDR+) or absence (DDR-) of pathogenic somatic and/or germline aberrations in DDR genes. Primary endpoint was OS, and secondary endpoints were time to alkaline phosphatase (ALP) progression, time to next systemic therapy and biochemical responses; comparing DDR+ and DDR– groups. Results: 93 pts were included in this two-centre retrospective study. Median age was 68 years. 56% received prior chemotherapy. Baseline characteristics where comparable between DDR status subgroups. 28 (30%) pts had mutations in DDR genes, most frequently occurring in ATM (8.6%), BRCA2 (6.5%), and CDK12 (4.3%) genes. DDR+ pts showed prolonged OS (median 36.3 vs. 17.0 months; HR 2.29; 95% CI 1.21-4.32; P= 0.01). Median time to alkaline phosphatase progression was 6.9 months for DDR+ pts and 5.8 months for DDR- pts (HR 1.48; 95% CI 0.87-2.50; P =0.15), and median time to next systemic therapy was 8.9 months for DDR+ pts and 7.3 months for DDR- pts (HR 1.58; 95% CI 0.94-2.64; P =0.08). A higher proportion of DDR+ pts completed Ra223 therapy (79% vs 47%; P= 0.05). No differences in biochemical (prostate-specific antigen, ALP) responses were seen. Conclusions: Pts harboring deleterious DDR aberrations more commonly completed Ra223, and derived a greater OS benefit. These findings need prospective confirmation, but support combination of Ra223 with PARPi or ATR inhibitors in DDR-defective mCRPC pts.
Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus
Authors: Anni A V Antikainen, Niina Sandholm, David-Alexandre Trégouët, Romain Charmet, Amy Jayne McKnight, Tarunveer S Ahluwalia, Anna Syreeni, Erkka Valo, Carol Forsblom, Daniel Gordin, Valma Harjutsalo, Samy Hadjadj, Alexander P Maxwell, Peter Rossing, Per-Henrik Groop
Journal: Cardiovascular Research (2020)

Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D.We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) = 1.32, P = 1.50 × 10-8], and rs6055069 on DEFB127 promoter (OR = 4.17, P = 2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P < 1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10-7).While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation.
Annals Story Slam - Voices of Medical Students and Residents: What Can Be Done to Build Trust
Authors: Kultaj Kaleka
Journal: Annals of Internal Medicine (2020)

Web Exclusives18 February 2020Annals Story Slam - Voices of Medical Students and Residents: What Can Be Done to Build TrustFREEKultaj KalekaKultaj KalekaCentral Michigan University, Mt. Pleasant, Michigan (K.K.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W20-0011 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Voices of Medical Students and Residents: What Can Be Done to Build Trust "Voices of Medical Students and Residents: What Can Be Done to Build Trust," by Kultaj Kaleka (Duration 2:50)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Central Michigan University, Mt. Pleasant, Michigan (K.K.)Current Author Address: Kultaj Kaleka; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 February 2020Volume 172, Issue 4Page: SS1 ePublished: 18 February 2020 Issue Published: 18 February 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.Loading ...
Digital ulcers: should debridement be a standard of care in systemic sclerosis?
Authors: Michael Hughes, Begonya Alcacer-Pitarch, Yannick Allanore, Murray Baron, Francesco Boin, Cosimo Bruni, Lorinda Chung, Francesco Del Galdo, Christopher P Denton, Marco Matucci-Cerinic
Journal: The Lancet Rheumatology (2020)