tbuckley/cabot-search huggingface dataset:
The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB).
Authors: A. Ari Hakimi, Yasser Ged, Jessica Flynn, Douglas R Hoen, Renzo G Di Natale, Kyle A Blum, Vladimir Makarov, Fengshen Kuo, Maria Isabel Carlo, Chung-Han Lee, Martin Henner Voss, Irina Ostrovnaya, Timothy An-thy Chan, Robert J. Motzer
Journal: Journal of Clinical Oncology (2019)

666 Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]
Characteristics of homologous recombination deficiency (HRD) in paired primary and recurrent high-grade serous ovarian cancer (HGSOC).
Authors: Jai Narendra Patel, Jahid Sehouli, Kirsten Timms, Cara Solimeno, Julia E. Reid, Jerry S. Lanchbury, Ioana Braicu, Silvia Darb-Esfahani, Mahrukh Ganapathi, Ram N. Ganapathi
Journal: Journal of Clinical Oncology (2015)

5534 Background: Defects in the HRD pathway, particularly those involving BRCA1/2, have a major impact on the response to DNA damaging platinum-based therapy used in patients with HGSOC. The objective of this study was to assess characteristics of HRD in paired primary and recurrent HGSOC specimens. Methods: HRD scores were determined in paired primary and recurrent specimens of HGSOC from 25 patients treated with adjuvant carboplatin and paclitaxel. BRCA1/2 mutation and BRCA1 methylation (including loss of heterozygosity (LOH) status), and HRD scores were characterized using tumor DNA-based assays. Results: All 50 samples analyzed yielded BRCA1/2 mutation and BRCA1 methylation assay data and 7 failed HRD analyses, leaving 19 primary-recurrent pairs available for comparative analysis of HRD. BRCA1/2 mutations (3/25, 12%) comprised only BRCA1, and LOH at BRCA1 was observed in all mutated tumors. All 3 mutant pairs had high HRD scores (range 46-76, 1 missing value in the primary). No reversion of mutations was observed in recurrent samples. In 3 primary-recurrent pairs with methylation and LOH at the BRCA1 locus, high HRD scores (range 55-72) were observed. A fourth pair was below the methylation threshold in the primary tumor but had high HRD scores in both primary and recurrent. Two primary-recurrent pairs had high HRD scores with intact BRCA1/2. HRD scores between primary and recurrent samples were highly correlated (r2 = 0.91). Scores were somewhat more likely to be higher in the recurrent tumor than in the primary, but the difference was not significant (mean = 2.6, paired t-test p-value = 0.11). Comparison of the genomic profile in paired samples revealed that while a number of tumors acquired additional genomic rearrangements that were different between the primary and recurrent sample, this did not significantly impact the HRD score. Conclusions: All markers of HRD examined were maintained between the primary and recurrent specimen. High HRD scores were prevalent (42%) and primarily linked to BRCA1 mutation and methylation. These data suggest that characterization of recurrent tumors may not yield alternative treatment strategies compared to analysis of the primary tumor.
A phase III, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer: Post-hoc analysis of PROSPER by prior therapy.
Authors: Ugo De Giorgi, Eleni Efstathiou, William R. Berry, Heather Ann Payne, Katarzyna Madziarska, Katharina Modelska, Xiaowei Guan, Jennifer Sugg, Joyce Leta Steinberg, Cora N. Sternberg
Journal: Journal of Clinical Oncology (2019)

185 Background: Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) are at high risk of developing metastatic CRPC. In the primary analysis of PROSPER, enzalutamide (ENZA) provided a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) in men with nmCRPC. Here we report the impact of prior therapy on MFS. Methods: Eligible men with nmCRPC, prostate-specific antigen (PSA) doubling time ≤ 10 months, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy and were randomized 2:1 to ENZA 160 mg or placebo (PBO). The primary endpoint was MFS. Results: 1401 men were enrolled, with a median age of 74 y (range, 50-95 y). In all men, ENZA reduced the risk of metastasis or death by 71% (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.24-0.35; P &lt; .0001). The treatment effect consistently favored ENZA regardless of whether men had prior bilateral orchiectomy, prior radiation, ≤1 or &gt; 1 prior hormonal therapy, or prior bone-targeting therapy (Table). Men who received &gt; 1 prior hormonal therapy had a shorter median MFS than those who received ≤1 line of hormonal therapy (5 months and 3 months in the ENZA and PBO groups, respectively). Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA treatment resulted in a clinically meaningful reduction in the risk of developing metastases or death irrespective of prior surgery, radiation, or bone-targeting therapy. MFS was longer in men who had received ≤1 prior hormonal therapy. Clinical trial information: NCT02003924. [Table: see text]
Detection and Prediction of Bioprosthetic Aortic Valve Degeneration
Authors: Timothy R.G. Cartlidge, Mhairi K. Doris, Stephanie L. Sellers, Tania A. Pawade, Audrey C. White, Renzo Pessotto, Jacek Kwiecinski, Alison Fletcher, Carlos Alcaide, Christophe Lucatelli, Cameron Densem, James H.F. Rudd, Edwin J.R. van Beek, Adriana Tavares, Renu Virmani, Daniel Berman, Jonathon A. Leipsic, David E. Newby, Marc R. Dweck
Journal: Journal of the American College of Cardiology (2019)

Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences. The authors sought to assess whether 18F-fluoride positron emission tomography (PET)-computed tomography (CT) can detect bioprosthetic aortic valve degeneration and predict valve dysfunction. Explanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography during 2 years of follow-up. All ex vivo, degenerate bioprosthetic valves displayed 18F-fluoride PET uptake that colocalized with tissue degeneration on histology. In 71 patients without known bioprosthesis dysfunction, 14 had abnormal leaflet pathology on CT, and 24 demonstrated 18F-fluoride PET uptake (target-to-background ratio 1.55 [interquartile range (IQR): 1.44 to 1.88]). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function compared with those without (annualized change in peak transvalvular velocity 0.30 [IQR: 0.13 to 0.61] vs. 0.01 [IQR: −0.05 to 0.16] ms−1/year; p < 0.001). Indeed 18F-fluoride uptake correlated with deterioration in all the conventional echocardiographic measures of valve function assessed (e.g., change in peak velocity, r = 0.72; p < 0.001). Each of the 10 patients who developed new overt bioprosthesis dysfunction during follow-up had evidence of 18F-fluoride uptake at baseline (target-to-background ratio 1.89 [IQR: 1.46 to 2.59]). On multivariable analysis, 18F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction. 18F-fluoride PET-CT identifies subclinical bioprosthetic valve degeneration, providing powerful prediction of subsequent valvular dysfunction and highlighting patients at risk of valve failure. This technique holds major promise in the diagnosis of valvular degeneration and the surveillance of patients with bioprosthetic valves. (18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome [18F-FAABULOUS]; NCT02304276)
Abstract 003: Metabolome-Wide Association Study With Habitual Physical Activity Among 4119 U.S. Participants
Authors: Ming Ding, Jessica Lasky-Su, Kathryn Rexrode, I-min Lee, Clary Clish, A Heather Eliassen, Walter Willett, Frank Hu, Peter Kraft
Journal: Circulation (2019)

Background: Being physically active has been associated with lower risks of cardiometabolic diseases. However, the biological mechanisms underlying these associations remain unclear, and can be investigated using a metabolomics approach. Objective: To identify plasma metabolites associated with habitual physical activity in a U.S. population. Methods: Our study population included 4119 participants in the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). Physical activity was assessed periodically by self-reported questionnaire starting from 1984 in NHS, 1989 in NHSII, and 1986 in HPFS. We used physical activity measured closest before blood collection as exposure. Metabolic profiling was conducted by liquid chromatography-mass spectrometry (LC-MS). Our study included 287 known metabolites, with 64% of them classified as lipids (58 triglycerides [TAGs], 13 diglycerides [DAGs], 13 cholesteryl esters [CEs], 6 lysophosphatidylethanolamines [LPEs], 37 phosphocholines [PCs], 10 lysophosphatidylcholines [LPCs], 24 phosphatidylethanolamines [PEs], and 25 carnitines). We examined associations of physical activity with plasma metabolites using linear regression, and corrected for multiple testing using tail probability of the proportion of false positives (TPPFP) and accounting for correlated tests using bootstrapping. Results: Using linear model adjusting for age, case-control status, labcode, smoking status, fasting status, alcohol intake, and diet quality, physical activity was significantly associated with 27 metabolites after correcting for multiple testing (TPPFP &lt;0.05). Among the 27 identified metabolites, four CEs, eight PCs, and three LPCs were positively associated with physical activity, and five TAGs and four DAGs were inversely associated. After additionally adjusting for body mass index (BMI), the associations of physical activity with the majority of identified metabolites were attenuated; physical activity remained positively associated with three CEs (C18:2, C16:0, and C18:1), three PCs (C36:4 PC-A, C36:0 PC, C34:3 PC plasmalogen), and one LPC (C18:2). Enrichment analysis showed that physical activity was significantly positively associated with the CE category (P value for enrichment=0.048). Conclusions: We identified seven metabolites that were significantly associated with physical activity after adjusting for BMI, which may help identify biomarkers of physical activity and provide insight into biological mechanisms underlying the beneficial effect of being physically active on cardiometabolic health.
Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer
Authors: Tomoya Kitani, Sang-Ging Ong, Chi Keung Lam, June-Wha Rhee, Joe Z. Zhang, Angelos Oikonomopoulos, Ning Ma, Lei Tian, Jaecheol Lee, Melinda L. Telli, Ronald M. Witteles, Arun Sharma, Nazish Sayed, Joseph C. Wu
Journal: Circulation (2019)

Background: Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who have cancer, but they often cause cardiovascular side effects that limit their use and impair patients’ quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison to the cardiotoxicity induced by conventional chemotherapies. Methods: We used the human induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing to further examine the effect of trastuzumab on iPSC-CMs. We also generated human induced pluripotent stem cells from patients receiving trastuzumab and examined whether patients’ phenotype could be recapitulated in vitro by using patient-specific iPSC-CMs. Results: We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium-handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-sequencing and subsequent functional analysis revealed mitochondrial dysfunction and altered the cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment than iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. It is important to note that metabolic modulation with AMP-activated protein kinase activators could avert the adverse effects induced by trastuzumab. Conclusions: Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.
Abstract P173: Blood Pressure Patterns in Young Adulthood Associated With Cardiovascular Disease and All-Cause Mortality by Middle Age: The CARDIA Study
Authors: Yuichiro Yano, Reis Jared, Lewis Cora, Stephen Sidney, Mark Pletcher, Ann Marie Navar, Eric Peterson, Michael Bancks, Hiroshi Kanegae, Samuel Gidding, Paul Muntner, Donald Lloyd-Jones
Journal: Circulation (2019)

Objectives: In young adults, which blood pressure (BP) patterns, determined over multiple clinic visits, are most associated with future risk for cardiovascular disease (CVD) and all-cause mortality remains unclear. We determined BP patterns during young adulthood most associated with CVD events and all-cause mortality by middle age. BP patterns included average systolic BP (SBP)/diastolic BP (DBP) levels, cumulative exposure to SBP/DBP, visit-to-visit SBP/DBP variability, and average annual change in SBP/DBP. Methods: We analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, which enrolled 5115 adults aged 18-30 years from 1985-1986, with up to 30 years of follow-up (through 2015). BP patterns were evaluated with measurements at Year 0 [baseline], and 2, 5, 7, and 10 years following baseline. We estimated visit-to-visit BP variability as variability independent of the mean (VIM). Average annual change of BP from the Year 0 to Year 10 exams was calculated using linear regression. Cox proportional hazards models were used to assess the associations between BP patterns and adjudicated CVD events (coronary heart disease, stroke, heart failure, and other vascular disease) and all-cause mortality. Results: At Year 10, the mean±standard deviation (SD) age of the 3,394 participants was 35.1±3.6 years, 46% were African American, 56% were female, and only 3% were taking antihypertensive medication. Cumulative exposure to SBP and average SBP levels were highly correlated (Pearson’s correlation = 0.94). Over a median follow-up of 19.2 years, 162 CVD events and 181 deaths occurred. Average SBP and DBP levels and VIM of SBP were associated with increased CVD risk (see table), with no interaction by race or sex (each p&gt;0.4). Only VIM of SBP was associated with all-cause mortality. Conclusions: Among young adults, the assessment of visit-to-visit SBP variability in addition to average SBP and DBP levels can help identify young adults who have an increased CVD risk and all-cause mortality by middle age.
Helen Salisbury: Disruptive innovation—technology is not the problem
Authors: Helen Salisbury
Journal: BMJ (2019)

Some technologies arrive gently, only gradually replacing what went before. This is what happened when motorised vehicles slowly challenged the dominance of the horse and cart. Others sweep in, and overnight the whole landscape changes. Can you remember trying to organise anything before email?

The term “disruptive innovation” was coined to describe this kind of transformative development, when a new product or service overturns existing ways of working and creates new markets.

In business there’s a tension between taking time to iron out the bugs in a new product and keeping ahead of your rivals. In healthcare, where the stakes are high, …
A phase II, randomized study of nivolumab (nivo) or nivo plus BMS-986205 with or without intravesical Bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC): CheckMate 9UT.
Authors: Noah M. Hahn, Sam S. Chang, Maxwell Meng, Neal D. Shore, Badrinath R. Konety, Gary D. Steinberg, Juergen E. Gschwend, Hiroyuki Nishiyama, Juan Palou Redorta, John Arthur Taylor, Ayanbola Elegbe, Alexandre Lambert, Li Zhu, Yuko Ishii, Toshiki Maeda, Bradley Raybold, Gary Grossfeld, Bruce S. Fischer, Mark Rutstein, Alfred Witjes
Journal: Journal of Clinical Oncology (2019)

TPS493 Background: Immune checkpoint inhibitors, including nivo (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. BMS-986205, a selective, potent, once-daily IDO1 inhibitor that works early in the IDO1 pathway, has demonstrated clinical activity in combination with nivo in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). These findings provide a rationale for investigation of nivo + BMS-986205 ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of nivo ± BMS-986205 ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC. Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component (&gt;50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with nivo ± BMS-986205 ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR), duration of CR in pts with CIS, and event-free survival for all pts without CIS. Secondary endpoints are progression-free survival and safety. This global study in 13 countries is underway, with a target enrollment of 436 pts. ( Clinical trial information: NCT03519256.
The Detection of ANTI-Platelet Factor 4 /Heparin Antibodies during the Post Chirurgical Period of LUNG Transplantation Is Associated with a Higher Frequency of ACUTE Cellular Rejection
Authors: Francois Parquin, Antoine Roux, Patrick Van Dreden, Elisabeth Longchampt, Dominique Francois, Leila Zemoura, Paunet-Bodo Michéle, Roselyne Bironien, Marc Vasse
Journal: Blood (2018)
Pretrial outlining quality assurance in PIVITOLBoost.
Authors: Elin Evans, Helen Mayles, Olivia Frances Naismith, Emma Hall, Alison Tree, John Staffurth, Isabel Syndikus
Journal: Journal of Clinical Oncology (2019)

50 Background: PIVOTALBoost is a Phase III randomised controlled trial (CRUK/16/018) of radiotherapy to prostate and pelvic nodes versus prostate alone with or without prostate boost. To minimise impact of target volume delineation (TVD) variation on trial outcome, pre-trial radiotherapy quality assurance (RTQA) was implemented to identify and correct potential variations. Methods: Participating centres offering a prostate boost submitted two pre-accrual outlining benchmark cases: one with a central zone boost (GTVpb) only and another with GTVpb (peripheral zone), CTVp/psv and CTVn. A detailed outlining protocol and diagnostic information were provided to centres. Submitted outlines were compared to consensus volumes created by the trial management group (TMG). The TMG deemed the volumes acceptable or as having acceptable or unacceptable variation. Detailed feedback was provided for each submission. Unacceptable variations required resubmission. Results: 32 investigators submitted pre-trial outlines. GTVpb was the most incorrectly outlined volume; 22 (69%) outliners had unacceptable errors for case 2 GTVpb, 17 (53%) for case 1 GTVpb. Most common GTVpb error was inferior extent of lesion followed by incorrect lesion outlined. 12 (38%) of outliners had unacceptable errors for CTVp/psv, most commonly due to delineation at the prostate apex. 8 (25%) outliners had unacceptable CTVn mostly due to incorrect vessel delineation. Of 26 (81%) outliners required to resubmit at least 1 case, 3(12%) required a second resubmission due to unacceptable errors on first resubmission. Conclusions: The majority of pre-trial outlining submissions had unacceptable errors requiring resubmission of at least one case. This was predominantly due to boost delineation error which is a relatively new skill for prostate clinical oncologists in the UK. This suggests robust on-trial RTQA is imperative to minimise further variation. Clinical trial information: ISRCTN80146950.