tbuckley/cabot-search huggingface dataset:
A phase II study of nivolumab in patients with high-risk biochemically recurrent (BCR) prostate cancer (PCa).
Authors: David Johnson Einstein, Xiao X. Wei, Lillian Werner, Huihui Ye, Carla Calagua, Glenn Bubley, Steven P. Balk
Journal: Journal of Clinical Oncology (2019)

TPS341 Background: Although androgen deprivation therapy (ADT) may be used for high-risk BCR PCa prior to radiographic metastases, evidence is lacking and toxicities are clear. Recent data show higher prevalence of programmed death-ligand 1 (PD-L1) expression in primary PCa than previously seen. Tumor PD-L1 expression also significantly correlates with risk of BCR, suggesting that inhibition of innate immune function could be associated with recurrence. Finally, immune-suppressive immune cells may increase after castration resistance, so the early-stage tumor microenvironment may differ from the castration-resistant setting in which prior studies were conducted. These data justify a novel trial investigating PD-1 inhibition in the setting of BCR. We hypothesize that PD-L1 expression in primary PCa is a marker of immunogenicity and therefore may predict for response to PD-1 inhibition. Methods: We designed a single-arm phase 2 clinical trial of nivolumab 480 mg every 28 days for men experiencing high-risk BCR. The primary endpoint is the proportion of patients experiencing PSA decline or stabilization (without symptomatic/radiographic progression) after 12 weeks of nivolumab; secondary endpoints are best PSA response, change in PSA doubling time, time to ADT initiation and to metastatic disease, and safety. The study will include one cohort with PD-L1 expression on tumor cells &gt;5% (“PD-L1-positive”), the other, PD-L1-negative, thus enriched for but not limited to PD-L1-expressing primary PCa. We are conducting correlative studies using tumor tissue and blood samples collected during treatment. We will perform next-generation sequencing on tissue to identify genomic biomarkers correlated with PD-L1 expression and with response to nivolumab. Using neoantigen prediction models, we will examine whether there are peripheral T cells present in nivolumab responders that recognize tumor-associated neoantigens and are expanded by PD-1 inhibition. We will evaluate subsets of tumor-infiltrating lymphocytes, including “exhausted” phenotypes, and other infiltrating immune cells. Finally, we will assess changes in peripheral immune cells and plasma cytokines as potential biomarkers. Clinical trial information: NCT03637543.
Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial.
Authors: Juan Francisco Rodriguez-Moreno, Guillermo de Velasco, Inmaculada Bravo Fernandez, Carlos Alvarez-Fernandez, Ricardo Fernandez, Sergio Vazquez-Estevez, Juan Antonio Virizuela, Pablo Gajate, Albert Font, Nuria Lainez, Arantzazu Martínez Barquín García, Sergio Ruiz-Llorente, Luis Beltran, Cristina Rodríguez-Antona, Pedro Berraondo, Jesús García-Donas
Journal: Journal of Clinical Oncology (2020)

542 Background: Cisplatin-based chemotherapy remains the perioperative treatment in muscle-invasive bladder carcinoma (MIBC). Recent evidence suggests that immune checkpoint inhibitors could be incorporated in this setting. Olaparib is a PARP inhibitor with well-established activity in HRD tumor. Results from trials assessing the combination of durvalumab and olaparib suggest a synergistic effect. However, a molecular characterization is crucial to warrant a rational development. Methods: A phase II clinical trial was designed to assess the impact of neoadjuvant treatment with the combination of durvalumab plus olaparib in the molecular profile of MIBC (NCT03534492; SOGUG-2017-A-IEC(VEJ)-2). Efficacy and safety were secondary objectives. Subjects with cT2-T4a MIBC aimed for cystectomy were treated during 6 to 8 weeks pre-cystectomy. Diagnostic and surgical samples, pre and postreatment blood samples have been collected for the molecular analysis. We present results regarding efficacy and safety. Results: From November 2018 to October 2019 28 patients have been enrolled. 52%/48% of patients had PS 0/1. Median age was 70. TNM stage was: pT2 in 73,6% patients, pT3 in 10.6%, pT4 in 15.8% and 10.6% presented nodal spread. 13 patients have completed neoadjuvant treatment so far and 12 have undergone cystectomy. A wound dehiscence and one death related to surgical procedures were postoperative complications. Pathological complete response rate is 44,5%. Radiological evaluation is ongoing. 10 serious adverse events non-treatment related have been communicated. Any grade of toxicity has been reported in 91% of patients but adverse events grade 3-4 was detected in only 8.3% of cases. Grade 1 pruritus was the unique IR adverse event described in one patient. PARP inhibitors-related adverse events were grade 1 nausea and vomiting (25%), and grade 1 anemia (25%). Conclusions: Preliminary clinical data suggest that Durvalumab in combination with Olaparib could be active and well-tolerated neoadjuvant treatment of MIBC. Molecular characterization and biomarker discovery will be presented separately. Clinical trial information: NCT03534492.
Epidemiology of basal and cutaneous squamous cell carcinoma in the U.K. 2013–15: a cohort study
Authors: Z.C. Venables, T. Nijsten, K.F. Wong, P. Autier, J. Broggio, A. Deas, C.A. Harwood, L.M. Hollestein, S.M. Langan, E. Morgan, C.M. Proby, J. Rashbass, I.M. Leigh
Journal: British Journal of Dermatology (2019)

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), together known as keratinocyte cancers (KCs), are the commonest cancer in white ethnic populations. Recent improvements to registry data collection in England has allowed more accurate analysis of the epidemiology of BCC and cSCC and for the first time we are able to provide an accurate (representative) tumour burden for KC in the U.K.To estimate the incidence of BCC and cSCC in the U.K.A cohort of patients with KCs between 2013 and 2015 were identified using linkage to diagnostic codes derived from pathology reports collected into the national cancer registry. Data from England's cancer registry were combined with data from Scotland, Northern Ireland and Wales. European age-standardized incidence rates (EASRs) of the first BCC and cSCC per patient per annum (PPPA) were calculated.In the U.K, the EASR of the first BCC and cSCC PPPA in 2013-15 were 285 and 77 per 100 000 person years, respectively (211 120 KCs total in 2015). The mean annual percentage increase was 5% between 2013 and 2015 for both BCC and cSCC. By counting the first KC PPPA, we include an additional 51% KCs compared with the previous reporting technique which counts only the first BCC and cSCC in a patient's lifetime, yet it represents a probable underestimation of 5-11% of the true tumour count.Based on an improved methodology, a more representative incidence of KC is presented, which is essential to healthcare planning and will lead to improved understanding of the epidemiology of KC. What's already known about this topic? Keratinocyte cancers (KCs) are the most common cancers affecting white ethnic populations. The incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) is increasing worldwide including the U.K., most commonly in elderly male Caucasian patients. These cancers are traditionally substantially underreported and frequently excluded from national cancer statistics. What does this study add? Using improved data collection methods in England and validated tumour-reporting techniques, we report the most accurate BCC and cSCC incidence data for the U.K. ever published. Identifying the first BCC and cSCC per patient per annum, the incidence of BCC and cSCC in the U.K. (excluding Wales) was 285 and 77 per 100 000 person years, respectively, between 2013 and 2015, with more than 210 000 KCs in the U.K. in 2015.
Epidemiology and genotype 3 subtype dynamics of hepatitis E virus in Belgium, 2010 to 2017
Authors: Vanessa Suin, Sofieke E Klamer, Veronik Hutse, Magali Wautier, Marjorie Jacques, Mona Abady, Sophie Lamoral, Vera Verburgh, Isabelle Thomas, Bernard Brochier, Lorenzo Subissi, Steven Van Gucht
Journal: Eurosurveillance (2019)

BackgroundHepatitis E virus (HEV) is an emerging public health concern in high-income countries and can cause acute and chronic hepatitis. Reported numbers of indigenously acquired HEV infection have increased in the past decade in many European countries. Since 2010, the National Reference Centre (NRC) for Hepatitis Viruses has been testing samples of suspected hepatitis E cases in Belgium.AimIn this surveillance report, we present the epidemiological trends of symptomatic HEV infections in Belgium, from the distribution by age, sex and geography to the molecular characterisation of the viral strains.MethodSerum samples of suspected cases sent to the NRC between 2010 and 2017 were analysed for the presence of HEV-specific IgM and RNA. Virus was sequenced for genotyping and phylogenetic analysis in all samples containing sufficient viral RNA.ResultsThe NRC reported an increase in the number of samples from suspected cases (from 309 to 2,663 per year) and in the number of laboratory-confirmed hepatitis E cases (from 25 to 117 per year). Among 217 sequenced samples, 92.6% were genotype 3 (HEV-3), followed by 6.5% of genotype 1 and 0.9% of genotype 4. HEV-3 subtype viruses were mainly 3f, 3c and 3e. HEV-3f was the most common subtype until 2015, while HEV-3c became the most common subtype in 2016 and 2017.ConclusionThe increasing trend of HEV diagnoses in Belgium may be largely explained by increased awareness and testing.
A flexible method for determining a biomarker positive population based on an efficacy target.
Authors: Chris Harbron, Howard M Mackey
Journal: Journal of Clinical Oncology (2015)

e13544 Background: A large burden is placed on clinical trials that simultaneously investigate efficacy of a new therapeutic agent along with the relevance of a potential predictive biomarker. Often, such biomarkers also require data driven methods to define biomarker positivity. Examples include establishing a threshold for the level of RNA expression of a particular gene or gene signature (Guijarro-Muñoz et al. Medical Oncology 2013) or the amount of protein and staining intensity by IHC (Pirker et al. Lancet Oncology 2012). A popular approach for investigating biomarker thresholds is the so-called ‘minimum p-value’ method (Jiang et al., Journal of the National Cancer Institute 2007). While this approach is flexible and relatively easy to implement, it operates independently of an efficacy target considered to be clinically meaningful. Methods: We propose a generalization of an existing approach that anchors the biomarker threshold to a clinically meaningful treatment effect (Mackey and Bengtsson, Contemporary Clinical Trials 2013). The proposed method flexibly models the efficacy-biomarker relationship in order to test significance in the identified biomarker positive population. Results: In sample sizes typical of phase 3 studies, this method performs favorably across a wide range of efficacy-biomarker relationships. Power is qualitatively higher in cases where the biomarker is not prognostic in the control group relative to cases where the biomarker is prognostic. The proposed method also performed well at controlling type 1 error in the biomarker positive population. Conclusions: This innovative approach builds upon existing methods to define biomarker positivity and confirm efficacy within the same phase 3 trial. This method may lead to a viable path for more efficient clinical development programs and increased precision in threshold determination.
Optimizing the use of androgen deprivation therapy in men with localized intermediate-risk prostate cancer in the era of modern dose-escalated radiation therapy.
Authors: Sagar Anil Patel, Kevin H. Nguyen, Alan K. Lee, David Jeffrey Demanes, Albert Chang
Journal: Journal of Clinical Oncology (2019)

109 Background: While level one evidence has shown an overall survival (OS) advantage with the addition of androgen deprivation therapy (ADT) to radiotherapy (RT) for intermediate risk prostate cancer (PCa), the benefit in the era of modern dose escalation is controversial, especially given the heterogeneity within this risk group. We assessed the impact of adding ADT to high dose RT on OS for intermediate risk PCa stratified by number of intermediate risk factors (IRF). Methods: We identified 114,339 men with intermediate risk PCa (Gleason 7, clinical stage T1-2, PSA &lt; 20 ng/mL) using the National Cancer Database. Men were stratified into the following subgroups based on the number of IRFs (Gleason 7, cT2b-c, PSA &gt; 10-20 ng/mL): A) Gleason 3+4 and no other IRF, B) Gleason 4+3 and no other IRF, C) two IRFs, and D) three IRFs. The addition of ADT to dose-escalated external beam RT (DE-EBRT, ≥ 75.6 Gy), brachytherapy (BT), or combination EBRT+BT on OS was assessed within each subgroup using Kaplan-Meier and log-rank tests in propensity score-matched cohorts in all men and subsequently only in those with Charlson-Deyo comorbidity index (CDI) of zero. Results: There was no OS benefit with the addition of ADT to DE-EBRT, BT, or EBRT+BT in groups A, B, and C, even after limiting the cohort to men with CDI = 0. However, in group D, the addition of ADT to DE-EBRT was associated with a trend for OS improvement in patients with CDI = 0 only (8-year OS with and without ADT 68.3% and 62.4%, respectively, log-rank P= .07). Conversely, there was a trend for OS decrement with the addition of ADT to DE-EBRT in men with CDI ≥ 1 (8-year OS with and without ADT 61.8% and 67.5%, respectively, log-rank P= .06). There was no OS benefit of ADT in group D treated with BT or EBRT+BT, regardless of comorbidity status. Conclusions: The OS benefit of ADT in men with intermediate risk PCa may be limited to those with 3 IRFs and minimal comorbidities treated with DE-EBRT. If prospectively validated, extreme dose escalation achieved with BT (alone or in combination with EBRT) may obviate the addition of ADT in all men with intermediate risk disease, especially in an era of advanced molecular imaging.
Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction
Authors: Anupam A. Kumar, Daniel P. Kelly, Julio A. Chirinos
Journal: Circulation (2019)

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.
Uptake of Video-Assisted Thoracoscopic Lung Resections Within the Veterans Affairs for Known or Suspected Lung Cancer
Authors: Amelia W. Maiga, Stephen A. Deppen, Jason Denton, Michael E. Matheny, Erin A. Gillaspie, Jonathan C. Nesbitt, Eric L. Grogan
Journal: JAMA Surgery (2019)

Minimally invasive lobectomy for early-stage lung cancer has become more prevalent. Video-assisted thoracoscopic surgery has lower rates of morbidity, better long-term survival, and equivalent oncologic outcomes compared with thoracotomy. However, little has been published on the use and outcomes of video-assisted thoracoscopic surgery within Veterans Affairs. There is a public assumption that the the Veterans Affairs is slow to adopt new procedures and technologies.To determine the uptake of video-assisted thoracoscopic surgery within the Veterans Affairs for patients with known or suspected lung cancer.In this retrospective cohort study of national Veterans Affairs Corporate Data Warehouse data from January 2002 to December 2015, a total of 11 004 veterans underwent lung resection for known or suspected lung cancer. Data were analyzed from March to November 2018.Open or video-assisted thoracoscopic lobectomy or wedge resection.Patient demographic characteristics and procedure and diagnosis International Classification of Diseases, Ninth Revision codes were abstracted from Corporate Data Warehouse data.Of the 11 004 included veterans, 10 587 (96.2%) were male, and the median (interquartile range) age was 66.0 (61.0-72.0) years. Of 11 004 included procedures, 8526 (77.5%) were lobectomies and 2478 (22.5%) were wedge resections. The proportion of video-assisted thoracoscopic lung resections increased steadily from 15.6% in 2002 to 50.6% in 2015. Video-assisted thoracoscopic surgery use by Veterans Integrated Service Networks ranged from 0% to 81.7%, and higher Veterans Integrated Service Network volume was correlated with higher video-assisted thoracoscopic surgery use (Pearson r = 0.35; 95% CI, 0.15-0.52; P < .001). Video-assisted thoracoscopic surgery use and rate of uptake varied widely across Veteran Affairs regions (P < .001 by Wilcoxon signed rank test).Paralleling academic hospitals, most lung resections are now performed in the Veterans Affairs using video-assisted thoracoscopic surgery. More research is needed to identify reasons behind the heterogeneous uptake of video-assisted thoracoscopic surgery across Veterans Affairs regions.
Real-world assessment of clinical outcomes among first-line (1L) sunitinib (SUN) patients (pts) with metastatic renal cell carcinoma (mRCC) by the international mRCC database consortium (IMDC) risk group.
Authors: Marie-France Savard, J Connor Wells, Jeffrey Graham, John A. Steinharter, Bradley Alexander McGregor, Frede Donskov, Georg A. Bjarnason, Ulka N. Vaishampayan, Aaron Richard Hansen, Marco Adelmo James Iafolla, Giovanni Zanotti, Lynn Huynh, Mei Sheng Duh, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2019)

610 Background: Prognostic factors such as the IMDC criteria have included all types of targeted therapy. This study assesses clinical outcomes and provide benchmarks for mRCC pts treated specifically with 1L SUN in the real world to provide contemporary benchmarks for outcomes and survival. Methods: Clear cell mRCC pts initiating SUN as 1L therapy between 2010-2018 were included in a retrospective database study. Kaplan Meier analysis was used to estimate median time to treatment discontinuation (TTD) and overall survival (OS: time to death) by IMDC risk groups based on Karnofsky Performance Status &lt; 80%, diagnosis to treatment interval &lt; 1 year, anemia, neutrophilia, hypercalcemia and thrombocytosis. Results: Among 1,769 1L SUN pts with clear cell in the RW clinical database, 318 (18%) had favorable, 1,031 (58%) had intermediate and 420 (24%) had poor IMDC risk. Across the favorable, intermediate, and poor risk groups, pts had similar mean age in years, gender distribution, and year of SUN initiation (age: 63.8, 62.9 and 62.6; male: 74%, 75%, and 72%; SUN initiation year of 2010-2013: all 71%). In the favorable risk group, 99% received nephrectomy vs 88% in intermediate and 66% in poor risk group. Median TTD was 15.0, 8.5, and 4.2 months (mos) in the favorable, intermediate, and poor risk groups, respectively, and was 7.1 mos in the combined intermediate/poor risk groups. Median OS was 52.1, 31.5, and 9.8 mos in the favorable, intermediate, and poor risk groups, respectively, and was 23.2 mos in the combined intermediate/poor risk groups. Conclusions: This real world study based on a contemporary cohort of 1L SUN mRCC pts found a median OS of 52 mos which sets a new benchmark for clear cell mRCC in the favorable risk group. OS in the intermediate and poor risk groups are similar to previous reports. This affects pt counselling and clinical trial design.
Emergency care in cancer patients: Data on 15,623 cases from a large volume single centre.
Authors: Carmelo Pozzo, Marcello Covino, Mariantonietta Di Salvatore, Emanuele Gilardi, Ernesto Rossi, Vincenzo Pio Di Noia, Davide Marsiliani, Chiara Cordischi, Elena Fasano, Evelina Forte, Antonio Astone, Francesco Franceschi, Carlo Barone
Journal: Journal of Clinical Oncology (2015)

e17577 Background: Cancer patients (pts) present often with acute syndromes requiring an urgent management. This scenario has dramatically changed during the last years due to the higher prevalence of cancer pts on active treatment, and specific drug–related safety issues. The aim of this study was to determine the main clinical characteristics, relevant needs and possible outcomes in the population of cancer pts admitted to our Emergency Department (ED). Methods: We performed a retrospective cohort study on 15,623 pts out of 1,101,259 adult pts (1.42%) admitted to our ED between January 2001 and December 2013 for cancer-related problems. Demographics, clinical findings and hospitalization rate were gathered from the administrative sources of the local database. Results: Mean age was 65.1± 14.8, women prevalence slightly higher. The majority of visits occurred during normal hours (77.6%) and working days (74.4%). Pts not requiring a urgent treatment, according to triage assessment, were 60.4%. Only 14.7% of pts were referred to ED by another physician (GPs, surgeon, medical oncologist). For 63.2% it was a self-decision and was not specified for the remaining group. The chief complaints were fever 21.5%, pain 27.7%, , asthenia 13.6%, dyspnea 13.1%, gastrointestinal (vomiting 15.3%, diarrhea 2.7%), hematologic (anemia 4.3%, neutropenia 1.9%, thrombocytopenia 0.5%). Complaints related, or possibly related, to an active antitumor treatment, i.e. chemotherapy and/or radiation therapy, are under evaluation and will be outlined at the meeting. Pts receiving an active treatment were 21.9%. The most common cancer sites were gastrointestinal (30.5%), lung (20.1%), ovarian (8.53%), breast (8.17%). Pts with metastatic disease were 21.2%. Hospitalization rate was 73.7%. Pts discharge due to symptoms improvement was 19.3%. Mortality at the ED was 0.9%. Hospitalization was refused by 3.7% of pts. Conclusions: A better understanding of emergency care needs for cancer pts is crucial for implementing the quality of care and optimizing the resources of the healthcare system. Further analyses and prospective studies are warranted to define possible outcomes and algorithms for the most appropriate treatments of cancer-related problems.