tbuckley/cabot-search huggingface dataset:
Role of genomic instability in immunotherapy with checkpoint inhibitors.
Authors: George Yaghmour, Manjari Pandey, Catherine Gorman Ireland, Kruti Patel, Sarah Elizabeth Nunnery, Daniel Powell, Scott Baum, Eric Wiedower, Lee Steven Schwartzberg, Michael Gary Martin
Journal: Journal of Clinical Oncology (2016)

3052 Background: Checkpoint inhibitors have shown significant activity against a variety of cancers. However, biomarkers that predict responses to these agents have remained elusive. We hypothesized that tumors with greater genomic instability generate a more robust immune response that results in better survival. Methods: We retrospectively identified patients (pts) with solid tumors that were treated with checkpoint inhibitors and that had received commercially available next generation sequencing (NGS) between 2013-2015. Based on the skewed distribution of genomic alterations pts in the top quintile were compared to the other 4 quintiles combined. This procedure was done before examining mortality to avoid selecting cutoff points that could accentuate the mutation-outcome relationship. The functional significance of VUS's in DNA damage repair pathways were predicted using PolyPhen. All p-values were two-sided and p-values less than 0.05 were considered statistically significant. Results: 50 pts were identified; most had either melanoma or NSCLC (top quintile 90% v others 86%, respectively). Median age (66 v 65) and median number of prior therapies (2 v 1) were similar. All pts had stage 4 disease. Top quintile pts had more genomic alterations (median 16.5) than the others (median 2) (p < 0.001); differences were both in median number of pathogenic mutations (3.5 vs. 1, p < 0.001) and VUS's (12.5 vs. 1, p < 0.001). Pathogenic alterations in cell cycle regulatory genes (100% versus 48%, p = 0.017) were more common in the top quintile. Overall survival was superior for pts in the top quintile (722 days) versus the others (432 days) [HR 5.78; CI 1.40 – 15.12; p = 0.029]. Similar trends were seen regardless of histology. Progression free survival numerically favored the top quintile [not reached vs. 89 days, HR 2.11; CI 0.80-4.45; p = 0.154] as did objective response rate (50%) vs. others (20%), p = 0.101. PD1 and PDL1 status by immunohistochemistry were not associated with outcomes. Conclusions: The use of immune checkpoint blockade in tumors with higher mutational load was associated with improved overall survival. Our results suggest that the evaluation of tumor genomes may be predictive of immunotherapy benefit.
UK newspaper reporting of the NHS cancer drugs fund, 2010 to 2015: a retrospective media analysis
Authors: Grant Lewison, Ajay Aggarwal, Philip Roe, Henrik Møller, Charlotte Chamberlain, Richard Sullivan
Journal: Journal of the Royal Society of Medicine (2018)

Objective We wished to explore how UK national newspapers had covered the creation and operation of the Cancer Drugs Fund from 2010 to 2015. This was introduced to provide cancer patients in England with access to drugs not appraised or approved by the National Institute for health and Care Excellence. Design We sought stories in nine newspapers from the Factiva database, and copied their salient details to a spreadsheet. They were categorised by whether they were supportive or critical of the Cancer Drugs Fund and their main arguments, which drugs they mentioned and for which cancers. Settings Not applicable Participants Not applicable Main outcome results Press coverage was mainly very positive, arguing for the Cancer Drugs Fund's extension to Scotland and Wales, and a bigger budget, but neglecting the lack of patient benefit and the severe side effects that sometimes occurred. Leading this support was the Daily Mail, whose influence (measured by the product of number of stories and the paper's circulation) was almost greater than that of the other newspapers combined. Results Press coverage was mainly very positive, arguing for the Cancer Drugs Fund’s extension to Scotland and Wales, and a bigger budget, but neglecting the lack of patient benefits and the severe side effects that sometimes occurred. Leading this support was the Daily Mail, whose influence (measured by the product of number of stories and the paper’s circulation) was almost greater than that of the other newspapers combined. Conclusions Although there was some critical analysis of the Cancer Drugs Fund, our analysis shows that most press coverage was largely positive and unrepresentative in comparison with the lack of overall benefits to patients and society. It is likely that it contributed to the Cancer Drugs Fund’s continuation despite mounting evidence of its ineffectiveness.
Chemotherapy and radiotherapy application for pancreatic cancer in Europe and USA: An international population-based study.
Authors: Lei Huang, Lina Jansen, Yesilda Balavarca, Lydia van der Geest, Valery Lemmens, Liesbet Van Eycken, Harlinde De Schutter, Tom Børge Johannesen, Maja Primic-Žakelj, Vesna Zadnik, Margit Mägi, Dianne Pulte, Petra Schrotz-King, Hermann Brenner
Journal: Journal of Clinical Oncology (2018)

4127 Background: The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This large-scale international population-based study aimed to investigate the trends and variations in the application of chemotherapy and radiotherapy for PaC in Europe and the US and to explore the application determinants. Methods: Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology, and End Results (SEER)-18 database during 2003-2014 were analyzed. Temporal trends and geographical variations in the application of chemotherapy and radiotherapy were quantified using age standardization. Associations between treatment and demographic and clinical characteristics were assessed using multivariable logistic regression. Results: A total of 141,533 PaC patients were analyzed. From 2003-2005 to 2012-2014, chemotherapy application rates increased in most countries and more strongly among resected cancers, while radiation rates were generally low with a slight decline or no obvious trend. In 2012-2014, 13.1% (Estonia) to 64.4% (Belgium) of patients with resected PaC and 18.1% (Slovenia) to 60.0% (Belgium) of those with unresected cancer underwent chemotherapy. Radiation was administered in 2.6% (the Netherlands) to 26.7% (the US) of resected and 0.7% (the US) to 6.2% (Belgium) of unresected tumors. Strong temporal and geographical variations were observed. Patterns and strengths of the associations between treatment administration and demographic and clinical factors including age, tumor TNM stage, and location differed substantially between resected and unresected diseases and varied greatly across countries. Conclusions: Administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and the US. The evidence from randomized trials majorly supporting chemotherapy does not seem to have been implemented into the wider clinical practice in many countries. The uptake strongly varied between countries, highlighting the need for standardization in PaC treatment to improve patient care.
Analysis of survival outcomes among ethnic minorities with pancreatic cancer treated at an urban academic cancer center.
Authors: Erin Jou, Michael Shusterman, Jennifer W. Chuy, Andreas Kaubisch, Santiago Aparo, Sanjay Goel
Journal: Journal of Clinical Oncology (2016)

e15734 Background: Black and Hispanic patients are underrepresented in clinical trials of pancreatic cancer. Studies suggest worse overall survival in blacks, but offer conflicting results for Hispanics. We investigated survival differences between Hispanics, non-Hispanic whites (NHW) and non-Hispanic blacks (NHB) treated at the Montefiore-Einstein Cancer Center (MECC) in Bronx, NY. Methods: We included patients treated for pancreatic adenocarcinoma at MECC between 2000 and 2015 via the MECC Cancer Registry. Demographics, clinical characteristics and treatment data were collected. The Kaplan-Meier method was used to report overall survival (OS) and a Cox proportional-hazards model was used to assess survival differences between Hispanics, NHBs, and NHWs adjusting for clinically relevant and statistically significant variables. Results: 505 patients were included in the study. 170 were Hispanic (24%), 188 NHB (37%), and 147 NHW (29%). Median age was 66 (range 31, 98). 46% were male. Baseline characteristics among the racial groups were similar except for age at diagnosis, SES, insurance, and chemotherapy status. Median OS among groups was similar for Hispanics (13.5 mo, 95% CI 10.5, 16.4), NHWs (12.1 mo, 95% CI 10.2, 14.0), and NHBs (12.5 mo, 95% CI 9.9, 15.2), p = 0.477. Median OS for Stage IV only was similar for Hispanics (7.2 mo, 95% CI 4.765, 9.701), NHWs (8.1 mo, 95% CI 6.628, 9.572), and NHBs (8.2 mo, 95% CI 5.423, 10.9). In univariate survival analysis, stage (HR 2.558, p = 0.001), age (HR 1.015, p = 0.001), smoking (HR 1.269, p = 0.025), and surgery (HR 0.362, p = 0.001) were significant. Multivariate analysis adjusting for age, sex, stage, smoking, and surgery revealed a HR for death for Hispanics of 0.916 (95% CI 0.677, 1.240, p = 0.569) compared to NHWs, and a HR for death of 1.011 (95% CI 0.786, 1.301, p = 0.931) compared to NHBs. The model showed a HR for death for NHBs of 0.925 (95% CI 0.711, 1.205, p = 0.565) compared to NHWs. Conclusions: In this cohort with significant minority patient representation, unlike historical data, Hispanic and NHB pancreatic adenocarcinoma patients experienced similar overall survival when compared to NHW patients.
Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML
Authors: Felicitas Thol, Razif Gabdoulline, Alessandro Liebich, Piroska Klement, Johannes Schiller, Christian Kandziora, Lothar Hambach, Michael Stadler, Christian Koenecke, Madita Flintrop, Mira Pankratz, Martin Wichmann, Blerina Neziri, Konstantin Büttner, Bennet Heida, Sabrina Klesse, Anuhar Chaturvedi, Arnold Kloos, Gudrun Göhring, Brigitte Schlegelberger, Verena I. Gaidzik, Lars Bullinger, Walter Fiedler, Albert Heim, Iyas Hamwi, Matthias Eder, Jürgen Krauter, Richard F. Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Arnold Ganser, Michael Heuser
Journal: Blood (2018)
Abstract 20031: Transcatheter Aortic Valve Replacement Using Transfemoral vs Transapical Approach: A comprehensive Meta-analysis Comparing 30-day & 1-year Cerebrovascular Event Rates
Authors: Kumar Sanam, Himanshu Aggarwal, Pankaj Arora, Saurabh Gaba, Vikas Bhatia, Navkaranbir S Bajaj
Journal: Circulation (2015)

Background: Transcatheter Aortic valve replacement (TAVR) has emerged as new technique for the management of patient with severe Aortic Stenosis (AS). Stroke is a potential complication associated ...
Potential prognostic markers for recurrence and survival in triple-negative breast cancer
Authors: K.V. Havrysh, G. Mukhametshina, S. Safina, S. Petrov, R.G. Kiyamova
Journal: Annals of Oncology (2018)

Background: Triple-negative breast cancer (TNBC) subtype is associated with an adverse outcome among BC patients. Since Overall Survival (OS) and recurrence prediction are significant to define suitable treatment strategies, an identification of prognostic markers for Disease-Free Survival (DFS) and OS is relevant. Here we aimed to estimate the effects of previously identified predictors of DNA-damaging therapy POLR2L, RAD50, SLC34A2, SMARCA5 and WDHD1 on OS and DFS in TNBC. Methods: Clinicopathological data of 1098 BC patients (TCGA Breast Invasive Carcinoma) and information of expression and copy number alterations (CNA) of selected genes were downloaded from the public cBioPortal site (http://www.cbioportal.org). Patients with TNBC (n = 116) excluding those who had mutations of BRCA1/BRCA2 were selected for analysis. The uni- and multivariate associations between OS/DFS and features, such as tumor stage, patient's age at diagnosis, expression and CNAs of genes of interest were evaluated using Cox Proportion Hazard models and Log-rank test. Statistical analysis was performed utilizing the computing environment R. Results: Among studied covariates, high mRNA expression of POLR2L (HR = 1.7; 95% CI: 1.16-2.48; p-value = 0.006) and RAD50 (HR = 1.9; 95% CI: 1.02-3.64; p-value = 0.043) genes and the progressive stage of disease (HR = 4.0; 95% CI: 2.08-7.68; p-value =3.15x10-5) were associated with worse OS of TNBC patients. Also high mRNA expression of POLR2L (HR = 1.9; 95% CI: 1.16-3.00; p-value = 0.01) gene and progressive stage of disease (HR = 3.379; 95% CI: 1.601-7.132; p-value = 0.001) were associated with increased risk of cancer relapse. All possible combinations of the examined genes and characteristics were tested to select a most powerful prognostic model. For OS (Log-rank test: p-value = 3.415x10-7) and DFS (Log-rank test: p-value = 3.331x10-5) the best multivariate Cox regression model included a combination of mRNA expression of POLR2L and RAD50 genes and tumor stage. Conclusions: Our findings display that the mRNA expression of POLR2L and RAD50 genes both separately and in combination with a stage of disease influence on OS and DFS of TNBC patients. Thus, POLR2L and RAD50 could be considered as new potential prognostic markers of TNBC. Legal entity responsible for the study: Research Laboratory "Biomarker", IFMB KFU. Funding: Program of Competitive Growth of Kazan Federal University. Disclosure: All authors have declared no conflicts of interest.
P01.124 The expression of CD40 correlates negatively with overall survival of gliomas
Authors: J Werner, S Kuhl, B Krischek, R Goldbrunner, M Timmer
Journal: Neuro-Oncology (2018)

Background: The prognosis of Glioblastoma (GBM) remains poor. Low-grade gliomas (LGG) are known to progress to GBM whilst the chance of survival decreases. The TNF-Receptor CD40 and the ligand CD40L have shown first value as biomarker regarding the prognosis of GBM. The present study evaluates the role of CD40/CD40L in LGG and GBM differentiating IDH-wild-type and IDH-mutant GBM. All data are based on patient-derived samples and expression was measured by real-time PCR. Samples of 75 grade II gliomas and 40 GBM were included in the study. RT-PCR was performed to measure CD40/CD40L expression, using SDHA as housekeeper. The TCGA-Data was used to run analysis on mRNA-expression. We could show, that patients with LGG and CD40 overexpression present shorter progression-free (43 vs. 29 months, Hazard Ratio 0.5715, p=0.0262) and overall survival (116 vs. 54 months, Hazard Ratio 0.3431, p<0.0001). Consistently, relapsed grade II gliomas show higher CD40 expression compared to primary grade II gliomas (p=0.0028). As in LGG, CD40 was a negative marker for overall survival (12 vs. 10 months, Hazard Ratio 0.5178, p=0.0491) in GBM. In this context, we could show a higher CD40 expression in IDH-wild-type GBM compared to IDH-mutant GBM. The strong cohorts of the TCGA datasets “Brain Lower Grade Glioma” and “Glioblastoma” enforced our findings with similar results for PFS and OS in LGG and GBM. CD40L showed no correlation with survival data. Summarizing, high expression of CD40 shows significant association with poor outcome in LGG and GBM; and is overexpressed in IDH-wild-type GBM.
Abstract 16924: Initial AMSA and Increased AMSA After CPR Predict Second Shock Success in Initially Shock-resistant VF During Out-of-hospital Cardiac Arrest
Authors: Ulrich Herken, Weilun Quan
Journal: Circulation (2015)

Purpose: Amplitude spectrum area (AMSA), which is calculated from the ventricular fibrillation (VF) waveform using fast Fourier transformation, has been recognized as a predictor of successful defibrillation (DF) and as an index of myocardial perfusion and viability during resuscitation. In this study, we investigated whether a change in AMSA occurring during CPR would predict DF outcome for subsequent DF attempts after a failed DF. We hypothesized that a patient responding to CPR with an increase in AMSA would have an increased likelihood of DF success. Methods: This was a retrospective analysis of out-of-hospital cardiac arrest patients who received a second DF due to initially shock-resistant VF. A total of 193 patients with an unsuccessful first DF were identified in a manufacturer database of electrocardiographic defibrillator records. AMSA was calculated for the first DF (AMSA1) and the second DF (AMSA2) during a 2.1 sec window ending 0.5 sec prior to DF. A successful DF attempt was defined as the presence of an organized rhythm with a rate ≥ 40 / min starting within 60 sec from the DF and lasting for &gt; 30 sec. After the failed first DF, all patients received CPR for 2 to 3 minutes before delivery of the second DF. Change in AMSA (dAMSA) was calculated as dAMSA = AMSA2 - AMSA1. Results: The overall second DF success rate was 14.5%. Multivariable logistic regression showed that both AMSA1 and dAMSA were independent predictors of second DF success with odds ratios of 1.24 (95% CI 1.12 - 1.38, p&lt;0.001) and 1.27 (95% CI 1.16 - 1.41, p&lt;0.001) for each mVHz change in AMSA or dAMSA, respectively. Conclusions: In initially DF-resistant VF, a high initial AMSA value predicted an increased likelihood of second shock success. An increase of AMSA in response to CPR also predicted a higher second shock success rate. Monitoring of AMSA during resuscitation therefore may be useful to guide CPR efforts, possibly including timing of second shock delivery. These findings also further support the value of AMSA as indicator of myocardial viability.
CD28 NULL T LYMPHOCYTES ARE EXPANDED IN YOUNG WOMEN WITH POLYCYSTIC OVARY SYNDROME
Authors: Giampaolo Niccoli, Rosanna Apa, Giovanna Liuzzo, Cristina Spaziani, Francesca Sagnella, Andrea Silenzi, Rocco A. Montone, Giuseppe Ferrante, Antonio Lanzone, Filippo Crea
Journal: Journal of the American College of Cardiology (2010)
Molecular profiling-guided therapy in gastroesophageal carcinoma: A single-institution experience.
Authors: Lionel Aurelien Kankeu Fonkoua, Jason Liao, Nelson S. Yee
Journal: Journal of Clinical Oncology (2017)

e15582 Background: Gastroesophageal carcinoma (GEC) including carcinoma of stomach (GC), gastroesophageal junction (GEJ), and esophagus (EC) is the 2 nd leading cause of cancer death worldwide. Chemotherapy and HER2-targeted therapy (trastuzumab) have shown limited efficacy. We aim to assess the impact of molecular profile (MP)-guided therapy (MPgt) by correlating expression of select biomarkers in GEC patients (pts) with survival. Methods: 27 GEC (11 GC, 9 GEJ, 7 EC) submitted to Caris Life Sciences for molecular profiling between 2011 and 2016 were analyzed and correlated with pt survival. The impact of MPgt was assessed by calculating the ratio of progression-free survival (PFS) on MPgt to PFS on the preceding empiric therapy. MPgt was deemed beneficial if PFS ratio ≥1.3. Results: In-situ hybridization indicated amplification of HER2 (15.4%) and c-MET (7.4%). Immunohistochemistry revealed increased expression of TOPO1 (57.7%), TOP2A (38.5%), HER2 (15.4%) and c-MET (6.9%), as well as decreased expression of TS (69.2%), ERCC1 (42.3%), and PGP (15.4%). These data suggest sensitivity to topoisomerase inhibitors, anthracyclines, trastuzumab, MET-targeted therapy, fluoropyrimidine, platinums, and taxanes, respectively. Expression of these markers was heterogeneous among pts, and a trend toward improved PFS was noted in pts with low/absent ERCC1 expression on platinum-based therapy ( P= 0.06). Of the 13 pts who had sufficient data to assess the benefit of MPgt, 5 (38%) achieved a PFS ratio ≥1.3. One pt with metastatic HER2-amplified EC who had initially demonstrated clinical benefit from trastuzumab-containing chemotherapy, developed a new HER2 and c-MET co-amplified lung metastasis. Conclusions: While MPgt was beneficial in 38% of pts, tumor-associated plasticity, clonal evolution, and adaptive resistance may have limited efficacy. The emergence of HER2 and c-MET co-amplified clones is a potential resistance mechanism in HER2-amplified GEC, and highlights combined inhibition of receptor tyrosine kinases as a therapeutic strategy. Further studies with expanded data sets will be needed to test the hypothesis that actionable targets can be used independently to predict treatment response in GEC pts.
Cytokine release syndrome: grading, modeling, and new therapy
Authors: Delong Liu, Juanjuan Zhao
Journal: Journal of Hematology & Oncology (2018)

Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review.
Depomedroxyprogesterone therapy for hot flashes in survivors of ER-expressing breast cancer: Impact on recurrence and survival.
Authors: Natalie Ertz-Archambault, Lana Rogoff, Heidi E. Kosiorek, Brenda Ernst, Karen S. Anderson, Barbara A. Pockaj, Richard J. Gray, Donald W. Northfelt
Journal: Journal of Clinical Oncology (2018)

e22116 Background: Survivors of ER-expressing operable breast cancer (ER+BC) generally do not receive hormone replacement therapy for menopausal symptoms due to concern about provoking recurrence of disease. Single dose depomedroxyprogesterone acetate (MPA) 400 mg IM has previously been shown (Loprinzi CL, et al. J Clin Oncol 2006;24:1409) to be the most effective non-estrogen strategy for menopausal hot flashes (HF) but long-term evidence for safety in survivors of ER+BC is lacking. Methods: Consecutive patients previously diagnosed with ER+BC, who received single dose MPA for HF between January 2005 and December 2012, were retrospectively identified in the breast cancer patient database at Mayo Clinic Arizona. Medical records were audited for breast cancer outcomes in these cases and in contemporaneous control patients with ER+BC who did not receive MPA, matched for age, stage of disease, and year of diagnosis. Exclusion criteria included DCIS or stage IV disease. Statistical comparisons of local-regional recurrence and event-free survival were performed by by Cox regression analysis. Efficacy analysis of MPA on HF in this cohort is in progress. Results: 92 patients who received single dose MPA were identified and matched 1:1 with contemporaneous controls. Median follow-up duration was 5.7 years in cases and 4.5 years in controls. Estimated local-regional recurrence free survival at 10 years was 85% (95% CI, 72-100%) in cases and 95% (95% CI, 86-100%) in controls. Matched pairs hazard ratio was 1.0 (95% CI, 0.06-16.0) for local-regional recurrence free survival. Estimated event-free survival at 10 years was 81% (95% CI, 69-97%) in cases and 76% (95% CI, 64-92%) in controls. Matched pairs hazard ratio was 0.38 (95% CI, 0.10-1.41) for event-free survival. Conclusions: In this retrospective, case-control study we were unable to identify a detrimental effect of single dose MPA therapy for HF in survivors of ER+BC. Single dose MPA may be acceptable for management of HF in this population.