tbuckley/cabot-search huggingface dataset:
Differential response to carfilzomib based on initial therapy with bortezomib in multiple myeloma.
Authors: Sarvari Yellapragada, Chizoba Ifeorah, Luke Fletcher, Gustavo Rivero, Zahida Yasin, Jordan Krieger, Alka Mulchandani, Andre Catic, Martha P. Mims
Journal: Journal of Clinical Oncology (2017)

e19515 Background: Proteasome inhibitors (PIs) are efficacious in multiple myeloma (MM). In randomized phase 3 studies Carfilzomib doubled the progression free survival (PFS) compared to Bortezomib from 9.4 mo to 18.7 mo (ENDEAVOR study) in relapsed and refractory MM. However concern for suboptimal Carfilzomib based therapy (CBT) response in patients (pt) progressing on Bortezomib based therapy (BBT) suggests “cross-resistance”. Methods: AfterIRB approval, all pt with symptomatic MM over the last 10 years at the Michael E. DeBakey VA Medical Center with initial BBT followed by salvage CBT at progression were included. The primary aim was to evaluate ORR (PR + VGPR+CR) and and PFS by the IMWG criteria, among relapsed/refractory pt treated with salvage CBT whether or not they had an initial BBT response (i.e., primary refractory+stable vs CR+PR+VGPR). Results: In this cohort, the median overall survival was 45 mo. Pt initially treated with BBT had an ORR of 17/19 (89.4%) and median PFS of 7.7 mo. For 12 pt attaining PR, PFS was 4.3 mo, whereas for those achieving CR/VGPR was 9.1 mo, p= 0.03. Two pt were primary refractory to BBT and also to CBT. For initially treated BBT responders the ORR with CBT was 68.4% (13/19), median PFS was 5.26 mo. 6/19 pt (32%) were CBT refractory. PFS during BBT for CBT responders versus CBT refractory patients was not statistically different. Among those who responded to both CBT and BBT there was no significant correlation between the PFS or depth of response (CR vs VGPR vs PR) with initial BBT and PFS with CBT. Conclusions: In our retrospective analysis, pt who exhibited primary resistance to initial BBT did not benefit from salvage therapy with CBT, raising the possibility that hard-wired PI-resistance mechanisms exist. Among BBT responders, CBT ORR was 68%. However the PFS with CBT was significantly shorter than the published literature of CBT in RRMM naïve to PI leading us to hypothesize that uncharacterized resistance mechanisms from “priming” bortezomib leads to inferior outcome with salvage CBT. We conclude that CBT can be attempted in those who respond to BBT independent of depth of response or PFS duration. However, alternative therapies should be considered in pt with primary refractoriness to BBT.
Hospital readmission rate for febrile neutropenia (FN) following high dose cytarabine (HiDAC) consolidation chemotherapy for acute myeloid leukemia (AML).
Authors: Caitlin Siebenaller, Tomas Radivoyevitch, Connie Cheng, Hetty Carraway, Sudipto Mukherjee, Anjali S. Advani, Aaron Thomas Gerds, Aziz Nazha, Jaroslaw P. Maciejewski, Marc A. Earl, Madeline Waldron, Mikkael A. Sekeres
Journal: Journal of Clinical Oncology (2017)

e18513 Background: FN is an anticipated complication of consolidation with HiDAC for AML, though precise descriptions of incidence, type, and severity of infection leading to FN are lacking. Since AML patients (pts) with FN after HiDAC are routinely readmitted to the hospital, there is a likely impact on measures of quality and value in this population. Methods: Our primary aim was to define the rate of FN inpatient readmissions among all HiDAC cycles. Secondary aims included: estimating rates of all-cause readmissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, and identify pts-specific risk factors associated with readmission. Readmission per patient were modeled using Poisson regression, with means proportional to total cycles exposed, and logistic regression for the probability of FN per treatment cycle. Results: We identified 150 AML pts ≥ 18 years of age, who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2016. The median age was 50 (range 19-69); 55% were female and 45% were male. For 417 HiDAC cycles analyzed (87% at 3000 mg/m2), all pts received flouroquinalone prophylaxis and the overall readmission rate was 49% (203/417), of which 86% (174/203) were for FN. Median time to FN hospital admission was 18 days (range 10-22) from the start of HiDAC. Of the 174 FN readmissions, 60% had documented infections. Of these infections, 35% were bacteremia, 29% other bacterial, 24% fungal, 6% sepsis, and 6% viral. Females had higher FN readmission rates (RR 1.7 (1.3, 2.4) p = 0.007), as did pts with higher BMI (RR 1.06 (1.01, 1.09) p = 0.005), while age and HiDAC dose were not associated with readmission. Only 34% of all readmissions were in the absence of a documented infection. Conclusions: The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable. Females and pts with higher BMI were more likely to be readmitted. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality.
Mutational landscape of non-small cell lung cancer (NSCLC) associated with chronic obstructive pulmonary disease (COPD).
Authors: Tomoya Kawaguchi, Yasuhiro Koh, Masahiko Ando, Shun-ichi Isa, Akihiro Tamiya, Akihito Kubo, Naoki Yoshimoto, Chiyoe Kitagawa, Hideo Saka, Kazuto Hirata, Akihide Matsumura
Journal: Journal of Clinical Oncology (2016)

8526 Background: A common developmental mechanism has been proposed between NSCLC and COPD; however the association is not fully understood. We conducted a prospective, multicenter molecular epidemiology study, the Japan Molecular Epidemiological lung cancer (JME) study (UMIN000008177) to address the relationship between driver mutations and environmental factors including smoking. A total of 901 surgical specimens were collected from newly diagnosed early stage NSCLC patients from July 2012 to December 2013, and somatic mutations and gene amplifications were assessed in 72 and 5 cancer-associated genes, respectively (Ito N, J Clin Oncol 32:5s, 2014). Methods: We retrospectively collected data of pulmonary function test from 107 cases in two medical centers (Kinki-chuo Chest Medical Center and Nagoya Medical Center) from the JME study to examine the molecular profile in lung cancer patients with COPD. We defined COPD as presence of FEV1/FEV < 0.7 and classified the severity based on the Global Initiative for Chronic Obstructive Lung Disease. Results: Seventy-two non-COPD and 35 COPD patients, including 20 mild, 14 moderate and 1 severe diseases, were identified. COPD patients included 29 smokers (median 65 pack years), 16 squamous cell carcinoma, and 19 adenocarcinoma. Tumor molecular analysis revealed that the mutational frequency in COPD and non-COPD patients were 14.3% and 0% in PIK3CA, 2.9% and 0% in AKT1, 2.9% and 0% in STK11 and 11.4% and 0% in NFE2L2, respectively. Notably, there was a significant difference in the frequency of PIK3CA (p = 0.003) and NFE2L2 (p = 0.004) between COPD and non-COPD groups, while no difference was observed in TP53 and KRAS mutations and PIK3CA amplification. In the moderate or severe COPD cases, the mutation rates were even higher in PIK3CA (26.7%) and NFE2L2 (20.0%). Half of the patients with NFE2L2 mutation had PIK3CA mutation simultaneously. Most base substitution patterns were C > T change in NFE2L2 or PIK3CA. Conclusions: The mutation of PI3K/AKT/mTOR pathway and NFE2L2 were frequently observed and co-developed in NSCLC patients with COPD. NSCLC associated with COPD could be a distinctive disease entity which has a unique mutational phenotype.
Oncological outcomes of positive surgical margins in partial nephrectomy for renal cell carcinoma.
Authors: Henrique T. S. Nonemacher, Mauricio Cordeiro, George Lins de Albuquerque, Fabio Galucci, Paulo Afonso de Carvalho, Leonardo Borges, Giuliano Betuni Guglielmetti, Diogo Assed Bastos, Rafael Coelho, Alvaro Sarkis, Carlos Dzik, William Carlos Nahas
Journal: Journal of Clinical Oncology (2017)

e16079 Background: The prognostic significance and optimal management of positive surgical margins following partial nephrectomy remain controversial. The association between positive margin and risk of disease recurrence in patients with clinically localized renal neoplasm undergoing partial nephrectomy was evaluated. Methods: We analyzed the records of 429 patients cases of non-metastatic renal cell carcinoma who underwent partial nephrectomy (PN) at our institution, from 2001 to 2016. Recurrence free-survival was evaluated using Kaplan–Meier method and the log rank test and Cox models adjusting for tumor size, grade, histology, pathological stage, focality and laterality. The relationship between positive margin and risk of relapse was evaluated independently for pathological high risk (Fuhrman grades III-IV) and low risk (Fuhrman grades I-II) groups Results: A positive surgical margin was found in 55 (12.8%) patients. Recurrence developed in 26 (6%) patients during a median follow up of 39 months. A positive margin was associated with an increased risk of relapse on multivariable analysis (HR 3.19, CI 95% 1.21 – 7.61 p=0.02) (Table). In a stratified analysis based on pathological features, a positive surgical margin was significantly associated with a higher risk of recurrence in cases of high risk (HR 13.8, CI 95% 4.19–45.9, p = 0.0005). Conclusions: Positive surgical margins after partial nephrectomy increase the risk of disease recurrence, primarily in patients with high-risk pathological features. [Table: see text]
Prevalence and heterogeneity of androgen receptor splice variants and intra-AR structural variation in patient with castration-resistant prostate cancer.
Authors: Luc Yves Dirix, Bram De Laere, Pieter-Jan van Dam, Tom Whitington, Markus Mayrhofer, Emanuela Henao Diaz, Gert Van den Eynden, Jean Vandebroek, Jurgen Del-Favero, Steven J Van Laere, Henrik Gronberg, Johan Lindberg
Journal: Journal of Clinical Oncology (2017)

11530 Background: Androgen receptor splice variant 7 (AR-V7) is linked to a priori resistance to abiraterone acetate and enzalutamide. However, AR-V7 negativity does not necessarily indicate responsiveness and up to 20% of AR-V7 positive patients do demonstrate moderate response to these second-line endocrine therapies. Methods: Peripheral blood samples from patients with CRPC (n = 30) starting a new line of systemic therapy were subjected to comprehensive profiling of AR. AR splice variant (ARV) profiling for eight isoforms was performed by targeted RNA-Seq on CellSearch-enriched circulating tumour cells. Low-pass whole-genome and targeted sequencing of the entire AR gene in plasma-derived circulating cell-free DNA allowed the assessment of copy number status and structural rearrangements, respectively. ARV expression, structural variation, copy number alterations and ligand-binding domain mutations were combined and correlated to clinicopathologic parameters. Results: Twenty-five out of 30 patients (83%) demonstrated an aberration in AR. Twenty out of 30 patients (66.7%) demonstrated AR amplifications. Interestingly, 15/30 patients had intra-AR structural variants, of whom 14 expressed ARVs. In the context of endocrine treatment, 15/26 (57.7%) patients were ARV-positive with 13/15 patients having less than 6 months benefit from their therapy (Fisher’s exact test, p = 0.0115). ARV expression was heterogeneous with 10/15 ARV-positive patients expressing several ARV. Notably, AR-V7 was most frequently detected, however AR-V3 was 3.5x more abundant (Wilcox signed rank, p = 0.0029). In 17 patients, a baseline AR profile was available and demonstrated how having any ARV was associated with progression-free survival (HR: 4.53, 95%CI: 1.424–14.41; p = 0.0105). In the poor response group, 6/17 (35.2%) were AR-V7 negative, of whom 4 carried other AR aberrations. Conclusions: Comprehensive AR profiling on liquid biopsies is feasible and provides new insights into the mechanisms driving endocrine resistance. Clinical validation, by means of a non-interventional, prospective and multicentric study, is essential and currently ongoing.
An open-label expanded-access study of trifluridine/tipiracil for metastatic colorectal cancer.
Authors: Robert J. Mayer, Axel Grothey, Howard S. Hochster, Steven J. Cohen, Vojislav M. Vukovic, Lukas Makris
Journal: Journal of Clinical Oncology (2017)

3559 Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) treated with standard chemotherapy and targeted-therapy drugs (Mayer et al. N Engl J Med 2015;372:1909-19). An expanded-access program (EAP) was started to provide access to FTD/TPI for patients with mCRC with similar eligibility and to further assess the safety of FTD/TPI in a “real-world” setting in US patients. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy with appropriate biologics and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to this open-label EAP. Patients received FTD/TPI 35 mg/m 2 twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. Sites reported duration of therapy, discontinuation due to disease progression, and adverse events (AEs) for each patient. Results: 549 patients were enrolled; 53.2% were male. Median duration of FTD/TPI therapy was 9.7 weeks, which was similar to US patients from RECOURSE (8.9). 10.2% of patients died during the study period, 9.7% due to disease progression. 76.1% of patients discontinued treatment due to disease progression and 4% discontinued due to AEs. Drug-related clinically significant AEs (all grades) are summarized in the table. Conclusions: Patients with refractory mCRC in this EAP had a similar exposure duration to that reported in US patients from RECOURSE, with no unexpected safety concerns. While gastrointestinal toxicity was lower in this population, this may be due to reporting of “significant” events. The clinical profile of FTD/TPI is confirmed in this larger, non-randomized “real-world” experience. Sponsorship: Taiho Oncology, Inc. Editorial Assistance: Complete HealthVizion. Clinical trial information: NCT02286492. [Table: see text]
Abstract 19203: LCZ696 Reduces Myocardial Infarct Size in a Rodent Model of Acute Myocardial Injury in the Setting of Hypertension
Authors: Rishi K Trivedi, David J Polhemus, Amy L Scarborough, Traci T Goodchild, David J Lefer
Journal: Circulation (2016)

Introduction: LCZ696, equimolar valsartan and sacubitril, is the first angiotensin receptor neprilysin inhibitor (ARNi) treatment for heart failure (HF). LCZ696 blocks the renin-angiotensin-aldoste...
“Precision” Public Health — Between Novelty and Hype
Authors: Merlin Chowkwanyun, Ronald Bayer, Sandro Galea
Journal: New England Journal of Medicine (2018)

Does the turn toward "precision" public health offer the opportunity for a reconceptualized, empowered public health enterprise — or might it represent an abandonment of the traditional mission of enhancing population well-being? And how novel is it, anyway?
Patient characteristics and correlation with sexual functioning and quality of life among female cancer survivors: Results of the WFU CCOP Research Base Protocol 97106.
Authors: Nevine M. Hanna, Doug Case, Emily Van Meter Dressler, David Duane Hurd, Michelle Joy Naughton, Michael Chan, Glenn Jay Lesser
Journal: Journal of Clinical Oncology (2018)

e22094 Background: Problems with sexual function are common following therapy for female cancer survivors, though assessments of causative factors are lacking. The goal of this study is to assess impact of patient characteristics on sexual function and quality of life (QOL) in female cancer survivors. Methods: Our institution previously conducted a 12-week, randomized, placebo-controlled trial of Arginmax in female cancer patients who were 6 months or more from active treatment and reporting problems with sexual interest, satisfaction, and functioning after therapy. Outcome measures were the Female Sexual Function Inventory (FSFI) and the Functional Assessment of Cancer Therapy - General (FACT-G). Assessments were done at baseline, 4, 8, and 12 weeks. As reported previously, Arginmax had no effect on sexual function in these women. Longitudinal mixed effects models were used to assess the effect of patient characteristics, including age, time since diagnosis, BMI, ovarian function, pelvic vs. non-pelvic primary, performance status, and race/ethnicity, on sexual quality of life outcomes over time. Results: 186 patients with a median age of 50 years were accrued between May 10, 2007 and March 24, 2010. 76% of the patients were non-Hispanic white. Most had breast or gynecologic cancer (78% and 12%, respectively). Age ( < 50 years vs. ≥ 50 years) showed a statistically significant effect on sexual function that was consistent over time. Older patients had a 2.5 unit lower score on the FSFI (SE = 1.1), p < 0.05. Time since diagnosis and performance status were significantly related to quality of life. Those who were more than 3 years past diagnosis had an average 4.4 (±1.8) unit higher QOL score over time than those who were diagnosed more recently while those with an ECOG of 0 had an average 9.9 (±3.8) unit higher QOL score over time compared to those with an ECOG of 1. Conclusions: Age is significantly associated with sexual function in female cancer survivors, while time since diagnosis and performance status were associated with QOL. Future considerations include examining psychosocial, partner factors, and medication intake on the FACT-G and FSFI scores. Clinical trial information: NCT00459134.
Prognostic significance of automated score of tumor infiltrating lymphocytes in oral cancer.
Authors: Muhammad Shaban, Syed Ali Khurram, Mariam Hassan, Sajid Mushtaq, Asif Loya, Nasir Rajpoot
Journal: Journal of Clinical Oncology (2018)

e18036 Background: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck region, with a rising incidence particularly in South Asian countries. Abundance of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment has been associated with good prognosis and response to therapy in a variety of cancers (Ruiter et al., Oncoimmunol 2017). Our goal in this study was to explore whether novel artificial intelligence (AI) based automated quantification of TIL abundance carries any prognostic significance for disease-free survival for OSCC patients. Methods: A total of 59 OSCC patients of South Asian origin were included in this study, including 19 patients with recurrent disease. A novel AI based algorithm was developed for recognition of tumor-rich and lymphocyte-rich regions in whole-slide images of Hematoxylin & Eosin (H&E) stained tissue slides from the OSCC patients after training the algorithm on just under half of the dataset (n = 27) with pathologist annotations. We then computed a statistical measure of co-localization of tumor and lymphocytic regions that we term here as the TIL Abundance score (or TILAb score). Finally, prognostic significance of the TILAb score for disease-free survival was investigated with the Cox proportional hazard analysis, using half of the dataset as a discovery subset to determine the best cutoff value of the TILAb score and the remaining half for validation purposes. Results: Our novel AI algorithm achieved high accuracy of 90% for the recognition of co-localised tumor and lymphocytic regions making the downstream analysis reliable. Higher TILAb score was significantly associated (p < 0.013) with better disease free survival on completely unseen data which is in agreement with previous findings based on manual TIL quantification. To the best of our knowledge, this is the first study to automate the quantification of TIL abundance from routine H&E slides of OSCC. Conclusions: The automated TIL abundance score shows prognostic significance similar to manual score but with the added advantages of a more rapid and objective quantification. Large-scale multi-centric validation is required to establish the TILAb score as a prognostic biomarker in OSCC.
Down-regulation of target gene expression in human white blood cells (hWBCs) by MRX34, a liposomal miR-34 mimic: Next generation sequencing (NGS) results from a first-in-human trial of microRNA cancer therapy.
Authors: Kevin Kelnar, Heidi J. Peltier, Andreas G. Bader
Journal: Journal of Clinical Oncology (2016)

e14078 Background: Each microRNA (miRNA) modulates the expression of hundreds of genes across distinct cellular pathways, giving miRNA-based therapy the potential to simultaneously repress multiple oncogenic processes in the tumor microenvironment, including growth and proliferation, resistance, cancer stem cells, metastasis, and immune evasion. The naturally occurring tumor suppressor miR-34a has been shown to down-regulate the expression of > 30 oncogenes (eg, MET, MEK1, PDGFR-α, CDK4/6, BCL2, WNT 1/3, NOTCH1, CD44), as well as genes involved in tumor immune evasion (eg, PD-L1, DGKζ). MRX34, a liposome-encapsulated miR-34a mimic, is a potential first-in-class miRNA therapy for cancer. Methods: In the MRX34-101 phase I trial (NCT01829971), patients with advanced malignancies under dexamethasone premedication received IV infusions of MRX34 daily for 5 d in week 1 with 2 weeks off in 21-d cycles (QDx5 schedule). Whole blood was collected pretreatment and at multiple time points during and post-infusion. Total RNA from hWBCs (LeukoLOCK method) was isolated (mirVana kit) and assessed for quality (Agilent 2100 Bioanalyzer). Whole transcriptome RNA sequencing (RNA-Seq) was then used to compare the relative expression levels of 99 experimentally confirmed and 443 predicted direct miR-34a target genes in pre- and post-dose samples. Results: Expression of the majority of established and predicted miR-34a target genes was repressed in hWBCs 24 hrs after the start of MRX34 dosing. The effect was dose dependent such that the number of down-regulated genes increased at higher MRX34 doses corresponding to increased exposure to and uptake of miR-34a in hWBCs. Conclusions: This NGS analysis of hWBC samples from patients treated with MRX34 in a first-in-human clinical trial of miRNA cancer therapy showed dose-dependent modulation of expression for validated and predicted miR-34a target genes, including key oncogenes. Our work suggests that MRX34 effectively delivers active miR-34a mimics to hWBCs in patients with cancer, and provides a potentially useful method to evaluate biomarkers of response to MRX34 therapy.