tbuckley/cabot-search huggingface dataset:
A differential response to cetuximab in patients with recurrent unresectable or metastatic head and neck cancer following immunotherapy (IO) exposure: An institutional experience.
Authors: Haythem Y. Ali, Zaid Abdel Rahman, Jawad Sheqwara
Journal: Journal of Clinical Oncology (2019)

e17500 Background: Metastatic head and neck cancer is a diagnosis with poor prognosis and very little in terms of available active therapy. Until recently the mainstay of therapy was chemotherapy with or without cetuximab. The regimen of cetuximab (C), platinum (P) and 5FU has a response rate(RR) of 36% in the first line setting, and a PFS of 5.6 months and OS of 10.1 months. In the setting of post first line therapy immunotherapeutic agents (IO) have average RR of 15% and median OS of 8 months. Methods: We studied all patients with metastatic or recurrent head and neck cancer who were treated with an IO at our institution between May 2016 and July 2018 evaluating their entire history of therapy. 19 patient were treated with IO at our institution in the designated period of whom 9 received nivolumab (N) and 10 received pembrolizumab ( P ). Patients treated on trials were excluded. Patients who received less than 1 cycle of therapy were also excluded. 7 of the 19 patients received an IO in the first line setting after being refractory or resistant to platinum containing definitive therapy, 7 received the IO after a cetuximab (C) containing first line regimen, 1 patient received IO in second line but was naïve to C and 4 received IO in the third line setting. Results: 3 of 19 patients treated with IO had partial response, there were no complete responses, 6 patients had stable disease as their best response and 10 patients progressed at the time of their first evaluation. 11 of 19 patients received additional therapy post IO. 10 patients received taxane based therapy 5 of whom the taxane was combined with C. Of the 5 patients who received a taxane and C combination 2 had CR, 2 had PR and one had PD. Of the 5 who received other taxane regimens, 1 had PR 1 had SD and 1 had PD, 2 expired prior to their first evaluation. The patient who received a non taxane regimen all had progressive disease. Of the 4 responding patients to C regimens 1 had SD during IO therapy and 3 had PD. The longest response duration to a C regimen post IO was 628 days. Conclusions: We observe an unusual response rate among patients treated with a combination of taxanes and cetuximab after IO therapy. This finding may relate to a modifying effect of IO on sensitivity to subsequent therapy. This observation merits further investigation.
Supramolecular therapeutics to treat the side effects induced by a depolarizing neuromuscular blocking agent
Authors: Xiangjun Zhang, Qian Cheng, Lanlan Li, Liqing Shangguan, Chenwen Li, Shengke Li, Feihe Huang, Jianxiang Zhang, Ruibing Wang
Journal: Theranostics (2019)

Succinylcholine (Sch) is the only depolarizing neuromuscular blocking agent widely used for rapid sequence induction in emergency rooms. Unfortunately, a variety of (sometimes lethal) adverse effects, such as hyperkalemia and cardiac arrest, are associated with its use, and currently there are no specific antidotes to reverse Sch or to treat these side-effects.
Association of the imbalance between early and late differentiated intra-tumor CD4 T cells with mutational burden in non-small cell lung cancer.
Authors: Ehsan Ghorani, James L. Reading, Jake Y. Henry, Marc Robert De Massy, Rachel Rosenthal, Andrew J.S. Furness, Assma Ben Aissa, Mariam Jamal-Hanjani, Nicolai Birkbak, Gareth Wilson, Roberto Salgado, Tom Lund, Crispin T. Hiley, Sherene Loi, Allan Hackshaw, Nicholas McGranahan, Benjamin M. Chain, Karl S. Peggs, Charles Swanton, Sergio A. Quezada
Journal: Journal of Clinical Oncology (2019)

2590 Background: CD4 T helper cells are key orchestrators of immunity in states of persistent antigen exposure. In chronic viral infection, loss of immune control is associated with CD4 differentiation skewing (CD4 ds ) resulting from decline of early progenitors and gain in abundance of exhausted and terminally differentiated subsets. Here, we set out to identify whether a similar process occurs within the tumour microenvironment, contributing to immune dysfunction. Methods: Multiregional samples of tumour and non-tumour lung tissue from patients with untreated, surgically resected non-small cell lung cancer (NSCLC) within the first 100 recruited to the prospective lung TRACERx study were analysed by high dimensional flow cytometry of tumour infiltrating lymphocytes (TILs) and paired bulk tumour exome and RNA sequencing. We additionally reanalysed publically available single T cell and bulk tumour RNA sequencing from patients with NSCLC. Results: Unsupervised clustering and dimension reduction revealed a heterogenous landscape of CD4 TILs, with evidence of CD4 ds in association with tumour mutational burden. Loss of PD1 - CCR7 + T central memory enriched early differentiated cells was accompanied by gain in abundance of PD1 + populations with exhausted (CD57 - ICOS hi CTLA4 hi ) and terminally differentiated effector (CD57 + Eomes + ) phenotypes. Further characterisation of these populations by single cell RNA sequencing revealed differential expression of key genes involved in transcriptional regulation, co-inhibition and co-stimulatory pathways. A validated gene signature of CD4 ds was associated with worse outcomes in TRACERx and TCGA cohorts. Conclusions: Our findings reveal remodelling of the CD4 differentiation landscape in association with tumour genomic characteristics, underscoring how mutational burden in the context of chronic stimulation may lead to loss of immune fitness and elucidating key regulatory pathways in potentially clinically relevant CD4 subsets.
Abstract 14922: A Systematic Review of the Association Between Biomarkers of Cardiovascular Disease and HIV/HCV Coinfection
Authors: Olatokunbo I Osibogun, Oluseye Ogunmoroti, Erin D Michos, Erica S Spatz, Babatunde Olubajo, Khurram Nasir, Moyses Szklo, Wasim Maziak
Journal: Circulation (2017)

Background: The incidence of HIV/HCV coinfection has been increasing with over 10 million people affected globally. The role biomarkers play as predictors of cardiovascular disease (CVD) risk among...
AB0435 REAL WORLD DATA OF A PATIENT COHORT WITH RHEUMATOID ARTRITIS TREATED WITH JAK/STAT INHIBITORS
Authors: Isabel de la Morena, Juan Alberto Paz Solarte, Diego Bedoya, Pilar Trenor Larraz
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> We present the real World data of a patient cohort with rheumatoid arthritis (RA) that received one of the two JAK/STAT inhibitors approved by the EMA for this indication. <h3>Objectives:</h3> To describe the Real World Data of a patient cohort attending Rheumatology consult of a reference hospital in Valencia with RA diagnosis and that were treated with JAK/STAT inhibitors. <h3>Methods:</h3> A descriptive retrospective study was carried out. There were revised medical histories of 28 patients with a RA diagnosis that attended our consults between 2017 and 2018. All 28 patients were JAK/STAT treatment receivers of one of the two JAK/STAT inhibitors approved: Tofacitinib 10 mg oral QD or Bariticinib 4 mg oral QD. There were collected patient baseline demographic data: sex, age, BMI, activity disease score measured by DAS28-CRP and visual pain analogue scale for patient's assessment (VAS). In addition, there were collected the previous synthetic(s) and biological (s) DMARD treatments, as well as the associated treatments. Efficacy and security were also analysed. There were assessed serum biochemical variables, among them acute phase reactants such as CRP and and ESR <h3>Results:</h3> DMARDb: Number of previous biological treatment DMARDc: Number of synthetic previous treatments With regards to efficacy, there were collected 6 treatment withdrawals: 1 primary treatment failure (in Tofacitinib Group) and 5 secondary treatment failures (1 in Baricitiib Group and 4 in Tofacitinib Group) and the mean treatment duration was 152 days. <h3>Conclusion:</h3> Despite the study population was small and the follow-up time was short, we highlight in our patients that both JAK inhibitor alternatives have shown a security and efficacy profile similar to the results shown in pivotal clinical trials. Despite the previous biological treatment failure and obesity are considered as predictors of bad response to treatment, in our cohort did not represent a high risk to treatment failure, it can be an alternative in the same scenary. <h3>Disclosure of Interests:</h3> Isabel de la Morena Speakers bureau: Abbvie, Celgene, Pfzier, UCB, Ghebro, Roche, Sanofi, Janssen., Juan Alberto Paz Solarte Employee of: He is working at UCB since December 2018, when the patient recruitment ended., Speakers bureau: Abbvie, Roche, Pfzier, Novartis, Celgene, Amgen, MSD, Janssen, Diego Bedoya: None declared, Pilar Trenor Larraz: None declared
Germline multigene panel testing in colorectal cancer: Precision therapy and clinical management implications.
Authors: Edward D. Esplin, Shan Yang, Scott T. Michalski, Daniel Esteban Pineda Alvarez, Stephen E Lincoln, Robert L. Nussbaum
Journal: Journal of Clinical Oncology (2019)

3582 Background: Recent studies suggest that the prevalence of abnormalities in homologous recombination deficiency (HRD) genes and other cancer genes not traditionally associated with colorectal cancer (CRC) may be more common in patients with CRC than previously appreciated. Herein, we investigate the efficacy of comprehensive multigene panels in patients with CRC to identify candidates for precision therapies. Methods: DNA sequencing and exon-level copy number analysis were performed in over 9000 patients (pts) referred because of personal history of colon cancer between 2013 and 2018 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary CRC panel; the patient data were de-identified and further analyzed for all 83 genes on a large hereditary cancer syndrome panel under an IRB-approved protocol. Results: Pathogenic/likely pathogenic (P/LP) findings were identified in 2101 of 9669 pts (21%), 1838 (19%) pts when MUTYH heterozygotes are excluded. When restricted to five Lynch syndrome (LS) genes, only 9% of patients had a P/LP finding, which increased to 15% of patients when 19 guidelines-based CRC genes were assessed. 137 pts (1.4%) had two or more P/LP variants. P/LP variants were in MLH1, MSH2, MSH6, PMS2, CHEK2, APC, MUTYH, BRCA2, ATM, BRCA1, PALB2, RAD50, BRIP1, TP53, EPCAM, among others, of which 1.4% were BRCA1/2. When a comprehensive multigene panel was utilized P/LP variants in genes with known therapeutic implications, such as in HRD and mismatch repair deficiency (MMRD), were detected in 1408 (14%) of patients, and 1670 (17%) had P/LP variants in genes with established clinical management guidelines. Conclusions: This study suggests that 1 in 5 patients with CRC harbor actionable germline variants, up to one-half of which remain undetected when only LS genes are tested. Comprehensive panel testing identified candidates for precision treatment and established management recommendations, and have clinical implications for both pts and their at risk family members.
The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML
Authors: Jennifer B. Dunlap, Jessica Leonard, Mara Rosenberg, Rachel Cook, Richard Press, Guang Fan, Philipp W. Raess, Brian J. Druker, Elie Traer
Journal: American Journal of Hematology (2019)

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, ∼30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, ∼40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next‐generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.
Online education about lung cancer immunotherapy: Outcomes over time.
Authors: Lori Keys Pender, Haleh Kadkhoda, Katie S. Lucero, Patti Repetto, Jacqueline Gearhart
Journal: Journal of Clinical Oncology (2019)

e18249 Background: The indications and use of immune checkpoint inhibitors (ICIs) in the treatment of advanced and metastatic lung cancer have grown dramatically since the first lung cancer drug approval in 2015. The rapid pace of change can make it difficult for oncologists to stay up to date with how best to integrate these news agents into treatment paradigms. The objective of this study was to assess trends over time in oncologists’ knowledge, competence, and confidence using ICIs in the treatment of lung cancer. Methods: A series of online continuing medical education (CME) activities about the role of ICIs in lung cancer treatment was launched in April 2014; 28 included multiple-choice knowledge/competence questions and a confidence question assessed on a 5-point Likert-type scale before and immediately after the activity. Activities that had at least 30 oncologists participate pre/post are included in this analysis. A pre-/post-assessment study design was used, and educational effect was assessed with Chi-square tests. Analyses were conducted to examine trends in knowledge, competence, and confidence over four years on a quarterly basis. Weighted averages in each of the outcomes were calculated by quarter. Results: A total of 132,370 learners participated from April 2014-March 2018, including 61,761 physicians, of whom 19,439 were oncologists. The average increases pre- to post-test for knowledge- (25 activities), competence- (18 activities), and confidence-based (9 activities) questions were 16%, 12%, and 7%, respectively (P &lt; 0.001 for all comparisons). The absolute increase in knowledge from pre-test in 2014 (41%) to post-test in 2018 (56%) was 14 percentage points; and for competence, 25% (from 28% in 2014 to 52% in 2018). The mean confidence rating pre-test in 2016 was 2.85 versus 3.16 post-test in 2018. Conclusions: Online CME improves oncologists’ knowledge, competence, and confidence using ICIs in the treatment of lung cancer at any given point in time; however, gaps remain, and given the wealth of new data that continue to emerge, on-going education is needed to reinforce and build upon existing knowledge, close persistent gaps, and increase oncologists’ confidence with this new therapeutic class.
A predictive model for survival in non-small cell lung cancer (NSCLC) based on electronic health record (EHR) and tumor sequencing data at the Department of Veterans Affairs (VA).
Authors: Nathanael Fillmore, Jamie Ramos-Cejudo, David Cheng, David P. Tuck, Ayesha Rizwan Sheikh, Daniel Chen, Danne Elbers, Feng-Chi Sung, Brett Johnson, Colleen Shannon, Karen Pierce-Murray, Kelly Gaynor, Corri Dedomenico, Sarah Schiller, Samuel Ajjarapu, Robert Hall, Siamack Ayandeh, Frank Meng, Mary T. Brophy, Nhan Do
Journal: Journal of Clinical Oncology (2019)

109 Background: Machine learning tools based on EHR data hold promise to help avoid unnecessary risks associated with lung cancer and its treatment. Additionally, molecular genetic profiling is becoming an integral tool for clinicians to individualize treatment for lung cancer. However, relatively few survival models have been built that integrate this data in individualized predictive models. Here, we combine real-world EHR and tumor sequencing data from the VA Precision Oncology Data Repository (PODR) to build accurate individualized survival predictions in newly-diagnosed NSCLC patients. Methods: We identified a cohort of 356 VA patients newly diagnosed with NSCLC for whom EHR, cancer registry, and targeted tumor sequencing data is available in PODR. We defined 41 features reflecting 15 baseline clinical and demographic characteristics from the EHR and registry, such as age, race, stage, histology, and therapy. We also defined features reflecting 206 clinically actionable somatic variants. We selected 5 important variants for inclusion in the model, as well as the total number of mutations. We trained a random forests algorithm to predict 1-year survival. Precision, recall, and area under the ROC curve (AUC) were assessed using 5-fold cross validation. Results: Mean age at diagnosis was 66 years. The majority of patients had late stage disease (15% stage I, 6% II, 15% III, 44% IV), and 59% of patients received systemic therapy. 45% died within 1 year of diagnosis, and 55% survived past 1 year. Our predictive model for 1-year survival achieves strong results. Cross-validated AUC is 0.79 (SD 0.08), precision is 0.79 (SD 0.07), recall is 0.74 (SD 0.07), suggesting that the trained model combining clinical and genomic features is effective at predicting 1-year survival. Conclusions: By integrating real-world EHR and sequencing data, we built a highly accurate predictive model of 1-year survival in NSCLC patients at the VA. Such a model, after ongoing validation in a larger cohort, offers the ability to make individualized predictions that could inform patient care to improve outcomes.
Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA).
Authors: Michele Bartoletti, Giacomo Pelizzari, Lorenzo Gerratana, Silvio Ken Garattini, Debora Basile, Camilla Lisanti, Lucia Bortot, Carla Corvaja, Mattia Garutti, Simona Scalone, Milena Nicoloso, Silvia Bolzonello, Elena Torrisi, Lucia Da Ros, Paola Di Nardo, Davide Lombardi, Giorgio Giorda, Gustavo Baldassarre, Roberto Sorio, Fabio Puglisi
Journal: Journal of Clinical Oncology (2019)

5564 Background: Patients (pts) experiencing a PS rOC are generally re-exposed to a platinum based-chemotherapy (CT). In this setting, the addition of a targeted agent like bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparison in randomized trials (RCTs), we have performed a NMA to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS rOC, according to BRCA status. Methods: We searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n = 3, 1563 pts) or PARPi (n = 5, 1839 pts). Only trials with PFS as primary endpoint were included. Trials in first line setting were excluded. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied. Results: In AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR] = 0.70, 95% CI 0.54-0.91, test of heterogeneity [I 2 ] = 40.5%). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR = 0.46, 95% CI 0.36-0.59, I 2 = 17.2%). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR = 0.87, 95% CI 0.63-1.20, I 2 = 35.7%) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV). Hazard ratio for PFS between PARPi, BEV and CT in the three cohorts are reported in the table. Conclusions: According to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts. [Table: see text]
Total neoadjuvant chemo (ctx; TNT) for locally advanced gastric cancer (GC): The Memorial Sloan Kettering Cancer Center experience.
Authors: Megan Greally, Vivian E. Strong, Sam S. Yoon, Daniel G. Coit, Joanne F Chou, Marinela Capanu, David Paul Kelsen, Yelena Yuriy Janjigian, David H. Ilson, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2019)

4046 Background: Peri-op chemo (ctx) and surgery is a standard in the treatment of GC, based on the MAGIC (NEJM 2006; 355:11) and FLOT4 (J Clin Oncol 35:4004 [abstr]) studies. However, less than half of patients (pts) completed ctx in the MAGIC and FLOT4 studies, mainly from issues delivering post-op therapy. We assessed safety and feasibility of TNT, where all ctx is given pre-op. Methods: We reviewed GC pts who received TNT or peri-op ctx and had surgery; decision for TNT was by physician preference, based on clinical or radiographic benefit to justify completing ctx pre-op. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank Sum tests. Post-op length of stay (LOS) was calculated from date of surgery (DOS) to date of discharge and surgical morbidity was determined using the Clavien-Dindo classification. Progression free survival (PFS) and overall survival (OS) were calculated from DOS using Kaplan-Meier methods and compared between groups using the log-rank test. Results: 120 pts were identified, median age 63, 62.5% male, 98% ECOG 0/1. 93 pts (77.5%) received peri-op ctx and 27 (22.5%) received TNT. In peri-op pts, 19%, 43% and 38% received FLOT, platinum/fluropyrimidine (FP) and ECF/EOX respectively. In TNT pts, 56%, 37% and 7% received FLOT, platinum/FP and ECF/EOX respectively. 57% had subtotal gastrectomy. Surgical outcomes were similar between groups; median LOS was 6 and 7 days (p = 0.31) in peri-op and TNT pts respectively. There was no significant difference in Clavien Dindo grade I-II or III-IV morbidity between groups (p = 0.103). There were no deaths. TNT pts received higher proportions of planned treatment than peri-op ctx pts: 90% vs. 60% FP (0.001); 85% vs. 41% platinum ( &lt; 0.001); 100% vs. 9% epirubicin (0.015) and 53% vs. 28% docetaxel (p = 0.169). At median follow-up of 19 months, median PFS and OS were not reached. There was no significant difference in PFS (p = 0.089) or OS (p = 0.59) between groups. Conclusions: TNT appears safe with no increase in post-op LOS or surgical morbidity observed. TNT pts had higher percentage drug delivery, suggesting potential benefit for administering all ctx before surgery. While longer survival follow-up is required, TNT may be considered in pts with locally advanced GC who are candidates for ctx.