tbuckley/cabot-search huggingface dataset:
Phase 1 study to evaluate safety and efficacy of nivolumab (nivo) + ipilimumab (ipi) + external beam radiotherapy (RT) in patients with metastatic melanoma.
Authors: Michael A. Postow, Susan Jane Knox, Debra Goldman, Katherine Panageas, Darragh Halpenny, Danielle McCabe, Mary J. Macri, Paul Schwarzenberger, Toni Ricciardi, Aileen Ryan, Ralph Rudolph Venhaus, Christopher Andrew Barker
Journal: Journal of Clinical Oncology (2018)

9550 Background: RT causes immunologic effects that enhance the efficacy of immune checkpoint blockade in preclinical models. No prospective clinical trial data exist for the safety and efficacy of combining RT with the nivo + ipi combination. Methods: We conducted a prospective study (NCT02659540) where patients with metastatic melanoma were treated with nivo (1 mg/kg) + ipi (3 mg/kg) every 3 weeks (Q3W) for up to 4 doses, with optional nivo maintenance Q2W per standard of care. Following the first nivo + ipi dose, patients were treated with conventionally fractionated RT (30 Gy in 10 fractions) to one melanoma metastasis. Treatment-related (TRAE) and treatment-emergent (TEAE, all causality) adverse events within the first 24 weeks of immunotherapy initiation were summarized overall and by CTCAE grade. Objective response rate (ORR) was assessed by RECIST 1.1 outside and within the irradiated fields. ORR rates were provided with binomial 95% confidence intervals (CI). Results: Ten patients (median age: 65 [range: 28-86] years; 6 female) received at least 1 dose of study therapy and were included in the safety analyses. One patient withdrew consent prior to efficacy assessment and was excluded from efficacy analyses. All patients had ≥1 any grade (G) TEAE. G3/4 TRAE occurred in 4 patients (40%), and G3/4 TEAE occurred in 7 patients (70%). G3/4 TRAE were anemia, thrombocytopenia, increased lipase, and pruritus. ORR outside of the irradiated field was 44% (4/9, 95% CI: 14-79%). Responses were also seen within the irradiated fields. Two patients died due to disease progression. Conclusions: This first prospective study in a small group of patients suggests it is safe to combine conventionally fractionated RT with nivo + ipi. Based on acceptable G3/4 TRAE in this fully accrued cohort testing conventionally fractionated RT, accrual is ongoing to a second cohort where patients receive higher dose per fraction RT with nivo + ipi. Clinical trial information: NCT02659540.
Safety of intra-arterial chemotherapy with osmotic opening of the blood brain barrier.
Authors: Jenny Firkins, Prakash Ambady, Joseph Alan Frank, Edward A. Neuwelt
Journal: Journal of Clinical Oncology (2018)

e14056 Background: Osmotic blood brain barrier disruption (BBBD) can increase drug delivery up to 100 fold in brain tumors when compared to IV delivery. The aim of this study was to evaluate the safety of osmotic opening of the blood brain barrier with hypertonic mannitol and administration of intra-arterial chemotherapy. Methods: A retrospective chart review was completed of all malignant brain tumor patients treated with BBBD at Oregon Health and Science University between 1997 and 2017. Variables assessed included standard demographics and death within 30 days of treatment. All toxicities were defined using the CTCAE (version 3 and 4). Results: Between 1997 and 2017, a total of 4018 BBBD procedures were completed (268 patients). Patients were treated on 6 IRB approved treatment protocols or off protocol. Primary central nervous system lymphoma and anaplastic oligodendroglioma accounted for 45% of patients. Most adverse events (AEs) were drug-related and only 5% of AEs were attributable to the BBBD procedure. Of these, 0.42% were associated with permanent neurological damage (Grade 3 or 4 SAE): 4 of these events by MRI were due to ischemia with minimal impact on quality of life, and 4 due to anterior cord syndrome (partially responsive to steroids) subsequent to iatrogenic intravascular streaming during vertebral artery infusion (Fortin et al, AJNR 1999). Subsequently this was eliminated by procedures to avoid intravascular streaming. Seizures, mainly focal and responsive to medical therapy, occurred within 24 hours of 257(6.4%) BBBD procedures, 89% (229) of which followed administration of methotrexate (MTX). Five patient deaths occurred within 30 days; 1 due to a brain stem stroke related to BBBD, 1 due to a pulmonary embolus, and 3 due to disease progression. Conclusions: Osmotic BBBD can be performed safely in brain tumor patients. Myelitis can be avoided but focal seizures from MTX appear to be a common occurrence but are transient and without sequela. Although invasive, permanent toxicities are rare.
Oncology education for family medicine (FM) residents and family physicians (FPs): A needs assessment survey.
Authors: Steven Yip, Daniel E. Meyers, Jeffrey James Sisler, Keith Wycliffe-Jones, Edward Kucharski, Christine Elser, Claire Temple-Oberle, Silvana Spadafora, Paris Ann Gfeller-Ingledew, Giuliani Meredith, Sara Kuruvilla, Nureen Sumar, Vincent C. Tam
Journal: Journal of Clinical Oncology (2018)

11014 Background: Cancer care demands in FM continue to grow. This study aimed to determine the current state of oncology education in FM and examine opinions regarding optimal FM oncology education. Methods: A survey was designed to evaluate ideal and current oncology teaching, topics and objectives in FM post graduate medical education (PGME) and continuing medical education (CME). The survey was pilot-tested and sent to FM residents and FM program directors (PDs) across Canada and FP Cancer Care Committee members of the College of Family Physicians of Canada. Results: From May 1 - August 31, 2017, 131 FM residents and 15 FM PDs affiliated with 16 of 17 Canadian medical schools and 42 FPs completed the surveys. The PGME survey results are in Table 1. Residents reported that the best way to learn oncology is through clinical experiences alone. PDs stated that case-based and didactic teaching are also important. Residents and PDs agreed that the most important topics are cancer prevention, cancer screening, breaking bad news, and palliative care. These topics were taught to 89-100% of residents. Yet, the other important topics of appropriate cancer patient referrals, managing cancer complications and post-treatment surveillance were only taught to 52%, 40% and 36% of residents, respectively. According to 40% of FPs, the amount of oncology CME completed was inadequate; 21% reported that CME inadequately updates their knowledge in cancer patient management. Conclusions: Current FM PGME oncology education is sub-optimal across Canada, although the degree differs between the opinions of the residents and PDs. Sub-optimal oncology teaching is also likely for FM CME. FM oncology education can be improved using suggestions generated from this survey. PGME results. Residents PDs There is an oncology clinical rotation 118/130 (91%) 15/15 (100%) There are oncology learning objectives 17/130 (13%) 5/15 (33%) Cancer topics are taught in clinic 73/127 (57%) 15/15 (100%) Oncology education provided is adequate 10/130 (8%) 3/15 (20%) Training adequately prepared me to care for cancer patients 11/130 (8%) 2/15 (13%) Standardized oncology learning goals, objectives and competencies would be useful 93/128 (73%) 8/15 (53%)
Peripheral blood T cell subset phenotype analysis in melanoma patients treated with combination nivolumab + ipilimumab compared to ipilimumab alone.
Authors: Michael Andrew Postow, Deborah Kuk, Matthew Adamow, Cristina Carrera, Phillip Wong, Michael A. Curran, Claire Frances Friedman, Parisa Momtaz, Alexander Noor Shoushtari, Jedd D. Wolchok, Paul B. Chapman, Margaret K. Callahan
Journal: Journal of Clinical Oncology (2016)

3073 Background: The combination of nivolumab and ipilimumab (N+I) has superior clinical activity vs. ipilimumab (I) alone. Research is needed to understand the immunologic mechanisms unique to N+I that may be related to its increased efficacy. Using peripheral blood (PB) from a randomized study, we compared immunologic changes in patients (pts) treated with N+I to changes observed in pts treated with I alone. Methods: 22 patients treated at Memorial Sloan Kettering Cancer Center on clinical trial CA209069 (Checkmate 069) were consented to an IRB-approved correlative protocol for collection of PB samples. Patients were randomized either to receive the combination of N+I (n = 11) or I alone (n = 11). PB was collected at baseline and every 3 weeks. The frequency and phenotype of T cell populations was determined using flow cytometry. Pharmacodynamic (PD) changes from baseline to just before the 2nd dose (week 3) in PB T cell populations were compared between patients receiving combination N+I vs. I alone. Results: The combination of N+I resulted in distinct PD effects on PB T cell phenotype compared to I alone. Within the CD8+ T cell compartment, Ki67+, CTLA-4+, and TIM3+ populations increased to a greater amount (p = 0.008, p = 0.002, and p = 0.004, respectively) in pts treated with N+I compared to I alone. Among CD4+ T cells, CTLA-4+ and FOXP3+ populations increased to a greater amount (p = 0.033 and p = 0.033, respectively) in pts treated with N+I compared to I alone. Among the CD4+FOXP3+ (Treg) cells, there were significant differences in the change in frequency of TIM3+ and PD-1+ Tregs in pts treated with N+I compared to I alone (p = 0.008 and p < 0.001, respectively). There were no significant differences between pts treated with N+I and I alone in the change in ICOS+CD8+ or ICOS+CD4+ T cells. Conclusions: In this small, single-institution, retrospective analysis, unique immunologic changes were seen in the PB of pts treated with N+I compared to I alone in some, but not all, examined T cell populations. Whether the different PD immunologic effects are related to the increased clinical activity of N+I vs. I alone requires additional study.
Causal modeling of CALGB 80405 (Alliance) to identify network drivers of metastatic colorectal cancer (CRC).
Authors: Rahul K Das, Leon Furchtgott, Jeffrey A. Meyerhardt, Andrew B. Nixon, Federico Innocenti, Daniel Cunha, Kelly Rich, Heinz-Josef Lenz, Donna Niedzwiecki, Eileen Mary O'Reilly, Fang-Shu Ou, Jeanne Latourelle, Diane Wuest, Boris Hayete, Iya Khalil, Alan P. Venook
Journal: Journal of Clinical Oncology (2018)

3570 Background: CALGB 80405 is a phase III clinical trial of FOLFOX/ FOLFIRI with randomly assigned cetuximab/ bevacizumab. Novel causal machine learning approaches to the study dataset may lead to valuable insights into CRC prognosis and management of CRC progression. Methods: Using a Bayesian causal machine learning and simulation platform, we built an ensemble of network models for overall survival (OS). We used 78 baseline clinical and demographic variables for 947 patients with wild-type KRAS tumors. Causal modeling identifies the set of conditional dependencies between variables leading to outcomes. Building an ensemble of causal models estimates model uncertainty and identifies key drivers by model consensus as measured by ensemble frequency (f). Counterfactual simulations were performed on this ensemble to identify causal drivers of disease. Results: Key causal variables of OS (f > 50%) include primary tumor side (f = 85%), aspartate aminotransferase (AST) and hemoglobin (HGB) concentrations (f = 100%, 91%), and tumor sites: local primary and intra-abdominal metastases (f = 85%, 89%). Counterfactual simulations, controlling for confounders, suggested a significant causal effect of the following variables on driving OS: AST (median hazard ratio (HR) = 1.3, 75th vs. 25th percentile value; 10th - 90th percentile interval: 1.2-1.4), HGB (0.8, 0.7-0.9), primary side (1.5, 1.0-1.7; right vs. left), and tumor sites (present vs. absent): local primary (1.3, 1.0-1.5), intra-abdominal (1.4, 1.1-1.6) and liver (1.1, 1.04-1.14) metastases. AST was a stronger biomarker of OS in patients with liver metastases (1.6, n = 705) than without (1.2, n = 242). Conclusions: Primary side, AST, HGB, and tumor sites (local primary, intra-abdominal, and liver) play a central role as independent drivers/biomarkers of OS. Availability of these measures at baseline will allow better risk stratification at initiation of treatment. Clinical trial information: U10CA180821, U10CA180882.
Comprehensive genomic characterization of urothelial carcinomas.
Authors: Amin Nassar, Renato Umeton, Kevin Lundgren, Lauren Christine Harshman, Eliezer Mendel Van Allen, Toni K. Choueiri, Graeme Steele, Joaquim Bellmunt, Kent William Mouw, Guru Sonpavde, David J. Kwiatkowski
Journal: Journal of Clinical Oncology (2018)

4527 Background: While the genetic characteristics of muscle-invasive bladder cancer have been studied in detail, there are few reports using the same genetic analysis platform to investigate differences and similarities among urothelial carcinoma (UC) derived from different sites and with differing degrees of invasion. Methods: We used targeted exome sequencing with Oncopanel to study 82 low-grade (LG) non-muscle invasive bladder cancer tumors (LG-NMIBC), 127 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancer tumors (MIBC), and 55 HG invasive upper tract urothelial carcinoma (UTUC) tissue samples. Oncopanel assesses 275-447 cancer genes for somatic mutations and copy number alterations without a paired normal. All single nucleotide variants (SNVs) that were considered likely germline were excluded. Clinico-pathological characteristics, mutation frequencies for 238, and tumor mutation burden (TMB) were determined for the 4 types of UC, and were compared using the χ2 test and Kruskall Wallis Test. Nominal p values were obtained, and the Benjamini-Hochberg fdr correction was employed to determine statistical significance (q < 0.1). Results: Key results are shown in the Table. Conclusions: In this series of uniformly analyzed UC samples of different kinds, we found that: 1) FGFR3, STAG2 and KDM6A mutations are highly enriched in LG-NMIBC; 2) HG-NMIBC, MIBC, and UTUC all have similar genetic alterations; and 3) TP53 and RB1 mutations are associated with all of the latter 3 types of UC in contrast to LG-NMIBC. Gene LG NMIBC HG NMIBC MIBC UTUC total q value N % N % N % N % % FGFR3 Alteration Yes/No 59/23 72/28 33/93 26/74 25/174 13/87 10/45 18/82 27/73 < 0.0001 TP53 Alteration Yes/No 3/79 4/96 59/67 47/53 118/81 59/41 26/29 47/53 45/55 < 0.0001 RB1 Alteration Yes/No 0/82 0/100 23/103 18/82 46/153 23/77 6/49 11/89 16/84 0.0012 STAG2 Alteration Yes/No 25/57 30/70 21/105 17/83 18/181 9/91 8/47 15/85 16/84 0.006 KDM6A Alteration Yes/No 38/44 46/54 47/79 37/63 49/150 25/75 12/43 22/78 32/68 0.024 FGFR2 Alteration Yes/No 1/81 1/99 9/117 7/93 2/197 1/99 0/55 0/100 3/97 0.072 TMB Mean 11.47 16.61 14.01 11.78 -
Diagnosis and management of <scp>NSAID</scp>‐Exacerbated Respiratory Disease (N‐<scp>ERD</scp>)—a <scp>EAACI</scp> position paper
Authors: Marek L. Kowalski, Ioana Agache, Sevim Bavbek, Arzu Bakirtas, Miguel Blanca, Grażyna Bochenek, Matteo Bonini, Enrico Heffler, Ludger Klimek, Tanya M. Laidlaw, Joaquim Mullol, Ewa Niżankowska‐Mogilnicka, Hae‐Sim Park, Marek Sanak, Mario Sanchez‐Borges, Silvia Sanchez‐Garcia, Glenis Scadding, Masami Taniguchi, Maria J. Torres, Andrew A. White, Aleksandra Wardzyńska
Journal: Allergy (2018)

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.
Elderly patient’s tolerance and efficacy for MAP-kinase inhibitors in a French melanoma real-life cohort.
Authors: Ondine Becquart, Bastien Oriano, Stéphane Dalle, Laurent Mortier, Marie Thérèse Leccia, Caroline Dutriaux, Sophie Dalac, Jean-Philippe Lacour, Julie De Quatrebarbes, Florence Brunet-Possenti, Philippe Saiag, Thierry Lesimple, Marie Beylot-Barry, Francois Aubin, Pierre-Emmanuel Stoebner, Catherine Lok, Brigitte Dreno, Raphael Porcher, Celeste Lebbe, Bernard Guillot
Journal: Journal of Clinical Oncology (2018)

e21536 Background: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since more than 50% of melanoma arise in > 65 years-old (yo). Combined BRAF and MEK targeted therapies (TT) are current standard regimen for BRAF V600 mutated metastatic melanoma (MM) since they overturned its prognostic. Except for subgroups of pivotal trials, little data are available for TT in this population. Methods: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT (dabrafenib, vemurafenib) and/or MEK TT (cobimetinib, trametinib), combined or not, were included from 2012 to 2017 in 3 groups: group 1 < 65 yo, group 2 between 65 and 75, and group 3 > 75, analyzed for tolerance and efficacy. Results: 353 patients were included: 231(65%) in group 1, 72 (20%) in group 2 and 50 (14%) in group 3. Median follow-up was 12 months (M). Median time of treatment was 6.9M. 80% had at least one Adverse Effects (AE). In all groups, most frequent AE (all grades) were mainly skin and subcutaneous, general and gastrointestinal disorders. 31% of AE were grade 3-4: 28% in group 1 and 3 but 46% in group 2 (p = 0.05). In all groups, no differences were observed in all AE grades proportion, dose modifications, interruptions and discontinuations. For each group, median overall survival was 20.1M (CI 95%: 15.5-27.9), 16.4M (11.3-30.2) and 16.3M (13.6-NR) respectively (p = 0.8). Median progression free survival was 7.8M (6.4-9.95), 6.5M (5.4-10.94), 11.5M (6.1-15.11) respectively (p = 0.4). Response rate was 59%, 51%, and 48% respectively (p = 0.6). In multivariate analysis, stage M1a/b and high LDH level at TT initiation were significantly predictive of poorer tolerance in whole population as well as ECOG > 0 in group 3 (p = 0.05). Conclusions: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients < 65yo. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, but onco-geriatric opinion is steel needed for patients over 75yo.
A retrospective study of anti-EGFR antibody therapy in small bowel adenocarcinoma.
Authors: Victoria Serpas, Kanwal Pratap Singh Raghav, Gauri R. Varadhachary, Robert A. Wolff, Michael J. Overman
Journal: Journal of Clinical Oncology (2018)

e16264 Background: The benefit of anti-EGFR therapy in RAS-wild type (WT) metastatic colorectal cancer (mCRC) is often extrapolated to metastatic small bowel cancer adenocarcinoma (mSBA). However, the efficacy of these agents in mCRC varies by sidedness with right sided colon cancers deriving no benefit. As the small bowel and right sided colon both arise from embryonic midgut, we sought to evaluate the activity of anti-EGFR therapy in SBA. Methods: A single-center, retrospective analysis of mSBA treated with anti-EGFR therapy from 2008 to 2017 at the University of Texas MD Anderson Cancer Center was conducted. All patients (pts) had confirmed pathology, received > 1 cycle of therapy, and had documented tumor response evaluation. Ampullary adenocarcinomas and pts enrolled on a clinical trial were excluded. Time to progression (TTP) and overall survival (OS) were calculated from the start of therapy using the Kaplan-Meier method. Results: A total of 25 pts with mSBA were treated with cetuximab (n = 19) or panitumumab (n = 6) as single agents (n = 7) or combined with chemotherapy (n = 18). Baseline characteristics were as follows: mean age 58 years, 52% female, poor differentiation 48%, and pre-disposing conditions 32% (inflammatory bowel disease in 6, Lynch syndrome in 2). Primary tumor site was duodenum (n = 7), jejunum (n = 9), ileum (n = 7), and unspecified (n = 2). All patients were KRAS exon 2 WT. KRAS exon 3 and 4 testing was done in 16 and 10 pts (all WT), respectively. NRAS testing was done in 11 pts (all WT). After a median follow-up of 34 months (m), median TTP was 3.3 m (95% CI: 2.6 – 4.0 m) and median OS was 13 m (95% CI: 1.7 – 24.3 m). Only 3 (12%) pts had disease regression, while 6 (24%) had stable disease (SD), and 16 (64%) had progressive disease as their best response. All 3 responders were treated in combination with irinotecan and had not previously progressed on irinotecan. For the 7 patients who received single agent anti-EGFR, median TTP was 2.2 m (95% CI: 1.2 – 3.2 m) and best response was SD in one patient. Conclusions: Anti-EGFR therapy, although effective in mCRC, has no notable activity in KRAS-WT SBA and should not be used outside of a clinical trial. The midgut derivation of both small bowel and right-sided colon cancer may explain this finding.