tbuckley/cabot-search huggingface dataset:
Feasibility of a high-throughput molecular tumor board (MTB) to provide clinical practice guidance following comprehensive molecular profiling (CMP).
Authors: Ari M. Vanderwalde, Gy Won Choi, Gregory A. Vidal, Jason Claud Chandler, Bradley G. Somer, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2016)

e18128 Background: Increasing availability of CMP has led to massive amounts of tumor-specific molecular information with uncertain clinical utility. We initiated a high-throughput MTB to review all CMP and make recommendations for care. We report the initial experience with clinical utility of these recommendations at a single institution. Methods: We adopted a policy of CMP for first line metastatic cancer in 2014. CMP was provided by one of two commercial providers with multiple -omic platforms including immunohistochemistry, in-situ hybridization, Next-Gen Sequencing (NGS) and RNAseq. NGS panels ranged between 44 genes probed for hot-spot mutations and 592 genes with whole exome coverage. Results were first reviewed by a single physician to select potentially actionable reports for discussion. MTB, with representation by medical oncology, genetics, pathology, and clinical trials, reviewed CMP reports in conjunction with patient clinical history and made consensus recommendations to the treating physician. Chart review was performed to determine clinical utility of MTB recommendations. Results: Between November 2014 and January 2016, 1247 CMP reports were reviewed, with lung, colorectal, and breast cancer represented most commonly (306, 237, and 146 reports). Of these 445 were selected for review, and 199 resulted in recommendations by MTB. Clinical trials available at our or nearby centers were recommended in 66% of reviewed cases. Recommendations for standard therapy based on molecular findings were made in 25% of cases, while non-standard approaches, including therapy approved for a different disease setting, were made in 17%. In 12% of cases additional germline testing was recommended. Chart review revealed that MTB recommendations were followed in 46% of evaluable patients (72/157). Outcomes of patients presented at MTB are under current review. Conclusions: Routine CMP followed by reflexive review and recommendations by a high-throughput MTB is feasible and shows promise as a means to provide clinical guidance in a substantial fraction of patients. MTB recommendations are particularly useful in identifying patients for clinical trials.
Acceptability of FitBit activity trackers for socioculturally diverse endometrial cancer survivors: A pilot study.
Authors: Eirwen Murray Miller, Amerigo Rossi, David Samuel, Carolina Ramirez, Shankar Viswanathan, Dennis Yi-Shin Kuo, Nicole Suzanne Nevadunsky
Journal: Journal of Clinical Oncology (2017)

e17103 Background: Endometrial cancer survivors are the least physically active of all cancer groups. In past feasibility studies of a physical activity intervention for obese endometrial cancer survivors, we have found high adherence and significant improvements in quality of life and body composition but low recruitment (48%). The primary objective of this study was to assess the acceptability the FitBit Alta activity tracker among socioculturally diverse endometrial cancer survivors. Methods: After IRB approval, patients were approached for study participation at the time of routine follow-up in gynecologic oncology clinic. Eligible patients included those with a history of stage I-IV endometrial cancer diagnosed within the past 10 years who were not undergoing active therapy at the time of study participation. Participants were instructed to wear a FitBit Alta for 30 days. At the conclusion of the study period, patients received a phone call to complete an acceptability questionnaire. After 30 days of use, the FitBits were returned to provide detailed daily activity data for the duration of the study period. Results: Of 37 eligible identified patients, 30 agreed to participate in the study (81%). Recruitment to this study was significantly higher as compared with our historical exercise lifestyle intervention (48%, p &lt; 0.01). Mean age was 65 and BMI 33 kg/m 2 (19-64kg/m 2 ). 70% reported stage I and II disease. Patients self-identified as 53% white, 23% black, and 33% Hispanic. 40% of patients had household incomes &lt; $60,000 per year. Preliminary data shows that patients walk between 2,500 and 12,000 steps per day. Conclusions: Recruitment to the FitBit Alta was significantly higher than historically reported exercise lifestyle interventions at our institution. Additional research is needed to understand retention and patient satisfaction with lifestyle interventions using wearable technology.
Outcomes in newly diagnosed diffuse large B cell lymphoma presenting with hepatic and/ or renal dysfunction.
Authors: Srinivasa Reddy Sanikommu, Hu Bei, Myra M. Robinson, Jigar S. Trivedi, Taylor Brown, Steven I. Park, Ryan Jacobs, Avalos Belinda, Edward Alan Copelan, Nilanjan Ghosh
Journal: Journal of Clinical Oncology (2018)

7558 Background: In DLBCL, hepatic and/or renal dysfunction may occur due to tissue infiltration with lymphoma, bulky lymphadenopathy leading to obstruction or tumor lysis leading to renal dysfunction. These patients are often excluded from clinical trials and there is paucity of data in this population. Recently, ASCO and Friends of Cancer Research joint statement emphasized to broaden the clinical trial eligibility criteria to make the results more representative. Therefore, we performed a retrospective study in this population. Methods: We obtained baseline characteristics, and assessed outcomes in patients with previously untreated DLBCL who presented with hepatic and/or renal dysfunction which led to ineligibility for prospective clinical trials at Levine Cancer Institute. Patients were treated with R-CHOP or R-EPOCH. Doxorubicin and vincristine were dose reduced for ≥ grade 3 hepatic dysfunction. Etoposide was dose reduced for either > grade 3 hepatic dysfunction or CrCl < 40ml/min. There were no dose reductions in cyclophosphamide or rituximab. Results: Of 146 contiguous patients screened, 20 met criteria for hepatic and/or renal dysfunction. Median follow up was 19.1 mo. Hepatic dysfunction, renal dysfunction or both were seen in 7 (35%), 9 (45%) and 4 (20%) patients respectively. Median time from consultation to starting treatment was 3 days. Cycle 1 was given as an inpatient in 18 (90%) patients. During cycle 1, dose reductions due to organ dysfunction were performed in 5 (25%) patients. Median time to reversal of impaired organ function was 12 days. By cycle 2, 18 (90%) patients received full dose chemotherapy. CR was obtained in 17 (85%) patients. The estimated 2-year OS was 80% (95% CI 62.5–97.5%). No deaths were due to organ dysfunction or drug toxicity. The results are comparable with chemoimmunotherapy in patients with DLBCL who present with normal hepatic and renal function. Conclusions: Rapid initiation of standard chemoimmunotherapy with dose adjustments based on degree of hepatic and/or renal dysfunction can lead to excellent outcomes in patients with DLBCL who present with organ dysfunction. Organ dysfunction related to lymphoma can reverse rapidly with chemoimmunotherapy.
High-accuracy HPV testing versus p16 IHC using multiple clinically relevant outcomes: The University of Chicago Experience.
Authors: Sara Kochanny, Corey Christian Foster, Arun Khattri, Ryan J. Brisson, Allison Dekker, Elaine Klema, Rajesh Acharya, Jeremy Segal, Mark W. Lingen, Nicole Cipriani, Alexander T. Pearson, Vassiliki Saloura, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2018)

6020 Background: The current most widely used standard for HPV status testing in head & neck cancer is p16 IHC. However, p16 IHC is a surrogate method which does not test directly for HPV genetic material and p16 expression is known to occur in HPV- tumors also. Furthermore, HPV strain identification can influence prognosis necessitating HPV typing. We have developed a dual testing method using both p16 IHC in combination with multiplex HPV PCR to accomplish the high sensitivity HPV testing with overall high specificity, sensitivity, and overall accuracy. Methods: As part of our clinical experience, we evaluated the HPV status of 317 patients with head & neck cancer suspicious for HPV involvement using a dual testing method with both p16 IHC and multiplex PCR. For discrepant cases where p16 and PCR do not agree, we confirmed status by performing genetic profiling (OncoPlus). The sensitivity and specificity of the method was tested with a combined validation cohort of 87 HPV negative (n = 48) and HPV positive (n = 39) tumor samples. Results: In our clinical experience with oropharyngeal HPV testing, including as part of de-escalation trials, we identified that 5% of oropharynx cases have false positive p16, where the PCR does not support HPV. 8% of PCR confirmed HPV positive cases were non-HPV16, which were associated with poorer prognosis. In the combined HPV- and HPV+ validation cohort, sensitivity was 97.4%, specificity 93.75%, PPV was 95%, NPV = 97.8%, with an overall accuracy of 95.4%. Conclusions: Dual testing by p16 and PCR is feasible, and increases accuracy. Using p16 alone results in a 5% false positive and 8% misclassification rate for HPV(-) and non-HPV16 cancers, respectively. In the era of de-escalation where treatment decisions are based on HPV status, it is critical to identify patients who are actually HPV(-) or non-HPV16. Such patients likely should not be treated on de-escalation trials unless appropriate safeguards are in place.
Molecular determinants of response and resistance to anti-PD-(L)1 blockade in patients with NSCLC profiled with targeted next-generation sequencing (NGS).
Authors: Matthew David Hellmann, Francisco Sanchez-Vega, Konnor La, Hira Rizvi, Darragh Halpenny, Andrew Plodkowski, Niamh Long, Walid Chatila, Philip Jonsson, Kathryn Cecilia Arbour, Jamie E. Chaft, Charles M. Rudin, Mark G. Kris, Michael F. Berger, Barry S. Taylor, Ahmet Zehir, Maria E. Arcila, Marc Ladanyi, Gregory J. Riely, Nikolaus Schultz
Journal: Journal of Clinical Oncology (2017)

9015 Background: Anti-PD-(L)1 therapy has revolutionized treatment for patients (pts) with NSCLC. We previously reported that non-synonymous tumor mutation burden (TMB) by whole exome sequencing associates with immunotherapy benefit. Targeted NGS is increasingly routine in clinical practice and may be a useful tool for predicting benefit to anti-PD-(L)1 blockade. Methods: Pts had advanced NSCLC treated with anti-PD-(L)1 (+/- aCTLA-4) therapy and profiling by hybrid-capture NGS of 341-468 genes (MSK-IMPACT). Efficacy assessed by RECIST v1.1; durable clinical benefit (DCB) defined as PR or SD &gt; 6mo. TMB and copy number alteration burden (“fraction of genome altered”, FGA) were normalized by size of genome covered. Comparisons were also made to a cohort of all NSCLCs profiled by MSK-IMPACT (n = 1679). Results: Of 437 evaluable pts treated with anti-PD-(L)1, 197 (45%) had NGS profiling, of whom 30% had DCB. TMB was higher in those with DCB vs no DCB (mean 10.2 vs 7.1 SNV/MB, p = 0.02) and compared to all NSCLCs ( &lt; 0.0001). DCB was more common and PFS was longer in pts with &gt; vs &lt; 85 th percentile TMB of all NSCLCs (Odds ratio 2.3, 95% CI 1.1-4.9, p = 0.03; HR = 0.59, p = 0.004), but were similar when dichotomized at the 50 th or 75 th percentile. FGA was higher in pts with no DCB compared to all NSCLCs (p = 0.02). Molecular signatures related to deficient homologous-recombination-based DNA repair and smoking were more common in DCB vs no DCB (p = 0.042, p = 0.058) and vs all NSCLCs (p = 0.026, p = 0.01). Compared to all NSCLCs profiled by NGS, alterations in STK11and EGFRwere enriched in no DCB (p = 0.0008, p = 0.02). Alterations in JAK2and CD274(PD-L1) were uncommon (2.1%, 1.6%) but exclusively associated with no DCB. For a subset (n = 52) of these cases also profiled by whole exome sequencing, comparison with targeted NGS will be presented. Conclusions: In pts with NSCLC, targeted NGS profiling is a routinely available tool that can provide insight into predicting benefit with anti-PD-(L)1 therapy. Increased TMB associates with clinical benefit. Increased copy number alterations (FGA) and alterations in genes including STK11, JAK2, and CD274 may associate with resistance to anti-PD-(L)1 therapy.
Core domain set for hidradenitis suppurativa trial outcomes
Authors: L. Thorlacius, J.R. Ingram, B. Villumsen, S. Esmann, J.S. Kirby, A.B. Gottlieb, J.F. Merola, R. Dellavalle, S.M. Nielsen, R. Christensen, A. Garg, G.B.E. Jemec
Journal: British Journal of Dermatology (2018)

Hidradenitis suppurativa (HS) is a skin condition that causes painful swollen red bumps in the folds of the body (underarms, under breasts, groin, and buttocks). It can be mistaken for bacterial abscess or boils, but HS is not caused by bacteria. HS occurs in about 0.1% to 4% of people worldwide. This study aimed to find out what clinical trials for HS should measure, such as symptoms (e.g. pain, itch), physical changes (e.g. skin redness or swelling), or impact on people's lives (e.g. quality of life). To do this, the study included two groups: people with HS and healthcare providers (physicians, pharmaceutical industry representatives, and regulatory representatives) and conducted online surveys and in‐person meetings with presentations and discussions as well as surveys to gather opinions on which measures to include. Thirteen countries and four continents were represented. The result of the meetings, discussions, and surveys showed that at least 70% of the people with HS and healthcare providers recommended that clinical trials include measures of: (1) pain (2) physical changes due to HS (e.g. redness); (3) quality of life changes due to HS specifically; (4) changes in the course of HS (e.g. flare‐ups) (5) global rating (i.e. overall rating, considering everything, of the severity of the condition) and (6) other symptoms (fatigue and drainage). This work is important because it included many different types of people who contribute to HS treatment, including the people who have HS, develop or regulate treatments, and treat people with HS. More work is coming and it will focus on how to measure in trials treating HS (what instruments to use).
Outcomes of pegfilgrastim (PFG) administration on the same day vs the day after chemotherapy (CTX) in the prophylaxis of chemotherapy-induced (Febrile) neutropenia (CIN/FN): Systematic review and meta-analysis.
Authors: Neda AlRawashdh, Ali McBride, Christopher Lee, Reem Diri, Alaa Bagalagel, Hussain Bakhsh, Hani M. Babiker, Karen MacDonald, Ivo Abraham
Journal: Journal of Clinical Oncology (2018)

e14510 Background: PFG should be administered 24-72 h after CTX, but there is a trend to administer it on the same day as CTX. The aim of our systematic review and meta-analysis (MA) was to compare the outcomes of using PFG on the same day vs day after CTX. Methods: Ten databases were searched. Outcomes included: FN in the CTX cycle 1 and across all cycles, grade IV and grades III/IV CIN, and CTX delays or dose reductions. Random effects MAs were conducted for comparative studies to estimate pooled odds ratios (OR) and 95% confidence interval. We merged comparative studies, using study arms as independent arms, with 1-arm same day studies to estimate pooled weighted rates. As the number of studies varied on outcomes of interest reported, estimates of the pooled weighted rates of these events in same-day vs day-after-CTX should be considered independent of each other. Results: 23 studies on same day PFG (17 with 2 arms, 6 with 1 arm) were retained. Studies varied in outcomes included. Odds (OR, 95%CI) of FN in the CTX cycle 1 (1.48, 1.15-1.90) and across cycles (1.37, 1.02-1.85) were higher for patients (pts) receiving PFG the day of CTX. There was no differential risk of grade IV CIN (1.39, 0.93-2.06), grades III/IV CIN (1.40, 0.71-2.71), CTX delays (0.522, 0.21-1.28) or CTX dose reductions (1.04, 0.32-3.35) between same-day and day-after-CTX pts. Pooled weight rates for both groups were 3.74% vs 2.51% for FN in cycle 1 (n1 = 6, n2 = 6 studies); 2.25% vs 1.79% for FN in any cycle (n1 = 17, n2 = 12); 6.41% vs 3.24% for grade IV CIN (n1 = 7, n2 = 7); 7.04% vs 3.22% for grade III/IV CIN (n1 = 6, n2 = 3); 3.05% vs 1.35% for CTX delays (n1 = 6, n2 = 2); and 1.43% vs 0.434% for CTX dose reductions (n1 = 7, n2 = 2). Conclusions: The rates of FN (cycle 1 and all cycles), CIN/FN grade IV or grades III/IV, CTX delays or CTX dose reductions were nominally low for pts administered PGF same-day and day-after-CTX. Despite these low rates, probabilistically, same-day patients may be at an increased risk of FN, but not of grade IV CIN (primary endpoint in PGF registration trials) and grades III/IV CIN. Same-day PGF pts are at no increased risk of disturbances to their CTX regimen.
A phase Ib study of ADI-PEG 20 plus pembrolizumab in advanced solid cancers.
Authors: Kwang-Yu Chang, Nai-Jung Chiang, Chia-Jui Yen, Shang-Yin Wu, Shang-Hung Chen, Amanda Johnston, John S. Bomalaski, Bor-Wen Wu, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2018)

2556 Background: Arginine deprivation with pegylated arginine deiminase (ADI-PEG 20) has been shown to upregulate tumor programmed death-ligand 1 (PD-L1) expression and T cell infiltration. Current phase Ib study is to explore the feasibility of combining ADI-PEG 20 with pembrolizumab in patients with advanced solid tumors. Methods: Eligibility criteria included treatment-failure patients with measurable lesions. Pre-treatment tumor biopsy was required. In the “3 + 3” designed dose-escalation part, patients were enrolled to receive ADI-PEG 20 36 mg/m2 at day 1, 8 and 15, and pembrolizumab (1 mg/kg or 200 mg) at day 1, every 3 weeks to determine the maximum tolerated dose (MTD) of pembrolizumab for expansion cohort study. In the expansion cohort part, patients with platinum-failed HNSCC would receive both ADI-PEG 20 and pembrolizumab (at MTD) from day 1; while patients in translation cohort who were required to have < 50% PD-L1 expressing tumors would receive 3 doses of weekly ADI-PEG 20 and a post-ADI-PEG 20 biopsy before the start of combination treatment. The primary endpoint was safety and tolerability. Secondary endpoints included progression-free survival, overall survival, response rate, and the changes of tumorous PD-L1 expression and T-cell infiltration after treatment with ADI-PEG 20 with and without pembrolizumab. Results: The recruitment of dose-escalation cohorts was completed between July 2017-January 2018. There was only one dose-limiting toxicity, grade 3 hepatitis, observed in a patient in 1 mg/kg dose level; while none in the 200 mg dose level. Among them, two (22.2%) had partial response (PR) and four (44.4%) had stable disease. The two PRs were in thymus cancer and nasopharyngeal carcinoma, with both having 100% tumor baseline PD-L1 expression. The most common grade 3/4 adverse event (AE) was neutropenia, which occurred in seven patients. For serious AEs, two had neutropenic fever lasting less than one week in the third week, and one had tumor bleeding because of tumor progression in the eighth week. The expansion cohorts are enrolling. Conclusions: Co-administration of ADI-PEG 20 and pembrolizumab is feasible. The major toxicity is neutropenia which is transient and manageable. Responses were observed with the regimen. Clinical trial information: NCT03254732.
Survey of UK doctors highlights blame culture within the NHS
Authors: Jacqui Wise
Journal: BMJ (2018)

A major survey of UK doctors reveals a bleak picture. Many feel they work in a dangerous and toxic environment with a blame culture which jeopardises patient safety and discourages learning and reflection.1

The survey of 7887 doctors—including GPs, junior doctors, and consultants—was carried out as part of a BMA project, Caring, Supportive, Collaborative, aimed at finding solutions to the challenges faced by the NHS.

Most doctors (78%) said that NHS resources are inadequate and that this significantly affects the quality and safety of patient services. Patient services have worsened, including waiting times for patients and staffing levels, they said. Around three quarters said that national targets and directives are prioritised over the quality of care.

The survey found that 95% of doctors …
A principled machine learning framework improves accuracy of stage II colorectal cancer prognosis
Authors: Neofytos Dimitriou, Ognjen Arandjelović, David J. Harrison, Peter D. Caie
Journal: npj Digital Medicine (2018)

Accurate prognosis is fundamental in planning an appropriate therapy for cancer patients. Consequent to the heterogeneity of the disease, intra- and inter-pathologist variability, and the inherent limitations of current pathological reporting systems, patient outcome varies considerably within similarly staged patient cohorts. This is particularly true when classifying stage II colorectal cancer patients using the current TNM guidelines. The aim of the present work is to address this problem through the use of machine learning. In particular, we introduce a data driven framework which makes use of a large number of diverse types of features, readily collected from immunofluorescence imagery. Its outstanding performance in predicting mortality in stage II patients (AUROC = 0:94), exceeds that of current clinical guidelines such as pT stage (AUROC = 0:65), and is demonstrated on a cohort of 173 colorectal cancer patients.
Novel small molecules induced ROS accumulation and antitumor activity based on an oxidative stress gene signature.
Authors: Andrew Asher Protter, Vernon Phan, Traci Mizuno, Kevin Kim, Brent Louie, Sidney Elmer, Damir Herman, Johan Grahnen, Pek Lum
Journal: Journal of Clinical Oncology (2018)

e14575 Background: Reactive oxygen species (ROS) homeostasis is crucial for cell survival. Drugs that possess anti-tumor effects by suppressing ROS metabolism in cancer cells have potential as a new class of cancer therapeutics. Methods: A computational engine (SMarTR) comprising an ensemble of machine learning algorithms was used to predict compounds with anti-tumor activity against a panel of human cancers. A chemical moiety was selected and novel, synthetic derivatives were characterized for viability effects. A gene expression sensitivity signature (GESS) was derived, validated using anti-tumor responses in culture and then used to predict tumors most likely to respond to these novel compounds across 2532 different human tumor samples. Two compounds from this series, AU-535 and AU-583, were analyzed further for effects on ROS accumulation, DNA damage, and apoptosis in cancer cells. Results: AU-535 and AU-583 achieved significant antitumor effects in multiple myeloma, prostate cancer, triple negative breast (TNBC) and ovarian cancer cell lines, inducing ROS accumulation, apoptosis (Annexin V staining) and DNA damage (nuclear gH2AX). The GESS profile indicated cell response to these compounds was dependent on expression of genes associated with ROS metabolism. Consistently, AU-535 treatment induced ROS and increased expression of genes related ROS response and metabolism. Importantly, GESS predicts 26.6% (388/1457) of multiple myeloma, 28.5% (215/755) of ovarian, 25.2 % (27/107) of prostate and 56.8% (121/213) of TNBC tumors would respond to agents with this pharmacology. AU-535 and AU-583 showed favorable pharmacokinetic profiles, with intrinsic clearance values of 62 and 11.1 uL/min/mg, respectively, with human liver microsomes, and 48.1% and 42.6%, respectively, oral bioavailability in in rats. Conclusions: Two novel small molecules with anti-cancer activities associated with ROS metabolism have been characterized in cancer cell models. A gene expression signature associated with response has been derived and predicts favorable responses in patients with multiple cancer types.