tbuckley/cabot-search huggingface dataset:
Can body composition (BC) be predictive for outcomes and severe toxicities (ST) in metastatic solid tumors patients (pts) treated with checkpoint inhibitor (CPI)? An analysis of 145 patients.
Authors: Sophie Cousin, Amandine Crombe, Antoine Giraud, Sylvestre Le Moulec, Maud Toulmonde, Michèle Kind, Antoine Italiano
Journal: Journal of Clinical Oncology (2018)

3069 Background: BC parameters have previously been associated with treatments toxicities, and worst outcomes in metastatic solid tumors pts. We studied association between BC parameters and their changes, with ST and outcomes in pts receiving CPI. Methods: Pts consecutively treated with CPI between December 2013 and December 2016 in our institute (Institut Bergonié, Bordeaux, France) for metastatic solid tumor and with a baseline computed tomography (CT0) scan <28 days before CPI beginning were included. BC parameters were assessed with Slice-O-Matic software V4.3 (Tomovision, Montreal, Canada), using third lumbar vertebra as standard landmark, normalized for height (cm2/m2). Results: 145 pts were included (73 female, median age: 62). 124 had a CT scan after 2 months of CPI (CT2). Tumor type was non small cell lung cancer in 80 (55%) pts. 68 pts had received >1 line of chemotherapy before. CPI treatment was: anti PD-1, anti PD-L1, anti PD-L1/CTLA-4 combination in 113, 13, and 19 pts, respectively. ST included: Grade III-V toxicity according to NCI-CTC v4.0, unscheduled hospitalization, definitive CPI treatment discontinuation. 15 pts (10.3%) had ST. None of the baseline clinical, nutritional, and BC parameters was associated with ST. In multivariate analysis, subcutaneous adipose tissue index (SATI) decrease >-10% between CT0 and CT2 was significantly associated with occurrence of ST (OR=5.3, p=0.027). Median Overall survival (OS) was 402 days. Median progression free survival (PFS) was 86 days. In multivariate analysis, 3 BC-related parameters were significantly associated with worse OS: body mass index < 25 (HR=2.375, p=0.030), Skeletal muscle index (SMI) decrease >-10% (HR=4.603, p=0.007), and visceral adipose tissue index (VATI) decrease >-10% (HR=8.470, p=0.030). Only SMI decrease >-10% was predictive of PFS (HR=3.643, p=0.001). Conclusions: Our results demonstrates that body composition is associated with clinical outcomes of cancer patients treated with CPI. Early decrease of SATI is predictive of ST whereas early decrease of skeletal muscle index and of VATI are associated with worse OS.
P01.034 Prospective evaluation of alternative therapies in glioma patients in France
Authors: E Le Rhun, C Lebrun Frenay, P Devos, A Darlix, V Lorgis, G Ahle, M Boone, L Taillandier, E Curtit, L Gras, V Bourg, C Ramirez, N Reyns, M Weller, N Simon
Journal: Neuro-Oncology (2018)

The main objective of this study was to explore the patterns of alternative therapy use, in parallel to the standard treatment, in glioma patients in France. Questionnaires were distributed during visits at hospital and filled in and returned anonymously by adult patients with histologically confirmed glioma and with an ECOG performance score of 0–2. The protocol was approved by the French authorities on April 13th, 2016. Descriptive analyses of the population as well as correlation analysis according to gender, age, WHO grade IV versus other, recurrent disease as declared by the patients versus none, were conducted. Two hundred questionnaires were collected. Patients were male in 65% of the cases. Median age was 46 (range 18–85). Forty-six patients had glioblastoma, 83 patients declared having recurrent disease. Patients declared taking a complementary treatment in 46.5% (mainly vitamins and other food supplements), having modified their diet (ketogenic diet, Servent-Schreiber diet, addition of curcuma) in 48%, and using another alternative medicine approach (mainly magnetism, acupuncture, sophrology), in 34%. In total, 69% of the patients declared using at least one of these approaches. No difference was observed according to gender, age or occurrence of a recurrence, however, glioblastoma patients used significantly more often at least one approach (p<0.0001). Information on these interventions were mainly derived from relatives or media. Cost was 200 euros per month or more in 25% for complementary treatment, in 20% for diet and in 5% for alternative medicine. These approaches were mainly considered as good for quality of life and experienced as efficient. Alternative therapies are frequently used by patients and should be discussed with patients and caregivers during the course of the disease to identify patient needs and preferences as well as potential interactions with tumor-specific treatments.
USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein
Authors: Siyuan Chen, Fenglin Yun, Yikun Yao, Mengtao Cao, Yifan Zhang, Jingjing Wang, Xinyang Song, Youcun Qian
Journal: The Journal of Experimental Medicine (2018)

Th2 immune response is critical for allergic asthma pathogenesis. Molecular mechanisms for regulating Th2 immunity are still not well understood. Here we report that the ubiquitin-specific protease USP38 is crucial for Th2-mediated allergic asthma. TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development. Consequently, USP38 was specifically required for TCR-induced production of Th2 cytokines and Th2 development both in vitro and in vivo, and USP38-deficient mice were resistant to asthma pathogenesis induced by OVA or HDM. Mechanistically, USP38 directly associated with JunB, deubiquitinated Lys-48-linked poly-ubiquitination of JunB, and consequently blocked TCR-induced JunB turnover. USP38 represents the first identified deubiquitinase specifically for Th2 immunity and the associated asthma.
PACSA: Phase II study of pazopanib in patients with progressive recurrent or metastatic (R/M) salivary gland carcinoma (SGC).
Authors: Joel Guigay, Jerome Fayette, Caroline Even, Didier Cupissol, Frederic Rolland, Frederic Peyrade, Brigitte Laguerre, Christophe Le Tourneau, Sylvie Zanetta, Laurence Bozec Le Moal, Christian Borel, Pascal Do, Laurence Digue, Jessy Delaye, Anne Auperin, François Bidault, Valerie Costes, Laura Faivre
Journal: Journal of Clinical Oncology (2016)

6086 Background: SGC of head and neck (SGCHN) are rare tumors including adenoid cystic carcinoma (ACC) and non-ACC, with no standard systemic treatment for R/M patients (pts). Pazopanib (Pb) is an oral small molecule inhibitor of VEGFR, PDGFR and KIT. We conducted a multicenter single arm phase II study to assess the antitumor activity of Pb in ACC and non-ACC SGCHN. Methods: Pts with confirmed progressive R/M SGCHN received Pb 800 mg daily until progression (PD). Response was assessed every 12 weeks (RECIST). Primary endpoint was the 6-mo PFS rate. Secondary endpoints included response rate (CR/PR), overall survival, toxicity. For ACC pts, the trial was designed with inacceptable and promising 6-mo PFS rates of 20% and 40%, requiring 43 evaluable pts (alpha error = 0.07, power = 0.93). For non-ACC pts, trial was exploratory on 20 pts. A study of tumor growth rates is ongoing. Results: From 2013 to 2015, 72 pts were enrolled: 49 ACC and 20 non-ACC (3 ineligible excluded) including 11 adenocarcinoma (ADK), M:F = 32:37, median age 59 yrs (range 27-84), PS 0-1 = 42:27, prior radiation: 64 (93%), prior systemic therapy: 40 (58%). The most frequent adverse events (AE) (% of pts) were fatigue (81%), nausea (59%), diarrhea (54%), high blood pressure (BP) (43%), and anorexia (33%). 31/69 pts experienced grade 3 AE, primarily fatigue and high BP. Two grade 4 AE (cerebrovascular stroke, hepatitis) and 1 death (infection) were possibly related to treatment. Median FU was 13 mo. Among 46 ACC pts evaluable for efficacy (3 non progressive excluded), best response was 1 (2%) PR, 35 (76%) SD, 10 (22%) PD. 4 pts withdrew, 7 discontinued therapy due to AE. 6-mo PFS rate was 43% (95%CI = 29;57) with 20 pts without PD at 6 mo, median PFS was 5.9 mo. Median OS was 16.6 mo with 1 year OS = 64.8%. For 18 non-ACC pts evaluable for efficacy (2 non progressive excluded), best response was 1 PR (6%), 13 SD (72%), 4 PD (22%). 4 pts discontinued therapy due to AE. 6-mo PFS rate was 50% (95%CI = 29;71), median PFS was 6.7 mo (8 mo for ADK), median OS was not reached with 1 year OS = 75%. Conclusions: There were no new safety signals, tolerance was as expected. PACSA is positive with a 6-mo PFS rate > 40% observed in ACC and non-ACC pts. Pb is promising and deserves further studies. Clinical trial information: NCT02393820.
Frailty as a predictor of complications in older patients undergoing radical cystectomy.
Authors: Thomas G. Clifford, Soroush T. Bazargani, Jie Cai, Anne K. Schuckman, Hooman Djaladat, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2016)

e16007 Background: Frailty has been described as a medical syndrome characterized by decreased physiologic reserve causing vulnerability to adverse outcomes. Our goal was to determine whether frailty measures can identify high-risk patients undergoing radical cystectomy (RC) and predict their surgical complication rates. Methods: Under IRB approval, we identified patients ≥65 undergoing RC. We prospectively measured frailty preoperatively using surrogates including hand dynamometry (grip strength), walking speed, shrinking (weight loss of ≥ 10 pounds within past year), exhaustion, and low physical activity. Patients were also prospectively scored using the Clinical Epidemiological Survey for Depression, Charlson Comorbidity Index (CCI), American Society of Anesthesiologists scoring system (ASA), Karnofsky performance status (KPS), and Eastern Cooperative Oncology Group (ECOG) performance status. 30 and 90-day postoperative data was recorded. Chi-square and multivariable logistic regression were performed for analysis. Results: A total of 62 patients were identified between 2/2014 and 6/2015 with an average age of 75 years. 42 (67.7%) and 49 (79.0%) patients had at least one postop complication within 30 and 90-days, respectively. On univariate analysis, shrinking was significantly associated with 30-day complications (p < 0.03). There was a similar trend in patients whose grip strength was frail (accounting for sex and BMI) (p = 0.06). Median number of 30 and 90-day complications was 2 (range 0-5) in those with shrinking compared to 1 (range 0-5) in those without (p < 0.004, p < 0.02). On multivariable analysis, frail grip strength was associated with increased complications after controlling for pathologic stage and albumin (OR 5.4, CI 1.4-21.0, p < 0.01). Other frailty measures (such as walking speed and activity level) and assessment tools (such as ECOG, CCI, and KPS) were not associated with postop complications (p > 0.05). Conclusions: Results of this prospective study suggest that grip strength and shrinking may be useful frailty measures predictive of postop complications in older patients undergoing RC. These measures may be useful for identifying patients at high risk for postop complications.
Gastric acid suppression (ASs) impact on the effectiveness of tyrosin kinase inhibitors (TKIs) in patients (p) with non-small-cell lung carcinoma (NSCLC).
Authors: Marcos Nieves, Jose Manuel Caro, Santiago Ponce Aix, Jose Miguel Ferrari
Journal: Journal of Clinical Oncology (2016)

e20641 Background: Erlotinib and gefitinib are TKIs approved for the treatment of NSCLC either EGFR status. Its absorption is dependent on the gastric pH, so concomitant use with ASs may decrease plasma levels and consequently its efficacy. The aim of this study is to determine whether coadministration of erlotinib and gefitinib with ASs affects progression-free survival (PFS) as it is a very common clinical practice. Methods: Retrospective observational study involving patients treated for ≥ 1 week with TKIs from January 2012 to December 2015 at our institution. ASs concomitant use was defined when ≥ 20% of prescription dates overlapped with TKI treatment duration. For PFS the Kaplan Meier and multivariate Cox regression analysis were used. Results: The median value for the PFS in patients with AS versus no AS was 84 days (95% CI, 65-101) versus 221 days (95% CI, 125-429) respectively with a value of p <0.0001 log-rank test. In multivariate Cox analysis the significant variables were ECOG, line of treatment and the presence of an AS for PFS hazard ratio of 1.79 (95% CI 1,42- 2,24), 1,63 (95% CI 1,28- 2,06) and 2,50 (95% CI 1,61 to 3,88) respectively. In EGFR mutant p no interaction was found probably due to small sample. It was examined with the mathematical model assumption, which was not broken with a p = 0,106 so the model was retained. Conclusions: This study suggests that the effectiveness of TKIs may be related to gastric Ph directly affecting disease progression, as in clinical practice, AS administration correlates significantly with a decrease in the effectiveness of TKIs studied. No AS (n = 45) AS (n = 118) p Age 67,13 (Sd 10,84) 70,61 (Sd 10,97) 0,07172 Sex Male 30 (66,7%) 75 (63,6%) 0,8513 Female 15 (33,3%) 43 (36,4%) TNM IIIA 2 (4,4%) 6 (5,1%) 1 IIIB 3 (6,7%) 7(5,9%) IV 40 (88,9%) 105 (89,0%) Brain Metastases 5 (11,1%) 24 (20,3%) 0,2509 ECOG 0 15 (36,6%) 26 (24,5%) 0,3794 1 19 (46,3%) 50 (47,2%) 2 6 (14,6%) 22 (20,8%) 3 1 (2,4%) 8 (7,5%) Line of treatment 1 11 (24,4%) 25 (21,2%) 0,6141 2 15 (33,3%) 33 (28,0%) 3 19 (42,2%) 60 (50,8%) EGFR Yes 13 (18,1%) 51 (43,2%) 0,2016 No 14 (31,1%) 28 (23,7%) NA 18 (40,0%) 39 (33,1%) TKI Erlotinib 34 (75,6%) 103 (87,3%) 0,1119 Gefitinib 11 (24,4%) 15 (12,7%)
A phase 1b/2 study of amcasertib, a first-in-class cancer stemness kinase inhibitor in advanced head and neck cancer.
Authors: Gregory Michael Cote, Nicole Grace Chau, Alexander I. Spira, William Jeffery Edenfield, Scott Andrew Laurie, Donald A. Richards, Stephen Lane Richey, Yuan Gao, Youzhi Li, Wei Li, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2017)

6032 Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib showed safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors during dose-escalation and RP2D expansion, including pts with advanced head &amp; neck cancer. Methods: Pts with advanced, pre-treated head &amp; neck cancers were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 10 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines every 8 weeks. Results: A total of 21 pts were enrolled, 15 with HNSCC and 6 with salivary or parotid gland cancers. Prior treatments included radiation in 90% (19/21), surgery in 71% (15/21) and prior systemic therapy in 90% (19/21, average 3 prior lines, range 1 to 6). Amcasertib was well tolerated with 43% of pts treated at 300 mg daily (n = 9), 33% at 150 mg BID (n = 7), 19% at 200 mg daily (n = 4), and 5% at 10 mg daily (n = 1). Grade 3 AE included diarrhea (n = 4) and nausea (n = 1). Among all patients who received an evaluation per RECIST (n = 16), the objective responses rate (ORR, proportion with partial response [PR] or complete response [CR] per RECIST) was 13% and the disease control rate (DCR, proportion with stable disease [SD] at 8 weeks, PR or CR) was 50%. At 12 months, in the intent-to-treat population (n = 21) 38% of pts were alive. Median overall survival (mOS) of 7.2 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced head and neck cancers who have received treatment with amcasertib. Objective response, prolonged disease control, and extended survival have been observed in this pre-treated population with a poor prognosis. Further clinical evaluation of amcasertib in patients with head and neck cancers is warranted. Clinical trial information: NCT01781455.
A multidisciplinary team dedicated to the management of patients treated with PD1 inhibitors: The Cochin hospital experience.
Authors: Pascaline Boudou-Rouquette, Jennifer ARRONDEAU, Diane Damotte, Frédéric Batteux, Nora Kramkimel, Olivier Huillard, Camille Tlemsani, Anne Jouinot, Jeanne Chapron, Lea Dehghani, Benoit Blanchet, Benjamin Terrier, Lionel Groussin-Rouiller, Marco Alifano, Karen Leroy, Romain Coriat, Marie-Pierre Revel, Nicolas Dupin, Jerome Alexandre, Francois Goldwasser
Journal: Journal of Clinical Oncology (2016)

e18208 Background: Anti-PD1 improve outcomes of patients (pts) with advanced melanoma and non-small cell lung carcinoma (NSCLC). Main issues, in real life, are the emergence of various associated toxicities termed immune-related adverse events (irAEs) and unique patterns of response. Methods: We created a program, with a specific multidisciplinary team, aiming to improve the diagnosis and management of these new AE, in routine practice. Pre-therapeutic biological and clinical assessments were prospectively performed for pts treated with nivolumab and pembrolizumab. A cancer nurse coordinator delivered information on symptoms related to irAEs and handed out a self- questionnaire to detect autoimmune signs. In parallel, monthly staff meetings were organized to facilitate collaboration and pt care. Results: From July 2015 to January 2016, forty-one pts (median age 69 years, range: 45-84) received at least one infusion of nivolumab (85%) or pembrolizumab (15%), for NCSLC (n = 30) or melanoma (n = 11). There were 23 (56%) men. A total of 201 cycles (median per pt: 4, range 1-14) were analyzed. All pts completed self-questionnaire and none declared dysimmunity history. The multidisciplinary monthly meeting included a median of 6 specialists and up to 13 specialists among: oncology, immunology, molecular biology, pathology, dermatology, endocrinology, diabetology, radiology, gastroenterology, hepatology, internal medicine, pharmacology and pulmonology. Seventeen pts (41.4%) presented an exacerbation of disease symptoms before the 3rd cycle. Six pts (14.6%) developed serious irAEs: insipid diabetes with hypophysitis, confusion, intestinal volvulus after 1st cycle (C1), pneumonitis (C2), pulmonary arterial hypertension (C5), colitis (C11). Four out of 32 evaluable pts (12.5%) had a partial response, within one after an initial pseudo-progression, according to RECIST criteria and are still under anti-PD1 after a median 6.7-month’s duration of treatment. Conclusions: A multidisciplinary group appears warranted to optimize the anti-PD1 toxicity management and improve knowledge.
Exploratory analysis of tumor growth rate (TGR) with lanreotide depot/autogel (LAN) in patients (pts) with neuroendocrine tumors (NETs) from the CLARINET study.
Authors: Martyn E. Caplin, Marianne E. Pavel, Philippe Ruszniewski, Nilani Liyanage, Christine Massien, Clarisse Dromain
Journal: Journal of Clinical Oncology (2016)

4096 Background: Antitumor activity of LAN in intestinal and pancreatic NETs was demonstrated in the phase 3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) vs placebo (PBO). TGR has been proposed as a novel measure with additional insights into tumor response in several other tumor types. Here, we undertook an exploratory analysis of TGR in NET pts in CLARINET. Methods: Pts with metastatic intestinal/pancreatic NETs received LAN 120 mg or PBO every 4 wks for 96 wks. Target lesions were assessed by central radiologic review based on RECIST v1.0. TGR (% variation of tumor volume per month) was calculated from sum-of-longest-diameters (SLD) of original target lesions (excluding new ones) on 2 CT scans during defined periods: 12–24 wks prior to randomization vs baseline (pretreatment); and baseline vs each visit or between consecutive visits. TGR pre- and post-treatment were compared between treatment groups. Results: Almost all pts were classified as stable on RECIST after 12 wks treatment (LAN, 90/96; PBO, 94/98), while a large proportion exhibited TGR changes. An immediate reduction in mean TGR was observed after only 12 wks treatment with LAN but not with PBO, resulting in a significant difference in TGR between treatments which was maintained at subsequent study visits (Table). Conclusions: TGR seems to provide an early and more precise characterization of treatment activity than RECIST criteria in NET pts. The potential of TGR requires validation as a pre-specified outcome measure in a prospective study. Clinical trial information: NCT00353496.TGR values at each study visit with LAN vs PBO. Treatment period (wks) N LAN, mean (95% CI) PBO, mean (95% CI) Difference, mean (95% CI) P-value Pretreatment 200 4.1 (2.6, 5.6) 3.3 (1.7, 4.8) 0.8 (–1.4, 3.0) 0.46 0–12 196 1.2 (-0.4, 2.7) 4.1 (2.6, 5.6) –2.9 (–5.1, –0.8) 0.008 12–24 174 2.0 (0.5, 3.5) 3.2 (1.7, 4.6) –1.2 (–3.3, 0.9) 0.28 24–36 154 1.8 (0.4, 3.2) 4.0 (2.6, 5.4) –2.2 (–4.2, –0.3) 0.03 36–48 132 –0.3 (–1.7, 1.3) 3.1 (1.5, 4.7) –3.4 (–5.6, –1.1) 0.003 48–72 108 1.3 (0.4, 2.1) 3.0 (2.0, 4.0) –1.7 (–3.0, –0.4) 0.009 72–96 90 0.6 (–0.5, 1.7) 3.1 (1.7, 4.6) –2.6 (–4.4, –0.7) 0.007
Exertional heat stress-induced gastrointestinal perturbations: prevention and management strategies
Authors: Rhiannon M J Snipe
Journal: British Journal of Sports Medicine (2018)

I investigated the effects of heat stress and nutrition strategies on gastrointestinal and associated systemic disturbances during endurance running. I aimed to identify the effect of heat stress on gastrointestinal perturbations during prolonged running and subsequently explore the effectiveness of nutrition prevention strategies.

Gastrointestinal disturbances are common during endurance running events affecting ≥60% of athletes and may contribute to impaired nutrition intake, poor performance and withdrawal from competition.1 2 The greatest prevalence of gastrointestinal and associated systemic disturbances (eg, endotoxaemia and cytokinaemia) has been reported during endurance running (≥2 hours of running at ≥60% maximal oxygen uptake (VO2max)) events held in the heat.1 No studies had previously explored the effects of heat exposure during endurance running on gastrointestinal symptoms and/or in conjunction with gastrointestinal integrity, systemic endotoxaemia and cytokinaemia. Further, research on prevention strategies targeting the underlying primary mechanisms, such as hyperthermia …