tbuckley/cabot-search huggingface dataset:
JAK inhibitors to suppress paclitaxel-resistant anaplastic thyroid cancer via IL-6 reduction.
Authors: Tomoyuki Fujita, Jia Liu, Mayu Myoujin, Satoko Shimada, Yuko Ishikawa, Minoru Fujimori
Journal: Journal of Clinical Oncology (2018)

e18093 Background: Anaplastic thyroid carcinoma (ATC) has a poor prognosis despite multimodal treatment approaches. Innovative strategies are required for treatment. Our primary aim was to determine the genes and pathways related to sensitivity to paclitaxel as biomarkers in ATC. Our secondary aim was to identify new genes and pathways as therapeutic targets in ATC Materials and Methods: Differences in cDNA microarray gene expression profiles before and after treatment with paclitaxel were analyzed in two ATC cell lines: KTA-3 cells, which are sensitive to paclitaxel, and TTA-2 cells, which are resistant to paclitaxel. GO Analysis and PAGE were performed to detect significant differences in pathway genes and transcriptionally regulated genes. The effect of a JAK inhibitor on ATC cells was examined in a cytotoxic growth-inhibition assay. IL-6 was measured using an ELISA. Results: Paclitaxel inhibited proliferation of KTA-3 ATC cells, but did not inhibit growth of TTA-2 ATC cells. GO analysis revealed that the JAK-STAT signaling pathway was most significantly increased in paclitaxel-resistant TTA-2 cells. Analysis of pathways affected by paclitaxel revealed that breast cancer susceptibility gene (BRCA)1-related genes, which are known to be associated with the JAK-STAT family, were the most upregulated. It is clear that JAK-STAT pathway was significantly downregulated in KTA-3 cells compared to TTA-2 cells after treatment with paclitaxel. One of the JAK inhibitors inhibited proliferation of TTA-2 cells (IC50 = 0.3 µM) and KTA-3 cells (IC50 = 0.037 µM). IL-6 was reduced by JAK inhibitor in TTA-2 cells and KTA-3 cells. Conclusions: Paclitaxel inhibits cell growth via downregulation of the JAK-STAT pathway. JAK inhibitors may be new drugs for treatment of paclitaxel resistant ATC. IL-6 may be a potential biomarker for treatment of JAK inhibitors.
Nivolumab-induced interstitial lung disease (ILD) in Japanese patients with non-small cell lung cancer: A study on risk factors using interim results of post-marketing all-case surveillance.
Authors: Hirotsugu Kenmotsu, Fumikazu Sakai, Terufumi Kato, Masahiko Kusumoto, Tomohisa Baba, Kazuyoshi Kuwano, Akihiko Gemma, Kazuhiko Nakagawa, Yoichi Nakanishi, Nobuyuki Yamamoto, Yoshihiko Ito, Yasuhiro Tahara, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2017)

9078 Background: We investigated case reports of ILD in patients receiving nivolumab for the treatment of unresectable, advanced or recurrent non-small cell lung cancer to identify risk factors for the occurrence of nivolumab-induced ILD. Methods: In Japan, post-marketing all-case surveillance of nivolumab is currently underway in patients with non-small cell lung cancer who received nivolumab from December 17, 2015 to March 31, 2016. The data were retrospectively analyzed using a multivariate stepwise logistic regression analysis with a level of significance of 5% to identify risk factors for the occurrence of nivolumab-induced ILD. Results: A total of 3,648 patients received nivolumab during the surveillance period, and data from 1,005 patients whose case report forms were available by November 30, 2016 were analyzed. Among them ILD was reported in 58 (5.8%). The median time to onset in 42 patients who were recovering or recovered from ILD was 50 days (range: 2 to 246 days). Eleven patients died of ILD. The following table summarizes univariate and multivariate analyses of risk factors for the occurrence of ILD. Conclusions: In this interim analysis of Japanese lung cancer patients treated with nivolumab, incidence of ILD as immune-related AE was 5.8%. Age, abnormal findings of chest CT, and treatment line were identified as risk factors for the occurrence of ILD during treatment with nivolumab. [Table: see text]
Defining the characteristics of medical oncology patients requiring inpatient hospital admission.
Authors: Krish Patel, Lowell T. Nicholson, Richard F. Riedel
Journal: Journal of Clinical Oncology (2016)

e18023 Background: Medical oncology patients have high rates of unplanned hospital admissions. The characteristics of these admissions and the medical needs of this patient population have not been clearly defined. The cost of cancer care is rising with much of that cost incurred in the last 6 months of life during acute inpatient care. The aim of this study was to define the main clinical characteristics and relevant needs in the population of oncology patients admitted to our inpatient oncology service. Methods: We performed a retrospective analysis of patients admitted to the solid tumor medical oncology service at Duke University Hospital from 1/1/2012 – 6/30/2012. We obtained patient, oncologic, and admission specific data by chart abstraction. Descriptive statistics were performed to characterize the study cohort. Results: A total of 749 admission encounters, representing 529 unique patients were analyzed. The median age of the patients was 64 years (range 22-96 years). The most common oncologic diagnoses for the admission encounters were lung cancer (22.6%), breast cancer (19.8%), and colorectal cancer (8.4%). The majority of admissions had recurrent or metastatic disease (74.1%). Patients were admitted for a variety of admission diagnoses and many had multiple admission diagnoses (54.7%). The most common admission related diagnoses were infection/sepsis (14.4%), metabolic laboratory abnormalities (14.0%), and pain management (11.7%). Most patients had a length of stay > 48 hours (65.8%) with mean length of stay of 4.4 days (range 1-22 days). Only a minority of patients required a non-endoscopic interventional or surgical procedure (17.9%). Conclusions: Oncology patients with recurrent or metastatic disease constitute the majority of patients admitted for inpatient medical care at our institution. Care needs encompass a variety of admission related diagnoses.
IBM Watson Evidence Service (WES): A system for retrieval, summation and insight generation of relevant clinical evidence for personalized oncology.
Authors: Fernando Jose Suarez Saiz, Alexandra Urman, Corey Sanders, Michael W Britt, Robert Nielsen, Rick J Stevens
Journal: Journal of Clinical Oncology (2018)

e18588 Background: There were ~49,300 clinical research publications in oncology in the last 10 years. Oncologists do not have the time to read them all. AI and computationally assisted systems may be able to bridge that gap. This system is designed to use cognitive technology to finding relevant clinical evidence in support of a particular treatment decision in the context of the patient case under consideration. Methods: A set of cancer relevant articles is defined using PubMed. Medline records are then processed for natural language processing(NLP) extraction using deep learning and term disambiguation, along with the relevant Medical Subject Heading (MeSH) terms in the record. NLP is completed by extraction of survival, response, toxicity and quality of life comparative effectiveness statements along with 18 distinct oncology relevant attributes. NLP accuracy is measured against expert-curated ground truth (GT) comprising ~500 articles. The extracted data is then processed and interpreted for medical understanding to extract meaning from the data. Some of these algorithms include multi drug and multi modal regimen detection, outcome, similar therapy identification, and study cohort identification. The articles are then matched to a particular case under consideration within the Watson for Oncology. Results are ranked by the level of relevance to the case under consideration, by the quality of the evidence and date of publication. Results: IBM WES runs on a corpus of approximately 60,000 abstracts covering 12 cancer types. The NLP accuracy for attributes extracted is all above 80%. The system then interprets and presents the data contained in the abstracts in a clinically relevant manner - identifying the most relevant articles for each of the over 15,000 cohort/treatment combinations currently supported by Watson for Oncology. Conclusions: We present a first of it’s class system that can read through vast amounts of unstructured and structured data, extract clinical outcome statements from research publications and classify those papers to common patient cohort characteristics in an efficient, clinically relevant manner.
Phase I trial of everolimus plus radiation therapy for salvage treatment of biochemical recurrence in prostate cancer patients following prostatectomy.
Authors: Vivek Narayan, Neha Vapiwala, Pearl Subramanian, John Paul Christodouleas, Justin E. Bekelman, Rosemarie Mick, Mary Walicki, Joanne Ciconte, Ramji Ramaswamy Rajendran, Naomi B. Haas
Journal: Journal of Clinical Oncology (2016)

e16617 Background: Up to half of patients treated with salvage radiation therapy (RT) for rising PSA ultimately develop a second biochemical recurrence (sBCR). Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin (mTOR) pathway can lead to tumor hypoxia and radioresistance. Everolimus is an mTOR inhibitor with both anti-tumor and radiosensitizing effects. Methods: We performed an investigator-initiated phase I study using a modified 3+3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard salvage RT for the treatment of BCR following prostatectomy. After a two-week run-in period of everolimus daily therapy, patients received prostate bed irradiation (15 IMRT, 1 proton) with daily cone beam CT localization in 37 fractions of 1.8 Gy each (total dose 66.6 Gy). Patients were monitored for both acute ( ≤ 90 days) and chronic ( > 90 days) treatment-related toxicities. sBCR was defined as a rise in PSA of > 0.5 ng/ml above nadir following the completion of protocol therapy. Results: 16 patients received everolimus at dose levels of 5 mg (dose level 1), 7.5 mg, or 10 mg daily in conjunction with RT. One patient withdrew consent after 7 days of everolimus and is unevaluable for follow-up. No dose-limiting toxicities were observed. The most common acute treatment related toxicities included: Grade 1/2 mucositis (63%), Grade 1/2 fatigue (44%), Grade 1/2 rash (56%), and Grade 1 urinary symptoms (63%). Three patients (19%) experienced a Grade 3 acute toxicity (N = 1 for rash, anemia, and neutropenia), and no patients experienced Grade ≥ 3 chronic toxicity. After a median follow-up time of 20.1 months, five patients (33%) developed sBCR. The median time to sBCR was 33.8 months (IQR 20.1 – 46.0 months). Conclusions: Everolimus at a dose of ≤ 10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy RT. As everolimus has anti-tumor efficacy in a variety of solid tumor malignancies, the use of everolimus with RT could be safely considered for further investigation in multiple solid tumors. Clinical trial information: NCT01548807.
TCT-630 New Indexes for Predicting Coronary Obstruction After Balloon-Expandable Transcatheter Aortic Valve Replacement
Authors: Yasushi Fuku, Tsuyoshi Goto, Akimune Kuwayama, Masanobu Ohya, Hidewo Amano, Shunsuke Kubo, Suguru Otsuru, Takeshi Shimamoto, Kazushige Kadota
Journal: Journal of the American College of Cardiology (2018)
Association Between Time to Defibrillation and Survival in Pediatric In-Hospital Cardiac Arrest With a First Documented Shockable Rhythm
Authors: Elizabeth A. Hunt, Jordan M. Duval-Arnould, Melania M. Bembea, Tia Raymond, Aaron Calhoun, Dianne L. Atkins, Robert A. Berg, Vinay M. Nadkarni, Michael Donnino, Lars W. Andersen
Journal: JAMA Network Open (2018)

Delayed defibrillation (>2 minutes) in adult in-hospital cardiac arrest (IHCA) is associated with worse outcomes. Little is known about the timing and outcomes of defibrillation in pediatric IHCA.To determine whether time to first defibrillation attempt in pediatric IHCA with a first documented shockable rhythm is associated with survival to hospital discharge.In this cohort study, data were obtained from the Get With The Guidelines-Resuscitation national registry between January 1, 2000, and December 31, 2015, and analyses were completed by October 1, 2017. Participants were pediatric patients younger than 18 years with an IHCA and a first documented rhythm of pulseless ventricular tachycardia or ventricular fibrillation and at least 1 defibrillation attempt.Time between loss of pulse and first defibrillation attempt.The primary outcome was survival to hospital discharge. Secondary outcomes were return of circulation, 24-hour survival, and favorable neurologic outcome at hospital discharge.Among 477 patients with a pulseless shockable rhythm (median [interquartile range] age, 4 years [3 months to 14 years]; 285 [60%] male), 338 (71%) had a first defibrillation attempt at 2 minutes or less after pulselessness. Children were less likely to be shocked in 2 minutes or less for ward vs intensive care unit IHCAs (48% [11 of 23] vs 72% [268 of 371]; P = .01]). Thirty-eight percent (179 patients) survived to hospital discharge. The median (interquartile range) reported time to first defibrillation attempt was 1 minute (0-3 minutes) in both survivors and nonsurvivors. Time to first defibrillation attempt was not associated with survival in unadjusted analysis (risk ratio [RR] per minute increase, 0.96; 95% CI, 0.92-1.01; P = .15) or adjusted analysis (RR, 0.99; 95% CI, 0.94-1.06; P = .86). There was no difference in survival between those with a first defibrillation attempt in 2 minutes or less vs more than 2 minutes in unadjusted analysis (132 of 338 [39%] vs 47 of 139 [34%]; RR, 0.87; 95% CI, 0.66-1.13; P = .29) or multivariable analysis (RR, 0.99; 95% CI, 0.75-1.30; P = .93). Time to first defibrillation attempt was also not associated with secondary outcome measures.In contrast to published adult IHCA and pediatric out-of-hospital cardiac arrest data, no significant association was observed between time to first defibrillation attempt in pediatric IHCA with a first documented shockable rhythm and survival to hospital discharge.
Anti-programmed death-1 antibody SHR-1210 (S) combined with apatinib (A) for advanced hepatocellular carcinoma (HCC), gastric cancer (GC) or esophagogastric junction (EGJ) cancer refractory to standard therapy: A phase 1 trial.
Authors: Jian-Ming Xu, Yun Zhang, Ru Jia, Yan Wang, Rongrui Liu, Gairong Zhang, Chuanhua Zhao, Yaoyue Zhang, Jianjun Zou, Quanren Wang
Journal: Journal of Clinical Oncology (2018)

4075 Background: A phase 1 (P1) study to assess the safety and efficacy of combination of S, a fully human IgG4 monoclonal antibody against PD-1 with PD-L1/PD-L2 plus Apatinib (A), a VEGFR2 inhibitor in patients (pts) with advanced HCC, GC, EGJ cancer. Methods: In P 1a dose escalation, pts received A (125, 250, 500mg, QD, 5 pts per cohort) and S (200 mg, Q2W) until unacceptable toxicity, disease progression. In phase 1b cohort expansion, pts received A at recommended P2 dose (RP2D) + S (200 mg, Q2W). Response was evaluated by RECIST v1.1. Results: At the cut-off data (Feb. 2. 2018), 42 pts (P 1a, n = 15; P 1b, n = 27) were enrolled. Median prior lines of therapy in HCC and GC were 1 and 2, respectively. In P1a stage, 3 DLTs (all grade 3 pneumonia) were observed in A 500mg cohort. The RP2D was A 250mg + S. In P 1b stage, the median treatment duration was 19 wks (range, 2-57 wks). 19 pts (58%) had ≥ grade 3 treatment-related adverse events (TRAEs). The ≥10% grade 3 TRAEs were hypertension (18%), increased AST (15%) and ALT (12%). These AEs were manageable, only 1 pt discontinued treatment due to TR grade 3 hyperbilirubinemia. There were no TR- deaths. The ORR and DCR in 36 evaluable pts in all 3 cohorts were 30.6% (n = 11) and 83.3% (n = 30), respectively. All 11 responses occurred in A 125mg (n = 1) and 250mg (n = 10) cohorts. Among 18 HCC pts (14 evaluable: A 125mg cohort, n = 4; A 250mg cohort, n = 9, A 500mg cohort, n = 1), all infected with HBV. The ORR and DCR were 50.0% and 85.7%, respectively. Notably, 2 pts in A 125mg cohort had initial SD at best response, and achieved PR after escalating A dose to 250 mg, therefore the ORR at A 250 mg dose level was 54.5% (6/11). The median progression-free survival (PFS) was not reached. All 7 pts with PR were still on treatment, 5 lasted for 47 weeks+. Of 24 GC or EGJ cancer pts (22 evaluable: A cohort, 250mg n = 20; 500mg, n = 2), the ORR in A 250mg cohort was 20.0% and DCR was 80.0%. The median PFS was 3.0 months. Conclusions: S + A at RP2D demonstrated manageable toxicity in HCC, GC or EGJ cancer pts. Particularly encouraging clinical activity (PR rate 54.5%) was observed in pts with pretreated, advanced HCC. Clinical trial information: NCT02942329.
Genetic variants of ATM and XRCC3 to predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer.
Authors: Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Martin D. Berger, Jordan David West, Yan Ning, Lisa Salvatore, Daniele Rossini, Carlotta Antoniotti, Ramu Inoue, Satoshi Matsusaka, Satoshi Okazaki, Yuji Miyamoto, Diana L. Hanna, Afsaneh Barzi, Fotios Loupakis, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

3579 Background: TAS-102 is an oral combination of trifluridine (FTD) and tipiracil hydrochloride. Incorporation of tri-phosphorylated FTD into DNA is the main anti-tumor mechanism of action. We hypothesized that homologous recombination (HR) of DNA double-strand breaks (DSB) will modulate TAS-102 efficacy. We therefore tested whether genetic polymorphisms in the HR pathway are associated with clinical outcomes in patients with refractory metastatic colorectal cancer (mCRC) treated with TAS-102. Methods: We analyzed genomic DNA extracted from 104 blood samples of two different cohorts: an evaluation set of 52 patients receiving TAS-102 (median age 61 years, male 44%, median follow-up time 6.4 months); and a control set of 52 patients receiving regorafenib without history of TAS-102 treatment (median age 64 years, male 44%, all patients deceased). Ten single nucleotide polymorphisms (SNPs) of seven genes in HR pathway (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) were analyzed by PCR-based direct sequencing for association with progression-free survival (PFS) and overall survival (OS). Candidate SNPs were selected by their frequency and potential function. Results: In univariate analysis, patients carrying any A allele in XRCC3 rs861539 had significant longer PFS (3.8 vs. 2.3 months, HR 0.44, 95%CI: 0.21-0.92, p = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95%CI: 0.08-0.79, p = 0.012) than those with the G/G variant. Patients with any G allele in ATM rs609429 had a longer OS compared to those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95%CI: 0.14-0.99, p = 0.022). In multivariate analysis, XRCC3 rs861539 showed marginal significance in PFS (p = 0.091) and OS (p = 0.056). ATM rs609429 remained significant for OS (p = 0.020). No significant differences were observed in the control group. Conclusions: Genetic variants in the HR pathway, ATM rs609429 and XRCC3 rs861539, may serve as predictive and prognostic markers in mCRC patients receiving TAS-102.
Safety and efficacy of combination olaparib (O) and temozolomide (T) in small cell lung cancer (SCLC).
Authors: Anna F. Farago, Benjamin Jacob Drapkin, Allison Charles, Beow Y Yeap, Rebecca Suk Heist, Christopher G. Azzoli, David Michael Jackman, J Paul Marcoux, David Allen Barbie, David T. Myers, Sarah Phat, Jun Zhong, Jane Bailey Grinnell, Lecia V. Sequist, Mari Mino-Kenudson, Shyamala Maheswaran, Daniel A. Haber, Aaron N. Hata, Nicholas John Dyson, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2018)

8571 Background: SCLC is a high-grade neuroendocrine malignancy with overall response rates (ORR) to second-line chemotherapy generally ranging from 10-30%. The poly(ADP-ribose) polymerase (PARP) inhibitor O has activity in SCLC in preclinical studies and may synergize with the alkylating agent T. Methods: We performed a single-arm phase 1/2 study of combination O/T in adults with SCLC. Eligibility criteria included histologically/cytologically confirmed incurable SCLC which had progressed following ≥ 1 platinum-based chemotherapy. O (tablet formulation) and T were administered orally on days 1-7 of 21-day cycles at escalating doses using a 3+3 design in the phase 1 portion, followed by a phase 2 expansion at the recommended phase 2 dose (RP2D). Response assessments were performed every 6 weeks. The primary endpoint of the phase 2 portion was ORR. We present data at a planned interim analysis after enrollment of 20 patients at the RP2D. Patient-derived xenografts (PDXs) were generated from a subset of patients prior to O/T and at progression. O/T activity was assessed in vivo in PDXs in a co-clinical trial. Results: 13 patients were enrolled to 4 escalating dose levels in the phase 1 portion, and 17 additional patients were enrolled at the RP2D, O 200 mg BID and T 75 mg/m2 QD. The median (m) age was 62.0 years (range 39.2-85.2) and m prior lines of therapy was 2 (range 1-7). The most common treatment emergent adverse events (AEs) related to study drugs across dose levels were thrombocytopenia (67%; 23% grade (g) 3-4), anemia (63%; 23% g 3-4), and neutropenia (50%; 47% g 3-4). There was one related g 5 AE due to pneumonia and neutropenia. Among 29 evaluable patients at all dose levels, ORR was 41.4% (95% CI 23.5-59.3), with responses seen in 10/19 and 2/9 platinum-sensitive and -resistant patients, respectively. The mPFS was 87 days (95% CI 48-159), the mOS was 220 days (95% CI 140-308), and the mDOR was 103 days. In PDX models, responses to O/T mirrored those in donor patients, and basal total PARylation was a strong predictive biomarker for sensitivity. Conclusions: O/T shows promising clinical activity in SCLC. Further exploration of dosing strategies and biomarkers in patients and PDXs is underway. Clinical trial information: NCT02446704.
Early presence of antiangiogenesis-related adverse events as a potential biomarker of antitumor efficacy in patients with metastatic gastric cancer treated with apatinib.
Authors: Xinyang Liu, Shukui Qin, Zhichao Wang, Jianming Xu, Jianping Xiong, Yuxian Bai, Wang Zhe-Hai, Yan Yang, Guo-ping Sun, Liwei Wang, Leizhen Zheng, Nong Xu, Ying Cheng, Weijian Guo, Hao Yu, Tian Shu Liu, Pagona Lagiou, Jin Li
Journal: Journal of Clinical Oncology (2017)

4052 Background: Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. Methods: We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria or hand and foot syndrome (HFS) in the first 4 weeks using Kaplan–Meier methods, Cox proportional hazard regression and logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model and risk scores were analyzed to predict overall survival (OS). Results: Presence of AEs in the first 4 weeks was associated with prolonged median OS (169 vs. 103 days, log-rank p=0.0039; adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.64-0.84, p=0.001), prolonged median progression-free survival (PFS, 87 vs. 62 days, log-rank p=0.0309; adjusted HR 0.69, 95%CI 0.53-0.91, p=0.007), and increased disease control rate (54.67% vs. 32.77%; adjusted odds ratio 2.67, p&lt;0.001). Results remained significant in landmark analyses. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting OS. Conclusions: Presence of HTN, proteinuria or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients. [Table: see text]