tbuckley/cabot-search huggingface dataset:
Prediction of hepatocellular carcinoma patient survival using machine learning classification rules.
Authors: Wei Zhou, Huan Chen, Wenbo Han, Ji He, Henghui Zhang
Journal: Journal of Clinical Oncology (2019)

e15649 Background: The outcome prediction of hepatocellular carcinoma (HCC) is conventionally determined by evaluating tissue samples obtained during surgical removal of the primary tumor focusing on their clinical and pathologic features. Recently, accumulating evidence suggests that cancer development is comprehensively modulated by the host’s immune system underlying the importance of immunological biomarkers for the prediction of HCC prognosis. However, an integrated predictive algorism incorporating clinical characteristic and immune features still remain to be established. Methods: We obtained respectable stage II HCC specimens, along with adjacent para-tumor tissues from 221 patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital, (Shanghai, China) from 2015 through April 2018. Characteristics such as CD8+, CD163+, tumor-infiltrating lymphocytes (TILs) were obtained for further model construction used to predict the status of 3 survival indexes: Overall Survival (OS ,≤ 24 or &gt; 24 month), Progression Free Survival (PFS, ≤ 6 or &gt; 6 month), and Recurrence/Death (RD). Mutual information and coefficient between each feature and the survival indexes were tested to remove low scoring features after data cleaning and standardization. Furthermore, recursive features selection was preformed to obtain the optimal features combination. Finally, supervised learning techniques include either boosting or bagging strategy were used to fit and predict model with a grid-search method optimizing the parameters. Meanwhile, a cross validation procedure with 0.2 proportion of test cohort was randomly carried out for 10 times to evaluate the model. Results: We finally confirmed 15 biomarkers from the 46 candidates as features for the survival status prediction by using a 221 patients cohort. Among them, the top 10 most important biomarkers, included both clinical and immune attributes. The AUC of our model for survival indexes (OS, PFS, RD) was ranged from 0.76 (RD) to 0.8 (PFS), and the accuracy was above 0.85. Conclusions: We describe the integrative analysis of the clinical and immune features which collectively contribute to the survival index of HCC. Machine learning techniques, such as Gradient Boosting and random forest classifier , have a great promise for using in HCC cancer survival prediction.
A randomized phase II trial of niraparib plus either nivolumab or ipilimumab in patients with advanced pancreatic cancer whose cancer has not progressed on platinum-based therapy.
Authors: Kim Anna Reiss, Rosemarie Mick, Mark H. O'Hara, Ursina R. Teitelbaum, Thomas Benjamin Karasic, Charles John Schneider, Peter J. O'Dwyer, Danielle Karlson, Stacy Cowden, Mary Jane Fuhrer, Erica L. Carpenter, Austin A Pantel, Mehran Makvandi, David A. Mankoff, Katharine Nathanson, Kara Noelle Maxwell, Gregory Lawrence Beatty, Susan M. Domchek
Journal: Journal of Clinical Oncology (2019)

TPS4161 Background: The treatment paradigm for advanced pancreatic ductal adenocarcinoma (PDAC) typically involves ongoing chemotherapy until either disease progression or clinical deterioration. A subset of patients with advanced PDAC have exceptional responses to platinum-based chemotherapy. We hypothesized that durable platinum sensitivity in patients with advanced PDAC might be indicative of a DNA repair deficiency, and that these patients may respond to a combination of niraparib, a PARP inhibitor, plus immune checkpoint blockade. Methods: We have enrolled 25 of 84 planned patients on study NCT 03404960. Eligibility criteria include inoperable PDAC and stability on platinum-based chemotherapy for ≥16 weeks without evidence of progressive disease. Patients who have progressed on platinum-based treatment or who have received prior therapy with PARP inhibitors are excluded. Patients are randomized to receive oral niraparib 200mg PO daily plus nivolumab 240mg IV every two weeks in continuous 28 day cycles or oral niraparib 200mg PO daily plus ipilimumab 3mg/kg IV every three weeks for four doses in continuous 21 day cycles. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include response rate, duration of response and overall survival. Paired biopsies are obtained, as well as serial blood collections for circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and peripheral blood mononuclear cells (PBMCs). Correlative assays will include germline whole exome sequencing and analyses of serially collected PBMCs, CTCs and ctDNA to identify genomic and immunologic innate and adaptive resistance mechanisms. Clinical trial information: NCT 03404960.
Correlation of circulating tumor DNA (ctDNA), tissue-based genomic profiling and clinical efficacy in the biomarker directed Ph1b trial in metastatic bladder cancer (BISCAY).
Authors: Danielle Carroll, Rob McEwen, Iwanka Kozarewa, Elizabeth Harrington, Anne L'Hernault, Jayantha Ratnayake, Richard Mather, Darren Hodgson, J Carl Barrett, Jan G. C. E. Cosaert, Pierre Emmanuel Brachet, Petros Grivas, Simon Chowdhury, Thomas Powles, Donal Landers
Journal: Journal of Clinical Oncology (2019)

4553 Background: BISCAY is a biomarker-directed Ph1b multi-arm platform study exploring the combination of targeted therapies with anti-PD-L1, Durvalumab, in advanced urothelial cancer. Methods: Next generation sequencing (NGS) of tumour tissue samples from &gt; 380 patients(pts) was performed using the FoundationOne assay alongside IHC for PD-L1. ct DNA from pts enrolled in trial modules at treatment initiation was profiled using the Guardant Health OMNI platform assessing a panel of 500 genes. For a subset of pts, serial plasma samples were also analysed to monitor early signs of response vs. resistance and changes in ct DNA dynamics using a bespoke NGS panel of 10 genes. Results: To date 149 pts have been actively enrolled across 7 different biomarker selected and unselected treatment modules. Across all screened pts the most prevalent genomic alterations in tumour tissue were TERT promoter (65%), TP53 (59%), KMT2D 21%, KDM6A 21%, with the most common CNV CDKN2A/ B loss (32 %). All enrolled pts tested had detectable ctDNA in plasma. Similar genomic alterations, both frequency and type, were detected in both plasma ctDNA and tumour tissue with high concordance for module specific biomarkers used for patient allocation (80% (8/10) for ATM, BRCA1 and 2). Alterations in putative biomarkers predictive of response to anti-PD-L1, such as HRR/MMR alterations and high bTMB levels ( &gt; 20mut/Mb) were observed in22% and 40% patient plasma samples, respectively. Correlations between biomarkers across modules treatment efficacy have been explored. Conclusions: All pts with advanced bladder cancer enrolled on BISCAY who were plasma profiled had detectable ctDNA; frequencies of genomic alterations (in both tumour tissue and plasma) were comparable to prior published data sets. ctDNA may be an attractive alternative to tissue-based NGS, providing comprehensive dynamic snapshots of genomic landscapes at the start and during therapy, and warrants further prospective investigation in trials.
Impact of asparaginase discontinuation on outcome in childhood ALL: A report from the Children’s Oncology Group (COG).
Authors: Sumit Gupta, Cindy Wang, Elizabeth A. Raetz, Reuven J. Schore, Wanda L. Salzer, Eric Larsen, Kelly W. Maloney, Leonard A. Mattano, William L. Carroll, Naomi J. Winick, Stephen Hunger, Mignon L. Loh, Meenakshi Devidas
Journal: Journal of Clinical Oncology (2019)

10005 Background: Asparaginase (ASP) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued due to toxicity. For allergic reactions, but not other toxicities, Erwinia Asparaginase (EA) is often substituted. The majority of treatment protocols use discrete, discontinuous periods of asparagine depletion. In the context of such protocols, the impact of EA substitution or complete ASP discontinuation is unknown. Methods: Patients age 1-30.99 years enrolled on frontline COG trials for B-ALL [standard risk (NCI SR): AALL0331; high risk (NCI HR) AALL0232] were included. The number of prescribed pegaspargase (PEG) doses varied by trial, risk strata, and randomization (Table). Maintenance therapy did not contain ASP. Landmark analyses starting at Maintenance compared event free survival (EFS) between those receiving all prescribed doses of PEG vs. those switched to EA but receiving all doses vs. those not receiving all ASP doses. Results: This study included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG discontinuation was 12.2±4.6% on AALL0331 and 25.4%±0.8% on AALL0232. In multivariable analyses adjusted for patient and disease variables, NCI HR patients who did not receive all prescribed ASP doses had inferior EFS [hazard ratio (HR) 1.5, 95% confidence interval (95CI) 1.2-1.9; p=0.002] compared to those receiving all prescribed PEG doses. Patients with EA substitution who completed their courses were not at increased risk (HR 1.1, 95CI 0.7-1.6; p=0.69). Sensitivity analyses excluding patients discontinuing ASP due to pancreatitis or thrombosis yielded similar results. NCI SR patients who discontinued ASP were not at elevated risk (HR 1.2, 95CI 0.9-1.6; p=0.23), except when analyses were restricted to NCI SR patients with slow early response (HR 1.7, 95CI 1.1-2.7; p=0.03). Conclusions: Discontinuation of ASP doses is associated with significantly inferior EFS and must be balanced against the risks of ASP re-challenge. Our results also illustrate the potentially severe consequences of EA shortages. Prescribed pegasparagase doses. [Table: see text]
Early clinical experience with the pan-FGFR inhibitor rogaratinib in patients with non-small cell lung cancer selected based on FGFR mRNA expression levels.
Authors: Markus Joerger, Byoung Chul Cho, Nicolas Mach, Cristina Caballero, Ross A. Soo, Manfred Wirth, Cyrus Sayehli, Alejandro Navarro, Bhumsuk Keam, Ana-Maria Piciu, Sebastian Bender, Hendrik Nogai, Peter Ellinghaus, Martin H. Schuler
Journal: Journal of Clinical Oncology (2019)

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for &gt; 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.
The promoting resilience in stress management (PRISM) intervention for parents of children with cancer: A randomized controlled trial.
Authors: Mallory R. Taylor, Miranda C. Bradford, Courtney C. Junkins, Erin K. Kross, J. Randall Curtis, Joyce P. Yi-Frazier, Abby R. Rosenberg
Journal: Journal of Clinical Oncology (2019)

10029 Background: Parents of children with cancer experience significant levels of distress, which may negatively impact surviving patients and family members. Positive psychology interventions have shown promise, but few address the well-being of parents. The objective of this study was to test the efficacy of a resilience intervention, Promoting Resilience in Stress Management-Parent (PRISM-P), among parents of children with cancer. Methods: This study was a phase 2, 1:1:1 RCT. Eligible participants were English-speaking parents of children 2-24 years-old receiving cancer-directed therapy at Seattle Children’s Hospital. PRISM-P is a skills-based program targeting resilience resources. Parents were randomized to usual care (UC), UC plus individual PRISM-P (1:1), or UC plus group PRISM-P (group). Parents completed surveys at baseline and 3 months measuring resilience (primary outcome, 10-item Connor Davidson Resilience Scale (CDRISC)) and other secondary outcomes including stress, social support, and benefit-finding. We performed an intention-to-treat analysis using unadjusted linear mixed-effects modeling to estimate PRISM effects on score change. With n = 25 per arm, we achieved 80% power to detect an effect size (CDRISC change) of 5.1 (Cohen’s d = 0.8) with a type 1 error rate of 0.05. Results: 107 parents enrolled. Of these, 94 (88%) completed baseline surveys and 77 (72%) completed 3 month surveys. Mean (SD) resilience score change in UC, 1:1 and group arms was -2 (3.5), 1 (5.3) and -1 (5.0), respectively. In mixed models, the estimated 1:1 PRISM benefit for resilience score change vs. UC was +2.8 (95% CI: 0.5,5.2, p = 0.02) while there was no evidence of a group benefit (beta 0.4, 95% CI: -2.1, 2.8, p = 0.76.). Models for secondary outcome score change found a PRISM advantage for benefit finding, where the 1:1 vs. UC difference was +0.5 (95% CI: 0.2, 0.8, p &lt; 0.01) and the group vs. UC difference was +0.4 (0.0, 0.7, p = 0.05). Conclusions: Compared to UC, 1:1 PRISM-P was associated with improved resilience change, and both PRISM-P intervention arms were associated with greater benefit-finding. Future studies will explore larger scale efficacy and alternative delivery design. Clinical trial information: NCT02998086.
Time from stereotactic body radiotherapy to immunotherapy as a predictor for outcome in metastatic non small cell lung cancer.
Authors: Rodney E Wegner, Stephen Abel, Shaakir Hasan, Richard White, Gene Grant Finley, Dulabh Monga, Athanasios Colonias, Vivek Verma
Journal: Journal of Clinical Oncology (2019)

9024 Background: Immunotherapy has changed the face of treatment for stage IV non small cell lung cancer (NSCLC), quickly becoming the standard of care. The appropriate timing of immunotherapy in the setting of other ablative therapies, namely stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), remains to be determined. We sought to use the National Cancer Database to examine trends in immunotherapy use as well as timing as it relates to SBRT/SRS in stage IV NSCLC patients. Methods: We queried the NCDB for patients with Stage IV NSCLC diagnosed between 2004-2015 that were treated with SRS or SBRT techniques (to any site) and had at least three months of follow up. Multivariable logistic regression was used to identify predictors of immunotherapy use. Receiver operator curve analysis was used to identify the optimal timepoint between SBRT and immunotherapy correlating with overall survival. Kaplan-meier curves were generated to determine overall survival. Multivariable cox regression was used to determine factors predictive of survival. A propensity score was generated and incorporated into Kaplan-meier and cox regressions to account for indication bias. Results: We identified 13,862 patients meeting the above eligibility criteria, 371 being treated with immunotherapy. The vast majority (75%) had chemotherapy as well. Patients with adenocarcinoma, treatment with chemotherapy, and more recent year of treatment were more likely to receive immunotherapy. Univariable Kaplan-meier analysis showed improved median survival with immunotherapy, 17 months vs. 13 months, p &lt; 0.0001. On multivariable propensity-adjusted cox regression significant predictors for improved overall survival were younger age, lower comorbidity score, lower grade, private insurance, and female gender. Using a cutoff of 21 days after start of SBRT, patients treated thereafter were more likely to survive longer, median survival of 19 months vs 15 months, p = 0.0335. Conclusions: Immunotherapy use in Stage IV NSCLC after SBRT has increased over time, mostly in patients with adenocarcinoma and in the setting of chemotherapy. In this analysis, outcomes were improved when immunotherapy was given at least three weeks after start of SBRT.
Operon Concatenation Is an Ancient Feature That Restricts the Potential to Rearrange Bacterial Chromosomes
Authors: Gerrit Brandis, Sha Cao, Diarmaid Hughes
Journal: Molecular Biology and Evolution (2019)

The last common ancestor of the Gammaproteobacteria carried an important 40-kb chromosome section encoding 51 proteins of the transcriptional and translational machinery. These genes were organized into eight contiguous operons (rrnB-tufB-secE-rpoBC-str-S10-spc-alpha). Over 2 Gy of evolution, in different lineages, some of the operons became separated by multigene insertions. Surprisingly, in many Enterobacteriaceae, much of the ancient organization is conserved, indicating a strong selective force on the operons to remain colinear. Here, we show for one operon pair, tufB-secE in Salmonella, that an interruption of contiguity significantly reduces growth rate. Our data show that the tufB-secE operons are concatenated by an interoperon terminator-promoter overlap that plays a significant role regulating gene expression. Interrupting operon contiguity interferes with this regulation, reducing cellular fitness. Six operons of the ancestral chromosome section remain contiguous in Salmonella (tufB-secE-rpoBC and S10-spc-alpha) and, strikingly, each of these operon pairs is also connected by an interoperon terminator-promoter overlap. Accordingly, we propose that operon concatenation is an ancient feature that restricts the potential to rearrange bacterial chromosomes and can select for the maintenance of a colinear operon organization over billions of years.
Abstract 15655: A Novel Large Animal Model of Accelerated Human-Like Coronary In-stent Neoatherosclerosis Formation
Authors: Yuxin Li, Hironori Haruta, Daiichiro Fuchimoto, Shunichi Suzuki, Kazumi Satou, Daisuke Kitano, Tadateru Takayama, Takafumi Hiro, Rika Kawakami, Seiichi Hirota, Taro Matsumoto, Hiroyuki Hao, Akira Onishi, Atsushi Hirayama
Journal: Circulation (2017)

Introduction: Our current understanding of coronary in-stent atherosclerosis derives solely from pathology and retrospective observational studies, all clinical, which provide only a single snapsho...
A phase III randomized study of nivolumab plus ipilimumab versus nivolumab for previously treated patients with stage IV squamous cell lung cancer and no matching biomarker (Lung-MAP Sub-Study S1400I, NCT02785952).
Authors: Lyudmila Bazhenova, Mary Weber Redman, Scott N. Gettinger, Fred R. Hirsch, Philip C. Mack, Lawrence Howard Schwartz, David R. Gandara, Jeffrey D. Bradley, Tom Stinchcombe, Natasha B. Leighl, Suresh S. Ramalingam, Susan S Tavernier, Katherine Minichiello, Karen Kelly, Vassiliki Papadimitrakopoulou, Roy S. Herbst
Journal: Journal of Clinical Oncology (2019)

9014 Background: Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. Methods: S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity. Results: From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. Outcomes based on PD-L1 and TBM subsets are shown in table. Response rates were 18% (12-25%) and 17% (11-24%) for N+ I and N. Median follow up for patients still alive was 17.4 m. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% and 16% of pts on N+I and N. There were 5 grade 5 AE in N+I arm and 1 in N arm. Conclusions: S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Clinical trial information: 02785952. [Table: see text]