tbuckley/cabot-search huggingface dataset:
PD-L1 expression in patients with unresectable stage III non-small cell lung cancer receiving chemoradiotherapy.
Authors: Nobuaki Mamesaya, Hirotsugu Kenmotsu, Eriko Miyawaki, Mie Kotake, Takahisa Kawamura, Haruki Kobayashi, Kazuhisa Nakashima, Shota Omori, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Hideyuki Harada, Yasuhisa Ohde, Masahiro Endo, Takashi Sugino, Takashi Nakajima, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2018)

e20530 Background: Approximately 30% of patients with stage IV non-small cell lung cancer (NSCLC) are reported to have with high tumor PD-L1 expression (tumor proportion score: TPS ≥ 50%). PD-L1 status is a biomarker of PD-1 antibodies for patients with stage IV NSCLC. Recently, a phase III study demonstrated the efficacy of durvalumab for stage III NSCLC patients receiving chemoradiotherapy (CRT). High PD-L1 expression is a candidate biomarker of PD-1/PD-L1 inhibitors for stage III NSCLC. However, the prevalence of high PD-L1 expression in patients with stage III NSCLC is unclear. Methods: We retrospectively reviewed 105 patients with unresectable stage III NSCLC who received definitive CRT in our institution from 2012 to 2017. The PD-L1 expression in pretreatment biopsy samples was assessed by immunohistochemistry using the 22C3 anti–PD-L1 antibody, and stratified into three groups (TPS < 1%, 1-49%, and ≥50%). Results: PD-L1 status was as follows: < 1%, 74 (70.5%); 1-49%, 21 (20%); and ≥50%, 10 (9.5%). There were no significant differences in patient characteristics or treatment efficacy among the groups (Table). Grade ≥2 radiation pneumonitis was observed in 4 patients (40%) in the high PD-L1 expression group (≥50%). Conclusions: These results suggest that PD-L1 expression ≥50% was less frequent in patients with stage III NSCLC than in those with stage IV NSCLC. In clinical settings, the pretreatment evaluation of PD-L1 status may not be useful in these patients. Table@ Patient characteristics and treatment efficacy according to PD-L1 status TPS < 1% N = 74 TPS 1-49% N = 21 TPS ≥50% N = 10 p value Patient characteristics Age (range), y 65 (46-81) 68 (60-82) 66 (40-77) 0.35 Gender (Male/Female) 58/16 18/3 8/2 0.76 Performance status (0/1/2) 41/32/1 14/7/0 6/4/0 0.88 Smoking status (Smoker/never-smoker) 66/8 21/0 10/0 0.16 Clinical stage (IIIA/IIIB/IIIC) 24/36/14 9/11/1 6/3/1 0.27 Histology (Ad/Sq /other) 46/22/6 11/9/1 4/4/2 0.44 EGFR mutation status (Mutant/wild/unknown) 5/50/19 0/12/9 1/4/5 0.23 Treatment efficacies and toxicity ORR, % 64.9 85.7 70 0.44 median PFS, m (95% CI) 10.6 (8.9-15.2) 11.9 (6.8-23.0) 9.2 (3.6-22.2) Radiation Pneumonitis (Grade ≥2), % 12.2 4.8 40.0
Influence of Varying Quantitative Fecal Immunochemical Test Positivity Thresholds on Colorectal Cancer Detection
Authors: Kevin Selby, Christopher D. Jensen, Jeffrey K. Lee, Chyke A. Doubeni, Joanne E. Schottinger, Wei K. Zhao, Jessica Chubak, Ethan Halm, Nirupa R. Ghai, Richard Contreras, Celette Skinner, Aruna Kamineni, Theodore R. Levin, Douglas A. Corley
Journal: Annals of Internal Medicine (2018)

Background: The fecal immunochemical test (FIT) is commonly used for colorectal cancer (CRC) screening. Despite demographic variations in stool hemoglobin concentrations, few data exist regarding optimal positivity thresholds by age and sex. Objective: To identify programmatic (multitest) FIT performance characteristics and optimal FIT quantitative hemoglobin positivity thresholds in a large, population-based, screening program. Design: Retrospective cohort study. Setting: Kaiser Permanente Northern and Southern California. Participants: Adults aged 50 to 75 years who were eligible for screening and had baseline quantitative FIT results (2013 to 2014) and 2 years of follow-up. Nearly two thirds (411 241) had FIT screening in the previous 2 years. Measurements: FIT programmatic sensitivity for CRC and number of positive test results per cancer case detected, overall and by age and sex. Results: Of 640 859 persons who completed a baseline FIT and were followed for 2 years, 481 817 (75%) had at least 1 additional FIT and 1245 (0.19%) received a CRC diagnosis. Cancer detection (programmatic sensitivity) increased at lower positivity thresholds, from 822 in 1245 (66.0%) at 30 µg/g to 925 (74.3%) at 20 µg/g and 987 (79.3%) at 10 µg/g; the number of positive test results per cancer case detected increased from 43 at 30 µg/g to 52 at 20 µg/g and 85 at 10 µg/g. Reducing the positivity threshold from 20 to 15 µg/g would detect 3% more cancer cases and require 23% more colonoscopies. At the conventional FIT threshold of 20 µg/g, programmatic sensitivity decreased with increasing age (79.0%, 73.4%, and 68.9% for ages 50 to 59, 60 to 69, and 70 to 75 years, respectively; P = 0.009) and was higher in men than women (77.0% vs. 70.6%; P = 0.011). Limitation: Information on advanced adenoma was lacking. Conclusion: Increased cancer detection at lower positivity thresholds is counterbalanced by substantial increases in positive tests. Tailored thresholds may provide screening benefits that are more equal among different demographic groups, depending on local resources. Primary Funding Source: National Cancer Institute.
PD-L1 expression on circulating tumor cells in patients with hepatocellular carcinoma.
Authors: Hee Yeon Kim
Journal: Journal of Clinical Oncology (2018)

e24095 Background: Recently, immunotherapies targeting the immune checkpoint interaction between programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown therapeutic potential in patients with advanced hepatocellular carcinoma (HCC). However, new biomarkers that may predict the benefits of immunotherapies are warranted. We investigated PD-L1 expression on circulating tumor cells (CTCs) in patients with HCC. Methods: Peripheral blood samples were collected from 35 patients with HCC. CTCs were isolated from patients with HCCs using antibodies against epithelial cell adhesion molecule (EpCAM), cytokeratin (CK), and CD45. PD-L1 expression on EpCAM+/CK+/CD45- CTCs were analysed by flow cytometry. Quantitative real-time PCR was performed to measure PD-L1 gene expression among EpCAM+ CTCs. Results: Patients were divided into two groups according to the presence of vascular invasion, lymph node metastasis, or distant metastasis (VNM-negative vs VNM-positive). Sixteen patients were categorized into VNM-positive group. PD-L1 expression on EpCAM+ CTCs was not different between two groups (VNM-negative, 32.0 ± 31.9 % vs VNM-positive, 26.0 ± 17.8 %; p value = 0.49). There was no difference in PD-L1 gene expression by real-time PCR between HCC patients with or without vascular invasion, lymph node metastasis, or distant metastasis (VNM-negative, 11.0 ± 8.4 vs VNM-positive, 10.9 ± 14.7 %; p value 0.97) Conclusions: Our study demonstrates that PD-L1 expression by CTCs is not related to tumor aggressiveness. The predictive value of expression of PD-L1 on CTCs should be further investigated in the current era of immune checkpoint blockade.
Survival analyses from a randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer with high tumor load (SCORPION trial).
Authors: Anna Fagotti, Giuseppe Vizzielli, Gabriella Ferrandina, Francesco Fanfani, Valerio Gallotta, Vito Chiantera, Barbara Costantini, Pasquale Alessandro Margariti, Salvatore Gueli Alletti, Francesco Cosentino, Lucia Tortorella, Giovanni Scambia
Journal: Journal of Clinical Oncology (2018)

5516 Background: Previous randomized multicenter trials determined that neoadjuvant chemotherapy (NACT) was non-inferior to primary debulking surgery (PDS) for both progression-free (PFS) and overall survival (OS) in advanced epithelial ovarian cancer (AEOC). We investigated whether NACT was superior to PDS in terms of PFS and postoperative morbidity in AEOC patients, endowed with high tumor load (HTL), in a single Institution committed toward maximal surgical effort. Methods: This was a superiority, randomized phase III trial registered on clinicaltrials.gov (No. NCT01461850). Tumor load was assessed by a laparoscopy predictive index (PI; Fagotti score). Women included had stage IIIC-IV disease and PI between 8 and 12 (HTL). They were randomly assigned (1:1 ratio) to undergo either PDS followed by adjuvant chemotherapy, or NACT followed by interval debulking surgery (IDS) and chemotherapy. Carbo-taxol based chemotherapy was performed in both arms. Co-primary outcome measures were PFS and postoperative complications; secondary outcomes were OS, and quality of life (QoL). Results on postoperative complications and QoL were previously published. Survival analyses were performed on intention-to-treat analysis (ITT), using Kaplan-Meier method. Results: From October 2011 to November 2016, 171 women were randomly assigned to PDS (n = 84) vs. NACT (n = 87). All were included in the ITT analysis. Overall median FU was 42 months (95% CI: 30-50 months). As of March 11, 2018, 137 (80.1%) disease progressions and 74 deaths (43.3%) had occurred. There was no significant difference for PFS between patients who underwent PDS vs. NACT (15 vs. 14 months) (HR = 1.06, 95%CI: 0.77-1.46; p = 0.72 log-rank test). Median OS was 41 months in the PDS arm and not reached in the NACT arm. Eighty-four women had PDS and 74 had IDS. Optimal residual tumor (≤ 1 cm) was obtained in 78 (92.8%) vs. 74 (100%) patients, respectively (p = 0.02). Seven (8.3%) deaths for post-operative complications were registered in the PDS vs. 0 in the NACT arm (p = 0.01). Conclusions: NACT was not superior to PDS in terms of PFS for AEOC patients endowed with HTL receiving maximal surgical effort. Clinical trial information: NCT01461850.
A phase I/II study of ixazomib (Ix) pomalidomide (POM) dexamethasone (DEX) in relapsed refractory (R/R) multiple myeloma: Initial results.
Authors: Amrita Y. Krishnan, Prashant Kapoor, Joycelynne Palmer, Shaji Kumar, Sagar Lonial, Myo Htut, Chatchada Karanes, Nitya Nathwani, Michael Alan Rosenzweig, Firoozeh Sahebi, George Somlo, Lupe Duarte, Stephen J. Forman, Jesus G. Berdeja
Journal: Journal of Clinical Oncology (2016)

8008 Background: Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI) and steroid are used to treat newly diagnosed and relapsed MM. While Ix, an oral PI with single agent activity can be combined with lenalidomide (LEN), patients(pts) with R/R MM are often LEN refractory. POM has single agent activity in LEN refractory pts, and can be combined with intravenous PI Carfilzomib (CAR) . An entirely oral regimen leveraging the efficacy of PI/POM in RR MM would be of benefit. Herein we report safety and preliminary efficacy data of the Ix/POM/DEX combination in Len R/R MM, a Multiple Myeloma Research Consortium trial. Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix and 2) evaluate anti-tumor activity of the triplet. Dose levels tested: Dose level (DL) 1: Ix 3mg d1,8,15; POM 4mg d1-21; DEX 40mg d1,8,15,22. DL2: Ix 4mg d1,8,15; with identical POM /DEX; 28day treatment cycles. Eligibility: R/R MM after > 1 prior therapy. LEN refractory, and ≤ grade(gr) 1 peripheral neuropathy PN. Pts treated until progression or unacceptable toxicity. Design: Phase I study utilized a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1. Results: To date, 21pts treated; 20 evaluable for toxicity. Six pts treated on DL1, 14 treated on DL2 -the MTD/Phase II dose (P2D). Median(range): age 63yrs (48-77); time from diagnosis: 3.7 years (1.0-8.9); prior therapies 3(1-6)/ prior transplant n = 17(85%); double(LEN/Bortezomib(BOR)) or triple(LEN/BOR/CAR) refractory 11(55%). Phase I: DL1 expanded to n = 6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL2. AEs related to POM +/- Ix in > 20% of pts: gr3 lymphocyte decrease, gr1 neutrophil decrease ≥ Grade3 AEs: anemia (n = 2); neutropenia (n = 6), thrombocytopenia (n = 3). Response: Gehan 1ststage of 2; n = 9 pts treated ORR:33% (1 VGPR, 2 PR); Clinical Benefit Response (CBR):67%; median cycles 1.5 (1-16); follow-up 1.3 months (0.8, 14.0). Including DL1 pts, ORR:40%. Conclusions: Full dose Ix with standard dose POM/DEX is well tolerated. Preliminary response rates are promising given that > 50% of pts were dual refractory and early into treatment course. Clinical trial information: NCT02119468.
TCT-700 Initial experience of magnesium bioresorbable scaffold implantation in acute coronary syndrome
Authors: Adrian Wlodarczak, Magdalena Lanocha, Artur Jastrzebski, MAciej Pecherzewski, Marek Szudrowicz, Waldemar Jastrzebski, Joanna Nawrot, Pawel Kozak, Maciej Lesiak
Journal: Journal of the American College of Cardiology (2018)
Clinical Outcome and Viral Genome Variability of Hepatitis B Virus–Induced Acute Liver Failure
Authors: Olympia E. Anastasiou, Marek Widera, Sandra Westhaus, Lejla Timmer, Johannes Korth, Guido Gerken, Ali Canbay, Daniel Todt, Eike Steinmann, Tatjana Schwarz, Jörg Timm, Jens Verheyen, Sandra Ciesek
Journal: Hepatology (2018)

Acute hepatitis B virus (HBV) infection remains a frequent cause of acute liver failure (ALF) worldwide. ALF occurs in 0.1%‐0.5% of infected patients. The aim of this study was to scrutinize the outcome of patients with HBV‐induced ALF and mutational patterns of HBV variants, which might contribute to ALF. From 2005 to 2016, 42 patients were treated for HBV‐induced ALF in the University Hospital Essen, Germany. Clinical and virological data from these patients were collected. As a control, 38 patients with acute hepatitis B (AHB) without liver failure were included. The HBV genome was sequenced by next‐generation sequencing (NGS). Mutations that were found by NGS were analyzed in vitro . Of 42 patients, 8 had ALF without spontaneous recovery (NSR): Seven patients underwent liver transplantation (LT) and one patient died before LT. Of 42 patients, 34 (81%) had spontaneous recovery (SR) and cleared the infection, achieving either anti‐HBs seroconversion or hepatitis B surface antigen (HBsAg) loss. HBV genotype (GT)‐D was the most frequent GT in patients with ALF. Mutations in HBV core, preS2, and small hepatitis B surface antigen (SHB) were more frequent in patients with ALF‐NSR compared with those with ALF‐SR or AHB. Amino acid deletions (del; 16‐22 and 20‐22) in preS2 and SHB mutation L49R were exclusively detected in patients with ALF‐NSR. In vitro analyses reveal that these mutations did not influence HBsAg secretion or infectivity. Conclusion: HBV GT‐D and increased variability in HBV core, preS2 region, and SHB are associated with a worse clinical outcome of acute HBV infection.
Effect of inhibition of 15-PGDH on Kras-driven tumor expansion through all-trans retinoic acid metabolism in the pancreas.
Authors: Takatsugu Ishimoto, Kota Arima, Yoshifumi Baba, Yo-ichi Yamashita, Hideo Baba
Journal: Journal of Clinical Oncology (2018)

e16197 Background: Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2 (PGE2). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) participates in the degradation of PGE2 and has attracted attention in recent years. Although inhibition of 15-PGDH is reported to lead to PGE2 accumulation, the role for pancreatic tumor progression is still unknown. The aim of this study is to elucidate the functional role of 15-PGDH during tumor progression in pancreas. Methods: We analyzed tissues obtained from 121 PDAC patients. Protein levels were evaluated by western blotting and flow cytometry, and metabolite levels were evaluated by liquid chromatography coupled to tandem spectrometry (LC/MS/MS). 15-Pgdh-/- mice were generated using the CRISPR-Cas9 system, and 15-Pgdh-/-; KrasG12D; Ptf1aCre/+ (PgKC) mice were generated by crossing 15-Pgdh-/- mice with KrasG12D; Ptf1aCre/+ (KC) mice. Results: We found that 15-PGDH expression is frequently down-regulated in PDAC cells and inversely correlated with the expression of ALDH1, major cancer stem cell marker, in human PDAC tissues. Moreover, ALDH1 expression was significantly associated with poor prognosis in PDAC patients. Pharmacological blockade of 15-PGDH led to PGE2 accumulation, and promoted growth and sphere formation through the expansion of ALDH1-positive cells in vitro and in vivo. We also elucidated the molecular mechanism that PGE2 accumulation by 15-PGDH inhibition increases CYP26A1 expression and subsequently depletes all-trans retinoic acid (ATRA), and results in ALDH1 up-regulation. Furthermore, genetic ablation of 15-Pgdh developed PDAC tumor through the expansion of ALDH1-positive cells in PgKC mice. Finally, ATRA replacement markedly reduced Aldh1 activity in pancreatic tumor cells. Conclusions: Our findings highlight the significance of PGE2 degradation pathway for PDAC tumor progression and indicate that the reduction of ALDH1-positive tumor cells via ATRA replacement might lead to tumor shrinkage.
Analysis of Work Requirement Exemptions and Medicaid Spending
Authors: Anna L. Goldman, Steffie Woolhandler, David U. Himmelstein, David H. Bor, Danny McCormick
Journal: JAMA Internal Medicine (2018)

This study estimates the number of Medicaid enrollees at risk of losing coverage if work requirements are implemented and calculates current Medicaid spending for those enrollees at the national level and among states with approved or pending waivers.
Case-only analyses for identifying genotypes that modify the effect of finasteride in the Prostate Cancer Prevention Trial (PCPT): SWOG S9217.
Authors: James Dai, Michael Leo LeBlanc, Phyllis J. Goodman, M. Scott Lucia, Ian Murchie Thompson, Tangen Catherine
Journal: Journal of Clinical Oncology (2018)

1551 Background: The Prostate Cancer Prevention Trial (PCPT) reported decreased risk of all prostate cancers but increased risk of high-grade prostate cancer in the finasteride arm. The aim of the present analysis was to identify genotypes that modify the effect of finasteride using case-only methods for estimating gene-treatment interactions. Methods: Germline genetic data from 1157 prostate cancer cases in the Prostate Cancer Prevention Trial (PCPT, NCT00288106) were analyzed by case-only methods. Genotypes included 357 single nucleotide polymorphisms (SNPs) from 83 candidate genes in androgen metabolism, inflammation, circadian rhythm and other pathways. Univariate case-only analysis was conducted to evaluate whether individual SNPs modified the finasteride effect on the risk of high-grade and low-grade prostate cancer. Case-only classification trees and random forests, which are powerful machine learning methods with resampling-based controls for model complexity, were employed to identify a predictive signature for genotype-specific treatment effects. Results: Accounting for multiple testing, a single SNP in SRD5A1 gene (rs472402) significantly modified the finasteride effect on high-grade prostate cancer (Gleason score > 6) in PCPT (p-value = 8×10-5, family-wise error rate < 0.05). Men carrying GG genotype at this locus had a 55% reduction of the risk in developing high-grade cancer (RR = 0.45, 95% C.I. [0.27, 0.75]). Additional effect-modifying SNPs with moderate statistical significance were identified by case-only trees and random forests. A prediction model built by the case-only random forest method classified 36% of PCPT men to have reduced risk of high-grade prostate cancer when taking finasteride, while the others have increased risk. No SNP-finasteride interaction was found for low-grade prostate cancer. Conclusions: Case-only methods identified SNPs that modified the effect of finasteride on the risk of high-grade prostate cancer in PCPT and predicted a subgroup of men who had reduced cancer risk by finasteride. Clinical trial information: NCT00288106.
Post hoc analysis of a phase III study to test the association between circulating <i>methylated glutathione s transferase (mGSTP1</i>) DNA levels and response to docetaxel (DTX) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Kate Lynette Mahon, Wenjia Qu, Hui-Ming Lin, Calan Spielman, Daniel Cain, Cindy Jacobs, Kim N. Chi, Johann S. De Bono, Celestia S. Higano, Susan J. Clark, Lisa Horvath
Journal: Journal of Clinical Oncology (2017)

5014 Background: GSTP1 inactivation is associated with CpG island hypermethylation in &gt; 99% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to DTX and overall survival (OS) in phase I/II mCRPC cohorts. This post hoc analysis of a phase III study aims to test the association between circulating mGSTP1 DNA levels and outcomes. Methods: The phase III SYNERGY study tested DTX +/- custirsen as 1 st line chemotherapy in mCRPC (n = 1022) with no OS benefit in the experimental arm. Serum samples were taken at baseline (BL) and preC3 of DTX +/- custirsen from 600 patients (pts) enrolled on the SYNERGY study. mGSTP1levels in free DNA were measured using a sensitive methylation specific PCR assay and correlated with PSA response, time to PSA progression (TTP) and OS. Results: On interim analysis of 300 pts, serum mGSTP1 was detectable at BL in 80% and preC3 in 44%. Undetectable preC3 mGSTP1 correlated with a ≥30% fall in PSA within 3m of starting DTX (p &lt; 0.001). Detectable BL and preC3 mGSTP1 predicted shorter TTP after DTX (BL; HR 1.6 95%CI 1.1-2.3; p = 0.01 and preC3 HR 2.2 95%CI 1.6-2.9; p &lt; 0.001). Detectable mGSTP1 at both time points predicted shorter OS (BL; median OS 18.4 vs 33.1m, HR 2.4 95%CI 1.6-3.7; p &lt; 0.001 and preC3; median OS 13.9 vs 29m, HR 2.7 95%CI 2.0-3.6; p &lt; 0.001). In those with detectable BL mGSTP1, 50% had undetectable preC3 mGSTP1 predicting &gt; 30% fall in PSA within 3m (p &lt; 0.001), improved TTP (HR 0.40 95%CI 0.29-0.57; p &lt; 0.001) and improved OS (25.2 vs 13.9 m HR 0.38 95%CI 0.28-0.51; p &lt; 0.001). On multivariable analysis including Hb, Karnofsky PS, LDH, PSA and visceral metastases, detectable preC3 mGSTP1 independently predicted shorter TTP (HR 1.9 95%CI 1.4-2.6; p &lt; 0.001). Detectable mGSTP1at both time points independently predicted OS (BL; HR1.8 95%CI 1.2-2.8; p = 0.006 and preC3; HR 2.2 95%CI 1.6-3.0; p &lt; 0.001). Results from the full cohort of 600 pts will be available for presentation at the meeting. Conclusions: This study should validate circulating mGSTP1 DNA as a marker of therapeutic benefit and prognosis in men with mCRPC receiving DTX and could be utilized for clinical management.