tbuckley/cabot-search huggingface dataset:
Combination chemotherapy with temsirolimus and trabectedin for recurrent clear cell carcinoma of the ovary: A phase II single arm clinical trial.
Authors: Masashi Takano, Hiroko Kouta, Yuji Ikeda, Naoki Sasaki, Kazuya Kudoh, Sayaka Ikeda, Tsunekazu Kita, Ryoko Kikuchi, Tomoko Goto, Kenichi Furuya, Yoshihiro Kikuchi
Journal: Journal of Clinical Oncology (2014)

5517 Background: Recurrent clear cell carcinoma (RCCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. A phase II trial to evaluate the effect of combination therapy with temsirolimus and trabectedin for patients with RCCC was performed. Methods: Simon's two-stage design was used. In the first stage, 9 patients were accrued. If there were no responder in these patients, the study would be stopped. Otherwise, eight additional patients will be accrued for a total of 17. If three or more responder were observed in 17patients, this design yields a type I error rate of 0.05 and power of 0.81 when the true response rate were 25%. Patients with RCCC were treated with weekly regimen using two drugs: 15mg/m2 of temsirolimus and 0.15mg/m2 of trabectedin (3 weeks, one week rest) with written informed consents. Treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. Results: Among 9 patients in the first stage, two responses were observed, and a total of 17 patients were analyzed in this study. There were no cases that discontinued the therapy due to toxicities. Median age was 60 years (range: 30-69), and median number of previous chemotherapy was 3 (range: 1-6). All cases were assessable by RECIST and CTCAE. One patient (6%) had a complete response (CR), and two cases (12%) achieved a partial response (PR), and 5 patients (29%) had a stable disease (SD) beyond three months, resulting in clinical benefit rate (CBR; CR+PR+SD>3month) of 47%. Median response duration in CBR case was 3.5 months (range: 3-24+). There were no cases that developed toxicities more than grade2. Conclusions: Combination therapy with temsirolimus and trabectedin was a candidate for salvage therapy for patients with RCCC. These results warrant further study in such clinical settings.
Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma:Â a Phase II Trial (GOAL)
Authors: Georg Hess, Andreas Hüttmann, Julia Meissner, Reinhard Marks, Martin Dreyling, Ulrich Keller, Thomas Ernst, Christiane Pott, Andreas Viardot, Oliver Deuster, Christina van Oordt, Matthias Theobald, Georg Lenz
Journal: Blood (2018)
Nivolumab for Relapsed or Refractory Classical Hodgkin Lymphoma (cHL) after Autologous Hematopoietic Cell Transplantation (auto-HCT): Extended Follow-up of the Phase 2 Single-Arm CheckMate 205 Study
Authors: Philippe Armand, Andreas Engert, Anas Younes, Hun Ju Lee, Armando Santoro, Pier Luigi Zinzani, John M. Timmerman, Graham P. Collins, Radhakrishnan Ramchandren, Jonathon B. Cohen, Jan Paul De Boer, Kerry J Savage, John Kuruvilla, Marek Trněný, Margaret A. Shipp, Mariana Sacchi, Anne Sumbul, Stephen M. Ansell
Journal: Blood (2018)
Adjuvant therapy for stage II and III colon cancer in elderly patients: NCDB analysis.
Authors: Samip R. Master, Lawrence Shi, Chintan Shah, Runhua Shi
Journal: Journal of Clinical Oncology (2018)

863 Background: Data on safety and efficacy of adjuvant chemotherapy for stage II and III colon cancer in elderly patients is area of controversy as these patients are underrepresented in clinical trials. We did a retrospective analysis of Medicare patients aged 70 or older with stage II and stage III colon cancer to investigate the adjuvant chemotherapy effect on colon cancer patients’ survival. Methods: Data was analyzed from 110, 993 men and women (≥ 70 years of age) registered in the National Cancer Database (NCDB) who were diagnosed with AJCC Stage II and Stage III colon cancer between 2004 and 2012 and had follow-ups to end of 2013. The primary predictor variable was adjuvant chemotherapy received, and overall survival was the outcome variable. Only patients with Medicare insurance were investigate for ease of analysis. Additional variables addressed and adjusted included gender, age, race, Charlson Comorbidity Index, the level of education, income, grade of tumor, distance traveled, facility type and diagnosing/treating facility. Results: The mean age was 79.5 years and SD was 5.9 years. In multivariate analysis, after adjusting for secondary predictor variables, receipt of adjuvant chemotherapy was a statistically significant predictor of overall survival of the stage II and stage III colon cancer. Relative to patients who did not receive adjuvant chemotherapy, the patients who got single agent adjuvant chemotherapy had 47.7% and those who were treated with multi agent chemotherapy had 49.8% decreased risk of mortality. There was no significant survival difference between single agent and multi agent adjuvant chemotherapy. Among the factors analyzed, age, gender, race, comorbidity index, diagnosing /treating facility and grade of tumor were found to be significant predictors of survival. Conclusions: Among the patients aged 70 years or older with stage II and stage III colon cancer, adjuvant chemotherapy lead to improved survival outcomes. However, survival difference between single agent vs multi agent adjuvant chemotherapy was not statistically significant.
Keynote 290: Pembrolizumab (pem) in combination with stereotactic body radiotherapy for resectable liver metastatic colorectal cancer.
Authors: Dustin A. Deming, David H. Kim, Kristina Matkowskyj, Nataliya Volodymyrivna Uboha, Sam Joseph Lubner, Noelle K. LoConte, Daniel Mulkerin, Daniel Abbott, Sharon M. Weber, Emily Winslow, Robert Jeraj, Mark A. Ritter, Scott Perlman, Jens C. Eickhoff, Michael Frederick Bassetti
Journal: Journal of Clinical Oncology (2018)

TPS874 Background: Colorectal cancer (CRC) is one of the few cancers in which aggressive local approaches to treat systemic metastases have resulted in clinical benefit. Despite these approaches 70-80% of patients (pts) with resectable metastatic disease will recur. The one-year recurrence rate for this population is ~40-50%. Immunotherapeutics have yet to be studied in this setting. To sensitize microsatellite stable (MSS) CRCs to immune therapies adjunctive therapies are required. Gross tumor microenvironments suppress systemic anti-cancer immune responses. Stereotactic body radiation therapy (SBRT) is commonly utilized to treat liver metastatic CRC, using very high doses of focused radiation to ablate tumors. This causes localized inflammation, a potential increase in immunogenic intra-tumoral and intra-lymphatic antigen release, and a rapid influx of responding immune cells. We hypothesize that radiotherapy-induced tumor necrosis, and surgical removal of the remaining immunosuppressive gross disease will enhance the immunogenicity of CRC and potentiate the effectiveness of PD-1 blockade. Methods: This is a single arm phase 1b investigator-initiated study (NCT02837263) to evaluate the use of pem in combination with ablative radiotherapy for the treatment of oligometastatic CRC. This study examines the sequential use of SBRT, then pem followed by resection of all known sites of disease and 6 months of adjuvant pem. Pts with MSS CRC with resectable liver metastatic disease who have received prior FOLFOX are eligible. The primary endpoints are safety/tolerability and the rate of cancer recurrence at 1 year. Secondary endpoints include time to disease recurrence, disease free survival and overall survival. This study is currently enrolling with a planned total accrual of 15 patients. Correlative studies examine PD-L1 status, tumor infiltrating lymphocytes, evidence of an abscopal effect, versican proteolysis as a novel immune biomarker, and the ability of multiparametric fluorodeoxyglucose (FDG) PET MR and fluorothymidine (FLT) PET CT to detect immune infiltration. Clinical trial information: NCT02837263.
Clinical Impact of Clonal Hematopoiesis after Autologous Stem Cell Transplantation for Lymphoma: A National Population-Based Cohort Study
Authors: Simon Husby, Favero Francesco, Christian Nielsen, Betina Sørensen, John Bæch, Jakob Werner Hansen, German G.R. Gonzalez, Bente Arboe, Lisbeth Pernille Andersen, Eva Kannik Hastrup, Anne Fischer-Nielsen, Susanne G Sækmose, Per Boye Hansen, Ilse Christiansen, Erik Clasen-Linde, Lene Meldgaard Knudsen, Kathrine Grell, Erik Kay Segel, Lene Hyldahl Ebbesen, Michael Thorsgaard, Pär L. Josefsson, Tarec Christoffer El-Galaly, Peter De Nully Brown, Joachim Weisenfeldt, Thomas Stauffer Larsen, Kirsten Grønbæk
Journal: Blood (2018)
Anti-tumor effect of Resveratrol and its potential for combination with immunotherapy
Authors: Brenda Soto, Jacquelyn Hank, Arthur Polans, Paul Sondel
Journal: Cancer Research (2008)

2152  Resveratrol (3, 4’, 5 - trihydroxy-trans-stilbene) is a natural compound which is currently being investigated for many possible health promoting activities. It has been shown to have anti-tumor effects on various types of cancer cells in vitro and in some animal models of cancer. Prior studies on the effect of t-RV on the immune system have found t-RV to be immunosuppressive in vitro and ex vivo in a dose-dependent manner, but not in vivo. We are currently examining the ability of t-RV to be combined with immunotherapy to treat cancer. Using proliferative and cytotoxicity assays we are defining a dose in vitro and a regimen in vivo that does not suppress the immune system and is additive or synergistic in mediating anti-tumor effects when combined with immunotherapy. In our in vitro studies high concentrations of t-RV (e.g. 50uM or higher) were found to inhibit the ability of PHA to stimulate proliferation of human peripheral blood mononuclear cells (PBMCs) measured by the ability of the cells to pass the dye CFSE to the daughter cells. Also, PBMCs were found to be arrested in the G1 phase of their cycle, at those same concentrations. We are currently examining the effects of various concentrations of t-RV on target and effector cells in cell-mediated cytotoxicity assays and antibody-dependent cell-mediated cytotoxicity assays. Also, studies on the effect of t-RV in vivo in neuroblastoma tumor-bearing animals are underway. Results from these investigations may shed light on ways of combining t-RV with immunotherapy for thetreatment of cancer.
Phase 1 trial of decitabine and CT antigen-specific vaccine in relapsed pediatric solid tumors.
Authors: Rani George, Deepa Kolaseri Krishnadas, Fanqi Bai, Lisa Diller, Suzanne Shusterman, Janice E. Sullivan, Kenneth G. Lucas
Journal: Journal of Clinical Oncology (2014)

10070 Background: The Cancer/Testis (CT) antigens MAGE-A1, MAGE-A3 and NY-ESO-1 are selectively expressed at varying levels on many pediatric solid tumor cells, including neuroblastoma (NB), and thus have the potential to be targeted for immune therapy by antigen-specific T cells. We have shown that the DNA methylating agent decitabine (DAC) upregulates CT antigen expression in a range of tumor types, leading us to evaluate the feasibility of combining DAC with a CT antigen-targeted dendritic cell (DC) vaccine in patients with relapsed solid tumors. Methods: In this two-institution trial, eligible patients had PBMCs collected by apheresis and transported to the lead center for vaccine preparation. The treatment regimen included 4 cycles of therapy: DAC 10mg/m2/day for 5 days, followed by 2 weekly vaccinations of autologous DC pulsed with overlapping peptide mixes derived from full-length CT antigen sequences. The toll-like receptor agonist imiquimod was used at vaccination sites to facilitate immune response. Peripheral blood was collected weekly and analyzed for CT antigen-specific antibodies and CD137+antigen-specific T cells by flow cytometry. Results: Fifteen patients have been enrolled (median age, 8.5 yrs); 10 with NB, 2 each with Ewing sarcoma and osteosarcoma, and 1 with rhabdomyosarcoma. DC vaccine preparation was successful for all 15 patients. Five patients did not receive vaccine due to disease progression. Of the 10 patients who received therapy, 3 completed all 4 cycles, and two, 3 cycles. Five patients received ≤ 2 cycles only, 4 due to disease progression and one due to a vaccine reaction. The major toxicity was neutropenia requiring growth factor support. Three of 7 NB patients in whom antigen-specific immune response was assessed had an increase in the number of CT antigen-specific CD8+CD137+ and/or CD4+CD137+T cells, while one had an antibody response to all three CT antigens. Conclusions: DAC followed by DC/CT antigen-targeted vaccine is well tolerated and highly feasible in heavily pretreated children with relapsed solid tumors, warranting further investigation in larger trials. Clinical trial information: NCT01241162.
Combining De-Glycosylating Agents with CAR-T Cells for Targeting Solid Tumors and Reducing Toxicity
Authors: Beatrice Greco, Katia Paolella, Barbara Camisa, Valeria Malacarne, Laura Falcone, Andrea Graziani, Chiara Bonini, Attilio Bondanza, Monica Casucci
Journal: Blood (2018)
The London Liver Cancer Score (LLCS): A novel and validated prognostic algorithm in hepatocellular carcinoma.
Authors: David James Pinato, Mitsuru Ishizuka, George Karamanakos, Carlo Smirne, Mario Pirisi, Keiichi Kubota, Rohini Sharma
Journal: Journal of Clinical Oncology (2014)

e15113 Background: The Barcelona Clinic Liver Cancer (BCLC) score is the standard staging system in hepatocellular carcinoma (HCC). However, there is substantial variation in terms of overall survival (OS) within each stage, making prognostication suboptimal. We developed a novel score based on a non-invasive liver functional nomogram and validated it as the London Liver Cancer Score (LLCS). Methods: Patients with radiologically/histologically proven HCC presenting to Hammersmith Hospital (n=112) were considered to produce a derivation dataset. Clinicopathologic variables including demographics, Child-Turcotte Pugh (CTP) class, stage were collected. The LLCS was generated: [age x AST x INR]/platelets. Martingale residuals plot identified an LLCS value of 20 as the optimal cut-off for survival analysis. Each variable was assessed for OS prediction in uni- and multivariate analyses. The LLCS was validated in a large, independent patient cohorts from Italy and Japan (n=766). Results: The 112 patients in the derivation set had median age 66 (20-83), CTP A 69%, intermediate/advanced BCLC 81% and median OS of 6.3 months. On univariate analysis LLCS (p=0.01), CTP (p<0.001), elevated ALP (p=0.005), tumour size >5 cm (p=0.002), intrahepatic spread (p<0.001), alfafetoprotein >400 ng/ml (p<0.001), macrovascular invasion (p=0.01) and metastatic disease (p=0.005) predicted for OS. The LLCS remained a multivariate predictor of OS in both derivation and validation set (p<0.01), and across each BCLC stage (p<0.01). Conclusions: The LLCS is an independent predictor of OS in HCC and further refines the prognostic ability of the BCLC. This could be used to stratify individuals for future studies.
Transdiagnostic dimensions of psychosis in the Bipolar‐Schizophrenia Network on Intermediate Phenotypes (B‐SNIP)
Authors: Ulrich Reininghaus, Jan R. Böhnke, UnYoung Chavez‐Baldini, Robert Gibbons, Elena Ivleva, Brett A. Clementz, Godfrey D. Pearlson, Matcheri S. Keshavan, John A. Sweeney, Carol A. Tamminga
Journal: World Psychiatry (2019)

The validity of the classification of non-affective and affective psychoses as distinct entities has been disputed, but, despite calls for alternative approaches to defining psychosis syndromes, there is a dearth of empirical efforts to identify transdiagnostic phenotypes of psychosis. We aimed to investigate the validity and utility of general and specific symptom dimensions of psychosis cutting across schizophrenia, schizoaffective disorder and bipolar I disorder with psychosis. Multidimensional item-response modeling was conducted on symptom ratings of the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale in the multicentre Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, which included 933 patients with a diagnosis of schizophrenia (N=397), schizoaffective disorder (N=224), or bipolar I disorder with psychosis (N=312). A bifactor model with one general symptom dimension, two distinct dimensions of non-affective and affective psychosis, and five specific symptom dimensions of positive, negative, disorganized, manic and depressive symptoms provided the best model fit. There was further evidence on the utility of symptom dimensions for predicting B-SNIP psychosis biotypes with greater accuracy than categorical DSM diagnoses. General, positive, negative and disorganized symptom dimension scores were higher in African American vs. Caucasian patients. Symptom dimensions accurately classified patients into categorical DSM diagnoses. This study provides evidence on the validity and utility of transdiagnostic symptom dimensions of psychosis that transcend traditional diagnostic boundaries of psychotic disorders. Findings further show promising avenues for research at the interface of dimensional psychopathological phenotypes and basic neurobiological dimensions of psychopathology.
Prevalence of MET and HER2 biomarkers in stage IV gastric cancer.
Authors: Robert D. Loberg, Rui Tang, Kelly Smith Oliner
Journal: Journal of Clinical Oncology (2014)

4048 Background: Estimates of the frequency of genomic alterations in MET and HER2 in gastric cancer vary widely, but alterations in MET are generally less common than alterations in HER2. We examined a large set of stage IV gastric cancer samples for variation in MET and HER2gene copy number. We also assessed HER2 protein expression in these samples. Methods: Formalin-fixed, paraffin-embedded (FFPE) stage IV gastric cancer tumor samples (N = 309) were collected in Russia (n = 195), China (n = 99), and other countries (n = 15). Samples were analyzed by fluorescence in situ hybridization (FISH) for MET gene amplification (Dako MET IQFISH pharmDx) and HER2 gene amplification (Dako HER2 IQFISH pharmDx) and by immunohistochemistry (IHC) for HER2 protein expression (Dako HercepTest). All assays were performed according to the manufacturer’s instructions. This is the first published use of the Dako MET IQFISH pharmDx assay. Cohen's kappa coefficient, a statistical measure that takes into account agreement that occurs by chance, was used to assess agreement between measurements. Results: We found MET gene copy number variation (≥ 5 copies) in 17 of 305 samples (6%), and MET gene amplification (MET/CEN-7 ≥ 2.0) in 12 of 305 samples (4%). The proportion of samples that were MET gene amplified was similar in the Chinese and Russian samples. We found HER2 gene copy number variation (≥ 5 copies) in 54 of 280 samples (19%), and HER2 gene amplification (HER2/CEN-17 ≥ 2.0) in 43 of 280 samples (15%). Of the 201 evaluable HER2 IHC samples, 22 (11%) were positive for HER2 protein expression. HER2 FISH and HER2 IHC results showed that HER2 gene amplification and protein expression commonly occur in the same tumors (kappa = 0.71 to 0.76). HER2 and MET FISH results showed that MET and HER2gene amplification rarely occur in the same tumors (kappa < 0.05); only one sample was amplified for both genes. Conclusions: MET gene amplification was observed in 4% of this large set of stage IV gastric cancer samples. Prevalence of HER2 gene amplification and expression was in the same range as found in previously published studies. Our results indicate that MET gene amplification and HER2 gene amplification may occur in different subpopulations of stage IV gastric cancers.
The Nucleotide Kinase Nadk Is Required for ROS Detoxification and Constitutes a Metabolic Vulnerability of NOTCH1-Driven T-ALL
Authors: Etienne De Braekeleer, Joanne Hsu, Celine Hervieu, Konstantinos Tzelepis, Stefano Indraccolo, Alan J. Warren, Irmela Jeremias, David Fernandez Antoran, Phil H Jones, Margaret A. Goodell, George S. Vassiliou
Journal: Blood (2018)
Overall impact of C-reactive protein for advanced renal cell carcinoma treated with tyrosine kinase inhibitors.
Authors: Tetsuo Fujita, Ken-ichi Tabata, Kazumasa Matsumoto, Daisuke Ishii, Kazunari Yoshida, Masatsugu Iwamura
Journal: Journal of Clinical Oncology (2014)

e15581 Background: Since the introduction of tyrosine kinase inhibitors, such as sorafenib and sunitinib, for the treatment of advanced renal cell carcinoma (RCC), significant objective responses have been revealed. C-reactive protein (CRP) has been recognized as an independent prognostic factor for advanced RCC in the cytokine era. Recently, some literature showed prognostic role of CRP for tyrosine kinase inhibitors. In the present study, we investigate the overall survival impact of CRP in patients with advanced RCC treated with sorafenib or sunitinib. Methods: Between April 2008 and December 2012, 92 consecutive patients with advanced RCC treated with either sorafenib or sunitinib were enrolled in the present study. Patients were divided into two groups according to the pretreatment CRP level of 0.30mg/dL which was provided by the manufacturer as normal values: (i) normal CRP (≤0.30mg/dL) cohort and (ii) elevated CRP (>0.30mg/dL) cohort. Kaplan-Meier overall survival analyses were performed. Effects on survival were assessed with multivariate regression using the Cox proportional hazards model. Results: Thirty-six patients were treated with sorafenib, and 56 patients were treated with sunitinib. In the sorafenib treatment group, the normal CRP cohort comprised 14 patients (38.9%) and the elevated CRP cohort comprised 22 patients (61.1%). The normal CRP cohort showed significantly longer overall survival than the elevated CRP cohort (median 42.0 vs 13.0 months, P = 0.0022). In the sunitinib treatment group, the normal CRP cohort comprised 17 patients (30.4%) and the elevated CRP cohort comprised 39 patients (69.6%). The normal CRP cohort showed significantly longer overall survival than the elevated CRP cohort (median 32.0 vs 12.0 months, P = 0.0036). On multivariate analysis, normal CRP was a predictor of overall survival in the sorafenib treatment group (P = 0.0107). Conclusions: Pretreatment normal CRP affected significantly longer overall survival in patients with advanced RCC treated with sorafenib or sunitinib. It could be a useful biomarker for survival to tyrosine kinase inhibitors.