tbuckley/cabot-search huggingface dataset:
Platelet count at baseline (Plt) and outcomes in patients (pts) with advanced hepatocellular carcinoma (HCC) treated with sorafenib (S) in CALGB80802 (Alliance) (C8).
Authors: Ghassan K. Abou-Alfa, Qian Shi, Jennifer J. Knox, Andreas Kaubisch, James Posey, Benjamin R. Tan, Petr Kavan, Rakesh Goel, Philip Edward Lammers, Tanios S. Bekaii-Saab, Vincent C. Tam, Lakshmi Rajdev, Robin Kate Kelley, Abby B. Siegel, Tyler Zemla, Imane H. El Dika, Alan P. Venook, Monica M. Bertagnolli, Jeffrey A. Meyerhardt, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2018)

e16107 Background: CALGB 80802 study determined that doxorubicin plus sorafenib did not improve survival (OS) compared to sorafenib. The association between platelet count and outcome of patients with HCC is inconsistent and controversial. A retrospective exploratory analysis evaluated the demographics, OS, time to progression (TTP), and progression free survival (PFS) by platelet count in HCC pts treated with sorafenib. Considering the negative outcome of CALGB 80802, the focus herein is on the standard of care sorafenib arm. Methods: The prognostic value of baseline platelet count was evaluated by Cox regression models, adjusting for clinical and pathological factors. Based on an average normal platelet cutoff level, patients were stratified on platelet count <150 and ≥150 × 109/L. Adjusted hazard ratios (HRadj) and 95% confidence intervals (CI) were reported. Results: 61 patients had platelet count <150 × 109/L and 109 had platelet count ≥150 × 109/L. Low platelet count <150 × 109/L was associated with male gender; low T stage, WBC count, ANC, and granulocyte count; high hemoglobin and bilirubin. High platelet count ≥150 × 109/L had shorter PFS and OS that did not reach statistical significance, and was significantly associated with shorter TTP (P=0.04), (Table). Conclusions: For sorafenib, TTP was significantly shorter among pts with platelet count ≥ 150 × 109/L. Platelet count < 150 × 109/L is suggestive of improved OS and PFS compared to pts with platelet count ≥ 150 × 109/L. Platelet count may be a prognostic factor of for patients with advanced HCC and warrants further study. Support: U10CA180821, U10CA180882; U10CA077202, U10CA180820, U10CA180888; Clinical trial information: NCT01015833.Platelet× 109/L Events (number) Median (months) HRadj (95% CI) P OS ≥ 150 93 7.6 1.26 (0.86-1.84) 0.25 < 150 51 13.4 Ref TTP ≥ 150 79 3.6 1.56 ( 2.00-2.41) 0.04 < 150 39 5.8 Ref PFS ≥ 150 100 3.4 1.39 (0.95-2.04) 0.08 < 150 54 5.0 Ref
RNA-Seq data analysis to identify enriched metabolic pathways and a prognostic signature in squamous cell lung cancer.
Authors: Jhajaira M Araujo, Claudio J. Flores, I. Tirado-Hurtado, Christian Diego Rolfo, Luis E. Raez, Alexandra Prado, Cesar H. Saravia, Joseph A. Pinto
Journal: Journal of Clinical Oncology (2018)

e24288 Background: Abnormal changes in the metabolism are cancer hallmarks and can be used as therapeutic targets. Our study aim was to identify enriched metabolic pathways in patients (pts) with squamous cell lung cancer (SQLC). Methods: We evaluated RNA-Seq data (RPKM) of Normal lung tissues and SQLC from GTEx (n = 320) and TCGA (n = 215), respectively. Genes in KEGG metabolism pathways were manually curated. Highly stable genes in the GTEx data was used to normalization. Overall, 2819 genes were evaluated in a Gene Set Enrichment Analysis (GSEA). The TCGA data was randomly divided in training (n = 150) and validation (n = 65) sets. The prognostic value for overall survival (OS) of the top 100 enriched genes (50 for each controls and pts) were assessed in the training group and a prognostic signature was developed then tested in the validation group and in two additional datasets profiled with microarrays (GSE30219 and GSE37745). Results: Eleven metabolic processes were enriched (FDR < 25%, p < 0.05): Pyrimidine metabolism, oxidative phosphorylation, purine metabolism, drug metabolism other enzymes, glutathione metabolism, steroid hormone biosynthesis, fructose and mannose metabolism, starch and sucrose metabolism, alanine aspartate and glutamate metabolism, aminoacylt RNA biosynthesis and ascorbate and aldarate metabolism. In the multivariate analysis of 25 genes related with the OS, four had independent prognostic value. Using the regression coefficients, the prognostic signature was: 0.14384*CPS1 - 0.77747*POLR3GL + 0.63354*TGFB1 - 0.30959*WARS). A cutoff value of -0.82 was able to distinguished pts at different risk in the discovery set (2.72; CI95%: 1.72-4.28; P < 0.001), in the validation set (HR = 15.86; CI95%:1.06-237.11; P = 0.045) and it was able to discriminate pts with different outcome in the microarrays sets when pts where stratified by the median of the prognostic score (GSE30219: HR = 1.55; CI95%: 0.84-2.86; p = 0.158; Breslow-test p-value = 0.047 and GSE37745: HR = 2.60; CI95%:1.46-4.63; p = 0.0001). Conclusions: The gene expression profile in metabolic processes was associated with the outcome of SQLC pts. These enriched pathways can become important and attractive therapeutic targets.
Long-term outcomes of accelerated BEP (bleomycin, etoposide, cisplatin) for advanced germ cell tumors: updated analysis of an Australian multicenter phase II trial.
Authors: Peter S. Grimison, Martin R. Stockler, Andrew James Martin, Luke Buizen, Nicola Jane Lawrence, Damien B. Thomson, Val Gebski, Michael Friedlander, Annie Yeung, Howard Gurney, Mark Rosenthal, Nimit Singhal, Ganessan Kichenadasse, Shirley S. Wong, Craig R. Lewis, Paul Austin Vasey, Guy C. Toner
Journal: Journal of Clinical Oncology (2016)

e16056 Background: We performed a single arm, multi-center, phase II trial of accelerated (dose-dense) BEP as first-line chemotherapy for advanced germ-cell tumours. Accelerated BEP was found to be feasible and tolerable, with promising efficacy (Grimison et al, Ann Onc 2014). Here we report on outcomes given long-term follow-up. Methods: Patients with extra-cranial advanced germ cell tumours of any risk group and radiologically measurable disease received cisplatin 20mg/m2 and etoposide 100mg/m2 on days 1-5, and pegylated G-CSF 6mg on day 6, all repeated every 2 weeks for 4 cycles (3 cycles for good risk). Bleomycin was given at 30kIU weekly to a total 12 doses (9 doses for good risk). Primary endpoint was regimen feasibility (previously reported). Results: 43 eligible patents were enrolled between February 2008 and November 2010 from 14 Australian sites. 12 had poor-risk disease, 16 intermediate-risk, and 15 good-risk. With a data cut-off of 1NOV15, median follow-up was 6.2 years (interquartile range: 5.7-6.5) for survival and 6.2 years (interquartile range: 5.7-6.4) for relapse. 8 patients have relapsed. 2 relapses occurred within 3 months of enrolment (refractory disease), 6 relapses occurred between 3-15 months (early relapse), no late relapses occurred. 3 patients have died (all following relapse; 1 died due to an unrelated malignancy). 5-year progression-free survival was 50% (95% CI: 21%-74%) for poor-prognosis, 94% (95% CI: 65%-99%) for intermediate-prognosis and 93% (95% CI: 61%-99%) for good-prognosis patients. 5-year overall survival was 92% (95% CI: 54%-99%) for poor-prognosis, 94% (95% CI: 63%-99%) for intermediate-prognosis and 100% (95% CI: NA) for good-prognosis patients. Conclusions: The long-term efficacy data of accelerated BEP remains promising. This trial and a similar UK study provide the rationale for a currently recruiting Australian-led international randomised trial comparing accelerated versus standard BEP. Clinical trial information: 12607000294459.
Temporal treatments and outcomes following acute myocardial infarction among cancer survivors: A population-based study, 1995-2013.
Authors: Inna Y. Gong, Andrew T Yan, Dennis T Ko, Winson Y. Cheung, Craig Earle, Stuart Peacock, Chris Gale, Marlous Hall, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2017)

10058 Background: There is little contemporary information regarding cardiac care and mortality differences following an acute myocardial infarction (AMI) between cancer survivors (CS) and non-cancer patients (NCP). Methods: All patients with AMI (1995-2013) in Ontario, Canada were identified through administrative databases and stratified into CS (solid or hematologic) and NCP. Those with cancer within 1 year of AMI were excluded. We used inverse probability treatment weight of propensity scores to balance confounders. Coronary intervention use and survival following index AMI were compared between CS and NCP using Modified Poisson and Cox modeling, and their temporal trends were examined. Results: Of 270,089 AMI patients (62.1% men; 87.8% &gt;65 yrs old for CS vs. 56.2% for NCP), 22,907 were CS (prostate 26%, colorectal 17%, breast 16%) and 247,182 NCP. From 1995-2013, coronary interventions usage increased similarly for both groups (Table). The overall 30-day use did not differ between CS and NCP (angiogram unadjusted 36% vs. 50%, adjusted RR 0.96, 95% CI 0.96-1.00, p=.21; percutaneous coronary interventions unadjusted 21% vs. 31%, adjusted RR 0.98, 95% CI 0.94-1.01, p=.21; bypass surgery unadjusted 5% vs. 7%, adjusted RR 0.95, 95% CI 0.87-1.04, p=.25). Unadjusted 30-day mortality following AMI decreased similarly for CS and NCP (Table). However, adjusted 30-day mortality was worse in CS (HR 1.09, 95% CI 1.04-1.15, p&lt;0.001). Over median follow-up of 11 yrs, CS had worse survival than NCP (HR 1.22, 95% CI 1.18-1.26, p&lt;0.0001). CS had higher risk of heart failure than NCP (HR 1.10, 95% CI 1.05-1.15, p&lt;0.0001), while myocardial (re)-infarction and stroke were similar (HR 0.99, 95% CI 0.96-1.02, p=.46; HR 1.09, 95% CI 1.00-1.18, p=.052). Conclusions: Following AMI, coronary intervention use increased and early mortality decreased comparably between CS and NCP over time. However, CS had worse short-term and long-term survival, suggesting that continued emphasis on cancer and cardiovascular care is needed to improve outcomes. [Table: see text]
Converting a tumor from checkpoint blockade-resistant to checkpoint blockade-sensitive: Immunotransplant for aggressive lymphoma.
Authors: Netonia Marshall, Linda Hammerich, Ranjan Upadhyay, Thomas Urban Marron, Joshua Brody
Journal: Journal of Clinical Oncology (2016)

e14538 Background: Lymphomas comprise the 5thmost common cancers in the U.S. and the majority of these are incurable with standard chemo-immunotherapy, thus, novel, mechanistically distinct therapies are needed, such as immunotherapy. Two promising classes of immunotherapy are: checkpoint blockade (e.g. anti-PD1 and anti-CTLA-4 antibody) and adoptive T-cell transfer lymphocytes into lymphodepleted recipients (e.g. CARs and TILs). Methods: In a PDL1(+), CD80/86(+) murine lymphoma model, we have developed a novel therapy combining these approaches into 'checkpoint-blockade-primed immunotransplant' comprised of: -treatment of tumor-bearing animals (donors) with anti-PD-1 and anti-CTLA-4 antibodies -splenocyte and bone marrow harvest and transfer to lymphodepleted/myeloablated (9Gy TBI) recipient Results: The combined therapy immunotransplant maneuver results in superior anti-tumor immunity compared to either checkpoint blockade or syngeneic transplant individually. Transferred T cells significantly increase surface and intra-cellular PD1 and CTLA-4, respectively, in both CD4 and CD8 T cells. Treatment of both tumor-bearing donor and recipient with anti-PD1 and anti-CTLA-4 antibodies induces cure of the majority of recipients, in a CD8 and IFNγ-dependent manner, despite the finding that antibody therapy alone (without transplantation and T cell transfer) induces minimal anti-tumor effect. Herein, we have demonstrated that T cells exposed to checkpoint blockade and transfer into the lymphopenic host demonstrate greater: -response to common γ-chain cytokines (per in vitro STAT5 phosphorylation) -in vitro production of IFNγ and TNF production in response to exposure to cognate tumor antigen -in vivo proliferation after exposure to tumor antigen Conclusions: Overall the data suggest both that: lymphopenia-exposed T cells become activated by checkpoint blockade and checkpoint blockade-exposed T cells become more activated by common γ-chain cytokines associated with lymphopenia. These data guide the development of combination therapies such as immunotransplant which we demonstrate is uniquely capable of curing the majority of established tumors.
The severity of psychiatric disorders
Authors: Mark Zimmerman, Theresa A. Morgan, Kasey Stanton
Journal: World Psychiatry (2018)

The issue of the severity of psychiatric disorders has great clinical importance. For example, severity influences decisions about level of care, and affects decisions to seek government assistance due to psychiatric disability. Controversy exists as to the efficacy of antidepressants across the spectrum of depression severity, and whether patients with severe depression should be preferentially treated with medication rather than psychotherapy. Measures of severity are used to evaluate outcome in treatment studies and may be used as meaningful endpoints in clinical practice. But, what does it mean to say that someone has a severe illness? Does severity refer to the number of symptoms a patient is experiencing? To the intensity of the symptoms? To symptom frequency or persistence? To the impact of symptoms on functioning or on quality of life? To the likelihood of the illness resulting in permanent disability or death? Putting aside the issue of how severity should be operationalized, another consideration is whether severity should be conceptualized similarly for all illnesses or be disorder specific. In this paper, we examine how severity is characterized in research and contemporary psychiatric diagnostic systems, with a special focus on depression and personality disorders. Our review shows that the DSM‐5 has defined the severity of various disorders in different ways, and that researchers have adopted a myriad of ways of defining severity for both depression and personality disorders, although the severity of the former was predominantly defined according to scores on symptom rating scales, whereas the severity of the latter was often linked with impairments in functioning. Because the functional impact of symptom‐defined disorders depends on factors extrinsic to those disorders, such as self‐efficacy, resilience, coping ability, social support, cultural and social expectations, as well as the responsibilities related to one's primary role function and the availability of others to assume those responsibilities, we argue that the severity of such disorders should be defined independently from functional impairment.
Breath mass ion biomarkers of breast cancer.
Authors: Michael Phillips, Renee N Cataneo, Cassie Lebauer, Mayur Mundada, Christobel Saunders
Journal: Journal of Clinical Oncology (2016)

e23076 Background: Breath contains volatile organic compounds (VOCs) that are biomarkers of breast cancer. Breath VOCs may be detected with gas chromatography mass spectrometry (GC MS), but computer-based spectral libraries frequently misidentify their chemical structures. However, breath mass ions provide intrinsically more robust biomarkers (e.g. in lung cancer) because they do not require spectral matching in a library. We investigated whether breath mass ion biomarkers could identify breast cancer. Methods: We re-analyzed data from a previous study of breath VOCs in 54 women with biopsy-proven breast cancer and in 204 healthy controls (stacks.iop.org/JBR/4/026003). Subjects were randomly assigned to a training set (2/3) and a test set (1/3). Chromatograms were processed with metabolomic analysis software (XCMS in R) in order to generate a table listing retention times with their associated ion masses and intensities, and binned into a series of 5 sec retention time segments. In the training set, mass ions in each time segment were ranked according to their diagnostic accuracy i.e. the area under curve (AUC) of the receiver operating characteristic (ROC) curve. We employed multiple Monte Carlo simulations to select the biomarker mass ions in each time segment that identified breast cancer with greater than random accuracy and combined those with the highest diagnostic accuracy in a predictive algorithm using multivariate weighted digital analysis (WDA). We then employed this algorithm to predict the diagnosis in the test set. Results: The training set WDA algorithm employing 21 mass ion biomarkers identified breast cancer with ROC curve AUC = 0.77. In the test set, this algorithm predicted breast cancer with ROC curve AUC = 0.79. Conclusions: Breath mass ions biomarkers accurately identified women with breast cancer.
Early clearance of plasma EGFR mutations as a predictor of response to osimertinib in the AURA3 trial.
Authors: Frances A. Shepherd, Vassiliki Papadimitrakopoulou, Tony Mok, Yi-Long Wu, Ji-Youn Han, Myung-Ju Ahn, Suresh S. Ramalingam, Tom John, Martin Sebastian, Willemijn Theelen, Gianluca Laus, Barbara Collins, Aleksandra Markovets, Kenneth S. Thress, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2018)

9027 Background: In the Phase III AURA3 trial (NCT02151981), osimertinib, a third-generation EGFR-TKI, had significantly greater efficacy than platinum-pemetrexed in patients (pts) with advanced NSCLC and T790M-mediated acquired resistance to first-line EGFR-TKI. We investigate whether the presence of plasma EGFR mutations at 3 and 6 wks post-osimertinib treatment (80 mg, once daily) is associated with clinical outcomes, and identify pre-existing genomic aberrations that may impact outcomes. Methods: EGFR mutation analysis (Ex19del/L858R/T790M) was conducted at baseline, wks 3 and 6, by droplet digital (dd)PCR (Biodesix). Next generation sequencing (NGS, Guardant Health; 73 genes) was conducted on baseline plasma samples to explore mechanisms of innate resistance. Clinical outcomes (median progression-free survival [mPFS], objective response rate [ORR]) were investigator assessed, per RECIST 1.1. Results: Of 207 pts with a valid plasma ddPCR result at baseline (all T790M+), 150 had detectable EGFR-TKI sensitizing mutations (EGFRm; Ex19del/L858R) and 57 did not. mPFS was 14.0 mo (95% CI 12.4, not calculable) in pts without detectable baseline EGFRm vs 8.3 mo (95% CI 6.9, 10.9) in pts with detectable baseline EGFRm; EGFRm allelic fraction in baseline plasma was not related to ORR or mPFS. Of the 129 pts with baseline EGFRm and evaluable plasma samples at wk 3, 48 had detectable EGFRm (EGFRm+) and 81 had undetectable EGFRm (EGFRm-). mPFS was 5.7 mo (95% CI 4.1, 9.7) in pts EGFRm+ vs 10.9 mo (95% CI 8.3, 12.7) in pts EGFRm-; hazard ratio (HR) 2.0 (95% CI 1.3, 3.2), p = 0.001; HR > 1 favors pts EGFRm-. ORR was 50% vs 82%, respectively. A similar trend was observed at wk 6 (n = 132): PFS, HR 2.8 (95% CI 1.8, 4.3), p < 0.0001. NGS of baseline plasma showed no association between pre-existing genomic aberrations (TP53, BRAF, KRAS, MET/HER2 amp) and clinical outcome; additional analyses are ongoing. Conclusions: In pts with tissue T790M+ NSCLC and detectable baseline plasma EGFRm, continued presence of EGFRm at wks 3 and 6 was associated with less favorable outcomes with osimertinib. Early dynamic changes of plasma EGFR mutations may predict clinical outcome in pts receiving osimertinib for T790M+ NSCLC. Clinical trial information: NCT02151981.
Detection of endoglin-expressing CTCs in patients enrolled in an adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (TAPPAS).
Authors: Vinod Ravi, Andrew Scott Brohl, Sant P. Chawla, Steven Attia, Richard F. Riedel, David A. Liebner, Katherine Anne Thornton, Atrayee Basu Mallick, Darren W. Davis, Mario Cervantes, Wen Liu, Keyi Zhu, Delia Alvarez, Charles P. Theuer, Steven Ian Robinson, Nicolas Penel, Silvia Stacchiotti, William D. Tap, Robin Lewis Jones, Robert G. Maki
Journal: Journal of Clinical Oncology (2018)

e23570 Background: Endoglin (CD105) is an essential angiogenic receptor expressed on Angiosarcoma (AS) tumor cells and vessels that is upregulated following hypoxia and promotes resistance to VEGF inhibition. TRC105, an endoglin antibody, combined with pazopanib (P) achieved durable complete responses in AS patients, with encouraging median PFS of 7.8 months in chemotherapy-refractory and P-naïve patients enrolled in a Phase 1/2 trial. Here we report the capture of endoglin expressing circulating tumor cells (CTCs) using ApoStream dielectrophoresis field flow assist from the whole blood of AS patients enrolled in the ongoing Phase 3 TAPPAS trial. Methods: AS CTCs were enriched by ApoStream from samples drawn prior to treatment, with either TRC105/P or single agent P, at C1D1 and 6 weeks following initiation of study treatment at C3D1. CTCs that expressed CD105 and DAPI (nucleus) by immunofluorescence that used a non-competing endoglin antibody were quantified. CD105+/DAPI+ CTCs were further characterized as atypical cells using Diff-Kwik staining. Results: Forty (40) blood samples (25 at C1D1, 15 at C3D1) from 28 patients were analyzed. Paired pre- and post-treatment samples were available for 13 patients. Endoglin+ CTCs were detected in 100% (40/40) of samples (median = 1.5/mL; range 0.13 - 1,172/ml). Endoglin+ CTCs decreased between C1D1 and C3D1 in 13 patients with paired samples treated with TRC105/P or single agent P (C1D1 mean = 184.3/ml; median = 1.5/ml; range 0.13 - 1172/ml); C3D1 mean = 6.39/ml; median = 0.88/ml; range 0.44 - 26/ml). Diff-Kwik staining confirmed the enriched CTCs had atypical morphology containing hemosiderin deposits and large irregularly shaped nuclei in all cases. Conclusions: ApoStream technology isolated endoglin+ CTCs from the whole blood of AS patients. Decreases in endoglin+ CTCs were observed following treatment with TRC105/P and/or single agent P. Clinical trial information: NCT02979899.