tbuckley/cabot-search huggingface dataset:
Correlation between mutation burden of tumor and immunological/clinical parameters in considering biomarkers of immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).
Authors: Yuki Owada, Satoshi Muto, Hironori Takagi, Takuya Inoue, Yuzuru Watanabe, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Ohsugi, Daisuke Tanaka, Emi Ito, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Hiroyuki Suzuki
Journal: Journal of Clinical Oncology (2017)

e23184 Background: There has been reported that mutation burden of solid tumor might probably be a predictive biomarker of efficacy of immune check point inhibitors, and the number of researches are still ongoing. Although the correlation of mutation burden between by whole exome sequence and by large targeted panel sequence has also been reported, neither method can be said to have solved technical and economical difficulty of using in clinical practice. Here we describe more convenient factors that can be used instead of mutation burden. Methods: 92 NSCLC patients with surgery during 2013-2015 in our institution were subjected for this study. Mutation burden in tumor samples was analyzed by whole exome sequence using Next Generation Sequencer. The major gene alteration was also analyzed by small targeted panel sequence. As immunological parameters, tumor infiltrating lymphocyte and PD-L1 expression in tumor were assessed by immunohistochemistry test using anti-CD8 antibody and anti-PD-L1 antibody. Statistical analysis was performed on mutation burden and the result of major gene alternation, immunohistochemistry, and clinical parameters. Results: There were 64 adenocarcinomas and 28 squamous cell carcinomas. The median value of mutation burden was 60 genes (10-502). The factors including squamous cell carcinoma, male, smoking history, EGFR-mutation negative, and TP53 alteration positive indicated close connection with higher mutation burden (p &lt; 0.001) There were no significant difference in PD-L1 expression of tumor and tumor infiltrating lymphocyte. Multiple regression analysis showed that negative EGFR-mutation and positive TP53 alteration contribute to higher mutation burden (p &lt; 0.05). Conclusions: Mutation burden in NSCLC tumor could be associated with EGFR-mutation and TP53 alteration status. These findings suggest that some major gene alteration make it possible to predict mutation burden, and could potentially be more simple predictive biomarkers of immune check point inhibitors.
Autotaxin: A possible new biological marker of endometrial cancer
Authors: R. de Nola, E. di Naro, L.M. Schonauer, M. Loverro, T. Marrano, A. Mazzocca
Journal: Annals of Oncology (2018)

Background: Endometrial cancer is the most common neoplasm of the female genital tract in Western Countries, with an incidence of 150000 new cases/year. Despite its high frequency, limited data are available about its molecular features. It is known that phospholipids play a key role in the cellular proliferation and dissemination in many human diseases. Some previous studies have demonstrated the importance of the lysophosphosphatidic acids' (LPAs) metabolism and their signalling pathways in human endometrial cells. LPAs are produced via phospholipase A2 (PLA2) and phospholipase D (PLD), also known as autotaxin (ATX). Methods: In the present work, we performed a prospective study involving 60 patients divided into three groups after a hysteroscopic guided biopsy: the first included 26 patients with a histological diagnosis of endometrial cancer; the second was made of 5 patients affected by histologically evidenced endometrial hyperplasia without atypia; the third was composed of 29 patients characterized by benign condition. All the groups underwent hysterectomy, with either open or laparoscopic surgery, and a second endometrial biopsy on the surgical specimen, in order to perform a quantitative real-time PCR using pre-designed ATX/PLD primers. Significant differences between groups were determined via unpaired two-way or one-way Student's t test and ANOVA. A P-value <0.05 was considered statistically significant. Results: From our data, we demonstrated a strong positive correlation between the gene expression of ATX in the surgical specimen and the endometrial cancers. Notably, we found other statistically significant results from the analysis of the population affected by endometrial cancer. In particular, the expression of autotaxin gene was higher in the endometrioid histotype, in case of type I endometrial cancer versus type II, in pre-menopausal women, in obese patients (BMI> 30) or in women with diabetes. Conclusions: We could consider a possible role of ATX as a biomarker of endometrial cancer, mostly in endometrioid histotypes, reflecting the pathogenic conditions of type I endometrial cancer. Legal entity responsible for the study: University of Bari, Italy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
A novel prostate cancer immunotherapy using prostate specific antigen peptides and Candida skin test reagent as an immunostimulant.
Authors: Mayumi Nakagawa, Al-Ola Abdallah, Hannah Coleman, Rodney Davis, Teri Landrum, Fade A. Mahmoud, Natasa Milojkovic, Mohamed Kamel, Chester Wicker, Konstantinos Arnaoutakis
Journal: Journal of Clinical Oncology (2016)

e14582 Background: Prostate cancer is the most common cancer and the second leading cause of cancer-related death among the male population in Western countries.Our group has shown that Candida skin test reagent can induce T-cell proliferation and interleukin-12 secretion by Langerhans cells in vitro. It has also been tested as a vaccine adjuvant for an investigational human papillomavirus therapeutic vaccine, and an increase in circulating T-helper type 1 (Th1) cells has been demonstrated in vaccine recipients. In the current work, the feasibility of using prostate specific antigen (PSA) peptides and Candida as a novel prostate cancer immunotherapy was evaluated. Methods: Regions of PSA protein likely to dissolve in a single acidic solution were selected, and 85% of PSA amino acid sequences were synthesized in 6 peptides (amino acids 1-40, 41-80, 81-120, 161-200, 201-240, and 241-261). Solubility of these peptides in solutions compatible for human use, maturation effects of these peptides on Langerhans cells by fluorescent activated cell sorter analysis, and recognition of these peptides by peripheral immune cells from prostate cancer patients using interferon-gamma enzyme-linked immunospot (ELISPOT) assay were evaluated. Results: The peptides were soluble in 10 mM succinate (pH5) with 5% glycine, and they demonstrated no maturation effects on Langerhans cells as determined by expression of CD40, CD80, CD86 and HLA-DR on the surface of monocyte-derived Langerhans cells from healthy donors. On the other hand, peripheral immune cells from 4 of 10 prostate cancer patients examined had positive responses in ELISPOT assay to one or more PSA peptide pools. Conclusions: It would be feasible to use these PSA peptides and Candida as a novel prostate cancer immunotherapy, and a proportion of prostate cancer patients seem to have immune cells with the ability to recognize these PSA peptides already. Therefore, this immunotherapy may enhance immune responses to PSA potentially leading to tumor regression.
BBI608-503-103HCC: A phase Ib/II clinical study of napabucasin (BBI608) in combination with sorafenib or amcasertib (BBI503) in combination with sorafenib (Sor) in adult patients with hepatocellular carcinoma (HCC).
Authors: Bassel F. El-Rayes, Donald A. Richards, Allen Lee Cohn, Stephen Lane Richey, Trevor Feinstein, Madappa N. Kundranda, Anthony B. El-Khoueiry, Jason M. Melear, Fadi S. Braiteh, Matthew Hitron, Waldo Feliu Ortuzar, Waheed Khan, Bo Xu, Wei Li, Youzhi Li, C J Li
Journal: Journal of Clinical Oncology (2017)

4077 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Amcasertib targets multiple serine threonine stemness kinases and inhibits Nanog and other cancer stemness pathways. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with sorafenib. Methods: A phase Ib/II open-label, multi-center study in adult patients with advanced HCC who have not received prior systemic chemotherapy was performed to determine the safety, tolerability, and recommended Phase II dose (RP2D) ,according to the criteria for DLT and for dose-escalation of Napabucasin (Arm 1), administered at 160 mg BID (dose level I) and at 240 mg BID (dose level II) in combination with sorafenib and of Amcasertib (Arm 2), administered at 100 mg QD (dose level I) and at 200 mg QD (dose level II) in combination with sorafenib. Results: 20 pts were enrolled, 10 in Arm 1 and 10 in Arm 2. 12 patients were evaluable for DLT determination; 2 pts d/c prior to starting protocol treatment; 11 pts received evaluation by RECIST, 6 pts in Arm 1 and 5 pts in Arm 2. The safety profile was consistent with that of each agent as monotherapy and most common AEs were attributed to (Sor) and included rash, PPE, grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. No signs of drug-drug interactions were observed in pharmacokinetics. Among all patients who received RECIST evaluation, Disease Control Rate (DCR=CR+PR+SD) for Arm 1 was 100% (6/6pts) and 100% (5/5pts) for Arm 2. DCR in ITT Arm 1 population was 67% and 50% in Arm 2. Median OS is not yet reached. Conclusions: In this phase Ib study, RP2D were determined for napabucasin and amcasertib to be safely combined with sorafenib at full dose, showing encouraging anti-tumor activity in patients with HCC who have not received prior systemic chemotherapy. A randomized phase II is schedule to start. Clinical trial information: NCD02279719. [Table: see text]
Clinical significance of CD8 and programmed death-ligand 1 (PD-L1) expression in patients with resectable non-small cell lung cancer.
Authors: Hye Ree Kim, Haa-Na Song
Journal: Journal of Clinical Oncology (2018)

e24251 Background: The aim of this study was to investigate and elucidate the clinical significance of the expressions of CD8 and programmed death-ligand 1 (PD-L1) in patients with resectable non-small cell lung cancer (NSCLC). Methods: Surgical tissue specimens were obtained from 136 patients with NSCLC who underwent surgical resection. The expression levels of CD8 and PD-L1 were assessed using tissue microarrays and immunohistochemistry. Results: Positive expression of CD8 and PD-L1 was present in 87 (64.0%) and 35 (25.7%) patients, respectively. The CD8-positive group showed significant increases in overall survival (OS) (median, 56.313 vs. 41.279 months; p = 0.012) and relapse-free survival (RFS) (median, 51.216 vs. 34.415 months; p = 0.005), compared with the CD8-negative group. In contrast to CD8, the PD-L1-negative group demonstrated significant increases in OS (median, 54.079 vs. 41.643 months; p = 0.044) and RFS (median, 48.526 vs. 35.398 months; p = 0.04), compared with the PD-L1-positive group. Two prognostic groups were stratified according to CD8 and PD-L1 expression; group 1 (CD8-positive/PD-L1-negative) versus group 2 (CD8/PD-L1 – positive/positive, negative/positive, negative/negative). Group 1 had better OS (median, not reached [NR] vs. 27.893 months; p < 0.001) and RFS (median, NR vs. 14.916 months, p < 0.001) than group 2. Multivariate analysis indicated that group 1 characteristics constituted an independent favorable prognostic factor for OS (hazard ratio [HR], 2.097, p = 0.01) and RFS (HR, 2.415; p < 0.001). Conclusions: Positive CD8 and negative PD-L1 expression might be useful favorable markers for OS and RFS in resectable NSCLC.
Abstract 13838: Smooth Muscle Cells Are the Origin of the Majority of Foam Cells in Atherosclerotic Lesions of Apolipoprotein E-deficient Mice
Authors: Ying Wang, Sima Allahverdian, Joshua A Dubland, Enyinnaya Asonye, Michael A Seidman, Gordon A Francis
Journal: Circulation (2016)

Background: Apolipoprotein E-deficient (ApoE -/- ) mice are the most frequently used model of human atherosclerosis. Foam cells in mouse lesions have been believed to be primarily macrophage-derived using traditional staining with macrophage markers. Recent studies indicated that smooth muscle cells (SMCs) comprise at least 50% of foam cells in human coronary atherosclerosis, and express reduced levels of ATP-binding cassette transporter A1 (ABCA1) when compared to intimal leucocytes. Identification of SMC-derived foam cells is challenging due to the absence of classic SMC markers and expression of macrophage markers by a high percentage of intimal SMCs in mouse and human lesions. Hypothesis: Unlike human atherosclerosis, foam cells in ApoE -/- mice are primarily macrophage- rather than SMC-derived. Methods: 8-week-old male and female ApoE -/- mice were fed a Western diet for 6 weeks to promote lesion development. Flow cytometry was used to estimate the proportion of leukocyte- and SMC-derived foam cells in cell suspensions from digested ascending aortas. Foam cells were identified by the neutral lipid dye BODIPY, and leukocyte-derived were distinguished from SMC-derived foam cells by expression of CD45 (a pan-leukocyte marker), and I-A/I-E (antigen presenting cell markers), which have not been reported to be expressed by SMCs. SMC origin was confirmed using a SMC-specific epigenetic lineage marker. ABCA1 level was also measured in the two foam cell populations. Results: 69.47±3.20 % (male) and 73.33±2.35 % (female) (mean ± SEM, n=9 each) of foam cells in ApoE -/- mouse lesions were CD45 and I-A/I-E negative, and were confirmed by SMC lineage marker to be predominantly SMC-derived. SMC-derived foam cells were thus significantly greater than leukocyte-derived foam cells in ApoE -/- mice ( P &lt;0.01), and exhibited three times lower ABCA1 protein than leukocyte-derived foam cells in both sexes. Conclusions: Contrary to our hypothesis, SMCs contribute the majority of foam cells in ApoE -/- mouse atherosclerosis. Impaired ABCA1 expression in SMC foam cells, as seen in human intimal SMC foam cells, suggests a likely mechanism for preferential SMC foam cell development in both species, and a potential target for atherosclerosis treatment and prevention.
Impact of precision medicine in refractory malignancies: A meta-analysis of 13,203 patients in phase I clinical trials.
Authors: Maria Clemence Schwaederle, Melissa M. Zhao, J. Jack Lee, Vladimir Lazar, Brian Leyland-Jones, Richard L. Schilsky, John Mendelsohn, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

11520 Background: Our goal was to compare patient outcomes between phase I studies of single agents that employed a personalized approach (defined as a biomarker-based selection strategy) versus those that did not. Methods: This analysis included 346 published phase I trials (351 arms) (January 1, 2011 to December 31, 2013; PubMed search). Meta-analysis and weighted pooled analysis were performed. Response rate (RR) (N = 351 arms; 13,203 patients), progression-free survival (PFS) (N = 45 arms; 1,700 patients), and toxic death rate (N = 351 arms, 13,203 patients) were compared for treatment arms that used a personalized strategy versus those that did not. Survival could not be analyzed (data provided in only 27 of 346 studies (N = 4 were personalized studies)). Results: Multivariable analysis (meta-regression and weighted multiple regression models) demonstrated that the personalized approach independently correlated with improved RR (30.6% vs 4.9%, P<0.0001) as well as prolonged median PFS (5.7 vs 2.95 months, P=0.0002). While most of the personalized arms (98.3%) used targeted agents, the majority of the arms employing targeted agents used a non-personalized approach, i.e., did not select patients using a cognate biomarker (76%). A sub-analysis within targeted arms (N = 234 arms) showed that those using a biomarker-based strategy had statistically improved RR compared to targeted arms that lacked a biomarker-based approach (31.1% vs 5.1%, P<0.0001). In addition, non-personalized targeted arms had comparable outcomes with arms that tested a cytotoxic agent: median RR 5.1% vs 4.7%, P = 0.63; respectively; median PFS 3.3 vs 2.5 months, P = 0.22. Personalized arms using a “genomic (DNA) biomarker” had higher RR than those using a “protein biomarker” (42% vs 22.4%, P = 0.001). Finally, the median treatment-related mortality was not statistically different for arms that employed a personalized strategy versus not (1.89% vs 2.27%, P=0.31). Conclusions: Analysis of phase I studies revealed that a personalized strategy was an independent predictor of improved outcomes (RR and PFS). In addition, studies that used targeted agents without a biomarker-based selection strategy had negligible response rates.
P04.08 GLIOTRAIN: Exploiting Glioblastoma intractability to address European research training needs in translational brain tumour research, cancer systems medicine and integrative multi-omics
Authors: A C O’Farrell, A T Byrne
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most frequent, aggressive and lethal of all brain tumours. 85% of patients die within two years. Thus, new treatment options are urgently required. To address this deficit, the Royal College of Surgeons in Ireland (RCSI) is leading a major new programme “GLIOTRAIN” (www.gliotrain.eu) that aims to identify new therapeutic strategies, while implementing state of the art genomics and systems medicine approaches to unravel resistance mechanisms. Here, we introduce the GLIOTRAIN initiative which received €3.8 million in September 2017 from the European Commission’s Horizon 2020 Marie Skłodowska-Curie Actions programme. The GLIOTRAIN consortium comprises 22 organisations (RCSI, University of Stuttgart, VIB, Luxemburg Institute of Health, Erasmus Medical Centre, The ICM Institute for Brain and Spinal Cord, GeneXplain GmbH, Agilent Technologies, ITTM Solutions, The International Brain Tumour Alliance, Cancer Trials Ireland, Champions Oncology Ltd., In silico Biotechnology, YUMAB GmbH, Mimetas B.V, Pepscope B.V, Teva Nederland B.V, CarThera, Oncurious N.V, University of Luxembourg, KU Leuven, University Medical Center Göttingen) across 8 countries and includes leading academics, clinicians, private sector and not-for-profit partners across the fields of brain tumour biology, multi-omics, drug development, clinical research, bioinformatics, computational modelling and systems biology. Fifteen GLIOTRAIN sub-projects will employ systems medicine, integrative multi-’omics and translational cancer biology platforms accessing clinically relevant models and patient data-sets. GLIOTRAIN will identify and interrogate novel therapeutic strategies for application in GBM, while simultaneously implementing state of the art next generation sequencing to unravel disease resistance mechanisms. The programme will implement systems-based analysis of known contributors of disease progression, and will further perform unbiased molecular profiling and computational modelling. GLIOTRAIN will address currently unmet translational research and clinical needs in the neuro-oncology field by interrogating innovative therapeutic strategies and improving the mechanistic understanding of disease resistance. Funding: GLIOTRAIN (www.gliotrain.eu) has received funding from the European Commission’s Horizon 2020 Marie Skłodowska-Curie Actions programme (Grant Agreement No. 766069).
Payers, patients, and physicians understanding of quality of life, functional status, and their importance relative to survival in triple-negative breast cancer.
Authors: Richard Edward White, Jennifer Floyd, Maria L. Lankford, Stewart Kaufman, Reshma L. Mahtani
Journal: Journal of Clinical Oncology (2017)

e18156 Background: Value has taken center stage in US oncology treatment as evidenced by the growth of value frameworks and value-based pricing/contracting. These efforts include assessment of quality of life (QoL), survival, and functional status (FS), but the perspectives of payers, patients, and physicians are relatively unknown. We explored the relationships between QoL, FS, and survival in triple negative breast cancer (TNBC) and their importance relative to each other among the 3 key interviewed groups. Methods: Hour-long phone interviews with 6 individuals with TNBC and web-assisted phone interviews with 6 payers and 6 medical oncologists in the US were conducted. Respondents were asked how they differentiate QoL and FS, and how, relative to survival, each impacts their view of TNBC treatment. Results: For payers, QoL and FS are commonly confused and viewed as both supplementary and less important than survival metrics; however, they do desire to understand how each predicts survival. Oncologists prioritized survival, other clinical endpoints, and safety, but believed QoL and FS were very important. Moreover, they assess QoL by the adverse events experienced while on treatment, and view FS as being more objective. For patients, QoL and FS are intermingled, falling under a broad category of QoL. FS was poorly understood, and survival was viewed as critical to meaningful QoL. The threshold at which QoL overrides survival was the point at which patients consider themselves a burden to others. Conclusions: The definitions of QoL and FS used by health services researchers who define “value” is out of sync with patients, payers, and sometimes physicians, making communication of this important information to the individuals interviewed difficult. While the perceived value of QoL and FS varies, and considering the limited treatment options available for TNBC, survival supersedes both measures such that QoL and FS are nearly disregarded. [Table: see text]
Use of contraceptive depot medroxyprogesterone acetate is associated with impaired cervicovaginal mucosal integrity
Authors: Irina A. Zalenskaya, Neelima Chandra, Nazita Yousefieh, Xi Fang, Oluwatosin E. Adedipe, Suzanne S. Jackson, Sharon M. Anderson, Christine K. Mauck, Jill L. Schwartz, Andrea R. Thurman, Gustavo F. Doncel
Journal: Journal of Clinical Investigation (2018)

BACKGROUND. Injectable depot medroxyprogesterone acetate (DMPA) is one of the most popular contraception methods in areas of high HIV seroprevalence. Evidence is accumulating that use of DMPA might be associated with an increased risk of HIV-1 acquisition by women; however, mechanisms of this association are not completely understood. The goal of this study was to gain insight into mechanisms underlying the possible link between use of DMPA and risk of HIV-1 acquisition, exploring transcription profiling of ectocervical tissues.