tbuckley/cabot-search huggingface dataset:
Use of cancer immunotherapies in advanced NSCLC: Persistant challenges among oncologists.
Authors: Tara Herrmann, Joanne Faysal, Haleh Kadkhoda, Lianne Wiggins, Saiama Naheed Waqar, Daniel Morgensztern
Journal: Journal of Clinical Oncology (2016)

e20592 Background: Checkpoint inhibitors represent a new standard of care for patients with advanced NSCLC. As part of an ongoing educational curriculum, assessment of oncologists' knowledge and practice patterns in the use of immunotherapies in patients with advanced NSCLC identified several gaps. This study’s objective was to assess continued areas of need in oncologists’ comfort level and comprehension of immune-related concepts related to the care of patients with advanced NSCLC. Methods: A panel was convened to address knowledge, competence, and performance gaps in the area of cancer immunotherapy (CIT). An educational curriculum of 5 activities focused on NSCLC was developed in 2015, and made available online. Intra-activity questions embedded in each activity allowed learners to self-report their comfort with and confidence in the use of CIT. Participants’ responses to knowledge- and case-based questions presented before and after exposure to education were collected to measure gains in knowledge. Confidentiality of respondents was maintained during data collection and analyses. Results: Among the 654 oncologists that participated, 7%-17% were very comfortable with prescribing CIT and managing associated side effects. Almost 75% of oncologists noted they were somewhat confident or not confidentin their abilities to work interprofessionally, and manage patients receiving CIT. In addition, although data continued to demonstrate the benefits of education on application of learnings, several gaps persisted. Specifically, 1) 38% of oncologists did not comprehend that PD-1 inhibitors block interaction with both PD-L1 and PD-L2, 2) 70% were unable to identify differences in clinical trial designs including what tissue(s) were examined to determine PD-L1 positivity, 3) 32% did not comprehend emerging data surrounding the correlation between PD-L1 positivity and efficacy of available agents, and 4) 25% did not recognize serious immune-related adverse events associated with CIT. Conclusions: Our study demonstrated that most oncologists are not comfortable with CIT. Therefore, there is a continued need on education on the biology, potential predictors for benefit and toxicity in patients treated with CIT.
Docetaxel in hormone-sensitive prostate cancer with low Gleason scores: A meta-analysis of randomized controlled trials.
Authors: Omer Dizdar, Deniz Can Guven, Gurkan Guner, Mustafa Erman, Mutlu Hayran
Journal: Journal of Clinical Oncology (2018)

e17032 Background: Recent trials showed improved overall survival (OS) with upfront use of docetaxel in addition to androgen deprivation therapy (ADT) in patients with hormone-sensitive prostate cancer (HSPC). We herein conducted a systemmatic review and meta-analysis to investigate the efficacy of docetaxel in different Gleason score subgroups in these trials. Methods: Randomized clinical trials (RCT) were identified after systematic searching of electronic databases (MEDLINE, PubMed, clinicaltrials.gov) and ASCO conference proceedings. Only RCT comparing ADT versus the combination of ADT plus docetaxel in patients with HSPC were included. The primary outcome measure was OS. Results were presented as hazard ratios (HR) with 95% confidence intervals (CI). We combined the HRs from each of the three trials in a meta-analysis using the random-effect model. Variation in risk ratios attributable to heterogeneity was assessed using the I-squared statistics. Results: Three eligible studies were included in this analysis (CHAARTED, GETUG-AFU-15 and STAMPEDE). STAMPEDE trial had two docetaxel arms (docetaxel+ADT and docetaxel+zolendronic acid+ADT) in comparison with ADT alone, and both arms were included as zolendronic acid had no effect on OS in this trial. Docetaxel-based chemotherapy plus ADT was associated with improved OS (HR: 0.74; 95% CI: 0.62-0.87; p < 0.001). Among patients with tumor Gleason score lower than 8, addition of docetaxel to ADT significantly improved overall survival [HR: 0.66, 95% CI: 0.52–0.85, p = 0.001]. There was a trend towards improved overall survival with docetaxel in patients with Gleason score of ≥8, although the magnitude of risk reduction was lower and did not achieve statistical significance [HR: 0.81, 95% CI: 0.64–1.02, p = 0.066]. Conclusions: This meta-analysis provides evidence that addition of docetaxel to ADT improves survival in HSPC and the benefit of docetaxel is particularly evident in patients with tumor Gleason score lower than 8. Given the OS benefit of abiraterone in the same setting, this data may be useful in tailoring treatment and in stratification of patients in comparative clinical trials of docetaxel in HSPC.
Physiologic Analysis and Clinical Performance of the Ventilatory Ratio in Acute Respiratory Distress Syndrome
Authors: Pratik Sinha, Carolyn S. Calfee, Jeremy R. Beitler, Neil Soni, Kelly Ho, Michael A. Matthay, Richard H. Kallet
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Pulmonary dead space fraction (Vd/Vt) is an independent predictor of mortality in acute respiratory distress syndrome (ARDS). Yet, it is seldom used in practice. The ventilatory ratio is a simple bedside index that can be calculated using routinely measured respiratory variables and is a measure of impaired ventilation. Ventilatory ratio is defined as [minute ventilation (ml/min) × Pa
Effects of a combination of antiangiogenic and antilymphangiogenic therapies on a death receptor-5 mediated antitumor immunotherapy in mice.
Authors: Yoko Tsukita, Tatsuma Okazaki, Riyo Komatsu, Mayumi Nihei, Makoto Kobayashi, Yasufumi Sato, Hideo Yagita, Masakazu Ichinose
Journal: Journal of Clinical Oncology (2017)

e23001 Background: In angiogenesis, VEGF-A and its receptor VEGFR-2, and in lymphangiogenesis, VEGF-C and VEGFR-3, play central roles. An anti-tumor immunotherapy using an agonistic antibody (Ab) to death receptor (DR)-5, the apoptosis inducing receptor, exhibits antitumor effects. VEGF-A or -C inhibition augmented the effects of immunotherapy. However, little is known about the effects of combining anti-angiogenesis, anti-lymphangiogenesis, and immunotherapy. Here, we combined sunitinib, which mainly inhibits VEGFR1-3 and PDGFRs, as anti-angiogenic and anti-lymphangiogenic therapies, with anti-DR-5 Ab as an immunotherapy in mice. Methods: Mice were injected with breast carcinoma 4T1 cells into the footpad, and treated with sunitinib and/or anti-DR-5 Ab. On day 14, mice were anesthetized, and the popliteal lymph nodes and tumors were isolated for immunohistochemistry, flow cytometry, hypoxia, and lymphatic flow analysis. To evaluate the tumor growth rate, mice were injected with 4T1 cells into the hindflank, treated with the combination or monotherapy and sacrificed on day 21. CD4 + and/or CD8 + T cells were depleted by anti-CD4 and/or anti-CD8 Ab, respectively. Results: Sunitinib decreased endothelial cells, pericytes, and hypoxic area densities in the tumors suggesting blood vessel normalization. Sunitinib also decreased the amount of evans blue injected into tumors and hyaluronic acid in tumors, suggesting improved lymphatic flow. In draining lymph nodes, sunitinib and anti-DR-5 Ab combination increased the numbers of activated dendritic cells and CD8 + T cells than controls. In tumors, the combination increased the numbers of infiltrating effector CD4+FOXP3- and CD8 + T cells compared to controls. Sunitinib and anti-DR-5 Ab combination augmented the decrease in the tumor growth rate compared to each mono-therapy. CD4 + and/or CD8 + T cell depletion showed anti-tumor effects of the combination were partially CD8 + T cell-dependent. Conclusions: Blood vessel normalization and improved lymphatic flow in tumors may improve circulation between the tumors and draining lymph nodes, which has a potential to augment the effects of immunotherapy.
Is preoperative chemotherapy related to the survival of patient operated for peritoneal colorectal carcinomatosis and can it induce complete pathological response?
Authors: Abdelkader Taibi, Rachid Kaci, anne Laure Naneix, Rea lo Dico, Clarisse Eveno, Gaetan Des Guetz, Muriel Mathonnet, Marc Pocard
Journal: Journal of Clinical Oncology (2016)

e15159 Background: Preoperative Systemic chemotherapy (pCT) often complements cytoreductive surgery and intraperitoneal chemotherapy in the peritoneal colorectal carcinomatosis (PCC) treatment. But the efficacy of this pCT is unproven. Moreover, the pCT assessment, using CT or MRI, is not accurate enough for imaging a response using RECIST criteria. In other cancers, obtaining a pathologic response after pCT and survival analysis, suggests interest of pCT strategy. For colorectal liver metastasis, complete tumor response is always significantly correlated with survival. The aim of this study is to evaluate histological response after pCT in PCC, using either histological classification (Blazer or tumor regression grade (TRG)) to evaluate interest of pCT. Methods: In a prospective data base for all cytoreductive surgery performed for PCC, we selected patient having: colon cancer – surgical biopsy of a PCC without PCC resection – and pCT. We compared both biopsies, before and after pCT for each patient. Evaluating pathologic response (PR) is defined as an objective measurement of tumor cell viability and fibrosis in nodules of peritoneal carcinomatosis. Blazer classification and TRG were used as described for liver colon metastasis. Results: 23 were analysed. According to Blazer classification, complete, major and minor PR was 17.5%, 52% and 30.5% respectively. According to TRG, PR was considered major, partial and absent in 61%, 9% and 30% respectively. Fibrosis was only detected in the nodules after pCT. Whatever classification is used, the survival of patients with a complete or major response was significantly higher than patients with minor response (median overall survival: 54 months versus 21,5 months, p < 0.05). Conclusions: This study demonstrates that complete histological tumor regression of PCC can be obtained after pCT, and is an important prognostic factor. This pathological response to pCT corresponds to a decrease in the number of viable tumor cells and the formation of fibrous tissue within the nodules. Both Blazzer classification and TRG can be used in clinical practice to evaluate the histological response after chemotherapy.
TCT-386 Ethnic differences in coronary luminal volume, left ventricular mass and CT-derived fractional flow reserve
Authors: Abdul Rahman Ihdayhid, Daniel Adams, Markus Goeller, Damini Dey, Udit Thakur, Grace Yap, Ren Yik Lim, Mourushi Isa, Michael Michail, James Cameron, Sujith Seneviratne, Brian Ko
Journal: Journal of the American College of Cardiology (2018)
Somatic alterations in the PTEN-PI3K-AKT-mTOR pathway in a cohort of 379 ovarian cancer patients.
Authors: Elizabeth Stover, Levi A. Garraway, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2016)

5572 Background: Somatic alterations in genes in the PTEN-PI3K-AKT-mTOR pathway are common in ovarian cancer. The frequency of pathway alterations varies among histologic subtypes. The PI3K/AKT pathway has also been linked to ovarian cancer platinum resistance. Methods: 379 patients with ovarian or fallopian tube cancer were enrolled in an IRB-approved protocol at Dana-Farber Cancer Institute and provided informed consent. Formalin-fixed tumor tissue underwent next-generation sequencing (NGS) of 300 cancer-associated genes (OncoPanel test), without germline analysis. Single-nucleotide variants (SNVs) and insertions/deletions in the targeted cancer genes were identified, as well as putative copy number variations and structural rearrangements. We determined the frequency of alterations in 10 genes in the PTEN-PI3K-AKT-mTOR pathway in the panel (AKT1, AKT2, AKT3, MTOR, PIK3CA, PIK3C2B, PIK3R1, PTEN, TSC1, and TSC2). Alterations in the entire cohort and across histologic subtypes were summarized with descriptive statistics. Results: About one-third of the ovarian cancer patients harbored aberrations in at least one of ten selected genes in the PTEN-PI3K-AKT-mTOR pathway. PIK3CA alterations were the most common (12%), primarily SNVs corresponding to known hotspot mutations. PTEN alterations were identified in ~10% of patients, including 27 SNVs and five 2-copy deletions. AKT2 amplifications were present in ~2%. Other alterations included deletions and truncating mutations in PIK3R1 and missense mutations in mTOR, TSC1, TSC2, and PIK3C2B. 70% of cases harbored a TP53 missense or nonsense mutation, and PTEN-PI3K-AKT-mTOR pathway alterations occurred both in the TP53 mutant and wildtype groups. Conclusions: We describe somatic mutations and copy number variations in the PTEN-PI3K-AKT-mTOR pathway in a large cohort of ovarian cancer patients. This study further demonstrates the feasibility of NGS of cancer-associated genes in formalin-fixed tissues. Preliminary correlations of genetics with survival and treatment response are being investigated. These data suggest potentially clinically actionable alterations and may inform the use of inhibitors of PI3K/AKT signaling in ovarian cancer.
IL-8 as PD biomarker for TGF-b antisense (OT-101) therapy: Results of a phase II trial.
Authors: Vuong N. Trieu, Wen Wang, Sanjive Qazi, Kevin Ng, Osmond D'Cruz, David Nam, Larn Hwang
Journal: Journal of Clinical Oncology (2017)

e15742 Background: Trabedersen (OT-101) is a phosphorothioate antisense specific for human TGF-β2 mRNA. In a Phase I/II study of OT-101 in patients with advanced pancreatic cancer (PAC) treated second line and beyond, improved Overall Survival (OS) was observed when OT-101 was followed with chemotherapy. Here, we examined the association between plasma levels of cyto-/chemokines and OS outcomes and identified IL-8 as a biomarker for improved OS. Methods: 37 patients with PAC were treated with OT-101 by IV infusion in escalating doses of 2 treatment schedules (7-days on, 7-days off and 4-days on, 10-days off). Plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of OT-101 therapy (140 mg/m 2 /day on a 4-days on, 10-days off cycle). IL-8 levels were measured in 12 patients before and during 3 cycles of treatment on Days 2 and 5. Maximum levels of IL-8 on Day 2 were subtracted from levels on Day 5 and these standardized scores were correlated with log10 transformed OS values. Feedback interactions with PK parameters were also investigated utilizing an ANCOVA model. Results: We observed OS of 14.5 months and 2.6 months for those treated with and without subsequent chemotherapies, respectively (p = 0.0009). Peak IL-8 levels were apparent after 2 days of OT-101 treatment. A significant regression and 95% CI was evident, whereby increasing difference of IL-8 following Day 2 vs Day 5 was positively correlated with OS (R 2 = 0.58, F 1,9 = 12.32, P = 0.0066). R- squared increased from 0.4955, p &lt; 0.0001, for all patients to 0.8524, p &lt; 0.0001, for patients without subsequent chemo and 0.9744, p &lt; 0.0001, for patients with subsequent chemo. The ANCOVA model for two PK parameters exhibited significant model fits (F 3,7 = 7.89, P = 0.012 for Simulated Vz Mean; F 3,7 = 8.18, P = 0.011 for Simulated Cl Mean) and the interaction effects resulted in lower p-values for the correlation of OS vs IL-8 levels. Conclusions: Peak of IL-8 response on Day 2 of OT-101 treatment was correlated with OS in PAC patients. The correlation existed between OS whether patients received subsequent chemo or not suggesting that the IL-8 spike is a PD biomarker for OT-101. Clinical trial information: NCT00844064.
A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors.
Authors: Amikar Sehdev, Yuanyuan Zha, Theodore G. Karrison, Linda A. Janisch, Ezra E.W. Cohen, Michael L. Maitland, Blase N. Polite, Michelle Turcich, Gini F. Fleming, Ravi Salgia, Navin R. Pinto, Thomas Gajewski, Marc Bissonnette, Mark J. Ratain, Manish Sharma
Journal: Journal of Clinical Oncology (2017)

TPS11628 Background: Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Metformin has shown anti-cancer activity through its cellular (e.g., AMPK activation) and systemic effects (e.g., inhibition of IGF-1). We conducted a pilot study to test the hypothesis that metformin may potentiate mTOR inhibition by sirolimus. Methods: An open-label, randomized study was conducted in which eligible patients with advanced solid tumors were started on sirolimus (3mg daily) alone for the first 7 days. On day 8, patients were randomized to either receive metformin XL (500 mg daily) plus sirolimus (Arm A) or sirolimus alone (Arm B) for until day 21. From day 22 onwards, all patients recieved metformin XL plus sirolimus. The pharmacodynamic (PD) biomarkers were collected at baseline, day 8 and day 22 of cycle 1. The primary endpoint was to compare the change in PD biomarker phospho-p70S6K, using a two-sample t test (log ratio D22/D8 in arm A vs. arm B). The phospho-p70S6K was measured in peripheral blood T cells using Western blot. The secondary endpoints were to assess objective response rate (RECIST 1.1), toxicity (CTCAE V4.0) and changes in the serum levels of PD biomarkers: fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, leptin and adiponectin using two-sample t tests. Results: 24 patients were enrolled, at which time an interim futility analysis was conducted. 18 patients were evaluable for the primary endpoint (8 in arm A; 10 in arm B). The mean log ratios D22/D8 in phospho-p70S6K in arms A and B were -0.12 (SD = 0.13) and -0.16 (SD = 0.29), respectively (P = 0.64). Of the 17 pts evaluable for response, the best response was stable disease in 9 patients and progressive disease in 8 patients. There were no dose-limiting or unexpected toxicities. Of the 21 patients evaluable for serum PD biomarkers, there were no significant differences between arms A and B in fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-BP1, IGF-BP3, leptin and adiponectin (P &gt; 0.05 for all). Conclusions: The addition of metformin to sirolimus, although well-tolerated, was not associated with significant changes in phospho-p70S6k and other PD biomarkers. Based on the results of the interim analysis, the trial was terminated. Clinical trial information: NCT02145559.
Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation
Authors: Yaoyao Zou, Siqi Xu, Youjun Xiao, Qian Qiu, Maohua Shi, Jingnan Wang, Liuqin Liang, Zhongping Zhan, Xiuyan Yang, Nancy Olsen, Song Guo Zheng, Hanshi Xu
Journal: Journal of Clinical Investigation (2018)

Fibroblast-like synoviocytes (FLSs) are critical to synovial aggression and joint destruction in rheumatoid arthritis (RA). The role of long noncoding RNAs (lncRNAs) in RA is largely unknown. Here, we identified a lncRNA, LERFS (lowly expressed in rheumatoid fibroblast-like synoviocytes), that negatively regulates the migration, invasion, and proliferation of FLSs through interaction with heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Under healthy conditions, by binding to the mRNA of RhoA, Rac1, and CDC42 - the small GTPase proteins that control the motility and proliferation of FLSs - the LERFS-hnRNP Q complex decreased the stability or translation of target mRNAs and downregulated their protein levels. But in RA FLSs, decreased LERFS levels induced a reduction of the LERFS-hnRNP Q complex, which reduced the binding of hnRNP Q to target mRNA and therefore increased the stability or translation of target mRNA. These findings suggest that a decrease in synovial LERFS may contribute to synovial aggression and joint destruction in RA and that targeting the lncRNA LERFS may have therapeutic potential in patients with RA.
Implementing a care model to enhance patient outcomes and limit liability in patients with incidental pulmonary nodules.
Authors: Ruth Raleigh, Vita McCabe, Alisa Soos, Alice Pichan, Beth Irene Lavasseur, Philip J. Stella, Rajeev Swarup, David Fugenschuh, Eric Ferguson, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2017)

e18247 Background: Patients with incidental pulmonary nodules are at risk for loss to follow-up due to fragmented health care delivery systems. The purpose of this study is to describe implementation of a care model to eliminate gaps in care for these patients. Methods: A multifaceted intervention was implemented to improve follow-up of incidental pulmonary nodules in at-risk patients. The intervention included education of all patients with incidental nodules in the emergency room and inpatient setting upon discharge. Other key steps included: (i) engagement of physician leadership, (ii) development of a patient tracking database, (iii) designation of a nurse navigator to ensure timely notification of radiological findings, (iv) ensuring patients received timely follow-up and (v) coordination communication with the primary care physician (PCP) or assistance in establishing a relationship with a PCP. Finally, smoking history was added to all CT body radiology reports to stratify risk and determine follow-up intervals using nationally accepted guidelines. The study was reviewed by the St Joseph Mercy Health System Institutional Review Board and was considered exempt. Results: Over the course of 36 months, 7,962 patients with incidental pulmonary nodules were identified by radiologists and flagged for entry into the follow-up program. 2.6% of patients enrolled were found to have lung neoplasms (68% of which were stage I, II or III non-small cell lung cancer). Conclusions: Integrated care models with a seamless combination of nurse navigation and optimal use of health information technology improves care and outcomes for patients with incidental pulmonary nodules while simultaneously mitigating liability for physicians and health care institutions.