tbuckley/cabot-search huggingface dataset:
Abstract P215: Presence of Comorbid Psychiatric Illness is Associated with Aortic Vascular Inflammation and Coronary Heart Disease Beyond Traditional Cardiovascular Risk Factors in Psoriasis
Authors: Tsion M Aberra, Aditya A Joshi, Joseph B Lerman, Justin A Rodante, Joanna I Silverman, Tarek Z Aridi, Marcus Y Chen, Nehal N Mehta
Journal: Circulation (2016)

Introduction: Psoriasis is a chronic inflammatory disorder associated with vascular inflammation (VI), measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and increased risk of MI. Coronary plaque composition by coronary computed tomography angiography (CCTA) predicts both CV risk and outcomes. Patients with psoriasis are more likely to suffer from comorbid depression and anxiety. Whether these comorbidities may accelerate the development of CVD in psoriasis is not well characterized. Hypothesis: We hypothesized that aortic VI and coronary plaque burden would be increased in patients with psoriasis who have depression and/or anxiety when compared to those with psoriasis who do not. Methods: Psoriasis patients were derived from an ongoing psoriasis study cohort. Patients who reported a history of depression and/or anxiety (n=40) on survey and age- and gender- matched patients who reported no history of psychiatric illness (n=40) were selected. Target-to-background ratio from FDG PET/CT was used to assess aortic VI and CCTA scans were analyzed for coronary plaque composition. Multivariate linear regression was performed to understand the effect of psychiatric diagnoses on VI and plaque burden after adjustment for CV risk factors (standardized β reported). Results: In unadjusted analyses, both aortic VI and coronary plaque burden were higher in psoriasis patients with comorbid depression or anxiety compared to those without (Table 1). After adjustment for Framingham Risk Score, body mass index, and statin use, VI (β=0.24, p=0.02), total plaque burden (β=0.13, p=0.04), and non-calcified burden (β=0.13, p=0.04) were associated with comorbid depression or anxiety. Conclusions: Patients with psoriasis who have comorbid depression or anxiety have increased aortic VI and coronary plaque burden, suggesting that identification of psychiatric diagnoses in psoriasis may be warranted for future CV risk reduction in this high risk population.
Application of capture-based sequencing in predicting pathologic response to neoadjuvant therapy in HER2-positive breast cancer.
Authors: Fei Ma, Wenna Wang, Jin Li, Lianpeng Chang, Yan-Fang Guan, Zongbi Yi, Ying Fan, Xiuwen Guan, Xuefeng Xia, Xin Yi, Binghe Xu
Journal: Journal of Clinical Oncology (2018)

e24073 Background: Pathologic complete response (pCR) to neoadjuvant therapy correlates with significantly improved survival in early-stage HER2-positive breast cancer (BC). Early indicators of pCR could conceivably be used to optimize treatment. This study aimed to reveal pCR-related genomic characteristics in both tissues and circulating tumor DNA (ctDNA). Methods: We enrolled 31 hormonal receptor (HR)-negative HER2-positive BC patients treated with neoadjuvant chemotherapy with or without trastuzumab from a single-center prospective study between January 2014 and June 2017 (ClinicalTrials.gov, NCT02041338). Twenty-two treatment naïve tumor tissues were obtained. Baseline plasma samples were collected from all 31 patients, among whom 22 plasma after 2 cycles of neoadjuvant treatment were sampled. Target-capture deep sequencing was performed to identify somatic genomic alterations. Clonal population structures were identified using PyClone. Results: TP53 and PIK3CA were the most frequently mutated genes in tumor tissues, detected in 77.3% (17/22) and 50% (11/22) of patients, respectively. The pCR rate of PIK3CA-mutated patients (18.2%, 2/11) was significantly lower than that of PIK3CA wild-type patients (72.7%, 8/11), (P = 0.03). Among patients treated with chemotherapy plus trastuzumab, all 8 patients with clonal PIK3CA-mutated did not achieve pCR. CtDNA was successfully detected in 26 of the 31 patients (83.9%) in whom somatic genomic alterations were identified. TP53 mutation, HER2 gene amplification and PIK3CA mutation were the most frequently somatic variants in the baseline plasma samples, detected in 54.8% (17/31), 41.9% (13/31) and 32.3% (10/31) of patients, respectively. Further analysis of the post-treatment plasmas showed that the pCR rate of ctDNA-negative patients after 2-cycle therapy was 87.5%, significantly higher than that in ctDNA-positive patients (18.2%; P = 0.005). Conclusions: In this study, the PIK3CA-mutation in tumor tissues associates with an unfavorable pCR rate to neoadjuvant chemotherapy plus trastuzumab. Analysis of post-treatment ctDNA offers a promising way to predict pCR in HER2-positive BC patients.
Modulation of the anti-tumor activity of VEGF blockade by metformin.
Authors: Mohamed Selmy, Elisabetta Zulato, Anna Pasto, Stefano Indraccolo
Journal: Journal of Clinical Oncology (2017)

e23009 Background: The payoff from first-generation angiogenesis inhibitors was commonly temporary, due to the development of intrinsic as well as acquired resistance. Apart from the vascular resistance due to circumventing VEGF blockade by proangiogenic factors, resistance has also been associated with assortment of resistant clones. Accordingly, a combination strategy was proposed to overcome such resistance. Metformin, as a potential candidate, has received considerable concern as an anticancer agent. Methods: IN-VITRO WORK;Cells were divided into normoxic and hypoxic groups. For both, four subgroups were developed; control, metformin, glucose deprivation and a subgroup in which cells were subjected to both glucose deprivation and metformin treatment. Cells were then subjected to analysis for Apoptosis, Cell cycle progression and western blot. IN-VIVO WORK; Tumor growth was assessed IGROV-1 subcutaneous xenografts. Animal were divided into four groups; control, Metformin, Bevacizumab and a fourth group receiving both drugs. Tumor growth was assessed along treatments and at time of sacrifice.After sacrificing animals, tumors were further analyzed for; necrosis, apoptosis, proliferative capacity, activation of AMPK and its downstream effectors. Results: Our in-vitro results suggested an anti-proliferative effect of metformin in terms of apoptosis, cell cycle arrest, AMPK activation and mTOR inhibition at various time points. In-vivo experiments revealed a significant decrease of tumor weight and proliferative capacity in tumors treated with both drugs and a trend toward a decrease in tumor growth along the treatment. Yet, there was no difference between the bevacizumab and the combination groups regarding AMPK activation suggesting another mechanism to exert the combination effect. The effect of Metformin on CSC percentage and viability was tested. Glucose deprivation plus hypoxia lead to increase in CSC population, while adding metformin to bevacizumab reverse this augmentation in CSC numbers. Conclusions: Study represents a proof of concept study demonstrating a positive modulatory effect of metformin addition to bevacizumab. Additional experimental work on a wider scale is running to ascertain the current results.
TCT-362 Checking the reality of the SYNTAX III Revolution trial: Comparison of the virtual heart team decision with the treatment executed
Authors: Jeroen Sonck, Daniele Andreini, Antonio Bartorelli, Thierry Folliguet, Ioannis Diamantis, Gloria Faber, Philipp Kaufmann, Johan De Mey, Mark La Meir, Kaoru Tanaka, Dries Belsack, Yoshinobu Onuma, Patrick Serruys
Journal: Journal of the American College of Cardiology (2018)
Understanding the Benefits of Bariatric Surgery
Authors: Margaret E. Smith, Amir A. Ghaferi
Journal: JAMA Surgery (2018)

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PRODIGE 2 phase III trial neoadjuvant in rectal cancer: Quality of life and results at 5 years.
Authors: Pierre-Luc Etienne, Eric Francois, Sophie Gourgou, Marta Jarlier, David Azria, Philippe Rouanet, Thierry Conroy, Olivier Bouche, Laurent Mineur, Veronique Vendrely, Jerome Doyen, Jean-François Seitz, Trevor Stanbury, Jean-Pierre Gerard
Journal: Journal of Clinical Oncology (2016)

3619 Background: The ACCORD 12 -PRODIGE 2 trial randomly assigned patients to receive radiotherapy (RTH) 45 Gy (CAP-45) with capecitabine or RTH 50 Gy with capecitabine and weekly oxaliplatin(CAPOX-50). The primary objective (complete sterilization of the operative specimen) was not met. This is an update of results at 5 years. Methods: Between November 2005 and July 2008, 598 patients were randomized. Inclusion criteria were: adenocarcinoma of the rectum accessible to digital examination, stage T3 or resectable T4 (or T2 distal anterior rectum) NX M0, < 80 years, PS 0-1. Updated carcinologic results were analyzed using the Kaplan-Meier method and Cox proportional-hazards models. Quality of life was assessed with the anal sphincter conservative treatment questionnaire (ASCT) and by reporting of erectile dysfunction (ED) [satisfaction degree varies from 1(ED) to 7 (normal)]. The evolution of the ED score and selected items from ASCT questionnaire was analyzed with a linear mixed model (LMM). Results: In the ITT population (median follow-up of 5 years), results were in CAP-45 arm and in CAPOX-50 arm, respectively : local recurrence rate 8.8% vs 7.8% (HR for 5y-local RFS 0.92[0.51 – 1.66], p = 0.78), disease free survival (DFS) 60.4% vs 64.7% (p = 0.25, HR = 0.86 [0.66-1,11]), overall survival (OS) 76.4% vs 81.9% (p = 0.056, HR = 0.71[0.50-1 .01]) and specific OS (p = 0.19, HR = 0.75[0.50 – 1.13]). No significant difference was observed in the evolution of the ED score between the two arms (p = 0.29). From ASCT questionnaire, social life disturbance rated from 1 to 4 (greater to no disturbance), with a 5y-median score of 3 (1-4) was not different between the two arms during follow-up (p = 0.15). Moreover, for the global satisfaction score rated from 1 to 7 (unsatisfied to very satisfied), and for the total score, no statistically significant difference was noted (p = 0.43 and p = 0.38 respectively). Conclusions: The quality of life and ED were not different between the two arms after five years of follow-up like the oncologic results as specific OS, DFS and local recurrence. The addition of oxaliplatin to chemoradiation with capecitabin has a minor impact on natural history of the locally advanced rectal cancer. Clinical trial information: NCT00227747.
Association of improved survival (OS) and tumor control (TC) with interleukin-2 (IL2) with development of immune-related events (IREs): Data from the PROCLAIMSM registry.
Authors: Brendan D. Curti, Gregory A. Daniels, David F. McDermott, Joseph Clark, Howard Kaufman, Jatinder Singh, Meenu Kaur, Theresa L. Luna, Nancy C. Gregory, Hong Hua, Michael Morse, Michael K.K. Wong, Janice P. Dutcher
Journal: Journal of Clinical Oncology (2017)

9528 Background: IREs are associated with immunotherapy (IT) for cancer and while reports suggest improvement in TC and OS with induced IREs, the long-term impact is unclear. IL2 has been the major IT for patients (pts) with renal cell carcinoma (RCC) and melanoma (MM) since 1992. We evaluated IREs reports in the PROCLAIM SM data base (2008-2016) of IL2-treated pts. Methods: Reports on 614 (MM) and 843 (RCC) pts were queried for IREs. IREs were categorized as occurring before, during, or after IL-2 and related to any checkpoint inhibitor (CPI). TC (CR+PR+SD) was compared between no IRE and IRE, using Fisher’s exact test. OS curves were estimated by Kaplan-Meier method, and comparison of no IRE/before IL2 with during/after IL2, was analyzed by log-rank test. Results: With a median (med) follow-up of 3.5+ years (range 1-8+ year), 140 IREs were reported in 118 pts (9.6% of all PROCLAIM SM pts): 93 (15%) in MM; 47 (5.6%) in RCC. 25 IREs were prior to IL2; 13 IREs were during IL2; 102 were after IL2. Of the latter 102, 31 were after IL2 and after subsequent CPI; 71 were attributed to IL2 only; and in 13, IREs were due to either IL2 or CPI. TC was 73% for IRE group vs 56% for no IRE group (p = 0.0054). OS was significantly greater for IRE group during/after IL2 compared to no IRE/before IL2 in MM, med 46 months (mo) vs 18 mo (p = 0.0001) and in RCC, med 61 mo vs 43 mo (p = 0.0196), independent of CPI IREs. Med # of IL2 doses was 19 in no IRE group, 39 in IRE during IL2 group, and 25 in IRE after IL2 group. IL2-related IREs were primarily vitiligo and thyroid dysfunction (70% of IL2 IREs), with limited further impact, while CPI-related IREs were often serious, requiring intervention (hypophysitis, colitis, hepatitis, uveitis) (52% of CPI IREs) and possibly chronic management. Conclusions: IREs following IL2 are associated with improved TC and OS. IREs resulting from IL2 and from CPIs are qualitatively different and likely reflect different mechanisms of action of immune activation and response.
Preliminary safety, pharmacokinetics, and pharmacodynamics of duvelisib plus rituximab or obinutuzumab in patients with previously untreated CD20+ follicular lymphoma.
Authors: Carla Casulo, Eric D. Jacobsen, Koen Van Eygen, Houston Eccleston Holmes, Jan P. Lemmens, Kerstin Allen, Lori Steelman, Veronica Campbell, Jylle Nevejans, Joseph Pearlberg, Andre Goy
Journal: Journal of Clinical Oncology (2016)

e19052 Background: Duvelisib (IPI-145), an oral dual inhibitor of PI3K-δ and -γ, is being evaluated as an oral therapeutic for hematologic malignancies as a monotherapy or in combination with anti-CD20 antibodies. Methods: CONTEMPO (NCT02391545) is an ongoing 2-part, 2-arm, Phase 1b/2 study evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of duvelisib combined with the anti-CD20 antibodies rituximab (DR) or obinutuzumab (DO) in patients with previously untreated CD20+ follicular lymphoma. Duvelisib is administered at 25 mg BID continuously in 28-day treatment cycles combined either with rituximab (375 mg/m2for 4 weekly doses, then 1 dose every 2 cycles) or obinutuzumab (1000 mg for 4 weekly doses, then 1 dose every 2 cycles). We report results from Part 1 which evaluated the safety of the combinations by monitoring adverse events (AEs) and dose limiting toxicities (DLTs). Results: Twelve patients were treated in Part 1 of the study (6 DR and 6 DO). At the time of data cut-off, patients had received duvelisib for a median of 2.5 (DR) and 1.9 (DO) months. No DLT occurred with DR. One DLT of treatment-related Grade 3 elevated lipase occurred with DO (Cycle 1). No serious AEs occurred on either arm, and no patient discontinued treatment. Four patients (1 DR; 3 DO) had ≥ Grade 3 AEs (DR: amylase increased, lipase increased; DO: neutropenia, ALT increased, lipase increased). Duvelisib was rapidly absorbed (tmax ~1 hour; Cmax ~910 ng/mL; single dose); after multiple doses, plasma steady state levels were ~500-540 ng/mL and approximately half of the duvelisib was transformed into its metabolite IPI-656. Postdose serum cytokine levels were decreased by Cycle 1 Day 8 compared to baseline. Preliminary activity will be reported at the time of the meeting. Conclusions: Combination of duvelisib 25 mg BID with rituximab or obinutuzumab was well tolerated in these patients, with one DLT observed. Both DR and DO arms were continued to Part 2 of the study, which is ongoing. Clinical trial information: NCT02391545.
EGFR reporting in stage IV adenocarcinoma of the lung: Demographic predictors of EGFR testing and survival.
Authors: Shagufta Shaheen, Liang Ji, Hamid Mirshahidi, Salman Otoukesh, Gayathri Nagaraj, Saied Mirshahidi, John W Morgan
Journal: Journal of Clinical Oncology (2018)

9100 Background: Tyrosine Kinase inhibitors (TKI) have changed the treatment paradigm in patients with stage IV adenocarcinoma of the lung (AdenoCa) harboring epidermal growth factor receptor (EGFR) mutation. Currently there are no guidelines for reflex pathologic testing or mandatory reporting of these mutations. Methods: Data for age, sex, race/ethnicity, SES, diagnosis year and EGFR mutation status (+/-) in Stage IV lung AdenoCa (2005-2015) were extracted from the population-based California Cancer Registry (CCR). Logistic regression assessed the proportion of AdenoCa patients that received EGFR testing by age, socioeconomic status quintile (SES), gender and race/ethnicity. Proportional hazards analysis evaluated survival by EGFR status. Among EGFR positive patients, demographic factor adjusted, lung cancer specific Cox proportional mortality hazards ratios (HR) were compared for use of TKI (Y/N). Results: Of the 23,674 patients, 3,916 (17%) had EGFR results in their report; this percentage increased for ordinally higher SES quintiles (Trend p < 0.001). Odds of EGFR testing (Y/N) increased from 2005 to 2015 (p < 0.001) and the odds ratio was higher for females vs. males (OR = 1.20;95%CI = 1.11-1.30;p < 0.001). Odds of EGFR testing was higher for Asian/Other and lower for non-Hispanic black patients vs. non-Hispanic white (OR = 1.32;95%CI = 1.20-1.45;p < 0.001 and OR = 0.86;95%CI = 0.74-0.99;p = 0.002), respectively. Among EGFR tested patients, 1,173 (30%) were positive, 2,618 (67%) negative and 125 (3%) had unknown status. Median survival time was 858 days and 390 days for TKI (Y/N). Adjusted HR for TKI (Y/N) was 0.61; 95%CI = 0.58-0.64; p < 0.001). Conclusions: These findings reveal that, in spite of EGFR testing recommendations, only about 17% of patients had evidence of testing. The trend for higher testing prevalence in higher SES quintiles and during recent years is consistent with more comprehensive insurance and improving compliance. These findings reveal remarkably increased survival for EGFR positive patients treated with TKI. These findings underscore the need for reflex pathologic testing for EGFR mutations in advanced lung AdenoCa to improve patient outcomes and avoid delays in treatment.
A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.
Authors: Linda R. Duska, Timothy Norman Showalter, Gina R. Petroni, Timothy Bullock
Journal: Journal of Clinical Oncology (2017)

TPS5601 Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.
Analysis of circulating tumor DNA and clinical correlates in patients with esophageal, gastroesophageal junction and gastric adenocarcinoma.
Authors: Ryosuke Okamura, Shumei Kato, Joel Micah Baumgartner, Hitendra Patel, Lawrence P. Leichman, Kaitlyn J. Kelly, Paul T. Fanta, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

e16031 Background: Esophageal, gastro-esophageal junction and gastric adenocarcinoma (herein gastroesophageal adenocarcinomas) are associated with poor prognosis and systemic treatment options are limited. To further understand the genomic landscape of gastroesophageal cancers and its clinical correlation, circulating tumor DNA (ctDNA) from patients’ plasma was evaluated using next-generation sequencing (NGS). Methods: We analyzed genomic alteration of 55 patients with gastroesophageal adenocarcinomas using clinical-grade NGS of ctDNA derived from patient plasma (54-73 gene panel) (Guardant Health). The test detects single nucleotide variants, as well as copy number amplifications, fusions and indels in selected genes. Results: Seventy-six percent (42/55) of patients had at least one genomic alteration and 69.1% (38/55) had at least one characterized alteration. The median number of alterations per patient was 2 (range, 0-15). TP53 (50.9%, 28/55), PIK3CA (16.4%, 9/55), ERBB2 (14.5%, 8/55) and KRAS (14.5%, 8/55) were most frequently aberrant characterized alterations. Thirty-one patients also had tissue NGS. Concordance between tissue and ctDNA ranged from 61.3% (TP53 alteration) to 87.1% (PIK3CA alteration). ERBB2 alterations were significantly associated with poor overall survival (P = 0.004, multivariate analysis). Among patients with ≥1 alteration, no two patients had identical molecular portfolios. All patients with at least one characterized alteration had theoretically targetable alterations by an FDA-approved agent (on- or off-label). Illustrative patients who were successfully managed with matched targeted therapies on the basis of ctDNA will be presented. Conclusions: Evaluation of ctDNA with NGS among gastroesophageal adenocarcinoma patients was feasible. Patients harbored heterogeneous patterns of genomics, with most having theoretically actionable alterations. Clinical trial information: NCT02478931.