tbuckley/cabot-search huggingface dataset:
Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers.
Authors: Min Wang, Chen Tian, Mingxia Ye, Lili Zhao, Wensheng Fan, Jianfei Wang, Wenbo Han, Wen Yang, Chenglei Gu, Mingxia Li, Zhe Zhang, Henghui Zhang, Yuanguang Meng
Journal: Journal of Clinical Oncology (2018)

e17543 Background: Gynecologic cancers account for approximately 18% of all female cancers. Since management options for advanced gynecologic cancers are limited, immune checkpoint blockade is a potential therapy to be investigated in several clinical trials. Despite being an emerging biomarker of sensitivity to immune checkpoint inhibitors, the tumor mutational burden (TMB) in Chinese patients with gynecologic cancer has not been well characterized yet. Methods: In total, 117 patients with gynecologic cancers were included in this study. Both tumor DNA and paired blood cell genomic DNA were isolated from formalin-fixed paraffin-embedded (FFPE) specimens and blood samples and subjected to enrichment for a 1.15 Mb-panel representing exonic regions from 1086 genes, followed by next-generation sequencing on an Illumina X10 platform. The captured sequencing data were further subjected to bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNVs) and short insertions/deletions (indels). In addition, TMB values were evaluated and analyzed. Results: TP53, PTEN, ARID1A, and PIK3CA alterations were significantly different in various types of gynecologic cancers (p = 0.001, 1.15E-07, 0.004, and 0.009, respectively). The median TMB of all 117 gynecologic tumor specimens was 0.37 mutations/Mb, with a range of 0-41.45 mutations/Mb. Despite the lack of significant difference, endometrial cancer cases had a higher median TMB than did cervical and ovarian cancer cases (p = 0.81). Younger gynecologic cancer patients (age < 40 years) had a significantly lower TMB than did older patients (age≥40 years) (p = 0.04). In addition, TMB was significantly increased with increasing clinical stage of disease (p = 0.001). PTEN alterations were commonly observed in patients with a moderate to high TMB (n = 8, 38.10%, p = 9.95E-04). Although limited by sample size, all of the patients with TSC2 (n = 3, p = 3.83E-11) or POLE (n = 2, p = 0.005) mutations had a moderate to high TMB. Conclusions: Patients with mutations in the PTEN, TSC2 or POLE gene have increased TMB. However, further large-scale, prospective studies are needed to validate our findings.
Abstract 038: 30-year Risk of Cardiovascular Disease in Adolescents With Severe Obesity: Benefit of Bariatric Surgery (Teen-LABS)
Authors: Justin R Ryder, Peixin Xu, Changchun Xie, Todd M Jenkins, Thomas H Inge, Aaron S Kelly, Elaine M Urbina
Journal: Circulation (2018)

Severe obesity in youth is associated with accentuated risks of chronic health problems. However, quantifying risk of cardiovascular disease (CVD) events later in life is challenged by long latent periods between risk factor development and overt disease outcomes. A 30-year CVD event risk score has been developed in the Framingham Offspring cohort to address this problem. The 30-year CVD event risks were estimated for adolescents with severe obesity prior to and up to 5 years after undergoing bariatric surgery. We hypothesized that adolescents with severe obesity would be at high risk for full CVD events within 30-years and that bariatric surgery would reduce that risk. Adolescents (n=215; mean age pre-op = 17 years; mean body mass index (BMI) = 53 kg/m 2 ) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) were used in this analysis. Data collected preoperatively and annually to 5 years were analyzed. A 30-year composite risk score (CVD event risk) was examined which included the following hard endpoints: coronary death, myocardial infarction, and stroke (fatal and nonfatal), coronary insufficiency, angina pectoralis, transient ischemic attack, intermittent claudication, and congestive heart failure. CVD event risk score requires the following risk factors for calculation: Sex, age, systolic blood pressure, antihypertensive treatment, smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, and BMI. Data are presented as mean (SD) with differences between time-points examined using linear mixed-models. Preoperatively, the likelihood of CVD events was 7.9 (6.7)%. Preoperatively, 52.6% of the cohort presented with &gt;5% risk of CVD events, 22.3% with &gt;10% risk of event, and 10.7% with &gt;15% risk of event. At 1-year post-surgery a significant reduction in CVD events (7.9 [6.7]% to 4.0 [3.4]%, p&lt;0.0001) was estimated. A reduction in proportion with &gt;5% (52.6% to 22.1%), &gt;10% (22.3% to 4.4%), and &gt;15% (10.7% to 1.7%) risk of CVD events was observed. These predicted benefits for full CVD events were sustained at 2 years (4.0 [2.9]%), 3 years (4.2 [3.8]%), 4 years (4.3 [3.1]%), and 5 years (4.8 [3.8]%) post-surgery, with similar &gt;5%, &gt;10%, and &gt;15% risks noted (p&lt;0.0001 for all years versus baseline). These data suggest that prior to bariatric surgery, the risk of CVD event within 30-years is pronounced. However, following bariatric surgery, risk of hard endpoints is substantially reduced for up to 5 years following surgery.
Characterization of germline genomic alterations in familial pancreas cancer.
Authors: Jennifer Brooke Goldstein, Li Zhao, Milind M. Javle, Michael J. Overman, Rachna T. Shroff, Gauri R. Varadhachary, Robert A. Wolff, Phillip Andrew Futreal, David R. Fogelman
Journal: Journal of Clinical Oncology (2017)

4116 Background: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival in patients with pancreatic cancer (PC). We retrospectively compared family history of such cancers with clinical outcomes and underlying molecular aberrations. Methods: A retrospective chart review was conducted of 350 metastatic PC patients treated with first line FOLFIRINOX and Gem/Abraxane at MDACC from 1/2010 -1/2016. Family history was defined as 1 st through 3 rd generation relatives with breast, ovarian, or pancreas cancer. Germline DNA was collected and sequenced using a familial cancer panel using an Illumina 2500. Average coverage was 200X. Platypus calls were analyzed for germline mutations. We assessed mutations in BRCA1, BRCA2, PALB2, MMR genes, ATM, and PolE. Results: Average age was 61. 60% of patients were male. We sequenced blood and tissue samples where available. We found at lease one mutation in 47 of 129 patients tested. There were 56 mutations identified among the 47 patients. Of patients with 0-1,2, or 3 or more affected family members we found mutations in 44%, 47%, and 29%, respectively. Patients with 3+ family members affected tended to have mutations in BRCA1 or PolE. Among the subset of patients with possible deleterious mutations, there were trends towards improved survival in pts with BRCA or PALB aberrations (307d vs 271d, p = ns) but worse outcomes in those with MMR gene defects (181d vs 387d, p = .126). Table 1 indicates outcomes based on number of family members with cancer and their associated mutations. Conclusions: Approximately one third of all patients tested had at least one germline mutation in previously described familial pancreas cancer genes. Screening for inherited cancer susceptibility genes may have prognostic value. [Table: see text]
AB0689 Extravascular manifestations of takayasu arteritis: historical cohort study in korea
Authors: O.C. Kwon, S.-W. Lee, Y.-B. Park, W.J. Seo, J.S. Oh, S. Hong, C.-K. Lee, B. Yoo, Y.-G. Kim
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Takayasu arteritis (TAK) is systemic disease characterised by large vessel involvement. Although the vascular characteristics of TAK are well characterised, there is no well-organised study demonstrating the extravascular manifestations of TAK. <h3>Objectives</h3> To evaluate the characteristics of extravascular manifestations of TAK, and to identify the association between vascular and extravascular manifestations of TAK. <h3>Methods</h3> TAK patients from two independent cohorts who fulfilled the 1990 ACR classification and encoded M314 according to ICD-10 code between <sup>January 2012</sup> and October 2017 were included in the study. Characteristics of the patients were retrospectively collected from the electronic dataset. A radiologist reviewed CT scans of all included patients to evaluate the pattern of vascular involvement and presence of sacroiliitis. Clinical findings including uveitis, skin lesion, oral ulcer, arthritis, and inflammatory bowel disease (IBD) were reviewed. Logistic regression analysis was performed to evaluate the association between vascular and extravascular manifestation. <h3>Results</h3> A total of 268 TAK patients were included. Mean age at diagnosis was 41.2±14.2 years and 236 (88.1%) were female. The most commonly involved vessel was common carotid artery (176 [65.7%]), and the most common type of vascular involvement was type V (120 [44.8%]). Extravascular manifestation of TAK was observed in 51 (19.0%) patients (table 1). The most common extravascular manifestation was arthritis (axial arthritis [sacroiliitis] [7.1%] and/or peripheral arthritis [6.0%]) (11.9%) followed by recurrent aphthous stomatitis (8.6%) and IBD (2.6%). In multivariable logistic regression analysis, the following factors were significantly associated with presence of arthritis (axial and/or peripheral arthritis): type IIB vascular involvement (adjusted OR 2.956, 95% CI 1.337–6.537, p=0.007) and erythrocyte sedimentation rate (ESR) (adjusted OR 1.014 95% CI 1.003–1.025, p=0.012). <h3>Conclusions</h3> Extravascular manifestations of TAK are not rare and observed in up to one-fifth of patients. The most common extravascular manifestation was arthritis including sacroiliitis (11.9%). Type IIb vascular involvement pattern and high ESR were significantly associated with arthritis in TAK. <h3>Acknowledgements</h3> None <h3>Disclosure of Interest</h3> None declared
A phase 2 study of NEO-102 (ensituximab), a novel chimeric monoclonal antibody, in adult patients (pts) with unresectable, metastatic colorectal cancer (mCRC).
Authors: Richard D. Kim, Nilofer Saba Azad, Michael Morse, Benjamin R. Tan, Elizabeth Poplin, Melony A. Beatson, Sharon Mavroukakis, Karen Cui, Philip M. Arlen, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2016)

3080 Background: NEO-102 is an investigational, novel, chimeric monoclonal IgG1 antibody raised against an immunogenic membrane fraction of an allogeneic CRC vaccine. It's target has sequence homology to MUC5AC, but is preferentially expressed in pancreatic cancer and CRC. NEO-102 demonstrates exquisite specificity to CRC, with a mechanism of action through antibody-dependent cellular cytotoxicity (ADCC). A phase 1/2 study was conducted to evaluate NEO-102 monotherapy in pts with refractory mCRC. Here we describe results from the phase 2 part of the study. Methods: This is a single-arm, open-label, multi-center trial. Eligibility includes age ≥ 18 years, ≥ 2 lines of prior standard chemotherapy, measureable disease. An IHC-based companion diagnostic assay was used to select pts with NEO-102 expression in > 20% of tumor cells. NEO-102 at 3 mg/kg was administered IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). The minimum sample size was 43 pts, assuming that treatment with NEO-102 will improve OS by 40% (7.0 months [mo]) vs a historical control of 5 mo (one-sided significance level of 10% and 80% power). Additional endpoints were response rate (by RECIST 1.1) and analysis of pt PBMCs for ADCC and immune cytokine profiling. Results: A total of 53 pts were enrolled and were evaluable for safety, 48 pts were evaluable for OS, and 37 were evaluable for response. 26 pts were male, 32 were white, and mean number of prior therapies was 5 (range 2‒9). 15 pts (31%) remain alive as of 31 Dec 2015 with an ongoing median OS of 6.8 mo (range 1.8‒25+ mo). 18 pts (48%) had stable disease in target lesions at the end of the first course (day 57). 38 pts received ≥ 4 doses (max 15+) of NEO-102. Grade 3 adverse events (AE) included anemia (1.3%), hyperbilirubinemia (0.9%), diarrhea (0.4%), fatigue (0.9%), headache (0.4%), nausea (0.4%), hypoxia (0.4%), and vomiting (0.4%). No grade 4 AEs were reported. Conclusions: In this phase 2 study of NEO-102 monotherapy in heavily pretreated pts with mCRC, OS was longer than the historical control, and NEO-102 was extremely well tolerated. Additional combination trials with NEO-102 are underway. Clinical trial information: NCT01040000.
Reportable actionability versus pragmatic actionability: Implementing precision medicine at three large health systems.
Authors: Michael A. Thompson, Ali Zaman, Alissa M Winzeler, Jonathan Kern, Aradhana Ghosh, Jonathan Hirsch, Jennifer Godden, James Leighton Weese, Maharaj Singh, Burton Larry Eisenberg, Michael J. Demeure, Nadia Z Haque, Spencer C. Hoover, Steven N. Kalkanis
Journal: Journal of Clinical Oncology (2018)

6539 Background: Precision medicine (PM) molecular panel (MP) testing report actionable findings with associated targeted therapies (including immunotherapies). However, these actionable findings “reported actionability” by molecular testing companies are often not realized as “pragmatic actionability” in the real world setting. We explored the concordance among PM MP therapy recommendations and subsequent drug treatment orders by clinicians at Aurora Health Care (AHC), Henry Ford Health System (HFHS), and Hoag Memorial Hospital Presbyterian (HMHP). Methods: Structured clinical, genomic report data, and treatment orders were obtained from the Syapse database. At AHC, HFHS, and HMHP, we identified 996 MP reports from 748 patients who received testing between 2014 and 2018. Results: 713 MP reports had “reported actionable” (positive) treatment recommendations and a subsequent treatment order across all 3 health systems. 24.4% (174/713) of MP reports were followed by a treatment order that matched to at least one reported actionable treatment. The translation from a MP-reported actionable finding to a prescribed treatment order was 28.1% (105/374) at AHC, 20.9% (9/43) at HFHS, and 20.3% (60/296) at HMHP, which has borderline statistical significance (p = 0.0563). Of the 713 MP reports analyzed, there was an average of 7.8 therapy recommendations per MP report. There were no significant rate differences in actionability of individual drug recommendations between the two molecular testing vendors examined. We did not examine the actionability of MP report recommendations for investigational agents. Conclusions: Of all 996 MP reports in the initial sample, only 17.5% resulted in a treatment order which matched a MP report recommendation. The translation of reported actionability to pragmatic actionability was consistent across all 3 health systems. This may reflect different definitions of “actionable” between molecular testing companies and clinicians as well as patient performance status changes over time, insurance coverage for off-label use, or referral to a clinical trial. Further research is warranted to understand the issues involved.
Patient comorbid conditions and cancer clinical trial participation.
Authors: Joseph M. Unger, Dawn L. Hershman, Mark Fleury, Riha Vaidya
Journal: Journal of Clinical Oncology (2018)

6540 Background: The American Society of Clinical Oncology (ASCO) recently recommended modernizing criteria related to comorbid conditions routinely used to exclude patients from clinical trials. We investigated how baseline comorbid conditions influence clinical-trial decision making and trial participation. We also modeled how reducing major trial comorbidity exclusion criteria might impact participation, to provide a benchmark for evaluation of the ASCO recommendations. Methods: Data were from a large national web-based survey of 5,499 cancer patients in the cancer treatment-decision-making process. Self-reported data on 18 comorbid conditions were collected. We examined how individual and combinations of comorbidities – using the “best” subset method – influenced patterns of trial discussions, offers, and participation. We also simulated how trial participation rates would change if individual and combinations of comorbidity exclusion criteria were removed. Logistic regression was used. Multivariable regression included adjustment for important demographic and socioeconomic variables. Results: Most patients (66%) had ≥1 baseline comorbidities. The most common comorbid condition was hypertension (35%). Hypertension, prior cancer, and hearing loss were most strongly and uniformly associated with outcomes; each increase in the number of these conditions (0 vs. 1 vs. ≥2) was associated with a decreased risk of trial discussions (11% lower, p = .02), trial offers (18% lower, p = .004), and trial participation (22% lower, p = .006). The removal of all comorbidity restrictions would generate an 18% relative increase in trial participation, or (if the overall participation rate is 5%) a 1% absolute increase. Conclusions: The presence of baseline comorbid conditions adversely impacts trial discussions, trial offers, and trial participation itself. Although the modernization of trial eligibility criteria will benefit many patients, this effort alone is unlikely to substantially increase trial participation rates overall.
Predictors of early vs late diffuse large B cell lymphoma (DLBCL) relapses in the Rituximab era.
Authors: Jasmin Jiemin Koh, Soon Thye Lim, Rehena Sultana, Tiffany Pool Ling Tang, Miriam Tao, Farid Mohamad, Eileen Yi Ling Poon, Jason Yongsheng Chan, Nagavalli Somasundaram
Journal: Journal of Clinical Oncology (2018)

e19553 Background: DLBCL has a 40% relapse rate in the rituximab era. Patients who relapse within a year do poorly even with salvage treatment. We aim to compare the clinical features and outcomes of patients who experience early relapse (ER-relapse within 2 years), late relapse (LR– relapse after 2 years) and those who achieve continuous complete remission (cCR- no relapse after 5 years) following curative intent treatment with rituximab-based chemotherapy (RBC). Methods: A retrospective analysis of patients diagnosed with de-novo DLBCL from 1992 to 2017, who received RBC was done. Data was obtained from the Singapore lymphoma study database. Comparisons of the clinical variables of patients with ER, LR and cCR were done using Chi-Square and T-test. Odds ratio (OR) of the outcome variables were calculated using Multinomial Logistic Regression. Overall survival and relapse free survival were estimated using the Kaplan Meier method. Results: Out of 472 patients, 135 had ER, 42 had LR and 295 had cCR. Median survival (95% CI) was 1.4 years (1.16-1.83), 9.86 years (6.86-13.31) and not reached for the 3 groups respectively. Relapse risk after 2 years and 5 years was 12.5% and 4.9% respectively. 98% of patients with residual disease at the end of treatment had ER. The odds of having an ER as opposed to a LR was higher in patients with high LDH [2.63 (1.57-4.42)], more than 1 extranodal site of disease [3.42 (2.56-5.430], and stage 3 or 4 disease [8.82 (4.10-19)] (p < 0.05 for all). Germinal centre or activated B cell subtypes of DLBCL did not predict for ER or LR. Multivariate analysis revealed that patients more than 60 years old or with central nervous system involvement were associated with ER. Conclusions: In the rituximab era, patients with ER have worse outcomes. Clinical factors rather than cell of origin data predicted for poor outcomes. The role of surveillance after 5 years may be limited given the low relapse rates, especially in the subgroup of patients less than 60 years old, with Stage 1 or 2 disease and in the absence of extranodal disease.
Medical image computing to assess tumor infiltrating CD8 T cells, tumor immune phenotype and response to anti-PD-1/PD-L1 immunotherapy in prospective phase 1 trials.
Authors: Roger Sun, Elaine Johanna Limkin, Maria Vakalopoulou, Laurent Dercle, Stephane Champiat, Shan Rong Han, Loic Verlingue, David Brandao, Samy Ammari, Linda Mahjoubi, Antoine Hollebecque, Jean-Yves Scoazec, Aurelien Marabelle, Christophe Massard, Jean-Charles Soria, Charlotte Robert, Nikos Paragios, Eric Deutsch, Charles Ferte
Journal: Journal of Clinical Oncology (2018)

3016 Background: The aim was to develop a radiomic estimator of tumor infiltrating CD8 T-cells, to assess its association with tumor immune phenotype, and to evaluate outcomes of cancer patients enrolled in phase 1 trials of anti-PD-1/PD-L1 monotherapy. Methods: Radiomic features were extracted from contrast-enhanced CTs for 135 patients from the prospective trial MOSCATO. For each patient, RNA-seq data were available and used to quantify CD8 T-cells. A radiomic signature of the expression of CD8 T-cells was trained using elastic-net method. Three independent cohorts were used for validation: (I) 119 patients from The Cancer Genome Atlas (TCGA) to validate the association with gene expression, (II) 100 tumors assumed as either immune-inflamed or immune-desert to analyze the association with the immune-phenotype, (III) 137 patients treated with anti-PD-1/PD-L1 monotherapy in phase 1 trials to assess clinical outcome. Clinical responses were defined according to RECIST1.1. Median value of the radiomic score was used to separate patients into two groups to assess the overall survival (OS). Results: The final radiomic signature kept eight features from the 83 initial ones, and was associated with the gene expression signature of CD8 T-cells in the TCGA validation set (AUC = 0.67, P = 0.002), and the inflamed tumors in the assumed immune-phenotype cohort (AUC = 0.76, P < 0.001). In the cohort of patients treated with immunotherapy, the radiomic score at baseline was higher in patients with objective response (CR + PR) or a controlled disease (SD + CR + PR) at 3 months (P = 0.049 and P = 0.050 respectively) and at 6 months (P = 0.025 and P = 0.013 respectively). OS was higher in patients with a high radiomic score (median OS: 24.3 vs 11.5 mo, HR = 0.58, P = 0.008), which remained significant when taking into account the number of lines of treatment, the Royal-Marsden-Hospital prognostic score, and the volume of the tumor (P = 0.002). Conclusions: The radiomic signature of CD8 T-cells was validated in three independent cohorts. It appears promising in estimating tumor immune phenotype and inferring outcomes of patients treated with anti-PD1/PD-L1 in a non-invasive way.