tbuckley/cabot-search huggingface dataset:
THU0522 CLINICAL MANIFESTATIONS AND COMPARISON OF SUBTYPES OF JUVENILE IDIOPATHIC INFLAMMATORY MYOPATHIES: DATA FROM THE REMICAM REGISTRY
Authors: Jesús Loarce-Martos, Carmen Larena, M. Ángeles Blázquez, Beatriz Joven-Ibáñez, Patricia Carreira, Francisco J López-Longo, Julia Martinez-Barrio, J.C. López Robledillo, Raquel Almodovar, María Jesús García de Yébenes, Laura Nuño
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Juvenile idiopathic inflammatory myopathies (JIIM) are a heterogeneous group of autoimmune diseases affecting children, characterized by symmetric muscular weakness, cutaneous rash and systemic organ involvement. Given its low incidence, there are few studies describing the characteristics of this disease and its subtypes in Spanish patients<sup>1</sup>. <h3>Objectives:</h3> To describe the demographic, clinical and analytical characteristics of patients with JIIM from the registry of inflammatory myopathies in Madrid community (REMICAM), and to compare those measures between polymyositis (PM) and juvenile dermatomyositis (JDM) subgroups. <h3>Methods:</h3> A multicentre retrospective study from the REMICAM registry was performed. Patients were selected if they were 18 years or younger at onset of JIIM and met definite or probable criteria for IIM by the modified Bohan and Peter criteria. We included patients with JDM or PM subgroups, overlap myositis patients were excluded. <h3>Results:</h3> 86 patients were included, 12 classified as PM and 74 as JDM. 70% were women and 96% were Caucasian. Mean age at diagnosis was 11.8 years in PM group vs 7.2 years in JDM group. 44% presented arthritis and 93% presented muscular weakness. Gottron sign was present in 76% of the patients, and calcinosis was present in 31.4%. Cardiac and pulmonary manifestations were rare (&lt;5%). There were no cases of neoplastic disease. Clinical features and complementary analysis are shown in table 1 and table 2. <h3>Conclusion:</h3> JDM was the most frequent form of MIIJ in our study (86%). The most frequent manifestations were the muscular and dermatological ones, but an important group also presented arthritis and fever. There was no statistical difference between both groups, regardless, myalgias and dysphagia were more common in JDM group, and they had higher CPK and aldolase values. PM patients were older, had more fever and arthritis, also, cytopenia and ANA positivity were more common. <h3>Reference:</h3> [1] Shah M, Mamyrova G, Targoff IN, Huber AM, Malley JD, Rice MM, et al. The Clinical Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies. Medicine (Baltimore). 2013 Jan;92(1):25–41. <h3>Disclosure of Interests:</h3> Jesús Loarce-Martos: None declared, Carmen Larena: None declared, M. Ángeles Blázquez: None declared, Beatriz Joven-Ibáñez Speakers bureau: Celgene, Novartis, MSD, Pfizer, AbbVie, and Janssen, Patricia Carreira: None declared, Francisco J López-Longo: None declared, Julia Martinez-Barrio: None declared, J.C. López Robledillo: None declared, RAQUEL ALMODOVAR: None declared, María Jesús García de Yébenes: None declared, Laura Nuño: None declared
A randomized, placebo-controlled, phase III trial-in-progress to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Jian-Ming Xu, Ken Kato, Richard Hubner, Eric Raymond, Yihuan Xu, Sumei Liu, Ibrahim Qazi, Harry H. Yoon
Journal: Journal of Clinical Oncology (2019)

TPS2656 Background: ESCC remains the predominant histological subtype of, and accounts for most deaths from, esophageal cancer. PD-1 inhibition has demonstrated antitumor activity and was generally well tolerated in patients (pts) with advanced unresectable or metastatic ESCC. Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Results from early phase clinical studies suggest single-agent tislelizumab was generally well tolerated and had antitumor activity in pts with solid tumors, including ESCC. Methods: This phase 3, randomized, placebo-controlled, double-blind study (NCT03783442) is designed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment of unresectable, locally advanced recurrent or metastatic ESCC. Adult pts with histologically confirmed ESCC that had metastatic disease either at first diagnosis or with a ≥6 month treatment-free interval will be eligible. Additional eligibility criteria include measurable/evaluable disease, ECOG performance score ≤1, and no prior anti-PD-(L)-1, PD-L2, or other first-line therapy or palliative radiation treatment ≤4 weeks before treatment. Approximately 480 pts will be randomized 1:1 to receive investigator-chosen chemotherapy (ICC) plus tislelizumab 200 mg IV Q3W or ICC plus placebo. Chemotherapy options include: platinum (cisplatin 60–80 mg/m 2 or oxaliplatin 130 mg/m 2 IV Q3W) plus 5-FU 750–800 mg/m 2 IV daily for 5 days Q3W; or platinum plus capecitabine 1000 mg/m 2 orally BID for 14 days Q3W; or platinum + paclitaxel 175 mg/m 2 IV Q3W. Progression-free survival and overall survival are coprimary endpoints; secondary endpoints include objective response rate, duration of response, and health-related quality-of-life. Safety will be assessed by monitoring adverse events, physical examinations, vital signs, and electrocardiograms. This study is actively enrolling. Clinical trial information: NCT03783442.
Impact of age and sex on chemotherapy (CTx) efficacy, toxicity and survival in early oesophagogastric (OG) cancer: A pooled analysis of 3265 patients from four large randomised trials (OE02, OE05, MAGIC &amp; ST03).
Authors: Avani Athauda, Matthew Guy Nankivell, Ruth E Langley, Derek Alderson, William H. Allum, Heike I Grabsch, Ian Chau, Naureen Starling, Stephen Falk, Adrian Crellin, Wasat Mansoor, Fareeda Coxon, Suzanne Darby, Joyce Thompson, Sebastian J. Cummins, Erica Beaumont, Nicholas West, Rupert Langer, Susan Pritchard, David Cunningham
Journal: Journal of Clinical Oncology (2019)

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts &lt;70 and ≥70 years and between males and females. Pts were allocated to receive neoadjuvant platinum and fluoropyrimidine +/- anthracycline and bevacizumab. Mandard tumour regression grade (TRG) and prevalence of ≥G3 toxicities were compared according to the same subgroups using Chi-squared test. Results: 3265 pts were included for survival analysis (2668 (82%) M, 597 (18%) F; 2626 (80%) &lt;70, 639 (20%) ≥70). A significant improvement in disease specific survival (DSS) (HR 0.78; p&lt;0.001) and OS (HR 0.78; p&lt;0.001) was observed in females vs males. Although OS was worse in older vs younger pts (HR 1.15; p=0.01) no significant difference in DSS was observed (HR 1.04; p=0.52). For those pts who underwent resection following neoadjuvant CTx, older patients (19 vs 13%; p=0.01) and female patients (19% vs 13%, p=0.02) were more likely to achieve more favourable Mandard TRG 1&amp;2 scores. Older pts experienced significantly more ≥G3 neutropaenia (30 vs 22%; p=0.004). Females experienced significantly more ≥G3 nausea (12 vs 7%; p=0.006), vomiting (10 vs 5%; p≤0.001) and diarrhoea (9 vs 4%; p=0.001). Conclusions: This study represents the largest pooled analysis of age and sex differences on safety of neoadjuvant CTx and survival in early OG cancer. Females had significantly improved survival while experiencing more GI toxicities. Older pts achieved comparable DSS and thus, dependent on fitness, should be offered the same treatment paradigm as younger pts.
Factors associated with one-year mortality after debulking surgery in older women with ovarian cancer.
Authors: Olga T. Filippova, William P. Tew, Roisin Eilish O'Cearbhaill, Yukio Sonoda, Kara C. Long-Roche, Oliver Zivanovic, Ginger J. Gardner, Dennis Chi, Armin Shahrokni
Journal: Journal of Clinical Oncology (2019)

e17069 Background: The objective of this study was to assess the factors associated with one-year mortality following cytoreductive surgery among women ≥65 years with epithelial ovarian cancer (EOC). Methods: Since 2011, patients aged 65 and older with advanced EOC, who underwent cytoreductive surgery within two months of initial visit, and had at least one year of follow up were included. Mortality data was retrieved from social security death index. Independent variables of interest were age, American Society of Anesthesiologist Physical Status (ASA-PS) classification, preoperative albumin, Memorial Sloan Kettering Frailty Index (MSK-FI), procedure time, intraoperative blood loss, 30-day minor and major adverse events, 30-day readmission and emergency room visits, stage, rate of suboptimal surgery, and receipt of neoadjuvant chemotherapy (NACT). Univariate analysis was performed to assess relationship between these variables and one-year mortality. Results: In total, 263 women (median age 70, range 65-88), of whom 26% had stage IV disease and 5% suboptimal surgery, were included. One-year mortality was 6.5% (n = 17), with six patients dying within six months. On univariate analysis, patients who died within the first year differed from those who were alive at one year in terms of length of stay (13 vs 9 days, p = 0.01), pre-operative albumin (3.8 vs 4.1, p = 0.01), major adverse events (29.4% vs. 12.2%, p = 0.04), and receipt of NACT (33.3% vs. 14.7%, p = 0.05). Patients who died within one year had an insignificant difference in MSK-FI (1.4 vs. 0.8, p = 0.08), and pre-operative hemoglobin (11.4 vs. 12.1, p = 0.06), as well as no difference in in age, ASA-PS, stage, procedure time, blood loss, minor adverse events, readmission and emergency room visits. Patients with suboptimal surgery did not have significantly higher one-year mortality rates, compared to those with optimal resection (11.8% vs. 4.5%, p = 0.5). Conclusions: Cytoreductive surgery in the selected group of older women is safe. In this cohort, age and ASA PS were not among factors associated with one year mortality. More robust risk stratification for this cohort is needed.
Somatic mutational profile of Merkel cell carcinoma treated with immune checkpoint blockade: Preliminary results from a planned multiplatform analysis.
Authors: Evan Rosenbaum, Ciara Marie Kelly, Christopher Andrew Barker, Travis Adamson, Hannah Kiesler, Jasreet Hundal, Alexander J. Paul, Michael D. McLellan, Jason Walker, William D. Tap, Daniel G. Coit, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2019)

e21064 Background: Merkel cell carcinoma (MCC) is an immunogenic neuroendocrine malignancy with promising responses to immune checkpoint blockade (ICB). Although ICB is standard of care in advanced MCC patients, approximately 50% of patients are resistant to ICB. Thus, it is crucial to identify biomarkers predictive of response. Methods: To understand the genomic landscape of MCC, we performed exome capture sequencing on 27 tumor and matched normal samples from 25 patients with MCC treated at Memorial Sloan Kettering. Herein, we report the analysis of 16 paired samples from 14 patients. Nonsynonymous, high-confidence somatic mutations were identified and tumor reads aligned to the Merkel cell polyoma virus (MCPyV) were quantified. Results: Tumor and matched normal samples were sequenced to a median target coverage depth of 53x and 79x reads, respectively. One sample was not analyzed due to inadequate coverage. The MCPyV genome was detected in 12 of 13 patients (92%). The median somatic mutation burden among analyzed samples was 19 nonsynonymous variants per exome (range: 8 - 120). No recurrent driver mutations were identified in any sample. Four samples lacked potential driver mutations and, among the remaining 11 samples, 36 putatively oncogenic mutations were detected in 33 genes (variant allele frequency: 0.08 – 1), including genes involved in the cell cycle checkpoint ( TP53, RB1), DNA damage repair ( ERCC4, FANCA, FANCD2), PI3K-AKT-mTOR ( PIK3CA, PIK3CG), and Notch ( NOTCH1, NOTCH2) pathways. One sample with undetected MCPyV DNA demonstrated loss of heterozygosity of both TP53 and RB1. Four samples contained strand coordinated clusters of mutations in more than 20 distinct gene regions, suggesting an APOBEC-high mutagenesis signature. Conclusions: The MCPyV genome was detected in most tumors analyzed and tumor mutation burden was low in such tumors, consistent with published literature. Analysis of an additional 11 sample pairs is ongoing, along with personalized neoantigen binding predictions on all samples. Immunohistochemistry (IHC) for PDL1 and CD8 expression is in progress. Associations between the aforementioned and response to ICB will be reported.
Esophageal cancer in Hispanic patients: A demographic analysis of the National Cancer Database.
Authors: Juan Ricardo, Jorge Conte, Talal Alkayali, Ahmed Salem, Jamie Huston, Ravi Shridhar, Kenneth L Meredith
Journal: Journal of Clinical Oncology (2019)

6561 Background: Hispanics are the fastest-growing minority accounting for 18% of the US population. The National Cancer Institute estimated 17,290 new cases of esophageal cancer (EC) in the US in 2018. Hispanics are reported to have lower EC prevalence. We sought to interrogate the demographic patterns of EC in Hispanics. Secondary objective was to examine evidence of socioeconomic disparities and differential therapy. Methods: We queried the National Cancer Database to identify patients with EC between 2005–2015. Patients were divided into two groups, Hispanic vs Non-Hispanic (NH). Demographics compared were age, sex, tumor data, surgical intervention, type of treatment, insurance status, income, residence area, and Charlson/Deyo score. Pearson’s Chi-square test was used to compare categorical variables. Groups were matched by propensity score-matched analysis (PSM). Survival analysis was estimated by the Kaplan-Meier method and associated log-rank test. P-value ≤0.05 was considered significant. Results: We identified 85,004 patients with EC; 3,205 were Hispanic (3.8%). In this US population we identified significant disparities between the Hispanic and NH groups. Statistically significant differences among Hispanics included higher prevalence of squamous EC (24.7% vs 19.6%), higher likelihood of stage IV cancer diagnosis (40.7% vs. 34.8%), younger age, higher uninsured status (10.4% vs 3%) with income &lt; $38,000 (26.4% vs 15.9%), and Charlson/Deyo score 0 (72.3% vs 70.7%) when compared to NH. However, Hispanics were less likely to have surgical intervention (29% vs 36.3) and overall less likely to receive any type of treatment (30.1% vs 26.1%). PSM showed that any treatment, insurance status and lower income were predictors of survival. Treated Hispanics survived longer than NH (median survival 17 vs 15 months). Overall survival at 5 years was 22% vs 17%, respectively, p &lt; 0.05. Conclusions: Despite lower prevalence of EC in Hispanics compared to NH, there is a disproportionately higher number of metastatic and untreated cases among Hispanics. This disparity may be explained by Hispanics' limited access to medical care exacerbated by their socioeconomic and insurance status. Further clinical and epidemiologic research is warranted to reveal other factors impacting these health disparities.
Precise prediction of the radiation pneumonitis with RPI: An explorative preliminary mathematical model using genotype information.
Authors: Lehui Du, Baolin Qu, Fang Liu, Na Ma, Shouping Xu, Wei Yu, Xiangkun Dai, Xiang Huang
Journal: Journal of Clinical Oncology (2019)

e14569 Background: Radiation pneumonitis (RP) is the most significant dose-limiting toxicity and is one major obstacle for the radiotherapy of lung cancer. Reliable predictive factors or methods are strongly demanded by radiation oncologists. The purpose of this study is by determining the effectiveness of both genetic and non-genetic factors on their impact on the development of RP, to develop a clinically practicable approach for the risk assessment of RP. Methods: One hundred eighteen lung cancer patients who received radiotherapy were enrolled. RP events were prospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE4.0). Seven hundred thousand single-nucleotide polymorphism (SNP) sites of each patient were tested via Generalized Linear Models via Lasso and Elastic-Net Regularization (GLMNET) to determine their synergistic effects on the risk of grade≥2 RP prediction. Non-genetic factors including patient characteristics and dosimetric parameters were separately assessed by statistic test for their association with the risk of grade ≥2 RP. Based on the results of the aforementioned analysis, a multiple linear regression model named Radiation Pneumonitis Index (RPI) was built, for the assessment of grade ≥2 RP risk. Results: No statistically significant association were found between the RP risk (grade ≥2) and any of the non-genetic factors. Twenty five effective SNPs for predicting the grade≥2 RP risk were discovered and their coefficients of the synergistic effect were determined. An RPI score defined only by the information about these 25 SNPs can successfully distinguish the grade ≥2 RP population with 100% specificity and 97.8% accuracy. Conclusions: Non-genetic factors including important dosimetric parameters may not play dominant roles in the development of RP. Genotype information alone can effectively predict the risk of grade ≥2 RP. The combination of genetics and mathematical algorithms can be a new direction for radiotherapy in the field of precision medicine.
Association of MAPK signaling subtypes with prognostic benefit for bevacizumab in left-sided metastatic colorectal cancer (mCRC) patients treated with FOLFIRI + cetuximab / bevacizumab (FIRE-3 trial).
Authors: Arndt Stahler, Sebastian Stintzing, Dominik Paul Modest, Ivan Jelas, Kathrin Heinrich, Lisa Miller-Phillips, Jobst C. von Einem, Ursula Vehling-Kaiser, Thomas Decker, Alexander Kiani, Ludwig Fischer von Weikersthal, Tobias Heintges, Christoph Kahl, Frank Kullmann, Werner Scheithauer, Markus H. Moehler, Pratyaksha Wirapati, Thomas Kirchner, Andreas Jung, Volker Heinemann
Journal: Journal of Clinical Oncology (2019)

3584 Background: We investigated the role of the MAPK pathway by mRNA expression profiles in microarrays of the FIRE-3 trial as it was formerly associated with prognosis. Methods: 451 patients provided eligible mRNA material for subsequent analyses of the MAPK pathway (295 genes). Non-negative matrix factorized (NMF) clustering for normalized mRNA microarray data (Almac Inc, Xcel Array) was performed for 2 to 6 ranks against randomized controls. Linear models with adjustment for multiple testing showed differential gene expression between groups. Single sample gene set enrichment analysis (ssGSEA) was used to compare differentially enriched hallmarks of cancer gene sets. Kaplan Meier method, log rank test and Cox regression analyses were performed to estimate overall (OS) and progression free survival (PFS) between MAPK subtypes. Results: NMF clustering built two groups of MAPK mRNA expression (coph: 0.91, silh: 1.00) without cohort-based bias in principal component analysis. Group MAPK1 (n = 238) was significantly associated with CMS2 (66.4 %), group MAPK2 (n = 213) with CMS4 (67.6 %, p &lt; 0.0001). 5.551 of 23.561 genes were significantly differentially expressed between MAPK subtypes. 49 cancer hallmark gene sets were significantly differentially enriched in ssGSEA ( MAPK1: myc targets, DNA repair, cell cycle, PI3K- AKT- mTOR pathway upregulation; MAPK2: EMT-related signatures, TGFß pathway, angiogenesis upregulation among others). In overall analysis, MAPK1 showed slightly better outcome than MAPK2 (OS: HR: 0.80, 95% CI: 0.65 – 0.99, p = 0.049; PFS: HR: 0.81, 95% CI: 0.66 – 1.00, p = 0.05). However, MAPK1 was significantly more favourable for bevacizumab treatment in OS ( MAPK1: 30.8 m, MAPK2: 19.4 m, HR: 0.56, 95% CI: 0.39 – 0.81, p = 0.002) and PFS ( MAPK1: 11.7 m, MAPK2: 9.8 m, HR: 0.68, 95% CI: 0.48 – 0.98, p = 0.038) in left sided tumors, while no difference was seen for cetuximab treatment, RAS and BRAF status. Conclusions: mCRC subtypes by MAPK mRNA expression might contain prognostic information for the treatment with bevacizumab beyond mutational status in patients with left sided tumors of the FIRE-3 trial.
Is microsatellite instability a negative prognostic factor in early stage endometrial cancer patients?
Authors: Sahin Lacin, Gozde Elif Tasar, Alp Usubutun, Zafer Arik, Yusuf Karakas, Deniz Yuce, Mehmet Coskun Salman, Ayse Kars
Journal: Journal of Clinical Oncology (2019)

e17107 Background: Endometrial cancer(EC) is a heterogeneous disease with diverse histological features and biological behaviour. Microsatellite instability (MSI) which occurs in cancerous tissue secondary to mismatch repair (MMR) defect of hereditary or somatic origin is a well-known feature further diversifying genetic tumor landscape. In this study, we aim to investigate the relationship between MSI and prognosis in patients with early stage EC. Methods: The patients diagnosed with EC between 2004 and 2017 were retrospectively analysed in the study. The demographic characteristics, disease stage, menopausal status, and clinical and laboratory values were noted. MLH1, MSH2, MSH6 and PMS2 antibodies were used to detect microsatellite status within the tumor tissue samples. Results: The mean age of the 93 patients and menopause was 60.6 ± 9.8 and 49.68 ± 4.5 years , respectively. The median follow-up period was 28 (1-110) months. At the time of diagnosis, number of the patients with stage IA, IB, II, III, and IV were 5, 64, 8, 14, and 2, respectively. Forty three patients were grad 1, 23 patients grad 2, and 27 patients were grade 3. In terms of microsatellite status, 59 patients (63.4%) were microsatellite stable (MSS) and 34 patients (36.6%) were microsatellite instable(MSI). There was no significant association between MSI and tumor stage or grade (X 2 = 1.97 p = 0.74 and X 2 = 3.2, p = 0.19, respectively). There was a significant relationship between peritumoral lymphocyte infiltration rate (pTIL) and MSI. PTIL ratio was higher in tumoral tissues with MSI, whereas pTIL was low in MSS tumor tissues (X 2 = 28.6, p &lt; 0.0001). Patients with MSI tended to have poorer survival than patients with MSS irrespective of disease stage; mOS rates were 76 and 91 months, respectively (p = 0.086). However, patients with early stage disease and MSI had significantly poorer survial in comparison to patients with similar disease stage and MSS: Overall survival rates for patients with MSI and MSS were 75.8 and 94.7 months, respectively (Log-rank p = 0.048). Conclusions: There is a limited number of studies assessing the association between MSI and clinical outcomes in EC. Our study hints at the presence of potential relationship between MSI and pognosis in patients with MSI. Similar to previous studies performed with various types of tumors we found that EC with MSI attract more immune cells to tumor microenvironments. Interestingly, patients with MSI tended to have poorer prognosis despite augmented immune-cell inftration.