tbuckley/cabot-search huggingface dataset:
The sharing of T cell clones in peripheral CD8+PD-1+ T cells with TILs is a novel biomarker predicting the efficacy of anti-PD-L1 therapy.
Authors: Jie-Fei Han, Zhijie Wang, Yuqi Wang, Jin Song, Jianchun Duan, Hua Bai, Yan-Fang Guan, Jie Wang
Journal: Journal of Clinical Oncology (2018)

e15007 Background: The optimal biomarker to select suitable patients for immune checkpoint blockades (ICBs) therapy remains to be well established. The dynamic variations of molecular alterations during ICBs treatment need to be better understood. Here, we explored a novel biomarker based on T cell receptor (TCR) repertoire (TcR) and traced the variations during PD-L1 blockade delivery. Methods: Patients treated with anti-PD-L1 clinical trials were enrolled in this pilot study (n = 8). Next-generation sequencing (NGS) was performed to assess molecular tumor burden index (mTBI) and estimate tumor mutational burden (TMB) based on a 1021 gene panel, for genomic DNA from tumor tissue and cfDNA. In TcR repertoire analysis, multiple PCR and NGS on the CDR3 region of TCR beta chain was used to reflect the distribution of T cell clones in TILs and peripheral CD8+PD1+ T cells. Results: A number of T cell clones (1-46) in tumor infiltrating lymphocytes (TILs) were shared in peripheral CD8+PD1+ T cells. The ratio of shared clones to top 100 clones in TILs ranged from 0.00% to 23.98%. Patients responding to anti-PD-L1 therapy showed higher ratio of shared clones than non-responding ones (12.98% vs. 0.95%; P = 0.022). Intriguingly, the ratio of shared clones to total CD8+PD1+ T cell clones of peripheral blood showed synchronized change consistent with mTBI and tumor burden. The estimated TMB by our 1021 panel had satisfying correlation with by WES based on TCGA database (R2= 0.98). Furthermore, the ratio of shared clones to top 100 clones in TILs showed better correlations with response to ICBs than estimated TMB, MSI and total CD8+PD-1+ clonality. Conclusions: The high ratio of shared clones to top 100 clones in TILs is a potential and promising biomarker to predict the efficacy of ICBs therapy and reflect the molecular variations during the treatment, which warrants the further validation in large cohort.
Neoadjuvant therapy in advanced melanoma.
Authors: Shalana O'Brien, Jimson Dsouza, Shirly Shohat, Neha Goel, Sanjay S. Reddy, Anthony J. Olszanski, Sujana Movva, Hong Wu, Jian Qin Yu, Miriam Lango, Jeffrey M. Farma
Journal: Journal of Clinical Oncology (2018)

e21555 Background: Treatment paradigms in advanced melanoma are evolving with the success of new targeted and immunotherapies. The purpose of this study is to explore the outcomes associated with neoadjuvant therapy for advanced melanoma at our institution. Methods: We performed a retrospective analysis of all patients diagnosed with melanoma who received neoadjuvant immunotherapy for locally and regionally advanced primary or recurrent disease at an NCI-designated Comprehensive Cancer Center. Demographic information, primary tumor staging and characteristics, treatment regimen, clinical and pathological responses, and radiologic reports were collected. Results: The analytic cohort consisted of 14 patients who either completed or are receiving neoadjuvant immunotherapy. 11 have a cutaneous primary and 3 have an unknown primary. Treatment regimens consisted of PD-1 inhibitor (n = 9), TVEC (n = 1), combination of PD-1 inhibitor and TVEC (n = 3) and combination of CCR2 and PD-1 inhibitors (n = 1). Prior therapy included Ipilimumab in 3 patients and radiation in 2 patients. 5 patients received neoadjuvant therapy for primary disease and 9 patients received neoadjuvant therapy for recurrent disease. 7 patients had overall clinical response (5 complete response (CR), 2 partial response (PR)), 3 patients had stable disease (SD) and 3 patients had progression. 8 patients underwent surgical resection after therapy, 4 of these patients had clinically SD, 1 patient had a PR and 3 patients had progression. Surgeries performed included excision of 2 primary and 2 recurrent sites, 5 lymph node dissections and 1 resection of in-transit disease. Median time to surgery from the start of immunotherapy was 7.5 months (range 0 - 14). 5 patients had a partial and 3 patients had a complete pathological response. 2 patients continued therapy after resection. An additional 6 patients are currently receiving immunotherapy with intent to undergo resection. Median follow-up time from diagnosis was 27 months (range 10 - 95). Conclusions: At our tertiary referral center select patients with locally and regionally advanced melanoma are considered for neoadjuvant immunotherapy with an overall response in 50% of patients. Further studies are currently pending which will likely validate our results.
Retrospective analysis of ipilimumab-induced diarrhea and/or colitis: A single centre review.
Authors: Marco Adelmo James Iafolla, Gregory Russell Pond, Elaine McWhirter
Journal: Journal of Clinical Oncology (2017)

e21064 Background: Ipilimumab is an effective medication in advanced melanoma but can cause severe diarrhea and colitis. This study identified the rate of ipilimumab-induced diarrhea/colitis at the Juravinski Cancer Centre (JCC), its associated factors for development, overall survival (OS) and progression free survival (PFS). Methods: The Ontario Patient Information System was used to retrospectively identify all melanoma patients at the JCC who were treated with ipilimumab 3 mg/kg IV every 3 weeks (September 2012 to June 2016). Patient demographics, medical history, prior melanoma treatments, diagnosis of ipilimumab-induced diarrhea/colitis, interventions to treat the diarrhea/colitis, and OS and PFS were collected. Descriptive statistics summarized characteristics and outcomes. Kaplan-Meier methods estimated time to event outcomes. Cox regression evaluated whether markers were prognostic for time to diarrhea/colitis diagnosis. Results: 71 patients were treated with ipilimumab at the JCC, of which 22 patients (31%) developed diarrhea/colitis of any Grade; 4 patients developed Grade 1, 5 patients Grade 2, 6 patients Grade 3, 3 patients Grade 4, and 4 patients had unclear Grade. 11 patients required prednisone 1-2 mg/kg and 2 patients required anti-TNF treatment to treat their diarrhea/colitis; 1 patient required colectomy due to perforation. 10 patients required treatment discontinuation due to diarrhea/colitis. Whole cohort median OS and PFS was 340 days (95% CI 205, 519) and 110 days (95% CI 91, 138), respectively. Univariate analysis showed that only inadequate hematologic function at time of first ipilimumab application was prognostic of diarrhea/colitis (HR = 6.42, 95% CI 1.44, 28.62; p = 0.015). Conclusions: Our OS, PFS, and rate of all grade ipilimumab-induced diarrhea/colitis are similar to published data, however our rate of Grade &gt; 2 is larger. Additional work is needed to identify risk factors for the development of this immune related adverse event.
EGFR and ERBB2 to determine the metastatic status of mediastinal lymph nodes in lung adenocarcinomas harbouring EGFR mutation.
Authors: Wanning Yang, Lei Xia, Zhenzhou Yang, Henghui Zhang
Journal: Journal of Clinical Oncology (2018)

e21215 Background: Primary bronchogenic carcinomais the leading cause of cancer-related deaths worldwide and a serious threat to human health.Radiotherapy is one of the fundamental treatments for lung cancer; however, thoracic tumour radiotherapy leads to radiation-induced lung injury (RILI) with a 5% to 15% incidence rate. The identification of predictive biomarkers of mediastinal lymph node metastases in lung cancer patients would be an important advancement in personalized cancer therapy. While mediastinal lymph node metastases is a major factor associated with poor prognosis in cancer, little is known of its molecular mechanisms. Methods: Ten patients with lung adenocarcinoma who underwent resection of the primary lesion and lymphadenectomy of mediastinal lymph nodes were included in this study. These 10 samples were divided into two groups: 5 patients for whom mediastinal lymph node metastases occurred within two years were grouped into the trans group, and the other 5 patients for whom mediastinal lymph node metastases did not occur within two years were grouped into the no-trans group. Both tumor RNA and tumor DNA were isolated from pre-treatment paraffin-embedded tumor tissue. Gene expression profiles were obtained using RNA-seq, and gene mutation profiles were obtained using NGS. Gene predictor sets were constructed by evaluating the statistical significance of the expression levels and the mutation frequency of selected genes. Results: Among the 10 samples, Half of the patients had mediastinal lymph node metastases were found to have high degree of EGFR mutations and ERBB2 expression, and the other half of patients did not had mediastinal lymph node metastases were found to have low degree of EGFR mutations and ERBB2 expression. Conclusions: The findings of this study showed that high mutation frequencies of EGFR and ERBB2 gene amplification may be predictors for mediastinal lymph node metastases of lung adenocarcinoma, which can confirm the lymph-node field radiotherapy and improve the efficacy of radiotherapy.
Abstract 13745: Heart Failure is Associated With Depletion of Core Intestinal Microbiota
Authors: Thorben Winkler, Mark Luedde, Femke-Anouska Heinsen, Malte C Ruehlemann, Martina E Spehlmann, Amer Bajrovic, Wolfgang Lieb, Andre Franke, Stephan J Ott, Norbert Frey
Journal: Circulation (2016)

Introduction: Despite current medical treatment approaches, mortality of chronic heart failure (HF) remains high. Novel treatment modalities are thus urgently needed. A recent theory proposes a possible impact of the intestinal microbiome on the incidence and clinical course of HF. This study sought to investigate, if there are specific changes of the intestinal microbiome in HF patients. Methods and Results: The intestinal microbiome of 20 patients with HF with reduced ejection fraction due to ischemic or dilated cardiomyopathy was investigated applying high-throughput sequencing of the bacterial 16S rRNA gene. Microbial profiles were compared to those of healthy matched controls (n=20). According to the Shannon diversity index (measuring the intra-individual alpha-diversity) based on the distribution of operational taxonomic units, HF cases showed a nominally significantly lower diversity index compared to controls (P nom. =0.01), testing for genera abundance showed a tendency towards a decreased alpha diversity of HF patients. Beta-diversity measures (inter-individual diversity) revealed a significant separation of HF cases and controls, (e.g. P weighted UniFrac =0.004). Assessing the individual abundance of core measurable microbiota, a significant decrease of Coriobacteriaceae , Erysipelotrichaceae and Ruminococcaceae was observed on the family level. In line, Blautia , Collinsella , Erysipelotrichaceae and Ruminococcaceae showed a significant decrease in HF cases on the genus level. Conclusions: HF patients showed a significantly decreased diversity of the intestinal microbiome as well as a downregulation of key intestinal bacterial groups. Our data point to an altered intestinal microbiome as a potential target in the pathogenesis and progression of HF. Figure: Differences of taxonomic groups between HF pat. and controls. ns: not significant (p&gt;0.05), *: p&lt;0.05, **: p&lt;0.01, ***: p&lt;0.001. before/after correction for multiple testing.
Effect of adjuvant therapy on resected gallbladder adenocarcinoma: A propensity score matched analysis of national data.
Authors: Gyulnara G. Kasumova, Omidreza Tabatabaie, Rebecca A. Miksad, Sing Chau Ng, Manuel M. Hidalgo, Jennifer F. Tseng
Journal: Journal of Clinical Oncology (2017)

e15669 Background: There is a paucity of data and no consensus regarding administration of adjuvant therapy after resection of gallbladder cancer. In the absence of a completed clinical trial, we retrospectively reviewed US cancer data. Methods: National Cancer Data Base was queried for patients diagnosed with gallbladder adenocarcinoma between 2004-2014 who underwent definitive resection for non-metastatic disease (pT1b, pT2, pT3, pN0, pN1, pNX) and had R0 and R1 resection margins. One-to-one propensity score matching was used to account for potential selection bias in patient and tumor characteristics. Kaplan-Meier method was used to compare overall survival. Results: Of 4830 patients identified, 1489 (30.8%) received adjuvant chemotherapy. Patients who received adjuvant chemotherapy were more likely to be younger, have private insurance or Medicare, have no comorbidities, higher T stage, and moderately to poorly differentiated tumors (all p-values &lt; 0.0001). The majority of patients who received adjuvant chemotherapy also received adjuvant radiation (58.0%). On unadjusted analysis, patients who received adjuvant chemotherapy had no difference in median overall survival compared to those who did not (25.8 vs 29.0 mo; p = 0.3060). After matching for sex, age, race, insurance, comorbidity, facility type, pT stage, lymph node status, resection margins (R0 vs R1), adjuvant radiation, and tumor grade no difference in median overall survival remained between patients who did (21.8 mo) and did not (22.6 mo) receive adjuvant chemo (p = 0.6843). However, after matching on the propensity to receive adjuvant radiation in addition to the above covariates, receipt of adjuvant radiation resulted in a persistently significant increase in median overall survival (27.8 vs 22.2 mo; p = 0.0005). Conclusions: After matching for potential confounders, there is no difference in overall survival for patients who did and did not receive adjuvant chemotherapy after R0/R1 resection for pT1b, pT2, and pT3 gallbladder adenocarcinoma; however, adjuvant radiation does appear to confer a survival advantage. These results support the current treatment guidelines until evidence from RCTs becomes available.
The retrospective analysis of nephrotoxicity for cisplatin dose of CRT compared 100mg/m<sup>2</sup> to 80mg/m<sup>2</sup> for head and neck cancer (HNC) patients.
Authors: Tomoyo Oguri, Kenji Nakano, Naoki Fukuda, Kuniki Kawaguchi, Tetsuya Urasaki, Masatoshi Nishizawa, Mayu Yunokawa, Makiko Ono, Shinichiro Taira, Junichi Tomomatsu, Takashi Toshiyasu, Hiroki Mitani, Shunji Takahashi
Journal: Journal of Clinical Oncology (2018)

e18067 Background: Concurrent chemoradiotherapy (CRT) with single agent cisplatin for patients with head and neck cancers (HNC) have been used as the standard treatment for a long time. Although recommended dose of cisplatin is 100mg/m2, we sometimes reduced cisplatin dose to 80mg/m2 depends on general condition in real world setting. It remains unclear whether the efficacy and the safety, especially in nephrotoxicity, for CRT of HNC patients with cisplatin dose 100mg/m2 or 80mg/m2 are different. Methods: We reviewed medical records of NHC patients who received CRT in our institute retrospectively. The primary objectives of this study were to evaluate the nephrotoxicity and the rate of patients treated with cumulative dose of cisplatin 200mg/m2 or more. Results: During January 2014 to October 2017, 261 HNC patients who received CRT were treated. The starting dose of cisplatin were 80mg/m2 in 118 patients vs 100mg/m2 in 143 patients, respectively. There were more patients over 70 years who received cisplatin in 80mg/m2 than 100mg/m2 (27.1% vs 4.2%, p < 0.001). The mean Creatinine Clearance (Ccr) obtained using the Cockcroft-Gaut at baseline was significantly lower in 80mg/m2 than 100mg/m2 (87.82 vs 97.28, p = 0.0022). There were no significantly differences in patient’s other characteristics as follows gender, performance states, pathology. The incidence of Grade 2 or higher elevation in creatinine was 2 (1.7%) in 80mg/m2 group and 4 (2.8%) in 100mg/m2 group, respectively (p = 0.554). The rate of change in CCR showed no difference between both groups (-5.73% in 80mg/m2 vs -7.63% in 100mg/m2, p = 0.2927), either. The rate of cumulative dose of cisplatin ≧200mg/m2 was significantly higher in 100mg/m2 than 80mg/m2 (97.2% vs 72.0%, p < 0.001). 2-year PFS rate was not significantly different between 80 mg/m2and 100 mg/m2in oropharynx (89.3% vs 88.2%, p = 0.7760) and in hypopharynx/ larynx (70.28% vs 80.92%, p = 0.4740), respectively. Conclusions: Cisplatin dose of CRT for HNC patients in 100mg/m2was feasible without increasing the nephrotoxicity and the rate of cumulative dose of cisplatin ≧ 200mg/m2 was higher compared to 80mg/m2.
Comparison of healthcare resource use and treatment among prostate cancer patients with and without DNA damage repair gene mutations.
Authors: Jinan Liu, Aimee Near, Joseph A. Chiarappa, Keiko Wada, Jenny Tse, Chakkarin Burudpakdee, Ajay S. Behl, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2018)

e17059 Background: DNA damage repair (DDR) gene mutations in prostate cancer (PC) have been associated with differences in prognosis and treatment (tx) response. This study compares healthcare resource utilization (HRU) and tx patterns in PC patients (pts) with and without pathogenic mutations in 24 DDR genes including BRCA1/2, ATM, TP53 and PTEN. Methods: Pts ≥18 years old that were newly diagnosed with PC from 6/30/2011 to 3/1/2016 were identified in IQVIA’s medical and prescription claims databases linked to FoundationOne genomic assay results; the first PC diagnosis was the index date. Pts had ≥6 months baseline and ≥12 months follow up information, and ≥1 medical claim and ≥1 prescription claim every 6 months during follow up. All-cause HRU and tx patterns were compared in pts harboring ≥1 DDR gene mutation (DDR+) vs. no mutation (DDR-). Results: A total of 348 pts were tested for DDR gene mutations, 274 DDR+ and 74 DDR-. Demographic and clinical features were similar for both cohorts (mean age 65 years, mean Charlson Comorbidity Index 0.64). TP53 (59%), PTEN (42%), and BRCA2 (15%) mutations were the most common DDR alterations. HRU and tx patterns were similar between cohorts in the first year of follow up, except that pts with DDR mutations had fewer visits to specialists other than oncologists, urologists, or general practitioners (82% vs. 93%, p < .05). Among 348 pts, 180 DDR+ and 48 DDR- pts had 2 years of follow up. Mean pharmacy use was higher in DDR+ pts (74.4 vs. 59.1 claims per pt, p < .05), and was driven by differences in PC-specific drugs (11.1 vs. 6.5 claims per pt, p < .05). Over 2 years, more DDR+ pts received androgen deprivation therapy (ADT) (84% vs. 63%, p < .05) and at least 1 tx for metastatic PC (41% vs. 19%, p < .05) than DDR- pts. Other non-PC specific pharmacy use and HRU categories (outpatient visits, laboratory, radiology, radiotherapy) were similar between cohorts. Conclusions: Non-pharmacy HRUs were similar between cohorts. The use of ADT and metastatic PC treatment were significantly higher in DDR+ compared to DDR- pts over 2 years of follow up. This suggests that pts with DDR gene mutations may have more aggressive disease and may benefit from genetically-targeted therapies.
TCT-655 Prevalence, Predictors, Prognostic Significance, and Effect of Techniques on Outcomes of Coronary Lesion Calcification following Implantation of Drug-Eluting Stents: A Patient-Level Pooled Analysis of Stent-Specific, Multi-center, Prospective IRIS-DES Registries
Authors: Cheol Hyun Lee, Jung-Min Ahn, Osung Kwon, Do-yoon Kang, Cheol Whan Lee, Seong-Wook Park, Duk-Woo Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
CX-01, an inhibitor of CXCL12/CXCR4 axis and of platelet factor 4 (PF4), with azacitidine (AZA) in patients with hypomethylating agent (HMA) refractory AML and MDS.
Authors: Eric Huselton, Amanda F. Cashen, Meagan Jacoby, Iskra Pusic, Rizwan Romee, Geoffrey L. Uy, John F. DiPersio, Peter Westervelt
Journal: Journal of Clinical Oncology (2018)

7027 Background: Outcomes are poor for older patients with AML and MDS who progress on HMAs. Blocking the CXCL12/CXCR4 axis may be therapeutic as this is essential for retention of malignant stem cells in the bone marrow (BM), where they may be protected from the genotoxic stresses of chemotherapy. CX-01 is a low molecular weight heparin derivative with minimal anticoagulant activity that disrupts the CXCL12/ CXCR4 axis, and neutralizes the activity of PF4, a negative regulator of megakaryopoiesis. We hypothesized that CX-01 would re-sensitize patients with HMA-refractory AML and MDS to AZA and mitigate thrombocytopenia. Methods: Patients with HMA-refractory INT-1 or greater MDS and AML received 7 day continuous infusion of CX-01 with 7 day AZA 75 mg/m2 in 28 day cycles. The primary objective was to assess the overall response rate (ORR). Results: To date, 20 patients were treated and 12 are evaluable for response with a BM biopsy after C2. The median age was 74 years. 9 patients had secondary AML, 7 had MDS INT-1, 2 had MDS INT-2, and 2 had de novo AML. 10 patients had poor risk cytogenetics and/or p53 mutations. Baseline BM showed a median 16% blasts. Patients were heavily pretreated, receiving a median of 6 cycles of prior HMA cycles (range 4-20) with 10 patients receiving > 1 prior line of therapy. Patients received a median of 2 cycles of CX-01 with AZA (range 0-5). Of the 12 evaluable patients, there was 1 complete response (CR), 3 marrow CRs (with incomplete count recovery), 7 stable disease, and 1 progressive disease for an ORR of 33%. There was no significant difference in baseline characteristics of responders and the rest of the cohort. 3 of 4 responders had hematologic improvement, 2 with normalization of platelet counts. Median duration of response is 212+ days, with 2 patients disease-free at 192 and 233 days, and all four responding patients still alive. CX-01 was well tolerated, with all severe AEs thought unlikely to be related to CX-01. Conclusions: CX-01 and AZA appears to have an encouraging response rate in HMA-refractory AML/MDS. Treatment was feasible with no instances of study related severe AEs. This trial is ongoing to evaluate the ORR and OS of all patients treated. Clinical trial information: NCT02995655.