tbuckley/cabot-search huggingface dataset:
DNA methylation profiling from circulating tumor DNA for early-detection of colorectal cancer.
Authors: Wei Zhang, Jinke Sui, Xianrui Wu, Fuao Cao, Guanyu Yu, Chenyang Wang, Zhihong Zhang, Bingsi Li, Shuai Fang, Han Han-Zhang, Zheng Lou, Haifeng Gong, Lianjie Liu, Nanxin Zheng, Liqiang Hao, Ping Lan
Journal: Journal of Clinical Oncology (2019)

e15076 Background: Colorectal cancer (CRC) develops as a result of neoplastic progression, which often takes decades, providing a window for early detection. Unfortunately, there has been little success in developing blood-based screening method due to the low amount of ctDNA present in the circulation, especially in patients with early stage disease. The role of aberrant DNA methylation, occurring very early in tumorigenesis, has been well elucidated. In this prospective study, we evaluated the potentiality of DNA methylation status obtained from ctDNA as an early detection method. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were extracted using modified wald-test with an adjusted p-value &lt; 0.05 and fold-change &gt; 2. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. We performed targeted bisulfite sequencing on plasma samples of 67 (stage I: 13, II:29, III: 23, IV: 2) Chinese CRC patients and 144 healthy individuals to construct a model for deriving markers that are differentially methylated and their associated weight. The model was validated in 2 independent cohorts. Results: We constructed a model using a support vector machine (SVM)-based machine learning classifier based on top 4,000 differentially methylated regions (DMRs) selected by random forest between tumor and normal plasma samples. Subsequently, 5-fold cross-validation with 100-time repeats were performed to gain a robust estimation of model performance, achieving a sensitivity of 91%, specificity of 98% and area under curve (AUC) of 98.6%. The model was subsequently validated in 2 independent cohorts: one consisted of 57 stage I-III CRC patients and 74 healthy individuals and another one with 47 stage IV patients and the same 74 healthy individuals. The model yielded a sensitivity of 83% and 95% for the early and late stage cohorts, respectively. A specificity of 95% was obtained for both cohorts. Conclusions: Our findings demonstrated the potential of profiling DNA methylation, which can effectively distinguish cancerous from healthy, for the purpose of screening. This method has potential to serve as a supplementary or alternative approach in early detection.
Retrospective analysis of outcomes of cisplatin (CDDP) versus non cisplatin based treatment regimens for concurrent chemoradiotherapy (CCRT) in locally advanced squamous cell head and neck cancer (LA-SCCHN).
Authors: Syed Muhammad Mushtaq Ashraf, Ali Mehmood Raufi, William R Barnett, James Benjamin Williams, Roland T. Skeel
Journal: Journal of Clinical Oncology (2019)

e17564 Background: Different dosing schedules of CDDP are being used as standard of care for CCRT in LA-SCCHN, but there are no adequately powered trials to directly compare other non-CDDP regimens with CDDP to identify the optimal CCRT regimen. Methods: After obtaining IRB approval, we reviewed medical records from hospital tumor registry for consecutive patients with LA-SCCHN to retrieve data regarding demographics, diagnosis and treatment with definitive CCRT between December 2012 and December 2016. All patients had followed up for at least 24 months after completion of treatment. Results: 155 patients were included in the analysis. They fell into 2 groups: 89 (57.4%) had been administered CDDP and 66 (42.6%) received non-CDDP based regimen. In the latter group, 30 (45.5%) received cetuximab, 30 (45.5%) received carboplatin with paclitaxel, 1 (1.5%) received carboplatin with 5-fluorouracil and 5 (7.6%) received carboplatin alone. The majority of patients in both groups had oropharyngeal involvement, approximately 65%. All patients completed treatment with intensity-modulated radiation therapy. Median age was 57 years in CDDP group and 67 years in non-CDDP group. Patients in both groups were predominantly male, Caucasian, with positive smoking history. 67% patients in CDDP &amp; 59% in non-CDDP group were HPV positive. The 2-year overall survival (OS) from initiation of treatment was 73.9% in CDDP and 62.1% in non-CDDP group (hazard ratio = 1.63, 95% CI 0.92 – 2.87, p = 0.092). Comparing non-CDDP regimens with CDDP, cetuximab appeared to confer better 2 year OS in HPV positive patients (HR 0.63, 95% CI 0.40 – 0.98, p = 0.040). Median time-to-treatment failure was 33 months in CDDP group and 24 months in non CDDP group. Conclusions: In this retrospective comparison, there was no significant difference in the 2 year overall survival in patients with locally advanced squamous cell head and neck cancers being treated with cisplatin based concurrent chemoradiotherapy regimen versus a non-cisplatin based regimen.
SP0212 HIGHLIGHTS FROM THE SCIENTIFIC PROGRAMME
Authors: Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> In this presentation we will review the most interesting findings from the scientific programme of this year"s EULAR meeting for for Health Care Professionals. <h3>Disclosure of Interests:</h3> Daniel Aletaha Grant/research support from: AbbVie, Bristol-Myers Squibb, and MSD, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB
Phase 1 study of AMG 119, a chimeric antigen receptor (CAR) T cell therapy targeting DLL3, in patients with relapsed/refractory small cell lung cancer (SCLC).
Authors: Lauren Averett Byers, Alberto Chiappori, Marie-Anne Damiette Smit
Journal: Journal of Clinical Oncology (2019)

TPS8576 Background: SCLC is an aggressive neuroendocrine tumor, with initial sensitivity to chemotherapy and radiotherapy often followed by chemoresistant disease progression. Notch signaling is a key regulator of neuroendocrine differentiation in SCLC, and delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors. DLL3 is expressed in most SCLC tumors but minimally expressed in normal tissues, suggesting that it may be a promising target for cancer immunotherapy. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane CAR that targets DLL3 and redirects cytotoxic T cell specificity to DLL3-positive cells. AMG 119 CAR T cells show potent killing of SCLC cells expressing DLL3 in vitro and inhibit tumor growth in an SCLC xenograft model in vivo. Methods: This phase 1 study will evaluate the safety and tolerability of AMG 119 administered as a single infusion in adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD). Secondary objectives are to evaluate preliminary evidence of antitumor activity, expansion and persistence of AMG 119, and trafficking of AMG 119 to the tumor in post-treatment biopsy. Key inclusion criteria include histologically confirmed SCLC with radiographically documented disease progression or recurrence after at least 1 platinum-based regimen, ECOG performance status 0–1, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. In the cell dose exploration phase, 3–4 patients will receive a single IV infusion of AMG 119 at each cell dose. Cell dose escalation/de-escalation decisions will be guided by a modified toxicity probability interval design. The dose expansion phase will seek to confirm the MTCD or RP2CD and obtain further safety and efficacy data. Clinical trial information: NCT03392064.
Comprehensive immune transcriptomic subtypes of colorectal cancer for development of precision immunotherapy.
Authors: Zhou Jing, Xueguang Guo, Jing Zhao, Xiaochen Zhao, Yuzi Zhang, Mengli Huang, Shangli Cai, Haitao Zhu
Journal: Journal of Clinical Oncology (2019)

e15078 Background: Immune checkpoint blockades (ICBs) have been approved for colorectal cancer (CRC) with microsatellite instability high (MSI-H). However, 50% to 60% MSI-H and almost 100% microsatellite stability (MSS) CRC patients can’t benefit from ICBs treatment. How to warm these “cold tumor” for boosting response to ICBs is still a problem. We aimed to integrate the expression signatures of T cell activation, exclusion and dysfunction to generate immune microenvironment subtypes which may guide precision immunotherapy. Methods: RNA-Seq of 596 CRC patients from The Cancer Genome Atlas were analyzed. T cell activation, dysfunction and exclusion signatures were calculated from TIDE model algorithm. Unsupervised clustering was used to classify CRC into various immune subtypes. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. COX regression multivariate analysis was applied to analyze the association of subtypes with overall survival (OS). Results: Compared with 543 patients with MSS, 83 patients had significantly higher expression of T cell activation related genes (including CD8A, CXCL9, CXCL10, GZMB, IFNG et al) and immune checkpoint genes (including PD-L1, PD-1, LAG3 et al.), but lower signatures scores of M2-like tumor-associated macrophage (TAM) and T cell exclusion ( all P value&lt;0.001). Based on expression signatures of myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF), M2-like TAM, cytotoxic T-lymphocytes (CTL) and PD-L1, all the patients were clustered into four subtypes. Cluster 4 was enriched by MSI-H and characterized with high T cell activation and moderate T cell dysfunction and exclusion. Comparatively, another MSI-H enriched Cluster 1 had both high CTL and T cell dysfunction which indicated that activated T cell might be escaped by tumor cell. Cluster 2 and Cluster 3 were enriched by MSS and characterized with moderate T cell activation and high T cell exclusion. In survival analysis, Cluster 4 had prolonged OS (HR [95% CI]=0.46 [0.27-0.80]) compared with Cluster 1, 2 and 3, after adjusted for age, pathological stage, tumor residue, MSI status, BRAF and PIK3CA mutations. In MSS, Cluster 4 also had better prognosis than the other three clusters (HR [95% CI]=0.38 [0.20-0.73]). Conclusions: Our findings provide evidence to guide further patient stratification in ICBs treatment. The distinct immune subtypes of CRC also paved the way of combination immunotherapy based on immune microenviroment to turn “cold tumor” into “hot tumor”.
Development and evaluation of a proxy for baseline ECOG PS in advanced non-small cell lung cancer (aNSCLC), bladder cancer (aBCa), and melanoma (aMM): An electronic health records (EHR) study.
Authors: Natalia Sadetsky, Ching-Yi Chuo, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2019)

e18194 Background: Performance status measured by ECOG PS (ECOG) predicts therapy choice, and overall survival (OS), but often not reported in routine care. EHR data include rich clinical information which Methods: In this retrospective analysis using Flatiron Health EHR-derived database we selected patients diagnosed from 2011-2018 with aNSCLC, aBCa, and aMM and ECOG reported between diagnosis and 1) therapy start, or 2) within 90 days. We used multivariable logistic regressions in a 75% development sample to model associations between selected sociodemographic, clinical and laboratory measures and poor ECOG (2+ vs 0-1) for each cancer. Predictive accuracy was assessed in 25% validation datasets. Kaplan-Meier analysis tested the associations between observed and predicted poor ECOG with OS. Results: The non-missing ECOG samples were 20,697 aNSCLC, 2627 aBCa, and 2558 aMM (out of 50,876, 6955, and 7917 respectively). The proportion of patients with ECOG 2+ ranged from 28.5% for aNSCLC to 15% for aMM. Higher number of comorbid conditions, older age, lowest BMI, higher number of metastases, abnormal albumin and hemoglobin and public insurance were associated with poor ECOG status. Predictive accuracy for poor baseline ECOG was 71.8% for NSLCL, 73.8% for aBca, and 85.4% for aMM). There was a consistent association between OS and observed and predicted baseline ECOG (Table 1). Conclusions: In a large cohort of cancer patients, routinely collected EHR data were used to predict baseline ECOG PS status. Complete ECOG status results may enhance evaluation of cancer treatment patterns and outcomes in EHR data. [Table: see text]
The Global POLAR program: Two pivotal placebo-controlled studies of calmangafodipir used on top of modified FOLFOX6 to prevent chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Maryam B. Lustberg, Per Pfeiffer, Camilla Qvortrup, Kei Muro, Marie Helene Bengtson, Malin Nittve, Christian Sonesson, Fumiko Nagahama, Yusuke Sonehara, Carl Stefan Carlsson
Journal: Journal of Clinical Oncology (2019)

TPS3616 Background: Oxaliplatin (OXA), is approved in combination with 5-FU/FA (5-fluorouracil/folinic acid; FOLFOX) for metastatic as well as in adjuvant colo-rectal cancer (CRC) treatment. CIPN is a common adverse event, after OXA treatment. The incidence of chronic CIPN is approximately 15% after a cumulative dose of 780 to 850 mg/m² and 50% after a cumulative dose of 1170 mg/m². OXA induced neuropathy, results in greatly reduced nitrated manganese superoxide dismutase (MnSOD) activity. Treatment with a superoxide dismutase mimetic, such as calmangafodipir (CAL), prevents and reverses oxaliplatin-induced neuropathies. This has been demonstrated in the PLIANT study, with CAL (Glimelius et al. 2017). Methods: The POLAR program is a Phase 3, multicenter, placebo (PLC)-controlled program of CAL to prevent CIPN, recruiting in US, Europe (B, D, ES, F,ES, I and UK) and Asia (J, SK, TW and HK) and is described below; POLAR A Patients with CRC, treatment of patients with Stage III or high-risk Stage II who are indicated for adjuvant modified FOLFOX6 (mFOLFOX6) chemotherapy for up to 6 months, randomized in a 1:1 ratio, each arm n = 140: A: CAL (5 µmol/kg) + mFOLFOX6 chemotherapy B: PLC + mFOLFOX6 chemotherapy POLAR M Patients with metastatic colorectal cancer (mCRC), who are indicated for first-line mFOLFOX6 chemotherapy for at least 3 months, without any pre-planned treatment breaks and will be randomized in a 1:1:1 ratio, each arm n = 140: A: CAL (2 µmol/kg) + mFOLFOX6 chemotherapy B: CAL (5 µmol/kg) + mFOLFOX6 chemotherapy C: PLC + mFOLFOX6 chemotherapy Primary objective is to compare CAL vs PLC with respect to the proportion of patients with moderate or severe chronic CIPN. The primary endpoint is; Patient reported symptoms as proportion of patients scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, assessed 9 months after the first dose of chemotherapy. In addition to conventional safety endpoints, Progressive Free Survival and Overall Survival are assessed in the POLAR M study. In the POLAR A study Disease Free Survival is one additional safety endpoint assessed. Results are expected during second half 2020. Clinical trial information: NCT03654729.
Association of high copy number instability (CNI) score with prognosis in patients with gastric cancer after surgical resection.
Authors: Yanling Zhang, Dandan Ren, Beibei Mao, Xue Song, Wanning Yang, Henghui Zhang, Lisheng Cai
Journal: Journal of Clinical Oncology (2019)

e15552 Background: As the fifth most common malignancies and the third leading cause of cancer death in the world, gastric cancer (GC) is often diagnosed in locally advanced or metastatic stage and, therefore, has a poor prognosis. Copy number instability (CNI) score, interpreted as the general measure of genomic instability, was reported as a prognosis predictor of some types of cancer, but its role in prognosis of GC patients remains unknown. The aim of the present study was to investigate its prognostic value in patients with GC after surgical resection and adjuvant chemotherapy. Methods: The present study included 120 patients who had received gastrectomy and adjuvant chemotherapy with stage II-IV GC. Follow-up was available for them. DNA was extracted from primary formalin-fixed paraffin-embedded (FFPE) tumor specimens and matched blood samples. Genomic profiles were analyzed by using a designed panel (1408 genes) based on next generation sequencing (NGS). Results: The most frequently mutated genes were TP53 (49%), PIK3CA (8%), RNF43 (6%) ERBB3 (6%) and APC (6%), and the most frequently amplified genes were TRPS1 (41%), COL1A2 (31%), CSMD3 (29%), ZFHX4 (29%), NAV3 (23%). CNI score was negatively correlated with OS, the CNI-high group had markedly shorter OS than CNI-low group ( p= 0.0093). In addition, there were statistically significant differences in OS between different clinical staging ( p= 0.0468). Moreover, the Cox proportional hazard model showed that CNI score was an independent prognosis factor in GC. Conclusions: The current study indicates that CNI score in primary tumor tissue is an independent predictive prognostic biomarker for GC.
Effect of cholangitis on pre-operative evaluation of regional lymphadenopathy by CT in pancreato-biliary malignancies.
Authors: Abhijit Chandra, Vivek Gupta, Saket Kumar, Pradeep Joshi, Vishal Gupta, Pavan Kumar Gorla, Akshay Anand Agarwal
Journal: Journal of Clinical Oncology (2019)

e15651 Background: Regional lymph nodes metastasis is a poor prognostic factor in pancreato-biliary malignancies. CT findings like lymph node size &gt; 10mm, irregular shape, heterogenous enhancement, conglomeration and infiltration can suggest metastatic involvement. Cholangitis can induce reactive changes in regional lymph nodes. This study aimed to find if episodes of cholangitis interfere with the pre-operative CT evaluation of regional lymphadenopathy in pancreato-biliary malignancies. Methods: Regional lymph nodes metastasis is a poor prognostic factor in pancreato-biliary malignancies. CT findings like lymph node size &gt; 10mm, irregular shape, heterogenous enhancement, conglomeration and infiltration can suggest metastatic involvement. Cholangitis can induce reactive changes in regional lymph nodes. This study aimed to find if episodes of cholangitis interfere with the pre-operative CT evaluation of regional lymphadenopathy in pancreato-biliary malignancies. Results: A total of 41 patients of gallbladder cancer and 20 patients of periampullary cancer were included. A total of 206 lymph node stations were sampled. In gallbladder cancer group, CT finding of lymph node size &gt; 10mm, ill-defined borders and conglomeration; while intra-operative findings were node size &gt; 10mm, hard consistency and necrosis on cut-section significantly predicted metastatic lymphadenopathy on univariate analysis. In multivariate analysis, size &gt; 10mm measured intra-operatively was the only significant predictor of metastatic lymphadenopathy.21.9% patients (9/41) had history of cholangitis pre-operatively. In this subgroup, none of the CT characteristic or intra-operative nodal feature significantly predicted malignant involvement. In periampullary cancer, nodal necrosis on intra-operative cut-section was a significant predictor of malignant involvement in univariate, but not in multivariate analysis. Subgroup analysis of patients with history of cholangitis (10/20) did not reveal any significant pre-operative or intra-operative lymph nodal feature predicting malignant involvement. Conclusions: In patients with gallbladder or periampullary cancer with history of cholangitis, the typical CT characteristics or the intra-operative characteristics of regional lymph nodes cannot be relied on to predict metastatic lymph node involvement. Thus, cholangitis affects the clinical staging of these malignancies.
A first-in-human study of, NUC-7738, a 3'dA phosphoramidate, in patients with advanced solid tumors or lymphoma (NuTide 701).
Authors: Hagen P Schwenzer, Stefan N. Symeonides, Elizabeth Ruth Plummer, Gareth P Bond, Sarah Patricia Blagden
Journal: Journal of Clinical Oncology (2019)

TPS3147 Background: Nucleoside analogs form the backbone therapy for both hematological and solid malignancies. However, their clinical effectiveness is severely limited by key cellular resistance mechanisms linked to increased breakdown, impaired activation and transport. NUC-7738 is a phosphoramidate transformation of cordycepin (3’-deoxyadenosine; 3’-dA), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3’-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3’-dATP, terminating DNA and RNA synthesis. Although 3’-dA has shown potent anti-tumor activity in non-clinical studies, it has not been successful in clinical studies mainly because of rapid enzymatic degradation by adenosine deaminase. NUC-7738 is not a substrate for adenosine deaminase and has been designed to bypass the key resistance pathways which have limited the clinical effectiveness of cordycepin. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors and lymphoma who have exhausted all standard treatment options. The primary objective is to determine the RP2D and schedule of NUC-7738. Secondary objectives include safety, PK/PD and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and dose administration schedule of NUC-7738 for Part 2. Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of patients with advanced solid tumors or lymphoma. The study initiated in Q1 2019. Clinical trial information: NCT03829254.