bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational signatures of early-onset colorectal cancer.
Authors: Marsoni Silvia , Zanardi Federica , Iannelli Fabio , Salviato Elisa , Ferrari Francesco , Luraghi Paolo , Lazzari Luca , Sartore-Bianchi Andrea , Siena Salvatore , Abrignani Sergio , Bodega Beatrice , Russo Antonio , Amirouchene-Angelozzi Nabil 
Published: May 2019

e15113 Background: Despite a reduction of Colorectal Cancer (CRC) incidence in western countries in the past decades, Early-Onset CRCs (EO-CRC, patients diagnosed with CRC ≤ 40 years old) incidence has increased. Although frequently occurring in the context of familial syndromes, EO-CRCs are mainly sporadic cases and phenotipically enriched for distal localisation and advanced stage at diagnosis. Whether EO-sporadic CRCs pathogenesis differs from that of normal-onset (NO) CRC and how this might impact incidence rates is currently unknown. This had prompted us to ask if, at the genetic level, “traces” of peculiar pathogenic processes could be identified in EO-specific (or -enriched) genetic signatures (GS). Methods: The mutational signatures of 424 TCGA CRC patient samples (19 EO and 405 ≥ 50 years at diagnosis) were analyzed and the similarity between each mutational profile and COSMIC GS was calculated using Bioconductor R package Mutational Patterns (doi: 10.1186/s13073-018-0539-0). Unsupervised hierarchical clustering of the samples according to similarity to GS was performed in single cohort and pooled analysis. Association between age and individual GS was assessed through grouped and linear correlation analysis. Results: EO-CRC patients were grouped in three main clusters: Cluster1 exposing a major similarity with GS10 (associated with defects in polymerase proofreading activity), Cluster2 showing stronger similarities with GS6 (associated with mismatch repair deficiency), and GS1 (associated with 5-MeC deamination) and Cluster3 presenting similarity with multiple GSs, such as 3 (associated with homologous recombination deficiency) and 5 (pathogenesis unknown). Overall this clustering was maintained when EO-CRC samples were pooled with NO CRC. Grouped and correlation analysis revealed no significant association between age and individual GSs, including GS1 (associated with age). Conclusions: These preliminary analyses show that the relative contribution of known GS is similar in EO and NO cohorts of patients. Possible enrichment for EO-CRC in specific signature clusters will be analysed on a wider sample series.
The mutational landscape of MSI-H and MSS colorectal cancer.
Authors: LI Enxiao , Hu Ying , Han Wenbo , Liu Tianshu , Lv Fang , Zhao Lili , Liu Yang , Chen Yanhui , Zhang Henghui 
Published: May 2019

e15122 Background: The microsatellite instability-high (MSI-H) phenotype confers good prognosis and greater response to immunotherapy in colorectal cancer(CRC). The mutational landscape of MSI-H CRC is unclear. This study was designed to illustrate the difference mutation profile between the MSI-H and microsatellite stable (MSS) CRC. Methods: Tumor tissue and matched blood samples from 40 patients with colorectal cancer were collected. Microsatellite instability (MSI) status were detected by PCR-amplified for five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). Mutation profiles were sequenced by a cancer gene-targeted NGS panel. Results: The tumor mutation burden(TMB) of the MSI-H CRC patients was significantly higher than those MSS CRC patients. Compared with the MSS CRC, MSI-H CRC involved more genes and pathways. Furthermore, we found the copy number variation (CNV) was different between the two groups. The copy number instability (CNI) score of MSI-H CRC patients was significantly lower than those MSS CRC patients. MSI-H CRC patients showed a higher frequency of TP53 gene CNV gain compared with MSS CRC (41% (7/17) in MSI-H CRC versus 13% (3/23) in MSS CRC). Conclusions: The mutational landscape are different between the MSI-H and MSS colorectal cancer. Compared with MSS colorectal cancer, the MSI-H colorectal cancer patients have higher tumor mutation burden(TMB) and lower copy number instability (CNI) score. Keywords: colorectal cancer, microsatellite instability, tumor mutation burden, copy number instability. Abbreviations CRC, colorectal cancer; TMB, tumor mutation burden; MSI-H, The microsatellite instability-high; MSS, microsatellite stable; CNV, copy number variation.
Rates of genotyping for KRAS, NRAS, BRAF, microsatellite instability (MSI), and mismatch repair (MMR) in metastatic colon cancer patients: Gaps and implications.
Authors: Gutierrez Martin , Price Kristin Sedgwick , Lanman Richard B. , Nagy Rebecca , Shah Irfan , Mathura Shivam , Norden Andrew David , Goldberg Stuart L. 
Published: May 2019

e15123 Background: Molecular genotyping is essential to optimal treatment selection in metastatic colon cancer (mCC) as mutations in exons 2,3,4 of KRAS and NRAS (expanded RAS) and BRAF V600E predict lack of response to anti-HER2 therapy, and microsatellite instability high (MSI-H) predicts positive response to immune checkpoint inhibitor (ICPI)s. The National Comprehensive Cancer Network (NCCN) first recommended molecular genotyping for mCC in 2009 and by 2016 recommended all pts with mCC have expanded RAS, BRAF, and mismatch repair deficiency (MMRd) testing. This study updates genotyping rates in metastatic colon cancer (mCC) in a real-world practice setting. Methods: We performed a retrospective review of genomic testing patterns from pts with mCC diagnosed between January 2013 and December 2017 from 22 academic and community health centers in the United States who contributed to COTA’s de-identified Real World Evidence database. Results: 563 pts with mCC were identified in the Cota database over the 5-year period. 341 (61%) pts with mCC had testing for KRAS, 130 (23%) for NRAS, 177 (31%) for BRAF, and 297 (53%) for MMRd. Testing rates for NRAS, BRAF and MMRd all increased from 2013 to 2017 but remained suboptimal with undergenotyping rates of 48%, 45% and 12% respectively by 2017. 33 (6%) pts received cetuximab and/or panitumumab without prior testing for both KRAS and NRAS, despite established lack of benefit. Between 2016 and 2017, when NCCN recommended testing for KRAS, NRAS, BRAF and MMRd, only 24% of mCC pts were tested for all biomarkers. Conclusions: Although molecular genotyping rates increased over the described 5-year period, since 2016, less than one quarter of all mCC pts in this cohort received guideline recommended genotyping. Approaches that may improve complete genotyping rates in mCC, such as plasma-based comprehensive genomic profiling, may improve optimal treatment selection and should be tested in prospective trials.
Risk of treatment-related death in carriers of pathogenic DPYD polymorphisms treated with fluoropyrimidine chemotherapy: A systematic review and patient-level analysis.
Authors: Rai Karan , Batukbhai Bhavina D O , Brooks Gabriel A. 
Published: May 2019

e15132 Background: Polymorphisms of the DPYD gene are present in 3-5% of the population and are associated with increased risk for grade ≥3 toxicity during treatment with fluoropyrimidine (FP) chemotherapy. Fatal toxicities in carriers of DPYD polymorphisms have been described in published reports, however reliable estimates of the risk of treatment-related mortality are lacking. Methods: We conducted a systematic review of the MEDLINE database to identify relevant manuscripts published before January 28, 2018. We searched for published studies of patients receiving standard-dose FP chemotherapy (5-fluorouracil or capecitabine) who had pre-treatment testing for ≥1 of 4 pathogenic DPYD polymorphisms (c.1236G > A/HapB3, c.1679T > G, c.1905+1G > A/*2A, and c.2846A > T) and who were systematically assessed for treatment-related toxicities. In the case of retrospective studies, we required that the cohort be defined by pretreatment characteristics (e.g., patients were not included on the basis of observed toxicity). Two reviewers extracted study- and patient-level data, with discrepancies resolved by consensus. The pooled data were analyzed to estimate the risk of treatment-related mortality among polymorphism carriers. Results: Of the 1290 references screened, 37 publications were included in the final analysis. Patient-level data identified 485 of 14,377 patients (3.4%) with pathogenic DPYD polymorphisms. There were 12 deaths among polymorphism carriers, resulting in a 2.5% risk of treatment-related mortality (95% CI 1.3-4.4%). Only 2 treatment-related deaths were reported in 13,892 patients without identified polymorphisms. Risk of death by genotype is shown in the table; two decedents were compound heterozygotes. Conclusions: Patients with pathogenic DPYD polymorphisms who are treated with standard-dose FP chemotherapy are at significant risk of death and can be prospectively identified through pharmacogenetic testing. [Table: see text]
The association between female hormonal supplementation and molecular types in colorectal cancer.
Authors: Chung Seung Won , Overman Michael J. , Morris Van K. , Fogelman David R. , Kee Bryan K. , Dasari Arvind , Raghav Kanwal Pratap Singh , Shureiqi Imad , Jiang Zhi-Qin , Jensen-Loewe Patricia A. , Wolff Robert A. , Eng Cathy , Menter David , Kopetz Scott , Davis Jennifer S. 
Published: May 2019

e15133 Background: In the US, colorectal cancer is the third most common malignancy in women. Postmenopausal hormone use has been associated with decrease in incidence of colorectal cancer however few studies have evaluated the relationship between hormone use and molecular profiles of advanced colorectal cancer. The aim of this study is to evaluate correlations between female hormonal supplementation use and colorectal cancer molecular, clinical, and pathologic features. Methods: We conducted a retrospective case-case study of female patients with metastatic or unresectable, locally advanced colorectal cancer on the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) protocol from 2010 to 2017. Post-menopausal hormone use was self-reported in an environmental survey as part of the ATTACC protocol. Molecular, clinical, and pathologic features were obtained through medical record review. Results: Among 258 female patients, 163 (63%) patients reported ever use of female hormonal supplementation. Ever use was significantly associated with BRAF V600E mutant tumors (OR 2.63, p-value 0.04). There was no association with KRAS, NRAS, PIK3CA mutations, microsatellite instability, or CpG island methylation. The mean age at diagnosis of ever users was 54.4 and mean of no supplement was 56.5 (p-value 0.07), indicating no age difference between ever and never users. Conclusions: Despite the overall protective effects of postmenopausal hormone use on colorectal cancer incidence, among those who develop colorectal cancer, our data suggest an association between female hormonal supplementation and BRAF mutation. Further studies are needed to evaluate this relationship in additional cohorts, interrogate the biological basis, and identify whether there is an association with survival of patients with metastatic or locally advanced colorectal cancer with estrogen or progestin supplement use.
Defining an IBD-like subgroup in consensus molecular subgroups of colorectal cancer and transcriptomic biomarker development for at-risk patients.
Authors: Scanlon Enya , Murphy Seamus J , Kennedy Richard D. , Blayney Jaine K. 
Published: May 2019

e15142 Background: Ulcerative colitis (UC), is a known risk-factor for colorectal cancer (CRC). 10% of UC-patients develop UC-specific CRC yet there are currently no biomarkers for early detection or understanding of drivers of disease. Unresolved inflammation is key in UC-CRC development, yet the aetiology is unclear. It is unknown if UC-CRC falls into a specific consensus molecular subgroup in the CMS classification (Guinney et al 2015). This bioinformatics approach aimed to identify patients at-risk of developing UC-CRC, whilst informing biological and clinical understanding of the disease. Methods: We used publicly available UC data and in-silico, cross platform, class label transfer (GECA) to determine mRNA similarity between UC/UC-CRC and sporadic CRC (sCRC) and to identify a UC-predominant CMS. Pathogenic mutations were identified for each CMS as well as gene set enrichment and survival analysis to determine UC-CRC behaviour comparative to sCRC. Transcriptional relationships were assessed via unsupervised and semi-supervised clustering by immune-signatures and scores to determine molecular patterns between phenotypes. We derived a gene list from UC data informed by clustering to stratify patients based on risk to UC-CRC progression. Results: UC-CRC featured predominantly in the NA group, with 3 attributed pathogenic mutations, an oxidative stress environment and neuroendocrine dysregulation. The subgroup had UC-like clinical features; younger age, distal tumour location and TP53 mutations along with the highest rate of cancer recurrence (~20%) and a unique cellular composition in CMS being highly immune and stromal. Importantly this immune signal was distinct from the interferon type signalling observed in CMS1 and was not associated with PD-L1 activation. Clustering revealed a loss of IFN-type gene expression in colon tissue as UC progressed to UC-CRC. Conclusions: The NA group was thought to be unclassifiable samples between CMS however, analysis shows UC-CRC enrichment with defined biological characteristics. We have identified novel biology that may inform the risk of developing UC-CRC and guide potential preventative and therapeutic approaches.
Characteristics of colorectal patients who discontinued oxaliplatin therapy.
Authors: Buchholz Alexander , Sahmoun Abe E , Kurniali Peter C. 
Published: May 2019

e15155 Background: The 3rd generation platinum-based drug, Oxaliplatin, is indicated for treatment of stage II-IV colorectal cancer (CRC). Oxaliplatin combination with Fluorouracil and Leucovorin (FOLFOX) yields a 5-year disease free survival rate of 78%. Oxaliplatin use is limited by dose-limiting side effects such as neurotoxicity, peripheral neuropathy, and hepatotoxicity. Between 60 and 95% of Oxaliplatin treated patients experience neurotoxicity. The incidence of neuropathy varies between 4 and 98%, and of hepatotoxicity between 10 and 50%. There are few effective treatments to prevent or modulate neurotoxicity although infusions of calcium and magnesium may be beneficial. We sought to understand the factors that influence the discontinuation of Oxaliplatin. Objectives: 1) Determine the characteristics of CRC patients who discontinued chemotherapy involving Oxaliplatin; and 2) Examine metabolic panel monitoring among CRC patients. Methods: A retrospective chart review of newly-diagnosed adult patients with CRC stages II, III, and IV at Sanford Health. We used SAS v.9.4 to analyze demographic and clinical data. All P were two-sided, and P < .05 were considered significant. IRB approval was obtained from Sanford Health and the University of North Dakota. Results: Data for 197 patients who received chemotherapy involving Oxaliplatin were studied. The mean [SD] age at diagnosis was 58.4 [± 12.9]. The majority 117 (59%) were male and 188 (96%) were White. 48% of patients had stage III and 35% had stage IV disease. 167 (85%) of patients received FOLFOX therapy. 56 (30%) discontinued Oxaliplatin. The median [range] number of cycles of chemotherapy completed before discontinuing Oxaliplatin was 8 [1-16]. Relative to patients who did not discontinue, patients who discontinued were significantly more likely to have of the descending colon (46% vs. 38%; P=0.023). Discontinuers were significantly more likely to experience moderate to severe symptoms (42% vs. 25%; P=0.032). Only 25 (13%) of patients had serum magnesium measured prior to starting chemotherapy. However, the median [range] serum potassium was significantly lower among discontinuers prior to starting chemotherapy (3.9 [3.2-5.3] vs. 4.1 [2.8-8.1]; P=0.023). Among patients (92%) who developed some form of peripheral neuropathy, the mean [SD] serum calcium was significantly lower among discontinuers (9.22 ± 0.52 vs. 9.40 ± 0.49; P=0.044). Conclusions: This study showed that serum potassium and calcium were significantly lower among patients who discontinued Oxaliplatin. Magnesium was measured rarely.
Personalized T cell therapy for metastatic colon cancer.
Authors: Ravindranathan Sruthi , Jajja Mohammad Raheel , Waller Alexandra , Bommireddy Ramireddy , Petersen Christopher , Selvaraj Periasamy , Yang Lily , Lesinski Gregory B. , El-Rayes Bassel F. , Flynn Brianna , Waller Edmund K. 
Published: May 2019

e15183 Background: Current immunotherapies fail to benefit patients with colon cancer, largely due to high molecular heterogeneity and low frequencies of tumor infiltrating lymphocytes. In this study, we are addressing this limitation via a novel technology to expand patient tumor specific T cells ex-vivo, using patient’s matched tumor and peripheral blood mononuclear cells (PBMCs). This technology utilizes tumor membrane vesicles (TMVs) made from excised tumor tissue, as a source of tumor associated antigens, and further modified to express IL-12 and B7-1 for ex-vivo expansion of tumor specific T cells. Additionally, the T cells are cultured with PI3K delta inhibitor (idelalisib) and vasoactive intestinal peptide antagonist (VIPhyb) to increase yield, polyfunctionality and in-vivo persistence. Methods: Matched tumor and blood were collected from consented colon cancer patients. TMVs were prepared from excised tumors by homogenizing and centrifuging the tumor over a sucrose gradient. TMVs were then made to express glycosyl phosphatidylinositol (GPI) linked IL-12 and B7-1 (decorated TMV) via a proprietary protein transfer technology. PBMCs isolated from matched blood were cultured in media with 10ug/ml decorated TMV with/without VIPhyb(3uM) and idelalisib (100nM) for 14 days. T cells were then phenotyped for percentage of IFN gamma secreting CD4+ and CD8+ T cells and injected into PDX mice bearing matched tumors (2 doses of 1 million and 4 million cells, 20 days apart). Results: 14 days after expansion, T cells expanded with decorated TMVs+VIPhyb+idelalisib (TMVs+drugs) resulted in significantly increased number of IFN gamma secreting CD8+ T cells (25% of T cells), when compared to T cells treated with decorated TMVs without VIPhyb and idelalisib (13% of T cells). Further, when injected to PDX mice bearing matched tumors, and followed for differences in tumor growth, we observed that on day 30 after T cell injection, while the tumor volumes increased 4.5-fold in the untreated group, the tumors in the TMVs+drugs group only increased 2.8-fold. Conclusions: In this study, we have thus developed a novel technology to expand patient tumor specific T cells ex-vivo, for adoptive T cell therapy against metastatic colon cancer.
Prognostic value of systemic immune-inflammation index in elderly patients with esophageal squamous cell cancer.
Authors: Ji Shengjun , Chen Qingqing 
Published: May 2019

e15500 Background: The aim is to assess the value of systemic immune-infflammation index (SII) in elderly patients with esophageal squamous cell cancer after radiotherapy. Methods: Total 128 patients larger than 65 years were included. The optimal threshold of SII was determined by establishing a receiver operating characteristic (ROC) curve, and the relationship between SII and prognosis was analyzed. Results: The ROC curve showed that the optimal threshold of the pretherapeutic SII for predicting the efficacy of radiotherapy was 700.97. Univariate analysis showed that SII was significantly associated with radiotherapy (P<0.001). The OS of the low SII group was 83.5%, 62.0%, 48.1% for 1 year, 2 years, and 3 years, respectively. The OS of the high SII group was 75.5%, 30.6%, 24.5% for 1 year, 2 years, and 3 years, respectively. The differences were statistically significant (all P<0.001). Univariate analysis showed that SII, N stage, and TNM stage were all related to the OS (all P < 0.01). Cox multivariate analysis showed that SII were independent prognostic factors. Conclusions: SII is a predictive index for elderly patients with esophageal squamous cell cancer after radiotherapy.
Safety and efficacy of neoadjuvant chemotherapy with S-1 and oxaliplatin plus apatinib for locally advanced gastric cancer.
Authors: Zheng Ya'nan , Yang Xiao , Ni Zhentian , Zhu Zhenglun , Xu Wei , Yang Zhongyin , Liu Wentao , Yan Min , Zhu Zhenggang , Li Chen 
Published: May 2019

e15503 Background: Locally advanced gastric cancer (LAGC) has a poor prognosis. Neoadjuvant chemotherapy can reduce tumor loading, degrade staging and increase possibility of complete resection, thus prolonging the survival of LAGC patients (pts). We conducted a phase II trial to assess the feasibility of SOX regimen in combination with apatinib (an anti-angiogenic agent) as neoadjuvant therapy in LAGC. Methods: This study recruited untreated LAGC pts with pathologically and/or cytologically confirmed adenocarcinoma. Treatment included three 21-day cycles of apatinib (oral, 500 mg qd; discontinued in the last cycle), S-1 (oral, 40-60 mg, bid, day 1-day 14) and oxaliplatin (iv, 130 mg/m2, day 1), followed by radical surgery after 4 weeks. The primary outcome was neoadjuvant therapy related toxicity, and the secondary outcomes included tumor response, R0 resection rate, postoperative pathological evaluation and surgical morbidity. Results: Between December 2, 2016 and August 1, 2018, 31 patients were enrolled. Total 29 patients were eligible for safety and efficacy analyses of SOXA as NAC. During NAC treatment, the incidence of adverse events (AEs, any grade) was 100%, and the incidence of grade 3/4 AEs was 34.48%. No treatment-related death. The ORR of 79.31% (95%CI, 60.28-92.01%) and DCR of 96.55% (95%CI, 82.24-99.91%) were achieved. One patient was evaluated as PD with hepatic metastasis after 3 cycles of preoperative chemotherapy, and this case was inoperable. Resection with curative intent was undertaken in 28 patients with R0 resection rate of 100%. Operative morbidity was observed in 12 of 28 patients including fever (9, 32.14%), anastomotic leakage (1, 3.57%), fat liquefaction of post-surgical incision (1, 3.57%), and gastroparesis (1, 3.57%). Additionally, after surgery 1 patient had pulmonary infection and 1 patient had pleural effusion. The median tumor regression was 90% on pathological findings after surgery. Conclusions: Neoadjuvant therapy with apatinib plus SOX for LAGC showed acceptable toxicity and promising efficacy.