bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significance of monitoring plasma vascular endothelial growth factor signals during treatment of colorectal cancer patients.
Authors: Kakizawa Nao , Suzuki Koichi , Ishikawa Hideki , Watanabe Fumiaki , Hasegawa Fumi , Kikugawa Rina , Tsujinaka Shingo , Futsuhara Kazushige , Miyakura Yasuyuki , Rikiyama Toshiki 
Published: January 2019

577 Background: Vascular endothelial growth factor (VEGF) signals may change during colorectal cancer (CRC) treatment, but monitoring real time changes has not been conducted. Methods: Blood monitoring was carried out to track changes in the status of VEGF ligands (A, C, and D) in CRC patients. Expression was determined by ELISA. Results: VEGF-A monitoring was performed in 148 CRC patients preoperatively and VEGF-C and -D monitoring was performed in 52 metastatic CRC patients. Patients with high VEGF-A had significantly shorter recurrence free survival (p = 0.00438). Univariate analysis associating with recurrence detected high VEGF-A, high pathological stage, and with lymph node metastasis were risk factors, and high VEGF-A was identified as an independent risk factor of recurrence by multivariate analysis. There was no significant difference in prognosis between metastatic CRC patients with high and low VEGF-D in early-line treatment, however, in late line patients with high VEGF-D had significantly worse prognosis than those with low VEGF-D (p = 0.0121). When they had treatment with bevacizumab, same result was seen in late line (p = 0.0416). VEGF-C showed no significant correlation with prognosis. Conclusions: Preoperative high VEGF-A is an important risk factor of recurrence and VEGF targeting drugs might be useful as an adjuvant chemotherapy for the patients with high VEGF-A. In late line chemotherapy, patients with high VEGF-D had poor prognosis in regardless of bevacizumab, therefore, they will be candidates of other anti-VEGF drugs than bevacizumab in late line chemotherapy. Measurement of plasma VEGF level can have benefit for the treatment of CRC patients to predict their recurrence and prognosis. It would be helpful for VEGF targeting drug selection and provide useful information for better treatment strategy.
Identification of site-specific genome alterations in metastatic colorectal cancer: Sub-study 003 of the SCRUM-Japan GI-SCREEN.
Authors: Mizukami Takuro , Takahashi Masaki , Sunakawa Yu , Yuki Satoshi , Kagawa Yoshinori , Takashima Atsuo , Kato Kyoko , Hara Hiroki , Denda Tadamichi , Moriwaki Toshikazu , Shiozawa Manabu , Oki Eiji , Satoh Taroh , Kawakami Hisato , Esaki Taito , Nishina Tomohiro , Okamoto Wataru , Yoshino Takayuki , Nakajima Takako Eguchi 
Published: January 2019

578 Background: Primary tumor sidedness is known to be an independent prognostic factor and a predictor for the efficacy of anti-EGFR antibody. However, limited information is available regarding the role of primary tumor site for the treatment of metastatic colorectal cancer (mCRC) patients (pts), including gene mutation profiles, prognosis, and prediction for treatment. This study was conducted as a sub-study of the SCRUM-Japan GI-SCREEN, the Nationwide Cancer Genome Screening Project in Japan. Methods: Among participants of the GI-Screen 2013-01-CRC, untreated pts with mCRC which samples were collected from primary site were eligible. DNA and RNA were extracted from FFPE tumor samples and then were analyzed by the Oncomine Cancer Research Panel detecting gene mutations, copy number variants (CNV), and fusions across 143 genes in a CLIA certified CAP accredited laboratory. The detected genomic variant data were classified according to genetic drivers of cancer including gain- and loss-of-function or single nucleotide variant based on the Oncomine Knowledgebase. Results: Among 1011 enrolled pts from Feb. 2015 to Mar 2017, a total of 561 samples were analyzed (median age, 66.0 years; 232 [41.4 %] female). Frequency of female, undifferentiated, mucinous or signet ring cell subtype were gradually increased as the primary site became the right side. Median site-specific survival was 22.4 months (m) in the cecum, 25.3 m in the ascending colon, 21.2 m in the transverse colon, 72.5 m in the descending colon, 36.5 m in the sigmoid colon, and 39.6 m in the rectum. Gene alterations differed in each primary site. Among frequently observed gene alterations, FBXW7 mutation in rectum, ATM mutation in transverse colon, BRAF and SMAD4 mutations in ascending colon significantly contributed to poor prognosis. Conclusions: This study revealed the site-specific survival and gene alterations in Japanese mCRC pts. These novel knowledges provide an intriguing background to investigate new targeted approaches in these pts and represent the progress toward precision medicine. We will analyze the site-specific therapeutic effect of molecular targeting agents, including anti-EGFR antibody. Clinical trial information: UMIN000031242.
Epigenetic priming prior to pembrolizumab in mismatch repair-proficient advanced colorectal cancer.
Authors: Murphy Adrian Gerard , Walker Rosalind , Lutz Eric R. , Parkinson Rose , Ahuja Nita , Zheng Lei , Jaffee Elizabeth M. , Azad Nilofer Saba 
Published: January 2019

591 Background: Pembrolizumab results in compelling responses in MMR-deficient CRC. However, most advanced CRC patients have MMR proficient (MMR-p) tumors resistant to PD1 blockade. DNA methyltransferases (DNMT) and histone deacetylases (HDAC) result in silencing of tumor suppressor genes. Preclinical combined HDAC/DNMT inhibition induces susceptibility to immune checkpoints and inhibit tumor growth by re-expressing silenced tumor suppressors. Methods: Single institution, open-label, randomized pilot study (NCT02512172) enrolling patients with advanced MMR-p CRC who progressed on ≥ 1 line of chemotherapy. Patients were randomized to A: oral 5-azacitidine (5AZA, CC486), B: romidepsin or C: combined 5AZA and romidepsin. Patients had pre-treatment biopsy, 14 days of epigenetic therapy with repeat biopsy. All groups began pembrolizumab 200 mg combined with epigenetic therapy until disease progression. Toxicity was assessed using CTCAE v4.0. Results: From 2016 to 2018, 24 patients enrolled with median age of 60 (range 40-69) and median treatment cycles was 3 (range 1-16). There were 2 deaths on study (1 acute kidney injury/ sepsis, 1 cardiac arrest, both unrelated to study drugs). The most common treatment-related hematological AEs in all arms were anemia (63%), lymphopenia (50%) and thrombocytopenia (29%). Most common treatment-related non-hematological AEs in arm A (n = 7) were diarrhea (86%), nausea (86%), fatigue (71%) and anorexia (71%); Arm B (n = 8) were fatigue (63%), dysgeusia (63%), anorexia (63%) and vomiting (63%); and Arm C (n = 9) were nausea (100%), vomiting (100%), fatigue (78%) and anorexia (67%). Treatment-related non-laboratory AEs ≥ grade 3 occurred in 0 patients in Arm A, 3 patients (38%) in Arm B and 3 patients (33%) in Arm C. The most common laboratory AEs in all arms were raised alkaline phosphatase (38%), increased ALT (33%), hyperglycemia (29%), and hypophosphatemia (29%). Conclusions: In this study, the combination of epigenetic agents 5-azacitidine and romidepsin with pembrolizumab is considered safe and generally tolerable in patients with advanced p-MMR colorectal cancer. Further comparison of pre- and post-treatment biopsies is required to determine predictors of response. Clinical trial information: NCT02512172.
Th17 cell pathway-related genetic variants in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC, and FIRE-3.
Authors: Tokunaga Ryuma , Cao Shu , Battaglin Francesca , Lo Jae Ho , Loupakis Fotios , Stintzing Sebastian , Naseem Madiha , Puccini Alberto , Berger Martin D. , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M , Weisenberger Daniel J , Liang Gangning , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef 
Published: January 2019

594 Background: Th17 cells constitute a subset of T-helper cells, and play a role in immune response to extracellular pathogens in the human intestinal tract. Further, Th17 cells are associated with tumor angiogenesis and enhanced efficacy of 5-FU treatment. We thus investigated associations between the Th17 cell pathway-related SNPs and clinical outcomes in patients with metastatic colorectal cancer (mCRC) treated with conventional chemotherapy. Methods: We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC, and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6, or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). Multivariable logistic regression and Cox regression were performed to evaluate the association between candidate SNPs in the Th17 cell pathway and clinical outcomes [tumor response (TR), progression-free survival (PFS), and overall survival (OS)] in each treatment cohort. The meta-analysis approach using the METASOFT software were implemented to quantify the prognostic effect of each SNP using the inverse-variance-weighted effect size, and also to evaluate the heterogeneity across cohorts using the Q statistic. SNPs were coded as additive, dominant, or recessive in the analysis. The Pegasus analysis was also used to identify effects across multiple SNPs and treatment arms. Results: Pathway analysis showed that the Th17 cell pathway was significantly associated with TR ( P = 0.011). There were suggestive associations of IL17F rs763780 with TR (log OR = 0.64, SE = 0.31; P = 0.038), of IL23R rs10889677 with TR (log OR = 0.37, SE = 0.18; P = 0.039), of IRF4 rs872071 with TR (log OR = -0.26, SE = 0.13; P = 0.037), and of IL21 rs2221903 with PFS (log HR = 0.33, SE = 0.15; P = 0.026), although these results were not significant after FDR adjustment. In addition, IL23R rs10889677 had suggestive heterogeneity of effects for PFS across the six cohorts after Cochran’s Q statistic ( P = 0.013). Conclusions: Th17 cell pathway-related SNPs may be predictors for the first-line chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies for mCRC.
Association of consensus molecular subtypes (CMS) with time to progression (TTP), progression free survival (PFS), and overall survival (OS) with second-line FOLFIRI ± regorafenib in metastatic colorectal cancer (mCRC).
Authors: Lee Michael Sangmin , Selitsky Sara R. , Parker Joel S. , Auman James Todd , Wu Yunhan , Hammond Kelli , O'Neil Bert , Sanoff Hanna Kelly , Innocenti Federico 
Published: January 2019

597 Background: LCCC1029 was a 2:1 randomized phase II trial of second-line FOLFIRI plus either regorafenib or placebo in mCRC that showed no statistically significant difference in PFS or OS. CMS, defined using gene expression, is prognostic for PFS and OS in previously untreated mCRC, but the impact of CMS in second-line treatment is unclear, as well as its impact on regorafenib efficacy. Methods: RNAseq on archival tumor tissue was successfully performed in 68 LCCC1029 patients (49 on regorafenib, 19 on placebo). A multinomial elastic net CMS classifier was trained using 6 CRC gene expression data sets with known CMS classification. We built our model with only CMS1-4 classified samples and then applied it to normalized and median adjusted RNASeq from LCCC1029 to classify all samples into CMS1-4. TTP, PFS, and OS were compared using Kaplan-Meier method and log-rank tests, and hazard ratios were estimated using Cox proportional hazards method. Results: Our model had > 93% sensitivity and specificity for CMS1-4 in the training data set; the 17% of non-consensus samples in the training data were predominantly labeled CMS2. We classified the LCCC1029 samples as CMS1 (12%), CMS2 (63%), CMS3 (4%), and CMS4 (21%). CMS was prognostic for TTP (log-rank p=0.03), with median for CMS1 of 2.0 months (95% CI 0.0-4.8) versus 5.6 months (5.3-5.9) for CMS2 and 7.8 months (5.5-10.1) for CMS4. There was a trend toward association between CMS and either PFS (log-rank p = 0.11) or OS (log-rank p = 0.085). CMS2 had superior OS compared to CMS1 (HR 0.39, 95% CI 0.17-0.87, p = 0.02). With our limited sample size, we found no significant interaction between CMS and treatment arm for TTP, PFS, or OS. Conclusions: CMS is associated with significant differences in TTP in second-line treatment of mCRC in LCCC1029, and specific CMS types also have differences in OS. Thus, the prognostic impact of CMS extends to second-line treatment in mCRC, meriting further study of CMS classification in additional non-first-line studies.
Detection of methylated BCAT1 and IKZF1 in stage II/III rectal cancer receiving chemoradiation.
Authors: Chen Chin-Tung , Tufts Lauren , Aggarwal Piyush , Heller Frederick , Weiser Martin R. 
Published: January 2019

602 Background: In liquid biopsy, analyses of circulating tumor DNA (ctDNA) in blood have been used as a tool in cancer screening, identifying tumor mutations and monitoring treatment responses/recurrences. Aberrant methylation of some genes have been associated with cancer. Two genes, BCAT1 and IKZF1, are highly methylated and specific to colorectal cancer (CRC) in blood. Detection of these two methylated genes in post-surgery samples also correlates with higher chance of recurrence. Here we investigated the presence of methylated BCAT1 and IKZF1 at multiple time-points for each patient. Methods: Plasma was extracted from blood within 4 hours of the blood collection. ctDNA were extracted from plasma and bisulphite converted using commercially available kits. Real-time qPCR was used to analyze the converted DNA in three replicates and deemed positive if at least one replicate detected either methylated BCAT1 or IKZF1. Quantification of both genes were determined using separate gene-specific standard curves. Results: Nine Stage II/III rectal cancer (RC) patients was enrolled into the study, with one pre-treatment blood draw and several subsequent draws collected throughout the treatment cycles. five patients tested positive for at least one of the methylated genes prior to treatment. Four of these five patients showed an immediate drop in detection for the assayed genes after one cycle of chemotherapy and either remains at low concentration or is undetectable through the rest of the treatment cycles. These patients either have partial or complete response to the treatment regimen. One patient with continuous high levels of methylated BCAT1 and IKZF1 post-treatment have recurred two months after surgery. Conclusions: Methylated BCAT1 and/or IKZF1 were detected in over 50% of the Stage II/III RC patients pre-treatment. This assay is sensitive to the effect of chemotherapy regimen. A significant number of these patients showed a partial/complete response to their treatment regimen and/or reduction in tumor burden, which is reflected in the loss of detection of these two genes. This study shows that this assay may be a viable tool to pair with Imaging for assessment of patient response to treatment regimen.
Lymphotoxin alpha functional germline genetic variant: A future prognostic factor in colorectal cancer?
Authors: Rocha Mariana , Leite-Pinheiro Fátima , Cardoso Beatriz , Del Rio Maria José , Lojo Teira Antonio , Pires Maria Anjos , Bastos Estela , Ribeiro Ricardo 
Published: January 2019

603 Background: Lymphotoxin alpha (LTa) is a proinflammatory cytokine expressed by inflammatory cells with a role in the regulation of tumor microenvironment (TM). A putatively functional genetic polymorphism in LTA, at locus +80 (Thr26Asn, rs1041981), has been associated with altered expression of LTa. Here, we sought to evaluate whether this polymorphism associates with two main endpoints (progression-free survival (PFS) and overall survival(OS)) in colorectal cancer (CRC). Methods: This retrospective cohort study was conducted in 166 CRC patients from a single tertiary hospital. Whole blood was used to isolate genomic DNA. Genotyping of LTA + 80 C > A was performed through real time-PCR allelic discrimination using specific Taqman probes, and confirmed by sequencing. Retrospective data and long-term outcomes were reviewed. Age and gender-adjusted logistic regression analyses were undertaken. Analyses were conducted after stratification by baseline lymphocyte count (LC) (LC < 1x103/µL vs. > 1x103/µL). Kaplan-Meier curves with Log-Rank test were used. Subsequent multivariate Cox regression proportional hazards models were calculated (P for retention > 0.1). Results: Participants’ median age was 65.9 (IR, 57.5-74.3) years, the majority were males (63%), and 58% with colon cancer. At diagnosis, 45,2% were stage III and 18,1% stage IV. The median follow up time was approximately four years (IQR, 25.5-67.0 months). We found a significant association in carriers of the A-allele to have lower LC on linear trend analysis (P for trend = 0.013). Multivariate comparisons between LTA genotypes of additive model showed an independent protective effect for heterozygous compared with C-homozygous in the association with disease progression (HR = 0.5, 95 CI = 0.3-0.97, P = 0.041), only in subjects with baseline LC >1x103/µL. In this group, a significant independent protective effect for all-cause mortality was observed in A-carriers (HR = 0.4, 95 CI = 0.1-0.97, P = 0.042). Conclusions: This LTA genetic variant in subjects with baseline LC > 1x103/µL is associated with PFS and OS in CRC. The understanding of the impact of this polymorphisms on the evolution of the disease can bring us new information on TM regulation.
Risk score and prognosis modeling based on mRNA expressivity in the tumor microenvironment of GI cancers.
Authors: Lee Sunyoung S. , Jerez Jessica , Elkhanany Ahmed , Farrukh Fateeha , Baird Andrew , Baird Stuart , Dolan Jillian 
Published: January 2019

608 Background: Stromal elements in the tumor microenvironment (TME) impact prognosis and response to therapy. Advances in mRNA-seq improved understanding of gene expressivity, but few models exist to model prognosis in association with mRNA expression. Methods: Clinical data and mRNA-seq of 1,715 patients (pts) – pancreatic adenocarcinoma (PAAD), colorectal adenocarcinoma (CRC), hepatocellular carcinoma (HCC), gastric adenocarcinoma (GAAD), esophageal adenocarcinoma (EsoAd), and esophageal squamous cell carcinoma (EsoSCC) – were obtained from TCGA. The expressivity of 191 genes enriched in cellular and structural components of the TME and clinical data were analyzed using machine learning, multivariable COX model, and Kaplan-Meier (KM) analysis to model risk score (RS) to predict prognosis. Results: Genes associated with good and poor prognosis were identified via machine learning and statistic methods. Higher RS represents worse prognosis with max RS = 1 (Table). In all 6 cancers, high P/G (the expression ratio of genes associated with poor to good prognosis) and old age are related to worse survival except EsoAd with younger pts having worse prognosis. The location of tumors in CRC and sex in HCC impact RS. When pts are grouped into 3 pt groups in each cancer, KM curves in pts with low, intermediate, and high RS are statistically different (p < 0.0001) with high hazard ratio (HR > 2). Conclusions: Analysis of large data was assisted by machine learning and statistics, identifying genes associated with survival and creating RS as a tool to predict prognosis. This provides valuable information about prognosis for pts encountered in the clinic when genomic profiles are given. Computational modeling to predict response to chemotherapy and immunotherapy is underway. [Table: see text]
A KRAS mutation is associated with an immunosuppressive tumor microenvironment in mismatch-repair proficient colorectal cancer.
Authors: Marco Michael , Chen Ching-Tung , Choi Seo-Hyun , Pelossof Raphael , Shia Jinru , Garcia-Aguilar Julio 
Published: January 2019

609 Background: KRAS-mutant (KRASmut) colorectal cancers (CRCs) are associated with worse prognosis and resistance to therapy. We have previously shown that KRASmut CRCs have different transcriptomic signature of stromal and immune-related genes compared to KRAS-wild type (KRASwt) tumors. Here, we validated the immune-related changes in the tumor microenvironment associated with the KRAS mutation in CRC to guide the design of novel immunotherapy strategies. Methods: The expression of different immune markers (T cells, B cells, macrophages, natural killer cells, and immune check ligands) were assessed using multiplex immunofluorescence (M-IF) technique in both tumor core (TC) and invasive margin (IM). Sequential slides were cut from paraffin blocks of CRC resected at our institute. Each slide was stained with 4 immune markers using M-IF technique. The stained slides were scanned, and quantification of immune cells was done using ImageJ software. Student’s t test was used for statistical analyses. DNA was extracted from each tumor and profiled for 420 cancer genes using targeted exome-capture sequencing (MSK-IMPACT assay). DNA mismatch-repair (MMR) proteins deficiency were analyzed by immunohistochemistry. Only MMR-proficient (pMMR) tumors were included. Results: A total of 39 patients with pMMR CRC were included. AJCC stages (I-III) were not different between KRASmut (n = 15) and KRASwt (n = 25) tumors. M2-macrophages (CD68+CD163+ cells) and IL-17-producing cells (IL17+ cells) were significantly higher (p = 0.002, and 2.9e-6 respectively), while T-helper cells (CD3+CD4+cells) were significantly lower (p = 3.9e-4) in TC of KRASmut tumors compared to KRASwt. Treg (CD3+CD4+FOXP3+cells) were significantly higher in IM of KRASmut tumors (p = 0.01). KRASmut tumors had significantly higher ratios of Treg:T-helper cells, and Treg:T cytotoxic cell (p = 0.008, and p = 0.04; respectively). Conclusions: KRAS oncogene is associated with more pro-tumorigenic (M2 macrophages, IL17 and Treg) and less anti-tumorigenic (CD4 T-helper) immune cells in CRC. These results can be used to guide further research to design novel immunotherapy strategies against KRASmut CRC.