bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between genetic variations involved in tumor dormancy related genes and clinical outcomes in Japanese patients with gastric cancer.
Authors: Wakatsuki Takeru , Páez David , Zhang Wu , Labonte Melissa Janae , Yang Dongyun , Azuma Mizutomo , Ning Yan , Volz Nico , Stintzing Sebastian , Bohanes Pierre Oliver , El-Khoueiry Rita , Koizumi Wasaburo , Watanabe Masahiko , Lenz Heinz-Josef 
Published: February 2017

43 Background: The major cause of cancer-related death is metastatic growth of disseminated tumor cells (DTCs) from the primary tumor despite approximate resection and adjuvant chemotherapy. Tumor dormancy is a stage in cancer progression in which micrometastases or residual tumor remains occult and asymptomatic until clinical appearance. The regulation of whether DTCs keep to a quiescent state or transit into a proliferative state can be explained through the interaction of the DTCs with the microenvironment, blood supply, and immunosurveillance. This suggests that host genetic background may impact this process. We tested our hypothesis whether polymorphisms involved in tumor dormancy related genes could predict clinical outcomes in gastric cancer (GC). Methods: One-hundred and sixty-nine Japanese patients with histolopathologically confirmed localized GC (stage Ib to IV; AJCC-6th) were enrolled from Kitasato East University Hospital and Fukushima Red Cross Hospital between 2002 and 2010. Twenty-four polymorphisms were selected from VEGF pathway genes, microenvironment related genes, and metastasis suppressor genes. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: The median age was 68 (31-88) years-old, and 64% of patients were males in this cohort. Pathological stages were 17% in stage Ib, 31% in stage II, 36% in stage III, and 17% in stage IV,. Almost all patients received D2 lymphadectomy based surgery and 65% patients received S-1 based adjuvant chemotherapy. The median follow-up periods were 4.0 years. NME1 rs2302254 was associated with significantly shorter disease-free survival (HR 1.555; 95%CI, 1.026-2.359; p=0.032). NME1 rs34214448 (HR 1.732; 95%CI, 1.082-2.770; p=0.036), PAI1 rs1799889 (HR 1.855; 95%CI, 1.032-3.333; p=0.02), and VEGF-A rs699946 (HR 1.678; 95%CI, 1.014-2.778; P=0.042) were associated with significantly shorter overall survival. Conclusions: NME1 rs2302254 may predict early recurrence of Japanese patients with GC. Additionally, survival after recurrence could be influenced by angiogenic factors in a synergic manner.
The prostaglandine E2 transporting organic anion transporting polypeptide OATP4A1: A potential prognostic marker in colorectal cancer?
Authors: Buxhofer-Ausch Veronika , Ausch Christoph A. , Bauer Heike , Mollik Marina , Larijani Aida , Bajna Erika , Svoboda Martin , Kallay Enikoe , Reiner Angelika , Kriwanek Stephan , Sebesta Christian , Hamilton Gerhard , Zeillinger Robert , Thalhammer Theresia 
Published: February 2017

430 Background: Organic anions transporters (OATPs) are important for tumor progression and therapeutic response by regulating cellular levels of hormones, second messenger proteins and drugs. OATP4A1 is a transporter of pro-inflammatory prostaglandin E2 and may contribute to cancer progression. Data on the expression of OATP4A1 and its clinical impact in primary colorectal cancer (CRC) is rare. Our study was designed to proof the overexpression of OATP4A1 in primary CRC. Methods: Frozen samples from 20 unselected CRC patients (pat) and five CRC cell lines were analyzed for OATP4A1 mRNA expression by real time PCR (mean level normalized to the calibrator, MNE). Immunohistochemistry was performed on paraffin- embedded tumor sections from 50 CRC pat., UICC 0-II (25/50 with subsequent relapse). An automatic quantitative image analysis program was applied to quantify OATP4A1 expression. Expression and intensity was correlated with clinical parameters and relapses. Results: Significant (p>0.05) higher levels of OATP4A1 mRNA were observed in 20 cancer samples as compared to adjacent non-cancerous tissue (2.44 vs. 0.46 MNE). The highest expression (9.85 MNE) was observed in a well-differentiated tumor sample. Similar high levels were observed in the COGA1A cell line, expression in the other cell lines ranged between 1.83 and 0.28 MNE. Immunoreactive staining for OATP4A1 was located in the membrane and occasionally in the cytosol of tumor cells, it was exclusively membrane located in the adjacent non-cancerous epithelial cells. The staining intensity was significantly higher in cancer cells compared to non-cancerous areas (1528±326 vs.376±218) while staining of stroma cells was only occasionally detectable. Surprisingly, the highest OATP4A1 levels were observed in immune cells (2839±381 vs.298±56). Data on the clinical impact of OATP4A1 in the early stage CRC pat. will be presented at the meeting. Conclusions: The profound expression of OATP4A1 in CRC cells and in the inflammatory infiltrates supports its implication on cancer progression. Suitability of OATP4A1 as a potential prognostic marker has to be established on a larger patient collective.
Effect of hangeshashinto on wound healing in hamster 5-fluorouracil-induced oral mucositis model with increased keratinocyte migration and reduced inducible prostaglandin E2.
Authors: Kono Toru , Kaneko Atsushi , Matsumoto Chinami , Hibino Tomoko , Shigenobu Tatsuro , Miyano Kanako , Fukutake Masato , Uezono Yasuhito 
Published: February 2017

432 Background: Chemotherapy-induced oral mucositis (COM) is common, but optimal treatment is not established. COM is characterized by prolonged damage with painful inflammation that involves pathological pain-evoking prostaglandin E2 (PGE2). We previously found that hangeshashinto (HST), a Japanese herbal medicine, was effective as a gargle for the treatment of COM and also reduced ulcer healing time in patients with grade 2 or worse COM by half in a randomized, placebo-controlled, double-blind clinical trial. However, little is known regarding the mechanisms underlying the anti-COM response elicited by HST. Thus, the aim of this study was to clarify the effects of HST on cell migration and PGE2 system. Methods: COM was induced in hamsters by a combination of 5-fluorouracil administration and mild abrasion of the cheek pouch, and healing was examined by measuring lesion size. Hamsters were given a diet containing 2% HST or a control diet throughout the experiments. To estimate the direct effects of HST, human oral keratinocytes (HOK) were used to assay migration and PGE2 production. Migration was evaluated 9–24 h after scratch wounding using sterile pipette tips. PGE2 was induced by addition of 10 ng/mL interleukin-1β, and the amount of PGE2 in 6 h culture fluids were measured by EIA. Results: Cheek pouch lesions induced by abrasion were aggravated by 5-fluorouracil. Lesions were significantly smaller in the HST group than in the control group. Migration of HOK was time-dependently increased by HST (30–100 µg/mL). Inducible PGE2 production was reduced by HST without cytotoxicity, while constitutive PGE2 was unchanged. Gene expressions of cyclooxygenase-2, phospholipase A2, and prostaglandin E synthase were down-regulated by exposure to HST, but cyclooxygenase-1 was not affected. Screening tests for active ingredients showed that berberine promoted scratch wound closure in HOK, and that gingerols, shogaols, and flavonoids significantly decreased PGE2. Conclusions: Our data suggest that the anti-COM mechanisms of HST involve the acceleration of wound healing in hamster COM model and inhibition of inducible PGE2 production in HOK.
Prediction of pathologic response of colorectal liver metastases (CRLM) to transcatheter hepatic therapy with irinotecan-eluting beads by hepatic activation of irinotecan.
Authors: Jones Robert Peter , Sutton Paul , Santoyo-Castelazo Anahi , Malik Hassan Zakria , Fenwick Stephen W , Terlizzo Monica , Poston Graeme John , Kitteringham Neil 
Published: February 2017

438 Background: For patients with CRLM, good pathologic response to neoadjuvant chemotherapy is associated with improved overall survival. However, systemic therapy can increase postoperative morbidity and mortality. DEBIRI gives sustained delivery of drug directly to tumor, maximising response and reducing systemic exposure. Predictive markers of response would allow selection of patients most likely to benefit. This study assessed drug metabolism within normal hepatic parenchyma as a predictor of pathologic response of CRLM to DEBIRI. Methods: Patients with resectable CRLM received single targeted DEBIRI (up to 200mg) 1 month pre-hepatectomy. Hepatic parenchyma was harvested at resection. Parenchymal drug metabolism and protein expression were characterised with a novel LC-MS/MS assay and western blot, and correlated with pathologic tumour response. Results: Ten patients assessed. Median residual tumour 30% (range 10-50%), necrosis 40% (range 40-60%) and fibrosis 20% (range 10-40%). Microsomal formation of SN-38 was 0.52-2.19 nmol/mg/min (mean 1.02), SN-38G 0.30-0.59 nmol/mg/min (mean 0.43), APC 0.1-0.24 nmol/mg/min (mean 0.18). There was a negative correlation between SN-38 production and degree of SN-38 glucuronidation (r2=0.42, p=0.04), with no difference between heterozygous/wild-type UGT1A1*28 patients. SN-38 production demonstrated a strong correlation with CES-2 expression (r2=0.96, p<0.001), with a strong correlation between the glucuronidation of SN-38 and UGT1A1 expression (r2=0.76, p=0.01). A moderate correlation between microsomal SN-38 production and degree of tumour necrosis was obtained (r2=0.30, p=0.07). A highly significant correlation between microsomal SN-38 production and degree of tumour fibrosis was observed (r2=0.54, p=0.01). Conclusions: Metabolism of irinotecan varies widely. Production of the active metabolite SN-38 is directly mediated by CES-2, and hepatic production of SN38 predicts degree of tumour fibrosis after DEBIRI. Metabolic profiling may offer a novel predictor of response to DEBIRI.
Prevalence of DPYD gene mutations among patients receiving 5-FU therapy.
Authors: Saam Jennifer , Bowles Karla , Korst Laurie , Kline Kendel , Roa Benjamin , Wagner Susanne , Eldredge Glenn , Abbott Brian L. , Kaldate Rajesh R. 
Published: February 2017

447 Background: Dihydropyrimidine dehydrogenase (DPYD) is the major enzyme that metabolizes 5-Fluoruracil (5-FU), a component of many chemotherapy regimens. Patients with a DPYD gene mutation have higher 5-FU plasma levels, leading to a 50-60% risk of a grade 3-4 toxicity. DPYD mutations have an estimated prevalence of 3-5% in the general population, but full sequencing is rarely performed in published studies. Analyses of the largest set of full DPYD gene sequencing test results from a commercial laboratory database are presented. Methods: A set of 3,083 patients was analyzed. Patient demographics (age, gender, ethnicity) and pre-test grade 3-4 toxicity status (none, 5-FU related, other) were obtained from the test request form. Descriptive analyses were performed to estimate mutation prevalence overall, and by toxicity and ancestry classifications, as well as to characterize mutations of interest. A subset of 24 patients tested for DPYD mutations in response to high 5-FU exposure levels was also analyzed. Results: The overall DPYD mutation prevalence was 7.3%. Mutations were present in 4.7% and 10.3% of patients experiencing none and at least one 5-FU related toxicity pre-test, respectively. Among patients with toxicities pre-test, the prevalence increased from 7.8% to 31.6% for those experiencing a single to all four toxicity types. Among 5-FU related toxicities, mutation prevalence was highest (18.5%) for hematopoietic events. The previously reported founder mutation IVS14+1G>A had a relative prevalence 42.7%, but 30.9% of these mutations were seen in patients not reporting a Western/Northern European ancestry. Among the subset of patients with high 5-FU exposure levels, 29% had a DPYD mutation showing a genetic causality. Conclusions: 5-FU in chemotherapy regimens remains widespread, yet DPYD gene testing utilization remains minimal. Most testing occurs post-treatment in response to a severe toxicity rather than pre-treatment, which would permit physicians to adapt treatment and reduce toxicity risk. Compared to previous studies, this study using full sequencing data from 3083 patients provides robust estimates of DPYD mutation prevalence and helps characterize DPYD mutations of particular interest.
Mutational analysis of locally advanced rectal cancer and response to neoadjuvant chemoradiation.
Authors: Russo Andrea Lyn , Ryan David P. , Borger Darrell R. , Wo Jennifer Yon-Li , Szymonifka Jackie , Kwak Eunice Lee , Blaszkowsky Lawrence Scott , Clark Jeffrey W. , Allen Jill N. , Zhu Andrew X. , Berger David L. , Cusack James C. , Haigis Kevin M. , Hong Theodore S. 
Published: February 2017

449 Background: Preoperative chemoradiation (CRT) is the standard of care for locally advanced rectal adenocarcinoma and leads to pathologic complete response (pCR) rates of 8-20%. pCR has been correlated with improved long term outcomes. Known mutations may contribute to lack of pCR. We retrospectively evaluated our single institution experience to determine rates and potential mutational and clinical predictors of pCR. Methods: With IRB approval, we reviewed 79 consecutive patients with stage II/III rectal adenocarcinoma, diagnosed from 7/2005–6/2010. Patients received preoperative CRT to 50.4 Gy and concurrent 5-FU based chemotherapy prior to total mesorectal excision. Primary endpoint was pCR rate by Dworak tumor regression grade. Mutations were analyzed on pre- and/or post-treatment tissue available for 47 patients with a multiplexed clinical assay on nucleic acid (SNaPshot), which tests for 130 mutations across 15 cancer genes. 32 patients did not have enough tissue for analysis. Other variables including T/N stage, grade, circumferentiality, distance to anal verge, tumor size (continuous, per cm), pre and post-CRT CEA levels, and treatment duration were evaluated using logistic regression analysis. Results: Median age was 58 years and 85% had stage III disease. Among 54% of patients with mutations assessed, the following were present: 37% KRAS, 3% APC, 3% BRAF, 5% NRAS, 4% PIK3CA, 8% TP53. TP53 testing was limited to common mutation sites. In the entire cohort, 20% had a pCR. No patients with BRAF, NRAS or KRAS mutations had a pCR. Patients with a pCR were more likely to have a post-RT CEA ≤ 2.5 (93% vs 62%, p=0.002) and no mutations identified (100% vs 38%, p=0.019). pCR patients had a trend to lower rates of KRAS mutations (0% vs 41%, p=0.1). On UVA, predictors of pCR included: post-RT CEA ≤ 2.5 (OR 8.6, 95% CI 1.03 – 71.9, p=0.047), insufficient tissue to analyze (OR 5.1, CI 1.45-18, p=0.011), and smaller tumor size (OR 0.69, CI 0.48 – 1.0, p=0.05). With a median follow-up of 30 months, there were 3 local and 6 distant recurrences. None with a pCR developed recurrence. Conclusions: Patients with the composite characteristics of being BRAF, KRAS, and NRAS wild type rectal cancer are more likely to have a pCR with preoperative CRT.
Comparative analysis of second and subsequent chemotherapy lines on short- and long-term survival of elderly Medicare metastatic colon cancer patients.
Authors: Hanna Nader , Onukwugha Ebere , Bikov Kaloyan A , Zheng Zhiyuan , Seal Brian S. , Mullins C. Daniel 
Published: February 2017

455 Background: Metastatic colon cancer (mCC) patients often receive multiple lines of chemotherapy as treatment (TX) to improve survival or quality of life, yet the “real world” benefits and risks of multiple TX lines have not been fully examined. Methods: Elderly (65+) SEER-Medicare patients diagnosed with mCC in 2003-2007 were followed until death or 12/31/09 to examine the survival benefits for different chemotherapy lines. The median time between diagnosis date and the starting date of 2nd line was 352 days. Therefore, we restricted comparative analysis of 2nd and subsequent chemotherapy TX lines to patients who survived at least 1 year after mCC diagnosis date. We used Cox regression framework and adjusted for patients’ TX and censoring histories by using inverse probability weighting method. Separate analyses were conducted for short (2 years) and long-term (5 years) survival to examine different benefits of 2nd and subsequent chemotherapy lines. Results: Of 2,600 elderly Medicare mCC patients diagnosed between 2003-2007 and who survived at least 1 year, 2,530 were dead by the end of 2009. Significant factors associated with long-term survival were 1st line therapy(HR = 0.76; p < 0.01), 2nd line therapy (HR = 0.83; p < 0.01) , and subsequent chemotherapy line therapy(HR = 0.85; p = 0.04), as compared to no therapy, age groups 95+ (HR = 3.07; p < 0.01), 85-94 (HR = 1.33; p < 0.01), and 75-84 (HR = 1.10; p = 0.04) as compared to 65+-74, Asian vs. White (HR = 0.71; p < 0.01), and zip code level household median income (HR = 0.98; p = 0.01). For short-term survival, the benefits of 2nd and subsequent chemotherapy lines were maintained until month 29. Patients with poor performance status were less likely to proceed to 2nd line therapy. No statistically significant variables predicting receipt of subsequent chemotherapy lines were identified. Conclusions: Among elderly Medicare mCC patients who survived at least 1 year after diagnosis, 1st line therapy improved both short and long-term survival. 2nd and subsequent chemotherapy line therapy reduced short-term mortality (2 years); however, they didn’t add any additional long term survival benefit (5 years) as compared to 1st line therapy.
Survival impact of surgical resection of primary tumor (SRPT) in metastatic colorectal cancer (mCRC): A population-based cohort study.
Authors: Ahmed Shahid , Leis Anne , Kanthan Selliah , Karim Safiya , Perron Thomas , Haider Kamal , Reeder Bruce , Pahwa Punam 
Published: February 2017

456 Background: Currently there is very low quality evidence available regarding survival benefit of SRPT in patients with mCRC. In the absence of randomization the reported benefit may reflect selection of younger and healthier patients with good performance status (PS). We have undertaken a retrospective cohort study to determine the survival benefit of SRPT in mCRC. Methods: A cohort of 1,378 patients with mCRC diagnosed between 1992-2005 in the province of Saskatchewan was evaluated. Kaplan-Meier curves were used to determine survival. Log-Rank test was done to compare survival between the two groups. Cox regression model was used to adjust survival for important prognostic variables. Results: Median age was 70 yrs (22-98) and M:F was 57:43. 27% had ECOG PS of >1 and 62% had a comorbid illness. 944 (69%) patients underwent SRPT. Among 1,378 patients, 40% were operated for tumor related symptoms (33% obstruction, 6% perforation, and 4% heavy bleeding, mutually nonexclusive). Median follow up time for whole cohort was 7.1 months (inter-quartile range 2.5-17.5). 42.3% received chemotherapy and 19.1% received 2nd generation therapy. Median survival of patients who received chemotherapy was 15.9 months. Patients who underwent SRPT had median overall survival of 18.3 months vs. 8.4 months if they did not have surgery (p<0.0001).On multivariate analysis 5FU-based chemotherapy (HR 0.53; 95%CI: 0.45-0.61), metastesectomy (HR 0.54; 95%CI: 0.45-0.64), SRPT (HR 0.55; 95%CI: 0.48-0.62), and 2nd generation chemotherapy (HR 0.65; 95%CI: 0.54-0.77) were correlated with a better survival whereas, elevated CEA level (1.56; 95%CI: 1.30-1.90), leukocytosis (HR 1.54; 95%CI: 1.33-1.80), ECOG PS >1 (HR 1.48; 95%CI: 1.30-1.69), low albumin (HR 1.44; 95%CI: 1.26-1.64), age ≥ 65 yrs (HR 1.21; 95%CI: 1.10-1.38), anemia (HR 1.16; 95%CI: 1.03-1.31), and symptomatic disease (HR 1.12; 95%CI: 1.0-1.26) were correlated with poor survival. Comorbid illness, smoking, and gender did not correlate with survival. Conclusions: This is the first large cohort study that reveals that SRPT in patients with mCRC improves survival independent of chemotherapy, age, functional status and comorbid illness.
Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer (mCRC): Final analysis—Hokkaido Gastrointestinal Cancer Study Group (HGCSG) trial.
Authors: Yuki Satoshi , Komatsu Yoshito , Fukushima Hiraku , Sasaki Takahide , Amano Toraji , Miyagishima Takuto , Hatanaka Kazuteru , Nakamura Michio , Tateyama Miki , Sakata Yuh 
Published: February 2017

460 Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853–860) previously demonstrated the non-inferiority of Irinotecan plus S-1 (IRIS) to FOLFIRI for mCRC, with progression-free survival (PFS) as the primary endpoint. We previously reported that IRIS plus bevacizumab (IRIS/Bev) is very effective as first-line treatment (Komatsu Y et al. Acta Oncol. 2012 May 4). We now report the final results of this study. Methods: Eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, ECOG performance status (PS) of 0-1, and no history of prior chemotherapy. S-1 (40-60 mg depending on patients body surface area) was given orally, twice daily for 2 consecutive weeks, and 100 mg/m2irinotecan and 5 mg/kg bevacizumab was given intravenously on day 1 and 15, followed by 2-week rest period, within a 4-week cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), PFS, and overall survival (OS). Results: A total of 53 patients were enrolled from October 2007 through March 2009. The results were reported for 52 patients with evaluable lesions. The clinical characteristics of the patients were as follows. The median age was 63.5 years (range, 48 to 82). The male:female ratio was 3:2. The most common grade 3 or 4 adverse events were neutropenia (27%) and diarrhea (17%). Grade 3 or 4 hypertension (21%) was attributed to bevacizumab, but there were no life-threatening adverse events, such as gastrointestinal perforation. On an intention-to-treat basis, OR was 63.5% [95% confidence interval (CI) 50.4-76.5%], and the disease control rate was 94.2%. With a median follow-up time of 51.7 months, median PFS was 17.0 months (95%C.I. 14.2-19.8 months) and median survival time was 39.6 months (95%C.I. 34.2-45.0 months). Conclusions: IRIS/Bev is a remarkably active and generally well-tolerated first-line treatment for patients with mCRC. Randomized control trial comparing this regimen with oxaliplatin containing regimen(XELOX or mFOLFOX6 plus bevacizumab: TRICOLORE study) is already started. Clinical trial information: NCT00569790.