bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heritable interleukin-17F (IL17F) gene variation and overall survival (OS) in pancreatic cancer patients (pts): Results from a genome-wide association study (GWAS) in CALGB 80303
Authors: Innocenti F. , Owzar K. , Cox N. , Evans P. , Kubo M. , Hollis D. , Mushiroda T. , Kindler H. L. , Nakamura Y. , Ratain M. J. 
Published: August 2020

4531 Background: CALGB 80303 was a randomized, phase III study in 602 advanced pancreatic cancer (PC) pts treated with gemcitabine plus either bevacizumab or placebo. No difference in OS was observed between the two arms (Kindler, ASCO 2007). As part of the study, we prospectively collected germline DNA for pharmacogenetic studies, originally focusing on the association of candidate genes with OS and toxicity. We subsequently amended the study to conduct a GWAS in order to identify other associations. Methods: Germline DNA was isolated from peripheral blood on 352 pts, and was typed for more than 550,000 SNPs using the Illumina550 platform. The associations between OS and SNPs were investigated using the log-rank test. A review of the clinical data and ancestry genomic analysis identified 294 pts who were clinically eligible and determined to be genetically European, and this subset was used for the primary analysis. Results: For the analysis of OS, pts in both arms were pooled, and two SNPs were associated with OS using genome-wide criteria (p≤10–7). This included an intergenic SNP on chromosome 15 (rs7174643), and a nonsynonymous SNP in the IL17F gene ( rs763780 ) with an allelic frequency of 3.9% (H161R, p<2.7x10–8). Median OS was significantly shorter for the H/R heterozygotes (3.1 months, 95% CI 2.3–4.3, n=23), as compared to the H/H homozygotes (6.8 months, 95% CI 5.8–7.3, n=271). This association remained highly significant when the analysis was stratified by extent of disease or previous radiotherapy. There was no evidence of an interaction with bevacizumab, suggesting that this SNP is prognostic rather than predictive. Conclusions: Heritable variation in IL17F may be a prognostic marker for PC. Wildtype (161H) IL17F is a pro-inflammatory, anti-angiogenic cytokine (Starnes, J Immunol 2001). The 161R mutant IL17F antagonizes wildtype IL17F (Kawaguchi, J Allergy Clin Immunol, 2006), potentially resulting in a pro-angiogenic effect. Replication studies in PC and other solid tumors are indicated. [Table: see text]
Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment in advanced gastric cancer: A nonrandomized multicenter AIO phase II study
Authors: Kanzler S. , Trarbach T. , Seufferlein T. , Kubicka S. , Lordick F. , Geissler M. , Daum S. , Galle P. R. , Moehler M. ,   German Arbeitsgemeinschaft Internistische Onkologie (AIO)
Published: August 2020

4534 Background: Cetuximab has demonstrated high efficacy in combination with irinotecan-based therapies in metastatic colorectal cancer and irinotecan/folinic acid/5-FU (IF) may be an effective alternative to cisplatin-based regimens in advanced gastric cancer. We therefore conducted a phase II AIO study to evaluate the tolerability and efficacy of cetuximab combined with IF as first-line treatment in patients with advanced gastric cancer. Methods: Patients (pts) were eligible with untreated adenocarcinoma of the stomach or oesophagogastric junction, with ECOG performance status (PS) < 2, measurable lesions and adequate organ functions. Pts received weekly cetuximab (first dose 400 mg/m2, subsequent doses 250 mg/m2) combined with chemotherapy consisting of irinotecan (80 mg/m2) plus 24 hours continuous infusion of sodium folinic acid (Na-FA: 200 mg/m2) and 5-FU (1500 mg/m2) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle. Treatment was continued until tumor progression and tumor assessments were performed every 2nd cycle. Results: Between Aug 2006 and Sep 2007, 49 pts were enrolled: 71% were males, median age was 63 years (range 33–77), median PS was 0 (65% pts), and 69% of pts and 31% of pts had gastric and oesophagogastric junction carcinomas, respectively. The median treatment time was 15.2 weeks (range 1.1–69.1). Grade 3/4 toxicities were diarrhoea (17% pts), skin reactions (13% pts), anorexia (9% pts), anaemia and fatigue (7%pts), allergic reactions, leucopoenia and neutropenia (4% pts each). Among 48 response-evaluable pts, the overall response rate (CR + PR) was 42% (CR 4%/PR 38%) and the tumour control rate was 73%. Median progression-free and overall survival times were 8.5 months (36.6 weeks; 95% CI 30.1; 48.1) and 16.6 months (71.1 weeks; 95% CI 50; 93.4), respectively. Conclusions: Cetuximab plus IF was well tolerated and encouraging survival data were observed. Cetuximab combined with chemotherapy in advanced or metastatic gastric cancer is under further investigation in an ongoing phase III trial. No significant financial relationships to disclose.
Impact of dihydropyrimidine dehydrogenase status of biopsy specimens on efficacy of irinotecan plus cisplatin, S-1, or 5-FU as first-line treatment of advanced gastric cancer patients in JCOG9912
Authors: Yamada Y. , Yamamoto S. , Ohtsu A. , Suzuki Y. , Nasu J. , Yamaguchi K. , Denda T. , Tsuji A. , Hara Y. , Boku N. ,   Gastrointestinal Oncology Study Group/Japan Clinical Oncology Group
Published: August 2020

4535 Background: JCOG9912 (randomized phase III trial) showed a significant non-inferiority of S-1 to 5-FU (P<0.001); however, either S-1 or irinotecan plus cisplatin (IP) failed to show superiority to 5-FU (P=0.034 and 0.055, respectively) in overall survival. Excision repair cross-complementing group 1 (ERCC1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are reportedly related to outcome of advanced gastric cancer (AGC) patients (pts) treated with IP or 5-FU. Efficacy analyses are performed to evaluate the status of ERCC1, TS, DPD and 5 biomarkers related to anticancer drug sensitivity in first-line pts treated with IP, S-1, or 5-FU monotherapy under controlled conditions. Methods: Blocks from endoscopic biopsy specimens of primary lesions before chemotherapy were available from 365 of 704 pts in JCOG9912. Using laser-captured microdissection and real-time RT-PCR, we analyzed mRNA expression of ERCC1, TS, DPD in paraffin-embedded specimens. Expression levels of each gene were categorized into low and high values at each median. Results: The subjects with available tissue for analysis were representative of all randomized pts; 232 samples were assessable for TS, 168 for DPD, and 235 for ERCC1. There were no statistical differences in patient numbers between 3 arms. Pts with high TS showed worse progression-free survival (PFS) compared with those with low TS (hazard ratio (HR):1.26 [95%CI: 0.97–1.63]) in all pts; there was no difference in PFS between DPD and ERCC1 expression level. IP showed better PFS than S-1 in low DPD (HR: 0.57 [95%CI: 0.32–1.01]) but not in high DPD (HR: 1.24 [95%CI: 0.76–2.04]); there was no clear difference in PFS between pts treated with IP and S-1 regardless of TS and ERCC1 expression status. S-1 showed almost consistently better PFS than 5-FU regardless of mRNA expression status. Conclusions: This large analysis showed the prognostic value of TS status in AGC pts and the predictive value of DPD status for IP and S-1 as first-line treatment. Studies of DPD as a predictive marker for IP activity in AGC are warranted in future personalized phase III. [Table: see text]
Meta-analyses of randomized trials assessing the interest of postoperative adjuvant chemotherapy and prognostic factors in gastric cancer
Authors: Buyse M. E. , Pignon J. ,   GASTRIC
Published: August 2020

4539 Background: Despite potentially curative resection of stomach cancer, 50%-90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) compared surgery alone (S) to adjuvant chemotherapy (S+CT), but definitive evidence is lacking. Our group has initiated an individual patient data (IPD)-based meta-analysis of all RCTs in the adjuvant gastric setting to quantify the potential benefit of S+CT over S, to study the role of various prognostic factors and their potential interactions with treatments. Methods: All RCTs closed to accrual at the end of 2003 were eligible. Trials with radiotherapy, intraperitoneal chemotherapy, or immunotherapy were excluded. The primary endpoint was OS, the secondary endpoint DFS. Baselines variables included age, sex, tumour size (T) and stage, type of resection (D0, D1, D2 or more), performance status (PS) and geographic area. The Logrank test was stratified by trial and treatment arm. Interaction with treatment was explored with Cox model stratified on trial. No multivariate analysis was performed due to the numerous missing data. Results: Thirty-one eligible RCTs (6,613 patients) were identified. As of December 2008, IPD were available from 16 trials (3,710 patients) with a median follow-up exceeding 8 years. OS benefit was significantly in favour of CT (HR=0.83, 95% CI 0.76–0.91, p <0.0001) with absolute benefit of 6.3% at 5 years. Were associated with lower survival, older age (>66 vs <50) (HR=1.51, 95%CI= 1.31–1.73), PS2 (HR=1.71, 95%CI=1.35–2.15), higher UICC stage (HR=1.41 per unit 95%CI=1.35–1.46) and T>1 (HR=1.57 per unit, 95%CI=1.47–1.67). There was also a strong geographical influence on prognosis (HR=0.30, 95%CI 0.26–0.34 and HR=1.26, 95%CI 1.13–1.41, respectively in Asia and in the US as compared to Europe). Treatment interactions were not identified for all but the stage. Treatment effect appeared slightly stronger for patients with higher stages (HR for treatment effect from 0.88 in stage I to 0.66 in stage IV). Conclusions: Our interim results show a modest but significant OS benefit in favour of adjuvant CT and confirm the impact of tumour staging as well as age and PS on OS. Asian patients have a much better survival than other patients. No significant financial relationships to disclose.
Hereditary diffuse gastric cancer (HDGC): Clinical characteristics of a prospective cohort of HDGC patients with and without CDH1 mutation and patients with sporadic GC
Authors: Shah M. A. , Pristyazhnyuk Y. , Jhawer M. , Coombes S. , Harlan M. , Randazzo J. , Perera R. J. , Pascarelli K. M. , Coit D. , Kelsen D. P. 
Published: August 2020

4543 Background: HDGC is an autosomal dominant cancer syndrome associated with early onset diffuse GC. Germline mutations in E-cadherin(CDH1) cause the disease but are identified in only 20–30% of pts meeting clinical criteria. We began a prospective multicenter GC registry to capture epidemiologic and family history data matched with DNA and tissue to characterize phenotypic and risk factor profiles and their associations with HDGC and other non-HDGC hereditable GC. Herein, we report the clinical characteristics of HDGC, the subset of HDGC pts with CDH1 mutation, pts with sporadic GC, and non-cancer controls. Methods: All patients with GC are eligible for registry participation. HDGC criteria: diffuse GC(< age 45), diffuse GC(< age 50) with 1 relative with GC, diffuse GC(any age) with 2 or more relatives with GC, or a personal or family history of diffuse GC with lobular breast cancer or signet ring colon cancer. Non-HDGC high risk pts: diagnosed < age 50 or with a family history of GC(at least one 1st degree or two 2nd degree relatives with GC), but do not meet HDGC criteria. Sporadic GC: diagnosed > age 50, without family history. Participants complete a family history and epidemiology/ risk factor questionnaire, and provide blood and tissue for repository. Results: 465 participants have enrolled since Jan 2006. Questionnaires are available from 331 participants(69%), see table . CDH1 mutations have been identified in 10 families(16%) and prophylactic gastrectomies in CDH1 mutation carriers have been performed in 8 pts, each without major complications. Pt demographics and epidemiology were not notably different amongst all groups. Conclusions: Except for age and histology, the demographic breakdown and epidemiology of HDGC pts with and without CDH1 mutation is similar to other non HDGC high genetic risk pts and similar to pts with sporadic GC. The GC registry will expand to international sites. (Supported by the DeGregorio Family Foundation) [Table: see text] No significant financial relationships to disclose.
Phase II study of combination therapy with docetaxel, cisplatin, and S-1 (DCS) for advanced gastric cancer: (KDOG 0601)
Authors: Nakayama N. , Koizumi W. , Sasaki T. , Tanabe S. , Nishimura K. , Higuchi K. , Takagi S. , Katada C. , Azuma M. , Saigenji K. 
Published: August 2020

4555 Background: Our previous phase I study (Oncology 2008, 75:1–7) provided evidence that combination chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is effective and well tolerated in patients with advanced gastric cancer. The present multicenter phase II study was conducted to confirm the efficacy and toxicity of DCS in advanced gastric cancer. Methods: Eligibility criteria included a histologically proved diagnosis of gastric adenocarcinoma with at least one measurable metastatic lesion, no previous treatment for gastric cancer except for surgery, an ECOG performance status of 0 to 2, and adequate organ function. Docetaxel (40 mg/m2) and cisplatin (70–60 mg/m2) were given intravenously on day 1, and S-1 was given orally at a dose of 40 mg/m2 twice daily from days 1 to day 14 of a 28-day cycle. Patients received a maximum of 6 cycles. Subsequently, patients were given repeated cycles of S-1 plus docetaxel (DS). The primary endpoint was the objective response rate. Results: 59 patients (47 men, 12 women) were enrolled. The median age was 62 (range: 35–75) years. PS 0/1/2 was 40/18/1. The median number of treatment cycles was 7 (DCS 6+DS 1: range, 1–20). Because myeloid suppression and renal dysfunction developed during the study, we lowered the recommended dose of cisplatin from 70 mg/m2 to 60 mg/m2. The dose of cisplatin was 70 mg/m2 in 19 patients and 60 mg/m2 in 40. The overall response rate was 81.3% (48/59; 95% CI, 80.7–91.2). The response rates with cisplatin 70 mg/m2 and 60 mg/m2 were 78.9% (95% CI, 60.5–97.2) and 82.5% (95% CI, 70.7–94.2), respectively. Tumor down-staging was achieved in 9 (18.7%) of the 48 patients who responded to treatment. The median survival time and median progression-free survival were not reached. Grade 3 or 4 major toxicity comprised leukopenia (44.0%), neutropenia (72.8%), anemia (15.2%), febrile neutropenia (13.5%), anorexia (6.7%), nausea (5.1%), vomiting (5.1%), fatigue (1.6%), and diarrhea (5.1%). There was one treatment-related death caused by the perforation of the primary tumor. This patient refused surgery. Conclusions: DCS was a well-tolerated regimen with a high response rate in patients with advanced gastric cancer. Cisplatin at a dose of 60 mg/m2 was considered adequately effective. No significant financial relationships to disclose.
Prognostic significance of the endoluminal ultrasound defined lymph node metastasis count in esophageal cancer
Authors: Twine C. , Rawlinson C. , Escofet X. , Blackshaw G. , Crosby T. , Roberts A. , Lewis W. 
Published: August 2020

4558 Background: TNM histopathological staging system for esophageal cancer is controversial, and will soon be revised to account for the relative burden of the number of lymph node metastases. The aim of this study was to assess the prognostic significance of endoluminal ultrasound (EUS) defined lymph node metastasis count (eLNMC) in patients with esophageal cancer. Methods: Two hundred and sixty-seven consecutive patients (median age 63 yr, 187 m) underwent EUS followed by stage directed multidisciplinary treatment [183 esophagectomy (92 neoadjuvant chemotherapy), 79 definitive chemoradiotherapy, and 5 palliative therapy]. The eLMNC was subdivided into four groups (0, 1, 2 to 4, >4) and the primary measure of outcome was survival. Results: Survival was related to EUS T stage (p<0.0001), EUS N stage (p<0.0001), EUS tumour length (p<0.0001), and the eLNMC (p<0.0001). Multivariable analysis revealed EUS tumour length (HR 1.071, 95% CI 1.008 to 1.138, p=0.027) and eLNMC (HR 1.302, 95% CI 1.133 to 1.496, p<0.0001) to be significantly and independently associated with survival. Median and 2 year survival for patients with 0, 1, 2 to 4, and >4 lymph node metastases were: 44 months and 71%; 36 months and 59%; 24 months and 50%; and 17 months and 32% respectively. Conclusions: The eLNMC was an important and significant prognostic indicator in patients with esophageal cancer, which should in future be reported and used to revise the perceived radiological stage, in order to inform stage directed multimodal therapy. No significant financial relationships to disclose.
Helicobacter pylori infection as an independent prognostic factor for locally advanced gastric cancer with curative resection
Authors: Kang S. , Hwang Y. , Lee H. , Jeong S. , Choi J. , Jo Y. , Han S. , Kim J. , Han J. 
Published: August 2020

4562 Background: A few studies reported the association between helicobacter pylori (HP) infection and better overall survival (OS) in resected gastric cancer patients (pts). Methods: We investigated the HP infection status and its association with clinicopathologic characteristics in 210 locally advanced gastric cancer patients (stage IB: 18, II: 61, IIIA: 62, IIIB: 31, IV: 38) who underwent adjuvant chemotherapy (CTX) after curative resection (≥D2 dissection). HP infection status in hematoxlin and eosin stained peritumoral tissue was graded according to the updated Sydney System and categorized as HP(-) (normal or mild infection) and HP(+) (moderate or marked infection) (Am J Surg Pathol 20:1161, 1996). Twenty-two pts received 5-FU, doxorubicin (DOX) CTX (5- FU 500 mg/m2 weekly for 36 wks, DOX 40 mg/m2 q 3 weeks x 12) with or without OK432, while 188 pts underwent 5-FU, mitomycin-C (MMC), and polysaccharide-K (PSK) CTX (5-FU 500 mg/m2 weekly for 24 wks, MMC 8 mg/m2 q 6 wks x 4, PSK 3 g/day for 16 wks) (Br J Cancer 84:186, 2001, Hepatogastroenterol 54:290, 2007). Results: The median follow-up duration of survivors was 125 (107–155) months. HP (-) was significantly correlated with Bormann type IV, larger tumor size (>5.5cm),and stage IIIB. In univariate analysis, patients with HP(-) (104 pts) demonstrated significantly poor 10-year OS compared with those with HP (+) (106 pts) (15.9% vs. 87.7%, p<0.0001). HP(-) was associated with poor outcome in all stages except stage IB (p=0.075). In multivariate analysis, HP(-) was the most significant independent prognostic factor of poor OS (hazard ratio 9.646, 95% CI 5.407–17.206, p<0.0001) followed by advanced stage (p=0.032), Bormann type IV (p=0.037) and old age (p=0.015). Conclusions: HP infection status seems to have strong prognostic significance in locally advanced gastric cancer. HP (-) pts may need intensified adjuvant treatment and careful follow-up. No significant financial relationships to disclose.
Polymorphism of nucleotide excision repair genes as predictors for clinical outcome in advanced gastric cancer patients treated with oxaliplatin-based chemotherapy
Authors: Hur H. , Song K. , Park C. , Hong Y. , Chun H. , Jeon H. 
Published: August 2020

4565 Background: The individual variations in treatment response and the toxicity of combination regimen of oxaliplatin and 5-fluorouracil with leucovorin (FOLFOX) for advanced gastric cancer patients have been reported. The aim of this study is to evaluate the influence of polymorphism of nucleotide excision repair genes that are involved in the metabolism of cisplatin on the clinical outcomes of gastric cancer patients treated with modified FOLFOX-6 chemotherapy. Methods: From March 2006 to December 2007, eighty-two patients with advanced gastric cancer were treated with modified FOLFOX-6 as the primary chemotherapy in our institution. Of these patients, 55 patients who were available for peripheral blood sampling before starting chemotherapy were enrolled in this study. Genomic DNA was extracted from mononuclear cells of patients’ blood. Four polymorphisms were investigated in three genes, ERCC, GSTP and XRCC. Results: The overall response rate (RR) was 40.0%. Median time to progression (TTP) and overall survival (OS) was 6 months (C.I.: 5.0 - 7.0 months) and 15.0 months (C.I.: 9.7 - 20.3 months). Grade 3 or 4 hematologic toxicities were presented in 17 patients (30.9%), gastrointestinal toxicities in 5 patients (9.1%), peripheral neuropathy in 5 patients (9.1%) and hepato-toxicity in 4 patients (7.3%). Most common types of polymorphism were G/G (67.3%) in XRCC1 Arg399Gln, A/A (74.5%) in GSTP1 Ile105Val, C/C (60.0%) in ERCC1 Asn118Asn and C/A (49.1%) in ERCC1 C8092A. The RR was significantly lower in patients with C/C type in ERCC1 C8092A gene than those with other type (25.0% vs 51.6%, p=0.046). However, there were no differences of TTP and OS among the polymorphisms in three genes. The rate of grade 3 or 4 hematologic toxicity was higher in patients with C/T or T/T in ERCC1 codon 118 gene than those with C/C type (45.5% vs 21.2%, p=0.057). Conclusions: We demonstrated that modified FOLFOX-6 chemotherapy was effective and tolerable. The polymorphism of C/C type in ERCC1 C8092A gene was found to be a predictive marker of the poor response and C/C type in ERCC1 Asn118Asn gene was to be a predictive marker of the hematologic toxicity. No significant financial relationships to disclose.
The prognostic impact of hypoxia-inducible factor-1α and VEGF, IGF-2, p21, p53 expression in gastric adenocarcinoma
Authors: Kakeji Y. , Mizokami K. , Sumiyoshi Y. , Yoshinaga K. , Saeki H. , Tokunaga E. , Endo K. , Morita M. , Kitao H. , Emi Y. , Maehara Y. 
Published: August 2020

4571 Background: Hypoxia caused by either radiation or chemotherapy induces various intracellular adaptive responses, which contribute to tumor progression. The clinicopathological characteristics of human gastric cancer and the clinical outcomes were analyzed to investigate the effects of the expression of hypoxia-inducible factor1α (HIF-1α) and some related proteins, such as, vascular endothelial growth factor (VEGF), insulin-like growth factor-2 (IGF-2), p21, and p53 on the prognosis of human gastric cancer. Methods: The expressions of HIF-1α, VEGF, IGF-2, p21, and p53 proteins were determined by immunohistochemistry in 216 specimens of primary gastric cancer. Results: Of all 216 patients, 85 (39.4%) showed a positive expression of HIF-1α. In addition, the HIF-1α expression positively correlated with the tumor size and depth of invasion, while it was also more frequent in tumors with lymphatic invasion and undifferentiated adenocarcinomas. Though the VEGF expression significantly correlated with the HIF-1α expression, the expressions of IGF-2, p21 and p53 did not show any correlation. HIF-1α-positive/p21-negative tumors had a lower apoptotic index, and the patients with such tumors also had a significantly poorer prognosis. Similarly, HIF-1α-positive/p53-positive tumors had a significantly poorer prognosis. A multivariate Cox regression analysis showed the depth of invasion, lymph node metastasis, and HIF-1α positivity to all be independent prognostic factors in patients with gastric cancer. Conclusions: Based on the above findings, HIF-1α is therefore considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1α protein overexpression with the loss of p21 expression or nonfunctional p53 thus tends to indicate a dismal prognosis. Controlling hypoxia, especially in the HIF-1α pathways, may therefore hold the key to a greater individualization of therapy and also lead to the development of new treatments for patients with gastric cancer. No significant financial relationships to disclose.