Background . The prognostic relevance of gastric tumor location has been reported and debated. Our study was conducted to examine the differences in clinicopathological features, prognostic factors, and overall survival (OS) between patients with proximal gastric cancer (PGC) and distal gastric cancer (DGC). Patients and Methods . Patients with PGC or DGC were identified from the China National Cancer Center Gastric Cancer Database (NCCGCDB) during 1997–2017. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models. Results . We reviewed 16,119 cases of gastric cancer patients, including 6,479 of PGC and 9,640 of DGC. PGC patients presented as older patients (61.5 versus 56.4 years, P< 0.001) and more males (82.9% versus 68.2%, P <0.001). Compared with DGC, PGC was more likely to be in later pT stage (pT3 and pT4, 65.0% versus 52.8%, P <0.001) and lymph node metastasis (54.8% versus 50.9%, P <0.001). In univariate analysis, PGC patients had a worse survival outcome in stage I (Hazard ratio [HR] = 2.04, 95% CI: 1.42-2.94) but a better prognosis in stage IV (HR = 0.85, 95% CI: 0.73-0.98) when compared to DGC patients. However, multivariate analysis demonstrated that PGC was not an independent predictor for poor survival (HR = 1.07, 95% CI: 1.00-1.14). Results from multivariate analysis also revealed that pT4, lymph node metastasis, distant metastasis, no gastrectomy, and Borrmann IV were independent predictors associated with poor survival for both PGC and DGC patients. Additional prognostic factors for PGC patients included underweight (BMI < 18.5) (HR = 1.29, 95% CI: 1.06-1.58), linitis plastica (HR = 2.13, 95% CI: 1.25-3.65), and overweight (23 ≤ BMI <27.5) (HR = 0.80, 95% CI: 0.71-0.90). During the 20-year study period, the 5-year OS increased significantly for both PGC and DGC, with the increase rate of 91.7% and 67.7%, respectively. Conclusion . In China, PGC significantly differed from DGC in clinicopathological characteristics and prognostic factors. However, there was no significant relationship between survival outcome and gastric tumor location.

Ubiquilin4 (Ubqln4), a member of the UbL-UBA protein family, serves as an adaptor in the degradation of specific substrates via the proteasomal pathway. However, the biological function of Ubqln4 remains largely unknown, especially in cancer. Here, we reported that Ubqln4 was downregulated in gastric cancer tissues and functioned as a tumor suppressor by inhibiting gastric cancer cell proliferation in vivo and in vitro. Overexpression of Ubqln4-induced cellular senescence and G1-S cell cycle arrest in gastric cancer cells and activated the p53/p21 axis. Moreover, Ubqln4 regulated p21 through both p53-dependent and p53-independent manners. Ubqln4 interacted with RNF114, an E3 ubiquitin ligase of p21, and negatively regulated its expression level, which in turn stabilized p21 by attenuating proteasomal degradation of p21. These effects of Ubqln4 were partly abrogated in gastric cancer cells upon silencing of p21. Our findings not only establish the anti-tumor potential of Ubqln4 in gastric cancer but also reveal a role for Ubqln4 in regulation of the cell cycle and cellular senescence via stabilizing p21.

Objective To describe clinical,pathological and prognostic characteristics in patients with rectal neuroendocrine tumors.Methods Retrospectively analyze the clinical and pathological data from 99 patients who were diagnosed with rectal neuroendocrine tumors and treated at hospitals in Dalian between January 2004 and December 2013.Cox proportional hazard models were used to estimate hazard ratios and 95％ confidence interval.Results Proctoscope,ultrasound,CT and MRI were commonly used auxiliary examination ways for the diagnosis of colorectal neuroendocrine tumors and the positive predictive value was 100.0％,58.6％,49.5％ and 70.6％ respectively.Chromogranin protein A,synaptophysin and neuron-specific enolase were commonly used immunohistochemical indicators and the positive predictive value was 74.7％,76.2％ and 32.7％ respectively.Major clinical manifestations included hematochezia in 36 patients (36.4％) and abdominal pain in 22 patients (22.2％).The mean tumor diameter was (7.2 ± 3.2) cm,primarily ＞ 2 cm,which make up 90％ of the overall tumors.The mean overall survival was (9.4 ± 0.2) years.Multivariate analysis confirmed that tumor size were the independent prognostic factor (P =0.03).Conclusion Non-functianal tumors account for most of the rectal neuroendocrine neoplasms and most cases did not have significant clinical symptoms.Tumor size has a significant influence on survival.

[Purpose] To analyze the clinicopathological characteristics and prognosis of rectal neuroendocrine tumor(RNET).[Methods] The clinical and pathological characteristics and prognosis of 109 patients with RNET were retrospectively analyzed.Kaplan-Meier method was used to calculate the overall 3-,5-and 10-year survival rate and Cox proportional hazard model was applied to analyze the prognostic factors.[Results] A total of 109 patients were included in the final analysis,including 91 cases (83.48％) of neuroendocrine tumor (NET),9 cases (8.26％) of neuroendocrine carcinoma (NEC) and 9 cases (8.26％) of unknown classification.The average age at diagnosis was (50.58± 11.90) years,male/female ratio was 1.51 and most cases were residents living in the urban area.The median follow-up duration was 8.12 (95％CI:7.32～8.85) years;the 3-,5-and 10-year overall survival rates were 91.23％ (95％ CI:83.83％ ～95.34％),88.20％ (95％ CI:80.14％ ～93.12％) and 84.20％ (95％ CI:74.85％～90.29％),respectively.Cox proportional hazard model showed that age (HR=5.80,95％CI:1.36～24.77),lymph node metastasis (HR=7.15,95％CI:2.27～24.83) and distant metastasis (HR=7.42,95％CI:1.98～27.76) were independent prognostic risk factors of RNET.[Conclusion] RENT usually occur in older(≥ 60 years old),male and urban residents with a good prognosis.Age,lymph node metastasis and distant metastasis are independent prognostic risk factors of RNET.

Gastric carcinoma is a heterogeneous malignant disease involving genetic factors. To identify predictive markers for gastric cancer treatment in Chinese patients, we evaluated the association between polymorphisms of the gene encoding cytochrome P450 2A6 (CYP2A6) and outcomes of S-1 plus oxaliplatin (SOX) chemotherapy treatment. Clinical data on 60 consecutive gastric cancer patients receiving SOX regimen were collected prospectively. We sequenced all exons of CYP2A6 and a total of 22 different polymorphisms were detected in the present study. Comprehensive analyses of these genetic polymorphisms were performed to determine their association with both safety and efficacy of SOX regimen. Our results showed that polymorphisms of CYP2A6 were associated with the safety and efficacy of SOX treatment. Among them, missense mutations CYP2A6 rs60823196 and rs138978736 could be possible risk factors (P < 0.05) for severe diarrhea induced by SOX, whereas CYP2A6 rs138978736 could be a conceivable predictor for overall survival of patients treated with SOX adjuvant chemotherapy. Further large-scale randomized prospective studies are warranted to confirm these findings.

Treatment algorithm has not been established for early gastric cancer with signet ring cell carcinoma (SRC), which has a reported low rate of lymph node metastasis (LNM) similar to differentiated cancer. A cohort of 256 patients with early gastric SRC at our center between January 2002 and December 2015 were retrospectively reviewed. Multivariate logistic regression analysis was used to determine the independent factors of LNM. A nomogram for predicting LNM was constructed and internally validated. Additional external validation was performed using the database from Cancer Institute Ariake Hospital in Tokyo (n = 1273). Clinical performance of the model was assessed by decision analysis of curve. The overall LNM incidence was 12.9% (33/256). The multivariate logistic model identified sex, tumor size, and LVI as covariates associated with LNM. Subsequently, a nomogram consisted of sex, tumor size, and depth of invasion was established. The model showed qualified discrimination ability both in internal validation (area under curve, 0.801; 95% confidence interval [CI], 0.729-0.873) and in external dataset (area under curve, 0.707; 95% CI, 0.657-0.758). Based on the nomogram, treatment algorithm for early gastric SRC was proposed to assist clinicians in making better decisions. We developed a nomogram predicting risk of LNM for early gastric SRC, which should be helpful for patient counseling and surgical decision-making.

Gastric cancer (GC) is the second leading cause of cancer-related mortality worldwide. The usual treatment of GC consists of surgery with additional adjuvant chemotherapy. In the present study, the feasibility and safety of adjuvant S-1 plus oxaliplatin (SOX) chemotherapy for patients with GC and the optimal dosage of S-1 were determined. Eligible patients were randomly assigned to either arm A (30 cases) receiving 70 mg/m2 S-1 (in two seperate half doses) daily or arm B (30 cases) receiving 80 mg/m2 S-1 (in two seperate half doses) daily. The S-1 was administered twice daily for 14 days followed by a 7-day rest period for the third week. A total of 130 mg/m2 oxaliplatin was administered on day 1 every 3 weeks for each arm. The cumulative rates of the relative total administration dose of S-1 at 100% in the 6th treatment course was 71.4% [95% confidence interval (CI), 56.5-90.3%] in arm A, which was significantly higher than 21.4% (95% CI, 10.5-43.6%) in arm B (P=0.001). The most common grade 3/4 toxicities were neutropenia (19.6%), thrombocytopenia (19.6%) and vomiting (16.1%). Grade 3/4 thrombocytopenia was observed in 7.1% of patients in arm A and in 32.1% of patients in arm B (P=0.019). With regard to the adverse events induced by S-1 administration, the incidence of diarrhea (3.6 vs. 42.9%; P<0.001) was significantly higher in arm B than in arm A, as anticipated. Collectively, adjuvant SOX therapy for GC is feasible and safe, and when combined with 130 mg/m2 oxaliplatin, 70 mg/m2/day S-1 appears to the optimal dose.

Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a de-ubiquitinating enzyme, which enzymatic activity relies on the C90 site. The function of UCHL1 is controversial in different types of cancer, and its role in gastric cancer progression remains unclear. In this study, immunohistochemistry staining was applied to detect the expression of UCHL1 in primary gastric cancer and liver metastases from gastric cancer. MKN45 and BGC823 cell lines with stable expression of de-ubiquitinase active UCHL1 or inactive UCHL1-variant C90S were established by lentiviral infection. The effect of UCHL1 on cell proliferation was evaluated by MTT and colony formation assays. The abilities of cell migration and invasion were determined by transwell assay. Protein expression levels were determined by Western blot. The results indicated that UCHL1 had a significantly higher positive expression rate in liver metastases from gastric cancer compared with primary gastric cancer. Overexpression of UCHL1 in MKN45 and BGC823 cells promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity. UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion. These findings demonstrated that UCHL1 promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity by activating Akt and Erk1/2, which may account for its higher positive expression rate in liver metastases from gastric cancer. UCHL1 could be a candidate biomarker and a therapeutic target for gastric cancer metastasis.

目的:在肝癌细胞HepG2中过表达外源NAIF1(核凋亡诱导因子1),探讨NAIF1的亚细胞定位以及对HepG2增殖和迁移能力的影响.方法:以真核表达质粒pEGFP-N1为对照组,pEGFP-N1-NAIF1为实验组,瞬时转染肝癌细胞HepG2,利用免疫印迹方法检测NAIF蛋白表达效率;以DAPI染核,荧光显微镜下观察绿色荧光蛋白定位,确定NAIF1的亚细胞定位;通过MTT方法绘制细胞增殖曲线;通过transwell小室法检测NAIF1对HepG2迁移能力的影响.结果:在肝癌细胞HepG2中,外源表达NAIF1主要定位于细胞核;与对照组HepG2/pEGFP-N1相比,HepG2/pEGFP-N1-NAIF1的细胞增殖、迁移能力下降(P＜0.05).结论:外源表达NAlF1蛋白定位于HepG2细胞核,过表达NAIF1抑制HepG2的细胞增殖与迁移能力,NAIF1可能作为肝癌治疗的潜在靶点.

Nuclear apoptosis-inducing factor 1 (NAIF1) could induce apoptosis in gastric cancer cells. Previously, we have reported that the expression of NAIF1 protein is down-regulated in gastric cancer tissues compared with the adjacent normal tissues. However, the role of NAIF1 in gastric cancer cells is not fully understood.

Nuclear apoptosis-inducing factor 1 (NAIF1) was previously reported to induce apoptosis. Moreover, the expression of NAIF1 was significantly down-regulated in human gastric cancer tissues compared to adjacent normal tissues. However, the mechanism by which the NAIF1 gene induces apoptosis is not fully understood. Our results show that NAIF1 was minimally expressed in all the tested gastric cancer cell lines. Our data also demonstrates that NAIF1 is localized in the nuclei of cells as detected by monitoring the green fluorescence of NAIF1-GFP fusion protein using fluorescent confocal microscopy. Next, a comparative proteomic approach was used to identify the differential expression of proteins between gastric cancer cell lines MKN45/NAIF1 (-) and MKN45/NAIF1 (+). We found five proteins (proteasome 26S subunit 2, proteasome 26S subunit 13, NADH dehydrogenase Fe-S protein 1, chaperonin containing TCP1 subunit 3 and thioredoxin reductase 1) that were up-regulated and three proteins (ribonuclease inhibitor 1, 14-3-3 protein epsilon isoform and apolipoprotein A-I binding protein) that were down-regulated in the MKN45 cells overexpressing NAIF1. We also discovered that NAIF1 could induce cell cycle arrest at G1/S phase by altering the expression of cell cycle proteins cyclinD1, cdc2 and p21. The differentially expressed proteins identified here are related to various cellular programs involving cell cycle, apoptosis, and signal transduction regulation and suggest that NAIF1 may be a tumor suppressor in gastric cancer. Our research provides evidence that elucidates the role of how NAIF1 functions in gastric cancer.

近年来,随着早期胃癌分子生物学及临床病理学的深入研究,对早期胃癌淋巴结转移规律及生物学行为有了新的认识[1]。大宗病例资料的研究表明[2],肿瘤病灶小于10 mm 的早期胃癌无淋巴结转移,10~30 mm的淋巴结转移平均为8.8%,病灶>30 mm时增加至19.2%。黏膜内癌淋巴结转移率为5.0%~6.1%,黏膜下癌为14.6%~25.0%。早期胃癌只侵犯1、2站淋巴结,很少至3站淋巴结。早期胃癌5年生存率黏膜癌为98%,黏膜下癌为88.7%。自1989年以来,日本学者深入研究发现,黏膜内癌、高分化、隆起型<20 mm、凹陷型<10 mm、无溃疡形成者,均无淋巴结转移[3]。这些研究结论为探索早期胃癌的改良手术奠定了临床实践的理论基础。

Objective To study the clinical features of gallbladder small cell carcinoma (GSCC),to improve the diagnosis and treatment of GSCC.Methods We retrospectively analyzed the clinical data of GSCC patients at our hospital from January 2000 to January 2012,and made a collective review of the literature.Results In this series,there were four female cases,one male case,the age at the first diagnosis was between 42-67,with the median age of 57.The main complain was pain and dis-comfort on the up and right abdomen.Tumor located in the bottom of gallbladder in 3 cases,and in the body in 2.Cholelithiasis was complicated in 4 cases.2 patients received radical resection of GSCC,followed by adjuvant chemotherapy of VP-16 and cisplatin,radioactive therapy in one.Postoperatively,these two were followed up for 45 and 32 mons with tumor free survival.3 cases received palliative resection,followed by adjuvant chemoradioactive therapy or intervention treatment,these three were followed up to 8,11,30 months respectively to their death for tumor recurrence.Conclusions GSCC is a rare disease,the initial symptoms are not often specific and easily misdiagnosed.The prognosis of GSCC is poor.

OBJECTIVE:To summarize and analyze the clinical feature, therapeutic methods and prognosis of gastric small cell carcinoma (SCC).METHODS:The clinical and pathological data of 41 patients diagnosed of gastric SCC were analyzed in this research. Also, the factors which may potentially affect the patients' survival outcome were evaluated. There were 35 male and 6 female patients. The age at diagnosis was 39-84 years, median age was 62 years. The 31 cases (75.6%) of gastric SCC patients were involved in the upper third of the stomach, 3 cases (7.3%) in the middle, 7 cases (17.1%) in the lower third.RESULTS:The time from the event of symptoms to final confirmation was 1 to 13 months, the median time was 3 months. The longest diameter of tumors was from 2.5 to 15.0 cm, the average was 6.5 cm. The 38 cases (92.7%) chosed surgery as the first treatment, among which 25 cases (61.0%) were performed radical tumor resection, 13 cases (31.7%) went through palliative resection, and 3 cases (7.3%) just employed chemotherapy. The initial II, III, IV stage were 2, 31 and 8 cases, respectively. The overall median survival time was 19 months, median disease free survival time was 11 months, 1-, 2-, 5-years survival rates were 70.7%, 46.3% and 36.6%, respectively. In univariate survival analysis, the tumor size (χ² = 5.565), change of the body weight (χ² = 3.688), type of operation (χ² = 11.747) and relapse or not (χ² = 17.966) were obviously correlaed with the prognosis (P < 0.05).CONCLUSIONS:Gastric SCC is a rare disease of the gastrointestinal tract, the misdiagnosis rate is high, and the prognosis is dismal. Muti-modality management, with radical surgical resection of the primary lesion followed by standard adjuvant-chemotherapy, affords better local disease control and a better survival outcome.

CCDC134 (coiled coil domain containing 134), a novel secretory protein, acts as an inhibitor of Erk1/2 and JNK/SAPK pathways. However, the role of CCDC134 in cancer development is still lacking. In this study, we found that CCDC134 expression significantly reduced in gastric cancer tissues compared with normal tissues (P < 0.001) and lesion tissues (P < 0.001). But no statistically significant difference was observed between normal and lesion tissues (P = 0.842). In vitro transient transfection of CCDC134-specific siRNA significantly promoted the migration and invasion of both the normal gastric epithelial cell line GES-1 and gastric cancer cell line AGS cells. Further analysis revealed that the attenuated expression of CCDC134 promoted the activation of Erk1/2 and JNK/SAPK, but had no effect on p38. The activation of Erk1/2 and JNK/SAPK was required for CCDC134-mediated migration and invasion. Besides, CCDC134-RNAi could induce the expression of MMP-2 and MMP-9, which are key molecules involved in regulating cell migration and invasion. Therefore, CCDC134 may be a candidate biomarker for malignant transformation. It plays a role in regulation of cell migration and invasion, and could be a therapeutic target of gastric cancer.

OBJECTIVETo summarize and analyze the diagnosis, clinical features and therapy of primary colorectal non-Hodgkin's lymphoma (NHL).METHODSThe clinicopathological data of 52 patients with primary colorectal NHL diagnosed and treated in our department from January 2000 to January 2010 were reviewed and analyzed retrospectively in this study.RESULTSThis group of patients was composed of 45 cases of B cell and 7 T cell lymphomas, including 33 males and 19 females, with a male to female ratio of 1.7:1, and the age at diagnosis was 16 - 74 years old, with a median age of 50 years. The ileocecal region was most frequently involved site, acounted for 48.1%. The common symptoms encountered were abdominal pain (66.7%), diarrhea (15.6%), blood stool (24.4%), and body weight loss (8.9%). All patients were eventually diagnosed by histopathology, and the DLBCL subtype took up 64.4%. Among the 45 cases of B cell subtype, 33 cases (73.3%) were of early stage (IE and IIE confirmed), and the 5-year survival rate was 78.1%, while those of stage IIIE and IVE comprised 26.7%, with a 5-year survival rate of 45.5% (P < 0.05). The 5-year survival rate of all patients was 71.1%. Surgery was employed in 36 cases, and 9 patients received chemotherapy alone. Radical surgery could significantly increase the patients' overall survival rate, as compared with the chemotherapy alone group and palliative surgery group (P < 0.05).CONCLUSIONSColorectal non-Hodgkin's lymphoma is a rare malignancy of the gastrointestinal tract. B cell type, male predominance and DLBCL subtype are most encountered manifestations in clinics. Multi-modality management with radical surgical resection of the primary lesion followed by standard chemotherapy, affords better local disease control, and a better survival outcome. Early detection and tailored immunotherapy can obviously prolong the long-term survival time.

OBJECTIVE:This study aims to explore the clinicopathologic characteristics and prognostic factors of gastric cancer patients with metachronous ovarian metastasis.METHODS:Clinicopathologic data were collected from 63 post-operative gastric cancer patients with metachronous ovarian metastasis. The patients were admitted to the Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College between January 1999 and December 2011. A log-rank test was conducted for survival analysis. Possible prognostic factors that affect survival were examined by univariate analysis. A Cox regression model was used for multivariate analysis.RESULTS:The incidence of ovarian metastasis was 3.4% with a mean age of 45 years. Up to 65.1% of the patients were pre-menopausal. The mean interval between ovarian metastasis and primary cancer was 16 months. Lowly differentiated carcinoma ranked first in the primary gastric cancers. The majority of lesions occurred in the serous membrane (87.3%). The metastatic sites included N2-3 lymph nodes (68.3%), bilateral ovaries (85.7%), and peritoneal membrane (73%). Total resection of metastatic sites was performed (31.7%). The overall median survival was 13.6 months, whereas the overall 1-, 2-, and 3-year survival rates were 52.5%, 22.0%, and 9.8%, respectively. The 5-year survival rate was zero. Univariate analysis showed that the patient prognosis was correlated with metastatic peritoneal seeding, vascular tumor embolus, range of lesion excision, and mode of comprehensive treatment with adjuvant chemotherapy (P<0.05). Multivariate analysis indicated that metastatic peritoneal seeding was an independent prognostic factor for gastric cancer patients with ovarian metastasis (P<0.01).CONCLUSION:Effective control of peritoneal seeding-induced metastasis is important for improving the prognosis of gastric cancer patients with ovarian metastasis.

OBJECTIVE:To analyze the clinical data and prognosis of gastric small cell carcinoma (GSCC), summarize recent progress in diagnosis and therapy of this disease reported in the literature, and to provide the theoretical basis for its appropriate treatment.METHODS:Clinicopathological data of 17 patients with pathologically confirmed GSCC, treated in our hospital between 1999 to 2012, were retrospectively reviewed.RESULTS:There were 16 males and 1 female, ranged from 46 to 75 years (mean 64.6 years). The tumor was located in the gastric cardia in 13 cases, three in the gastric fundus, and one in the gastric body. All the 17 patients received surgery and 10 of them received postoperative adjuvant chemotherapy, one received preoperative adjuvant chemotherapy. Thirteen patients were followed up. Among them, two 1ived for 40 months all along, the other 3 cases died of recurrence and extensive metastasis in 6 month after operation. The median survival was 13.0 months. The median survival of the patients with and without lymph node metastasis were 42 months and 13 months, respectively. The median survival time of stage II and III patients were 24 months and 14 months, respectively.CONCLUSIONS:It is difficult to make a definite diagnosis before or during the operation for GSCC. Radical operation could be done according to other gastric cancers and lymph node dissection could be simplified. Postoperative chemotherapy with the same scheme as lung small cell carcinoma may help to improve the outcome and prolong the survival of the patients.

Objective:To examine metastatic gastric cancer patients who underwent surgery after chemotherapy and to determine the factors affecting survival. Methods:Clinical data on metastatic gastric cancer patients who underwent surgery after chemotherapy were retrospectively analyzed. The overall survival data were evaluated through the Kaplan-Meier method, Log-rank test, and Cox haz-ards regression. Results:The median age was 46 (22~74), and the median overall survival rate (OS) was 19 months (4~59 months). Response to chemotherapy (23.0 m for PR and 14.5 m for SD, P=0.045) and resection of the primary tumor (23.0 and 5.5 m, respective-ly, P=0.017) affected OS. No single factor was related to OS according to Cox regression. Conclusion:Surgical removal of the primary tumor is recommended for metastatic gastric cancer patients with positive response to chemotherapy and with a primary tumor that can be resected.

Gastric cancer (GC) is the fourth most common type of cancer, accounting for an estimated one million new cases annually worldwide. Locally advanced GC often recurs, even following curative surgical resection. Therefore, there is a need for an effective adjuvant chemotherapy regimen. The aim of this trial was to investigate the maximum tolerated dose (MTD) of S-1 when administered in combination with oxaliplatin in postoperative GC patients. Oxaliplatin was administered at a fixed dose of 130 mg/m2 on day 1. S-1 was administered from day 1 to 14 of a 3-week cycle and escalated by 10 mg/m2/day from 60 to 80 mg/m2/day. A total of 15 patients were enrolled in this study. No dose-limiting toxicities (DLTs) occurred at level 1 (S-1, 60 mg/m2; n=3). One case of DLT (grade 3 vomiting) occurred at level 2 (S-1, 70 mg/m2; n= 6), whereas 2 cases of grade 3 vomiting were observed at level 3 (S-1, 80 mg/m2; n=6). Based on these results, the MTD of S-1 was initially determined to be 70 mg/m2. Furthermore, we observed that cytochrome P450 2A6 (CYP2A6) 41349640C>G was associated with severe neutropenia (C/C vs. C/G vs. G/G = 0 vs. 33.33 vs. 100%; P=0.03297, Fisher's exact test) during the entire course of the treatment.