Ken Nishimura

Impacts of fluorouracil-metabolizing enzymes on the outcomes of patients treated with S-1 alone or S-1 plus cisplatin for first-line treatment of advanced gastric cancer†‡

A phase III trial of S‐1 plus cisplatin (SP) versus S‐1 alone, for first‐line treatment of advanced gastric cancer (SPIRITS trial), has shown that overall survival was better in patients treated with SP than with S‐1 alone. In the present retrospective biomarker study, we aimed to develop a methodology to identify the patients with advanced gastric cancer who would respond better to S‐1 alone than SP. We studied 120 patients who received S‐1 alone or SP for first‐line chemotherapy for advanced gastric cancer, and quantitatively evaluated mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase, vascular endothelial growth factor‐A, and epidermal growth factor receptor in paraffin‐embedded specimens of primary tumors. Multivariate survival analysis in patients who received S‐1 monotherapy (66 patients) demonstrated that low TP expression (hazard ratio: 2.55 (95% CI: (1.33 to 4.89)), low TS (2.71 (1.36 to 5.37)), and high OPRT (0.33 (0.13 to 0.86)) were significant predictors of long overall survival. In patients with lower expression of both TP and TS (n = 23) than their cutoff values, the S‐1 alone group (n = 15) had longer overall survival than the SP group (n = 8; median overall survival, 18.2 months vs. 9.4 months), whereas the frequency of overall adverse events in the S‐1 alone group tended to be lower than that in SP group. Our results suggest that these biomarkers are useful for selection of patients with advanced gastric cancer in whom treatment with S‐1 alone will yield survival benefit.

Endoscopic submucosal dissection (two-point fixed ESD) for early esophageal cancer.

Background:  We have been attempting to improve the safety, reliability and simplicity of endoscopic submucosal dissection for the treatment of early esophageal cancer and to shorten the time needed for this operation.

A multicenter, phase I dose-escalating study of docetaxel, cisplatin and S-1 for advanced gastric cancer (KDOG0601).

Objective: This dose-escalation study of a combination of docetaxel, cisplatin and S-1 investigated the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) and antitumor activity in advanced gastric cancer. Patients and Methods: Patients received docetaxel (40 mg/m2), cisplatin (DIV on day 1) and S-1 (40 mg/m2 p.o., twice daily, on days 1–14 every 28 days). The starting dose of cisplatin was 60 mg/m2 (level 1); the dose was escalated to 70 (level 2) and 80 mg/m2 (level 3) in a stepwise fashion. Results: Fourteen patients were enrolled. The MTD of cisplatin was 80 mg/m2 (level 3). DLT was grade 3 diarrhea, febrile neutropenia and delayed resumption of treatment. The RD of cisplatin was considered to be 70 mg/m2 (level 2). DLT was liver dysfunction, occurring in only 1 patient at level 2. The response rate was 69.2% (9/13). Conclusions: For combined treatment with docetaxel, cisplatin and S-1 in patients with advanced gastric cancer, RD were docetaxel 40 mg/m2, cisplatin 70 mg/m2 and S-1 80 mg/m2/day. This regimen yields a high rate of tumor response and can be administered safely. Phase II studies of this regimen are under way.

Quadruple therapy with ecabet sodium, omeprazole, amoxicillin and metronidazole is effective for eradication of Helicobacter pylori after failure of first-line therapy (KDOG0201 Study).

Background and object:  An antiulcer agent, ecabet sodium, is active against Helicobacter pylori. The aim of the present study was to clinically examine whether eradication therapy, which includes ecabet sodium, is effective in eradication of H. pylori after failure of first‐line therapy.

Outcomes and precautions of endoscopic submucosal dissection for undifferentiated-type early gastric cancer.

Objectives: Since the development of techniques for endoscopic submucosal dissection (ESD), the indication range of endoscopic resection (ER) has been extended in early gastric cancer (EGC) treatment. For undifferentiated-type EGC, tumors with an intramucosal depth of invasion, no ulceration and a diameter of 20 mm or less were included in the expanded indications for ER in the Japanese Gastric Cancer Treatment Guidelines 2010. Nonetheless, because of difficulty in detecting lesions that meet the criteria for ER, the number of endoscopically resected cases of undifferentiated-type EGC is less than that of differentiated-type EGC. Methods: We retrospectively investigated the outcomes of ESD in 38 patients with 40 lesions of EGC in which the dominant pathological type was confirmed to be undifferentiated (signet ring cell carcinoma, poorly differentiated adenocarcinoma, mucinous adenocarcinoma) on histological examination of resected specimens. Results: Margin involvement and submucosal infiltration were common noncurative factors. Precise evaluation of the area and depth of lesions is a problem to be solved. Among a total of five patients with involved or uncertain horizontal margins, one of two patients who underwent additional surgery had residual cancer, and one of three patients who were observed had recurrence. Conclusions: Undifferentiated-type EGC with a positive horizontal margin may relapse after ESD. It is therefore essential to precisely evaluate the area of the lesion and to perform resection with an adequate safety margin to decrease the risk of recurrence.

The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure

BackgroundAs the World Health Organization grading system for gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) may not always correlate with tumor progression, it is imperative that other independent predictors of tumor progression be established. To identify such predictors, we conducted a retrospective histopathological study of hindgut NETs, obtained from endoscopic procedures, and used statistical analyses to evaluate predictive factors.MethodsWe first obtained clinicopathological data of cases of hindgut NETs. Tissue sections from tumor samples were prepared and subjected to pathological examination. In particular, we calculated the microvessel density (MVD) and lymphatic microvessel density (LMVD) values, and performed appropriate statistical analyses.ResultsA total of 42 cases of hindgut NETs were selected for the study, 41 from the rectum and 1 from the sigmoid colon. Based on the Ki-67 labeling index, 34 cases were classified as NET G1 tumors and 8 as NET G2 tumors. MVD values ranged from 1.4/mm2 to 73.9/mm2 and LMVD values from 0/mm2 to 22.9/mm2. MVD and LMVD were identified as risk factors for venous and lymphatic invasion of hindgut NETs. Moreover, MVD positively correlated with the maximum diameter of the tumor.ConclusionsTumor progression of NETs may cause angiogenesis and lymphangiogenesis, via an unknown mechanism, as well as lymphovascular invasion. Angiogenesis likely plays an important role in occurrence and progression in the initial phase of hindgut NETs.

Usefulness of two-point fixed endoscopic submucosal dissection for superficial esophageal neoplasms

BackgroundEndoscopic submucosal dissection (ESD) is becoming widely regarded as a highly complicated but useful treatment for superficial esophageal neoplasms. However, the technique tends to be associated with adverse events. To evaluate the safety and utility of two-point fixed ESD for superficial esophageal neoplasms, and to discuss future directions.MethodsBetween December 2006 and December 2013, we performed two types of ESD procedures, the two-point fixed ESD that uses continuous countertraction to ensure a sufficient operative field was performed in 107 patients and conventional ESD was performed in 80 patients. Short-term outcomes and adverse events were evaluated. This study was retrospective study from a single institution.ResultsSignificant differences were observed between conventional ESD and the two-point fixed ESD with regard to the operation time, tumor positive and unknown vertical margins of the resected specimen, perforation as an adverse event, mediastinal emphysema, and postoperative stenosis.ConclusionThe two-point fixed ESD is a very useful method compared with the conventional procedure.

The feasibility and safety conversion surgery in stage IV gastric cancer.

164 Background: Conversion surgery could be an option for stage IV gastric cancer when distant metastasis (M1) is disappeared by palliative chemotherapy, however, feasibility, safety and efficacy of surgery after long-term chemotherapy remains unclear. Methods: This retrospective study examined 21 gastric cancer patients who underwent curative conversion surgery between 2001 and 2013. Postoperative complications were evaluated according to the Clavien-Dindo classification. Overall survival (OS) was estimated by Kaplan-Meier method. Results: Median follow-up period (range) was 43.9 months (7.2-72.1 months). The number of M1 factors was one in 17 patients and two in 4, including metastases to non-regional lymph node in 11, peritoneum in 11, and liver in 3. The regimen of chemotherapy was S-1/CDDP in 11 patients, S-1/docetaxel/CDDP in 5, S-1/docetaxel in 2, 5FU/leucovorin/paclitaxel in 1, CPT/CDDP in 1, and S-1 monotherapy in 1. The median duration from initiation of chemotherapy to disappearance of M1 facto...

Randomized phase III trial of irinotecan plus cisplatin versus irinotecan alone after S-1 based chemotherapy failure for patients with advanced and recurrent gastric cancer (AGC) (TCOG GI-0801).

61 Background: S-1based chemotherapy is the standard first-line chemotherapy for AGC in Japan. Currently, there is no high level evidence established for second-line treatment. Irinotecan (CPT-11) plus cisplatin (CDDP) are active in AGC. The combination of these 2 agents is synergistic effect in preclinical and clinical studies. We conducted a phase III study of CPT-11 plus CDDP (CP) compared with CPT-11 alone (C) in patients with AGC refractory to S-1 based chemotherapy. Methods: Patients with previously treated with S-1-based chemotherapy for AGC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either CPT-11 60 mg/m2 plus CDDP 30 mg/m2 on day 1 every 2 weeks or CPT-11 150mg/m2on day 1 every 2 weeks. The primary endpoint is progression free survival (PFS). The statistical design is based on superiority hypothesis; PFS is 110days in CP, 65days in C; two-sided α=0.05, 1-β=0.8; and planed accrual is 130 pts. Secondary endpoints include Overall Survival (OS), Time to Treatmen...