Kento Nakatani

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.

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.

Clinical outcomes of endoscopic oblique aspiration mucosectomy for superficial esophageal cancer.

BACKGROUND EMR is now a widely accepted option for the treatment for superficial esophageal cancer (SEC). However, studies of medium-term to long-term outcomes are scarce. OBJECTIVE To evaluate outcomes in patients with SEC who are undergoing medium-term to long-term follow-up after endoscopic oblique aspiration mucosectomy (EOAM). DESIGN A single-center retrospective study. SETTING Kitasato University East Hospital, Sagamihara, Kanagawa, Japan. PATIENTS AND INTERVENTIONS From November 1999 to October 2005, 85 patients with SEC underwent EOAM. All tumors were macroscopically classified as the superficial type on the basis of preoperative endoscopic and EUS findings. Patients were followed-up, with an endoscopy every 6 months. MAIN OUTCOME MEASUREMENTS Therapeutic efficacy, complications, and follow-up results. RESULTS The rate of complete resection was 82.5% (70/85). In patients who underwent an incomplete resection, argon plasma coagulation and heat probe coagulation were, in addition, performed. The median longest diameter of the resected specimens was 25 mm. The median time required for a resection was 27 minutes. There was no perforation. Bleeding after an EOAM occurred in 1 patient (1.2%). Esophageal stenosis developed in 8 patients (9.4%). All strictures were managed by endoscopic balloon dilation, and symptoms improved. The median follow-up period after EMR was 36 months (range 6-72 months). Local recurrence occurred in 5 patients (5.9%); the nonrecurrence rate was 96.4% at 1 year, 95.0% at 2 years, and 93.4% at 3 years. As additional treatment, argon plasma coagulation was performed in 4 patients, and endoscopic mucosal dissection was conducted in 1 patient. CONCLUSIONS EOAM is a safe, easy, and effective procedure for the treatment of SEC that can be completed within a short time. The rate of local recurrence is low on medium-term to long-term follow-up.

A rare case of histologically mixed-type intramucosal gastric cancer accompanied by nodal recurrence and liver metastasis after endoscopic submucosal dissection

biopsy of the spleen: high clinical efficacy and low risk in a multicenter Italian study. Am J Hematol 2001;67:93-9. 9. Fritscher-Ravens A, Mylonaki M, Pantes A, et al. Endoscopic ultrasound-guided biopsy for the diagnosis of focal lesions of the spleen. Am J Gastroenterol 2003;98:1022-7. 10. Saftoiu A, Vilmann P, Guldhammer Skov B, et al. Endoscopic ultrasound (EUS)-guided trucut biopsy adds significant information to EUS-guided fine-needle aspiration in selected patients: a prospective study. Scand J Gastroenterol 2007;42:117-25. 11. Wittmann J, Kocjan G, Sgouros SN, et al. Endoscopic ultrasoundguided tissue sampling by combined fine needle aspiration and trucut needle biopsy: a prospective study. Cytopathology 2006;17: 27-33. Department of Medicine (I.I.E.H., A.K., K.M.M., K.E.F.), Department of Pathology (K.E.S.), Department of Surgery (K.M.A.-E.), University of Pittsburgh Medical Center, Division of Gastroenterology, Hepatology, and Nutrition (A.K.), VA Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA.

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.

Argon plasma coagulation for superficial esophageal squamous-cell carcinoma in high-risk patients.

AIM To evaluate the usefulness and safety of argon plasma coagulation (APC) for superficial esophageal squamous-cell carcinoma (SESC) in high-risk patients. METHODS We studied 17 patients (15 men and 2 women, 21 lesions) with SESC in whom endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and open surgery were contraindicated from March 1999 through February 2009. None of the patients could tolerate prolonged EMR/ESD or open surgery because of severe concomitant disease (e.g., liver cirrhosis, cerebral infarction, or ischemic heart disease) or scar formation after EMR/ESD and chemoradiotherapy. After conventional endoscopy, an iodine stain was sprayed on the esophageal mucosa to determine the lesion margins. The lesion was then ablated by APC. We retrospectively studied the treatment time, number of APC sessions per site, complications, presence or absence of recurrence, and time to recurrence. RESULTS The median duration of follow-up was 36 mo (range: 6-120 mo). All of the tumors were macroscopically classified as superficial and slightly depressed type (0-IIc). The preoperative depth of invasion was clinical T1a (mucosal cancer) for 19 lesions and clinical T1b (submucosal cancer) for 2. The median treatment time was 15 min (range: 10-36 min). The median number of treatment sessions per site was 2 (range: 1-4). The median hospital stay was 14 d (range: 5-68 d). Among the 17 patients (21 lesions), 2 (9.5%) had recurrence and underwent additional APC with no subsequent evidence of recurrence. There were no treatment-related complications, such as bleeding or perforation. CONCLUSION APC is considered to be safe and effective for the management of SESC that cannot be resected endoscopically because of underlying disease, as well as for the control of recurrence after EMR and local recurrence after chemoradiotherapy.

Clinical significance of evaluating primary lesions in patients with gastric cancer who receive chemotherapy.

BackgroundIn Western countries, the response of gastric cancer to chemotherapy is evaluated by assessing measurable metastatic lesions (MMLs) according to the response evaluation criteria in solid tumors (RECIST). In Japan, the response of primary lesions is assessed according to local Japanese criteria. We compared the response to chemotherapy as evaluated by these two sets of criteria.MethodsPatients with unresectable, advanced gastric cancer who had primary lesions and had received first-line chemotherapy were studied. Responses of MMLs were evaluated with RECIST. Responses of primary lesions were evaluated with the Japanese criteria. Median survival times (MSTs) were compared according to treatment response by each set of criteria.ResultsData from 341 patients were analyzed. Of the 242 patients with MMLs, 108 were MML responders and 134 were MML nonresponders. MST was significantly longer in MML responders (293 days; 95% confidence interval [CI], 244–342) than in MML nonresponders (159 days; 95% CI, 127–191; P < 0.0001). According to the Japanese criteria, there were 128 primary-lesion responders and 213 primary-lesion nonresponders. MST was significantly longer in responders (304 days; 95% CI, 266–342) than in nonresponders (168 days; 95% CI, 143–193, P < 0.0001). Of the 99 patients without MMLs, 26 were primary-lesion responders and 73, primary-lesion nonresponders; MST was significantly longer in the former (300 days; 95% CI, 266–334) than in the latter group (173 days; 95% CI, 111–235; P = 0.019).ConclusionThe responses of primary lesions according to the Japanese criteria and the responses of MMLs according to the RECIST were both significantly related to the MST. Use of the RECIST alone might bias the evaluation of treatment response because response cannot be evaluated in patients without an MML.