Hiroyuki Narahara

Comparison of EMR and endoscopic submucosal dissection for en bloc resection of early esophageal cancers in Japan

BACKGROUND EMR and endoscopic submucosal dissection (ESD) are now being increasingly used for the treatment of esophageal cancers. However, their efficacies in smaller lesions have not been compared. OBJECTIVE For effective use of these methods, we compared the results of ESD and 2 major EMR methods for treating esophageal cancers of <or=20 mm. DESIGN A retrospective study. SETTING A cancer-referral center. PATIENTS A total of 136 patients with 171 lesions <or=20 mm who presented between January 2002 and October 2007 were enrolled. MAIN OUTCOME MEASUREMENTS En bloc and curative resection. RESULTS Of the 171 lesions, 168 were squamous-cell carcinoma and 3 were adenocarcinoma. The en bloc resection rates decreased in the order of ESD (100%), EMR using a transparent cap (EMRC) (87%), and 2-channel EMR (71%). However, the differences showed only marginal significance. The curative resection rate of ESD (97%) was significantly higher than those of the other 2 methods. Furthermore, the curative resection rate of EMRC (71%) was significantly higher than that of 2-channel EMR (46%). In lesions <15 mm, the en bloc and curative resection rates were significantly higher for EMRC (100% and 86%, respectively) than 2-channel EMR (86% and 51%, respectively), whereas no significant differences were found between the en bloc and curative resection rates of EMRC and ESD. There were no differences in the complication rates. LIMITATIONS A single-center, retrospective analysis. CONCLUSIONS ESD was found to be the best endoscopic resection method, even for smaller esophageal cancers. EMRC would be a good alternative to ESD for lesions <15 mm.

Phase II Study of a Combination of S-1 and Paclitaxel in Patients with Unresectable or Metastatic Gastric Cancer

Objectives: A phase II study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to evaluate the efficacy and tolerability in unresectable or metastatic gastric cancer. Patients and Methods: Twenty-nine patients with unresectable and/or metastatic gastric cancer were enrolled in the study. Paclitaxel 50 mg/m2 was administered on days 1 and 8. S-1 was administered orally at 40 mg/m2 b.i.d. for 14 consecutive days, followed by a 1-week rest. The primary endpoint was the response rate. Secondary endpoints were safety and overall survival. Results: The overall response rate in 29 patients was 48.3%, differentiated 36.4% and undifferentiated 55.6%. The median survival time was 13.9 months. Grade 3 or higher toxicity was observed in neutropenia (3.4%), diarrhea (3.4%), bilirubin (3.4%) and neuropathy (3.4%). Conclusions: Combination chemotherapy of weekly paclitaxel and S-1 demonstrated tolerable toxicity and efficacy. This regimen will be one of the initial treatment options for unresectable or metastatic gastric cancer.

More effective endoscopic resection with a two-channel colonoscope for carcinoid tumors of the rectum.

PURPOSE: Complete resection of small carcinoid tumors of the rectum is difficult with conventional polypectomy, because these tumors are most often located in the submucosal layer of the rectal wall. To completely remove these tumors, we used a two-channel videocolonoscope with which both a grasping forceps and a polypectomy snare could be used simultaneously. We evaluated its clinical usefulness in comparison with one-channel colonoscopic polypectomy. METHODS: At Osaka Medical Center for Cancer and Cardiovascular Diseases, seven carcinoid tumors in seven patients were removed with a one-channel videocolonoscope from 1985 to 1992. In 1993 and 1994, ten tumors in nine patients were removed with a two-channel colonoscope. RESULTS: The rate of complete removal of carcinoid tumors with a two-channel videocolonoscope (9 of 10 tumors, 90 percent) was significantly higher (P<0.05) than with a one-channel videocolonoscope (2 of 7 tumors, 29 percent). No complications occurred during or after endoscopic resection with a two-channel colonoscope. CONCLUSIONS: Endoscopic resection with a two-channel colonoscope is a useful and safe method for resection of small carcinoid tumors of the rectum.

Phase II Study of a Combination of Irinotecan and S-1 in Patients with Advanced Gastric Cancer (OGSG0002)

Background/Aims: To investigate the efficacy and safety of the combination therapy of irinotecan (CPT-11) plus S-1 in patients with advanced gastric cancer at the dose recommended by a previous phase I study. Methods: A total of 23 patients received 80 mg/m2 of CPT-11 on days 1 and 15, and S-1 at a dose level set on the basis of the body surface area (BSA): 40 (BSA <1.25 m2), 50 (BSA ≧1.25 to <1.5 m2) or 60 mg (BSA ≧1.5 m2) b.i.d. was given from days 1–21. Results: The overall response rate was 47.8% (11 of 23, 95% confidence interval, CI: 27.4–68.2%). The median time to progression (TTP) was 210 days (95% CI: 145–322 days) and the median survival time was 394 days (95% CI: 241–484 days). The incidence of grade 3 or 4 hematological and non-hematological toxicity was 17.4 and 8.7%. The most common hematological toxicity was anemia and the most common non-hematological toxicity was diarrhea. Conclusion: The combination therapy of CPT-11 and S-1 provided prolonged TTP with low toxicity, and the results warrant a further phase III study to define the efficacy in improvement of survival in patients with advanced gastric cancer.

Multi-Center Phase II Study for Combination Therapy with Paclitaxel/Doxifluridine to Treat Advanced/Recurrent Gastric Cancer Showing Resistance to S-1 (OGSG 0302)

BACKGROUND A pre-clinical study demonstrated that paclitaxel induced thymidine phosphorylase in the tumor tissues. The combination of paclitaxel and doxifluridine is expected to exert extra anti-tumor effects. We evaluated the efficacy of this combination in patients with unresectable or recurrent gastric cancer who had been previously treated with S-1. METHODS Registration was started to enroll 35 patients with advanced/recurrent gastric cancer, who were selected among those with measurable lesions fitting to response evaluation criteria in solid tumors, and with resistant to S-1 treatment. This regimen is consisted of paclitaxel, 80 mg/m(2), iv on days 1 and 8; and doxifluridine, 600 mg/m(2), po on days 1-14. The treatment was repeated every three weeks. Primary endpoint was response rate (RR); and secondary endpoints were overall survival (OS), progression free survival (PFS) and onset rate of adverse events. RESULTS From September 2003 to March 2005, 35 patients were registered: including 28 men; 7 women; median age of 66 years (range, 49-75 years); and performance status (PS) levels were, zero with 21 and one with 14 patients. In 33 eligible patients, except two, clinical usefulness was evaluated resulting in RR of 18.2% (partial response, 6; stable disease, 15; progressive disease, 10; and not evaluable, 2 patients). Median survival time was 321 days and median PFS was 119 days. Severe adverse events were found in three patients to discontinue the present treatment. CONCLUSIONS The combination of paclitaxel and doxifluridine might be a treatment of choice as a second line chemotherapy for patient undergone S-1 treatment.

K‐ras point mutation is associated with enhancement by deoxycholic acid of colon carcinogenesis induced by azoxymethane, but not with its attenuation by all‐trans‐retinoic acid

The effects of deoxycholic acid (DCA) with and without all‐trans‐retinoic acid (ATRA) on the incidence of colon tumors induced by azoxymethane, the incidence of K‐ras point mutation in colon tumors and the labeling index of colon mucosa were investigated in male Wistar rats. Rats received 5 weekly injections of 7.4 mg/kg body weight of azoxymethane. From the start of the experiment, all rats in 3 groups also received chow pellets containing 0.3% DCA with and without s.c. injections of 0.75 or 1.5 mg/kg body weight of ATRA every other day until the end of week 45. Oral administration of DCA significantly increased the incidence of colon tumors in week 45. Concomitant use of DCA and ATRA at either dose significantly attenuated the enhancement by DCA of colon tumorigenesis. Administration of DCA significantly increased the incidence of K‐ras point mutation in colon tumors and the labeling index in the colon mucosa. Combined administration of DCA and ATRA significantly reduced the labeling index of colon mucosa, which was increased by DCA, but did not affect the incidence of K‐ras point mutation in colon tumors. These findings suggest that DCA enhances development of colon tumors and that this enhancement is attenuated by ATRA. A possible mechanism of this enhancement is induction of K‐ras point mutation. However, decreased cell proliferation in the colon mucosa may be closely related to the attenuation of DCA‐enhanced colon tumorigenesis, but not suppression of K‐ras point mutation. Int. J. Cancer 88:157–161, 2000.

Phase I and Pharmacokinetic Study of S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer

Objective: A dose-escalation study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the dose-limiting toxicities (DLTs) in advanced gastric cancer. Patients and Methods: Twelve patients were enrolled. S-1 was given orally at a fixed dosage of 40 mg/m2 b.i.d. for 14 consecutive days, followed by a 1-week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8 at a dose of 50, 60, 70 or 80 mg/m2, depending on the DLTs. Treatment was repeated every 3 weeks. A pharmacokinetic study was conducted in an additional 5 patients on days 7 and 8 during the first course given at the RD. Results: The MTD of paclitaxel was presumed to be 60 mg/m2, because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). DLT was observed in 1 out of 8 patients at a dose of 50 mg/m2. Therefore, the RD of paclitaxel was estimated to be 50 mg/m2. The preliminary response rate was 62.5% (5/8) at the RD. There were no significant pharmacokinetic interactions between S-1 and paclitaxel. An adequate plasma paclitaxel concentration for an antineoplastic effect was achieved with weekly doses of 50 mg/m2. Conclusion: Weekly paclitaxel combined with S-1 was demonstrated to exhibit a tolerable toxicity profile with therapeutic plasma concentration at the dose of 50 mg/m2. This regimen could represent a novel and low toxic combination for advanced gastric cancer.

Polaprezinc Attenuates Helicobacter pylori‐Associated Gastritis in Mongolian Gerbils

Background. The ammonia‐monochloramine system plays an important role in Helicobacter pylori‐associated gastric mucosal injury. Polaprezinc, a new antiulcer agent, has a scavenging action against monochloramine. The aim of the experiment was to investigate the inhibitory effects of polaprezinc on the H. pylori‐induced gastritis in Mongolian gerbils.

Cooperative Clinical Trial of Photodynamic Therapy for Early Gastric Cancer With Photofrin Injection® and YAG-OPO Laser

Background and Objective: Photodynamic therapy (PDT) treats malignant tumors using photosensitizers and light. We employed a new pulse laser as the excitation light source for PDT, i.e. an optical parametric oscillator (OPO) system pumped by a Q-switched Nd:YAG laser, because it provides extremely high peak power. Study Design/Materials and Methods: The effects of PDT using the photosensitizer Photofrin® and the new laser were evaluated in 12 patients with early gastric cancer. Results: Complete responses (CR) were obtained in 75% of 12 assessable patients, CR was observed in all cases with mucosal carcinoma (response rate 100%). Regarding toxicity, mild photosensitivity was seen in one case and it lasted several weeks. The other major side effect was decrease of total protein, which was observed in six patients (40%), lasting several months. There were no serious abnormalities in symptoms or laboratory tests. Conclusion: We conclude that the YAG-OPO laser is suitable as an excitation light source for PDT.

Induction by bombesin of peritoneal metastasis of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

Background. We investigated the effect of the gastrointestinal regulatory peptide, bombesin, on the development of peritoneal metastasis from gastric cancers induced in rats by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), and on Rho activity in the gastric cancers. Methods. Rats were allocated to three groups. All groups received MNNG (100 μg/ml) solution for 25 weeks from the start of the experiment. Group 1 (controls) received olive oil injections from the start of MNNG treatment; group 2 animals received alternate-day s.c. injections of bombesin (40 μg/kg body weight) in olive oil from the start of the experiment until the end of the experiment at week 52; and group 3 received the s.c. bombesin injection on alternate days from week 26 until week 52. The effect of bombesin on Rho activity in gastric cancer was examined by Western blotting. Results. Bombesin given from the start of the experiment (group 2) and after the MNNG treatment (group 3) both significantly increased the incidence of gastric cancer metastasis, compared with controls, at week 52: The incidence of metastasis was significantly higher in group 2 than in group 3. Bombesin from the start of the experiment (group 2) significantly increased the incidence of tumors with deeper invasion or more infiltrative growth pattern, or lymphatic vessel tumor invasion, while bombesin after MNNG treatment (group 3) significantly increased the incidence of lymphatic vessel invasion. Bombesin also increased the activity of Rho protein in the tumors. Conclusion. Bombesin significantly increased the incidence of peritoneal metastasis from gastric cancers through the activation of Rho protein.