Hideyuki Mishima

Molecular characteristics of poorly differentiated adenocarcinoma and signet-ring-cell carcinoma of colorectum

In a series of 45 poorly differentiated adenocarcinomas (por) and 7 signet‐ring‐cell carcinomas (sig) of the colorectum, K‐ras gene mutation, p53 immunostaining and microsatellite instability (MSI) were analyzed for a comparison with 46 cases of colorectal carcinomas of the well or moderately differentiated type (well/mod). In addition, the mutations of simple repeated sequences in the transforming‐growth‐factor‐β type‐II receptor (T β R‐II) gene and the BAX gene were analyzed as possible targets for DNA replication errors. Mutation of the K‐ras gene in the por, sig and well/mod specimens was detected in, respectively, 22%, 11% and 48%, positive immunostaining for p53 in 41.8%, 28.6% and 60.3%, and MSI in 36%, 30% and 4%. Frameshift mutation of the T β R‐II gene was detected in 27.5% of the por and none of the sig specimens, while corresponding figures for mutation of the BAX gene were 15.7% and 0%. Significant differences between the por and well/mod tumors were found in the occurrence of K‐ras mutation at codons 12 and 13, and MSI. Clinicopathologically, the tumor status of por with MSI was found to significantly correlate with the tumors location in the proximal colon. In cases without MSI and sig, no frameshift mutation of either the T β R‐II or the BAX gene was found. These results suggest that poorly differentiated and signet‐ring‐cell carcinomas have a genetic background different from that of well or moderately differentiated carcinomas of the colorectum, and that DNA‐replication error is at least partly involved in the carcinogenesis of these specific types of colorectal carcinomas. Int. J. Cancer (Pred. Oncol.) 84:33–38, 1999.

New Technique of Laparoscopic-Assisted Excision of a Cholecystocolic Fistula: Report of a Case

Abstract Cholecystocolic fistula is a rare complication of gallstone disease that is most commonly diagnosed at the time of surgery. It is generally considered to be a contraindication to laparoscopic cholecystectomy because of the difficulties involved in its management intraoperatively. Laparoscopic stapling or suturing techniques have been reported as feasible and safe methods for repairing such fistulas; however, these procedures are not always able to be performed due to technical difficulties. We exteriorized a cholecystocolic fistula through an umbilical incision, whereby it was repaired safely and easily. This report describes our new technique for managing a cholecystocolic fistula found incidentally during a laparoscopic cholecystectomy.

Effect of Preoperative Immunonutrition on Body Composition in Patients Undergoing Abdominal Cancer Surgery

PurposePreoperative immunonutrition may induce changes that modulate stress responses and improve the outcome of patients undergoing abdominal cancer surgery. We evaluated the effectiveness of preoperative immunonutrition using an immune-enhancing diet product called Impact.MethodsForty patients aged 20–75 years, who were scheduled to undergo abdominal cancer surgery, were given Impact for 5 days preoperatively, at 1000 ml/day, in addition to a regular diet. We took various measurements before and after Impact administration.ResultsAll but two patients tolerated a daily intake >900 ml (mean: 924 ml). The serum retinol-binding protein level increased from 3.21 to 3.76 mg/dl and the arginine level increased from 91.9 to 112.0 mmol/ml after Impact intake. The urinary excretion of uracil increased significantly, from 57.6 to 88.9 mmol/g creatinine, as did the content of n-3 fatty acids and the n-3/n-6 ratio in membrane phospholipids from the white blood cells. These changes were not observed in the two patients who did not tolerate Impact. There was no significant improvement in clinical outcome.ConclusionsPreoperative immunonutrition was well tolerated by cancer patients. It induced structural changes in the white blood cell membranes and increased the body store of arginine and nucleotides. These effects may modulate the response to surgical stress.

An icteric type hepatocellular carcinoma with no detectable tumor in the liver: report of a case.

A 70-year-old man was admitted to our hospital with obstructive jaundice. Computed tomography revealed a tumor in the left intrahepatic bile duct extending to the common bile duct without any significant lesions in the liver. Cholangiography showed a filling defect due to an intraductal tumor. Cytology of the bile juice was negative and tumor markers were carcinoembryonic antigen 5.7 ng/ml, carbohydrate antigen 19-9 49 U/ml, α-fetoprotein 9 ng/dl, and PIVKA-II 19 200 AU/ml. With a preoperative diagnosis of hilar bile duct carcinoma, a laparotomy was performed. The common bile duct was filled with a tumor and it extended into the bilateral intrahepatic bile ducts. The intraductal tumor was removed together with the extrahepatic bile ducts. An intraoperative histological examination of the tumor showed a well-differentiated hepatocellular carcinoma. No lesions were detected in the liver by ultrasonography, palpation during the operation, or a computed tomography scan after the operation. At 1 year postoperatively, no recurrence has been seen in this patient.

FOLFIRI Plus Bevacizumab 5 mg/kg Versus 10 mg/kg as Second-line Therapy in Patients with Metastatic Colorectal Cancer Who Have Failed First-line Bevacizumab Plus Oxaliplatin-based Therapy: A Randomized Phase III Study (EAGLE Study)

We planned a multicenter randomized phase III study to evaluate the efficacy of appropriate dose of bevacizumab (5 or 10 mg/kg) with FOLFIRI in patients with advanced/metastatic colorectal cancer who have failed prior bevacizumab plus oxaliplatin-based therapy. The primary endpoint is progression-free survival. The secondary endpoints are the toxicity, response rate, time to treatment failure, overall survival, overall survival from the start of the first-line treatment and second progression-free survival (time duration from the initiation of the first-line treatment until progression after the protocol treatment). A total of 370 patients were considered to be appropriate for this trial.

Does 1 Year Adjuvant Chemotherapy with Oral 5-FUs in Colon Cancer Reduce the Peak of Recurrence in 1 Year and Provide Long-term OS Benefit?

The objective of our study was to clarify the characteristics of survival and hazard function in patients who received adjuvant chemotherapy after surgery for colon cancer. The data of 2848 patients with curatively resected colon cancer were analyzed; we used the patient data provided by the Japanese Foundation for Multidisciplinary Treatment for Cancer in three trials, namely, JFMC7-1 (n = 869), JFMC7-2 (n = 978) and JFMC15 (n = 1001). The total number of events were 605 (overall survival) and 724 (disease-free survival). The disease-free survival events consisted of 117 cases of death and 607 cases of disease recurrences. Logrank test showed a borderline significant difference in both overall survival (P = 0.0452) and disease-free survival (P = 0.0462). The 5 year overall survival proportion was 0.769 (control) and 0.802 (treated), and the absolute drug effect was 3.3%. The difference between the 5 year disease-free survival proportion (0.728 [control] and 0.760 [drug]) was 3.2%, which is almost similar to the result of overall survival. The disease-free survival curve of the treated group differed from that of the control group after 1 year, whereas the overall survival curve of the treated group became distinct from that of the control group after 2 years. The hazard rate plots indicated the possibility that 1 year adjuvant chemotherapy with oral 5-fluorouracils may translate the short-term reduction in the risk of recurrence in patients with resected colon cancer into a delayed advantage in overall survival.

Pectoralis myocutaneous flap with T-tube drainage for cervical anastomotic leakage after salvage operation

We report a patient with complications of cervical esophageal anastomosis after esophagectomy for cancer. A 61-year-old woman with advanced cervical esophageal cancer underwent radical chemoradiotherapy (66 Gy, 5-fluorouracil, and cisplatin), after which salvage surgery was performed because of residual malignancy. Anastomotic leakage occurred at the right side of the pharyngojejunostomy, causing an abscess to form around the right carotid artery and internal jugular vein. The debrided abscess space was filled with a vascularized pectoralis major myocutaneous flap replenished around a T-tube, and continuous suction of the anastomotic drainage was performed through the T-tube. Treatment was successful, and the patient was discharged. We introduce a promising new method that proved effective and safe for treating a patient with leakage of the cervical esophagus anastomosis after salvage surgery following radical chemoradiotherapy.

The effects of chemotherapy on primary small bowel cancer: A retrospective multicenter observational study in Japan

Small bowel cancer is relatively rare among gastrointestinal tract cancers, including esophageal, gastric and colorectal cancers. The majority of cases of small bowel cancer are diagnosed at an advanced stage, resulting in poor outcomes. The clinical effects of chemotherapy on small bowel cancer have been investigated in a limited number of studies from Europe and the USA. However, they have not yet been fully investigated in Asian countries, including Japan. This retrospective multicenter observational study was designed to investigate the efficacy of chemotherapy on small bowel cancer. A questionnaire survey was conducted in 28 hospitals affiliated with the Osaka University Hospital. We retrospectively reviewed the medical records of 61 patients with small bowel cancer (32 patients who were unable to undergo curative resection or had unresectable distant metastases and 29 who underwent curative resection), treated between 1996 and 2009, to evaluate the outcomes and the efficacy of chemotherapy. There was no significant difference in the overall survival between the patients undergoing curative resection with postoperative adjuvant chemotherapy and those without postoperative adjuvant chemotherapy. In patients with non-curative resection or unresectable distant metastases, the response rate to chemotherapy was 31.6% and the overall survival was significantly higher compared to that without chemotherapy (P=0.008). The study results suggested that chemotherapy is effective for Japanese patients with small bowel cancer who cannot undergo curative resection or have unresectable distant metastases.

Sequential Treatment with Irinotecan and Doxifluridine: Optimal Dosing Schedule in Murine Models and in a Phase I Study for Metastatic Colorectal Cancer

Background: Irinotecan (CPT-11) and doxifluridine (5′-DFUR) are active agents against colorectal cancer. Each drug, however, has the possibility of causing diarrhea. Methods and Results: First, we determined the optimal dosing regimen in murine models. CPT-11 (i.v., q2d ×3) and 5′-DFUR (p.o., qd ×14) were administered to mice bearing a human colorectal cancer xenograft model. Diarrhea was stronger in the simultaneously administered schedule but not much stronger in the sequentially administered schedule compared with monotherapies. Both schedules yielded similar antitumor efficacies. Next, we conducted a phase I study combining CPT-11 on days 1 and 15, and 5′-DFUR on days 3–14 and 17–28 every 5 weeks in 19 patients with metastatic colorectal cancer. The doses of CPT-11 ranged from 80 to 150 mg/m2 and those of 5′-DFUR from 800 to 1,200 mg. Diarrhea of grade 3/4 developed in only 1 patient at 100 mg/m2/800-mg doses. Dose-limiting toxicities were hyperbilirubinemia and skipping doses due to fatigue at 150 mg/m2/1,200-mg doses. Conclusion: For the phase II study, the recommended dose was set at CPT-11 150 mg/m2 and 5′-DFUR 800 mg.

Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial

BACKGROUND Adjuvant chemotherapy with oral fluoropyrimidine alone after D3/D2 lymph node dissection improves disease-free survival and overall survival in patients with stage III colon cancer. Adjuvant S-1 has been shown to be non-inferior to uracil and tegafur plus leucovorin in terms of disease-free survival. This study aims to confirm the non-inferiority of S-1 compared with capecitabine as adjuvant treatment in patients with stage III colorectal cancer. METHODS This study was an open-label, non-inferiority, randomised, phase 3, multicentre trial done in 56 Japanese centres to assess the non-inferiority of S-1 to capecitabine as adjuvant chemotherapy. Eligible patients were aged 20-80 years with stage III colorectal adenocarcinoma, as defined by the presence of an inferior margin of the primary tumour above the peritoneal reflection; R0 resection; and colectomy with D3 or D2 lymph node dissection. Patients were randomly assigned (1:1) to receive eight courses of capecitabine (1250 mg/m2 orally twice daily, days 1-14, every 21 days) or four courses of S-1 (40 mg/m2 orally twice daily, days 1-28, every 42 days). Randomisation was done via phone call, fax, or web-based systems to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component adjusted by institution, tumour location (colon vs rectosigmoid and upper rectum), number of positive lymph node metastases (≤3 vs ≥4), and surgical technique (conventional vs non-touch isolation). The primary endpoint was disease-free survival with a non-inferiority margin for the hazard ratio (HR) set at 1·24, analysed by intention to treat. This trial was registered with UMIN Clinical Trial Registry, number UMIN000003272. FINDINGS Between March 1, 2010, and Aug 23, 2013, 1564 patients were randomly assigned to capecitabine (n=782) or S-1 (n=782), all of whom were included in the efficacy analysis; 777 patients in the capecitabine group and 768 in the S-1 group were included in the safety analysis. At the prespecified second interim analysis after final accrual, 258 (48%) of 535 required events were reported, and the Data and Safety Monitoring Committee recommended early publication because S-1 could not show non-inferiority compared with capecitabine for disease-free survival. With a median follow-up of 23·7 months (IQR 14·1-35·2), 3-year disease-free survival was 82·0% (95% CI 78·5-85·0) for the capecitabine group and 77·9% (74·1-81·1) for the S-1 group (HR 1·23, 99·05% CI 0·89-1·70; one-sided pnon-inferiority=0·46). The most frequent grade 3 or higher adverse events in the capecitabine group were hand-foot skin reactions (123 [16%] of 777 patients), and in the S-1 group were diarrhoea (64 [8%] of 768 patients) and neutropenia (61 [8%]). There was one (<1%) treatment-related death in each group. INTERPRETATION Adjuvant capecitabine remains one of the standard treatments for stage III colorectal cancer in Japan; S-1 is not recommended. FUNDING National Cancer Center and Ministry of Health, Labour and Welfare of Japan.