Genichi Nishimura

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms among women and the third largest number among men. Many new methods of treatment have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2014 for treatment of colorectal cancer (JSCCR Guidelines 2014) have been prepared as standard treatment strategies for colorectal cancer, to eliminate treatment disparities among institutions, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding among health-care professionals and patients by making these guidelines available to the general public. These guidelines have been prepared as a result of consensuses reached by the JSCCR Guideline Committee on the basis of careful review of evidence retrieved by literature searches and taking into consideration the medical health insurance system and actual clinical practice in Japan. They can, therefore, be used as a guide for treating colorectal cancer in clinical practice. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions of the Guideline Committee, controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories, on the basis of consensus reached by Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2014.

Intraoperative lavage for cytological examination in 1,297 patients with gastric carcinoma

BACKGROUND This study examined the clinical value of intraoperative peritoneal lavage for cytological examination in patients with gastric cancer. Peritoneal dissemination is the most frequent mode of recurrence for this tumor. METHODS A retrospective of lavage findings, other factors, and outcome was performed in 1,297 patients with gastric cancer who underwent intraoperative peritoneal lavage. RESULTS The 5-year survival rate of patients with positive lavage cytology was only 2%. Patients who underwent curative resection and had negative cytology had a significantly better 5-year survival rate (P < 0.001). Even among patients with macroscopic peritoneal dissemination, the survival rate was significantly better with negative cytology, which reflected fewer free cancer cells in the peritoneal cavity. Serum concentrations of carcinoembryonic antigen and carbohydrate antigen 19-9 were significantly higher in patients with positive cytology. Multivariate analyses indicated that intraoperative cytological findings was an independent prognostic factor for survival, and was the most important factor for predicting peritoneal recurrence. CONCLUSIONS Intraoperative peritoneal lavage cytology is important in predicting survival and peritoneal recurrence in gastric cancer.

Effects of intraoperative chemohyperthermia in patients with gastric cancer with peritoneal dissemination

BACKGROUND The most common cause of noncurative resection and recurrence is gastric cancer is peritoneal seeding. However, the results of treatment of peritoneal dissemination with chemotherapy have been poor with 5-year survival rates of 0%. METHODS A new in vitro thermochemosensitivity test was performed on gastric cancer cells obtained from 19 surgically resected specimens by using tetrazolium-based colorimetric assay (MTT assay). A novel treatment of the intraoperative chemohyperthermia was undertaken in 83 patients with gastric cancer with peritoneal dissemination. After aggressive resection of primary tumor, lymph nodes, and peritoneal metastases, warmed saline solution containing mitomycin C 30 mg, etoposide 150 mg, and cisplatin 300 mg was introduced into the peritoneal cavity via a closed circuit continuous hyperthermic peritoneal perfusion (CHPP) for 60 minutes to keep the abdominal temperature at 42 degree to 43 degrees C by means of a heat exchange mechanism. RESULTS The in vitro thermochemosensitivity test that 43 degrees C enhanced the cytotoxin effects on gastric cancer cells under clinically achievable drug concentrations. During CHPP, drug concentrations of cisplatin, mitomycin C, and etoposide in the perfusate remained statistically higher than in the peripheral venous circulation. Among 43 evaluable patients with residual peritoneal seeding, eight (19%) and nine (21%) exhibited complete response and partial response, respectively. The overall 1- and 5-year survival rates were 43% and 11%, respectively. Patients who underwent complete resection survived significantly longer than those with residual disease, and those with complete response had a significantly better prognosis than did those with partial response, and nonresponders. One-year survival rates with complete response, partial response or nonresponders were 88%, 27% and 22%, respectively. Five patients survived longer than 5 years. CONCLUSIONS Our triple treatment combining surgery and CHPP is an effective therapy for selected patients with gastric cancer with peritoneal dissemination.

Inverse association of nm23-H1 expression by colorectal cancer with liver metastasis

The expression of nm23-H1 mRNA and protein was studied in colorectal cancers by Northern blotting and immunohistochemistry. All 21 colorectal cancers studied by Northern blotting had increased levels of nm23-H1 mRNA relative to the adjacent normal colonic mucosa. Increased nm23-H1 protein expression was also observed in all 36 colorectal cancer cases including those studied by Northern blotting. There was no significant correlation between nm23-H1 expression and tumour histology, serosal invasion, lymphatic invasion, venous invasion, or lymph node metastasis. However, the expression of both mRNA and protein was significantly lower in tumours associated with liver metastasis than in those without such metastasis. These observations indicate that the nm23 gene may play a role in the suppression of liver metastasis of colorectal cancer.

Detection of sentinel and non-sentinel lymph node micrometastases by complete serial sectioning and immunohistochemical analysis for gastric cancer

BackgroundWe investigated the presence and distribution of the sentinel and the non-sentinel node micrometastases using complete serial sectioning and immunohistochemical staining (IHC), to inspect whether lymph node micrometastases spread to the sentinel lymph nodes first.MethodsA total of 35 patients, who underwent gastrectomy with a sentinel lymph node biopsy for gastric cancer, were enrolled in this study. Total of 1028 lymph nodes of 35 patients having gastric cancer without metastasis of lymph node by permanent section with hematoxylin and eosin staining (H&E) were selected. There were 252 sentinel nodes and the other 776 were non-sentinel nodes. All nodes were sectioned serially and stained alternately with H&E and IHC. Lymph node micrometastases was defined as proving to be positive first either the IHC or the complete serial sectioning.ResultsMicrometastases were detected in 4 (11%) of the 35 patients, 6 (0.58%) of 1028 nodes. Of these 4 patients, 3 had micrometastases exclusively in sentinel nodes, and the other had micrometastasis in both sentinel and non-sentinel nodes. There was no patient who had the micrometasitases only in non-sentinel nodes.ConclusionThese results support the concept that lymph node micrometastasis of gastric cancer spreads first to sentinel nodes.

PTD classification: proposal for a new classification of gastric cancer location based on physiological lymphatic flow

BackgroundWe propose a new classification for the location of gastric cancer — the PTD classification (i.e., zones P, T, and D; see below), with the zones classified according to the physiological lymphatic flow.MethodsThree hundred and thirty-six patients with T1 or small T2 gastric cancer who underwent sentinel node mapping at our hospital were enrolled. The relationship between the location of the gastric cancer and the physiological lymphatic flow derived from sentinel node mapping was investigated. Lymphatic basins were defined as lymphatic zones divided by the stream of stained lymphatic canals.ResultsOne hundred and forty-six patients underwent standard gastrectomy with more than D2 dissection and the other 190 patients underwent function-preserving gastrectomy with the omission of lymph node dissection outside the lymphatic basin. In the former group, the progression pattern of lymph node metastasis was observed; nodal metastasis occurred in sentinel nodes first, and rarely extended outside the lymphatic basin. In the latter group, none of the patients have had a recurrence. The PTD classification we propose is as follows: the dividing line between the proximal region (zone P) and the transitional region (zone T) is the line that links the point of the watershed between the left gastroepiploic artery and right gastroepiploic artery, to the point that is the inflow point of the first descending branch of the left gastric artery; and the dividing line between zone T and the distal region (zone D) is an arc at a radius of 8 cm from the pylorus. There were no lymphatic basins within the right gastric artery area for tumors located in zone T.ConclusionThe advantage of the PTD classification is that if the PTD classification were to be used as a guide for gastric resection procedures, preservation of the pylorus would become possible without diminishing the prognosis in patients with cT1N0 cancer located in zone T.

Expression of Vascular Endothelial Growth Factor D Is Associated with Lymph Node Metastasis in Human Colorectal Carcinoma

Objective: Expression of vascular endothelial growth factor (VEGF)-D by tumors is associated with metastasis to lymph nodes in mice. However, there are few reports concerning the clinical significance of VEGF-D protein in human carcinoma. Methods: After confirming production of VEGF-D by eight colorectal carcinoma cell lines, we investigated relationships between the expression of VEGF-D protein, lymph node metastasis and postoperative survival in 83 colorectal carcinoma patients. mRNA levels in cell lines were evaluated using the real-time reverse transcriptase-polymerase chain reaction, and protein was detected by Western blotting in cell lines and by immunohistochemistry in resected tissues using an antibody recognizing the processed form of the molecule. Results: Immunohistochemistry showed VEGF-D-positive staining in 26 of the 83 carcinomas (31%). There was a significant relationship between the presence of VEGF-D protein and the incidence of lymph node metastasis (p < 0.01). Multivariate logistic regression analysis revealed that VEGF-D protein expression was an independent factor affecting lymph node metastasis (p < 0.01). Nonetheless, the presence or absence of VEGF-D protein had no significant impact on the survival of the patients (p = 0.15). Conclusion: These results suggest that the expression of VEGF-D protein could be useful in predicting the nodal status of colorectal carcinoma patients.

Alteration of β‐catenin expression in esophageal squamous‐cell carcinoma

β‐catenin regulates cadherin‐mediated cell‐cell adhesion and also functions as a signaling molecule. In this study, we examined the expression pattern of E‐cadherin, α‐catenin and β‐catenin in 22 cases of esophageal squamous‐cell carcinoma by Western‐blot analysis. Expression of E‐cadherin, α‐catenin and β‐catenin was lower in carcinomas than in normal esophageal mucosa in 4 cases (18.2%) for E‐cadherin, 6 cases (27.3%) for α‐catenin and 9 cases (40.9%) for β‐catenin. Expression of β‐catenin was not always correlated with that of E‐cadherin. Over‐expression of β‐catenin was observed in 3 cases (13.6%). Of 3 cases that presented with over‐expression of β‐catenin, 2 showed cytoplasmic staining by immunohistochemistry. Nuclear localization of β‐catenin was observed in one case that had higher β‐catenin level in tumor tissue (1.4‐fold higher than normal mucosa). The genomic DNA sequences of the β‐catenin and the APC gene were analyzed. No mutation of the β‐catenin gene was observed in any cases. Silent mutation of the APC gene was found in all the cases that showed over‐expression or nuclear localization of the β‐catenin protein. These results indicate that alterations of the cadherin‐catenin complex may play an important role in a sub‐set of esophageal carcinogenesis. Furthermore, it is suggested that β‐catenin over‐expression is not caused by genetic alteration of either the β‐catenin or the APC gene. Int. J. Cancer 85:757–761, 2000.

Human chorionic gonadotropin in colorectal cancer and its relationship to prognosis.

The presence of human chorionic gonadotropin in large bowel cancers was studied immunohistochemically using an immunoperoxidase technique. HCG-positive tumour cells were present in 42 of 194 adenocarcinomas examined (22.0% of colon cancer and 21.2% of rectal cancers). On histological grading, the hCG-positive rate tended to rise as the degree of differentiation decreased. HCG was detected more frequently in cancers invading the total bowel wall (27%) than in those invading the partial wall (17.1%). Lymph node, liver or peritoneal metastases were present more frequently in hCG-positive tumours than in hCG-negative tumours. Furthermore, there was an intimate correlation between the presence of hCG-positive tumour cells and CEA doubling times in nine cases with untreated liver metastasis. The survival rate for patients with tissue hCG-positive cells was lower than for those with hCG-negative tumours. Thus, the presence of tissue hCG in colorectal cancers may be a biological marker of prognostic significance.

Trypsinogen expression and early detection for peritoneal dissemination in gastric cancer

The most reliable method for the diagnosis of peritoneal dissemination of gastric cancer at the present time is cytological examination of ascitic fluid, which is unavailable to patients without ascites or may be inadequate for those with ascites containing few cancer cells. It has been reported recently that human gastric cancer immunoreacted with a monoclonal antibody against pancreatic trypsinogen. We therefore examined the expression of trypsinogen as a new marker for the early diagnosis of peritoneal dissemination of gastric cancer.