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The clinical situation of familial adenomatous polyposis (FAP) in Japan has changed in the period since the last analysis of data of the Japanese Polyposis Center. To reevaluate our data and elucidate the changes we analyzed the records of the 1390 FAP patients in 900 families registered with the Polyposis Committee of the Japanese Society for Cancer of the Colon and Rectum. In the 13-year period 1990-2003, clinical differences between men and women with FAP diminished. The postoperative prognosis was substantially better in patients without advanced colorectal cancer (stageor = T2) than in those with early cancer or no cancer. Mean age at death improved from 42.5 years in the period before 1990 to 46.0 years, and it was a result of a decreased proportion of deaths from colorectal cancer. The distribution of colorectal cancer in FAP patients was similar to that in the general population. Desmoid tumors accounted for about 10% of deaths in the recent 13 years (1990-2003). The cumulative risk of rectal cancer in the preserved rectum was 12% at 10 years and 23% at 15 years. The registry system in Japan revealed a new clinical situation in FAP patients, and the findings of this study will be useful to improve the prognosis of patients with FAP.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit experimental carcinogenesis and their use in humans has been related epidemiologically to a reduced risk of colorectal polyps and cancer, although the mechanism involved is not known. We found that aspirin triggered the death of SW948 human colorectal adenocarcinoma cells through activation of an apoptotic pathway. Exposure of SW480 and SW948 cells to 25 mu M aspirin for 5 h resulted in the detatchment of cells from the monolayer culture at 48 h. SW948 cells with continuous exposure to 25 mu M aspirin exhibited various morphological and biochemical characteristics of apoptosis, including compact patches of condensed nuclear chromatin, and DNA fragmentation. These in vitro data suggest that apoptosis may play a role in the antitumor effect of aspirin and other NSAIDs and that the induction of apoptosis may provide an attractive therapeutic target in colorectal carcinogenesis.

It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson's two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive.

We have previously shown that increased intestinal contraction after small bowel transplantation was associated with marked enhancement in the nonadrenergic, noncholinergic (NANC) intrinsic neural component. In the present study, we examined the effect of three NANC neurotransmitters (substance P, neurotensin, and cholecystokinin-octapeptide, CCK-OP) on jejunal longitudinal muscle strips after syngeneic total small bowel transplantation in rats. Fourteen rats were divided into a normal control group (n = 7) and a group tested 4 weeks after transplantation (n = 7). A superfusion system was used to evaluate the in vitro effects of the three neuropeptides in the presence of atropine and guanethidine. In the control group, maximum contractile response to substance P, neurotensin, and CCK-OP was 5.16 +/- 0.30, 1.46 +/- 0.15, and 1.13 +/- 0.17 mg tension/mg wet weight, respectively, while the values for the transplanted group were 5.71 +/- 0.29, 2.52 +/- 0.17, and 1.20 +/- 0.18 mg tension/mg wet weight. These results show that neurotensin-induced contraction increased significantly after transplantation, but substance P appeared to be the dominant NANC neurotransmitter in both normal and transplanted small bowel.

To investigate the mechanism of colon carcinogenesis, the loss of heterozygosity and Kras mutation were analyzed in 24 advanced FAP carcinomas, 20 advanced non-FAP carcinomas, and 111 FAP polyps with distinct histopathological dysplasia. Allele loss was observed in advanced FAP carcinomas most frequently on chromosome 5q (38%), 17p(57%), 18(36%) and 22q(35%). Non-FAP carcinomas exhibited allele losses similar to those in the FAP carcinomas. The frequency of allele loss in polyps from FAP patients was low, but it was higher in more advanced polyps; the loss was observed on chromosome 5q (24%) in severe adenomas, and on chromosome 5q (25%) and 17p(30%) in intramucosal early carcinomas. Kras mutations were detected in 50% of the advanced FAP carcinomas. The mutation frequency in polyps was lower than that in advanced carcinomas, the frequency increasing with polyp size. The present results suggest, in addition to the FAP gene on chromosome 5q, a significant role of cumulative changes in multiple tumor suppressor genes and the Kras gene during the development of colon tumors.

In order to identify hereditary non-polyposis colorectal cancer (HNPCC) in Japan, we analyzed clinical characteristics of 10 families of colorectal cancer (CRC) with two or more affected relatives in our department (the personal series) and of 39 families reported as familial CRC or cancer family syndrome in Japanese literatures (the reported series). The characteristics of CRC in the reported series in comparison with general CRC were earlier onset, higher incidence of multiple tumor, predominance in the proximal colon, and excess of multiple primary cancer in the other organs. They were similar to those of USA and Finland except for more frequent association with gastric cancer in the reported series. Gastric cancer patient with onset in age of 60 or younger in family history of CRC may be regarded as a clinical marker suggestive for HNPCC. The reason for failure to demonstrate the characteristics of HNPCC in the personal series is to be further clarified by study with our data based on larger scale.

To investigate the mechanisms controlling human gallbladder contraction, especially to determine the role of neural factors, the gallbladder response to various stimuli was evaluated in eight normal subjects using realtime ultrasonography. In addition, plasma cholecystokinin (CCK) levels were measured using a region-specific antibody (OAL 656). Intramuscular injections of CCK-8 and of cerulein induced mean maximal ejection fractions (EF max) of 50% +/- 6% and 58% +/- 4%, respectively. The mean EF max after ingestion of a fatty meal was 44% +/- 3%, while the EF max after a fat-restricted meal was significantly lower (17% +/- 4%). Oral water and sham feeding also significantly induced gallbladder contractions (EF max; 25% +/- 4% and 12% +/- 4% respectively) that were eliminated by premedication with atropine. The plasma CCK rose significantly after exogenous administration of CCK-8 and after ingestion of a fatty meal. The peak CCK concentration released after fatty meals was almost identical to that after exogenous CCK-8 loading. In contrast, plasma CCK levels showed no change after the fat-restricted meal, oral water and sham feeding. These findings suggest that not only CCK but also the cholinergic pathway may play important roles in the control mechanism of human gallbladder contraction.

We searched for germ-line mutations of the APC gene in 79 unrelated patients with familial adenomatous polyposis using a ribonuclease protection analysis coupled with polymerase chain reaction amplifications of genomic DNA. Mutations were found in 53 patients (67%); 28 of the mutations were small deletions and 2 were 1- to 2-base-pair insertions; 19 were point mutations resulting in stop codons and only 4 were missense point mutations. Thus, 92% of the mutations were predicted to result in truncations of the APC protein. More than two-thirds (68%) of the mutations were clustered in the 5' half of the last exon, and nearly two-fifths of the total mutations occurred at one of five positions. This information has significant implications for understanding the role of APC mutation in inherited forms of colorectal neoplasia and for designing effective methods for genetic counseling and presymptomatic diagnosis.