Surgery for ulcerative colitis in 1,000 patients.

BACKGROUND AND AIMS: Ileal pouch-anal anastomosis (IPAA) has become the standard treatment for patients with ulcerative colitis (UC) who ultimately require a colectomy. Herein, we report results of our 24-year experience with that surgical method at our hospital. PATIENTS AND METHODS: Data were collected regarding surgical procedures and postoperative pathologic diagnoses for 1,000 UC patients, with early and late complications also noted. The pouch functioning rate was calculated using the Kaplan-Meier method. RESULTS: We performed 1,000 operations for UC over a 24-year period. The mean patient age at the time of operation was 35 years, and the most frequent indication for a colectomy was intractable disease. The overall rates of pouch success after 10 and 20 years were 97% and 89%, respectively. During the study period, 944 patients underwent IPAA at our hospital, of whom 12 (1.3%) were eventually diagnosed with Crohn's disease (CD). Pouch success was higher in patients with UC, with a functioning ileal pouch after 10 and 20 years found in 97% and 92%, respectfully, whereas the proportions of patients with CD and a functioning ileal pouch were lower at 82% and 20%, respectively (p < 0.01). CONCLUSION: A restorative proctocolectomy with an IPAA is a safe procedure, with low rates of mortality and major morbidity. We do not recommend routine application of IPAA in any subset of patients with known CD.

[Genetic polymorphism related to diversity of the individual aging].

In recent years, the advancements in aging research have led to a deeper understanding of the aging process and have also greatly changed our perception towards aging. In addition, the Human Genome Project has provided information on the human genome and has provided a study base for the elucidation of the molecular mechanisms underlying aging. It is interesting to note that the causative gene of Hutchinson-Gilford progeria syndrome was identified at the same period of the Human Genome Project completion, and it was expected that all the genes related to the human aging process would be identified. However, many phenomena regarding the molecular mechanisms underlying aging still remain unknown. Understanding these mechanisms is necessary in order to control aging process.

GENETICS. The Human Variome Project.

An ambitious plan to collect, curate, and make accessible information on genetic variations affecting human health is beginning to be realized.

Frequency of immunohistochemical loss of mismatch repair protein in double primary cancers of the colorectum and stomach in Japan.

PURPOSE: Colorectal cancer and gastric cancer are the two most commonly associated malignancies in Japan. We examined mismatch repair deficiency in the tumors of patients with primary colorectal and gastric cancers retrospectively. METHODS: In 103 cases and 102 healthy control subjects, surgical specimens of colorectal and gastric cancer underwent immunohistochemical analysis of mismatch repair proteins (hMLH1 and hMSH2) and microsatellite instability testing. RESULTS: Immunohistochemical and microsatellite instability testing produced similar results. High microsatellite instability in colorectal cancer was found in 23 of 103 cases (23 percent) with colorectal and gastric cancers, and in 8 of 102 healthy control subjects (8 percent). Twelve (12 percent) had mismatch repair deficiency in both colorectal and gastric cancers, and both tumors had loss of the same mismatch repair protein (hMLH1, n = 5; hMSH2, n = 7). They had the first cancer at a younger age, with a higher frequency of familial colorectal cancer than the others. Seventeen had mismatch repair deficiency in either tumor, which showed loss of expression of hMLH1. Multiple cancers and right-sided colon cancers developed more frequently in patients with mismatch repair deficiency. CONCLUSIONS: Patients with both colorectal and gastric cancers are more likely to have phenotypic evidence of hereditary nonpolyposis colorectal cancer than patients with colorectal cancer only. Among patients with double tumors, 12 percent showed a common deficiency in the same mismatch repair protein in both tumors by immunohistochemistry, and they should undergo genetic counseling for germline mutational analysis. Immunohistochemistry was effective in detecting mismatch repair deficiency of colorectal and gastric cancer as well as microsatellite instability testing, and may be more practical to perform phenotypic analysis of tumors because of its cost-effectiveness.

Does a selective cyclooxygenase-2 inhibitor (tiracoxib) induce clinically sufficient suppression of adenomas in patients with familial adenomatous polyposis? A randomized double-blind placebo-controlled clinical trial.

BACKGROUND: There have been few placebo-controlled randomized double-blind studies of the clinical effects of selective cyclooxygenase-2 (COX-2) inhibitors on the regression of colorectal tumors. This study was designed to examine the regressive effect of a selective COX-2 inhibitor, tiracoxib (JTE-522), on colorectal polyps in patients with familial adenomatous polyposis (FAP), and its safety. METHODS: Sixty-one patients with FAP diagnosed by Japanese criteria were assigned randomly to receive placebo or JTE-522, at either 150 mg or 200 mg, once daily orally for 26 weeks. Prior to and at the end of the medication period, endoscopy was performed. Adenomas located near an india-ink tattoo injected at the first colonoscopy were identified and measured. The response variables were the percent changes from the baseline in polyp numbers and in specified polyp diameters. Any adverse events that appeared in at least four persons were taken into consideration and compared between the JTE-522 treatment groups and the placebo group. RESULTS: No change in polyp number (median, 0) was observed in any of the three groups. There were no differences between the placebo group and the two treatment groups in the change in polyp size. JTE-522 was well tolerated. CONCLUSION: Our findings, in keeping with other reports on COX-2 inhibitors, indicated that the inhibition of a COX-2 with a moderate dose of a selective COX-2 inhibitor did not induce clinically sufficient regression of adenomas in patients with FAP in a limited (6-month) medication period.

Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis.

PURPOSE: Desmoid tumors are locally aggressive and can be fatal in familial adenomatous polyposis (FAP) patients if they are not suitable for surgery or radiation therapy. Here, we prospectively investigated the efficacy of a chemotherapeutic regimen involving doxorubicin (DOX) and dacarbazine (DTIC) for inoperable FAP-associated desmoid tumors. PATIENTS AND METHODS: From an initial group of 120 FAP patients, seven of the 11 individuals with symptomatic unresectable desmoid tumors that were unresponsive to conventional hormone therapy were enrolled onto this study. The general chemotherapy regimen comprised four or five cycles of DOX (20 mg/m2 daily) plus DTIC (150 mg/m2 daily) throughout 4 days of drip intravenous infusion (day 1 through 4) every 28 days, followed by the cyclooxygenase-2 inhibitor meloxicam (10 mg/m2). The primary end point was relapse-free survival. The secondary end points included toxicity, clinical improvement, and tumor regression according to computed tomography. RESULTS: Significant tumor regression was observed clinically and radiologically in all seven patients. Three patients showed a complete response. The average progression-free survival period was 74.0 months (range, 32.5 to 107.5 months). Three patients showed grade 3 adverse events with no treatment-related mortality. All seven patients survived and remained without tumor progression. An adenomatous polyposis coli germline-mutation analysis revealed no mutations in the specified regions. CONCLUSION: A chemotherapeutic regimen of DOX plus DTIC followed by meloxicam is an effective and safe treatment for FAP-associated desmoid tumors. This modality should be considered for use as first-line chemotherapy in symptomatic desmoid tumors that are unresponsive to conventional medical therapy, due to the absence of useful presymptomatic markers.

[Clinical genetics for hereditary cancers: from the viewpoint of physicians working at a hospital specialized in cancer].

In our daily practice, we provide clinical genetic consultation for patients at risk for hereditary cancers. The clinical characteristics of hereditary cancer syndromes in adults differ from those of hereditary diseases in children, although both involve genetic disease. One major difference is the difficulty in diagnosing hereditary cancers. Genetic testing has enabled us to diagnose HNPCC and familial breast and ovarian cancers. Another difference is the possibility to improve the outcomes of hereditary cancer syndromes by medical intervention. Intentional surveillance thus plays a key role in the management of hereditary cancer syndromes. These features make genetic counseling essential for hereditary cancer syndromes, including genetic testing and lifelong disease management. Networking among genetic disease specialists is particularly necessary. Clinical geneticists should be responsible for not only genetic disease but also for genomic information about cancer, with the ultimate goal of providing "order-made" medical consultation and services. Another important goal is the establishment of systems for the comprehensive care of patients and for the career development of specialists to provide regional-based care for persons who have or are at risk for hereditary cancers, including future generations.

[Gene testing of hereditary cancer on comprehensive gene medical examination support system].

It has been estimated that genetic factors or a combination of genetic and environmental factors play a role in the development of 10-15% of all cancers. A genetic cause of hereditary cancer has been identified in more than 40 diseases till now. For preventing this cancer, gene testing is essential because it has no definite clinical marker as in hereditary non-polyposis colorectal cancer: HNPCC. Much more experience must be accumulated in this testing at the clinical base in order to increase specificity and sensitivity while safeguarding ethical, legal and social issues (ELSI). Recently, the Personal Information Protection Law was enforced. Gene inspection involving hereditary cancer should be carried out under a comprehensive gene medical examination organization. It is important for the family doctor, medical specialist, and gene inspection person in charge to cooperate closely with one another, and this will be a subject of future study.

[Genetic counseling].

The emergence of molecular genetics into a routine medical service is demanding a paradigm shift in medical practice. An adequate reformation of its discipline and technology is required in every field of medical service including nursing. In 2000, the JFCR hospital founded a Familial Cancer Center to provide genetic counseling and genetic testing for cancer patents. Based upon our experiences with 250 families having various cancers, we have attempted to extract issues to be addressed in further detail.

Germline mutations of the MYH gene in Japanese patients with multiple colorectal adenomas.

Germline mutations of the MYH gene have been revealed to associate with the recessive inheritance of multiple colorectal adenomas in Caucasian population. However, MYH mutations in Japanese patients have not yet been clarified. In an assessment of MYH mutations, we examined 35 Japanese patients with multiple colorectal adenomas who had neither dominant inheritance of colorectal tumors, nor germline APC mutations. One patient had a homozygous biallelic MYH mutation, R231C and three independent patients had monoallelic MYH mutations at a splice-site on exon 11 (IVS10-2 A to G). These four patients had 21 to around 100 colorectal adenomas and 1-3 synchronous colorectal carcinomas. The most common mutations in Caucasian patients, Y165C and G382D, were not detected in our Japanese cases. The MYH mutations detected in Japanese patients were novel and different from those detected among Caucasian, Indian and Pakistani patients, which suggests the existence of ethnic differentiation in MYH mutations.

Mechanism of carcinogenesis in familial tumors.

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.

Familial breast and ovarian cancers.

About 60% of familial breast and ovarian cancers in Japan involve germline mutations of the BRCA1 or BRCA2 ( BRCA1/2) genes. These genes contribute to genetic stability and DNA repair and act as tumor suppressor genes. Mutation analysis of the BRCA1/2 genes has improved our understanding of both common mutation patterns in Japanese patients and the clinicopathological features of BRCA1/2-related cancers. BRCA1-related breast cancers are characterized by poor prognosis, a low rate of estrogen receptor positivity, and histological predominance of solid-tubular carcinoma. BRCA1-related ovarian cancers are associated with a high frequency of serous adenocarcinoma and a good outcome. Further large-scale studies are needed to delineate genotype-phenotype relations and penetrance in BRCA1/2-related breast and ovarian cancers in Japan. The development of systems for clinical genetics in Japan, including genetic counseling, has led to the increased use of genetic testing for the clinical management of BRCA1/2-related cancers. Three options are available for carriers of BRCA1/2 mutations: intensive surveillance, chemoprevention, and prophylactic surgery. Studies done in other countries indicate that prophylactic surgery effectively prevents the development of breast and ovarian cancers in carriers of BRCA1/2 mutations. However, prophylactic mastectomy remains controversial in Japan, and now systematic intensive surveillance is generally performed for the prevention of breast cancer in women at high risk. Early detection of ovarian cancer remains challenging, resulting in increased acceptance of the need for prophylactic oophorectomy in women at risk. This review summarizes experimental and clinical findings about familial breast and ovarian cancers, including data on Japanese patients.

A clinical overview of familial adenomatous polyposis derived from the database of the Polyposis Registry of Japan.

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 (stage > or = 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.

[Familial tumor syndrome and ectopic hormone-producing tumors].

It has been thought that endocrine tumors occurred through interactions of multiple environments factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to obtain the character of a malignant cell by influence of many factors. Several percent of all tumors have obvious familial aggregation. These entity are called familial cancer. Familial cancer syndrome is well defined for colorectal cancer and breast cancer, but an endocrine neoplasia is the one, too. Ectopic hormone producing tumors are kinds of endocrine tumors, and have the characteristics, which they generate in many organs multicentrically. The phenomena suggest that the patient with these disorders may possess strong genetic predisposition. Among endocrine neoplasia, multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease(VHL) are well defined genetic disorder with autosomal dominant inheritance, and the reliable genes were previously identified as MEN1, RET, and VHL, respectively. At this opportunity, we interpret for these three disorders.

Colon cancer in a 14-year-old female with turner syndrome: report of a case.

A 14-year-old female with Turner syndrome (karyotype 45,X) had a history of abdominal pain with distention, constipation, and fever. She was first operated on for the suspicion of appendicitis, failed to improve, and was later hospitalized for further investigation and treatment. Studies demonstrated an obstructing tumor of the transverse colon, and an emergency laparotomy was performed. The final diagnosis was a signet-ring cell carcinoma of the colon with diffuse peritoneal dissemination and metastasis to paracolic lymph nodes. On the basis of this case, we report the association of Turner syndrome with malignancies and also some aspects of colon cancer in childhood.

Familial adenomatous polyposis associated with multiple endocrine neoplasia type 1-related tumors and thyroid carcinoma: a case report with clinicopathologic and molecular analyses.

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.

Anticipation phenomenon in familial adenomatous polyposis:an analysis of its origin.

AIM:To analyze the origin of the anticipation phenomenon, which means earlier death in successive generation in familial adenomatous polyposis.METHODS:The study subjects were 2161 patients with familial adenomatous polyposis and their 7465 first degree relatives who were members of 750 families registered at our Polyposis Registry. The ages at death and cumulative mortality rates in theparent, the proband, and the child generations were compared for both all subjects and the patients alone.RESULTS:In the patients over 5 years of age, the mean age at death was 50.9 years for the parent, 42.3 years for the proband, and 33.3 years for the child generations, respectively a(c)(P < 0.001). The deceased rates in the three generations were 90.7%, 51.3% and 23.1% of the patients, respectively, and this difference was the main cause of the anticipation measured by parent-child paring method. The cumulative mortality rates for all subjects failed to show anticipation, however the cumulative mortality rates for the patients showed the anticipation. The anticipation phenomenon was shown by any parent-child pairing methods for the deceased patients. Other important causes of the anticipation were different proportion of causes of death between generations a(c)(P <0.001), and a low proportion of detected or deceased patients (P < 0.001) in the child generation.CONCLUSION:Anticipation in familial adenomatous polyposis may be caused by parent child paring methods as well as several intergenerational biases.