Genomic structure of the transforming growth factor beta type II receptor gene and its mutations in hereditary nonpolyposis colorectal cancers.

To characterize the tumorigenetic role of the transforming growth factor beta type II receptor (RII) gene, we defined its genomic structure, which consists of seven exons. The sequences of exon-intron junctions were determined to facilitate mutation analysis of each exon. Twenty-five carcinomas and five adenomas from hereditary nonpolyposis colorectal cancer patients were analyzed for mutations in the entire coding region. Four missense mutations (two in adenomas and two in carcinomas) were found in the 10 cases carrying the polyadenine deletions in one allele. These results indicate that RII shares the two-hit inactivation mechanism with tumor suppressor genes and that mutations of it may occur in the early stage of tumorigenesis.

Infrequent germ-line mutation of the E-cadherin gene in Japanese familial gastric cancer kindreds.

Germ-line mutation of the E-cadherin gene was reported in familial gastric cancer (FGC) kindreds from New Zealand. Therefore, we analyzed all of the exons of E-cadherin by PCR-single-strand conformational polymorphism analysis in 16 patients from 14 Japanese FGC kindreds. However, no germ-line mutation was detected, suggesting that a predisposition to FGCs by E-cadherin gene mutation is infrequent in Japanese cases.

Beta-catenin and adenomatous polyposis coli (APC) mutations in adenomas from hereditary non-polyposis colorectal cancer patients.

To clarify the roles of the adenomatous polyposis coli (APC) and beta-catenin genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesis, we searched for their mutations in 14 HNPCC adenomas with microsatellite instability (MSI). Seven (50%) adenomas exhibited somatic APC mutations, five of which were frameshift mutations and the other two nonsense ones. However, the APC mutational spectrum of these adenomas was similar to that of sporadic colorectal tumors. Two adenomas (14.3%) with undetectable APC alterations showed missense mutations at codon 45 (TCT to TTT or to CCT) in beta-catenin. The MSI frequency in adenomas with beta-catenin mutations was significantly higher than that with APCones (P<0.001), indicating that mutations of beta-catenin rather than APC are strongly associated with MSI. These data suggest that adenomas with beta-catenin activating mutations and some with APC inactivating mutations may be precursors of HNPCC colorectal cancers.

The epidemiology of endometrial cancer in hereditary nonpolyposis colorectal cancer.

Family members from hereditary nonpolyposis colorectal cancer (HNPCC) families are at an increased risk of developing endometrial cancer. The present study was performed to investigate the epidemiology of endometrial cancer associated with HNPCC. Data on 125 cases of endometrial cancer from HNPCC families were collected from seven countries. The mean age at diagnosis was 48 years (range: 27-72 years). Fifty-seven percent of the cases were diagnosed under 50 years of age and 98 percent under 65 years. The mean ages at diagnosis of endometrial cancer were not significantly different between the countries. At the time of the investigation, 58 of the 125 cases had died (mean age at death: 59 years; range: 32-88 years). Fifteen of the 125 (12%) patients died from endometrial cancer. In 75 of the 113 (61%) endometrial cancer cases, a second primary cancer occurred. Most of these cancers (54 out of 75) were colorectal cancers. In 18 (15%) of the cases of endometrial cancers, more than two primary cancers occurred. In conclusion, endometrial cancer in HNPCC develops at a significant earlier age than in the general population. More than half of the cases had a second primary tumor. Endometrial cancer is an infrequent cause of death in the HNPCC families. A prospective study is warranted to assess the value of surveillance for endometrial cancer in these families.

A case of lymphoblastic lymphoma with aberrant morphologic feature.

We report a case of 33-year-old Japanese female who had B-cell lymphoblastic lymphoma with Burkitt's lymphoma (BL)-like morphologic feature. Both breasts were involved and the resected tissue showed starry sky macrophages and a proliferation of lymphoblasts containing lipid droplets. The nucleus of the lymphoblast was oval or indented. The neoplastic cells examined expressed TdT, CD10, CD14, CD38, and WH14 (a marker of pre-B cell leukemia/lymphomas). Southern blotting analysis showed a rearrangement of the immunoglobulin heavy chain gene and germline configurations of T-cell receptor gene and c-myc 3rd exon gene. The immunophenotype and genotype of this neoplasm were different from those of previously reported BLs, but identical to those of B-cell lymphoblastic lymphoma. This case, therefore, was regarded as B-cell type lymphoblastic lymphoma containing lipid droplets.

Clinical characteristics of breast cancer patients with family history.

This study was conducted to acquire information as to the clinicopathological characteristics of breast cancer patients with family history. Of 583 patients with breast cancer, 60 (10.3%) had family history in at least one relative within the second-degree. The affected family member was most frequently a sister (43%), followed by the mother (23%) and an aunt (20%). Comparison of the data for the patients between with and without family history revealed no significant differences for any of mean age, menopausal status, histological type, histological staging, and estrogen receptor status. Although the sample size was small, neither the survival rate nor the bilaterality of disease was influenced by the family history of breast cancer.

[Efficacy of Cepharanthin for preventing leukopenia and thrombocytopenia induced by chemotherapy in breast cancer patient--prospective randomized study].

A prospective randomized study was carried out to evaluate the efficacy of Cepharanthin (CEP) on leukocytopenia and thrombocytopenia during chemotherapy in breast cancer patients. The CEP group (51 patients) was administered CEP by 60 mg/day p.o.. The control group (55 patients) was not administered CEP in all the times. The rate of leukocytopenia was significantly lower (p less than 0.05) in the CEP group than in the control. But the recovery periods from nadir to normal range in WBC were not significantly different between the two groups. The average of nadir of WBC in the leukocytopenia patients was higher in the CEP group than in the control, but it was not significant. In MMVC group and MMC + TAM group, the rate of leukocytopenia was significantly lower in the CEP group than in the controls. The obvious efficacy of CEP for thrombocytopenia was not obtained in this study. We conclude that CEP showed an efficacy on preventing leukocytopenia induced by chemotherapy in breast cancer patients.

[Chemotherapy with mitoxantrone for the treatment of recurrent breast cancer].

Two cases of recurrent breast cancer are reported in which chemotherapy with mitoxantrone proved remarkably effective. Case 1 was a 61-year-old postmenopausal female. At 32 postoperative months, multiple metastases of lung and bone were found. Following unsuccessful treatment with anthracyclin and an antiestrogenic agent, we used MVP modified therapy (mitoxantrone (MIT) 16 mg and vincristine (VCR) 1.6 mg once per 4 weeks and medroxyprogesterone acetate (MPA) 1,200 mg/day) and 5'-deoxy-5-fluorouridine (5'-DFUR) 800 mg/daily. After 12 cycles were performed, the patient showed a partial response (PR) (nearly complete response (CR)) on a chest X-ray and bone scintigram. Case 2 was a 49-year-old premenopausal female. At 42 postoperative months, a local recurrence was found and resection was performed. However, after endocrine therapy with goserelin acetate (ZOL) and chemotherapy with CAF (cyclophosphamide, adriamycin and 5-FU) and UFT, local recurrence and pleural effusion were found 6 months after surgical operation. We then used MVP modified chemotherapy and endocrine therapy with ZOL. The patient showed a PR at 9 cycles after therapy. MVP modified chemotherapy is considered an effective treatment for recurrent breast cancer, especially for adriamycin or epirubicin resistant breast cancer.

[The evaluation of pamidronate therapy for bone metastases from breast cancer].

We devised a method to evaluate comprehensively the therapy to alleviate the pain of bone metastases from breast cancer according to the three items of bone pain and effects of analgesia and radiology. In 12 patients, we evaluated the therapeutic effect of pamidronate as an alleviative treatment for the pain of bone metastases from breast cancer. Bone pain was evaluated on a 6-grade scale, as was use of analgesics. Improvement in bone pain, in addition to improvement in use of analgesia, was evaluated as markedly improved, improved, unchanged, aggravated, no pain or undeterminable. Radiological improvement in bone lesions was evaluated as markedly improved, improved, unchanged, aggravated or undeterminable. An overall evaluation was made by combining the above two. In this evaluation method, pamidronate therapy resulted in an evaluation of markedly improved in 2 patients, improved in 5, unchanged in 4 and aggravated in 1, demonstrating that the therapy was very useful as an alleviative treatment for the pain of bone metastases from breast cancer. The evaluation method, in which pain, a subjective complaint, is combined with use of analgesics, an objective factor, and to which radiological evaluation is added for further objectively, may in the future to be applicable for evaluation of various alleviative treatments of pain of bone metastases.

[K-ras gene mutations in adenomas from familial adenomatous polyposis].

A 18-year-old woman underwent total colectomy for familial adenomatous polyposis. In order to clarify the significance of K-ras mutations in early colorectal carcinogenesis, K-ras mutations were analyzed in multiple adenomas by PCR-SSCP method. A total of 256 adenomas were found throughout the entire colon and rectum, and the distribution was a sparse type. The correlation between K-ras gene and clinicopathological factors was examined in 90 adenomas. There was no correlation among K-ras mutations and anatomical distribution, or morphological classification, but K-ras mutation was more frequent in severe compared with slight atypia. We investigated the correlation between the size of adenoma in the horizontal and vertical directions and K-ras mutation. K-ras mutation was more frequent in the horizontal size greater than 6 mm in diameter, and also more frequent in vertical size greater than 20 mm in height. It was concluded that the adenomas detecting K-ras mutations might have proliferating potential, and would be applied to determine polypectomy.

[Telomerase activity in colorectal cancer--a semi-quantitative procedure].

Telomerase maintains telomere at the end of chromosome and stabilizes chromosome. It is thought to have important roles in cancer progression and cell immortality. We evaluated the role of telomerase expression in colorectal carcinogenesis. Materials included 13 colonic adenomas, 9 early colorectal cancers, 32 advanced colorectal cancers, 5 metastatic tumors, and 30 non-cancerous colon mucosas. The telomerase activity was analyzed using TRAP-eze (Oncor Inc.) for a semi-quantitative method. The positive rate of telomerase activity was 13.3% in non-cancerous colonic mucosa, 15.4% in colonic adenomas, 77.8% in early colorectal cancers, 93.8% in advanced colorectal cancers, and 100% in metastatic tumors; the mean value was 18.0, 29.9, 65.8, 97.0 and 161.3. The correlation between telomerase activity and tumor size, histologic type, or depth of invasion was noted. Sensitivity, specificity and accuracy were on the order of 89%, 98% and 93% at the cut-off level as two times the mean value of non-cancerous mucosa. Telomerase had an important role in carcinogenesis, and progression of colorectal cancer, and it was suggested to be useful for a tumor marker.

[The breast cancer-prone family: clinical study of familial breast cancer].

Familial breast cancer are clinically characterized by early age of onset, the increased frequency of multiple primary malignant neoplasms including bilateral breast cancer and non-left-side dominance with regard to the site of onset. The genetic consideration of the pedigrees suggests that familial clustering of breast cancer is related to the autosomal dominance of susceptibility, polygenes and incomplete penetrance. The additive effects obtained by combining the genetic with the environmental factors are recognized in familial breast cancer. Clinical surveys and follow-ups of breast-cancer-prone families are required to facilitate the early detection and treatment.

[Clinical investigation of familial clustering of cancer].

Five cancer-prone families, i.e., a colorectal cancer family, a gastric cancer family, two breast cancer families and a cancer family without organ specificity are reported, and familial clustering of cancer was investigated clinically. It was strongly suggested that familial clustering of cancer was related to genetic factors. The clinical characteristics of cancer-prone families were a familial tendency to cancer, early age of onset, an extraordinary frequency of multiple primary malignant neoplasms and an autosomal dominant mode of gentic transmission. The clinical significance of noting familial clustering of cancer is to extract groups at high risk for cancer, to detect early cancerous lesions and to make early therapeutic decisions.

Second primary breast cancer following thyroid cancer: report of two cases.

Two cases of second primary breast cancer following thyroid cancer are presented. The association between breast and thyroid cancer is reviewed from the literature, but no common etiologic factor is found between the two neoplasms in our experience.

Zinc, iron, and copper contents of Xenopus laevis oocytes and embryos.

Zinc is essential for vertebrate development; its deficiency results in multiple congenital malformations. Knowledge of the zinc biochemistry that underlies embryologic development is very limited. This has led us to investigate the zinc, iron, and copper contents of Xenopus laevis oocytes and embryos. Stage 1-6 oocytes, isolated from ovaries, and stage 1-40 embryos, obtained by in vitro fertilization techniques, were washed in metal-free water prior to digestion by 70% ultrapure HNO3. The metal content of the digests was analyzed by atomic absorption spectrometry. Stage 6 oocytes contain 65.8 +/- 4, 31.1 +/- 3, and 0.68 +/- 0.2 ng of zinc, iron and copper, respectively. The corresponding concentrations are 1, 0.5, and 0.01 mM in 1 microliter eggs. The metal content varies as a function of egg maturation. The zinc content increases from 3-7 to > 60 ng by stages 3 and 6, respectively. A similar pattern is noted for iron, which increases from 2-5 to 30 ng at analogous stages. In contrast, the copper content remains virtually unchanged in oocytes undergoing maturation. Importantly, the total of all three metals does not vary throughout the first 50 stages of development, when all tadpole organs are forming. Hence, the full complement of zinc, iron, and copper needed for incorporation into apoproteins during development is already present at a time when oocyte maturation is completed. The specific metalloproteins that store, donate, and accept these metals during induction and organogenesis and the alterations caused by metal deficiency can now be identified.

[ Carcinoma of the remnant stomach following surgical treatment of quadruple cancers].

A case of five metachronous carcinomas is reported. The patient was a 57-year-old male with carcinomas of the stomach, colon, rectum, and lip. A new malignancy was detected in the remnant stomach. This case suggests that frequent follow-ups and cancer screening are required for cancer patient, considering the possibility of subsequent malignancy.

[A case of familial breast cancer].

The occurrence of breast cancer in 5 members of a family is reported. No specificity of the location, staging or histological typing of the lesions was observed in these cancers. But the characteristics of "hereditary breast cancer", early onset and the occurrence of metachronous double cancers, were observed. As for heredity, it is suspected to be autosomal dominant trait; on the other hand it is more appropriate to assume a poly genic pattern. Recognizing the importance of familial cancer occurrence, it may be possible to detect early cancerous lesions in family members.

[Study on carbohydrate antigen NCC-ST-439 in breast cancer].

We evaluated the clinical significance of serum NCC-ST-439 (ST439) in sera from 20 healthy women, 8 patients with benign breast disease and 105 patients with breast cancer (79 primary, 26 recurrent) by using enzyme immuno-assay (EIA). No false positive case was noted in the measuring of ST439 for healthy women and patients with benign breast disease. The positive rates of ST439 were 23% (18/79) in primary breast cancers and 50% (13/26) in recurrent breast cancers. The serum levels of ST439 in stage I breast cancer was significantly higher (p less than 0.05) than those in healthy women, but there was no significant difference among each stage. The serum levels of ST439 were not significantly different among the subsets such as T, n, m and histological types. The high levels of serum ST439 were observed in two cases with mucinous carcinoma. Although there were no relation between ST439 and receptor status, the higher serum levels of ST439 were observed in postmenopausal patients than premenopausal ones. The positive frequency of serum ST439 in stage I and II breast cancers was higher than that of CEA, TPA or CA15-3, while the positive rate in recurrent breast cancer was the lowest among 4 tumor markers. These results suggest that ST439 is a useful tumor marker for not only detecting the recurrence of breast cancer but also diagnosing primary breast cancer in early stage.