Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer.

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165-7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25-6.64).

A phase I study and pharmacologic evaluation of irinotecan and carboplatin for patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy.

BACKGROUND: The objectives of the current study were to determine the maximum tolerated dose (MTD) of irinotecan and carboplatin in combination, to evaluate the efficacy and toxicity of the combination in patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy, and to examine the pharmacokinetics and pharmacodynamics of both drugs by using the Chatelut formula. METHODS: Patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy were treated with a combination of irinotecan and carboplatin. Carboplatin was administered as a 60-minute intravenous infusion on Day 1 and was followed by irinotecan, which was administered as a 90-minute intravenous infusion on Days 1, 8, and 15. Six dose levels of irinotecan (in mg/m(2))/carboplatin (mg . mL/min) were planned: 50 mg/m(2)/4 mg . mL/minute, 60 mg/m(2)/4 mg . mL/minute, 50 mg/m(2)/5 mg . mL/minute, 60 mg/m(2)/5 mg . mL/minute, 50 mg/m(2)/6 mg . mL/minute, and 60 mg/m(2)/6 mg . mL/minute. The carboplatin dosage was calculated by using the Chatelut formula. Treatment was repeated at 28-day intervals. RESULTS: In total, 19 patients in cohorts of 3 to 5 patients received irinotecan and carboplatin at 5 dose levels. The dose-limiting toxicities were Grade 4 neutropenia and Grade 4 thrombocytopenia. The MTD of the irinotecan/carboplatin combination was 60 mg/m(2)/5 . mg mL/minute. Partial responses were observed at higher dose levels. Pharmacologic studies demonstrated that administration of the dosage estimated with the Chatelut formula instead of the Chatelut formula with adjustment for serum creatinine resulted in a slightly excessive dose of carboplatin. CONCLUSIONS: The recommended dose for the Phase II study was irinotecan 60 mg/m(2) on Days 1, 8, and 15 with carboplatin 5 mg/mL . minute on Day 1 repeated every 4 weeks.

Versatile lotus petal flap for vulvoperineal reconstruction after gynecological ablative surgery.

OBJECTIVE: The objective of the present work was to assess the efficacy and complications of the use of the lotus petal flap in the vulvoperineal reconstruction among female patients treated for vulvar malignancies. METHODS: Between December 2000 and April 2003, five patients underwent vulvoperineal reconstructions with the fasciocutaneous skin flaps elevated from gluteal folds immediately after vulvoperineal ablative surgeries at National Cancer Center Hospital, Tokyo, Japan. RESULTS: The mean surface area of vulvoperineal tissue defects was 157.9 cm(2) (64.0-195.0 cm(2)), which could be filled completely by bilateral lotus petal flaps. The mean length of follow-up was 18 months (7-32 months). All flaps successfully survived without fatal necrosis. In postoperative follow-up, all patients had no complaint of pain and no abnormal sensation at the site of flap or at the donor site, and the lotus petal flap caused no severe damage to excretion, mobility of the hip, or the sensation in the vulvoperineal area. The gluteal fold could make the donor-site scar stand out in all patients. CONCLUSION: The lotus petal flap is thought to be one of the most ideal reconstructive procedures for vulvoperineal region from various viewpoints of oncology, function, wound healing, and cosmetic surgery.

Cisplatin, paclitaxel and escalating doses of doxorubicin (TAP) in advanced ovarian cancer: a phase I trial.

BACKGROUND: The objectives of this phase I trial were to determine the maximum tolerated dose (MTD) and the recommended dose (RD) for phase II/III trials of doxorubicin (DOX) combined with paclitaxel (PTX) and cisplatin (CDDP) in patients with advanced ovarian cancer (AOC). METHODS: Twenty-eight patients with stage III/IV AOC received fixed doses of PTX (110 mg/m(2) over 24 h on day 1) and CDDP (75 mg/m(2) on day 2) and an escalating dose of DOX (20, 30, 40 or 50 mg/m(2) on day 1) every 3 weeks. The patients received up to six cycles of chemotherapy. At level 1, one of the original dose-limiting toxicities (DLTs), grade (G) 4 neutropenia lasting for 4 days or longer, occurred in four of six patients. The criterion for DLT was amended to 'G4 neutropenia lasting for 8 days or longer accompanied with G4 leukopenia' and four additional patients were evaluated at level 1. RESULTS: According to the new criteria, DLT was observed only in one of nine patients except one ineligible patient at level 1 and two of six patients at level 4. G4 neutropenia and G4 leukopenia occurred in 85% and 44%, respectively, in the first course of chemotherapy. Non-hematological toxicity was generally mild or moderate. MTD was not determined at the planned dose levels. A clinical response was observed in 16 of 19 (84%) evaluable patients. Further dose escalation was not performed and RD was determined as level 4 because more than 30% of cycles required some modification of chemotherapy at level 4. CONCLUSION: The combination of TAP including 50 mg/m(2) of DOX is feasible and well tolerated as first line chemotherapy in AOC, warranting further study of this regimen.

Pulmonary metastasectomy for uterine cervical cancer: a multivariate analysis.

BACKGROUND: This study evaluated the results of resection of pulmonary metastases from cervical cancer. METHODS: A total of 7,748 patients with primary stage Ib or II cervical cancer underwent curative initial treatment consisting of radical hysterectomy or radiotherapy in 22 hospitals. Of the 7,748 patients, 29 (0.37%) patients had pulmonary metastases, which were detected after a disease-free period after initial treatment (radical hysterectomy or radiotherapy) and were resected with the intention to cure by June 30, 1998. RESULTS: The 5-year disease-free survival rate after pulmonary metastasectomy for all patients was 32.9%. Patients with one or two pulmonary metastases had a 5-year disease-free survival rate of 42.2% compared with 0% for patients with three or four metastases (p = 0.0003). Patients with squamous cell cancers had a 5-year disease-free survival rate of 47.4% compared with 0% for patients with adenosquamous cell cancers or adenocarcinoma (p = 0.0141). On multivariate analysis, the significant prognostic variables for disease-free survival were two or fewer metastases (p = 0.0232) and squamous cell cancer (p = 0.0168). CONCLUSIONS: Cervical cancer patients with pulmonary metastases after initial treatment (radical hysterectomy or radiotherapy) could expect to achieve long-term disease-free survival by pulmonary metastasectomy when there are two or fewer metastases diagnosed as squamous cell cancer.

Difference in cytoplasmic localization pattern of neutral mucin among lobular endocervical glandular hyperplasia, adenoma malignum, and common adenocarcinoma of the uterine cervix.

To investigate whether the cytoplasmic localization pattern of neutral mucin differs between lobular endocervical glandular hyperplasia (LEGH) and cervical adenocarcinoma (CxAd), including minimal-deviation adenocarcinoma (MDA), or adenoma malignum, alcian blue (pH 2.5)/periodic acid-Schiff (AB-PAS) staining was performed to formalin-fixed paraffin-embedded tissue sections of 13 lesions of LEGH and 53 tumors of CxAd, including 6 tumors of MDA. The cytoplasmic localization of neutral mucin was classified as a "whole cytoplasmic pattern," in which neutral mucin filled the cytoplasm entirely, or as an "apical pattern," in which neutral mucin was localized in the subsurface area only. Cytoplasmic neutral mucin patterns were detected in all 13 cases of LEGH and in 19 cases (36%) of CxAd, including five cases of MDA. The localization of neutral mucin was always the whole cytoplasmic pattern in 13 cases of LEGH, but was the apical pattern in these 19 cases of CxAd. The other 34 cases of CxAd, including 1 case of MDA, corresponded to the acid mucin pattern stained purple or blue or no staining pattern by AB-PAS. Among the 53 cases of CxAd, the apical neutral mucin pattern was an indicator of poorer patient prognosis by univariate and multivariate analyses. The examination of cytoplasmic localization of neutral mucin might be applicable, not only to differential diagnosis between LEGH and CxAd, including MDA, but also to estimate clinical aggressiveness of CxAd.

Early invasive adenocarcinoma of the uterine cervix: criteria for nonradical surgical treatment.

OBJECTIVE: This retrospective study was undertaken to identify selection criteria for nonradical surgery for early invasive adenocarcinoma of the uterine cervix. METHODS: Seventy-nine patients with surgically treated cervical adenocarcinomas (with invasion to 5 mm or less) were examined clinicopathologically. The evaluation of stromal invasion was conducted according to the FIGO (1995) staging system. RESULTS: The mean age was 46 (range: 29-73) years, and the median follow-up was 118 (9-348) months. Definitive treatment modalities included radical hysterectomy in 71 (89.9%) cases, modified radical hysterectomy in 2 (2.5%), and simple extrafascial hysterectomy without pelvic lymphadenectomy in 6 (7.6%). Postoperative adjuvant external radiation therapy was given to 5 (6.3%) patients. The histological subtypes were endocervical in 37 (46.8%) cases, endometrioid in 32 (40.5%), and adenosquamous in 10 (12.7%). Forty-one (51.9%) patients had lesions with up to 3 mm of stromal invasion; of these, 24 (58.5%) had lesions with up to 7 mm of horizontal extension (stage IA1). Thirty-eight (48.1%) patients had lesions with stromal invasion greater than 3 mm and no greater than 5 mm; of these, 4 had lesions with no wider than 7 mm of horizontal extension (stage IA2). Of 73 patients with pelvic lymphadenectomy, one (1.4%) tumor (depth: 5 mm; width: 15 mm) had node metastases. Parametrial involvement was present in one (1.4%) patient (lesion depth: 5 mm; lesion width: 16 mm). None had adnexal metastasis. Eighty-eight percent of the patients with stromal invasion up to 3 mm had well-differentiated adenocarcinoma, compared to 53% of the patients with lesions invading more than 3 mm. Of all of the patients, 5 (6.3%) patients who received curative radical hysterectomies had recurrences and died. Among 5 patients, one patient with central pelvic recurrence had a lesion invading to a depth of 3 mm and width of 7 mm, and the others had lesions with more than 3 mm of invasion and 15 to 36 mm of width. CONCLUSIONS: Patients with early invasive adenocarcinoma to a depth of 3 mm or less stromal invasion, including those who meet the criteria for FIGO stage IA1, may be treated with simple extrafascial hysterectomy without lymphadenectomy and oophorectomy.

Different pattern of loss of heterozygosity among endocervical-type adenocarcinoma, endometrioid-type adenocarcinoma and adenoma malignum of the uterine cervix.

It is unclear which chromosome arms frequently show loss of heterozygosity (LOH) in adenocarcinoma of the uterine cervix. To identify such chromosomal arms, LOH on 52 different chromosome loci was examined using laser capture microdissection and PCR-LOH analysis in 25 common-type adenocarcinomas, comprising 13 cases of endocervical type, 12 cases of endometrioid type and 7 cases of adenoma malignum without the component of conventional endocervical-type adenocarcinoma (designated as "pure" form). In adenocarcinomas of endocervical type and endometrioid type, LOH was commonly detected on chromosome arms 17p (62% and 50%, respectively), 1p (33% and 67%) and 22q (40% and 33%). In addition, endocervical-type adenocarcinoma frequently (> or = 30%) showed LOH on 18p (71%), 19q (50%), 19p (38%) and 16q (38%), whereas endometrioid-type adenocarcinoma frequently showed LOH on 10q (43%) and 5q (40%). LOH was only sporadically detected on 9q, 18q, or 21q in 3 of 7 cases of "pure" adenoma malignum. In a case of coexistence of "pure" adenoma malignum and adenocarcinoma in situ (AIS), LOH on 1q, 5p, 11p, 17p, 18p and 18q was detected only in AIS. LOH was accumulated on a number of chromosome arms in the adenocarcinoma at the early developmental stage before stromal invasion. Chromosomal arms that are prone to show LOH appeared to differ between the 2 types of cervical adenocarcinoma. We could suggest that "pure" adenoma malignum is of clonal and neoplastic nature in view of the detection of LOH.