Phase I/II study of tandem cycles of high-dose chemotherapy followed by autologous hematopoietic stem cell support in women with advanced ovarian cancer.

The objectives of this study were to investigate the tolerability of a novel high-dose chemotherapy (HDC) regimen with peripheral blood progenitor cell (PBPC) support in patients with pretreated advanced ovarian cancer and to determine the maximum-tolerated dose (MTD) of topotecan in this setting. Advanced ovarian cancer patients previously treated with platinum-based first-line therapy were enrolled. After PBPC mobilization and harvesting, patients received three consecutive cycles of HDC with PBPC support. Cycle 1 was carboplatin area under the concentration curve 20 and paclitaxel 250 mg/m(2). Cycle 2 was topotecan starting at 5 mg/m(2), dose escalated in 2 mg/m(2) increments, and etoposide 600 mg/m(2). Cycle 3 was thiotepa 500 mg/m(2). After each cycle, PBPCs were infused. Granulocyte colony stimulating factor (5 microg/kg/day) was administered until neutrophil recovery occurred. Seventeen patients were enrolled; all were safety evaluable. The most common nonhematologic toxicity was grade 3 mucositis (44%). Engraftment of PBPCs was successful in all patients after each cycle, and no treatment-related deaths occurred. Of 14 patients with measurable disease, 5 (36%) had complete responses, 2 (14%) had partial responses, and 4 (29%) had stable disease. The median progression-free and overall survivals were 7 and 18 months, respectively. The MTD of topotecan was not reached. The tolerability and activity of this regimen in patients with advanced ovarian cancer warrant further investigation.

Loss of heterozygosity of chromosome 17 in human borderline and invasive epithelial ovarian tumors.

Polymerase chain reaction (PCR) analysis of microsatellite polymorphisms corresponding to four loci which map to chromosome 17p and 11 loci which map to chromosome 17q was performed to screen for loss of heterozygosity (LOH) in paired normal and tumor tissues from 27 cases of borderline epithelial ovarian tumors (BEOT) and 32 cases of invasive epithelial ovarian cancers (IOC). LOH was observed in six of 27 (22%) of the borderline tumors and in 29 of 32 (90%) of the invasive ovarian cancers (P<0.001). At all 15 loci studied, a lower percentage of allelic loss was detected in borderline tumors (0-14%) vs invasive cancer (8-93%). At eight loci this difference was statistically significant. For IOC, one common loss region was identified on chromosome 17p and four distinct common loss regions were on chromosome 17q, which supports the notion that multiple tumor suppressors may reside on chromosome 17 in IOC. These data suggest that LOH on chromosome 17 is an infrequent event in BEOT compared with IOC and therefore may not be important in the distinct pathogenesis of BEOT.

Pseudomyxoma peritonei: a review of 23 cases.

OBJECTIVE: To review the experience at the Massachusetts General and Brigham and Women's Hospitals with 23 women treated for pseudomyxoma peritonei between 1961 and 1991. METHODS: Patients were identified retrospectively from the tumor registry at the Massachusetts General and Brigham and Women's Hospitals, and all charts were reviewed. The median follow-up interval was 2.5 years (range 3 months to 31 years). RESULTS: The mean age at diagnosis was 58 years (range 26-76). Pseudomyxoma peritonei was found in association with ten (44%) ovarian tumors of borderline malignancy, nine (39%) ovarian cystadenocarcinomas, and four (17%) appendiceal cystadenocarcinomas. Three patients had synchronous tumors in the ovary and appendix. All patients underwent surgical staging and cytoreduction. Eleven patients received postoperative therapy and, of these, nine developed a recurrence; 12 patients received no further therapy and, of these, three developed a recurrence. However, these groups were not pathologically comparable. With respect to survival, of the ten patients with borderline malignancies, seven had no evidence of disease, one was alive with disease, and two died of disease. For the nine patients with ovarian cystadenocarcinomas, three had no evidence of disease, one was alive with disease, and five died of disease (median time to death 18 months). For the four patients with appendiceal carcinomas, two had no disease, one was alive with disease, and one died with disease. Among all 23 patients, 12 (52%) developed a recurrence, with a range of time to first recurrence of 3 months to 19 years. Eight women required at least one additional laparotomy because of accumulation of gelatinous material. CONCLUSIONS: Although pseudomyxoma peritonei is associated with borderline and well-differentiated tumors, recurrence is common and the prognosis after recurrence is guarded. Involvement of the appendix is common; therefore, appendectomy is indicated when pseudomyxoma is encountered. To date, surgery has been the only effective therapy for this disease, and adjuvant therapy has not been shown conclusively to be of benefit.

Human papillomavirus typing in patients with Papanicolaou smears showing squamous atypia.

Three hundred sixty consecutive patients followed at the Massachusetts General Hospital Colposcopy Clinic had HPV typing performed from exfoliated cervical cells by a commercially available dot blot hybridization assay. This assay tests for three groups of HPV types: 6/11, 16/18, and 31/33/35. Of this group, 171 patients were referred because of a Papanicolaou (Pap) smear showing squamous atypia. Of the 171 patients referred for squamous atypia, 17 (10%) had histologic evidence of CIN. Thirty-three of the 171 (19%) had detectable HPV DNA, and 28 of the 33 had high-risk HPV types (16/18, 31/33/35). Of the 17 women with CIN, only 6 (35%) had high-risk types and 11 (65%) had no HPV DNA detected. Of the 28 women with atypia and high-risk HPV types, only 6 (21%) had CIN. This study demonstrates that commercially available HPV typing when used in patients with Pap smears showing squamous atypia is not clinically useful in identifying patients for colposcopic referral.

The hibernating male golden hamster as a model for studying homologue pairing, chiasma formation and disjunction during spermatogenesis.

Although many studies have been made in an attempt to understand the mechanisms of chromosome pairing and genetic recombination, data on mammalian oogenesis and spermatogenesis are sparse. In the experiments reported here, spermatogenesis of the hibernating male golden hamster was used to test the effect of hibernation in the cold on some essential aspects of meiosis in this species. It was demonstrated that this physiologic state can result in increased duration of preleptotene synthesis of deoxyribonucleic acid (DNA), abnormalities in bivalent pairing, reduced crossing-over, and increased chromosomal nondisjunction. These data provide evidence of the usefulness of this model for further studies of these genetic phenomena in a male mammal.

Aging and aneuploidy in human oocytes and follicular cells.

The incidence of chromosomal aneuploidy in the oocyte and surrounding follicular cells in women of different ages was investigated. Oocytes and granulosa cells derived from ovarian specimens from a random population of 289 adult patients ages 16 to 76 years undergoing gynecologic surgery for nonovarian pathology were cultured for short periods, and cytogenetic preparations were scored for chromosome number and morphology. Of 91 oocytes harvested at second meiotic metaphase, five oocytes revealed a chromosomal abnormality. Cytogenetic analysis of the granulosa cells revealed aneuploid cells as well as complements with structural changes. A significant difference between the percentage of granulosa cell aneuploidy in the 25 to 34 years group and all other age groups was found, suggesting a decrease of the tendency for granulosa cells to exhibit aneuploidy in older age groups. Previous reports of aneuploidy in human ovary and other somatic cell types suggest that follicular cells behave differently in their response to aging. There also would appear to be a difference between the chromosomal response of oocytes and granulosa cells to aging.