Audrey P. Garrett

Garrett, Audrey P. MD, MPH; Wenham, Robert M. MD, MSc; Sheets, Ellen E. MD Author Information

We explored the possible pathogenetic pathway for mucinous ovarian tumorigenesis by examining the k-ras mutational patterns in ovarian mucinous tumors (OMTs) with benign, borderline, and invasive epithelium in which the different types of mucinous epithelium are in close proximity. Sixteen patients with ovarian mucinous borderline tumors (OMBTs) and 4 patients with grade 1 ovarian mucinous adenocarcinomas (OMCs) were selected for the presence of a single histologic section which contained a clear "transition" zone from benign mucinous epithelium to borderline mucinous epithelium, and in four cases, to invasive epithelium. A PixCell II Laser Capture Microscope was used to microdissect and retrieve benign, borderline, and invasive epithelium separately from the 20 OMTs. Normal ovarian stroma from the same histologic section in each case was also microdissected and retrieved for use as a control. k-ras mutations were detected in these samples by PCR-SSCP analysis followed by direct PCR cycle sequencing. k-ras mutations were found in 8/16 (50%) of the OMBTs and 2/4 (50%) of the grade 1 OMCs. In 6 of these 10 cases (4 in OMBTs, 2 in grade 1 OMCs), the same k-ras mutation was found in both the benign and borderline (and invasive) regions. In 3 cases in which k-ras mutations were identified, the mutation was found in either the benign or borderline tissue samples alone, and in one case, two distinct mutations were found. No k-ras mutations were identified in the normal ovarian stroma. The presence of a k-ras mutation in adjacent benign and borderline regions of a single OMT may suggest a progression in the development of OMTs from benign to borderline and grade 1 OMCs. k-ras mutations, when they occur, are likely early genetic changes but may not alone be sufficient for malignant transformation of ovarian epithelium.

OBJECTIVE: To investigate the efficacy and toxicity of methotrexate (MTX) given intravenously (i.v.) at a dose of 100 mg/m2 i.v. bolus and 200 mg/m2 infusion over 12 hours followed by folinic acid in the primary treatment of gestational trophoblastic tumors (GTTs). STUDY DESIGN: We reviewed the records of patients at the New England Trophoblastic Disease Center who had received MTX infusion at a dose of 100 mg/m2 i.v. bolus and 200 mg/m2 infusion over 12 hours followed by folinic acid as primary therapy for GTTs that did not resolve with uterine evacuation alone. Data on the patients' age, gravity and parity, disease stage (by FIGO and WHO criteria), antecedent pregnancy, presenting level of hCG, metastatic status, courses of chemotherapy required to achieve remission, toxicity related to chemotherapy treatments and time to normalization of hCG were recorded. RESULTS: One hundred ninety-two patients with persistent GTTs were treated with the MTX infusion protocol between December 1985 and December 2000. One hundred twenty-four patients (64.6%) achieved complete remission with the MTX infusion protocol. Complete remission was induced in 108 (87.1%) with a single course of chemotherapy; 12 others achieved remission with a single additional course of MTX. All patients found to be resistant to MTX therapy later achieved remission with other chemotherapy. Minimal toxicity was experienced during MTX treatment. CONCLUSION: MTX infusion with folinic acid is effective and well tolerated as primary single-agent therapy for nonmetastatic and low-risk metastatic GTT.