Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters, and folate receptor (FR) α. Whereas in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and immunohistochemistry). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ∼2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent anti-proliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FRα and/or PCFT over RFC. When IGROV1 cells were pretreated with AGF94 at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FRα was knocked down in IGROV1 cells with lentiviral shRNAs. Two FRα knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [3H]folic acid and [3H]AGF154 by FRα, but maintained high levels of [3H]AGF154 uptake by PCFT compared to non-targeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a non-targeted control, attributable to residual FRα- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune deficient mice were likewise sensitive to AGF94. Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance.

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The incidence of endometrial cancers diagnosed on biopsy that have no residual cancer identified at hysterectomy is not well studied. The aim of our study was to determine the incidence and long-term follow-up of this "vanishing cancer" phenomenon. All slides from the initial biopsy/curettage and hysterectomy specimens were reviewed and the diagnosis confirmed by a gynecologic pathologist. The entire endometrium was serially sectioned and submitted for histologic examination. Clinical and pathologic variables were analyzed, including patient demographics, tumor histologic type and grade, stage, biopsy method, adjuvant therapy, surgical procedure, recurrence, and disease-specific survival. We identified 23 biopsy-proven cases of endometrial cancer with no residual disease on hysterectomy specimen. Of the 23 patients, 15 (65.2%) were diagnosed as endometrioid, 6 (26%) serous, 1 clear cell (4.3%), and 1 (4.3%) serous intraepithelial carcinoma. Seventeen underwent dilatation and curettage, and 6 had endometrial biopsy as the primary procedure. The median follow-up was 8.8 years (range, 1.2 to 17 y). Only 2 cases with serous carcinoma underwent adjuvant chemotherapy, and none received radiation therapy. Only 1 patient died of disease after 27 months and was diagnosed as FIGO grade II endometrioid carcinoma on dilatation and curettage. The inability to identify cancer in a hysterectomy specimen for biopsy-confirmed carcinoma does not indicate technical failure. Although there is no specific standard treatment for patients with "vanishing endometrial cancer," the prognosis is excellent; however, close follow-up is suggested.

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BackgroundThis is a Phase I trial demonstrating safety and tolerability of intravaginal curcumin for future use in women with cervical neoplasia.ObjectiveThe objective of this study was to assess the safety, tolerability, and pharmacokinetics of intravaginal curcumin in healthy women.Study designWe conducted a 3+3 dose-escalation Phase I trial in a group of women aged 18–45 years. Thirteen subjects were given one of four doses of curcumin powder (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) packed in gelatin capsules, which was administered intravaginally daily for 14 days. The primary end point for this study was safety based on severe adverse events regarding laboratory toxicity, clinical findings, and colposcopic abnormalities. We administered an acceptability questionnaire to assess product experience and attributes.ResultsNo dose-limiting toxicities (0/13) were experienced (95% confidence interval: 0.0%–22.8%) in this study. The pharmacokinetics data demonstrated that curcumin and curcumin conjugates were not measurable in the serum and negligible in the urine of the study participants. Although 23 adverse events occurred during the course of the trial, all events were grade I based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and were resolved by the end of the study in an average of 9 days. Fifty-six percent of the adverse events were related to the study drug, which included genital pruritus (23% of subjects), vaginal discharge (100%), vaginal dryness (15%), abnormal prothrombin (23%), and hypokalemia (8%).ConclusionIntravaginal curcumin was well tolerated by all subjects and safe. In this Phase I trial, there were no severe adverse events observed at any of the administered dose levels. All adverse events were grade I and did not result in early termination of the study. There was no evidence of systemic absorption or significant local absorption of intravaginally administered curcumin.

Vaginal hysterectomy has comparable rates of perioperative complications when compared with robotic and laparoscopic approaches and should be considered as a primary surgical approach in the growing armamentarium of minimally invasive approaches for hysterectomy for benign conditions.

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