Metformin targets ovarian cancer stem cells in vitro and in vivo.

PURPOSE: Studies in non-gynecologic tumors indicate that metformin inhibits growth of cancer stem cells (CSC). Diabetic patients with ovarian cancer who are taking metformin have better outcomes than those not taking metformin. The purpose of this study was to directly address the impact of metformin on ovarian CSC. METHODS: The impact of metformin on ovarian cancer cell line growth and viability was assessed with trypan blue staining. Aldehyde dehydrogenase (ALDH) expressing CSC were quantified using FACS®. Tumor sphere assays were performed to determine the impact of metformin on cell line and primary human ovarian tumor CSC growth in vitro. In vivo therapeutic efficacy and the anti-CSC effects of metformin were confirmed using both tumor cell lines and ALDH(+) CSC tumor xenografts. RESULTS: Metformin significantly restricted the growth of ovarian cancer cell lines in vitro. This effect was additive with cisplatin. FACS analysis confirmed that metformin reduced ALDH(+) ovarian CSC. Consistent with this, metformin also inhibited the formation of CSC tumor spheres from both cell lines and patient tumors. In vivo, metformin significantly increased the ability of cisplatin to restrict whole tumor cell line xenografts. In addition, metformin significantly restricted the growth of ALDH(+) CSC xenografts. This was associated with a decrease in ALDH(+) CSC, cellular proliferation, and angiogenesis. CONCLUSIONS: Metformin can restrict the growth and proliferation of ovarian cancer stem cells in vitro and in vivo. This was true in cell lines and in primary human CSC isolates. These results provide a rationale for using metformin to treat ovarian cancer patients.

Gardasil™ HPV vaccination: surveillance of vaccine usage and adherence in a military population.

OBJECTIVES: To investigate the usage patterns and adherence rates with the quadrivalent HPV (qHPV) vaccine at Naval Medical Center San Diego. METHODS: This retrospective, cross-sectional study was conducted by using AHLTA (Electronic Health Record of DoD) to identify all qHPV recipients between 2006 and 2009. Charts were reviewed to extract demographic variables and immunization schedules for association analysis. Subjects were assigned intention-to-treat (ITT) if they initiated the series and reached the 1-year anniversary after dose-1 or in-progress (IP) if the series was incomplete and within 1-year. ITT subjects were designated non-adherent or adherent based on 1-2 or 3 doses received. RESULTS: 6792 females and 46 males with respective mean ages (years) of 19 (95% CI: 10-29) and 27 (95% CI: 9-46) initiated the qHPV series. The evaluable ITT population consisted of 5088 females and 31 males. The adherence rate for females was 32% (1656/5088) versus 3% (1/31) for males. For females, adherence declined from 45%, 24%, to 14% with respect to increasing age: 8-17, 18-26, 27-50years. Adherence declined accordingly by beneficiary status: dependent daughters (43%), spouses (21%) and active duty (16%); and by clinic of vaccine initiation: Pediatrics/Adolescent (45%), Primary Care (38%), Immunization (21%), and OB/GYN (9%). Males were predominantly active duty 84%, vaccinated through immunization clinics 84%, and poorly adherent 3%. CONCLUSIONS: Optimal HPV immunization efficacy is derived from vaccine adherence and HPV naivety. This study of qHPV adherence has provided insight into real-world suboptimal use post-marketing. Usage patterns and adherence rates were significantly associated with demographic characteristics.

Nerve-sparing radical hysterectomy using modern bipolar electrosurgical instruments based on the ForceTriad energy platform.

OBJECTIVE: To describe and evaluate a novel technique of nerve-sparing radical abdominal hysterectomy with pelvic lymphadenectomy (NSRH/PLND) using the bipolar Ligasure Atlas sealer/divider and Bissenger bipolar shears. METHODS: Retrospective study of 4 consecutive patients who underwent NSRH/PLND for stage IB1-IIB cervical carcinoma was conducted. Resection of the cardinal and uterosacral ligaments was performed with the Ligasure Atlas. Pelvic autonomic nerve dissection and lymphadenectomy were completed with the bipolar shears. Outcomes were collectively analyzed. RESULTS: Mean operative time was 251 minutes (range, 230-265). Blood loss averaged 625 mL (range, 400-900). Average LOS was 5 days (range, 4-5). Average duration until normal postvoid residual volume was 17 days (range, 10-24). No perioperative complications were encountered. CONCLUSION: Bipolar surgical instrumentation offers many advantages. The Ligasure Atlas provides efficient sealing and division of vascular pedicles, while the bipolar shears allow precise and fine dissection. Our results demonstrate the "bipolar sealer and shears technique" a preferable method of NSRH/PLND.

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer.

BACKGROUNDEpidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODSThirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTSMetformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSIONTranslational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATIONClinicalTrials.gov NCT01579812.

Recurrent postpartum anaphylaxis with breast-feeding.

BACKGROUND: Anaphylaxis associated with breast-feeding is a rare but potentially life-threatening event. CASE: This woman reported anaphylaxis with three previous pregnancies while breast-feeding. With her fourth pregnancy she was treated with corticosteroids and antihistamines after delivery. Despite treatment, she developed urticaria, facial edema, and throat tightening, less severe than prior episodes. Her symptoms resolved with epinephrine and antihistamine but recurred with subsequent breast-feeding. On postpartum day 4 she had no symptoms while breast-feeding. CONCLUSION: Three cases of postpartum breast-feeding anaphylaxis have been reported. Although the pathophysiology is unclear, it may involve the decrease in progesterone and rise of prolactin causing mast cell degranulation. Avoidance of nonsteroidal antiinflammatories and prophylaxis with corticosteroids and antihistamines may offer the best protection.

Infectious diseases mimicking ovarian carcinomatosis.

Infectious diseases can present similar to ovarian cancer and occur concomitantly with ovarian pathology. With increased worldwide travel and migration of populations, infections endemic to developing countries can emerge in the United States. We present 2 cases of infectious diseases mimicking ovarian carcinomatosis. Two Filipino women presented with abdominal distension and had evaluations suggestive of advanced gynecologic malignancy. The first patient underwent surgery and was found to have peritoneal tuberculosis. Intra-operative pathology from the second case revealed ovarian carcinoma with schistosomal granulomas of the intestines. Tuberculosis and schistosomiasis should be considered when treating women with gynecologic malignancies, especially those from abroad or who have spent time overseas. Correct identification of infectious etiologies allows for pharmacological intervention and can minimize unnecessary surgical procedures.

Myxoid leiomyosarcoma of the Bartholin gland.

BACKGROUND: Myxoid leiomyosarcomas originating from the Bartholin gland are exceedingly rare. Only one other case of a Bartholin gland myxoid leiomyosarcoma has been reported. CASE: Our patient presented with a 10 cm mass on her vulva, which was presumed to be a Bartholin gland cyst. Pathology showed a high-grade myxoid leiomyosarcoma with positive margins. She was treated with left radical hemivulvectomy, laparoscopic hysterectomy with bilateral salpingo-oophorectomy, and six cycles of adjuvant chemotherapy. She is now 1 year from completion of therapy and remains disease-free. CONCLUSION: All solid vulvar masses should be thoroughly evaluated with a low threshold for biopsy. Treatment should consist of complete resection. Hormonal manipulation, chemotherapy, and radiation should be considered as potential adjuvant treatment options.