Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines

A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy/safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) in women with low CA-125 platinum-sensitive ovarian cancer

Objectives: The primary objective of this study (MORAb-003-011/ENGOT-ov27) was to determine if farletuzumab (FAR) had superior efficacy compared with placebo (PLB) in improving progression-free survival (PFS) when added to carboplatin (carbo)/paclitaxel (pacli) or carbo/PLD, in subjects with platinum-sensitive ovarian cancer in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125). CA-125 inhibits target cell killing via antibody-dependent cellular cytotoxicity, thereby reducing the efficacy of immunotherapeutic antibodies. Subgroup analysis in a prior randomized Phase III study±FAR suggested that subjects with CA-125 levels ≤3 x upper limit of normal (ULN), showed superior PFS (hazard risk [HR] = 0.49) and overall survival (OS, HR = 0.44) compared with PLB. Methods: Eligibility included age ≥18 years old, CA-125 ≤3 x ULN (105 U/mL), high-grade serous epithelial ovarian cancer, and previous treatment with debulking surgery and first-line platinum-based chemotherapy. Subjects received 6 cycles with either carbo/pacli every 3 weeks or carbo/PLD in combination with either FAR [5 mg/kg weekly] or PLB in a 2:1 ratio. Maintenance treatment with FAR (5 mg/kg weekly) or PLB was given until disease progression. Tumor assessments were every 6 weeks during the Combination Treatment Phase and every 9 weeks during the Maintenance Treatment Phase. The study was designed to detect a PFS HR of 0.667 (33.3% risk reduction) with FAR compared with PLB with approximately 85% power and a 1-sided type I error rate of 0.10. The comparison of PFS between treatment groups was based on the log-rank test. The HR was estimated based on Cox\u27s proportional-hazards model. Results: A total of 214 subjects were randomized and enrolled, 142 with FAR+chemotherapy (FAR-CT) and 72 with placebo+chemotherapy (PLB-CT). The median PFS in the Intent-to-Treat [ITT] Population was not significantly different between treatment groups; 11.7 months (95% confidence interval [CI]: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for FAR-CT and PLB-CT, respectively (HR = 0.89; 80% CI: 0.71, 1.11). An interim analysis of OS showed no significant difference between treatment groups. The overall response rate (ORR) was 69.6% in 96 subjects treated with FAR-CT versus 73.5% in 50 subjects treated with PLB-CT (p=0.53). No significant differences between treatment groups were observed for any other efficacy parameters. The safety profile of the 2 treatment groups was similar except for an increase in interstitial lung disease among the FAR cohort. Interstitial lung disease occurred in 7 of 141 (5.0%) subjects treated with FAR-CT (1 with Grade 1, 4 with Grade 2, and 2 with Grade 3) and none in subjects treated with PLB-CT. Conclusions: The combination of FAR-CT did not show signals of superior efficacy compared with PLB-CT in improving PFS or other efficacy parameters in subjects with platinum-sensitive recurrent ovarian cancer in first relapse who had low CA-125 levels. No new safety concerns were identified with the combination of FAR-CT. Since FAR binds to the folate receptor alpha, a novel antibody-drug conjugate has been developed and clinical studies are ongoing to assess the safety/efficacy of this modification. Clinical Trial Registry: NCT02289950

The K-Technique: A Novel Technique for Laparoscopic Apical Suspension Using Barbed Sutures.

OBJECTIVES: Hysterectomy is among the most common gynecologic procedures performed for women, second only to cesarean sections, and the proportion of it performed laparoscopically continues to increase. Addressing apical support at the time of the hysterectomy is crucial to minimizing the risk of posthysterectomy prolapse. Barriers to addressing apical support include the lack of experience in laparoscopic suturing and knot tying that require advanced skills and dexterity. The K-technique is a novel modification of the uterosacral ligament suspension procedure using the knot-less barbed suture technology, rendering suturing easier and quicker to perform. METHOD: The vaginal cuff epithelium is closed with 2 unidirectional barbed sutures that are started at the lateral fornices and ran until the midsection. The same sutures will then serially purchase the anterior and posterior vaginal endopelvic fascia and the midsegment of the uterosacral ligament. Two more passes are thrown through the same structures, yet farther laterally, back and forth. A video illustration of the procedure is attached. RESULTS: Eighteen patients underwent the procedure with no urinary tract injuries documented by cystoscopy and no postoperative morbidity documented during the 6-week postoperative follow-up period. Limited short- and long-term follow-up data are reassuring, but more will be needed to confirm the efficacy of barbed sutures in prolapse repair. CONCLUSIONS: The K-technique combines the conventional uterosacral ligament suspension concept with the ease, effectiveness, and safety of barbed sutures. The technique might aid the surgeon to add the apical vaginal support when indicated

Adjuvant therapy of uterine clear cell carcinoma: a review

PURPOSE: Uterine clear-cell carcinoma (UCCC) is a rare subset of type II endometrial carcinoma with a poor prognosis relative to the most common type of endometrioid carcinoma. Due to its rarity, there has been limited direct evidence of the efficacy of specific adjuvant therapy posthysterectomy in women with UCCC. We present a review of current literature regarding adjuvant therapy of uterine clear cell carcinoma. METHODS: We searched for English-language publications through Pubmed using a combination of the following key words: endometrial carcinoma, clear cell carcinoma, recurrence, prognosis, adjuvant therapy, radiation treatment and chemotherapy. Due to the rarity of UCCC, studies were not limited by design or number of patients. RESULTS: There is a paucity of randomized prospective controlled studies focusing on UCCC adjuvant therapy. Findings have largely been derived from retrospective studies of type II endometrial carcinomas or all endometrial cancers as a group. Very few retrospective studies were found to focus on UCCC adjuvant therapy, although certain larger studies did have subset analyses of UCCC patients. CONCLUSIONS: For early stage disease, locoregional radiotherapy, especially vaginal brachytherapy, has evidence of efficacy. The therapeutic gain of radiotherapy may be further improved with the addition of systemic chemotherapy. Evidence for combined radiation therapy with systemic chemotherapy in women with advanced stage UCCC has remained debatable. UCCC-specific studies are needed to determine the best adjuvant therapy for UCCC without the confounding effects of USC and other endometrial cancers

Adjuvant therapy of uterine clear cell carcinoma: a review.

PURPOSE: Uterine clear-cell carcinoma (UCCC) is a rare subset of type II endometrial carcinoma with a poor prognosis relative to the most common type of endometrioid carcinoma. Due to its rarity, there has been limited direct evidence of the efficacy of specific adjuvant therapy posthysterectomy in women with UCCC. We present a review of current literature regarding adjuvant therapy of uterine clear cell carcinoma. METHODS: We searched for English-language publications through Pubmed using a combination of the following key words: endometrial carcinoma, clear cell carcinoma, recurrence, prognosis, adjuvant therapy, radiation treatment and chemotherapy. Due to the rarity of UCCC, studies were not limited by design or number of patients. RESULTS: There is a paucity of randomized prospective controlled studies focusing on UCCC adjuvant therapy. Findings have largely been derived from retrospective studies of type II endometrial carcinomas or all endometrial cancers as a group. Very few retrospective studies were found to focus on UCCC adjuvant therapy, although certain larger studies did have subset analyses of UCCC patients. CONCLUSIONS: For early stage disease, locoregional radiotherapy, especially vaginal brachytherapy, has evidence of efficacy. The therapeutic gain of radiotherapy may be further improved with the addition of systemic chemotherapy. Evidence for combined radiation therapy with systemic chemotherapy in women with advanced stage UCCC has remained debatable. UCCC-specific studies are needed to determine the best adjuvant therapy for UCCC without the confounding effects of USC and other endometrial cancers

Survival outcomes and patterns of failure in women with stage IIIC

Objectives Para-aortic lymph node involvement in women with endometrial carcinoma (EC) is a poor prognostic factor. Many studies have included women with stage IIIC 2 in cohorts of patients with advanced stage disease. The aim of this study was to analyze survival outcomes and patterns of failure in women with solely stage IIIC 2 EC. Methods We identified women with FIGO stage IIIC 2 EC who underwent surgical staging at our institution. In addition to descriptive analyses of patient demographics, tumor characteristics, and adjuvant treatment received, univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). Results A total of 72 women were included in this study cohort. The median follow-up time was 43 months. The median number of positive para -aortic lymph nodes was one. Of the 61 women (84.7%) who received adjuvant therapy, 40 women (65.6%) received chemotherapy and radiation therapy (CRT), 17 women (27.9%) received chemotherapy alone (CT), and only 4 women (6.6%) received radiation therapy alone. Thirty-seven women (51.4%) experienced disease recurrence. Distant metastasis was the most common pattern of failure (73%). Five-year RFS, DSS, and OS were 48%, 51%, and 48%, respectively. Due to small study size, our exploratory multivariate analysis demonstrated that histologic grade was the only significant prognostic factor for DSS ( p = 0.03) and OS ( p = 0.02). The type of adjuvant therapy did not sustain its independent predictive significance for RFS, DSS and OS. Conclusions Our findings suggest that almost half of women with stage IIIC 2 can be cured with surgical staging and adjuvant therapies. The most common pattern of failure was distant metastasis calling for further optimization of systemic therapy

Survival outcomes and patterns of failure in women with stage IIIC

OBJECTIVES: Para-aortic lymph node involvement in women with endometrial carcinoma (EC) is a poor prognostic factor. Many studies have included women with stage IIIC2 in cohorts of patients with advanced stage disease. The aim of this study was to analyze survival outcomes and patterns of failure in women with solely stage IIIC2 EC. METHODS: We identified women with FIGO stage IIIC2 EC who underwent surgical staging at our institution. In addition to descriptive analyses of patient demographics, tumor characteristics, and adjuvant treatment received, univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS: A total of 72 women were included in this study cohort. The median follow-up time was 43 months. The median number of positive para-aortic lymph nodes was one. Of the 61 women (84.7%) who received adjuvant therapy, 40 women (65.6%) received chemotherapy and radiation therapy (CRT), 17 women (27.9%) received chemotherapy alone (CT), and only 4 women (6.6%) received radiation therapy alone. Thirty-seven women (51.4%) experienced disease recurrence. Distant metastasis was the most common pattern of failure (73%). Five-year RFS, DSS, and OS were 48%, 51%, and 48%, respectively. Due to small study size, our exploratory multivariate analysis demonstrated that histologic grade was the only significant prognostic factor for DSS (p=0.03) and OS (p=0.02). The type of adjuvant therapy did not sustain its independent predictive significance for RFS, DSS and OS. CONCLUSIONS: Our findings suggest that almost half of women with stage IIIC2 can be cured with surgical staging and adjuvant therapies. The most common pattern of failure was distant metastasis calling for further optimization of systemic therapy

Nonspecific tumor markers in the era of value based medicine: Role of CA 19-9 in the pelvic mass workup

Background: When encountering a pelvic mass, CA 125 and CEA are usually obtained to evaluate for ovarian or colon cancer. The clinical importance of ordering a CA 19-9 level is unknown. Does it offer valuable information or merely add confusion and additional workup if elevated? Methods: 3,370 women were retrospectively identified via CPT codes for pelvic mass and CA 19-9. Initial analysis reviewed the subspecialty of the primary investigator using CA 19-9 in their initial workup, and its correlation to a gynecologic pathology. In the cases where an OBGYN was the primary investigator additional tumor markers, age, race, menopausal status, imaging, surgical interventions and final pathology were further analyzed. Results: Out of 3,370 women 982 had an abnormal CA 19-9. The distribution of subspecialties that utilized CA 19-9 in their initial work up was Hematology Oncology 31.6%, Internal Medicine 18.7%, Gastrointestinal 18.2%, Gynecology 9.2%, Surgery 8.8%, Emergency Medicine 5.7%, Transplant 4.9%, and Family Medicine 2.9%. Of the patients evaluated by Gynecology, 32.2 % were found to have elevated CA19-9 which led to additional work-up of the upper GI tract in 18.9% including MRI, and PET preoperatively. Further analysis revealed that there was no correlation between the elevation of CA 19-9 and whether the tumor was malignant or benign [p value = 0.45] even after being adjusted for: menopausal status, presence of endometriosis, or pathology including mucinous cell type. Conclusions: The majority of adnexal masses are benign; the main goal of diagnostic evaluation is to exclude malignancy. Value based medicine is implemented to help improve health care quality, and efficient utilization of health care resources. Based on this retrospective analysis the use of CA 19-9 in evaluation of a pelvic mass does not offer information that directly improves patient outcome, but rather correlates to the increased misuse of health care resources

Thlaspi montanum L. (BR0000010535356)

Belgium Herbarium image of Meise Botanic Garden