Ramey D. Littell

Loss of Cables, a Cyclin-Dependent Kinase Regulatory Protein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer

Endometrial cancer is the most common gynecological cancer in Western industrialized countries. Cables, a cyclin-dependent kinase binding protein, plays a role in proliferation and/or differentiation. Cables mutant mice are viable, but develop endometrial hyperplasia and carcinoma in situ at a young age. Exposure to chronic low levels of estrogen results in development of endometrial cancer, similar to that observed in the postmenopausal female. In vitro and in vivo studies demonstrate that levels of Cables mRNA in benign human endometrial epithelium are up-regulated by progesterone and down-regulated by estrogen. Furthermore, nuclear immunostaining for Cables is lost in a high percentage of cases of human endometrial hyperplasia and adenocarcinoma, which are likely the product of unopposed estrogen. The loss of Cables immunostaining in the human endometrial cancer samples correlates with a marked decrease in Cables mRNA. Ectopic expression of Cables in human endometrial cells dramatically slows cell proliferation. Collectively, these data provide evidence that Cables is hormonally regulated and is involved in regulating endometrial cell proliferation. In addition, loss or suppression of Cables may be an early step in the development of endometrial cancer.

Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation.

OBJECTIVE: To estimate the incidence of occult uterine sarcoma and leiomyosarcoma in hysterectomies for leiomyomas and the risk associated with their morcellation. METHODS: We conducted a population-based cohort study. All uterine sarcomas from 2006–2013 in an integrated health care system were identified. Age- and race-specific incidences of occult uterine sarcoma were calculated. Kaplan-Meier survival analysis was performed. Crude and adjusted risk ratios of recurrence and death associated with morcellation at 1, 2, and 3 years were estimated using Poisson regression with inverse probability weighting. RESULTS: There were 125 hysterectomies with occult uterine sarcomas identified among 34,728 hysterectomies performed for leiomyomas. The incidence of occult uterine sarcoma and leiomyosarcoma was 1 of 278 or 3.60 (95% confidence interval [CI] 2.97–4.23) and 1 of 429 or 2.33 (95% CI 1.83–2.84) per 1,000 hysterectomies. For stage I leiomyosarcoma (n=111), eight (7.2%) were power and 27 (24.3%) nonpower-morcellated. The unadjusted 3-year probability of disease-free survival for no morcellation, power and nonpower morcellation was 0.54, 0.19, and 0.51, respectively (P=.15); overall survival was 0.64, 0.75, and 0.68, respectively (P=.97). None of the adjusted risk ratios for recurrence or death were significant except for death at 1 year for power and nonpower morcellation groups combined (6/33) compared with no morcellation (4/76) (5.12, 95% CI 1.33–19.76, P=.02). We had inadequate power to infer differences for all other comparisons including 3-year survival and power morcellation. CONCLUSION: Morcellation is associated with decreased early survival of women with occult leiomyosarcomas. We could not accurately assess associations between power morcellation and 3-year survival as a result of small numbers.

Defining the extent of cables loss in endometrial cancer subtypes and its effectiveness as an inhibitor of cell proliferation in malignant endometrial cells in vitro and in vivo

Loss of Cables expression is associated with a high incidence of endometrial hyperplasia and endometrial adenocarcinoma in humans. The Cables mutant mouse develops endometrial hyperplasia and following exposure to chronic estrogen develops early endometrial adenocarcinoma. The objectives of the current study were to determine if: 1) loss of Cables expression occurred in high grade endometrioid adenocarcinoma, uterine serous and clear cell carcinoma as observed in endometrial hyperplasia and low grade endometrial adenocarcinoma; 2) overexpression of Cables inhibited cell proliferation in endometrial cancer (EC) cells in vitro and in vivo; and 3) progesterone could regulate the expression of Cables mRNA. Hyperplastic endometrium and low and high grade endometrioid adenocarcinoma showed loss of Cables expression when compared to benign control secretory endometrium. Loss of Cables expression in serous and clear cell tumors was similar to that observed in endometrioid adenocarcinomas with greater than 80% showing loss of protein expression. Treatment of EC lines with progesterone increased cables expression in low-grade EC whereas it had no effect on cables expression in cells derived from high-grade EC. The progesterone-induced increase in cables was abrogated in the presence of a progesterone receptor (PR) antagonist, suggesting the PR mediates the increase. Cables overexpression inhibited cell proliferation of well differentiated EC cells and had no effect on the poorly differentiated EC cells. The capacity to form tumors was dramatically reduced in the Cables overexpressing cell lines compared to those cells containing the control vector. Collectively these results suggest that Cables is an important regulator of cell proliferation and loss of Cables expression contributes to the development of all types of EC.

Extent of extracranial disease is a powerful predictor of survival in patients with brain metastases from gynecological cancer

Central nervous system metastasis from gynecological malignancy is a rare phenomenon that has been described in the past 30 years. The objective of this study is to analyze the treatment modalities and prognostic factors for brain metastases from gynecological tumors that predict prolonged survival. A retrospective chart and pathology review of 47 patients diagnosed with a gynecological tumor with brain metastasis in 1994–2004 was performed. Thirty patients had undergone initial diagnosis and treatment at our institution, and 17 patients were referred following primary treatment at an outside institution. Adjusted Chi-square, Kaplan–Meier survival estimates, log-rank tests, and Cox regression analysis were utilized for statistical analysis of the total cohort. Of the 3146 patients with newly diagnosed gynecological cancer in this 10-year period, 30 developed brain metastasis demonstrating an incidence of 0.95%. Overall median survival from the time of diagnosis of brain metastasis was 7.5 months (95% CI 4–15, range 9 days–64 months) and 40% survival at 1 year. Multivariate analysis revealed evidence of extracranial disease at time of metastasis diagnosis predicted decreased survival (hazard ratio 6.207), while papillary serous histology (hazard ratio 0.42), and use of any chemotherapy (hazard ratio 0.24) predicted longer survival. No other patient or tumor characteristics were found to be independent prognostic indicators affecting survival. Despite the ominous prognosis associated with the development of brain metastasis, these retrospective data suggest that multimodal therapy with whole brain radiation therapy, chemotherapy, and surgical resection of metastases in selected patients without evidence of extracranial and with solitary or multiple lesions can prolong survival.

Low-molecular-weight heparin (dalteparin) in women with gynecologic malignancy

OBJECTIVE: To compare the efficacy of dalteparin, a low-molecular-weight heparin, to unfractionated heparin (UFH) in the prevention of deep venous thrombosis (DVT) and pulmonary embolism in patients after surgery for gynecologic malignancy. METHODS: The medical records of all patients undergoing major surgery on the Gynecologic Oncology Service at the Massachusetts General Hospital from July 2002 through April 2003 were reviewed. Patients with confirmed malignancy were included. Between July 1, 2002, and November 15, 2002, dalteparin (5,000 U subcutaneously each day) was used for postoperative prophylaxis for DVT and pulmonary embolus. After November 15, 2002, the method of prophylaxis was changed to UFH (5,000 U subcutaneously every 8 hours) exclusively. Patients were evaluated for DVT or pulmonary embolus based on clinical suspicion using computed tomographic angiography, ventilation and perfusion scan, or lower extremity doppler. RESULTS: A total of 214 patients were identified who met study criteria. Dalteparin was administered to 103 patients, and UFH was administered to 111. The rates of clinically significant DVT or pulmonary embolus in patients receiving dalteparin and UFH were 8.9% and 1.2%, respectively (P = .009). Major risk factors for DVT or pulmonary embolus, including age, obesity, duration of surgery, and type of malignancy, did not differ between groups. There were no significant differences in bleeding complications or transfusion requirements between groups. CONCLUSION: The low-molecular-weight heparin dalteparin dosed 5,000 U daily is inadequate postoperative prophylaxis in women undergoing surgery for gynecologic cancer. In addition, heparin administered every 8 hours was not associated with increased bleeding complications. The use of dalteparin at the doses used in this study should be questioned until a large randomized trial shows efficacy in these high-risk patients. LEVEL OF EVIDENCE: II-2

Adjuvant gemcitabine-docetaxel chemotherapy for stage I uterine leiomyosarcoma: Trends and survival outcomes

OBJECTIVE To assess recent trends of administering adjuvant gemcitabine-docetaxel (GD) chemotherapy for Stage I uterine leiomyosarcoma, and to compare disease-free and overall survival between women who received and did not receive adjuvant GD chemotherapy. METHODS All patients diagnosed with Stage I uterine leiomyosarcoma in a California-Colorado population-based health plan inclusive of 2006-2013 were included in a retrospective cohort. Adjuvant GD chemotherapy rates, clinico-pathologic characteristics and survival estimates were assessed. RESULTS Of 111 women with Stage I uterine leiomyosarcoma, 33 received adjuvant GD (median 4cycles), 77 received no chemotherapy, and 1 patient excluded for non-GD chemotherapy. GD-chemotherapy and no-chemotherapy groups were similar with respect to age, stage (IA/IB), uterine weight, mitotic index, body mass index, and Charlson comorbidity score. Non-Hispanic white women were twice as likely to receive adjuvant chemotherapy as non-white or Hispanic women (37.7 vs. 17.1%, P=0.02). The proportion of women receiving adjuvant GD chemotherapy increased from 6.5% in 2006-2008 to 46.9% in 2009-2013 (P<0.001). There was no significance difference in unadjusted Kaplan-Meyer estimated disease-free (P=0.95) or overall survival (P=0.43) between GD-chemotherapy and no-chemotherapy cohorts. Corresponding adjusted Cox proportional hazard ratios for adjuvant GD chemotherapy compared to no chemotherapy were 1.01 (95% confidence interval [CI] 0.57-1.80, P=0.97) for recurrence and 1.28 (95% CI 0.69-2.36, P-0.48) for mortality. CONCLUSIONS Use of adjuvant GD chemotherapy for Stage I uterine leiomyosarcoma has increased significantly in the last decade, despite unclear benefit. Compared to no chemotherapy, 4-6cycles of adjuvant GD chemotherapy does not appear to alter survival outcomes.

Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation

Uterine leiomyomas are the most common indication for hysterectomy in the United States. Leiomyomas may be indistinguishable from malignant uterine sarcomas, which occur rarely and have a poor prognosis. Although the use of laparoscopic hysterectomy and power morcellation has substantially reduced morbidity of surgery for uterine leiomyomas, there has been increasing concern over peritoneal dissemination of occult uterine sarcomas for which there was no preoperative or operative suspicion. To address these concerns, the US Food and Drug Administration issued a warning in November 2014 against use of power morcellators in most women undergoing hysterectomy for uterine leiomyomas. Estimates of the incidence of uterine sarcoma among women undergoing hysterectomy for leiomyomas have been obtained primarily from single-center studies or studies conducted in tertiary-based practices. These articles include a broad range of publication dates (1990–2012) and small numbers of patients. Interpretation of data from these studies is challenging because of small numbers of sarcomas and morcellation procedures per study as well as flawed methodology. This population-based cohort study was performed to estimate the incidence of occult uterine sarcoma and leiomyosarcoma in hysterectomies for leiomyomas and the risk associated with their morcellation. Data were abstracted for all uterine sarcomas identified after surgery from 2006 to 2013 in an integrated health care system. Ageand race-specific incidence rates for occult uterine sarcoma were calculated. Kaplan-Meier survival analysis was performed to estimate the unadjusted cumulative 3-year disease-free and overall survival probabilities. Poisson regression with inverse probability weighting was used to estimate crude and adjusted risk ratios (aRRs) of recurrence and death associated with morcellation at 1, 2, and 3 years. Hysterectomies were categorized as 3 groups: no morcellation, power morcellation, and nonpower morcellation. Among 34,728 hysterectomies performed for leiomyomas, 125 were identified with occult uterine sarcomas. The incidence of occult uterine sarcoma and leiomyosarcoma in women with hysterectomy for leiomyomas was 1 of 278 or 3.60 (95% confidence interval [CI], 2.97–4.23) per 1,000 and 1 of 429 or 2.33 (95% CI, 1.83–2.84) per 1,000 hysterectomies. There were 111 stage I leiomyosarcomas. Among these, power and nonpower morcellation occurred in only a small number (8 [7.2%] and 27 [24.3%]). For stage I leiomyosarcomas, the unadjusted probability of disease-free 3-year survival with no morcellation, power morcellation, and nonpower morcellation was 0.54, 0.19, and 0.51, respectively (P = 0.15); overall 3-year survival was 0.64, 0.75, and 0.68, respectively (P = 0.97). With the adjusted data, none of the aRRs for recurrence or death were significant except for death at 1 year for power and nonpower morcellation groups combined (6/33) compared with no morcellation (4/76); the aRR was 5.12, with a 95% CI of 1.33 to19.76; P = 0.02). Differences for all other comparisons including 3-year survival and power morcellation could not be estimated because of the small number of events and inadequate power. These data demonstrate association of morcellation with decreased early survival for women with occult leiomyosarcomas. Associations between power morcellation and 3-year survival could not be accurately assessed as a result of small numbers. www.obgynsurvey.com | 214 Copyright