Outcomes of women treated with progestin and metformin for atypical endometrial hyperplasia and early endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: Progestin therapy is the recommended fertility-sparing management of atypical endometrial hyperplasia or early-stage endometrial cancer in reproductive-aged women. Our objective was to evaluate disease relapse after progestin and metformin versus progestin therapy alone in patients with endometrial hyperplasia or cancer. Our secondary outcomes were disease remission, clinical pregnancy and live birth rate. METHODS: A systematic review of the literature was conducted (MEDLINE, Web of Science, Cochrane Library, CINAHL, LILACS, clinicaltrials.gov) from inception to April 2021. Studies of reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer who received progestin and metformin or progestin alone for fertility-sparing management, were included in the review. Early endometrial cancer was defined as grade 1, stage 1 disease. Exclusion criteria included women with higher grade endometrial cancer and when conservative management was not for fertility-sparing purposes. Data are presented as odds ratios (ORs) and 95% confidence intervals (CIs) with fixed or random effects meta-analysis. Quality scoring was based on the Newcastle-Ottawa and Jadad scales. RESULTS: In total, 271 reports were identified and six studies met the inclusion criteria. These studies included 621 women; 241 (38.8%) patients received combined therapy and 380 (61.2%) received progestin therapy alone. Relapse rates were lower for progestin and metformin than for progestin therapy alone (pooled OR 0.46, 95% CI 0.24 to 0.91, p=0.03). The remission rates were not different (pooled OR 1.35, 95% CI 0.91 to 2.00, p=0.14). Women who received progestin and metformin achieved pregnancy and live birth rates similar to those who received progestin therapy only (pooled OR 1.01, 95% CI 0.44 to 2.35, p=0.98; pooled OR 0.46, 95% CI 0.21 to 1.03, p=0.06). CONCLUSION: For reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer, progestin and metformin therapy compared with progestin therapy alone is associated with lower relapse rates, and similar remission, clinical pregnancy and live birth rates. PROSPERO REGISTRATION NUMBER: CRD42020179069.disease remission.

Targeted metabolomic profiling of low and high grade serous epithelial ovarian cancer tissues: a pilot study.

INTRODUCTION: Epithelial ovarian cancer (EOC) remains the leading cause of death from gynecologic malignancies and has an alarming global fatality rate. Besides the differences in underlying pathogenesis, distinguishing between high grade (HG) and low grade (LG) EOC is imperative for the prediction of disease progression and responsiveness to chemotherapy. OBJECTIVES: The aim of this study was to investigate, the tissue metabolome associated with HG and LG serous epithelial ovarian cancer. METHODS: A combination of one dimensional proton nuclear magnetic resonance (1D H NMR) spectroscopy and targeted mass spectrometry (MS) was employed to profile the tissue metabolome of HG, LG serous EOCs, and controls. RESULTS: Using partial least squares-discriminant analysis, we observed significant separation between all groups (p < 0.05) following cross validation. We identified which metabolites were significantly perturbed in each EOC grade as compared with controls and report the biochemical pathways which were perturbed due to the disease. Among these metabolic pathways, ascorbate and aldarate metabolism was identified, for the first time, as being significantly altered in both LG and HG serous cancers. Further, we have identified potential biomarkers of EOC and generated predictive algorithms with AUC (CI) = 0.940 and 0.929 for HG and LG, respectively. CONCLUSION: These previously unreported biochemical changes provide a framework for future metabolomic studies for the development of EOC biomarkers. Finally, pharmacologic targeting of the key metabolic pathways identified herein could lead to novel and effective treatments of EOC.

Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134.

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-κB/TNFα signaling pathway. Importantly, SW IV-134 slowed tumor growth and improved survival in murine models of pancreatic cancer. Our data support further study of this novel therapeutic and this drug delivery strategy because it may eventually benefit patients with pancreatic cancer.

Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer.

BACKGROUND: Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy. METHODS: In the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo. RESULTS: We have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-қB activation and TNFα-dependent cell death. CONCLUSIONS: Our findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.

Patterns of care, predictors, and outcomes of chemotherapy in elderly women with early-stage uterine carcinosarcoma: a population-based analysis.

OBJECTIVE: To examine the patterns of care, predictors, and impact of chemotherapy on survival in elderly women diagnosed with early-stage uterine carcinosarcoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify women 65 years or older diagnosed with stage I-II uterine carcinosarcomas from 1991 through 2007. Multivariable logistic regression and Cox-proportional hazards models were used for statistical analysis. RESULTS: A total of 462 women met the eligibility criteria; 374 had stage I, and 88 had stage II uterine carcinosarcomas. There were no appreciable differences over time in the percentages of women administered chemotherapy for early stage uterine carcinosarcoma (14.7% in 1991-1995, 14.9% in 1996-2000, and 17.9% in 2001-2007, P=0.67). On multivariable analysis, the factors positively associated with receipt of chemotherapy were younger age at diagnosis, higher disease stage, residence in the eastern part of the United States, and lack of administration of external beam radiation (P<0.05). In the adjusted Cox-proportional hazards regression models, administration of three or more cycles of chemotherapy did not reduce the risk of death in stage I patients (HR: 1.45, 95% CI: 0.83-2.39) but was associated with non-significant decreased mortality in stage II patients (HR: 0.83, 95% CI: 0.32-1.95). CONCLUSIONS: Approximately 15-18% of elderly patients diagnosed with early-stage uterine carcinosarcoma were treated with chemotherapy. This trend remained stable over time, and chemotherapy was not associated with any significant survival benefit in this patient population.

Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3.

BACKGROUND: The targeted delivery of cancer therapeutics represents an ongoing challenge in the field of drug development. TRAIL is a promising cancer drug but its activity profile could benefit from a cancer-selective delivery mechanism, which would reduce potential side effects and increase treatment efficiencies. We recently developed the novel TRAIL-based drug platform TR3, a genetically fused trimer with the capacity for further molecular modifications such as the addition of tumor-directed targeting moieties. MUC16 (CA125) is a well characterized biomarker in several human malignancies including ovarian, pancreatic and breast cancer. Mesothelin is known to interact with MUC16 with high affinity. In order to deliver TR3 selectively to MUC16-expressing cancers, we investigated the possibility of targeted TR3 delivery employing the high affinity mesothelin/MUC16 ligand/receptor interaction. METHODS: Using genetic engineering, we designed the novel cancer drug Meso-TR3, a fusion protein between native mesothelin and TR3. The recombinant proteins were produced with mammalian HEK293T cells. Meso-TR3 was characterized for binding selectivity and killing efficacy against MUC16-positive cancer cells and controls that lack MUC16 expression. Drug efficacy experiments were performed in vitro and in vivo employing an intraperitoneal xenograft mouse model of ovarian cancer. RESULTS: Similar to soluble mesothelin itself, the strong MUC16 binding property was retained in the Meso-TR3 fusion protein. The high affinity ligand/receptor interaction was associated with a selective accumulation of the cancer drug on MUC16-expressing cancer targets and directly correlated with increased killing activity in vitro and in a xenograft mouse model of ovarian cancer. The relevance of the mesothelin/MUC16 interaction for attaching Meso-TR3 to the cancer cells was verified by competitive blocking experiments using soluble mesothelin. Mechanistic studies using soluble DR5-Fc and caspase blocking assays confirmed engagement of the extrinsic death receptor pathway. Compared to non-targeted TR3, Meso-TR3 displayed a much reduced killing potency on cells that lack MUC16. CONCLUSIONS: Soluble Meso-TR3 targets the cancer biomarker MUC16 in vitro and in vivo. Following attachment to the tumor via surface bound MUC16, Meso-TR3 acquires full activation with superior killing profiles compared to non-targeted TR3, while its bioactivity is substantially reduced on cells that lack the tumor marker. This prodrug phenomenon represents a highly desirable property because it has the potential to enhance cancer killing with fewer side-effects than non-targeted TRAIL-based therapeutics. Thus, further exploration of this novel fusion protein is warranted as a possible therapeutic for patients with MUC16-positive malignancies.

Intestinal perforation in gynecologic oncology: do all patients benefit from surgical management?

OBJECTIVE: To identify those patients with gynecologic cancers and intestinal perforation in whom conservative management may be appropriate. METHODS: A retrospective review was performed of all gynecologic oncology patients with intestinal perforation at our institution between 1995 and 2011. The Kaplan-Meier method and Cox proportional hazards models were used to analyze factors influencing survival. RESULTS: Forty-three patients met the study criteria. The mean age was 59 years (range: 38-82 years). A large number of patients had peritoneal carcinomatosis and history of bowel obstruction. Surgery was performed in 28 patients, and 15 were managed conservatively. Overall mortality at 1, 3, 6, and 12 months was 26%, 40%, 47%, and 59%, respectively. Only cancer burden at the time of perforation was independently predictive of mortality. Patients with peritoneal carcinomatosis, distant metastasis, or both were at 42 times higher risk of death than those with no evidence of disease (95% CI: 3.28-639.83), and at 7 times higher risk of death than those with microscopic/localized disease (95% CI: 1.77-29.94). When adjusted for the extent of disease spread, management approach (conservative vs. surgical) was not a significant predictor of survival (p≥0.05). The length of hospital stay (19 days vs. 7 days) and the complication rate (75% vs. 26.7%) were significantly higher in the surgical group than in the non-surgical group (p<0.05). CONCLUSIONS: Patients who develop intestinal perforation in the setting of widely metastatic disease have a particularly poor prognosis. Aggressive surgical management is unlikely to benefit such patients and further impairs their quality of life.

The risk of lymph node metastasis with positive peritoneal cytology in endometrial cancer.

OBJECTIVE: To determine the correlation between positive peritoneal cytology (PPC) and lymph node metastasis in patients with endometrial cancer grossly confined to the uterus. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only patients with endometrial cancer grossly confined to the uterus who had undergone a complete staging procedure (lymph node removal) were included. Statistical analysis used the χ2 test and logistic regression models. RESULTS: A total of 22,947 patients were identified. Positive peritoneal cytology was present in 3.5% of the patients. The incidence of lymph node metastasis was significantly higher among patients with PPC compared to those with negative peritoneal cytology for all histologic types examined (P < 0.0001): endometrioid adenocarcinoma, 28.7% versus 6.9%; adenocarcinoma not otherwise specified, 35.4% versus 5.8%; clear cell/serous carcinoma, 41.4% versus 19.0%, and carcinosarcoma,; 38.4% versus 14.4%. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of lymph node metastasis (P < 0.0001). CONCLUSION: Our data indicate that patients with positive washings are at significant risk of nodal metastasis and adverse prognosis. Although no longer a part of the current International Federation of Gynecology and Obstetrics staging criteria, peritoneal cytology status should continue to inform clinical decision making in endometrial cancer.

Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer.

OBJECTIVE: In light of the recent changes in the International Federation of Gynecology and Obstetrics (FIGO) staging system, the objective of this study was to determine the prognostic significance of positive peritoneal cytology (PPC) among patients with early stage endometrial cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with stage I/II endometrial cancer who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analyses used Chi-square test, Kaplan-Meier log rank, and Cox proportional hazards models. RESULTS: A total of 14,704 patients were identified: 14,219 with negative peritoneal cytology (NPC) and 485 with positive peritoneal cytology. More patients with PPC compared to those with NPC were diagnosed with high-risk factors such grade III disease (40.2% vs. 23.8%, p<0.0001), and unfavorable histologic types such as clear cell/serous carcinoma (17.5% vs. 7.5%, p=<0.0001) and carcinosarcoma (9.3% vs. 5.6%, p<0.0001). When compared to patients with negative peritoneal cytology, survival was significantly worse among patients with positive peritoneal cytology (p<0.0001): 5-year disease specific survival 95.1% vs. 80.8% in endometrioid adenocarcinoma; 78.0% vs. 50.4% in clear cell/serous cancer; and 64.7% vs. 32.3% in carcinosarcoma. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of poor survival (p<0.0001) in all histologic types examined. CONCLUSION: PPC is an independent risk factor in patients with early stage endometrial cancer. Although, no longer a part of the current FIGO staging criteria, peritoneal cytology status should still be considered for accurate risk-stratification of these patients.

Evaluating the significance of location of lymph node metastasis and extranodal disease in women with stage IIIC endometrial cancer.

OBJECTIVE: To determine the prognostic significance of location of lymph node metastasis and extranodal disease for women with stage IIIC endometrial cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used Chi-square test, Kaplan-Meier method, and Cox proportional hazards model. RESULTS: A total of 2559 women were identified; 1453 stage IIIC1, and with 906 stage IIIC2 tumors. Compared to stage IIIC1; more stage IIIC2 patients demonstrated high-risk factors such as grade III disease (p<0.001), unfavorable histologic types (p=0.01), concurrent disease at other extrauterine sites (p<0.001), and greater than two positive lymph nodes (p<0.001). While the 5-year disease specific survival was comparable (p>0.05) among node positive patients found to have positive peritoneal cytology (44.0%), adnexal/serosal metastasis (42.9%), and vaginal/parametrial involvement (41.8%); it differed individually in all three categories from those with nodal metastasis alone (67.0%, p<0.001). Among women with extranodal disease, the location of nodal metastasis had no effect on survival (HR=0.92; 95% CI, 0.74-1.14). For women with node only stage IIIC tumors, those patients with positive para-aortic nodes were more likely to die from their tumors (HR=1.40; 95% CI, 1.12-1.75). CONCLUSION(S): Location of lymph node metastasis is prognostic in patients with nodal disease alone, and not in those with extranodal disease. Extranodal disease is associated with a poor prognosis and should be regarded in conjunction with location of lymph node metastasis for risk-stratification in stage IIIC endometrial cancer.

Stage III uterine carcinosarcoma: 2009 International Federation of Gynecology and Obstetrics Staging System and Prognostic Determinants.

OBJECTIVES: (1) To determine the significance of positive peritoneal cytology and pelvic versus para-aortic lymph node involvement in uterine carcinosarcoma. (2) To evaluate the impact of isolated retroperitoneal lymph node involvement (IIIC-N) versus retroperitoneal lymph node involvement plus other evidence of extrauterine disease spread (IIIC-N+) on survival in patients with stage IIIC uterine carcinosarcoma. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used χ, Kaplan-Meier method, and Cox proportional hazards model. RESULTS: A total of 690 women were identified. When comparing overall survival between patients with disease spread to uterine serosa and/or adnexa and those with positive peritoneal cytology, there was no significant difference (25.4% vs 15.5%, P = 0.2). However, although the 5-year overall survival was comparable between patients with positive pelvic lymph nodes and those with positive para-aortic lymph nodes (22.1% vs 25.4%, P = 1.0), it was significantly worse in stage IIIC-N(+) compared to stage IIIC-N patients (15.0% vs 33.4%, P < 0.001). Only patient's age (P < 0.001), race (P = 0.03), stage (P < 0.03), and lymphadenectomy (P < 0.001) were independent predictors of survival after adjusting for other contributing factors. In addition, the results of unadjusted analysis concerning the survival difference between different stage groups were confirmed on multivariate analysis. CONCLUSIONS: Positive peritoneal cytology is associated with poor prognosis in uterine carcinosarcoma, comparable to current International Federation of Gynecology and Obstetrics stage IIIA classification of disease. Although there does not seem to be a significant survival difference between patients with positive pelvic versus those with para-aortic lymph nodes, the prognosis seems to be much worse in patients with stage IIIC uterine carcinosarcoma with other evidence of extrauterine disease spread, suggesting the need for more aggressive therapy.

Stage IIA1 versus stage IIA2 cervical cancer: does the new staging criteria predict survival?

OBJECTIVE: (1) To determine the correlation of 2008 International Federation of Gynecology and Obstetrics staging system with survival in patients with stage IIA cervical cancer, (2) to elucidate the treatment patterns in stage IIA1 and stage IIA2 cervical cancer, and (3) to investigate whether radical hysterectomy or radiation influenced overall survival. METHODS: Data were extracted from the Surveillance, Epidemiology and End Results database between 1988 and 2005. Statistical analysis used χ test, Kaplan-Meier method, Cox regression, and logistic regression. RESULTS: Of the 560 women, 271 (48.4%) had stage IIA1, and 289 (51.6%) had stage IIA2 cervical cancer. Stage IIA2 patients were younger than stage IIA1 patients (mean age, 49 years vs 54 years; P = 0.01). Stage IIA1, compared with stage IIA2, differed significantly regarding the administration of primary radiation (47.2% vs 64.7%, P < 0.001) and adjuvant radiation (60.5% vs 77.5%, P = 0.006). The following variables were significantly associated with the performance of radical hysterectomy: patient age, 65 years or younger, tumor size, ≤ 2 cm or lesser, high tumor grade, and nonsquamous tumor histology. The incidence of adjuvant radiation after radical hysterectomy was high (48% [tumor size, ≤ 2 cm] to 86% [tumor size, >6 cm]). The 5-year overall survival was not significantly different between stages IIA1 and IIA2 (65.8% vs 59.5%, P = 0.2). Only patient age (P = 0.01), tumor size (P = 0.02), and lymph node status (P = 0.002) were independent predictors of survival. When controlled for other contributing factors, there was no significant difference in survival between patients treated by radical hysterectomy and primary radiation. CONCLUSIONS: The 2008 International Federation of Gynecology and Obstetrics staging criteria is not an independent predictor of survival in stage IIA cervical cancer. Given the equivalent efficacy of radical hysterectomy and radiation, attention should be paid to the high risk of adjuvant radiation in these patients.

Intra-operative detection of nodal metastasis in early stage cervical cancer: a survey of the practice patterns of SGO members.

OBJECTIVES: To determine the practice patterns of members of Society of Gynecologic Oncologists (SGO) in different clinical situations involving the intra-operative detection of nodal metastasis in early stage cervical cancer. METHODS: A study questionnaire was mailed to the current members of SGO (n=874). Data were collected using an internet survey database. Frequency distributions were determined, and non parametric tests were performed. RESULTS: Thirty percent SGO members responded (n=274). Only 38.6% routinely performed an intra-operative frozen section evaluation of the lymph nodes. Of these; most (79%) did not abort the radical hysterectomy (RH) for an isolated microscopically positive pelvic lymph node. The likelihood of aborting RH for microscopic nodal involvement increased however with number of positive pelvic lymph nodes (21% with 1, 40% with 2-3, and 61% with >3 positive pelvic lymph nodes), involvement of para-aortic lymph nodes (61%), or bilaterally positive lymph nodes (54%). Similarly, a large number did not complete the RH due to gross involvement of pelvic (45%) or para-aortic lymph node/s (69%). Most (90%) completed the lymphadenectomy before aborting RH. When completing RH, the majority tailored its extent to perform a less radical resection. Variables significantly associated with the likelihood of completing RH in different clinical situations included: location of current practice (West), practice type (private), years in practice (>15 years), and number of cases seen per year (>10/month). CONCLUSION: Practice patterns of SGO members are considerably diverse, which is reflective of the conflicting evidence available in the literature. Well designed studies are required to determine the best overall approach.

Prognostic analysis of ovarian cancer associated with endometriosis.

OBJECTIVE: The objective of the study was to evaluate the prognosis of ovarian cancer arising in endometriosis. STUDY DESIGN: We retrospectively compared 42 cases of endometriosis-associated ovarian cancer (EAOC) with 184 cases of ovarian carcinoma without endometriosis (OC). RESULTS: The median age in the EAOC group was 52 vs 59 years in OC (P < .05). In comparison with OC, the EAOC patients were more likely to have low-grade (21% vs 8%; P = .04) and early-stage tumors (International Federation of Gynecology and Obstetrics I and II combined) (49% vs 24%; P = .002). Clear cell (21% vs 2%) and endometrioid (14% vs 3%) tumors were more frequent in EAOC, whereas mucinous tumors were more prevalent in OC (P = .001). The median survival (199 vs 62 months) and the 5 year survival (62% vs 51%) were better for EAOC when compared with OC (P = .038). After controlling for age, stage, grade, and treatment, association with endometriosis was not an independent predictor of better survival in ovarian cancer. CONCLUSION: As such, EAOC has a much better survival rate than OC. This could be explained by the higher prevalence of early-stage and low-grade tumors in EAOC when compared with OC.

Validation of tumor size as staging variable in the revised International Federation of Gynecology and Obstetrics stage I leiomyosarcoma: a population-based study.

INTRODUCTION: Tumor size has been introduced as a staging variable in the 2008 International Federation of Gynecology and Obstetrics (FIGO) staging system for stage I leiomyosarcoma. In the prior 1988 FIGO staging system, leiomyosarcoma used the same staging criteria as endometrial cancer including cervical involvement. In this large population-based study, we validate the use of tumor size for purposes of risk stratification among stage I leiomyosarcoma patients. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Kaplan-Meier log rank and Cox proportional hazards models were used for survival analysis and to identify possible predictors for survival. RESULTS: The identified cohort included 819 women: 158 (19.3%), 2008 FIGO stage IA and 661 (80.7%), 2008 FIGO stage IB leiomyosarcoma. The 5-year overall survival rate was better in stage IA than in stage IB leiomyosarcoma (76.6% vs 48.4%, P < 0.001). Similarly, the 5-year overall survival rates were significantly different (P < 0.001) among women with different tumor size categories: 5 cm or smaller, 5.1 to 10 cm, and larger than 10 cm (76.6%, 52.9%, and 41.9%, respectively). The difference in 5-year overall survival rates between women with and without cervical involvement was significant (28.5% vs 55.3%, P = 0.014). Although age (P < 0.001), cervical involvement (P = 0.014), tumor grade (P < 0.001), tumor size (P < 0.001), performance of salpingo-oophorectomy (P = 0.001), and stage (P < 0.001) were all significant prognostic factors on univariate analysis, only age (P = 0.007), tumor size (P < 0.001), tumor grade (P < 0.001), and performance of salpingo-oophorectomy (P = 0.02) were significant predictors on multivariate analysis. Variables not found significant on univariate analysis (hence excluded from the Cox model) included lymphadenectomy, radiation, and race. CONCLUSIONS: The new staging system using tumor size is better for risk stratification in stage I leiomyosarcoma compared with the 1988 FIGO staging system of endometrial cancer.

Should radical hysterectomy be aborted on intraoperative detection of nodal tumor metastasis in early stage cervical cancer?

BACKGROUND/OBJECTIVES: In the United States, type 1 to 3 radical hysterectomy (RH) is used for the treatment of early stage (I-IIA) cervical cancer (ESCC). In the event that nodal metastasis is detected intraoperatively, completion of the procedure is controversial. Here, we present a review of the literature regarding clinical management of patients with ESCC with intraoperative diagnosis of nodal metastasis. MATERIALS AND METHODS: An electronic search of PubMed and OVID for the English-language literature published between 1980 and 2008 was performed. Studies regarding completion or abandonment of RH on intraoperative detection of nodal metastasis in ESCC were reviewed to evaluate the impact of either approach on overall survival, recurrence rate, and complication rate. RESULTS: This review was unable to document a difference in overall survival greater than 10% between the aborted and completed RH groups, and the difference was not statistically significant. No clear relationship was found between completion of RH and pelvic control or morbidity. Although urinary complications including bladder dysfunction and fistulae were unique to the completed RH group, radiation-related complications such as radiation cystitis, radiation proctitis, and bone necrosis were seen primarily in the aborted RH group. CONCLUSIONS: Given the lack of significant difference in survival, further studies are needed to evaluate the impact of completing versus aborting RH on pelvic control and morbidity to reach a definitive conclusion.

The impact of a multidisciplinary conference in the management of cervical cytological and histological abnormalities: a university hospital experience.

OBJECTIVE: This study evaluates the impact of a cytology-colposcopy correlation conference (CCCC) on the management of preinvasive cervical lesions in a university hospital. METHODS: This is a retrospective analysis of 130 consecutive cases from the colposcopy clinic at our University Health Center that were presented in the CCCC during a period of 1 year (November 2006 to October 2007). Variables examined to assess the usefulness of CCCC included the actual number of times there was a recorded change in the diagnosis or management recommendation secondary to presentation in the conference. The algorithms from the 2001 American Society of Colposcopy and Cervical Pathology consensus guidelines for the management of cytologic and histologic abnormalities were used to identify the patients in whom the conference recommendations were a deviation from the standard society recommendations. RESULTS: The diagnosis was changed on review of the original cytology or biopsy 24 times (13%), downgraded 13 times (7%), and upgraded 11 times (6%). The conference recommendations were a modification of the standard 2001 American Society of Colposcopy and Cervical Pathology guidelines 38 times (21%) in 34 patients. The most common triage change was the recommendation for observation of unexplained high-grade cytology with negative or lower-grade biopsy (73%), followed by observation of high-grade lesion on biopsy (27%). This recommendation, while an option in the 2006 guidelines, was not given as a choice in the 2001 guidelines. CONCLUSIONS: The CCCC at our institution provided significant input into the management of patients with preinvasive cervical lesions, anticipating some of the changes made in the 2006 guidelines.

Ovarian and uterine carcinosarcomas: a comparative analysis of prognostic variables and survival outcomes.

INTRODUCTION: Carcinosarcomas (malignant mixed Mullerian tumor) of the female genital tract are rare tumors associated with poor outcome. The objective of this study was to identify site-specific differences by comparing carcinosarcomas originating in the uterus and the ovaries. METHODS: Data on patients with uterine and ovarian carcinosarcomas were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Kaplan-Meier log rank and Cox proportional hazards models were used for survival analysis and for identification of possible predictors for survival. RESULTS: The identified cohort included 3683 women of whom 2759 (75%) have uterine carcinosarcoma and 924 (25%) have ovarian carcinosarcomas. The patients with uterine carcinosarcoma were older than the patients with ovarian carcinosarcoma (median age, 67 vs 65 years; P < 0.001). The women with uterine carcinosarcoma compared with those with ovarian carcinosarcoma were more often African American (17.3% vs 6%; P < 0.001) and presented more often with localized disease (47% vs 10.8%; P < 0.001). Uterine carcinosarcoma compared with ovarian carcinosarcoma differed significantly with regard to the performance of lymphadenectomy (62.6% vs 41.2%; P < 0.001) and the administration of radiotherapy (38.2% vs 4.8%; P < 0.001). When controlled for the extent of disease spread, uterine carcinosarcoma had a more aggressive clinical course and shorter survival compared with ovarian carcinosarcoma. Although age (P < 0.001), race (P = 0.01), stage (P < 0.001), lymphadenectomy (P < 0.001), and radiation (P < 0.001) were all significant prognostic factors in uterine carcinosarcoma, only age (P < 0.001), stage (P < 0.001), and lymphadenectomy (P < 0.001) were significant predictors in ovarian carcinosarcoma. CONCLUSION: Although uterine carcinosarcoma presents at an earlier stage than ovarian carcinosarcoma, it has a worse prognosis compared with ovarian carcinosarcoma, with a similar extent of disease spread. Improved survival observed in lymphadenectomy group lends support to its routine performance in patients with uterine and ovarian carcinosarcomas.

Clinical trials and progress with paclitaxel in ovarian cancer.

Paclitaxel is a front-line agent for ovarian cancer chemotherapy, along with the platinum agents. Derived from the Pacific yew tree, Taxus brevifolia, paclitaxel has covered significant ground from the initial discovery of its antineoplastic properties to clinical applications in many forms of human cancers, including ovarian cancer. Although much has been published about the unique mechanism of action of this agent, several issues remain to be resolved. Finding the appropriate dosage schedule for paclitaxel in chemo-naïve and recurrent ovarian cancer, defining the role of paclitaxel in maintenance chemotherapy, and elucidating the mechanisms of taxane resistance are areas of intense research. Newer forms of taxanes are being manufactured to avoid troublesome adverse effects and to improve clinical efficacy. These issues are reviewed in detail in this paper with an emphasis on clinically relevant evidence-based information.