Bakkum‐Gamez, Jamie N.

Accurate risk stratification of smooth muscle tumors (SMTs) is essential for appropriate patient management. Yet, the rarity of SMTs of the vagina and vulva makes development of a prognostically meaningful classification system challenging. While 2 classification methods for vulvar SMTs and 1 for vaginal SMTs have been proposed, it is our experience that many pathologists tend to apply criteria for uterine SMTs when evaluating vulvovaginal tumors. We retrospectively reviewed a large cohort of vulvovaginal SMTs with clinical follow-up and evaluated which method most accurately classified tumors according to patient outcome. A total of 71 tumors, 53 vaginal (75%) and 18 vulvar (25%), from 71 patients were identified. All tumors were centrally examined for degree of cytologic atypia, morphology (spindled, epithelioid, myxoid), mitotic index per 10 high power fields, atypical mitotic figures, tumor cell necrosis, ischemic necrosis, tumor interface (circumscribed or infiltrative) and margin status. Clinical features were recorded for each patient. Follow-up was available for 63 patients (89%), and ranged from 1 to 234 months (median: 64 mo). While site-specific and uterine criteria showed equally excellent sensitivity in classifying smooth muscle neoplasms as leiomyosarcoma according to patient outcome, uterine criteria showed improved specificity relatively to site-specific methods in classifying tumors as nonsarcoma according to patient outcome. We recommend that uterine SMT criteria and nomenclature be adopted for evaluation and classification of vulvovaginal SMTs.

Abstract Background: Endometrial cancer is highly curable when detected early, but clinical symptoms are often missed. Most cancers arise in women with abnormal postmenopausal bleeding (PMB). However, PMB is not specific for endometrial cancers. In previous reports, the prevalence of endometrial cancer in women with PMB was reported to range from 3-25%. Because of the importance for guiding clinical management and endometrial cancer risk prediction, we conducted a systematic review and meta-analysis to obtain precise prevalence estimates of endometrial cancer in women with PMB. Methods: A systematic review and meta-analysis summarized all peer-reviewed studies reporting endometrial cancer prevalence in women with PMB, published before Sept. 1, 2016. We calculated a pooled prevalence estimate and 95% confidence interval (CI) using a random-effects model, and quantified heterogeneity across studies using the I2 statistic. Subgroup meta-analyses were performed to investigate sources of variability according to selection criteria for endometrial thickness (ET) and hormone replacement therapy (HRT). We also stratified by study location to determine whether prevalence estimates varied by country or region if ≤5 studies included per country. Results: 105 studies were included, contributing data for 37,000 women with PMB and 3,028 with cancer from 34 countries. Overall, the pooled prevalence of endometrial cancer in women with PMB was 11% (95% CI 10-12%), with I2 =94.3%. Among studies that selected women with a minimum ET (≥ 4mm; n=14), the pooled prevalence of endometrial cancer was 17% (95% CI 14-20%) compared with studies that did not select for ET (10%, 95% CI 9-11%). In studies that excluded women using HRT (n=34), the pooled prevalence of endometrial cancer was 15% (95% CI 12-17%) compared with studies that did not exclude women using HRT (9%, 95% CI 8-10%). Stratification by study location revealed variation in prevalence estimates. For example, in the United States (n=9) and the United Kingdom (n=16), prevalence of endometrial cancer was 4% (95% CI 2-7%) and 5% (95% CI 4-6%), respectively, whereas in Italy (n=14), the prevalence was 11% (95% 8-14%). Regional differences were also observed, ranging from 8% (95% CI 3-14%) in South Central Asia (n=5) to 18% (95% CI 12-23%) in Southern Europe (n=11). Conclusions: The overall prevalence of endometrial cancer among unselected women with PMB is approximately 10% with substantial heterogeneity across studies. Marked geographic differences in the prevalence endometrial cancer were observed. Factors related to selection for ET and/or HRT use may partially contribute to this variability. Risk prediction models depend on precise prevalence estimates for accurate prediction and utility in clinical management. More research is needed to test the applicability of endometrial cancer risk prediction models in high-risk subgroups and in study populations from diverse geographic regions. Citation Format: Megan A. Clarke, Beverly J. Long, Arena Del Mar Morillo, Jamie N. Bakkum-Gamez, Nicolas Wentzensen. The prevalence of endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2017-275

BACKGROUND: Increasing numbers of robotic hysterectomies (RH) are being performed. To provide ventilation (with pneumoperitoneum and steep Trendelenburg position) for these procedures, utilization of lung protective strategies with limiting airway pressures and tidal volumes is difficult. Little is known about the effects of intraoperative mechanical ventilation and high peak airway pressures on perioperative complications. We performed a retrospective review to determine whether patients undergoing RH had increased pulmonary complications compared to total abdominal hysterectomy (TAH). METHODS: We performed a single center retrospective review comparing the intraoperative, anesthetic, and immediate and 30-day postoperative course of patients undergoing RH to TAH, including intraoperative ventilatory parameters and respiratory complications. Patients undergoing TAH (201) from 2004 to 2006 were compared to RH (251) from 2009 to 2012. It was our hypothesis that patients undergoing RH would have increased incidence of postoperative pulmonary complications. A secondary hypothesis was that morbid obesity predicts pulmonary complications in patients undergoing RH. Complications were compared between groups using Fisher’s exact test. To account for potential confounders, the primary analysis was performed for a subgroup of patients matched on the propensity for RH. RESULTS: A total of 351 RH and 201 TAH procedures are included. Higher inspiratory pressures were required in ventilation of the RH group (median [25th, 75th] 31 [26, 36] cm H 2 O) than the TAH group (23 [19, 27] cm H 2 O) ( P < .001) at 30 minutes after incision. Peak inspiratory pressures at 30 minutes after incision for RH increased according to increasing body mass index group ( P < .001). There were 163 RH and 163 TAH procedures included in the propensity matched analysis. From this analysis, there were no significant differences in cardiopulmonary complications between RH and TAH (0.6% vs 1.2%; odds ratio = 2.0, 95% confidence interval = 0.2–2.4; P = 1.00). Surgical site infection was significantly lower in the RH compared to TAH group (0.6% vs 8.6%; P < .001). Hospital length of stay was longer for those who underwent TAH versus RH (median [25th, 75th] 2 [2, 3] vs 1 [0, 2] days; P < .001). CONCLUSIONS: There was no significant difference in perioperative complications in obese and morbidly obese women compared to nonobese undergoing RH. Patients undergoing RH had shorter hospital stays, fewer infectious complications, and no increase in overall complications compared to TAH. Higher ventilatory airway pressures (RH versus TAH and obese versus nonobese) did not result in an increase in cardiopulmonary or overall complications. We believe that peritoneal insufflation attenuates the effect of high airway pressures by raising intrapleural pressure and reducing the gradient across terminal bronchioles and alveoli. Thus, we propose that lung protective strategies for patients undergoing RH account for the markedly elevated intraperitoneal and intrapleural pressures, whereas transpulmonary airway pressures remain static. This reduced transpulmonary gradient attenuates the strain on lung tissue that would otherwise be imposed by ventilation at high pressures.

Purpose of reviewDetection of endometrial cancer at an early stage leads to better oncologic outcomes. To date, a screening test for endometrial cancer does not exist.Recent findingsEvolving knowledge of molecular changes involved in endometrial cancer carcinogenesis paired with sensitive and high-throughput technological advancements are a promising combination that can be leveraged to detect tumor DNA and proteins. These molecular biomarkers can be identified in biospecimens collected via minimally invasive and noninvasive approaches. Exploiting lower genital tract secretions as a biospecimen also allows for patient self-sampling.SummarySuccessful development of a screening test for endometrial cancer using self-collected lower genital tract biospecimens has the potential to increase accessibility to care and improve patient compliance.

Abstract Purpose: Ovarian cancer (OC) patients received maximum benefits when complete dissection with no macroscopic disease is achieved. It has been suggested that surgical outcome is associated with tumor biology and therefore can be predicted from tumor molecular characteristics such as gene expression levels. Noticeably, several debulking-associated genes have been independently reported based on meta-data analysis and further validations in individual center's cohorts. Furthermore, a recent OC study of the cancer genome atlas (TCGA) project revealed the presence of four expression subtypes in high-grade serous ovarian cancer (HGSOC). We have independently confirmed this association with prognosis in our OC cohort. With the awareness that surgical practices and rates of complete resection vary among institutions, we sought to evaluate whether expression changes of previously reported debulking-associated genes are associated with complete dissection in a HGSOC cohort in a center with an aggressive surgical approach. Further, we also tested if the HGSOC four expression subtypes are associated with complete dissection. Experimental Design: We constructed a cohort of 262 stage III/IV HGSOC patient cases diagnosed in Mayo Clinic between 1993 and 2011. Cases were categorized into two groups based upon debulking outcome: 84 complete resection cases with no gross visible residual disease (RD0), 178 cases with residual disease greater than 0 cm (RD1). Tumor mRNA expression was previously measured using Agilent 4x44k platforms. Eight previously published debulking-associated genes were evaluated for their expression differences between RD0 and RD1 patient groups using t-test: FABP4, ADH1B, POSTN, CXCL14, FAP, NUAK1, PTCH1 and TGFBR2. For testing subtype-debulking associations, we first quantified molecular subtype activation scores of individual tumors using single-sample gene set enrichment analysis (ssGSEA), and computed standardized scores after permutation-based scaling adjustments to account for gene set size difference. Then, standardized subtype scores are associated with complete dissection (RD0) vs. other surgical outcome (RD1) using logistic regression. The independent subtype-associations were further evaluated by adjusting known debulking outcome factors, including age, ascites, tumor grade and stage. Results: For eight previously reported debulking-associated genes, only one demonstrated a significant expression difference between RD0 and RD1 groups: CXCL14, t-test p-value = 9.2x10-3. When comparing debulking vs. HGSOC subtypes, we observed a significantly reduced probability of complete resection for the mesenchymal subtype (p-value = 1.1x10-2, OR = 0.56, 95% CI [0.35, 0.87]). Consistent with this observation, we have previously described the mesenchymal subtype as a poor prognosis group. On the other hand, the immunoreactive subtype was associated with a higher likelihood of complete resection (p-value = 9.4 x 10-3, OR=2.19, 95% CI = [1.22, 4.01]). The significant associations between these two subtype activities and complete resection in advanced stage disease remained after adjusting for age, ascites, tumor grade and sub-stage: mesenchymal (p-value = 1.5 x 10-2 ,OR = 0.48, 95% CI = [0.26, 0.85]); immunoreactive subtype (p-value = 4.8 x 10-2 , OR = 2.11, 95% CI = [1.04, 4.53]). Conclusion: This single center HGSOC analysis demonstrates the important of validation of debulking signatures in centers with diverse rates of complete resection. We were only able to validate an association with complete resection for one of eight previously reported debulking-associated genes. We also showed that HGSOC subtypes have significant associations with likelihood of complete dissection. Further studies are warranted for confirming subtype associations in other institutional HGSOC cohorts. Citation Format: Chen Wang, Jamie Bakkum-Gamez, Andrea Mariani, William Cliby, Ellen Goode. Tumor expression subtypes of high-grade serous ovarian cancer demonstrate associations with likelihood of complete resection: a single-center study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B80.

Purpose Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS. Patients and Methods In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs. Results In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P = .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P = .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab. Conclusion The addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS.

Abstract Edmonston vaccine strains of measles virus (MV) have significant antitumor activity in mouse xenograft models of ovarian cancer. MV engineered to express the sodium iodide symporter gene (MV-NIS) facilitates localization of viral gene expression and offers a tool for tumor radiovirotherapy. Here, we report results from a clinical evaluation of MV-NIS in patients with taxol- and platinum-resistant ovarian cancer. MV-NIS was given intraperitoneally every 4 weeks for up to 6 cycles. Treatment was well tolerated and associated with promising median overall survival in these patients with heavily pretreated ovarian cancer; no dose-limiting toxicity was observed in 16 patients treated at high-dose levels (108–109 TCID50), and their median overall survival of 26.5 months compared favorably with other contemporary series. MV receptor CD46 and nectin-4 expression was confirmed by immunohistochemistry in patient tumors. Sodium iodide symporter expression in patient tumors after treatment was confirmed in three patients by 123I uptake on SPECT/CTs and was associated with long progression-free survival. Immune monitoring posttreatment showed an increase in effector T cells recognizing the tumor antigens IGFBP2 and FRα, indicating that MV-NIS treatment triggered cellular immunity against the patients' tumor and suggesting that an immune mechanism mediating the observed antitumor effect. Our findings support further clinical evaluation of MV-NIS as an effective immunovirotherapy. Cancer Res; 75(1); 22–30. ©2014 AACR.