Optimizing Perioperative Venous Thromboembolism Chemoprophylaxis on a Gynecologic Oncology Service.

BACKGROUND: Perioperative venous thromboembolism (VTE) is a significant cause of morbidity and mortality after gynecologic cancer surgery. Here we report a quality improvement intervention to increase perioperative VTE chemoprophylaxis compliance. STUDY DESIGN: All operations performed by a gynecologic oncologist at a tertiary urban university medical center admitted to the hospital for at least one midnight were included. Using a pre/post design with a washout period, we sought to increase perioperative VTE chemoprophylaxis compliance from 22% in the historical control (HC) cohort to 90% in the quality improvement (QI) cohort. The perioperative VTE chemoprophylaxis process was standardized by addressing four domains: preoperative VTE chemoprophylaxis, surgical time-out, postoperative VTE chemoprophylaxis, and intervention education and compliance tracking. Pearson's chi-square test was used to compare HC vs QI cohort compliance. RESULTS: There were 130 surgical cases in the HC cohort and 131 in the QI cohort. Forty-two percent underwent laparotomy, and 57% had cancer at the time of operation. VTE chemoprophylaxis compliance improved from 22% in the HC cohort to 82% in the QI cohort (p < 0.001). Preoperative VTE chemoprophylaxis compliance improved from 76% in the HC cohort to 94% in the QI cohort (p < 0.001), and postoperative VTE chemoprophylaxis compliance improved from 27% to 87% (p < 0.001). Thirty-day postoperative VTE occurred in three patients (2%) in the HC cohort and none in the QI cohort (p = 0.08). CONCLUSIONS: A low-cost and low-technology QI initiative intervention improved perioperative compliance with VTE chemoprophylaxis.

Uterine serous carcinoma: key advances and novel treatment approaches.

The incidence and mortality rates from endometrial cancer continue to increase worldwide, while rates in most other cancers have either plateaued or declined considerably. Uterine serous carcinoma represents a fraction of all endometrial malignancies each year, yet this histology is responsible for nearly 40% of all endometrial cancer-related deaths. These deaths disproportionately affect black women, who have higher rates of advanced disease at diagnosis. Molecular genetic analyses reveal major alterations including TP53 mutation, PIK3CA mutation/amplification, ERBB2 amplification, CCNE1 amplification, FBXW7 mutation/deletion, PPP2R1A mutation, and somatic mutations involving homologous recombination genes. Clinical risk factors for uterine serous carcinoma include advancing age, a history of breast cancer, tamoxifen usage, and the hereditary breast-ovarian cancer syndrome. Surgery remains the cornerstone of treatment. Recent advances in our understanding of uterine serous carcinoma molecular drivers have led to development of targeted therapeutics that promise improved outcomes for patients. Overexpression or amplification of HER2 in uterine serous carcinoma carries a poor prognosis; yet this actionable target has led to the incorporation of several anti-HER2 therapies, including trastuzumab which, when added to conventional chemotherapy, is associated with improved survival for women with advanced and recurrent HER2-positive disease. The combination of pembrolizumab and lenvatinib is also a promising targeted treatment strategy for women with uterine serous carcinoma, with a recent phase II study suggesting a 50% response rate in women with recurrent disease. Several trials examining additional targeted agents are ongoing. Despite years of stalled progress, meaningful, tailored treatment options are emerging for patients with this uncommon and biologically aggressive endometrial cancer subtype.

Society of Gynecologic Oncology recommendations for fellowship education during the COVID-19 pandemic and beyond: Innovating programs to optimize trainee success.

In approximately ten months' time, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 34 million people and caused over one million deaths worldwide. The impact of this virus on our health, relationships, and careers is difficult to overstate. As the economic realities for academic medical centers come into focus, we must recommit to our core missions of patient care, education, and research. Fellowship education programs in gynecologic oncology have quickly adapted to the "new normal" of social distancing using video conferencing platforms to continue clinical and didactic teaching. United in a time of crisis, we have embraced systemic change by developing and delivering collaborative educational content, overcoming the limitations imposed by institutional silos. Additional innovations are needed in order to overcome the losses in program surgical volume and research opportunities. With the end of the viral pandemic nowhere in sight, program directors can rethink how education is best delivered and potentially overhaul aspects of fellowship curriculum and content. Similarly, restrictions on travel and the need for social distancing has transformed the 2020 fellowship interview season from an in-person to a virtual experience. During this time of unprecedented and rapid change, program directors should be particularly mindful of the needs and health of their trainees and consider tailoring their educational experiences accordingly.

Systematic Review of Intraoperative Assessment Tools in Minimally Invasive Gynecologic Surgery.

OBJECTIVE: To collect, summarize, and evaluate the currently available intraoperative rating tools used in abdominal minimally invasive gynecologic surgery (MIGS). DATA SOURCES: Medline, Embase, and Scopus databases from January 1, 2000, to May 12, 2020. METHODS OF STUDY SELECTION: A systematic search strategy was designed and executed. Published studies evaluating an assessment tool in abdominal MIGS cases were included. Studies focused on simulation, reviews, and abstracts without a published manuscript were excluded. Risk of bias and methodological quality were assessed for each study. TABULATION, INTEGRATION, AND RESULTS: Disparate study methods prevented quantitative synthesis of the data. Ten studies were included in the analysis. The tools were grouped into global (n = 4) and procedure-specific assessments (n = 6). Most studies evaluated small numbers of surgeons and lacked a comparison group to evaluate the effectiveness of the tool. All studies demonstrated content validity and at least 1 dimension of reliability, and 2 have external validity. The intraoperative procedure-specific tools have been more thoroughly evaluated than the global scales. CONCLUSION: Procedure-specific intraoperative assessment tools for MIGS cases are more thoroughly evaluated than global tools; however, poor-quality studies and borderline reliability limit their use. Well-designed, controlled studies evaluating the effectiveness of intraoperative assessment tools in MIGS are needed.

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in advanced stage and recurrent uterine serous carcinoma (USC). The significance of tumoral HER2 expression in early-stage disease has not been established. METHODS: This multi-center cohort study included women with stage I USC treated from 2000 to 2019. Demographic, treatment, recurrence, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0-3+. Equivocal IHC results (2+) were further tested with fluorescence in-situ hybridization (FISH). HER2 positivity was defined as 3+ IHC or FISH positive. RESULTS: One hundred sixty-nine patients with stage I USC were tested for HER2; 26% were HER2-positive. There were no significant differences in age, race, stage, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. Presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p = .003). After a median follow-up of 50 months, there were 43 (25.4%) recurrences. There were significantly more recurrences in the HER2-positive cohort (50.0% vs 16.8%, p < .001). HER2 positive tumors were associated with worse progression-free (PFS) and overall survival (OS) (p < .001 and p = .024). On multivariate analysis, HER2 positive tumors were associated with inferior PFS (aHR 3.50, 95%CI 1.84-6.67; p < .001) and OS (aHR 2.00, 95%CI 1.04-3.88; p = .039) compared to HER2-negative tumors. CONCLUSIONS: Given its significant association with worse recurrence and survival outcomes, HER2 positivity appears to be a prognostic biomarker in women with stage I uterine serous carcinoma. These data provide support for clinical trials with anti-HER2-directed therapy in early-stage disease.

Are ethnic and racial minority women less likely to participate in clinical trials?

OBJECTIVES: Given the disparity that exists in enrollment of minorities to oncology clinical trials, the objective of our study was to assess whether race is associated with willingness to participate in gynecologic oncology clinical trials in a rural Southern academic medicine setting. Our secondary aim was to determine whether willingness to participate is impacted by an educational intervention. METHODS: A single institution prospective survey study was performed at an academic medical center. Women presenting to the gynecologic oncology clinic with a current or prior diagnosis of gynecologic malignancy were approached to participate. The validated Attitudes to Randomized Trials Questionnaire (ARTQ) assessed willingness to participate in clinical trials. Relevant demographic and clinical data were abstracted. Characteristics were compared between those willing and unwilling to participate in clinical trials with a chi-square test for categorical variables and Wilcoxon rank sum tests for continuous data. RESULTS: We enrolled 156 participants (50% White, 50% non-White) from May 2017 to January 2018. The minority group included 35% non-Hispanic Black, 9% Hispanic, 4% Asian, and 2% other. Median age was 63 years with endometrial cancer being the most common diagnosis (48%). On initial screen, only 35% were willing to participate in a clinical trial. Willingness to participate did not differ between race, age, marital status, education level, cancer type, stage, or mode of treatment. Rates improved to 82% after being provided additional educational information. Following education, White women and those with more education were significantly more willing to participate in clinical trials than their minority and less educated counterparts. CONCLUSIONS: Willingness to participate improved among all sub-categories following an educational intervention. The increase in willingness was less robust among racial and ethnic minorities, suggesting that different tools are needed for recruitment of minorities to gynecologic oncology clinical trials.

The addition of metformin to progestin therapy in the fertility-sparing treatment of women with atypical hyperplasia/endometrial intraepithelial neoplasia or endometrial cancer: Little impact on response and low live-birth rates.

OBJECTIVE: Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. METHODS: A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999-2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. RESULTS: Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m2, and 28.4 months, respectively. Fifty-eight women (63%) received Prog and 34 (37%) received Prog-Met. Overall, 79% (n = 73) of subjects responded to treatment with a CR of 69% (n = 63). There was no difference in CR (p = 0.90) or time to CR (p = 0.31) between the treatment cohorts. Overall, 22% experienced a disease recurrence. On multivariable analysis, EC histology was the only covariate associated with a decreased Prog response (HR 0.48; p = 0.007). Only 17% of the cohort achieved a live-birth pregnancy, the majority of which required assisted reproductive technologies (81%) and occurred in the Prog treatment group. CONCLUSIONS: Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.

Immunotherapy: Checkpoint Inhibitors in Lynch-Associated Gynecologic Cancers.

OPINION STATEMENT: Research into novel therapies for gynecologic cancers is underfunded, and as a result, we are still playing catchup with other solid tumors in the realm of immune checkpoint inhibition. This is despite the fact that two of the most common gynecologic cancers in the USA have strong biologic rationales for response to these agents. Work is now underway to demonstrate safe and effective therapies for our patients. As we better understand the immune system, and more specifically the tumor microenvironment, we will be able to achieve complete responses. The immune system can learn, adapt, and provide ongoing surveillance; if only we could mimic its abilities.

Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.

PURPOSE: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Image-guided high-dose-rate intracavitary brachytherapy in the treatment of medically inoperable early-stage endometrioid type endometrial adenocarcinoma.

PURPOSE: The purpose of this case series is to describe the treatment and outcomes of a cohort of patients with inoperable early-stage endometrioid endometrial cancer with 3D image-guided high-dose-rate (HDR) intracavitary brachytherapy. MATERIALS AND METHODS: A review was performed of patients with early-stage endometrial cancer who underwent primary radiation treatment between 2010 and 2016. Staging and treatment planning were performed CT, pelvic ultrasound, and pelvic MRI. Gross tumor volume (GTV) was defined as the MRI or ultrasound demonstrated endometrial stripe width, with the entire uterine corpus, cervix, and proximal vagina representing the clinical target volume (CTV). Dosimetry calculations were performed in each fraction of HDR brachytherapy. RESULTS: Eight patients received external beam radiation therapy followed by intracavitary HDR brachytherapy. Seven patients underwent intracavitary HDR brachytherapy alone. In all patients, mean cumulative dose to 90% (D90) of GTV was 95.99 Gy in equivalent dose in 2 Gy fractions (EQD2, α/ß = 10). Mean cumulative D90 EQD2 to CTV was 51.64 Gy. Average follow-up was 29 months. Four patients died from concurrent disease(s) at an average of 2.83 years after completion of treatment. Except for 1 (6.6%) patient who recurred at 9 months following completion of treatment, all patients remained disease-free for the remainder of follow-up. CONCLUSIONS: In patients who are poor surgical candidates and have early-stage endometrioid type endometrial carcinoma, image-guided HDR intracavitary brachytherapy carries minimal side effects and a high response rate.

Patient perceptions and willingness to participate in clinical trials.

OBJECTIVE: To evaluate gynecologic oncology patients' perceptions and willingness to participate in randomized clinical trials (RCT) among an inner city population. METHODS: Informed consent was obtained. Demographics were collected and willingness to participate in a RCT was measured by the Attitudes on Randomized Trials Questionnaire (ARTQ). The Hospital Anxiety and Depression Scale estimated levels of anxiety and depression. A Perception Survey was created and tested as a screening tool for patients considering RCTs. Standard statistical tests were used. RESULTS: One hundred and one women participated, 54 (53.5%) were black, 31 (30.7%) were white, non-Hispanic and 15 (14.9%) were Hispanic. Screening for anxiety and depression revealed an 18.8% rate of moderate to severe anxiety and an 11.9% rate of moderate to severe depression. Willingness to participate in a RCT as measured by ARTQ scores was not significantly associated with race, levels of anxiety or depression. Twenty-eight percent of women would agree to participate in a clinical trial at baseline. An additional, 33 (32.7%), for a total of 61.4%, indicated agreement after targeted education with no statistical differences by race or psychological stressor. However, sixty-one percent of these women were black. The Perception Survey approximated the results of the ARTQ with reasonable accuracy (AUC 0.758, p<0.001) CONCLUSIONS: Neither race nor psychological stressor were significant indicators of willingness to participate in a RCT. Targeted education resulted in a majority of patients indicating willingness to participate in trials, especially among black women. Additionally, a novel screening tool was tested and performed well in this setting.

Incisional hernia formation and associated risk factors on a gynecologic oncology service: an exploratory analysis.

PURPOSE: The aim of this study is to identify the rate of incisional hernias and associated risk factors following a vertical midline laparotomy on a gynecologic oncology service. METHODS: This is a retrospective cohort study of patients that underwent a laparotomy through a vertical midline abdominal incision between September 1998 and November 2012. Hernias and various factors were identified including demographics, disease comorbidities, intraoperative variables, and suture technique. Assessment of association with hernia formation was performed using Cox regression and log-rank test. RESULTS: Two hundred and fifty-two patients with follow-up of at least 30 days were identified. Mean age was 59 years (range 21-88 years) and mean BMI was 35.9 kg/m(2) (range 17.2-84.4 kg/m(2)). Sixteen (6.3 %) developed incisional hernias with a median follow-up of 1.7 years (range 1 month to 13 years). The estimate of the 5-year probability of being hernia-free is 86 % (95 % CI 76.5-91.9). Average age of patients who developed a hernia was 66.2 years while average age of those without hernia was 58 years (p < 0.05). There was a significant association of hypertension with incisional hernia occurrence (p = 0.0035, log-rank test). Cancer was present in 100 % of patients that developed hernias and 73 % (172/236) of those that were hernia-free (p = 0.0041, log-rank test). By univariate analysis the risk of developing an incisional hernia was higher, if the abdominal fascia was closed with loop sutures (HR 4.6, 95 % CI 1.49-13.94; p = 0.008). By multivariable analysis incisions closed with loop suture had more than a fivefold increased risk of developing a hernia (HR 5.2, 95 % CI 1.65-16.39; p = 0.005). Presence of both hypertension and utilization of loop sutures had the highest risk of incisional hernia development (HR 7.1, 95 % CI 2.28-22.4; p = 0.001). CONCLUSION: Wound complications including incisional hernias contribute to morbidity in gynecologic oncology patients. Older age, hypertension, utilization of loop sutures, and cancer were found to be associated with hernia formation after laparotomy through a vertical midline abdominal incision. The use of loop sutures to close the abdominal fascia should be investigated further.

Radiation therapy with concurrent chemotherapy for locally advanced cervical carcinoma: outcome analysis with emphasis on the impact of treatment duration on outcome.

Objective. To assess the effectiveness and toxicity of carboplatin concurrent with pelvic external beam radiation and low-dose rate brachytherapy and to assess the impact that adherence to the treatment plan has on outcomes. Methods. Retrospective chart review of 56 patients treated from January 2001 to December 2010. Results. Median follow-up was 68 months. Optimal dose of radiation (ORT) was defined as a minimal cervical dose exceeding 70 Gy, point A dose of 80-90 Gy, and duration not exceeding 56 days. Only 50% received ORT. In multivariable analyses we only found ORT to be statistically significant predictor for progression-free survival (PFS) and overall survival (OS) (HR [95% CI] for non-ORT vs. ORT: 2.4 [1.2, 5.1], P = 0.014 for PFS and 2.2 [1.1, 4.6], P = 0.035 for OS). The 5-year PFS in patients who received ORT was better than that in patients who received non-ORT, 56% vs. 22% (95% CI: [36%, 72%] vs. [9%, 39%]). Patients who received ORT had a better 5-year OS as well (59% vs. 33%; 95% CI: [38%, 75%] vs. [16%, 51%]). Conclusion. Patients with locally advanced cervical cancer treated with weakly carboplatin or cisplatin, teletherapy, and low dose-dose rate brachytherapy have poorer outcomes when treatment duration is prolonged.

Multi-gene expression predictors of single drug responses to adjuvant chemotherapy in ovarian carcinoma: predicting platinum resistance.

Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples.

Localized cavernous hemangioma of the uterus involving adenomyotic foci.

Localized cavernous hemangioma of the uterus is an extremely rare lesion that often presents with heavy uterine bleeding and/or pelvic pain. Though more cases exist for pregnant women, some isolated case reports involve non-pregnant women. The diagnosis is difficult and requires a high index of clinical and radiological suspicion. Here we describe a clinically and radiologically unsuspected case of a localized cavernous hemangioma in a 27-year-old woman, with a prior history of an uneventful Cesarean section. Surgical excision of the lesion at the cornu of the uterus was performed. Histopathology revealed a cavernous hemangioma involving the endomyometrium and invading the foci of adenomyosis. A cavernous hemangioma localized to a portion of the uterus may be clinically silent during pregnancy and throughout delivery thus making it difficult to detect. Though rare, it may be an important differential in any female patient who presents with non-responsive uterine bleeding and/or unremitting pelvic pain.

Cervical stromal invasion predicting survival in endometrial cancer.

OBJECTIVE: To estimate the extent to which cervical stromal invasion would predict survival. METHODS: Cases of stage II endometrioid endometrial adenocarcinoma from three academic institutions were reviewed. A gynecologic pathologist reevaluated archived slides and measured the depth of cervical stromal invasion. Clinical data were abstracted and statistical analysis performed. RESULTS: Of 116 cases, 31 (27%) had gland involvement and 85 (73%) cervical stromal invasion. Cervical stromal invasion was categorized as the inner two thirds (n=59 [69%]) compared with the outer third (n=26 [31%]). Women with outer third cervical stromal invasion compared with those with inner two-thirds cervical stromal invasion were more likely to be aged at least 65 years (69% compared with 46%, P=.038), have at least 50% myometrial invasion (77% compared with 44%, P=.004), lymphvascular space invasion (46% compared with 20%, P=.016), and to have died (50% compared with 19%, P=.004). Overall survival for patients with no invasion and inner two-thirds cervical stromal invasion did not differ (106 compared with 146 months, P=.89). Survival for outer third cervical stromal invasion was 91 months (P=.021). Multivariable analysis found deep myometrial invasion (hazard ratio 3.1; confidence interval [CI], 1.2-8.2), lymphvascular space invasion (hazard ratio 3.2; CI 1.2-8.4), and outer third cervical stromal invasion (hazard ratio 2.8; CI 1.1-7.2) were independent predictors of death. CONCLUSION: Deep (outer third) cervical stromal invasion is an independent predictor of death in stage II endometrial cancers and these patients should receive radiation therapy. Superficial cervical stromal invasion did not increase risk of death and adjuvant radiation for this patient group may not be necessary. LEVEL OF EVIDENCE: III.

The role of in vitro directed chemotherapy in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) continues to be the most lethal gynecologic malignancy. Efforts to personalize chemotherapy treatments by utilizing in vitro tumor assays to predict chemotherapeutic response have been tested in both the primary and recurrent treatment setting. To date, several retrospective studies have suggested improved response rates to predicted chemotherapeutic agents. However, a prospective, controlled trial merely found equivalence between in vitro prediction and empirical treatment selection. This review summarizes the current data regarding in vitro directed chemotherapy in EOC.

Evaluation of EVI1 and EVI1s (Delta324) as potential therapeutic targets in ovarian cancer.

PURPOSE: The MDS1 and EVI1 complex locus (MECOM) at 3q26 gives rise to several alternatively spliced transcripts implicated in leukemic oncogenesis. Overexpression of EVI1 in ovarian cancer has led to a proposed oncogenic role. Our objective was to evaluate the therapeutic potential of EVI1 and EVI1s (also known as Delta324) in ovarian cancer. METHODS: Expression of EVI1 mRNA and protein isoforms was evaluated in ovarian cancers, normal ovaries, benign ovarian neoplasms, and fallopian tube fimbria. Effects of EVI1 isoform overexpression and knockdown on proliferation, cisplatin-induced apoptosis, and double stranded DNA breaks were investigated. RESULTS: EVI1 and EVI1s mRNAs were ubiquitously expressed in ovarian cancers and benign gynecologic tissues examined, with highest expression of both isoforms noted in the cancer samples. The EVI1s to total EVI1 mRNA ratio was uniform among the examined tissues. In contrast, EVI1 protein isoform levels were undetectable in normal ovarian tissues, and highest in serous ovarian cancers. EVI1 protein expression patterns were similar between serous ovarian cancer samples, fallopian tube fimbria, and benign neoplasms. Expression of EVI1 or EVI1s did not increase proliferation in EVI1-null OVCAR8 cells. Total and isoform selective knockdown of EVI1 isoforms in EVI1 expressing ovarian cancer cells had no effect on proliferation, cisplatin-induced apoptosis, or gamma-H2AX levels in ovarian cancer cells. CONCLUSION: Our data do not support a role for EVI1 or EVI1s in ovarian cancer cell proliferation or response to DNA damage. Further research is required before EVI1 can be considered an oncogene or a therapeutic target in ovarian cancer.

Temozolomide in advanced and recurrent uterine leiomyosarcoma and correlation with o6-methylguanine DNA methyltransferase expression: a case series.

INTRODUCTION: Our objective was to retrospectively review temozolomide in advanced and recurrent uterine leiomyosarcoma and to determine if tumor O-methylguanine DNA methyltransferase (MGMT) expression correlated with clinical response. METHODS: All patients with advanced or recurrent uterine leiomyosarcoma who received temozolomide during treatment were retrospectively identified. Relevant clinical and pathologic data were collected and compared. O-Methylguanine DNA methyltransferase expression was assessed by immunohistochemistry and scored by a gynecologic pathologist blinded to clinical outcomes. RESULTS: From 1999 to 2008, 9 cases of leiomyosarcoma were diagnosed; 6 patients received temozolomide. Median follow-up was 54 months (range, 4-114 months). There was 1 patient with complete response, 1 durable partial response (27+ months), 3 stable disease (range, 3-10 months), and 1 progressive disease. Overall, 5 out of 6 patients derived clinical benefit. The patient with a complete response recurred 18 months after her last cycle. Median progression free interval was 15.4 months (95% confidence interval, 9.4-21.4). Two patients died of disease. Temozolomide was well tolerated with no dose-limiting toxicities, and no dose adjustments were required in 64 prescribed cycles. The MGMT expression was inversely correlated with response to temozolomide. Patients with tumors negative for MGMT expression had a median progression free interval of 18.5 months compared with 3 months for those whose tumors were positive, although not statistically significant. CONCLUSIONS: Temozolomide is an easily administered, well-tolerated chemotherapeutic option in advanced or recurrent uterine leiomyosarcomas with a reasonable response rate. Assessment of MGMT expression may identify a subset of patients that will respond optimally to this therapy.

When 'never-events' occur despite adherence to clinical guidelines: the case of venous thromboembolism in clear cell cancer of the ovary compared with other epithelial histologic subtypes.

OBJECTIVE: To determine the incidence of clinically significant venous thromboembolism (VTE) in women diagnosed with clear cell carcinoma of the ovary (CCC-O) interpreted in the context of Centers for Medicare and Medicaid Services (CMS) 'never-events.' METHODS: Using the institutional pathology Tumor Registry at the Massachusetts General Hospital (MGH), all women diagnosed with a CCC-O from 1994 to 2004 were identified. Controls with epithelial ovarian cancer of other histologies were matched for stage, age and year of diagnosis. Medical records were abstracted and pathology reviewed. All patients had surgical staging and/or cytoreductive surgery by a Gynecologic Oncologist at the MGH. All patients received appropriate peri- and post-operative prophylaxis with subcutaneous heparin and/or sequential compression devices. VTE was diagnosed with standard imaging techniques when clinical suspicion arose. RESULTS: Fifty-eight (58) women were diagnosed with CCC-O during the study period, 43 of whom had complete data available for analysis. Patients with Stage I or II disease comprised 70% of the patients. The mean age of the cohort was 55 and the mean weight 71 kg. Eighty-six (86) age, stage, and year of diagnosis matched controls were selected. The majority of controls had serous tumors (47%) with the remainder being endometrioid (33%), mucinous (14%), transitional cell (2%), sarcoma (2%) and mixed (2%). CCC-O was often seen in association with endometriosis 70% compared with 22% of controls (p<0.0001). Overall, 18 of 43 CCC-O patients (42%) had VTE while only 19 of 86 control patients (22%) had VTE (p=0.024, OR=2.5 CI 1.1504-5.60). The rate of VTE was not influenced by weight or smoking. In the CCC-O patients, seventeen percent (17%) of VTE was diagnosed at presentation while 50% was diagnosed postoperatively and 33% at the time of disease recurrence or progression. Overall, including cases and controls, late stage disease was more likely associated with VTE (18 of 39, 46%) vs. early stage disease (19 of 90, 21%), p=0.004. CONCLUSIONS: Women with CCC-O have a 2.5-times greater risk of disease related VTE than women with other histologies of epithelial ovarian cancer despite adherence to prophylactic guidelines. Given the high rate of VTE postoperatively as well as with disease recurrence, one should consider indefinite therapeutic anticoagulation in women with CCC-O. The case of CCC-O is one example of the impracticality of payment denial for 'never-events,' as VTE arises despite best efforts at prevention.