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Objective To describe the incidence, complications, and trends associated with ureteral surgeries on a gynecologic oncology service in the context of a fellowship training program over a 24-year period. Methods We conducted a retrospective cohort analysis of ureteral surgeries by gynecologic oncologists at either Moffitt Cancer Center or Tampa General Hospital from 1997 to 2020. Patient characteristics, predisposing factors, location and type of injury, repair method, postoperative management and complications were abstracted from the medical record. The recent cohort (2005–2020) was compared to our prior series (1997–2004). Results Eighty-eight cases were included. The average number of ureteral surgeries per year decreased from 5.75 (1997–2004) to 2.63 (2005–2020). Of 46 iatrogenic injuries, 45 were recognized and repaired intraoperatively. Ureteral transection was the most common type (85% [39 of 46]) and the distal 5 cm was the most common location of injury (63% [29 of 46]). Ureteroneocystostomy was the most common method of repair (83% [73 of 88]). Postoperative management, including stenting and imaging, has not changed significantly. Length of urinary catheter usage decreased in the recent cohort without associated complications. Five patients had major postoperative complications and 4 involved the urinary tract. Of those with follow-up, 96% (66 of 69) of ureteroneocystostomies and 75% (9 of 12) of ureteroureterostomies had radiologically normal urinary tracts. Conclusions Ureteral surgery is necessary in the case of injury or involvement with invasive disease. There has been a decrease in number of procedures. Ureteroneocystostomy has remained the most common method of reconstruction for both injury and resection with acceptable postoperative complication rates.

PURPOSE Cervical cancer remains a major health challenge in low- to middle-income countries. We present the experiences of two centers practicing in variable resource environments to determine predictors of improved radiochemotherapy treatment. METHODS AND MATERIALS This comparative review describes cervical cancer presentation and treatment with concurrent chemoradiotherapy with high-dose-rate brachytherapy between 2014 and 2017 at the National Radiotherapy Oncology and Nuclear Medicine Center (NRONMC) in Korle-Bu Teaching Hospital, Accra, Ghana, and Moffitt Cancer Center (MCC), Tampa, FL. RESULTS Median follow-up for this study was 16.9 months. NRONMC patients presented with predominantly stage III disease (42% v 16%; P = .002). MCC patients received para-aortic node irradiation (16%) and interstitial brachytherapy implants (19%). Median treatment duration was longer for NRONMC patients compared with MCC patients (59 v 52 days; P < .0001), and treatment duration ≥ 55 days predicted worse survival on multivariable analysis (MVA; P = .02). Stage ≥ III disease predicted poorer local control on MVA. There was a difference in local control among patients with stage III disease (58% v 91%; P = .03) but not in survival between MCC and NRONMC. No significant difference in local control was observed for stage IB, IIA, and IIB disease. CONCLUSION Although there were significant differences in disease presentation between the two centers, treatment outcomes were similar for patients with early-stage disease. Longer treatment duration and stage ≥ III disease predicted poor outcomes.

Objective Tumor spill during surgical treatment is associated with adverse oncologic outcomes in many solid tumors. However, in minimally invasive hysterectomy for endometrial cancer, intraoperative tumor spill has not been well studied. This study examined surgeon experiences and practices related to intraoperative tumor spill during minimally invasive hysterectomy for endometrial cancer. Methods A Cross-sectional survey was conducted to The Society of Gynecologic Oncology. Participants were 220 U.S. gynecologic oncologists practicing minimally invasive hysterectomy for endometrial cancer. Interventions were 20 questions regarding surgeon demographics, surgical practice patterns (fallopian tubal ablation / ligation, intra-uterine manipulator use, and colpotomy approach), and tumor spill experience (uterine perforation with intra-uterine manipulator and tumor exposure during colpotomy). Results Nearly half of the responding surgeons completed subspeciality training >10 years ago (50.5%), and 74.1% had annual surgical volume of >40 cases. The majority of surgeons used an intra-uterine manipulator during minimally invasive hysterectomies for endometrial cancer (90.1%), and 87.2% of the users have experienced uterine perforation with an intra-uterine manipulator. Almost all surgeons performed colpotomy laparoscopically (95.9%), and nearly 60% had experienced tumor spill while making colpotomy (59.8%). Nearly 10-15% of surgeons have changed their postoperative therapy as a result of intraoperative uterine perforation (11.8%) or tumor spill (14.5%). Surgeons infrequently ablated or ligated fallopian tubes prior to performing the hysterectomy (14.1%). Conclusion Our survey study suggests that many surgeons experienced intraoperative tumor spillage during minimally invasive hysterectomy for endometrial cancer. These findings warrant further studies examining its incidence and impact on clinical outcomes.

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Highlights • Vascular injury remains a rare but potentially morbid complication of gynecologic oncologic surgery. • The inferior vena cava was the most common site of injury. • Lymph node dissection was the most common time for a vascular injury to occur. • Suture repair or ligation was required to adequately resolve the majority of vascular injuries., Objective Vascular injury during major gynecologic cancer surgery is a rare but potentially fatal complication. The purpose of this study was to review our experience with major vascular injury during gynecologic cancer surgery. Methods This was a retrospective chart review of women undergoing surgery by our gynecologic oncology department from 7/1/99 to 6/30/20 who had a major vascular injury. We identified women who sustained a vascular injury by a combination of CPT code and medical record searches, fellow case logs and a list maintained for an ongoing quality assurance program. Data were expressed as median and range for continuous variables and as frequency and percentage for categorical variables. Fisher’s exact test was used to analyze differences in complication rates between groups. Results Major vascular injury was identified in 52 patients and procedures. The inferior vena cava was the most common site of injury, 32.7% (17/52), followed by the external iliac vein, 23.1% (12/52). Lymph node dissection was the most common time for a vascular injury to occur 51.9% (27/52). The majority of injuries required suture repair, 80.8% (42/52). Estimated blood loss in cases with vascular injury ranged from 100 mL to massive unquantifiable blood loss in the case of an aortic injury. Patients required a median of 2units of packed red blood cells. Postoperative complications included anemia requiring blood transfusion, 19.6% (9/46) and venous thromboembolism, 19.6% (9/46). Conclusions Vascular injury remains a rare but potentially morbid complication of gynecologic oncologic surgery. Prompt recognition and management are imperative in minimizing persistent bleeding and complications.

To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer.This multicenter retrospective study examined women aged50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy.During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged.Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

ObjectivesTo determine if linear measurements of adiposity from pre-operative imaging can improve anticipation of surgical difficulty among endometrial cancer patients.MethodsEighty patients with newly diagnosed endometrial cancer were enrolled. Routine pre-operative imaging (MRI or CT) was performed. Radiologic linear measurements of the following were obtained: anterior-to-posterior skin distance; anterior skin to anterior edge of L5 distance (total anterior); anterior peritoneum to anterior edge of L5 distance (visceral obesity); and posterior edge of L5 to posterior skin distance (total posterior). Surgeons completed questionnaires quantifying preoperative anticipated operative difficulty and postoperative reported operative difficulty. The primary objective was to assess for a correlation between linear measurements of visceral fat and reported operative difficulty.ResultsSeventy-nine patients had questionnaires completed, preoperative imaging obtained, and surgery performed. Univariate analysis showed all four linear measurements, body mass index, weight, and anticipated operative difficulty were associated with increased reported operative difficulty (P< 0.05). Multivariate analysis demonstrated that body mass index and linear measurements visceral obesity and total posterior were independently associated with increased reported operative difficulty (P< 0.05). Compared with body mass index, the visceral obesity measurement was more sensitive and specific for predicting increased reported operative difficulty (visceral obesity; sensitivity 54%, specificity 91 %; body mass index; sensitivity 38%, specificity 89%). A difficulty risk model combining body mass index, visceral obesity, and total posterior demonstrated better predictive performance than any individual preoperative variable.ConclusionsSimple linear measurements of visceral fat obtained from preoperative imaging are more predictive than body mass index alone in anticipating surgeon-reported operative difficulty. These easily obtained measurements may assist in preoperative decision making in this challenging patient population.

OBJECTIVE. The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS. This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I–IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS. Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36–2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39–2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION. In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.

OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P < 0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P = 0.02). When stratified by disease-free interval, women with a disease-free interval ≥6 months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P = 0.002); conversely, in women with a disease-free interval

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare and commonly characterized as benign tumors, with infrequent reports of metastasis and recurrence. Treatment recommendations have not been well established, particularly for more advanced cases. We present the first reported death from a metastatic UTROSCT, summarize the available literature, and describe characteristics common to UTROSCTs with aggressive features. In this case, a 49-year-old woman presented with abdominal distension and pain; initial imaging and diagnostic workup suggested metastatic epithelial ovarian cancer to be the cause. The patient subsequently underwent neoadjuvant chemotherapy followed by optimal cytoreductive surgery and adjuvant chemotherapy. Final pathology revealed UTROSCT with omental and peritoneal metastases. She then underwent adjuvant chemotherapy with subsequent recurrence and died 15 months after her initial diagnosis. Our analysis of this case and the available literature led us to identify pathologic risk factors that may help predict aggressive UTROSCT behavior., Highlights • Uterine tumors resembling ovarian sex cord tumors are rare and generally considered benign. • Few aggressive/metastatic cases have been reported, and we report on the first death from this disease. • Analysis of the literature allowed for identification of potential pathologic risk factors of aggressive disease. • Better identifying these risk factors could help guide treatment recommendations for this tumor type.

Introduction To evaluate clinical outcomes, pattern of failure, and toxicity after high-dose intensity-modulated radiation therapy (IMRT) for advanced vulvar cancer. Methods In this IRB approved retrospective study, the charts of women with histologically confirmed, non-metastatic vulvar cancer consecutively treated at our institution from 2012 to 2018 were reviewed to identify patients that received high-dose IMRT with curative intent. The treatment compliance, toxicities, and patterns of failure were investigated. Actuarial local, regional and distant recurrence and survival were estimated using Kaplan-Meier method and compared using log rank test. Results Twenty-six patients were identified, 23 were unresectable, and 3 refused surgery. Fifteen patients (58%) had inguinal node metastases; 10(38%) had pelvic node metastases. Elective surgical staging of groins was performed in 9-patients. Median tumor dose was 65.4Gy. Concurrent platinum-based chemotherapy was administered in 22(84.6%) patients. Complete response (CR) was achieved in 21/26 (80.7%) patients. Five patients had persistent disease following treatment and one sustained recurrence 5-months following radiotherapy. All persistent or recurrent disease occurred inside the irradiated volume. Median follow-up was 19 months (3–52 months). Actuarial 1-year local, regional and distant controls were 72.4%, 85.4%, and 86%, respectively. One and 2-year overall survivals were 91% and 62%, respectively. Complete response at 3-months was a strong predictor for overall survival (1-yr OS 73% vs 27%, HR 7.1 (95% CI 1.2–44); p = 0.01). Lymph node metastases adversely affected overall survival (2-yr OS 49% vs. 83%, p = 0.09). Grade 3–4 late urinary and soft-tissue toxicity was seen in 5 patients. Tumor doses >66 Gy (p = 0.03) and prior pelvic radiotherapy (p = 0.002) predicted grade 3–4 toxicity. Conclusion High-dose IMRT for vulvar cancer achieves high rates of local control with acceptable dose dependent long-term toxicity.

e17553 Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics and treatment tolerance limit the dosing of chemotherapy. And/or changes in tumor and host-tumor biology limit treatment efficacy. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin(C) AUC 5 every 3 weeks and paclitaxel(P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Total muscle mass, total fat mass, skeletal muscle index (SMI) and fat index were computed. Plasma concentrations were collected at pre-established time points for both C1D1 of C and P and concentration-time data was analyzed by non-compartmental methods. Area under the curve (AUC)0-INF, volume of distribution(Vd), clearance (Cl), half-life, and mean residence time were calculated. Free C concentrations were determined in plasma ultrafiltrate and assayed, along with P plasma concentrations, by liquid chromatography-tandem mass spectrometry. Toxicity was assessed as first cycle nadir ANC and G4 hematologic(H) or grade 3-4 non-hematologic(NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible. All patients but one received 3 cycles of chemotherapy and median dose intensity was 100% (range 33.3-100%). Mean 1st cycle nadir ANC was 1.29 (range 0.06-9.0). 10/17 (59%) patients experienced G4 H and/or G3-4 NH toxicity. SMI was associated with C AUC (r -0.50, p < 0.05), and both total muscle (r = 0.61) and total fat (r = 0.53) were associated with C Vd. We did not find a correlation of P pharmacokinetics with body composition. A lower SMI was associated with 1st cycle G4H toxicity (p = 0.02), while C AUC had a borderline trend only (p = 0.15). Age was associated with a lower Vd (r -0.63, p = 0.009) and Cl (r -0.67, p = 0.004) of C. There was no significant age trend in the body composition parameters. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Toxicity appeared driven by low skeletal muscle index, in part via affecting carboplatin pharmacokinetics, and showed no significant age trend. The explanation for age-related changes in prognosis is more likely to lay with changes in tumor and host-tumor biology, which are being analyzed.

Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy.In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes.Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA.Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA.

OBJECTIVE: To examine clinico-pathological characteristics and outcomes of uterine carcinosarcoma (UCS) in women aged ≥80 years. METHODS: This is a secondary analysis of a previous multicenter retrospective study examining 906 women with stage I–IV UCS who underwent primary hysterectomy. Patient demographics, treatment types, tumor characteristics, and survival were examined across aged ≥80 (n = 82 [9.1%]), aged 60–79, (n = 526 [58.1%]), and aged < 60 (n = 298 [32.9%]). RESULTS: Women in the aged ≥80 group were more likely to be Caucasian, undergo simple hysterectomy without lymphadenectomy, and receive no postoperative therapy (all, P < 0.05). Tumors in the aged ≥80 group were more likely to have high-grade carcinoma, heterologous sarcoma, and sarcoma dominance but less likely to have lympho-vascular space invasion (all, P < 0.05). Lymphadenectomy did not improve survival in the aged ≥80 group (P > 0.05), whereas lymphadenectomy was protective for survival in the younger groups (both, P < 0.05). Postoperative chemotherapy was associated with improved progression-free survival (PFS) in the aged ≥80 group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22–0.89, P = 0.021). With chemotherapy treatment, women in the aged ≥80 group had PFS similar to those in the aged 60–79 group (HR 0.97, 95%CI 0.51–1.83, P = 0.92). In contrast, without chemotherapy treatment, women in the aged ≥80 group had significantly decreased PFS compared to the aged 60–79 group (HR 1.62, 95%CI 1.09–2.40, P = 0.016). Similar associations were observed for postoperative radiotherapy. CONCLUSION: Nearly 10% of women with UCS are aged ≥80 that are characterized by aggressive tumor factors. Postoperative therapy but not extensive surgery may improve survival in this age group.

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

OBJECTIVE: To examine significance of sarcoma dominance (SD) patterns In uterine carcinosarcoma (UCS). METHODS: This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. RESULTS: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35–1.69, and hetero/dominance 1.47–1.64) and CSS (adjusted-HR ranges: 1.52–1.84 and 1.66–1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). CONCLUSION: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy.

Uterine carcinosarcoma (UCS) is a rare type of high-grade endometrial cancer (EC) that has been understudied with population-based statistics due to its rarity. This study examined temporal trends in the proportion of UCS among women with EC.This is a retrospective observational study examining The Surveillance, Epidemiology, and End Results program between 1973-2013. Primary EC cases were eligible for analysis, and a time-specific proportion of UCS was examined during the study period.UCS was seen in 11,000 (4.7%) women among 235,849 primary EC cases. Mean age at UCS diagnosis increased from 65.9 to 71.7 years between 1973-1989 and then decreased from 71.7 to 67.0 years between 1989-2013 (both, p0.001). Proportion of Black women significantly increased during the study period (11.9%-20.0%, p0.001), whereas the proportion of White women decreased from 86.0% to 60.5% between 1987-2013 (p0.001). There was a significant increase in the proportion of UCS among primary EC from 1.7% to 5.6% between 1973-2013 (p0.001). Among type II ECs (n=76,118), the proportion of UCS also increased significantly from 6.0% to 17.5% between 1973-2013 (p0.001). An increasing proportion of UCS was seen in both young and older women but the magnitude of interval increase was larger in the older age group between 1973-2013 (60 years, from 1.3% to 3.3%. p0.001; and ≥60 years, from 2.6% to 7.0%, p0.001).Our study demonstrated that the proportion of UCS has significantly increased among EC, accounting for more than 5% in recent years.

Sister Mary Joseph's nodule is sometimes the first sign of an internal malignancy, including gastrointestinal, gynecological, or malignancy of unknown primary. It is rarely the sole presentation of a primary peritoneal cancer. In this report, we present the case of a 70-year-old female with umbilical drainage and a computed tomography scan consistent with solitary umbilical nodule. Excision of the nodule revealed adenocarcinoma of likely müllerian origin. Surgical staging did not show any evidence of malignancy with the exception of pelvic washings. She was considered to have primary peritoneal adenocarcinoma and was treated with adjuvant chemotherapy.

Background and Objectives To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. Methods This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. Results The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. Conclusion Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.

Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers. Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated. Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles. Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle. ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

Summary: Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates the development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis. In contrast to its antagonistic effects on tumor angiogenesis, EGFL6 blockage did not affect normal wound healing. These findings have significant implications for development of anti-angiogenesis therapies. : Noh et al. identify EGFL6 as an angiogenic target that is selectively present in tumor endothelial cells in a hypoxic tumor microenvironment. EGFL6 blockade exerts robust anti-angiogenic and anti-tumor effects without affecting wound healing. These findings suggest an important approach for effectively targeting tumor angiogenesis. Keywords: tumor endothelial cells, ovarian cancer, chitosan nanoparticles, tumor vasculature, wound healing

5534 Background: Cervical cancer remains a global health challenge particularly in low to middle income countries with under resourced healthcare systems. We present the experiences of two centers practicing in variable resource environments to determine predictors of improved radiochemotherapy outcomes. Methods: This retrospective review describes baseline demographic and clinicopathologic characteristics of cervical cancer patients treated with concurrent chemotherapy and radiation between 2014 and 2017 at the National Radiotherapy Oncology and Nuclear Medicine Center (NRONMC) in Korle Bu Teaching Hospital, Accra, Ghana and Moffitt Cancer Center, Tampa, Florida, USA. Results: Ghanaian patients presented at an older median age (56 vs. 49 years, p < 0.001), with predominantly stage IIIB disease (43% vs. 16%, p < 0.001) and squamous cell histology (89% vs. 79%, p < 0.001). Median treatment duration was longer for Ghanaian patients (58 vs. 52 days, p < 0.001). Ghanaian patients were less likely to receive concurrent chemotherapy (68% vs. 100%, p < 0.001) and interstitial brachytherapy implants (0 vs 19%, p < 0.001). No Ghanaian patients received a radiation boost to pelvic or paraortic lymph nodes (p < 0.001). Ghanaian patients had lower local control (64% vs. 93%, p < 0.001) and overall survival (82% vs. 95%, p = 0.02) at 24 months, respectively. For stages IB, IIA, IIB, IIIB, 24 month local control rates for NRONMC vs. Moffitt patients were (60% vs. 93%; p = 0.05), (89% vs. 100%; p = 0.35), (91% vs. 91%; p = 0.89), (53% vs. 91%; p = 0.02) and 24 month OS rates were (85% vs. 100%; p = 0.06), (100% vs. 100%; p = 0.48), (85% vs. 96%; p = 0.2), (73% vs. 91%; p = 0.24), respectively. Treatment duration > 55 days predicted poorer overall survival on multivariable analysis (MVA). Stage ≥III disease predicted poorer local control on MVA. Conclusions: Significant differences were noted in treatment and disease characteristics between the two centers. Feasible improvements for patients treated at NRONMC include removing financial barriers to chemotherapy access, improving radiotherapy delivery capacity to reduce treatment delays, and screening programs to reduce advanced disease presentation.

TPS5596 Background: There is no consistent recommendation for management of metastatic cervical cancer beyond first line therapy with chemotherapy and bevacizumab. Pembrolizumab is now approved for PD-L1 positive or MSI-H/dMMR metastatic or recurrent cervical cancer. Numerous pre-clinical studies have provided evidence to combine radiation therapy with immune checkpoint inhibition to improve response rates. The evidence is strongest for short course, hypofractionated radiation regimens. We hypothesize treatment with atezolizumab with hypofractionated radiation therapy will improve objective response rate (ORR) compared with atezolizumab alone in patients with recurrent, persistent, or metastatic cervical cancer. Methods: The study is designed as a prospective, single arm, nonrandomized, open-label, phase II trial of stereotactic body radiation therapy (SBRT) with 24 Gy in 3 fractions to patients with ≥ 2 metastatic sites followed 1 week later by atezolizumab (1200 mg IV every 3 weeks) for patients with recurrent, persistent, or metastatic cervical cancer. Dose reductions will not be allowed. The primary objective of the study is to evaluate the ORR by Immune-Modified Response Evaluation Criteria in Solid Tumors (irRECIST) criteria following SBRT and atezolizumab. Secondary endpoints include progression free survival, overall survival, local control, and adverse events. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, mutation burden, TCR repertoire etc.) for association with clinical benefit. A total of 26 patients will be enrolled. An interim analysis will be performed to assess efficacy after 13 patients become evaluable.This study is open with 2 patients enrolled at the time of submission. Clinical trial information: NCT03614949.

OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I–IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P < 0.001) and had a past history of malignancy (100% versus 12.7%, P < 0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P = 0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P = 0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P = 0.48) and disease-specific survival (64.0% versus 59.1%, P =0.39).After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P =0.60)anddisease-specific survival(adjusted-hazard ratio0.68,95% confidence interval 0.36 to 1.29, P = 0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

Objective To quantify the impact of perioperative β blocker use on survival after primary cytoreductive surgery for epithelial ovarian cancer. Methods We conducted a multi-center retrospective study of all women who underwent primary cytoreductive surgery for ovarian cancer (2000 − 2010). One institution had routinely used perioperative β blockers for patients “at risk” for coronary events. The other institution did not routinely use perioperative β blockers. Demographic, operative, and follow up data were collected. Cox proportional hazards models were used to assess the effect of β blockers on progression-free interval (PFI) as well as overall survival (OS). Results Out of 185 eligible patients, 70 received β blockers and 115 underwent cytoreductive surgery without perioperative β blockers. Both groups were similar in demographics. A history of hypertension was present more often in the β blocker group compared to the group that did not receive β blockers (22% and 6%, p = 0.002). PFI in β blocker group was greater at 18.2 vs. 15.8 months (p = 0.66). The OS in the β blocker group was significantly higher at 44.2 vs. 39.3 months (p = 0.01). In multivariate analysis, perioperative β blocker use was associated with significant improvement in OS (HR 0.68 (0.46–0.99); p = 0.046). Conclusion Our study showed an association between perioperative β blocker use and longer overall survival in patients undergoing primary ovarian cancer cytoreductive surgery. A prospective randomized clinical trial in this population would further validate these results.

The aim of this study was to review treatment and outcomes for neuroendocrine tumors (NETs) of the cervix at a National Cancer Institute–designated Comprehensive Cancer Center. Data for women with NET of the cervix treated at our institution, since 1999, were collected. Progression-free survival (PFS) and overall survival (OS) were assessed with respect to age, tumor size, tobacco use, lymph node status, stage of disease, and type of treatment. Among 18 patients (median age, 44 years), 9 (50%) had tumors larger than 5 cm and advanced-stage disease (IB2-IV). Seven recurrences were noted (39%). Median PFS was not reached, and median OS was 72.2 months. Surgery was the only factor significantly associated with both PFS and OS (3-year PFS, 90% vs 30%, P = 0.01; 3-year OS: 89% vs 18%, P = 0.019). Age 40 years or younger and absence of lymph node metastases correlated significantly with PFS, with a trend toward improved OS. Recurrences were less likely with stage IA to IB1 compared with stages IB2 to IVA and IVB (hazards ratio, 0.33; P = 0.054), with median OS of 72.2, 19.2, and 7.4 months, respectively (P = 0.002). Although patients with tumors 4 cm or smaller had better outcomes, this factor did not reach statistical significance. Chemotherapy, radiation therapy, and tobacco use were not associated with survival. Neuroendocrine tumors of the cervix present at a relatively young age, with bulky tumors and advanced-stage disease. Surgery, younger age, smaller tumor size, early stage, and absence of lymph node involvement seem to be associated with improved survival. Nonetheless, optimal management is yet to be determined, and multimodality treatment is advocated.

Purpose: Surgical stress has been suggested to facilitate the growth of preexisting micrometastases as well as small residual tumor postoperatively. The purpose of this study was to examine the effects of surgical stress on ovarian cancer growth and to determine underlying mechanisms responsible for increased growth. Experimental Design: To mimic the effects of surgery, we did a laparotomy or mastectomy under isoflurane inhalation on athymic nude mice 4 days after i.p. tumor cell injection. Propranolol infusion via Alzet pumps was used to block the influence of sympathetic nervous system activation by surgical stress. Results: In both HeyA8 and SKOV3ip1 models, the mice in the laparotomy and mastectomy groups had significantly greater tumor weight (P < 0.05) and nodules (P < 0.05) compared with anesthesia only controls. There was no increase in tumor weight following surgery in the β-adrenergic receptor–negative RMG-II model. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for β-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment. Conclusion: These results indicate that surgical stress could enhance tumor growth and angiogenesis, and β-blockade might be effective in preventing such effects.

BACKGROUND: Research suggests that glucose levels in cancer patients may be an important prognostic indicator. In ovarian tumors, increased expression of glucose transporter 1 (GLUT1), a transmembrane protein responsible for glucose uptake, is related to shorter survival time in ovarian cancer patients. This study tested the hypothesis that higher presurgical glucose levels predict shorter disease-specific survival time and time to recurrence in ovarian cancer patients. METHODS: Nonfasting plasma glucose levels were determined for 74 patients with ovarian cancer at the time of their presurgical consultation and for 125 ovarian cancer patients in an independent validation set. Survival time and time to recurrence (disease-free interval [DFI]) were ascertained from medical records. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) for survival time and DFI in relation to glucose level, adjusting for body mass index (BMI), stage, grade, and cytoreduction as appropriate. RESULTS: Higher glucose levels were associated with shorter survival times in univariate analyses (HR, 1.88; P = .05). Multivariate analysis adjusting for stage showed that higher glucose levels were associated with shorter survival times (HR, 2.01; P = .04) and DFI (HR, 2.32; P = .05). In the validation set, higher glucose levels were associated with shorter survival times (HR, 2.01; P = .02) and DFI (HR, 2.48; P = .001) in univariate analysis, although glucose was not independent of the effect of cytoreduction when predicting survival time in this latter set. CONCLUSIONS: These findings contribute to mounting evidence that glucose levels have prognostic value in ovarian carcinoma. Cancer 2009. © 2009 American Cancer Society.

Androgen insensitivity syndrome (AIS) is a disease that can be X-linked recessive or sporadic in nature. Patients with complete AIS are phenotypically female individuals with an XY genotype. During embryonic development, the testicular tissue present in patients with AIS produces Mullerian Inhibiting Substance, which blocks the development of the upper one third of the vagina, uterus and ovaries, while a lack of androgen receptors results in female-appearing external genitalia. Complete AIS patients tend to present as amenorrheic females during adolescence. This case report presents a unique situation in which a public health screening campaign, for abdominal aortic aneurysms, led to an incidental finding and work-up resulting in two separate, yet related diagnoses: androgen insensitivity syndrome (AIS) and sertoli cell adenoma. This case also highlights the importance of a comprehensive physical examination with emphasis on wide differential diagnosis. It underscores the importance of considering the complicated ethics surrounding patient disclosure when dealing with a sensitive diagnosis.

BACKGROUND: While there is an increasing trend of ovarian conservation at the time of surgical treatment for young women with stage I cervical cancer, the risk for subsequent ovarian cancer after ovarian conservation has not been well studied. OBJECTIVE: We sought to examine the incidence of and risk factors for metachronous ovarian cancer among young women with stage I cervical cancer who had ovarian conservation at the time of hysterectomy. STUDY DESIGN: The Surveillance, Epidemiology, and End Results Program was used to identify women aged

Background: A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M.D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in patients with ovarian cancer. Methods: Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n = 271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival. Results: Of the nine cardiovascular events tracked during follow-up, venous thromboembolism [VTE; HR, 3.2; 95% confidence interval (CI), 1.8–5.5] and pulmonary hypertension (HR, 8.5; 95% CI, 3.9–18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (HR, 1.02; 95% CI, 1.01–1.04) were related to decreased survival. Conclusion: Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer. Impact: Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE, and pulmonary hypertension in conjunction with cancer therapy. Cancer Epidemiol Biomarkers Prev; 22(11); 2102–9. ©2013 AACR.

Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P=0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.

TPS5612Background: Recurrent epithelial ovarian, fallopian, and peritoneal cancer (EOC) is the leading cause of gynecologic cancer death. EOC is an immunogenic tumor and infiltrating lymphocytes ex...

To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer.All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain.There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002).Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer.

Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib and oxaliplatin may be an attractive approach for this disease. Clin Cancer Res; 17(16); 5367–78. ©2011 AACR.

This study aimed to investigate the antitumor and antiangiogenic effects utilizing a novel therapy regimen of metronomic topotecan and pazopanib, a multireceptor tyrosine kinase inhibitor. In vitro (Western blot) and in vivo dose-finding experiments were done following pazopanib therapy in ovarian cancer models. Pazopanib and metronomic (daily) oral topotecan therapy was examined in an orthotopic model of ovarian cancer. Tumor weights, survival, and markers of the tumor microenvironment [angiogenesis (CD31 and pericyte coverage), proliferation (Ki-67), and apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling)] were analyzed by immunostaining following therapy. Pazopanib therapy reduced vascular endothelial growth factor receptor 2 (VEGFR-2) activity in vitro and vivo in a dose-dependent manner. Compared with control mice, pazopanib reduced tumor weight by 28% to 82% (P < 0.01 in the SKOV3ip1 model) and metronomic topotecan reduced tumor weight by 40% to 59% in the HeyA8 (P = 0.13) and SKOV3ip1 (P = 0.07) models. Combination therapy had the greatest effect with 79% to 84% reduction (P < 0.01 for both models). In the SKOV3ip1 and A2780 models, mouse survival was significantly longer (P < 0.001 versus controls) with pazopanib and metronomic topotecan therapy. Pazopanib therapy reduced murine endothelial cell migration in vitro in a dose-dependent manner following VEGF stimulation and decreased tumor microvessel density and pericyte coverage when given in combination with metronomic topotecan. Tumor cell proliferation decreased in all treatment arms compared with controls (P < 0.01 for combination groups) and increased tumor cell apoptosis by 4-fold with combination therapy. Pazopanib therapy in combination with metronomic topotecan therapy showed significant antitumor and antiangiogenic properties in preclinical ovarian cancer models and warrants further investigation as a novel therapeutic regimen in clinical trials. Mol Cancer Ther; 9(4); 985–95. ©2010 AACR.