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1.  Conversion from robotic surgery to laparotomy: A case-control study evaluating risk factors for conversion 
Gynecologic oncology  2014;134(2):238-242.
Objectives
To determine risk factors associated with conversion to laparotomy for women undergoing robotic gynecologic surgery.
Methods
The medical records of 459 consecutive robotic surgery cases performed between December 2006 and October 2011 by 8 different surgeons at a single institution were retrospectively reviewed. Cases converted to laparotomy were compared to those completed robotically. Descriptive statistics were used to summarize the demographic and clinical characteristics.
Results
Forty of 459 (8.7%, 95% CI 6.3%-11.7%) patients had conversion to open surgery. Reason for conversion included poor visualization due to adhesions (13), inability to tolerate Trendelenburg (7), enlarged uterus (7), extensive peritoneal disease (5), bowel injury (2), ureteral injury (1), vascular injury (1), bladder injury (1), technical difficulty with the robot (2), and inability to access abdominal cavity (1). 5% of cases were converted prior to docking the robot. On univariate analysis preoperative diagnosis (p=0.012), non-White race (p=0.004), history of asthma (p=0.027), ASA score (p=0.032), bowel injury (p=0.012), greater BMI (p<0.001), need for blood transfusion (p<0.001), and expected blood loss (p<0.001) were associated with conversion. On multivariate analysis, non-White race (OR 2.88, 95% CI 1.39-5.96, p=0.004), bowel injury (OR 35.40, 95% CI 3.00-417.28, p=0.005), and increasing BMI (OR 1.06, 95% CI 1.03-1.09, p<0.001) were significantly associated with increased risk for conversion. Prior surgery was not associated with conversion to open surgery (p=0.347).
Conclusion
Conversion to laparotomy was required for 8.7% of patients undergoing robotic surgery for a gynecologic indication. Increasing BMI and non-white race were identified as the two preoperative risk factors associated with conversion.
doi:10.1016/j.ygyno.2014.06.008
PMCID: PMC4125462  PMID: 24937481
2.  Consequences of Universal MSI/IHC in Screening Endometrial Cancer Patients for Lynch Syndrome 
Gynecologic oncology  2014;134(2):319-325.
Objective
Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer.
Methods
The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6, or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing.
Results
In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome. 42% were seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome. 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel, and limited insurance coverage.
Conclusions
There are several barriers to genetic counseling and testing follow up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.
doi:10.1016/j.ygyno.2014.06.009
PMCID: PMC4125501  PMID: 24933100
3.  Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer1 
Gynecologic oncology  2014;134(2):346-355.
OBJECTIVE
Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells.
METHODS
Cell proliferation in the ECC-1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay. Apoptosis and cell cycle were detected by Annexin V assay and propidium iodide staining, respectively. Reactive oxygen species and cell adhesion were assessed using ELISA assays. Invasion was analyzed using a transwell invasion assay. Mitochondrial DNA damage was confirmed using qPCR. The effects of simvastatin on the AKT/mTOR and MAPK pathways were determined by Western blotting.
RESULTS
Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells. Simvastatin treatment resulted in G1 cell cycle arrest, a reduction in the enzymatic activity of HMG-CoA, induction of apoptosis as well as DNA damage and cellular stress. Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT/mTOR pathway in the ECC-1 and Ishikawa cells. Minimal change in AKT phosphorylation was seen in both cell lines. An increase in phosphorylated S6 was seen in ECC-1 and a decrease was seen in Ishikawa. Treatment with simvastatin reduced cell adhesion and invasion (p<0.01) in both cell lines.
CONCLUSION
Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells, possibly through modulation of the MAPK and AKT/mTOR pathways, suggesting that statins may be a promising treatment strategy for endometrial cancer.
doi:10.1016/j.ygyno.2014.05.015
PMCID: PMC4125536  PMID: 24880141
endometrial cancer; statins; simvastatin; MAPK pathway; AKT/mTOR pathway; invasion
4.  A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients 
Gynecologic oncology  2014;134(2):233-237.
Objectives
Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications.
Methods
Women with a body mass index (BMI)≥30kg/m2 undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7mm Jackson-Pratt drain below Camper’s fascia, closure of Camper’s fascia with 3-0 plain catgut suture and skin closure with staples.
Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway.
Results
105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30–39.9 kg/m2 had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m2 (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI<40kg/m2 (OR 0.40, 95% C.I.: 0.18–0.89).
Conclusion
This surgical protocol lead to a decreased rate of wound complications among women with BMI 30–39.9 kg/m2.
doi:10.1016/j.ygyno.2014.06.012
PMCID: PMC4157586  PMID: 24952366
5.  Minimally invasive surgery for endometrial cancer: Does operative start time impact surgical and oncologic outcomes? 
Gynecologic oncology  2014;134(2):248-252.
Objective
Recent literature in ovarian cancer suggests differences in surgical outcomes depending on operative start time. We sought to examine the effects of operative start time on surgical outcomes for patients undergoing minimally invasive surgery for endometrial cancer.
Methods
A retrospective review was conducted of patients undergoing minimally invasive surgery for endometrial cancer at a single institution between 2000 and 2011. Surgical and oncologic outcomes were compared between patients with an operative start time before noon and those with a surgical start time after noon.
Results
A total of 380 patients were included in the study (245 with start times before noon and 135 with start times after noon). There was no difference in age (p=0.57), number of prior surgeries (p=0.28), medical comorbidities (p=0.19), or surgical complexity of the case (p=0.43). Patients with surgery starting before noon had lower median BMI than those beginning after noon, 31.2 vs. 35.3 respectively (p=0.01). No significant differences were observed for intraoperative complications (4.4% of patients after noon vs. 3.7% of patients before noon, p=0.79), estimated blood loss (median 100 cc vs. 100 cc, p=0.75), blood transfusion rates (7.4% vs. 8.2%, p=0.85), conversion to laparotomy (12.6% vs. 7.4%, p=0.10). There was no difference in operative times between the two groups (198 minutes vs. 216.5 minutes, p=0.10). There was no association between operative start time and postoperative non-infectious complications (11.9% vs. 11.0%, p=0.87), or postoperative infections (17.8% vs. 12.3%, p=0.78). Length of hospital stay was longer for surgeries starting after noon (median 2 days vs. 1 day, p=0.005). No differences were observed in rates of cancer recurrence (12.6% vs. 8.8%, p=0.39), recurrence-free survival (p=0.97), or overall survival (p=0.94).
Conclusion
Our results indicate equivalent surgical outcomes and no increased risk of postoperative complications regardless of operative start time in minimally invasive endometrial cancer staging, despite longer length of hospital stay for surgeries beginning after noon.
doi:10.1016/j.ygyno.2014.06.007
PMCID: PMC4286393  PMID: 24945591
6.  An ex vivo assay of XRT-induced Rad51 foci formation predicts response to PARP-inhibition in ovarian cancer 
Gynecologic oncology  2014;134(2):331-337.
Objective
BRCA-positive ovarian cancer patients derive benefit PARP inhibitors. Approximately 50% of ovarian cancer tumors have homologous recombination (HR) deficiencies and are therefore “BRCA-like,” possibly rendering them sensitive to PARP inhibition. However, no predictive assay exists to identify these patients. We sought to determine if irradiation-induced Rad51 foci formation, a known marker of HR, correlated to PARP inhibitor response in an ovarian cancer model.
Methods
Ovarian cancer cell lines were exposed to PARP-inhibitor ABT-888 to determine effect on growth. Rad51 protein expression prior to irradiation was determined via Western blot. Cultured cells and patient-derived xenograft tumors (PDX) were irradiated and probed for Rad51 foci. In vivo PDX tumors were treated with ABT-888 and carboplatin; these results were correlated with the ex vivo ionizing radiation assay.
Results
Three of seven cell lines were sensitive to ABT-888. Sensitive lines had the lowest Rad51 foci formation rate after irradiation, indicating functional HR deficiency. Approximately 50% of the PDX samples had decreased Rad51 foci formation. Total Rad51 protein levels were consistently low, suggesting that DNA damage induction is required to characterize HR status. The ex vivo IR assay accurately predicted which PDX models were sensitive to PARP inhibition in vitro and in vivo. ABT-888 alone reduced orthotopic tumor growth by 51% in A2780ip2 cell line, predicted to respond by the ex vivo assay. Three PDX models' response also correlated with the assay.
Conclusions
The ex vivo IR assay correlates with response to PARP inhibition. Analysis of total Rad51 protein is not a reliable substitute.
doi:10.1016/j.ygyno.2014.05.009
PMCID: PMC4221419  PMID: 24844596
Ovarian cancer; PARP inhibitor; Homologous recombination deficiency; Rad51
7.  Physician pain and discomfort during minimally invasive gynecologic cancer surgery 
Gynecologic oncology  2014;134(2):243-247.
Objective
Despite increasing awareness of physical strain to surgeons associated with minimally invasive surgery (MIS), its use continues to expand. We sought to gather information from gynecologic oncologists regarding physical discomfort due to MIS.
Methods
Anonymous surveys were e-mailed to 1,279 Society of Gynecologic Oncology (SGO) members. Physical symptoms (numbness, pain, stiffness, and fatigue) and surgical and demographic factors were assessed. Univariate and multivariate analyses were performed to determine risk factors for physical symptoms.
Results
We analyzed responses of 350 SGO members who completed the survey and currently performed >50% of procedures robotically (n=122), laparoscopically (n=67), or abdominally (n=61). Sixty-one percent of members reported physical symptoms related to MIS. The rate of symptoms was higher in the robotic group (72%) than the laparoscopic (57%) or abdominal group (49%) (p=0.0052). Stiffness (p=0.0373) and fatigue (p=0.0125) were more common in the robotic group. Female sex (p<0.0001), higher caseload, (p=0.0007) and academic practice (p=0.0186) were associated with increased symptoms. On multivariate analysis, robotic surgery (odds ratio [OR] 2.38, 95% CI 1.20-4.69) and female sex (OR 4.20, 95% CI 2.13-8.29) were significant predictors of symptoms. There was no correlation between seeking treatment and surgical modality (laparotomy 11%, robotic 20%, laparoscopy 25%, p= 0.12).
Conclusions
Gynecologic oncologists report physical symptoms due to MIS at an alarming rate. Robotic surgery and female sex appear to be risk factors for physical discomfort. As we strive to improve patient outcomes and decrease patient morbidity with MIS, we must also work to improve the ergonomics of MIS for surgeons.
doi:10.1016/j.ygyno.2014.05.019
PMCID: PMC4265466  PMID: 24887354
laparoscopy; robotic surgery; laparo-endoscopic single-site surgery (LESS); pain; numbness; discomfort; fatigue
8.  Can you ask? We just did! Assessing sexual function and concerns in patients presenting for initial gynecologic oncology consultation 
Gynecologic oncology  2015;137(1):119-124.
Objectives
To describe patterns of response to, and assess sexual function and activity elicited by, a self-administered assessment incorporated into a new patient intake form for gynecologic oncology consultation.
Methods
A cross-sectional study of patients presenting to a single urban academic medical center between January 2010 and September 2012. New patients completed a self-administered intake form, including six brief sexual activity and function items. These items, along with abstracted medical record data, were descriptively analyzed. Logistic regression was used to assess the association between sexual activity and function and disease status, adjusting for age.
Results
Median age was 50 years (range 18–91, N = 499); more than half had a final diagnosis of cancer. Most patients completed all sex-related items on the intake form; 98% answered at least one. Among patients who were sexually active in the prior 12 months (57% with cancer, 64% with benign disease), 52% indicated on the intake form having, during that period, a sexual problem lasting several months or more. Of these, 15% had physician documentation of the sexual problem. Eighteen women were referred for care. Providers reported no patient complaints about the inclusion of sexual items on the intake form.
Conclusions
Nearly all new patients presenting for gynecologic oncology consultation answered self-administered items to assess sexual activity and function. Further study is needed to determine the role of pretreatment identification of sexual function concerns in improving sexual outcomes associated with cancer diagnosis and treatment.
doi:10.1016/j.ygyno.2015.01.451
PMCID: PMC4518539  PMID: 25582823
Gynecologic neoplasms; Sexuality; Sexual function
9.  Patterns of Care, Predictors, and Outcomes of Chemotherapy in Elderly Women with Early-Stage Uterine Carcinosarcoma: A Population-Based Analysis 
Gynecologic oncology  2014;133(2):242-249.
Objective
To examine the patterns of care, predictors, and impact of chemotherapy on survival in elderly women diagnosed with early-stage uterine carcinosarcoma.
Methods
The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify women 65 years or older diagnosed with stage I-II uterine carcinosarcoma from 1991 through 2007. Multivariable logistic regression and Cox-proportional hazards models were used for statistical analysis.
Results
A total of 462 women met the eligibility criteria; 374 had stage I, and 88 had stage II uterine carcinosarcoma. There were no appreciable differences over time in the percentages of women administered chemotherapy for early stage uterine carcinosarcoma (14.7% in 1991–1995, 14.9% in 1996–2000, and 17.9% in 2001–2007, P=0.67). On multivariable analysis, the factors positively associated with receipt of chemotherapy were younger age at diagnosis, higher disease stage, residence in the eastern part of the United States, and lack of administration of external beam radiation (P<0.05). In the adjusted Cox-proportional hazards regression models, administration of three or more cycles of chemotherapy did not reduce the risk of death in stage I patients (HR: 1.45, 95% CI: 0.83–2.39) but was associated with non-significant decreased mortality in stage II patients (HR: 0.83, 95% CI: 0.32–1.95).
Conclusions
Approximately 15–18% of elderly patients diagnosed with early-stage uterine carcinosarcoma were treated with chemotherapy. This trend remained stable over time, and chemotherapy was not associated with any significant survival benefit in this patient population.
doi:10.1016/j.ygyno.2014.02.021
PMCID: PMC4501483  PMID: 24561247
carcinosarcoma; outcomes; patterns of care; chemotherapy
10.  Risk Factors for HPV Infection among American Indian and White Women in the Northern Plains 
Gynecologic oncology  2011;121(3):532-536.
Objective
American Indian (AI) women living in the Northern Plains have high incidence and mortality rates for cervical cancer. We assessed risk factors for human papillomavirus (HPV) infection among AI and White women.
Methods
We tested cervical samples for HPV infection obtained from women ages 18-65 years attending 2 rural AI reservation clinics in South Dakota (n = 235) and an urban clinic serving predominantly White women (n = 246). Patients self-reported information on HPV risk factors. We used percentages and chi-square tests to compare risk factors, and logistic regression with HPV status as the outcome to quantify the association between HPV and risk factors.
Results
AI women had more risk factors than White women, including younger age, less education, less vegetable consumption, more sexual partners, younger age at first sexual experience and first pregnancy, and more pregnancies (p values ≤ 0.003). AI women more often endorsed recreational drug use, history of sexually transmitted diseases, and current smoking; White women reported more alcohol consumption (p values < 0.001). In multivariate analysis, younger age and current smoking were associated with higher odds of HPV infection in AI women, whereas a higher number of sexual partners was associated with higher odds of HPV infection in White women.
Conclusions
AI women have a high burden of risk factors for HPV disease, and associations with HPV infection appear to differ by community. Knowledge of specific risk factors in AI populations may provide targets for public health officials to decrease HPV infection and disease.
doi:10.1016/j.ygyno.2011.02.032
PMCID: PMC4498572  PMID: 21414655
cervical cancer; American Indian; risk factors; screening; health disparities; human papillomavirus
11.  A PHASE II EVALUATION OF TRABECTEDIN IN THE TREATMENT OF ADVANCED, PERSISTENT, OR RECURRENT UTERINE LEIOMYOSARCOMA: A GYNECOLOGIC ONCOLOGY GROUP STUDY 
Gynecologic oncology  2011;124(1):48-52.
OBJECTIVE
To estimate activity and safety of trabectedin 1.5 mg/m2 IV over 24 hours every 3 weeks (1 cycle) in uterine leiomyosarcoma.
METHODS
Patients with chemotherapy naive, advanced, persistent or recurrent uterine leiomyosarcoma, acceptable organ function and PS ≤ 2 were eligible. A two-stage design was utilized. Three responses were required in the first stage to initiate the second stage; the target sample size was 40 for the combined stages. If the true response rate was 10%, the study design provided a 95% chance of correctly classifying the treatment as “inactive.” Conversely, if the true response rate was 30%, then the average probability of correctly classifying the treatment as active would be 90%.
RESULTS
Twenty patients were eligible and evaluable. The median number of cycles was 10 (123 total cycles, range 2–29). The number of patients with partial responses was 2 (10%; 95% confidence interval of 1.2%–31.7%). Response durations were 3.3 and 5.7 months. Ten patients had stable disease (50%). The median progression-free survival (PFS) and overall survival were 5.8 months and greater than 26.1 months (median not reached), respectively. Observed grade 3/4 toxicity included: neutropenia 16/20 (1 infection); thrombocytopenia 3/20; metabolic 3/20; anemia, gastrointestinal and vascular 1/20 each. There were no treatment related deaths nor cases of liver failure.
CONCLUSIONS
Although a second stage of accrual was not indicated based on the overall response rate, the drug was well tolerated.
doi:10.1016/j.ygyno.2011.09.019
PMCID: PMC4497524  PMID: 21996263
Trabectedin; Uterine Cancer; Leiomyosarcoma
12.  Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary 
Gynecologic oncology  2014;135(1):81-84.
Objective
Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma.
Methods
A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed.
Results
Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p = 0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p < 0.001).
Conclusion
Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.
doi:10.1016/j.ygyno.2014.07.100
PMCID: PMC4492474  PMID: 25093288
Lynch Syndrome; Ovarian cancer; Microsatellite instability; Mismatch repair; Endometrioid ovarian carcinoma; Clear cell ovarian carcinoma
13.  Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer 
Gynecologic oncology  2014;134(1):104-111.
Objective
Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined.
Methods
Nine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, 0.1 to 1 μM) for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown.
Results
Greater than 50% inhibition of OVCAR8, HEY and ID8-IP ovarian carcinoma cell growth occurred with 0.1 μM PF-271 in anchorage-independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3-IP, A2780, and 5009-MOVCAR was not affected by 0.1 μM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition.
Conclusions
Differential responsiveness to FAK inhibitor treatment were observed. Intrinsic low merlin protein levels correlated with PF-271-mediated anchorage-independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials.
doi:10.1016/j.ygyno.2014.04.044
PMCID: PMC4065804  PMID: 24786638
ovarian cancer; focal adhesion kinase; merlin; tumor; biomarker
14.  Safety and Tolerance of Radical Hysterectomy for Cervical Cancer in the Elderly 
Gynecologic oncology  2014;134(1):36-41.
Background
Despite institutional studies that suggest that radical hysterectomy for cervical cancer is well tolerated in the elderly, little population-level data is available on the procedure’s outcomes in older women. We performed a population-based analysis to determine the morbidity, mortality, and resource utilization of radical hysterectomy in elderly women with cervical cancer.
Methods
Patients recorded in the Nationwide Inpatient Sample with invasive cervical cancer who underwent abdominal radical hysterectomy between 1998–2010 were analyzed. Patients were stratified by age: <50, 50–59, 60–69, and ≥70 years. We examined the association between age and the outcomes of interest using chi square tests and multivariable generalized estimating equations.
Results
A total of 8199 women were identified, including 768 (9.4%) women age 60–69 and 462 (5.6%) women ≥70 years of age. All cause morbidity increased from 22.1% in women <50, to 24.7% in those 50–59 years, 31.4% in patients 60–69 years and 34.9% in women >70 years of age (P<0.0001). Compared to women < 50, those >70 were more likely to have intraoperative complications (4.8% vs. 9.1%, P=0.0003), surgical site complications (10.9% vs. 17.5%, P<0.0001), and medical complications (9.9% vs. 19.5%, P<0.0001). The risk of non-routine discharge (to a nursing facility) was 0.5% in women <50 vs.12.3% in women ≥70 (P<0.0001). Perioperative mortality women ≥70 years of age was 30 times greater than that of women <50 (P<0.0001)
Conclusion
Perioperative morbidity and mortality are substantially greater in elderly women who undergo radical hysterectomy for cervical cancer. Non-surgical treatments should be considered in these patients.
doi:10.1016/j.ygyno.2014.04.010
PMCID: PMC4158005  PMID: 24768851
Cervical cancer; cervical carcinoma; radical hysterectomy; hysterectomy; elderly; surgery; early-stage
15.  Impact of obesity on chemotherapy management and outcomes in women with gynecologic malignancies 
Gynecologic oncology  2015;138(1):201-206.
Objective
To describe the effects of obesity on the pharmacokinetics and dosing of chemotherapies and provide recommendations for chemotherapy management in obese women with gynecologic malignancies.
Methods
PubMEd and MEDLINE databases were searched for articles published before June 2014. Only English-language articles were considered. 84 manuscripts were reviewed and 66 were included. Search terms included: obesity, overweight, body mass index, body surface area, glomerular filtration rate, chemotherapy, ovarian cancer, endometrial cancer, inflammation, and pharmacokinetics,
Results
Obese cancer patients have worse clinical outcomes, compared with non-obese patients. This may be because of differences in pharmacokinetics, metabolic dysregulation, or physicians' decisions to reduce chemotherapy dose-intensity during treatment to minimize toxicities. A 2012 American Society of Clinical Oncology Clinical Practice Guideline recommends using actual body weight for chemotherapy dosing in all patients treated with curative intent, irrespective of obesity, to avoid compromising clinical outcomes, including progression free survival (PFS) and overall survival (OS). In women with gynecologic cancers most studies demonstrate no difference in PFS or OS when obese patients receive the same chemotherapy dose intensity as non-obese patients, except perhaps with bevacizumab.
Conclusions
Chemotherapy dose-intensity is a critical determinant of cancer outcomes and should be maintained in all patients, irrespective of obesity. Future studies should prospectively examine the impact of obesity on clinical outcomes (adverse events, survival) to improve the care of this growing population of patients who are at risk for inferior clinical outcomes.
doi:10.1016/j.ygyno.2015.04.002
PMCID: PMC4469517  PMID: 25870918
Obesity; Chemotherapy; Dosing; Pharmacokinetics; Ovarian cancer; Endometrial cancer
16.  The Future of Vaccines for Cervical Cancer 
Gynecologic oncology  2008;109(2 0):S48-S56.
Cervical cancer continues to cause significant morbidity and mortality worldwide, making prophylactic cervical cancer vaccines an important focus for cervical cancer prevention. The increasing accessibility of these vaccines worldwide has the potential to greatly decrease the incidence and burden of disease in the future. However, current prophylactic vaccines offer no therapeutic benefit for persons already infected with human papillomavirus types targeted by vaccines or persons with precancerous lesions or cervical cancer. The protection offered by current vaccines is primarily against human papillomavirus types used to derive the vaccine, although partial cross-protection for related virus types has been observed. Herein, we describe findings from preclinical and clinical studies that employ vaccine strategies that have the potential to shape the future of vaccines against cervical cancer. Modalities include prophylactic strategies to target more oncogenic virus types by using the minor capsid antigen L2 and/or by increasing the number of types used to derive virus-like particle vaccines. Therapeutic strategies include the development of vaccines against human papillomavirus early proteins (targets for cellular immunity) for the resolution of precancerous lesions and cervical cancer. Future applications of existing VLP-based vaccines are also discussed.
doi:10.1016/j.ygyno.2008.01.004
PMCID: PMC4487634  PMID: 18482559
17.  Patterns and utility of routine surveillance in high grade endometrial cancer 
Gynecologic oncology  2015;137(3):485-489.
Objective
To evaluate surveillance methods and their utility in detecting recurrence of disease in a high grade endometrial cancer population.
Methods
We performed a multi-institutional retrospective chart review of women diagnosed with high grade endometrial cancer between the years 2000 and 2011. Surveillance data was abstracted and analyzed. Surveillance method leading to detection of recurrence was identified and compared by stage of disease and site of recurrence.
Results
Two hundred and fifty-four patients met the criteria for inclusion. Vaginal cytology was performed in the majority of early stage patients, but was utilized less in advanced stage patients. CA-125 and CT imaging were used more frequently in advanced stage patients compared to early stage. Thirty-six percent of patients experienced a recurrence and the majority of initial recurrences (76%) had a distant component. Modalities that detected cancer recurrences were: symptoms (56%), physical exam (18%), surveillance CT (15%), CA-125 (10%), and vaginal cytology (1%). All local recurrences were detected by symptoms or physical exam findings. While the majority of loco-regional and distant recurrences (68%) were detected by symptoms or physical exam, 28% were detected by surveillance CT scan or CA 125. One loco-regional recurrence was identified by vaginal cytology but no recurrences with a distant component detected by this modality.
Conclusions
Symptoms and physical examination identify the majority of high grade endometrial cancer recurrences, while vaginal cytology is the least likely surveillance modality to identify a recurrence. The role of CT and CA-125 surveillance outside of a clinical trial needs to be further reviewed
doi:10.1016/j.ygyno.2015.03.047
PMCID: PMC4484273  PMID: 25838164
Surveillance; High grade; Endometrial cancer; Recurrence; Survival
18.  Prognostic Factors for Response to Cisplatin-based Chemotherapy in Advanced Cervical Carcinoma: a Gynecologic Oncology Group Study 
Gynecologic oncology  2009;116(1):44-49.
Purpose
Cisplatin-based combination chemotherapy is considered standard treatment for advanced/recurrent cervical carcinoma; however, the majority of patients do not respond. This study was undertaken to identify the prognostic factors and develop a model predictive of (non-) response to chemotherapy.
Methods
Four-hundred twenty-eight patients with advanced cervical cancer who received a cisplatin-containing combination in three Gynecologic Oncology Group (GOG) protocols (110, 169 and 179) were evaluated for baseline clinical characteristics and multivariate analysis was conducted to identify factors independently prognostic predictive of response using a Logistic regression model. A predictive model was developed and externally validated using an independent GOG protocol (149) data.
Results
Multivariate analysis identified five factors (African-American, performance status [PS] > 0, pelvic disease, prior radiosensitizer and time interval from diagnosis to first recurrence ≤ one year) independently prognostic of poor response. A simple prognostic index was derived based on the total number of risk factors. When patients were classified into three risk groups (low risk: 0–1 factor; mid risk: 2–3 factors; high risk: 4–5 factors), patients with 4–5 risk factors were estimated to have a response rate of only 13%, and median progression-free and overall survival of 2.8 months and 5.5 months, respectively. The accuracy of the index was supported by both internal and external datasets.
Conclusions
A simple index based on five prognostic factors may have utility in clinical practice to identify the women who are not likely to respond to the cisplatin-containing regimens. This subgroup of patients should be considered for non-cisplatin chemotherapy or investigational trials.
doi:10.1016/j.ygyno.2009.09.006
PMCID: PMC4470610  PMID: 19853287
cervical cancer; cisplatin; tumor response; prognostic factor
19.  A Phase II Evaluation of AMG 102 (Rilotumumab) In The Treatment Of Persistent Or Recurrent Epithelial Ovarian, Fallopian Tube Or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study 
Gynecologic oncology  2013;132(3):526-530.
Purpose
This open-label, multi-institutional Phase II trial evaluated activity and safety of rilotumumab (AMG 102), a monoclonal antibody that targets HGF (hepatocyte growth factor), the ligand for the MET receptor, in women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer.
Patients and methods
Women were eligible for treatment with rilotumumab if they had measurable disease, a performance status of 0, 1 or 2, previously received platinum-based therapy with a progression-free interval of <12 months or a second recurrence, and adequate bone marrow and organ function. Patients received rilotumumab 20 mg/kg IV every 14 days until evidence of unacceptable toxicity or disease progression. The study utilized co-dual primary endpoints of tumor response and six-month PFS to assess the efficacy of rilotumumab. Secondary endpoints included the frequency and severity of adverse events and the duration of progression-free and overall survival.
Results
Thirty-one women enrolled and received rilotumumab. All were eligible for analysis. One patient achieved a complete response (3.2%; 90% CI 0.2 – 14%), and two women had 6-month PFS (6.5%; 90% CI 1.1 – 19%). Most adverse events were grade 1 or 2, with no grade 4 adverse events. Grade 3 adverse events were gastrointestinal (4), metabolic (3) anemia (3), a thromboembolic event(1), ventricular tachycardia(1), hypotension during infusion(1) and fatigue(1). The study was stopped after the first stage of accrual.
Summary
Rilotumumab was well-tolerated, but had limited activity. The level of activity does not warrant further evaluation of rilotumumab as a single agent in patients with ovarian cancer.
doi:10.1016/j.ygyno.2013.12.018
PMCID: PMC4469031  PMID: 24361733
AMG 102; rilotumumab MET; HGF; scatter factor; ovarian cancer; clinical trial
20.  Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study 
Gynecologic oncology  2012;127(3):451-455.
Background
Metastatic and recurrent, platinum resistant cervix cancer has an extremely poor prognosis. The Gynecologic Oncology Group has studied >20 cytotoxic drugs or drug combinations in the second-line, phase II setting of advanced, drug resistant cervix cancer.
Methods
Nanoparticle, albumin-bound paclitaxel (nab-paclitaxel) was administered at 125 mg/m2 IV over 30 minutes on days 1, 8 and 15 of each 28 day cycle to 37 women with metastatic or recurrent cervix cancer that had progressed or relapsed following first-line cytotoxic drug treatment. A flexible, 2-stage accrual design that allowed stopping early for lack of treatment activity was utilized. Because of slow patient accrual, the second stage was not completed.
Results
Of 37 patients enrolled, 2 were ineligible due to no prior cytotoxic chemotherapy, which left 35 eligible patients evaluable for response and tolerability. All of the eligible patients had 1 prior chemotherapy regimen and 27 of them had prior radiation therapy with concomitant cisplatin. The median number of nab-paclitaxel cycles were 4 (range 1–15). Ten (28.6%; CI 14.6%–46.3%) of the 35 patients had a partial response and another 15 patients (42.9%) had stable disease. The median progression-free and overall survival were 5.0 and 9.4 months, respectively. The only NCI CTCAE grade 4 event was neutropenia in 2 patients (5.7%) which resolved following dose reduction. Grade 3 neurotoxicity was reported in 1 (2.9%) patient and resolved to grade 2 following dose discontinuation.
Conclusions
Nab-paclitaxel has considerable activity and moderate toxicity in the treatment of drug resistant, metastatic and recurrent cervix cancer.
doi:10.1016/j.ygyno.2012.09.008
PMCID: PMC4459779  PMID: 22986144
Nab-paclitaxel; GOG; Cervix cancer; Drug resistant cervix cancer
21.  A Randomized Phase III Trial in Advanced Endometrial Carcinoma of Surgery and Volume Directed Radiation Followed by Cisplatin and Doxorubicin with or without Paclitaxel: A Gynecologic Oncology Group Study 
Gynecologic oncology  2008;112(3):543-552.
Objectives
After surgical debulking and volume-directed irradiation of the pelvis/para-aortic lymph nodes, treatment was randomized to compare recurrence-free survival (RFS) and toxicity between two chemotherapy regimens for the treatment of women with advanced stage endometrial carcinoma.
Methods
Treatment was randomized between 6 cycles of cisplatin [C] (50 mg/m2) and doxorubicin [D] (45 mg/m2) with or without paclitaxel [P] (160 mg/m2). Initially in paclitaxel treated patients and, after May 2002, all patients received granulocyte growth factor with each cycle.
Results
Of 659 patients enrolled following surgery, 552 eligible patients were randomized to chemotherapy after irradiation. Accrual closed to Stage IV patients in June, 2003. Approximately 80% completed six cycles of chemotherapy. Three deaths resulted from bowel complications and one death was due to renal failure. Hematologic adverse events, sensory neuropathy and myalgia, were more frequent and severe in the paclitaxel arm (p< 0.01) which was confirmed by Quality of Life assessments. Percentage of patients alive and recurrence-free at 36 months was 62% for CD vs. 64% for CDP. The hazard of recurrence or death relative to the CD arm stratified by stage is 0.90 (95% CI is 0.69 to 1.17, p=0.21, one-tail). However, in subgroup analysis, CDP was associated with a 50% reduction in the risk of recurrence or death among patients with gross residual disease (95% CI: 0.26 to 0.92). Stage, residual disease, histology/grade, positive para-aortic node and cytology, pelvic metastases and age were significantly associated with RFS.
Conclusion
The addition of paclitaxel to cisplatin and doxorubicin following surgery and radiation was not associated with a significant improvement in RFS but was associated with increased toxicity.
doi:10.1016/j.ygyno.2008.11.014
PMCID: PMC4459781  PMID: 19108877
Advanced Endometrial Carcinoma; Surgery; Radiation and Chemotherapy
22.  A phase II study of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine and ovarian cancers☆ 
Gynecologic oncology  2009;113(3):327-330.
Objectives
A phase II trial designed to evaluate the safety and efficacy of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine or epithelial ovarian cancers.
Methods
Eligible patients with recurrent epithelial ovarian or uterine cancers were treated with weekly topotecan 3.5 mg/m2 and docetaxel 30 mg/m2 for 3 consecutive weeks. Cycles were repeated every 4 weeks for 6 cycles or until evidence of disease progression, unacceptable toxicity, or death. Response was assessed as per RECIST or Rustin’s criteria. Time to best response and overall survival were calculated using Kaplan–Meier statistical methods.
Results
Twenty-seven patients registered, of which 24 were evaluable for response. The majority of patients had received 2 prior chemotherapy regimens. Of the total 86 cycles of chemotherapy that were administered, there were three grade 4 (all neutropenia) and ten grade 3 toxicities. Six of the grade 3 non-hematologic toxicities were unrelated to treatment. There were 8 dose delays and 4 dose reductions. The overall response rate was 25% (95% CI: 7.7%–42.3%, 8% CR, 17% PR), and 38% of the patients had clinical benefit (95% CI: 18.1%–56.9%; CR+PR+13% SD). The median duration of response was 8.5 months (range 3–19 months). The median overall survival was 18.5 months (range 1.8–50.7 months).
Conclusion
The combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated patient population. Patients with platinum-resistant tumors had clinical benefit and should be considered for further study with this regimen.
doi:10.1016/j.ygyno.2009.02.018
PMCID: PMC4451225  PMID: 19307014
Ovarian cancer; Uterine cancer; Chemotherapy; Topotecan; Docetaxel; Clinical trial
23.  Extragenital adenosarcoma: A case report, review of the literature, and management discussion 
Gynecologic oncology  2009;115(3):472-475.
Background
Müllerian adenosarcoma is a rare mixed epithelial-mesenchymal tumor. An extragenital site of origin and sarcomatous overgrowth are associated with aggressive clinical behavior.
Case
We present a rare case of extragenital adenosarcoma with sarcomatous overgrowth and coexistent endometrioisis. She was treated with initial cytoreductive surgery and chemotherapy. She underwent a second surgery for management of a high-grade bowel obstruction, due to pathologically confirmed recurrent intraperitoneal adenosarcoma. A complete clinical response was achieved with liposomal doxorubicin, and the patient remains disease-free eighteen months after completion of chemotherapy.
Conclusion
Liposomal doxorubicin appears to be an active agent for the treatment of adenosarcoma with sarcomatous overgrowth. In addition, we conclude from our review of all reported cases of extragenital adenosarcoma that concurrent endometriosis may represent a favorable prognostic factor.
doi:10.1016/j.ygyno.2009.07.033
PMCID: PMC4451226  PMID: 19712965
24.  Cervical cytology and multiple type HPV infection: A study of 8,182 women ages 31–65 
Gynecologic oncology  2014;133(3):405-408.
Objective
Determine the rates of single and multiple type Human Papillomavirus (HPV) infection in women in the United States ages 31–65 with known cervical cytology results.
Methods
Type-specific HPV analyses were conducted using the first samples of women who had HPV typing performed by Access Genetics as part of cervical cancer screening between July 2007 and May 2011. Women 31–65 years at testing with associated abnormal cytology results were included. The odds of abnormal cytology (compared to normal results) for multiple vs. single HPV infections were calculated for each cytology sub-type and odds ratios (OR) and 95% confidence intervals (CI) are reported.
Results
The analysis included 8,182 women. The majority (67.7%) had ASCUS cervical cytology. A total of 329 (4.0%) were positive for 2 or more HPV types. For all cervical cytology subtypes considered (ASCUS, ASCUS-H, LSIL or HSIL), women with multiple type infections were more likely to have abnormal cytology (compared to normal cytology) with the highest OR associated with HSIL (OR 1.81 (1.26–2.60)). When analyzing HPV type 16 alone, women with multiple type infections were more likely to have abnormal cytology, with the highest OR associated with HSIL cytology (OR 2.98 (1.57–5.64)). Few women had HPV type 18 infections and no results reached statistical significance. Results based on phylogenic family organization focusing on the alpha 9 phylogenic family showed similar results as HPV type 16.
Conclusions
Women ages 31–65 with multiple type HPV infections were more likely to have abnormal cytology than those with single HPV type infections.
doi:10.1016/j.ygyno.2014.03.552
PMCID: PMC4040336  PMID: 24657488
HPV; Epidemiology; Cervical Cytology; Multiple Infections
25.  Preoperative quality of life and surgical outcomes in gynecologic oncology patients: A new predictor of operative risk? 
Gynecologic oncology  2014;133(3):546-551.
Objective
Quality of life (QoL) for women with gynecologic malignancies is predictive of chemotherapy related toxicity and overall survival but has not been studied in relation to surgical outcomes and hospital readmissions. Our goal was to evaluate the association between baseline, pre-operative QoL measures and 30-day post-operative morbidity and health resource utilization by gynecologic oncology patients.
Methods
We analyzed prospectively collected survey data from an institution-wide cohort study. Patients were enrolled from 8/2012 – 6/2013 and medical records data was abstracted (demographics, comorbid conditions, and operative outcomes). Responses from several validated health-related QoL instruments were collected. Bivariate tests and multivariable linear and logistic regression models were used to evaluate factors associated with QoL scores.
Results
Of 182 women with suspected gynecologic malignancies, 152 (84%) were surveyed pre-operatively and 148 (81%) underwent surgery. Uterine (94; 63.5%), ovarian (26; 17.5%), cervical (15; 10%), vulvar/vaginal (8; 5.4%), and other (5; 3.4%) cancers were represented. There were 37 (25%) cases of postoperative morbidity (PM), 18 (12%) unplanned ER visits, 9(6%) unplanned clinic visits, and 17 (11.5%) hospital readmissions(HR) within 30 days of surgery. On adjusted analysis, lower functional well-being scores resulted in increased odds of PM (OR 1.07, 95%CI 1.01-.1.21) and HR (OR 1.11, 95%CI 1.03-1.19). A subjective global assessment score was also strongly associated with HR (OR 1.89, 95%CI 1.14, 3.16).
Conclusion
Lower pre-operative QoL scores are significantly associated with post-operative morbidity and hospital readmission in gynecologic cancer patients. This relationship may be a novel indicator of operative risk.
doi:10.1016/j.ygyno.2014.04.002
PMCID: PMC4058761  PMID: 24726615
Quality of life; Surgical complications; Postoperative recovery

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