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Patients with advanced epithelial ovarian cancer (EOC) alive without progression at a landmark time-point of 10 years from diagnosis are likely cured. We report the proportion of patients with Stage III EOC who were long-term disease-free survivors (LTDFS≥10 years) following either intraperitoneal (IP) or intravenous (IV) chemotherapy as well as the predictors of LTDFS.Data from 3 mature NRG/GOG trials (104, 114, 172) were analyzed and included demographics, clinicopathologic details, route of administration, and survival outcomes of patients living ≥10 years assessed according to the Kaplan-Meier method. Cox regression survival analysis was performed to evaluate independent prognostic predictors of LTDFS.Of 1174 patients randomized, 10-year overall survival (OS) was 26% (95% CI, 23-28%) and LTDFS ≥10 years was 18% (95% CI, 16-20%). Patients with LTDFS ≥10 years had a median age of 54.6 years (p0.001). Younger age (p0.001) was the only independent prognostic factor for LTDFS≥10 years on multivariate Cox analysis.Approximately 18% of patients were LTDFS ≥10 years. They form the tail end of the survival curve and are likely cured. Our results provide a comparative benchmark to evaluate the impact of PARP inhibitors in 1st line maintenance trials on survival outcomes.

Despite current guidelines recommending women with ovarian cancer receive genetic risk evaluation by a genetic counselor, utilization has historically been low. We sought to assess the feasibility and effectiveness of a week-long mobile Application for Genetic Information on Cancer (mAGIC) intervention aimed to persuade women with ovarian cancer to pursue genetic counseling.The mobile application intervention was based on the Fogg Behavior Model, and consisted of three parts: (1) identifying barriers, (2) developing motivators, and (3) providing triggers to action. The Health Belief Model was used to guide content development. We conducted a prospective, randomized, controlled pilot trial among 104 untested women with a history of epithelial ovarian, primary peritoneal or fallopian tube cancer with the primary objective of increasing uptake of cancer genetic counseling services.Utilization of cancer genetic counseling services improved in both study arms over historical controls, however there was no statistically significant difference between them (intervention: 54.5% versus control: 38.6%; p = 0.14). However, compared to controls, women randomized to the mAGIC intervention demonstrated greater knowledge of hereditary cancer (0-10 scale; 9.4 ± 1.0 vs. 7.1 ± 1.5; p 0.0001), which persisted for at least three months. Additionally, 96% of women in the intervention group reported they had talked with their family about genetic counseling compared to 77% in the control group (p = 0.01).The mAGIC intervention did not result in increased uptake of genetic counseling, however it provided significant secondary benefits, including increased participants' knowledge about hereditary ovarian cancer, self-efficacy, and their reported communication with family members. ClinicalTrials.gov Identifier: NCT02877862.

Objective Natural killer (NK) cells are lymphocytes well suited for adoptive immunotherapy. Attempts with adoptive NK cell immunotherapy against ovarian cancer have proven unsuccessful, with the main limitations including failure to expand and diminished effector function. We investigated if incubation of NK cells with interleukin (IL)-12, IL-15, and IL-18 for 16 h could produce cytokine-induced memory-like (CIML) NK cells capable of enhanced function against ovarian cancer. Methods NK cells were preactivated briefly with IL-12, IL-15, and IL-18, rested, then placed against ovarian cancer targets to assess phenotype and function via flow cytometry. Real-time NK-cell-mediated tumor-killing was evaluated. Using ascites cells and cell-free ascites fluid, NK cell proliferation and function within the immunosuppressive microenvironment was evaluated in vitro. Finally, CIML NK cells were injected intraperitoneal (IP) into an in vivo xenogeneic mouse model of ovarian cancer. Results CIML NK cells demonstrate enhanced cytokine (IFN-γ) production and NK-cell-mediated killing of ovarian cancer. NK cells treated overnight with cytokines led to robust activation characterized by temporal shedding of CD16, induction of CD25, and enhanced proliferation. CIML NK cells proliferate more with enhanced effector function compared to controls in an immunosuppressive microenvironment. Finally, human CIML NK cells exhibited potent antitumor effects within a xenogeneic mouse model of ovarian cancer. Conclusions CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid. These findings provide a strategy for NK cell-based immunotherapy to circumvent the immunosuppressive nature of ovarian cancer.

Objectives: Cytomegalovirus (CMV) is a common infection that establishes latency in healthy people. CMV has been associated with alterations of the immune compartment leading to improved responses, while inflammation has been shown to adversely impact outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer in the presence or absence of inflammation. Methods: A total of 106 patients with serous ovarian cancer from 2006 to 2009 were analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG) and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction. Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10, >10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared by group using log-rank tests and Cox proportional hazards regression models adjusting for age at surgery. Results: Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-, 19 (17.9%) CMV−/CRP+, and 23 (21.7%) CMV−/CRP−. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months (95% CI: 9.0–21.1) and 31.7 months (95% CI: 25.0–48.7), respectively, with a significantly worse RFS (aHR: 1.85, 95% CI: 1.05–3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17–3.82, P = 0.01) compared to CMV−/CRP− (RFS = 31.2 months (95% CI: 16.0–56.4) and OS = 63.8 months (95% CI: 50.7–87.0)). CMV+/CRP− group displayed the longest OS (89.3 months). Conclusions: Previous exposure to CMV and high CRP at surgery portended worse RFS and OS compared to women who tested negative. The CMV+/CRP− group had the longest OS, indicating that CMV status alone, in the absence of inflammation, may be protective.

Purpose To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel. Methods Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment. Results A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19–1.72, P Conclusion Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.

To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors.Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC).The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors.The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

Objectives The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. Methods Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations , and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. Results Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53–3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10–7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04–4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. Conclusions A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.

Objectives: Identify if CMV reactivation allows for expansion of a special adaptive (natural killer) NK cell population with enhanced ability to kill ovarian cancer and determine if in a setting of increased inflammation (high CRP levels), this inflammatory response decreases the immunologic effect on tumor cells with an overall decrease in NK cell function and in cytokines necessary to activate immunogenic attacks. Methods: Serum (n=20 benign, 36 cancer) and ascites samples (n=18) collected in a prospective study at the time of surgery for HGSOC were evaluated for CMV and inflammation. CMV status and systemic inflammation were measured by immunoassay for CMV immunoglobulin G (IgG), dPCR for CMV DNA and C-reactive protein (CRP). Samples were categorized as reactive or non-reactive for CMV and positive or negative for CRP (≤10, >10 mg/L). Additionally, 32 HGOSC samples were measured for IL-6. Data were analyzed using SAS 9.4 (Cary, NC). P-values ≤ 0.05 were considered statistically significant. Flow cytometry was used to evaluate adaptive NK cells and assess cytotoxicity. Results: CMV reactivated patients had increased adaptive NK cells (NKG2C+CD57+) in serum and ascites compared to CMV non-reactived patients (p=0.043, p=0.077). In the serum, patients that were positive for CMV reactivation and were CRP negative had increased adaptive NK cells compared to patients that were CMV reactive and CRP positive. Elevated IL-6 levels in the serum and ascites correlated with CRP positive samples. There was no correlation between adaptive NK levels in blood and ascites in benign patient samples (r2=-0.03, p=0.46), however there was a positive correlation between adaptive NK levels in blood and ascites of ovarian cancer patient samples (r2=0.37 p=0.002). Adaptive NK cell levels correlate in CMV IgG positive cancer samples (r2=0.55, p=0.003), however CMV IgG negative samples did not correlate (r2=-0.04, p=0.45). Download : Download high-res image (45KB) Download : Download full-size image Conclusions: These findings suggest CMV reactivation increases the prevalence of adaptive NK cells in ovarian cancer patients.

Objective Natural killer (NK) cells represent a powerful immunotherapeutic target as they lyse tumors directly, do not require differentiation, and can elicit potent inflammatory responses. The objective of these studies was to use an IL-15 super-agonist complex, ALT-803 (Altor BioScience Corporation), to enhance the function of both normal and ovarian cancer patient derived NK cells by increasing cytotoxicity and cytokine production. Methods NK cell function from normal donor peripheral blood mononuclear cells (PBMCs) and ovarian cancer patient ascites was assessed using flow cytometry and chromium release assays ±ALT-803 stimulation. To evaluate the ability of ALT-803 to enhance NK cell function in vivo against ovarian cancer, we used a MA148-luc ovarian cancer NOD scid gamma (NSG) xenogeneic mouse model with transferred human NK cells. Results ALT-803 potently enhanced functionality of NK cells against all ovarian cancer cell lines with significant increases seen in CD107a, IFNγ and TNFα expression depending on target cell line. Function was also rescued in NK cells derived from ovarian cancer patient ascites. Finally, only animals treated with intraperitoneal ALT-803 displayed an NK dependent significant decrease in tumor. Conclusions ALT-803 enhances NK cell cytotoxicity against ovarian cancer in vitro and in vivo and is able to rescue functionality of NK cells derived from ovarian cancer patient ascites. These findings suggest that ALT-803 has the potential to enhance NK cell-based immunotherapeutic approaches for the treatment of ovarian cancer.

Objectives The purpose of this study was to determine the level of heterogeneity in high grade serous ovarian cancer (HGSOC) by analyzing RNA expression in single epithelial and cancer associated stromal cells. In addition, we explored the possibility of identifying subgroups based on pathway activation and pre-defined signatures from cancer stem cells and chemo-resistant cells.

Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo.The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth.Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice.Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy.

Objective The aim of this study is to 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 31–65years 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 8182 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.

Obesity increases risk for endometrial neoplasia, but neither the pathophysiology nor the effects of weight loss on the risk are well established. We attempted to characterize the molecular profile of the endometrium of asymptomatic women with morbid obesity before and following bariatric surgery-induced weight loss.59 asymptomatic, morbidly obese women underwent endometrial sampling before bariatric surgery; 46 (78%) of these returned one year later for re-biopsy (median weight loss of 41kg). Duplicate samples from these specimens were scored for expression of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Ki-67 by two independent, blinded pathologists using an H-score [staining intensity (0-3)×(percent of tissue involved)].The prevalence of hyperplasia pre-operatively was 7% overall and 10% among patients not on an anti-estrogen. ER H-scores were similar before and after surgery overall (median 190 and 196 respectively, p=0.82), but patients with hyperplasia had higher pre-operative H-scores (median 256, p0.001) and experienced greater H-score drops, than those without hyperplasia (-112 vs +50, p=0.028). In two patients with persistent hyperplasia at one year, ER H-scores fell to levels that were similar to those without pathology. One patient who developed hyperplasia during the study period had a rising ER H-score. Patients with hyperplasia had higher median PR H-scores pre-operatively (284 vs 188, p=0.01), which normalized through greater drops (75 vs 0, p=0.053). AR H-scores dropped significantly after surgery (13 vs 2, p=0.015), but were similar between patients with and without hyperplasia (p=0.33). Weight loss did not affect Ki-67 proliferation index.Asymptomatic morbidly obese patients have a high prevalence of occult hyperplasia, characterized by relatively high hormone receptor expression. These profiles appear to normalize with weight loss and in advance of pathologically identifiable changes. These data suggest a potential role for screening this population as well as the possibility that weight loss may be a valid treatment strategy for risk reduction.

We aimed to evaluate the feasibility and tolerability of hyperthermic intraperitoneal carboplatin (HIPEC-carboplatin) following secondary cytoreduction for recurrent, platinum-sensitive ovarian cancer.In a single institution prospective, pilot study, ten patients underwent secondary cytoreductive surgery followed by HIPEC-carboplatin at 1000 mg/m(2). Consolidation (6 cycles) was with platinum-based regimens. Adverse and quality of life were measured throughout treatment.Twelve patients were enrolled of which 2 were excluded (one each for extra-abdominal disease indentified before surgery and suboptimal cytoreduction). All 10 remaining patients received prescribed HIPEC-carboplatin. There were no intra-operative complications or AEs attributable to HIPEC-therapy. Grade 1/2 nausea was the most common post-operative toxicity (6/10 patients). Two patients had grade 4 post-operative neutropenia and thrombocytopenia but only one experienced transient treatment delay. The median hospital stay was 5.5 days. 69/70 (98%) of planned chemotherapy doses were ultimately delivered with 1 patient electively forgoing her final treatment. At a median (range) follow-up of 16 (6-23) months, three patients have recurred at 8, 14, and 16 months from surgery. The median disease-free and overall survivals have not been reached. Fact-O scores were significantly lower following surgery (126 vs. 108, p.01), but improved by completion of therapy (108 vs. 113, p=0.27).HIPEC-carboplatin at 1000 mg/m(2) following optimal cytoreduction for ovarian cancer is feasible. Surgical complications were not observed, and post-operative AEs were largely within expected ranges. Consolidation using standard platinum-based regimens was feasible following HIPEC-carboplatin, and preliminary survival data suggests efficacy. Further investigation of HIPEC-carboplatin in the setting of debulkable cancer recurrence is warranted.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer therapy with few efficacious treatments.We enrolled 70 patients with CIPN in a randomized, double-blinded, sham-controlled, cross-over trial to determine if photobiomodulation (PBM)±physiotherapy reduced the symptoms of neuropathy compared to sham treatment. At the conclusion of follow-up, sham-arm patients could cross-over into a third arm combining PBM and physiotherapy to determine if multimodal treatment had additive effects. Treatment included 30minute sessions 3-times weekly for 6weeks using either PBM or sham therapy. Neuropathy was assessed using the modified total neuropathy score (mTNS) at initiation and 4, 8, and 16weeks after initiating treatment.Sham-treated patients experienced no significant change in mTNS scores at any point during the primary analysis. PBM patients experienced significant reduction in mTNS scores at all time points. Mean changes in mTNS score (and corresponding percent drop from baseline) for sham and PBM-group patients respectively were -0.1 (-0.7%) and -4.2 (-32.4%) at 4weeks (p0.001), 0.2 (0.0%) and -6.8 (-52.6%) at 8weeks (p0.001), and 0.0 (0.1%) and -5.0 (-38.8%) at 16weeks (p0.001). Patients who crossed over into the PBM/PT-group experienced similar results to those treated primarily; changes in mTNS score from baseline were -5.5 (-40.6%) 4weeks (p0.001), -6.9 (-50.9%) at 8weeks (p0.001), and -4.9 (-35.9%) at 16weeks (p0.001). The addition of physiotherapy did not improve outcomes over PBM alone.Among patients with CIPN, PBM produced significant reduction in neuropathy symptoms.

Despite increased use of integrative medicine in cancer therapy, little data exist on its efficacy. This prospective, randomized, pilot trial sought to evaluate the feasibility of combined modality integrative medicine (CM-IM) in women with ovarian cancer (OvCA) and evaluate its effects on quality of life (QoL), chemotherapy toxicity and immunologic profiles.Women with newly diagnosed OvCA requiring chemotherapy were offered enrollment. Those randomized to the experimental arm received hypnosis, therapeutic massage and healing touch with each cycle of chemotherapy. The control arm received chemotherapy without CM-IM. All patients completed QoL questionnaires prior to cycles 1, 3 and 6, and 6-months after chemotherapy. Immunologic profiles were measured. Statistical analysis was based on intent-to-treat. Student's t-test and Fischer's exact-test were used to determine differences.Forty-three women enrolled. All women randomized to CM-IM were successfully treated. There were no statistical differences between the groups in age, stage, grade, histologic cell type, CA125 levels, or surgical cytoreductive status. There was no difference in overall QoL measurements. Re-hospitalization rates, treatment delays, anti-emetic use, and infection rates were similar. Immunologic profiles revealed no difference between arms for WBC or salivary IgA levels. Women receiving CM-IM had consistently higher levels of CD4, CD8 and NK cells, although this did not reach statistical significance.Prospective clinical evaluation of integrative medicine for women with gynecologic malignancy is feasible. This first, pilot study of CM-IM in gynecologic oncology demonstrated no improvement in QoL or chemotherapy toxicity. Integrative medicine-associated improvements in immunologic profiles warrant further investigation.

To determine the disease characteristics and comorbidities predictive of vulvar cancer specific mortality and five year overall survival among older women, ages 65 and above.A retrospective analysis was conducted of women diagnosed with vulvar cancer at a single regional cancer center from 1989 to 2003, with a follow up to 2009. Treatment records were extracted for: demographics and treatment information, Eastern Cooperative Oncology Group (ECOG) performance status and Charlson comorbidity index score. Probability of death from vulvar cancer was estimated using cumulative incidence, treating death by other known and unknown causes as competing risks. Predictors of overall survival were determined using multivariate Cox regression analyses.One hundred forty-six women were identified, with a median age at diagnosis of 79 years (range 65-95). Median follow up was 5.0 years (range 0.1-16.7 years). The cumulative incidence of vulvar cancer-specific mortality was 13% (95% CI: 0.08-0.19) at year one, 24% (95% CI: 0.17-0.31) at year three and 26% (95% CI: 0.19-0.33) at year five. Use of adjuvant therapy or surgical procedure performed did not differ by age at diagnosis (p=0.807 and 0.663) according to age group (65-74, 74-84 and 85+). Increasing age, Charlson comorbidity index score, lymph node involvement and type of surgery performed were associated with increased risk of death from any cause (all p0.05).Among women aged ≥65, vulvar cancer specific mortality was most significant in the first three years after diagnosis. Conversely other causes of mortality which can be attributed to comorbid conditions steadily increased with time.

Objectives (1) To determine the response rate of advanced, recurrent, or persistent carcinoma of the cervix to ifosfamide, paclitaxel, and carboplatin chemotherapy; (2) to determine the progression free interval and survival rate in patients treated with this regimen; (3) to describe the toxicities associated with this regimen; and (4) to evaluate the quality of life of patients while on treatment. Methods Eligible patients had histologically proven stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. Chemotherapy was given on day 1 of a 28-day cycle: mesna (600mg/m 2 ) prior to ifosfamide (2g/m 2 ), paclitaxel (175mg/m 2 ), carboplatin (AUC 5). Response rates were determined according to RECIST criteria. Toxicity was graded according the National Cancer Institute's common toxicity criteria. Quality of life measurements were obtained using the FACT-Cx. Results Twenty-eight patients participated in this study, with 21 evaluable for response rate. Overall, 7 patients (33%) had a demonstrated objective response (4 complete responses, 3 partial responses). Stable disease was documented in 3 patients. The overall median survival for all patients was 10months. Median progression free survival for evaluable patients was 5.0months. Bone marrow suppression was the most common toxicity. There were no negative effects of this treatment regimen on quality of life assessments. Conclusion Ifosfamide, paclitaxel, and carboplatin is an effective regimen in treating advanced or recurrent carcinoma of the cervix and has an acceptable toxicity profile.

Objective Effective patient –clinician communication at diagnosis is important, yet decreased provider time for face-to-face interactions makes traditional paradigms in cancer care difficult. We evaluated the effects of an educational video on patients' distress, cancer knowledge, coping skills and attitudes regarding learning about cancer at the time of ovarian cancer diagnosis. Methods An educational video was developed in which oncology professionals, women with ovarian cancer, and their relatives discussed cancer information and experiences. Women admitted for initial diagnostic surgical staging for ovarian cancer were randomized to the educational or placebo video. Before and after the video, patients completed measures of (1) ovarian cancer information, (2) emotional distress, (3) learning attitudes, and (4) coping self-efficacy. Outcomes were analyzed for differences in mean change between intervention and placebo groups using t -tests. Results Fifty-nine subjects were randomized (30 intervention/29 placebo). The majority were advanced staged, white, insured, high school educated, employed, and rated their disease seriousness as high. Anxiety, general distress and cancer-specific distress were high. Pre-post video: distress and self-efficacy between groups were unchanged, intervention subjects answered more knowledge items correctly ( p =0.0004) and developed more negative learning attitudes ( p =0.037). Following the educational video, patients who developed more negative attitudes also had increased intrusive thinking ( p =0.046), a sign of increased distress. Conclusions Video presentation of cancer-related information increases learning under conditions of high distress and disease threat however, it is not without risk for some. Differing information needs may affect women's emotional response under these conditions.

Objective. The goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Fulvestrant, a novel estrogen receptor (ER) antagonist, has proven clinically beneficial and well-tolerated in treating recurrent breast cancer. Ovarian cancer often expresses ER and may respond to anti-estrogen therapy. We evaluated fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Methods. Patients with ER-positive, multiply recurrent ovarian or primary peritoneal carcinoma and either measurable disease according to RECIST criteria or an abnormal and rising CA-125 were eligible for enrollment. Treatment consisted of single agent fulvestrant, 500 mg IM on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until either intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as CT scans bimonthly. The primary endpoint was clinical benefit (CB=complete response (CR)+partial response (PR)+stable disease (SD)) at 90 days. Results. Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose. Patients had received a median of 5 prior chemotherapeutic regimens (range: 2-13). We observed one CR (4%), one PR (4%), and 9 patients with SD (35%) using modified-Rustin criteria (CA-125 level). Using modified-RECIST criteria 13 patients (50%) achieved SD. The median time to disease progression was 62 days (mean 86 days). Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients). Conclusions. Fulvestrant is well-tolerated and efficacious. Objective response rates are low, but disease stabilization was common.

To compare the clinical behavior and outcomes of low- and high-grade endometrial stromal sarcomas (LGESS and HGESS), respectively.Patients with endometrial stromal sarcoma from five different institutions were identified and reviewed for clinicopathologic variables, surgical management and outcomes. Statistical calculations including Chi-square, t-test and survival using the Kaplan-Meier method with the log rank test were performed.One hundred and five patients were identified with 72 having LGESS, 31 with HGESS and 2 having unclassified tumors. The mean age was 50 years for patients with LGESS and 64 years for those with HGESS (p0.0001). In patients with LGESS, 68% (49 patients) had disease confined to the uterine corpus or cervix compared to 39% (12 patients) in HGESS (p=0.002). The median overall survival was 53 months for HGESS and had not yet been reached in LGESS with 87.8% alive at 80 months (p0.0001). In HGESS patients with extrauterine disease, the presence of residual disease greater than 2 cm had a significant effect on median survival. Median survival was 52 months for those who underwent optimal cytoreduction versus 2 months for those with suboptimal residual disease (p=0.007). The impact of cytoreduction was not seen in LGESS patients with extrauterine disease with 82.1% alive at 78 months.Low-grade and high-grade endometrial stromal sarcomas represent two distinct clinical entities and should be treated as such. Survival in patients with high-grade tumors appears to be related to amount of residual disease at the completion of initial surgery and would suggest the need for aggressive cytoreduction. The role of surgical staging and optimal adjuvant therapy remains unclear.

Introduction Studies have suggested that PET scans can differentiate between leiomyomas and leiomyosarcomas. Our experience, however, shows that PET scan-positive smooth muscle tumors are not necessarily malignant. Case reports Three patients with cancer underwent PET imaging. In all three, the most worrisome finding was a PET scan-positive uterine tumor. After surgical extirpation, all three uterine tumors were found to be benign smooth muscle neoplasms. Discussion To explore the potential reason these tumors were positive on PET imaging, we performed a detailed histopathologic and immunohistochemical study of all specimens. Pathologic evaluation revealed a leiomyoma, a cellular leiomyoma, and a stromomyoma. There was no association between an increased Ki67 (proliferative) index and positivity on PET imaging. Increased vascularity, however, appeared to be a feature common to the leiomyomas that were PET-positive.

Introduction Optimal pain control after major surgery contributes to a patient's recovery and satisfaction. The use of liposomal bupivacaine in subcostal transversus abdominis plane (TAP) blocks for postoperative pain control after robot assisted abdominal surgery has yet to be studied. Methods We conducted a prospective randomized controlled observer-blinded study comparing bilateral subcostal TAP blocks with bupivacaine to bilateral subcostal TAP blocks with liposomal bupivacaine. These were performed prior to the patient undergoing robot assisted hysterectomy. The patients' pain scores, opioid use, side effects, and satisfaction were followed for 72h after injection. Results Total opioid use in the first 72h after injection was significantly decreased in the group that received liposomal bupivacaine compared to bupivacaine. Patients in the liposomal bupivacaine group had significantly lower maximal pain scores at all time periods studied as well as decreased incidence of nausea/vomiting. There was a trend toward decreased length of stay in the liposomal bupivacaine group. Conclusion Subcostal TAP blocks with liposomal bupivacaine decreased the total opioid requirement for the first 72h after robot assisted hysterectomy when compared to subcostal TAP blocks with bupivacaine.

Background Anti-estrogen therapy appears to have efficacy in a subset of ovarian cancers, as demonstrated in multiple phase II studies. Identifying sensitive patients early in treatment may allow for targeted, low-toxicity primary therapy or prevention of recurrence. We have previously demonstrated that the likelihood of response to letrozole could be improved by patient selection based on estrogen-pathway marker expression. We sought to identify ovarian cancer biomarkers that might indicate sensitivity to fulvestrant, an estrogen receptor antagonist. Methods Tissue samples from the primary tumors of patients enrolled in a phase II study of fulvestrant for the treatment of multiply-recurrent ovarian cancer were embedded randomly in a tissue microarray (TMA). Estrogen receptor alpha (ERα) expression was assessed by both conventional immunohistochemistry (IHC) and quantitative immunofluorescence (IF) (AQUA) while expression of 14 other estrogen-regulated markers was assessed by quantitative IF and correlated with clinical outcomes. Results Almost half of patients experienced clinical benefit (CR+PR+SD) at 90days despite a median of 5 previous treatment regimens. 24 of 26 patient samples were available and included in the TMA. ERα expression, measured either by conventional IHC or by AQUA analysis, was associated with clinical benefit, while TFF1 and vimentin expression (measured by IF AQUA score) was predictive of progression-free survival. Conclusions These results confirm our previous observation that clinical ovarian cancer includes a subset of tumors with sensitivity to estrogen pathway blockade. Expression profile of sensitive tumors appears to be detectably different from insensitive tumors, suggesting that further improvements in treatment efficacy can be obtained through appropriate patient selection.

Objective To determine if there is an advantage to combination chemotherapy and radiation for optimally resected stage IIIC endometrial cancer (EC). Methods A multicenter retrospective analysis of patients with EC from 1991 to 2008 was conducted. Inclusion criteria were lymph node assessment and optimally resected disease. Recurrence-free (RFS) and overall survival (OS) were analyzed using Kaplan–Meier method and Cox proportional hazards model. Results 265 patients with optimally resected stage IIIC EC were identified. Postoperative therapies included radiotherapy in 17% (n=45), chemotherapy in 17% (n=46), and both chemotherapy and radiation in 61% (n=161). Three-year RFS was 56% for chemotherapy alone, compared to 73% for radiation alone, and 73% for combination therapy (p=0.12). Those receiving chemotherapy alone had the worst 3-year OS (78%) compared to either radiotherapy alone (95%) or combination therapy (90%) (p=0.005). After adjustment for stage and grade those treated with chemotherapy alone were at a 2.2 fold increased risk of recurrence (95% CI, 1.2 to 4.2; p=0.02) and 4.0 fold increased risk of death (95% CI, 1.6 to 10.0; p=0.004) compared to those treated with chemotherapy and radiation. In contrast there was no significant difference in RFS [HR=1.0 (95% CI, 0.5 to 2.0; p=0.92)] or OS [HR=1.1 (95% CI, 0.3 to 3.6; p=0.91)] for those treated with radiation alone compared to those treated with chemotherapy and radiation. Conclusion Adjuvant therapy with either radiation alone or chemotherapy and radiation was associated with improved outcomes for patients with optimally resected stage IIIC EC compared to those treated with chemotherapy only.

We sought to determine if patient age influenced chemotherapy completion rate, complication rate, or progression free survival (PFS) among patients who received intraperitoneal (IP) chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancers.Charts for patients receiving IP chemotherapy between January 2006 and September 2009 were reviewed at three institutions. Primary outcomes included completion rate of planned IP chemotherapy, complication rate, and PFS. Completion rates were categorized as 0-49%, 50-99%, or 100% of planned treatments were delivered. The tolerability of IP versus intravenous (IV) chemotherapy was also compared among patients ≥ 70 years.One hundred nine patients receiving IP chemotherapy were identified, 86 were70 years and 23 were ≥ 70 years. All patients received IP cisplatin and paclitaxel in combination with IV paclitaxel or docetaxel. Patients ≥ 70 years old were less likely to complete all planned cycles of IP chemotherapy than the younger cohort (OR = 0.33, 95% CI 0.13-0.83, p = 0.01), but there was no significant association between age and complication rate or PFS (p = 0.82 and p = 0.68, respectively). Optimally debulked patients ≥ 70 years receiving IV chemotherapy completed more cycles than patients ≥ 70 receiving IP chemotherapy (p0.01).Although elderly patients appear to tolerate fewer cycles of IP chemotherapy, they do not have higher objective complication rates or impaired PFS compared to younger patients. Age alone should not limit access to IP chemotherapy.

Background. With the pharmacokinetic advantages of intraperitoneal chemotherapy delivery and the increased popularity of immunotherapy and gene therapy, intraperitoneal catheters have moved to the forefront as a delivery system in cancer treatment. This delivery system, however, carries with it an intrinsic morbidity warranting attention in the often prolonged chemotherapy regimens demanded by cancer patients. Case. In reviewing the literature of intraperitoneal catheter complications, there is no other cited case of a peritoneal catheter erosion into intestine presenting as an enterovaginal fistula. Our patient, diagnosed with persistent ovarian carcinoma, had a peritoneal Tenckoff catheter placed for chemotherapy. Many months after termination of the chemotherapy and 15 months after placement, she presented with bowel contents per vagina. A CT scan revealed an abdominopelvic abscess encompassing the detached catheter which embedded in the rectosigmoid colon, allowing direct communication to the upper vagina. The catheter was removed and the abscess was drained. Conclusion. Intraperitoneal catheters have a morbidity that persists after nonuse. Therefore, intraperitoneal catheters should be removed if they are not being used.

Objective We sought to evaluate the outcomes and feasibility associated with delivering sequential chemotherapy and radiation in advanced stage endometrial cancer. Methods We conducted a retrospective analysis of patients treated at the University of Minnesota with sequential chemotherapy and radiation for advanced stage endometrial cancer from 1999 to 2007. Inclusion criteria were endometrial cancer patients treated with comprehensive surgical staging followed by adjuvant therapy consisting of sequential chemotherapy, radiation, and consolidation chemotherapy in a "sandwich" fashion. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan–Meier (KM) method. Results Twenty-three patients met entry criteria and were included in the analysis. The median age was 57 years (range 28–78). The majority of patients were stage III (78%) and the most common histologic type was serous (52%). The combination of a taxane and carboplatin was administered in 100% of cases. All planned cycles of chemotherapy were completed (100%) with the majority being prescribed six cycles (82%). Of the 23 patients, 5 progressed of which 3 died during the follow up period. The KM estimate of 1, 3, and 5 year PFS is 100%, 80%, and 74%, respectively. The KM estimate for 1, 3, and 5 year OS is 100%, 88% and 79%, respectively. Conclusion Adjuvant therapy delivered in a "sandwich" fashion was feasible, well-tolerated and resulted in excellent long-term progression free and overall survival. A prospective study is currently ongoing at our institution.

Background Despite increasing use of intraperitoneal chemotherapy the optimal delivery strategy and regimen remain undetermined. Catheter-related complications have been reported in 3–34% of cases across a number of platforms and port styles, but few data compare different catheters directly. We sought to evaluate the complication rate of two separate intraperitoneal chemotherapy port delivery systems used within a single practice. Methods We reviewed the medical records of all patients who underwent port placement in our practice (two surgical centers) from January, 2006 through October, 2008. Data extracted included: demographics, medical co-morbidities, port type, timing of placement, intraoperative procedures, reasons for discontinuation of IP chemotherapy, and number of completed cycles. Results We identified 85 patients who had intraperitoneal ports placed. Four patients were excluded from this analysis: 2 declined chemotherapy and 2 were treated at other institutions and follow-up data was insufficient. Fifty-two (64%) of the 81 patients analyzed had a fenestrated port placed, and 29 (36%) had single lumen ports. In 67 cases (83%) the port was placed at the time of initial cytoreductive surgery. In 14 patients (17%) it was placed as a secondary event. The groups were well matched for age, stage, BMI, and medical co-morbidities though the group with single lumen catheters had more antecedent surgeries. We observed no significant difference between patients with single lumen or fenestrated ports with regard to: number of intraperitoneal treatments, catheter-related complications, hematologic outcomes, and rates of discontinuation. Conclusions A low rate of catheter-related complications is observed with both systems. The majority of discontinuations were due to hematologic complications and did not appear to be intrinsic to catheter choice.

Objective. Brain metastasis from uterine cancer is a rare event. Consequently, the optimal management strategy is not defined. We reviewed our institution's experience with brain metastasis from endometrial cancer along with the extant medical literature to develop management recommendations. Methods. Twenty patients with CNS metastasis were identified. Information regarding symptoms, treatment, and survival was collected. The Kaplan–Meier method was used to compare survival data. Results. The incidence of CNS metastasis was 0.97%. Median patient age at initial diagnosis of endometrial cancer was 62.0 years and 64.0 years at diagnosis of brain metastasis. Most patients initially presented with advanced FIGO stage: 9 stage IVB, 4 stage IIIC, 4 stage IIIA, 2 stage IB, and 1 stage IA. The median interval from diagnosis of endometrial cancer to diagnosis of brain metastasis was 11.5 months (range 0.6–73.6). Median survival after diagnosis of brain metastasis was 2.0 months (range 0.1–39.2). Improved survival was seen in patients treated with multimodal therapy compared to patients who only received whole brain radiotherapy (WBRT) ( p =0.0001) or compared to patients who received no treatment ( p =0.009). No difference in survival was seen between patients treated with WBRT versus no therapy. The survival advantage associated with multimodal therapy was also supported by case reports and case series in the literature. Conclusions. Based upon the data presented along with the medical literature, multimodal therapy appears to improve the survival of patients with CNS metastasis from uterine cancer.

Introduction. Endometrial stromal sarcomas (ESS) are a rare gynecologic malignancy. The optimal management of this cancer remains unclear, although previous reports have failed to demonstrate a clear benefit to adjuvant chemotherapy or radiation. With the successful application of directed biological therapy in other sarcomas, a review of the behavior and biology of this disease is warranted. Objectives. To review outcomes and patterns of failure in patients with endometrial stromal sarcoma diagnosed over 31 years at our institution and the relationship to protooncogene c-kit expression. Materials and methods. Hospital records and pathology were reviewed for 28 patients with endometrial stromal sarcomas [19 low-grade (LGESS) and 9 high-grade (HGESS)] treated between 1972 and 2003. Archival tissue samples from 16 patients were available and stained with CD 117 (c-kit) antibody (1:25 dilution). Staining intensity was graded 1+ to 3+ and distribution of the cellular staining as focal (10–30% of the cells), intermediate (30–60% of the cells), or diffuse (>60% of the cells). Positive tumors had more than 10% of cells comprising the neoplasm display immunoreactivity. Results. We found a significant difference in 5-year overall survival between LGESS and HGESS ( P = 0.001). There was no significant difference in overall survival for patients with local versus advanced disease ( P = 0.53) or in overall survival for those who underwent lymphadenectomy and those who did not ( P = 0.92). 50% of patients received postoperative radiation with no difference in disease-free or overall survival ( P = 0.68 and P = 0.53). Ten patients relapsed (36%, four HGESS and six LGESS). Seven of sixteen (43.8%) tumor samples expressed detectable c-kit. Five of seven (71%) were HGESS, and the other two (22%) were LGESS tumors. The median survival of patients with c-kit-positive versus c-kit-negative tumors was 12 and 47 months, respectively. Conclusions. This study confirms the superior overall prognosis of LGESS relative to HGESS, despite the similar rates of relapse. Although hard to assess, due to population heterogeneity and small numbers, adjuvant chemotherapy and radiation appear to be of limited benefit. Expression of c-kit was common, especially in high-grade lesions and may represent a potential therapeutic target.

Objective Studies in several solid tumors have shown that the presence of occult metastasis in the bone marrow or peripheral blood is highly predictive of decreased disease-free and overall survival. Our objective was to determine the incidence of circulating ovarian or primary peritoneal cancer cells in the peripheral blood at the time of disease diagnosis, or recurrence, and to determine the prognostic significance of these occult metastasis. Methods Peripheral blood was drawn preoperatively from 91 women thought to have newly diagnosed or recurrent epithelial ovarian or primary peritoneal carcinoma. All samples underwent a tumor-enriched immunocytochemical assay. Results Sixty-four women were found to have epithelial ovarian or primary peritoneal cancer. Of the 64 women with cancer, 12 had evidence of circulating cancer cells in their peripheral blood (18.7%). Characteristics were compared between those with circulating cancer cells and those without, using Fisher's exact test or the Wilcoxon–Mann–Whitney test, as appropriate. Women with circulating cancer cells had statistically more grade 3 tumors than women without. At a mean follow-up of 18.7 months (SD 6.7 months), analysis using Kaplan–Meier estimation and the log-rank test indicated that survival curves did not differ between patients with and without circulating cancer cells. Conclusion Ovarian and primary peritoneal cancer, which historically has been thought to spread primarily by direct cell seeding throughout the abdominal cavity, can have circulating cancer cells in the peripheral blood. The clinical utility of identifying circulating cancer cells is yet to be defined.

integrative genomic analyses of publicly available mutational and DNA copy number data to identify hypermutated cancers and to infer underlying mutational processes driving hypermutation. Results: We identified 395 hypermutated tumors in 16 diverse tumor types representing ~3.6% of all cancers. Of these, 47% of patient tumors possessed somatic hypermutation that could not be explained by an established exogenous mutagen, environmental exposure, or known defect in DNA repair. Hypermutationwasmost common in endometrial cancer andwas observed in 69% of samples. Defects in DNA polymerase episilon and/or in mismatch repair drives hypermutation in endometrial cancers. Colorectal and stomach carcinomas also had hypermutation as a recurringmutational subtype observed in 26% and 24% of samples, respectively. Despite the identification of hypermutation in disparate tumor types, ovarian and cervical carcinomas did not have any samples with this phenotype (p b 0.0001). We used allelic abundance data to help determine the temporal sequence of somatic events in endometrial cancers with multiple defects potentially contributing to the observed hypermutation. Conclusion: Somatic hypermutation is most commonly found in endometrial, colorectal and stomach carcinomas but absent in ovarian and cervix carcinomas. We exploit big data to explore uncommon cancer phenotypes like somatic hypermutation across cancer types, bridging the gap between complex mutational landscapes to help inform clinical decisions.