Trusted authorities can change minds and shift norms during conflict.

The reintegration of former members of violent extremist groups is a pressing policy challenge. Governments and policymakers often have to change minds among reticent populations and shift perceived community norms in order to pave the way for peaceful reintegration. How can they do so on a mass scale? Previous research shows that messages from trusted authorities can be effective in creating attitude change and shifting perceptions of social norms. In this study, we test whether messages from religious leaders-trusted authorities in many communities worldwide-can change minds and shift norms around an issue related to conflict resolution: the reintegration of former members of violent extremist groups. Our study takes place in Maiduguri, Nigeria, the birthplace of the violent extremist group Boko Haram. Participants were randomly assigned to listen to either a placebo radio message or to a treatment message from a religious leader emphasizing the importance of forgiveness, announcing the leader's forgiveness of repentant fighters, and calling on followers to forgive. Participants were then asked about their attitudes, intended behaviors, and perceptions of social norms surrounding the reintegration of an ex-Boko Haram fighter. The religious leader message significantly increased support for reintegration and willingness to interact with the ex-fighter in social, political, and economic life (8 to 10 percentage points). It also shifted people's beliefs that others in their community were more supportive of reintegration (6 to 10 percentage points). Our findings suggest that trusted authorities such as religious leaders can be effective messengers for promoting peace.

The Management of Women's Health Care by Internists With a Focus on the Utility of Ultrasound.

Adult women require routine care for the acute and chronic health problems found in both sexes, and they require specialized care for women's health problems, including disease prevention, disease screening, and disease management. Internists should direct primary care and participate in specialized care and to the extent possible follow guidelines published by various professional organizations. They should understand the use of ultrasound in breast cancer screening, the management of pregnancy, and other gynecologic problems, including vaginal bleeding, pelvic pain, and investigation for pelvic malignancy. Finally, all management decisions need discussions on the potential benefit or harm in each step of a woman's care with an emphasis on personal preferences.

Accuracy of Intraoperative Frozen Section Diagnosis of Borderline Ovarian Tumors by Hospital Type.

STUDY OBJECTIVE: To compare the accuracy of frozen section diagnosis of borderline ovarian tumors among 3 distinct types of hospital-academic hospital with gynecologic pathologists, academic hospital with nongynecologic pathologists, and community hospital with nongynecologic pathologists-and to determine if surgical staging alters patient care or outcomes for women with a frozen section diagnosis of borderline ovarian tumor. DESIGN: Retrospective study (Canadian Task Force classification II-1). SETTING: Tertiary care, academic, and community hospitals. PATIENTS: Women with an intraoperative frozen section diagnosis of borderline ovarian tumor at 1 of 3 types of hospital from April 1998 through June 2016. INTERVENTIONS: Comparison of final pathology with intraoperative frozen section diagnosis. MEASUREMENTS AND MAIN RESULTS: Two hundred twelve women met the inclusion criteria. The frozen section diagnosis of borderline ovarian tumor correlated with the final pathologic diagnosis in 192 of 212 cases (90.6%), and the rate of correlation did not differ among the 3 hospital types (p = .82). Seven tumors (3.3%) were downgraded to benign on final pathologic analysis and 13 (6.1%) upgraded to invasive carcinoma. The 3 hospital types did not differ with respect to the proportion of tumors upgraded to invasive carcinoma (p = .62). Mucinous (odds ratio, 7.1; 95% confidence interval, 2.1-23.7; p = .002) and endometrioid borderline ovarian tumors (odds ratio, 32.4; 95% confidence interval, 1.8-595.5; p = .02) were more likely than serous ovarian tumors to be upgraded to carcinoma. Only 88 patients (41.5%) underwent lymphadenectomy, and only 1 (1.1%) had invasive carcinoma in a lymph node. CONCLUSIONS: A frozen section diagnosis of borderline ovarian tumor correlates with the final pathologic diagnosis in a variety of hospital types.

Identifying the need to refine the potential patient risk factors for niraparib-induced thrombocytopenia.

OBJECTIVE: Niraparib is a poly (ADP-ribose) polymerase inhibitor (PARP) approved for use in maintenance therapy for ovarian cancer that is associated with the unpredictable grade 3/4 thrombocytopenia. This study was conducted to refine patient dosing recommendations for niraparib based upon clinical practice observations of grade 3/4 thrombocytopenia. METHODS AND MATERIALS: Six patient cases were reviewed to identify similarities in patient factors. An in vitro study was conducted using healthy volunteer blood spiked with Niraparib concentrations ranging from 0 ng/mL to 5000 ng/mL. Manual platelet counts were evaluated at different time intervals for each concentration and compared to untreated controls. Data was then analyzed based on percent change in platelet count versus untreated control for each concentration/time point. RESULTS: In three patients with body weight > 80 kg and platelet count >200 × 109/L, decreased creatinine clearance (CrCl) <60 mL/min was identified as potential signal. An additional three patients with weights below 77 kg and/or baseline platelet counts <150 × 109/L were re-evaluated, and it was observed that all had decreased CrCl of <60 mL/min. Albumin <3.5 g/dL was also observed in some patients with thrombocytopenia. The in vitro study, observed a direct concentration-dependent relationship between niraparib and thrombocytopenia. CONCLUSION: The data suggests that renal insufficiency and hypoalbuminemia may be associated with the development of niraparib-induced thrombocytopenia. Moreover, the preliminary in vitro studies also demonstrated a concentration-dependent relationship between niraparib and direct toxicity to platelets.

Cost-Effectiveness of Niraparib and Olaparib as Maintenance Therapy for Patients with Platinum-Sensitive Recurrent Ovarian Cancer.

BACKGROUND: The recent approval of olaparib and niraparib as maintenance therapy can significantly affect the management of ovarian cancer. Clinical benefits, however, come with trade-offs in adverse events and costs. OBJECTIVE: To evaluate the cost-effectiveness of new ovarian cancer poly-ADP ribose polymerase (PARP) inhibitor therapies, olaparib and niraparib, as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer. METHODS: A decision tree model was constructed to evaluate the costs and effectiveness of olaparib and niraparib compared with placebo from a U.S. health care sector perspective. Costs included drug costs and costs of disease monitoring and management of adverse events throughout the treatment course. Costs were estimated from RED BOOK, Medicare reimbursement rates, and the literature and reported in 2017 U.S. dollars. Clinical effectiveness was measured in progression-free survival (PFS) life-years based on clinical trial results (NCT00753545, NCT01874353, and NCT01847274). The incremental cost-effectiveness ratio (ICER) was computed by dividing the incremental cost by the incremental effectiveness. RESULTS: At base case, niraparib was the more effective treatment option with slightly higher PFS, followed by olaparib. The ICERs for niraparib and olaparib compared with common baseline placebo were $235K and $287K per PFS life-year, respectively, with olaparib extended-dominated by niraparib. Both drugs were associated with lower ICERs in patients with a gBRCA mutation than in patients without a gBRCA mutation. One-way sensitivity analysis suggested that drug prices and PFS could affect ICERs significantly, but the ICERs remained above $100K per PFS life-year within the plausible ranges of all parameters. Probabilistic sensitivity analysis suggested that niraparib was associated with higher net benefits compared with placebo only when willingness-to-pay (WTP) values were above $210K per PFS life-year thresholds. CONCLUSIONS: PARP inhibitors niraparib and olaparib will extend PFS in platinum-sensitive recurrent ovarian cancer patients but are also associated with high drug acquisition costs. The base case ICERs were around or above $250K per PFS life-year in this model. No formal cost-effectiveness WTP threshold for health technology assessment exists in the United States. At a reference WTP of $100K per PFS life-year, the PARP inhibitors may not be cost-effective options. DISCLOSURES: This study was unfunded. The authors have nothing to disclose.

Quality Improvement to Demonstrate the Lack of Reliability of the Human Papillomavirus mRNA Assay to Identify Women With Latent Human Papillomavirus Infections.

OBJECTIVE: To assess the consistency between human papillomavirus (HPV) mRNA testing in women with a history of previous HPV infections diagnosed by HPV DNA assay and the potential effects on follow-up HPV screening. METHODS: This was a quality improvement study that used data from a pathology laboratory software database reviewed from November 2014 to June 2016 to identify female patients aged 30 years or older with greater than one HPV-positive result, including one or more HPV mRNA assay results and one or more documented HPV DNA assay results for comparison. Previous correlative cytology and colposcopic histopathology were also documented. American College of Obstetricians and Gynecologists' cervical cancer screening guidelines were used to compare potential differences in follow-up recommendations. RESULTS: Four hundred twenty-five charts for female patients 30 years of age or older were identified with one or more prior high-risk HPV infections by DNA assay. There was a 69.3% difference in HPV mRNA results compared with previous HPV DNA-positive results. There was a potential change in follow-up for 71.7% of patients with one prior high-risk-HPV-positive result and 60.0% of patients with two or more prior high-risk HPV-positive results. There were 231 colposcopy reports evaluated in this study. Of these, 62 (26.8%) were abnormal colposcopy reports, including 45 low-grade squamous intraepithelial lesions, 15 high-grade squamous intraepithelial lesions, and two cancers. Twenty-five (40.3%) abnormal colposcopy findings were in patients with a history of at least than two prior HPV DNA-positive results and a report of currently being HPV-negative with the mRNA assay. CONCLUSION: The HPV mRNA assays are less sensitive for detection of latent HPV infections compared with HPV DNA assays. Based on these data and the potential change in follow-up care, the HPV mRNA assay should not be used for a primary screening tool for cervical cancer. Many pathology laboratories have shifted to using the HPV mRNA assay without clear discussion with gynecologists about the effects on patient follow-up. The type of HPV assay being used should be documented and any HPV mRNA result confirmed by HPV DNA assay.

Evaluation Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus in Combination With Anticancer Drugs in Human Cancer Orthotopic Mouse Models.

OBJECTIVE: To determine the activity of fucoidan from Undaria pinnatifida (UPF) and Fucus vesiculosus (FVF) when given in combination of chemotherapy drugs using selected human breast or ovarian cancer orthotopic mouse models. METHODS: Mice were inoculated with 1 × 106 cells of TOV-112d, MCF-7, or ZR-75 subcutaneously or SKOV3-GFP-Luc intraperitoneally on day 0. MCF-7 and ZR-75 mice were administered with estradiol valerate 2 mg/kg in 0.2 mL castor oil subcutaneously two days prior to cell inoculation. Mice were randomized to one of six arms (N = 10/arm) paclitaxel, UPF/paclitaxel, FVF/paclitaxel, tamoxifen, UPF/tamoxifen, or FVF/tamoxifen. Tumors were measured three times per week for 28 days. RESULTS: Improved activity was observed with UPF or FVF in combination with tamoxifen in both the MCF-7 and ZR-75D breast cancer mouse models. Decreased activity of paclitaxel was observed when given in combination with UPF or FVF in both breast cancer mouse models. The combination of FVF/tamoxifen in the TOV-112d ovarian cancer mouse model had improved activity but no there was difference observed with the UPF/tamoxifen in either ovarian cancer mouse model. No difference was observed with combination of UPF or FVF with paclitaxel in human ovarian cancer SKOV3 or TOV-112d orthotopic mouse models. CONCLUSION: This study did confirm that UPF/FVF in combination with tamoxifen did not decrease tamoxifen activity in both breast and ovarian cancer, with some potential to improve activity compared to tamoxifen alone in breast cancers. Previous in vitro studies had suggested UPF and FVF had overall synergistic activity with paclitaxel; however, in the current in vivo human cancer mouse model studies there was no change in paclitaxel activity when given in combination with UPF or FVF in either of the two human ovarian cancer models. Furthermore, this study demonstrated that UPF or FVF given in combination with paclitaxel had a potential antagonistic effect in breast cancer models. Additional studies are warranted to delineate mechanisms contributing to variation in the in vivo activity when given in combination with paclitaxel. As a first step, a clinical pharmacokinetic study evaluating impact of FVF/UPF given in combination with chemotherapy in patients with solid tumors is underway.

Managing Variant Interpretation Discrepancies in Hereditary Cancer: Clinical Practice, Concerns, and Desired Resources.

Variant interpretation is a complex process, and classification may vary between sources. This study aimed to determine the practice of cancer genetic counselors regarding discrepancies in variant interpretation and to identify concerns when counseling these discrepancies. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. The vast majority of counselors (93%) had seen a variant interpretation discrepancy in practice. A large majority (96%) of respondents indicated that they conducted their own research on reported variants. Most respondents cited variant databases as the most common resource utilized in researching variants. Approximately 33% of counselors spent 45 min or more of extra time researching a discrepancy compared to researching a variant with a single classification. When asked how they approached counseling sessions involving variant interpretation discrepancies, the free responses emphasized that counselors considered family history, clinical information, and psychosocial concerns, showing that genetic counselors tailored the session to each individual. Discrepancies in variant interpretation are an ongoing concern for clinical cancer genetic counselors, as demonstrated by the fact that counselors desired further resources to aid in addressing these discrepancies, including a centralized database (89%), guidelines from a major organization (88%), continuing education about the issue (74%), and functional studies (58%). Additionally, most respondents reported that the ideal database would be owned by a non-profit organization (59%) and obtain information directly from laboratories (91%). This investigation was the first to address these discrepancies from a clinical point of view. The study demonstrates that discrepancies in variant interpretation are a concern for clinical cancer genetic counselors and outlines the need for additional support.

Preclinical Evaluation of Safety of Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus for Use in Cancer Treatment.

OBJECTIVES: To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. METHODS: Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations. Four hepatic metabolism phase II pathways-glutathione S transferase (GST), quinone oxidoreductase (QOR), catechol-O-methyltransferases (COMT), and uridine di-phosphate (UDP)-glucuronosyltransferase (UGT)-were evaluated with validated immunoassays. Growth inhibition assays were performed with each fucoidan alone and in combination with chemotherapy agents in a panel of human cancer cell lines. In vivo studies evaluated safety and immune modualtion. RESULTS: CYP450 inhibition was observed with FVF. The GST, QOR, and UGT pathways had no changes. UPF and FVF both interacted with COMT. No growth inhibitory activity in cancer cell lines was observed. UPF and FVF had synergistic activity with paclitaxel or tamoxifen and additive activity with topotecan. In vivo, FVF decreased HeLa human cervical tumor growth and both FVF and UPF decreased TOV-112D human ovarian tumor growth. Otherwise, no significant change in tumor growth was observed. FVF immune modulation of IgG and IL-6 was observed (p<0.03). CONCLUSION: At higher doses, UPF and FVF may have limited potential for drug-supplement interactions, with either CYP450 or COMT hepatic metabolism pathways. Additional studies are warranted to evaluate to confirm findings of fucoidans in combination with chemotherapy.

Zika Virus: Epidemiology, Pathogenesis and Human Disease.

The Zika virus is a positive sense, single-stranded RNA arbovirus in the Flaviviridae family, genus Flavivirus. This virus was initially isolated in Africa and is transmitted to nonhuman primates and humans by mosquitoes. Initial reports describe sporadic mild viral infection with fever, arthralgia, myalgia and conjunctivitis in Africa and Asia. However, its geographic distribution has significantly increased, and it has caused large outbreaks in the Yap Islands in 2007, in French Polynesia in 2013 and in Brazil in 2015. Multiple cases of Guillain-Barre´ syndrome occurred in French Polynesia and Columbia during outbreaks, and infections in pregnant women in Brazil have been associated with microcephaly and fetal loss. The viremic phase in humans is short, and diagnosis usually depends on positive immunoglobulin M titers with serum neutralization tests for confirmation. Treatment is directed at symptoms; there are no antiviral drugs available. Transmission can also occur through sexual contact with infected men and through blood transfusion. Prevention is important in women and includes limiting travel to endemic areas when possible, control of mosquito populations and condom use when appropriate. The Centers for Disease Control and Prevention is actively involved in tracking these infections and providing up-to-date information.

Evaluation of Active Hexose Correlated Compound (AHCC) in Combination With Anticancer Hormones in Orthotopic Breast Cancer Models.

OBJECTIVE: To determine the impact on antitumor activity when active hexose correlated compound (AHCC) in combination with anticancer hormonal agents in orthotopic mouse models of human estrogen receptor positive breast cancer and evaluate impact of AHCC on aromatase activity. METHODS: The study consisted of 7 treatment arms (n=10) conducted in 2 breast cancer mouse models: MCF-7 and ZR-75. Treatment groups included untreated, vehicle, AHCC 50 mg/kg, AHCC 50 mg/kg + tamoxifen 10 mg/kg, tamoxifen 10 mg/kg, AHCC 50 mg/kg + letrozole 10 µg/mouse, or letrozole 10 µg/mouse. All treatments were administered daily by oral gavage for 12 weeks. Tumors were measured 3 times a week. In vitro estrone and 17ß-estradiol enzyme immunoassay was used to evaluate aromatase activity. RESULTS: There was no difference in the activity with the combination of AHCC + tamoxifen compared with tamoxifen ( P = 0.29). In the ZR-75 model (catechol- O-methyltransferase [COMT] wild-type), there was no difference in activity with the letrozole + AHCC compared with letrozole. However, in the MCF-7 model (COMT variant), AHCC + letrozole resulted in a decrease in activity compared with letrozole ( P < 0.01). Immunoassay data suggested that AHCC is a potential inducer of aromatase activity. In both tumor models, there was cytotoxicity observed with AHCC compared with untreated ( P < 0.02). CONCLUSION: AHCC did not change the activity of tamoxifen. AHCC may have some interaction with letrozole in patients with COMT variant genotype. AHCC had cytotoxicity that warrents additional studies to evaluate its potential role for consolidation/prevention of breast cancer.

Morphoproteomics Identifies the EZH2 and SIRT1 Pathways as Potential Blocks to Differentiation in Yolk Sac Tumor of the Ovary and Provides Therapeutic Options: a Case Study.

Yolk sac tumor of the ovary is a rare but highly malignant and aggressive germ cell tumor. The objective of this case study of an ovarian yolk sac tumor was to identify putative pathways that are known to pose a block in differentiation, both in early embryogenesis and in tumorigenesis, that might be amenable to low toxicity therapies designed to promote differentiation to a more benign state and prevent recurrent disease in such tumors. The enhancer of Zeste homolog 2 (EZH2), a histone methyl transferase, and silent mating type information regulation 2 homolog 1 (SIRT1), a NAD+ histone deacetylase, are two such pathways.

Effectiveness of cyanoacrylate microbial sealant in the reduction of surgical site infection in gynecologic oncology procedures: A phase III single institution prospective randomized trial.

OBJECTIVES: Surgery is a cornerstone for patients with gynecologic malignancies. Surgical site infections (SSI) remain a source of post-operative morbidity. Consequences range from escalated costs, delay in adjuvant therapy, and increased morbidity. Our primary objective was to evaluate the effectiveness of a cyanoacrylate microbial sealant (CMS) to reduce post-operative SSI following laparotomy for suspected gynecologic malignancy. METHODS: Patients were randomized using a 1:1 allocation to receive either standard skin preparation or standard preparation with CMS and stratified by BMI. Patients were followed for 6weeks for SSI. Demographic data was collected through the EMR. Associations between SSI, use of CMS, and clinicopathologic factors were explored using descriptive statistics, chi-square and multivariate analysis. RESULTS: 300 patients underwent randomization. Median age of the cohort was 58. Arms were matched and there was no difference in rate of medical comorbidities. Mean BMI was 38.8kg/m2 in patients randomized to BMI≥30 and 26.3kg/m2 randomized to BMI<30. Surgical characteristics for the entire cohort: 66% malignancy, 91% clean-contaminated, 21% bowel surgery, 25% transfusion. Seventy-six (25%) patients developed a SSI: 43 patients (28%) treated with CMS, compared to 33 (21%) patients treated without CMS (p=0.18). Multivariate model demonstrated that BMI≥30 (p<0.005), surgery for malignancy (p=0.010), transfusion in the OR (p<0.001), and closure with staples (p=0.0005) were associated with post-operative SSI. CONCLUSIONS: Patients presenting to a gynecologic oncologist for surgery frequently present with multiple risk factors for SSI and laparotomy is complicated by surgical-site complications in up to 30% of cases. The addition of CMS alone does not appear to reduce risk of overall SSI. Additional risk-reducing strategies including use of antimicrobial agents and optimization of modifiable risk factors prior to surgery should be explored as pathways for reducing this significant post-operative morbidity.

Chemotherapy Response Rates Among Patients With Endometrial Cancer Who Have Elevated Serum Platelets.

OBJECTIVE: This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer. METHODS: From 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. χ² Test and Student t test were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival. RESULTS: There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46-5.38; P < 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26-3.98; P < 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56-1.88, P = 0.93). CONCLUSIONS: Patients with endometrial cancer who have an elevated serum platelet count greater than 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range.

Multiple biopsies and detection of cervical cancer precursors at colposcopy.

PURPOSE: Women with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies. METHODS: The Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies. RESULTS: In the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone. CONCLUSION: Collection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy.

Outcomes of cervical cancer and positive para-aortic lymph nodes in the modern era of chemoradiation.

OBJECTIVE: Patients with cervical cancer with positive para-aortic lymph nodes have a poor prognosis. Our primary aim was to describe outcomes among this subgroup in the era of modern chemoradiation. METHODS: Patients with histologically confirmed cervical cancer metastatic to their para-aortic lymph nodes diagnosed between 1998 and 2011 and treated with curative intent were included in this analysis. Surgicopathologic, demographic, and outcome data were collected. Descriptive and survival statistics were generated to evaluate overall survival (OS) and progression-free survival (PFS) and to compare outcomes by treatment. P values were generated using both Wilcoxon and log-rank methods and listed respectively. RESULTS: The median PFS was 19 months. The median OS was 23.4 months. The median PFS for radiation only was 14 months and for chemoradiation was 20 months (P = 0.27 and 0.60, respectively). There was no difference in median OS for the radiation-only group versus chemoradiation. The median OS stratified by stage was 32 months (stage I), 21 months (stage II), 19.4 months (stage III), and 19.8 months (stage IV; P = 0.17 and 0.22). CONCLUSIONS: Our study shows a median OS of 23 months, which is less than what was documented in the literature. Despite the use of modern chemoradiation therapy, most of the cohort died within 3 years. The low OS presented in our study highlights the limitations of the current treatment regimens and the need for identification of for more effective therapy.

Referrals to phase I clinical trials in a gynecologic oncology unit.

OBJECTIVES: Previous reviews of phase I clinical trials report limited response rates. Development of novel biologic agents and trials designs have increased these rates. A contemporary appraisal of phase I clinical trials in gynecologic malignancies could help validate these findings. METHODS: Retrospectively reviewed records for 410 patients with gynecologic malignancies treated in a phase I unit, January 1999 to October 2012. Patient characteristics and treatment outcomes were abstracted and analyzed. RESULTS: Patients enrolled in 43 different phase I trials, 17 phase Ia, 17 phase Ib dose escalation and 9 dose expansion. 9 trials (21%) investigated unique cytotoxic delivery methods, 15 (35%) conventional cytotoxic plus novel agents and 19 (44%) novel agents alone. For patients treated in the first-line setting, 90 (74.4%) achieved CR, 20 (16.5%) PR, 9 (7.4%) SD and 2 (1.7%) PD, yielding an overall response rate of 90.9%. In patients treated for recurrent disease, 2 (1.6%) achieved CR, 11 (8.9%) PR, 57 (46.0%) SD and 54 (43.5%) PD, yielding a response rate of 11% and an overall clinical benefit rate of 57%. Response rate for molecular targeted therapies was 11.5% with an overall clinical benefit rate of 46.2%. Patients with prior anti-angiogenic exposure had comparable median PFS to those who had not been previously exposed (3.5 vs. 4.0 months, p = 0.29). CONCLUSIONS: Results support referral of gynecologic cancer patients for phase I clinical trials. Patients with advanced, heavily pretreated disease fare at least as well as they do on phase II trials and a proportion of them can attain an objective response or stabilization of their disease.

Phase II trial of vaginal cuff brachytherapy followed by chemotherapy in early stage endometrial cancer patients with high-intermediate risk factors.

OBJECTIVE: To determine the progression free survival (PFS), toxicity, and patterns of failure for early stage, high-intermediate risk (H-IR) patients in a phase II trial with adjuvant vaginal cuff brachytherapy (VCB) and three cycles of carboplatin and paclitaxel. METHODS: Surgically staged patients with stage I-IIb endometrial cancer with H-IR factors were treated with VCB (2100cGy) followed by three cycles of carboplatin (AUC 6) and paclitaxel (175 mg/m(2)). The primary endpoint was PFS at 2 years, with toxicity and sites of failure as secondary endpoints. Toxicity was assessed by patient report (CTCAE v. 3) as well as by delays or dose modifications in treatment. RESULTS: All patients completed VCB and 19/23 (83%) completed both VCB and 3 cycles of chemotherapy. Mean time to complete VCB was 14.5 days with minimal acute toxicity noted. At 6 months, all toxicity related to VCB had resolved. In total 60 cycles of chemotherapy were given, with one dose reduction (1.6%) for grade 2 neuropathy and seven delays (11.6%) in treatment due to hematologic toxicity. At a median follow-up of 44.5 months, 91% of patients remained progression free at 2 years. Four patients experienced a recurrence; they recurred both locally and distant. CONCLUSIONS: Adjuvant therapy with VCB and chemotherapy is well tolerated in a population of patients with H-IR endometrial carcinoma and provides 2 year PFS of 91%. A randomized trial is currently underway to assess whether combined VCB and chemotherapy reduces the rate of recurrence compared to external beam radiation therapy (EBRT) in this patient population.

Distance traveled for treatment of cervical cancer: who travels the farthest, and does it impact outcome?

OBJECTIVE: To evaluate the impact of distance from residence to treatment center on disease characteristics and recurrence of cervical cancer. MATERIALS AND METHODS: A single-institution retrospective chart review of patients treated for cervical cancer during 2006-2011 was performed. Demographic, socioeconomic, and clinicopathologic characteristics were recorded. Distance traveled from home to treatment facility was calculated and categorized. Recurrence and follow-up data were extracted; progression-free survival and overall survival were calculated. SAS version 9.2 was used for statistical analysis. RESULTS: Two hundred nineteen patients met the study criteria; 75% were Caucasian. Forty-nine percent used tobacco. Twenty-five percent had stage III/IV disease. Insurance type was 46% private, 25% Medicaid, 20% Medicare, and 9% uninsured. Distance between residence and hospital was less than 15 miles (29%), 15 to 30 miles (21%), 30 to 50 miles (17%), and more than 50 miles (33%). Median follow-up period was 23 months (range, 1-65). Caucasians were more likely to travel more than 30 miles to a treatment center (P = 0.018) Non-Caucasians were less likely to have private insurance (P = 0.0005) and more likely to recur (P = 0.0045). Recurrence was highest (50%) in African Americans. Travel of more than 30 miles was not associated with age, stage, histology, tobacco abuse, employment, clinical trial enrollment, primary chemoradiation for stage IB disease, or delayed radiation. Travel of more than 30 miles was associated with government insurance (P = 0.029) and a trend toward unemployment (P = 0.059). Four-year progression-free survival (53% vs 52%; P = 0.992) and overall survival (57% vs 62%; P = 0.73) were similar between less than or more than 30-mile travel. CONCLUSIONS: Fifty percent of the patients reside more than 30 miles from treating hospital. Despite farther travel, stage of disease, clinical trial enrollment, treatment type, radiation completion, and recurrence rates were similar among patients with cervical cancer. Non-Caucasians are less likely to travel more than 30 miles.

Vaginal cancer: the experience from 2 large academic centers during a 15-year period.

OBJECTIVE: Limited data regarding the natural history, management, and prognosis of vaginal cancer exist owing to the relative disease rarity. MATERIALS AND METHODS: A retrospective chart review was performed at 2 institutions to identify women receiving treatment for vaginal cancer between 1990 and 2004. Demographics, risk factors, histology, International Federation of Gynecology and Obstetrics stage, treatment, and treatment-related complications were recorded. Statistical Analysis Software (SAS) version 9.2 was used. RESULTS: A total of 110 patients were identified in the 2 university databases. Median age was 63 years (range = 36-93 years), and 84% were white; 73% had squamous cell carcinoma, 40% were ever users of tobacco, and 64% had no abnormal Pap smear results. Of the patients, 83% had early-stage (I or II) disease. Treatment varied by stage with increasing use of radiation with advancing stage. Recurrence was 24%, 32%, and 53% for stage I, II, and III/IV disease, respectively. After a median follow-up of 21 months, progression-free survival was 59, 35, and 23 months for stage I, II, and III/IV disease, respectively. Overall survival was 106, 58, and 34 months for stage I, II, and III/IV disease, respectively. Age greater than 60 years (p = .0339; hazard ratio [HR] = 2.162), advanced stage (p = .0004; HR = 2.475), and tobacco use (p = .0004; HR = 1.02) were negatively associated with survival. Thirty percent developed a significant complication (fistula, stricture, cystitis, or proctitis), and 21% developed a vesicovaginal and/or rectovaginal fistula. There was no association of fistula development with age, stage, tobacco use, histological finding, or treatment history (including radiation therapy). CONCLUSIONS: Age, stage, and tobacco abuse seem to be negatively associated with survival in vaginal cancer. However, no risk factors were associated with fistula development.