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To date, The Cancer Genome Atlas (TCGA) has provided the most extensive molecular characterization of invasive cervical cancer (ICC). Analysis of reverse phase protein array (RPPA) data from TCGA samples showed that cervical cancers could be stratified into 3 clusters exhibiting significant differences in survival outcome: hormone, EMT, and PI3K/AKT. The goals of the current study were to: 1) validate the TCGA RPPA results in an independent cohort of ICC patients and 2) to develop and validate an algorithm encompassing a small antibody set for clinical utility. Subjects consisted of 2 ICC patient cohorts with accompanying RPPA and clinical-pathologic data: 155 samples from TCGA (TCGA-155) and 61 additional, unique samples (MCW-61). Using data from 173 common RPPA antibodies, we replicated Silhouette clustering analysis in both ICC cohorts. Further, an index score for each patient was calculated from the survival-associated antibodies (SAAs) identified using Random survival forests (RSF) and the Cox proportional hazard regression model. Kaplan-Meier survival analysis and the log-rank test were performed to assess and compare cluster or risk group survival outcome. In addition to validating the prognostic ability of the proteomic clusters reported by TCGA, we developed an algorithm based on 22 unique antibodies (SAAs) that stratified women with ICC into low-, medium-, or high-risk survival groups. We provide a signature of 22 antibodies which accurately predicted survival outcome in 2 separate groups of ICC patients. Future studies examining these candidate biomarkers in additional ICC cohorts is warranted to fully determine their clinical potential. • The prognostic ability of TCGA RPPA signatures was validated. • Expression data from 22 antibodies predicts cervical cancer survival risk. • A subgroup of the 22 antibodies associate with clinical features of cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose To examine the effect of celecoxib on cervical intraepithelial neoplasia 3 (CIN 3). This is a NRG Oncology/Gynecologic Oncology Group study with translational biomarkers. Patients and methods Patients with CIN 3 were randomized to celecoxib 400 mg once daily (67 patients) or placebo (63 patients) for 14–18 weeks. The primary outcome measure was histologic regression. A test of equal probabilities of success between two therapies was conducted, using Fisher's Exact Test at alpha = 10% and 90% power when the treatment arm boosted the probability of success by 30%. Translational analysis included cervical tissue HPV genotyping, COX-2 expression in biopsies, and serum celecoxib and VEGF levels. Results In primary analysis, histologic regression was not significantly higher in the celecoxib group (40%) than in the placebo group (34.1%). However, exploratory analyses suggest patients with high serum VEGF levels exhibited greater regression in the celecoxib arm (47.3%) than in the placebo arm (14.3%). Regression rates were similar by treatment group in patients with low VEGF. VEGF levels increased over time in the placebo group, but remained the same in the treatment group. COX-2 expression in cervical biopsies declined from pre-treatment to the end of treatment with celecoxib; it did not change with placebo. Conclusions Celecoxib at 400 mg once daily for 14–18 weeks did not significantly decrease the severity of CIN 3 compared with placebo except, possibly, in subjects with high baseline VEGF. Therefore, serum VEGF levels might identify patients who may benefit from celecoxib or other therapies, personalizing future chemoprevention trials for CIN 3. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Studies have suggested that polymorphisms in genes involved in immune recognition and antigen presentation are associated with cervical cancer risk. We sought to replicate a recent study which reported an association between specific SNPs on CD83 and cervical cancer and to further explore whether effects varied by age, clinical stage (in situ versus invasive), and histology (squamous carcinomas versus adenocarcinomas). Methods: We evaluated the association between SNPs on CD83 and cervical cancer in a multicenter case-control study of cervical cancer conducted in the Eastern United States (263 cases, 307 controls), focusing on the five SNPs (RS9296925, RS853360, RS9230, RS9370729, RS750749) previously found to be associated with cervical cancer. We also pooled data from the Eastern U.S. (263 cases) with those from the original report (377 cases) to assess the effects of CD83 on the age at diagnosis, disease stage, and histology. Risk estimates (ORs) and 95% confidence intervals were estimated using logistic regression; trend tests were performed under an additive model. Results: Consistent with the original report, carriers of the CT or CC genotypes for one of the five CD83 SNPs evaluated (rs750749) demonstrated a 30% and 50% reduction in disease risk, relative to carriers of the more common TT genotype (p-trend=0.02). Two additional SNPs also resulted in consistent findings (rs9296925: p-trend=0.07 and rs9370729: p-trend=0.08), although the effects observed did not reach statistical significance at the 0.05 level. Pooled evaluation of cases from the two aforementioned studies suggested differences in the distribution of susceptibility alleles by histology; adenocarcinoma cases were more likely to be carriers of the susceptibility alleles for SNP rs9370729 (p-trend=0.02) and SNP rs750749 (p-trend=0.09). No differences were observed in the age or stage of diagnosis of carriers for CD83 susceptibility alleles relative to non-carriers. Conclusions: We confirm an association between CD83 polymorphisms and cervical cancer and suggest the possibility that CD83-disease associations might be heterogenous by tumor histology. [Copyright &y& Elsevier]

Abstract: Objectives: To evaluate survival after detection of recurrent cervical cancer by FDG-PET in symptomatic versus asymptomatic patients. Methods: This is a prospective registry study of 103 patients treated with definitive chemoradiation for advanced cervical cancer who demonstrated no abnormal FDG uptake (a complete metabolic response, CMR) on their 3-month posttherapy FDG-PET. Their median age was 48 years (range 26–84). The clinical stages were Ib in 38, IIa in 1, IIb in 39, and IIIb in 25. All patients underwent subsequent surveillance FDG-PET. Patients were grouped according to symptom status at the time of the surveillance FDG-PET. Recurrence sites and survival data were analyzed. Results: The median time from the 3-month posttherapy FDG-PET to the first surveillance FDG-PET was 13 months. 25 patients (25/103; 24%) were symptomatic at the time of surveillance FDG-PET and 21 of these had FDG-PET findings indicative of recurrence. 78 patients (78/103; 76%) were asymptomatic and 9 of these had tumor recurrence detected by PET. All recurrences were confirmed by biopsy or radiologic progression. The recurrences in the 21 symptomatic patients were loco regional in 4 and distant in 17. The 9 asymptomatic patients had isolated loco regional disease in 8 and distant disease in 1. All patients received treatment for recurrence. The three-year cause-specific survival for symptomatic recurrences was 19% versus 59% for asymptomatic recurrences (p =0.09). Conclusions: Surveillance FDG-PET can detect asymptomatic recurrent disease that is potentially amenable to salvage therapy. Prospective investigation of surveillance PET is warranted. [Copyright &y& Elsevier]

Abstract: Objective. : The objective of our study was to determine the accuracy of gynecology residents'' colposcopic impressions. Methods. : A retrospective review of colposcopic examinations was performed. Colposcopic impressions were compared to cervical biopsy and the results stratified by level of residency training. κ Statistics were calculated to determine the strength of correlation between impression and biopsy results. Results. : Agreement within one-step between cervical histology and the colposcopic impression was found in 351 (77%) of the subjects. Histology impression agreement occurred in 92% of the nurse practitioner procedures, 77% of the second year resident (R2) cases, 75% of R3 colposcopies and 73% of the R4 procedures. The association between cervical biopsy and impression was highly significant (P <0.0001). However, the strength of the correlation was only slight (κ =0.197). The κ value was highest for the nurse practitioners (0.376, fair correlation) and lowest for the R3 residents (0.110, slight correlation). The positive predictive value for the association of any colposcopically detected abnormality with any histologic abnormality was 64.1%. The overall PPV was highest for the nurse practitioners (79.3%) and lowest for the R2 residents (58.7%). Conclusions. : While the colposcopic impressions of gynecology residents were accurate, there was little difference in the accuracy of colposcopic assessment based upon the level of resident training. [Copyright &y& Elsevier]

Abstract: Objective: To assess the efficacy and toxicity profile in patients with recurrent ovarian or primary peritoneal cancer treated with topotecan at 2.5 mg/m2 days 1 and 8 plus vinorelbine at 25 mg/m2 days 1 and 8 every 3 weeks. Materials and methods: Eligibility criteria included patients with recurrent primary peritoneal or epithelial ovarian cancer with either platinum-resistant or platinum-sensitive disease. Patients were required to have a performance status of ≤2 and normal hepatic and renal function. Response to therapy and toxicity were assessed using standard criteria. Chi square and Student''s t-tests were used as appropriate. Survival was assessed with Kaplan–Meier method. Results: All 40 patients enrolled were assessable for response. The median age of the patients was 58 years (range 30–82). Median treatment-free interval was 4.0 months. A total of 216 cycles of chemotherapy were administered with a median of 5.0 cycles per patient. Overall median TTP with this treatment regimen was 19 weeks (range 2–136 weeks). The response rate was 30% overall, and the response for platinum-sensitive and platinum-resistant patients was 44% (95% CI:22–69%) and 18% (95% CI:5–40%) respectively. Median progression-free survival was 3.0 months (range 1–9 months). Median overall survival was 16.4 months (range 1.5–51.7 months). Assessment of toxicity by patient showed 58% demonstrating grade 3/4 neutropenia with the vast majority being uncomplicated. No severe non-hematological toxicity was observed. Conclusion: Administration of topotecan and navelbine is feasible with demonstrable activity and tolerable toxicity. This regimen may be considered especially in platinum-sensitive patients if a non-platinum based doublet is desired. [Copyright &y& Elsevier]

Abstract: Objective.: Radical hysterectomy with regional lymphadenectomy is the surgical procedure of choice for stage IA–IIA cervical carcinoma. The goal of this study was to evaluate the outcome of patients with no residual tumor (T0) in their hysterectomy specimens. Methods.: An analysis of all women who underwent type II or III hysterectomy for invasive cervical cancer from 1989 to 2005 was performed. The pathologic data and clinical outcome of each patient was documented. T0 subjects were compared to the remainder of the cohort. Survival was evaluated with the Kaplan–Meier method. Results.: A total of 594 patients were identified. No residual tumor was noted in the hysterectomy specimens of 171 (29%). T0 patients had earlier stage tumors than the controls (IA 32%, IB 68%) (p <0.0001). Lymphadenectomy was performed in 89% of the T0 subjects. No T0 patients had lymphatic or parametrial disease. The median node yield was similar between the T0 group and those with residual tumors (24 vs. 25) (p =0.34). Adjuvant therapy was not administered to any of the T0 subjects. There were no recurrences and no cancer-related deaths in the T0 patients. Kaplan–Meier analysis revealed an improved disease free (p <0.0001) and overall survival (p <0.0001) for the T0 subjects compared to women with residual tumors. The results were similar when the analysis was restricted to stage IB1 patients (p =0.0004 and 0.002). Conclusions.: A T0 radical hysterectomy specimen indicates a curative therapy. This subgroup of patients has a favorable prognosis with minimal risk of recurrence. Patients with T0 tumors may be candidates for less intensive, abbreviated follow-up. [Copyright &y& Elsevier]

Abstract: Purpose: To determine if brachytherapy alone is adequate adjuvant local therapy in patients classified as intermediate risk after complete surgical staging for endometrioid adenocarcinoma. Methods: Between 1991 and 2004, 78 patients with FIGO stage IA–II (occult) disease meeting the eligibility criteria of GOG 99 received adjuvant radiotherapy following complete surgical staging (total abdominal hysterectomy and bilateral salpingo-oophorectomy, peritoneal cytology, and pelvic±para-aortic lymphadenectomy) for endometrioid adenocarcinoma at Washington University in St. Louis. Forty-two patients received postoperative vaginal brachytherapy alone and 36 received postoperative pelvis external radiotherapy (XRT) and vaginal brachytherapy. Fifty-two patients were classified as having high intermediate risk disease and 26 patients had low intermediate risk disease as defined by GOG 99. Median follow-up for all patients was 55 months. Results: The 5-year overall and disease-free survivals for all patients were 86% and 89%, respectively. There was no difference in 5-year disease-free survivals among patients classified as high intermediate risk vs. low intermediate risk (p =0.26) or in terms of radiation treatment received (p =0.95). There were two patients that had >grade 2 gastrointestinal complications, both were treated with external radiotherapy and vaginal brachytherapy. Conclusions: Vaginal brachytherapy alone results in minimal morbidity and is adequate local therapy for intermediate risk patients with endometrioid adenocarcinoma after complete surgical staging. [Copyright &y& Elsevier]

Abstract: Objective. : To assess the efficacy and toxicity profile in patients treated with topotecan at 2.0 mg/m2/day×3 days every 3 weeks. Materials and methods. : Eligibility criteria included patients with recurrent primary peritoneal or epithelial ovarian cancer with ≥6 months elapsed from time of prior platinum treatment. Patients were required to have a performance status of ≤2 and normal hepatic and renal function. Response to therapy and toxicity was assessed using standard criteria. Chi-square and Student''s t tests were used as appropriate. Survival was assessed with Kaplan–Meier method. Results. : All 40 patients enrolled were assessable for response. The mean age of the patients was 63.2 years (range 43–85). Median time to progression from initial treatment was 11.8 months. A total of 286 cycles of chemotherapy were administered with an average of 7.1 cycles per patient. Overall median time to progression (TTP) with 3-day topotecan treatment was 21 weeks (range 6–43 weeks). Of the 33 patients with measurable disease, 24% (11–42%, 95% CI) demonstrated a response. Seven patients had CA-125 evaluable disease with a response of 43% (10–89%, 95% CI). Median progression-free survival (PFS) was 16 weeks (range 12–21 weeks, 95% CI). Median overall survival was 106 weeks (range 76–117 weeks, 95% CI). Assessment of toxicity by patient showed 90% demonstrating grade 3/4 neutropenia with the vast majority being uncomplicated. No severe non-hematological toxicity was observed. Conclusion. : Administration of topotecan as a 3-day regimen is feasible with demonstrable activity and tolerable toxicity. Critical comparison to the 5-day regimen in a randomized fashion is warranted. [Copyright &y& Elsevier]

The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients. Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated. 361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p -value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p -value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p -value = 0.02) and hazard ratio (HR) for progression of 0.66 (p -value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables. SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation. • NME1 and EGFR were the candidate genes most strongly associated with progression in this endometrial cancer patient cohort. • SNP rs13222385 in EGFR also remained significant after adjusting for prognostic clinical variables. • Although hypothesis generating, further work is needed to validate these findings and assess for other predictive SNPs. [ABSTRACT FROM AUTHOR]

Objective No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment. Methods This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t -test (for marker expression) and Kaplan-Meier test (for correlations). Results On univariate analysis, primary ovarian disease, CA-125 < 81 units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19–5.93; p = 0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls ( p < 0.0001). None of the molecular markers were significantly associated with survival. Conclusions Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases. [ABSTRACT FROM AUTHOR]

Objectives: There remains a need to develop targeted therapies for recurrent AGCT that produce measurable tumor responses. The FOXL2C134W mutation is identified in nearly all AGCT. In a genetically engineered mouse model utilized by Cluzet et al., tumorigenesis was associated with the inactivation of p53 and Rb pathways, increased circulating androgens, estradiol, and antimullerian hormone along with decreased FOXL2 abundance [1]. By examining the pathways involved in granulosa cell development, including limitations on GnRH-induced apoptosis, aromatase induction, and increased androgen expression, a novel treatment regimen is proposed for recurrent AGCT: bicalutamide (androgen receptor antagonist), exemestane (aromatase inhibitor), and leuprolide acetate (gonadotropin-releasing hormone receptor agonist) to block excess steroidogenesis seen in AGCT. Methods: Six patients identified at our institution with recurrent AGCT and tumor AR positive (by Leica IHC-AR27 antibody) were treated with bicalutamide 50mg PO once daily, Exemestane 25mg PO once daily, and Leuprolide acetate 3.75mg IM every four weeks. All patients were heavily pre-treated, with two to seven prior lines of therapy and had undergone two to seven surgeries. Prior treatment lines consisted of prior chemotherapy, hormonal therapy, and targeted therapies, including bevacizumab and everolimus. Patients were monitored for toxicities and for response to treatment via surveillance exams, inhibin B levels and CT scans. Results: Based on RECIST v1.1 criteria, of the six patients receiving bicalutamide, exemestane, and leuprolide acetate, two patients had a partial response, four patients had stable disease and one patient had progressive disease. Strong AR expression in 95% of cells was identified in the tumors of patients who had a partial response. This drug combination has been well-tolerated. There has been one hospitalization for disease-related complications; no other grade 3 or higher toxicities reported thus far. Conclusions: Based on the response of our institutional cohort and the rationale behind the antiandrogen/aromatase inhibitor/GnRH agonist combination in recurrent AGCT, this regimen of bicalutamide/exemestane/leuprolide acetate is a promising treatment. An NRG concept has been submitted to proceed with a single-arm, multicenter phase II study of this regimen in patients who meet the criteria of recurrent AGCT, AR expression, measurable disease, and one prior line of therapy. [ABSTRACT FROM AUTHOR]

Objective The immune system is critical for controlling the progression of HPV cervical disease and the development of cancer. This study aimed to identify cervical cancer susceptibility alleles in candidate immune-modulating genes. Methods Our family-based study involved a cohort of 641 probands (women with ICC/CIN III) and their biologic parents or siblings (641 trios). In the discovery phase (stage 1), involving 288 of the trios, 80 tag single nucleotide polymorphisms (SNPs) in 11 immune-modulating genes (IFNG, IFNGR1, IFNGR2, JAK1, JAK2, STAT1, STAT6, IL12A, TNF, LTA and LTB) were evaluated on the GoldenGate platform. We used the combined dataset for a total of 641 trios (stage 2) and the Taqman platform to validate the SNPs that had proved significant in the discovery dataset. The transmission disequilibrium test was used to detect significant shifts in allelic transmissions in the datasets. Results Two SNPs in JAK2 and one SNP in STAT6 showed significant allelic association with cervical cancer in the stage 1 discovery dataset and were replicated in the larger joint analysis stage 2 dataset (JAK2 rs10815144, P = 0.0029 and rs12349785, P = 0.0058; and STAT6 rs3024971, P = 0.0127). An additional SNP in exon 19 of JAK2 (rs2230724) was also examined in the combined dataset due to its strong linkage disequilibrium (LD) with rs10815144. It was also significant (P = 0.0335). Conclusions Our results suggest an association of SNPs in JAK2 and STAT6 with cervical cancer. This association should be investigated in additional cervical cancer populations. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Aberrant expression of SOX4 in endometrial cancer has been identified and partially was contributed to hypermethylation of miR-129-2. Other miRNAs are suspected to influence SOX 4 as well. The current study seeks to identify other hypermethylated miRNAs that regulate SOX4 in endometrial carcinomas. Methods: Methylation levels of miRNA promoter regions were measured by combined bisulfite restriction analysis (COBRA) and pyrosequencing assays. Gene expression was determined by RT-qPCR. Methylation level of a miRNA locus was corrected with clinicopathologic factors for 252 gynecological specimens. Results: In silico analysis identified 13 miRNA loci bound on the 3′-UTR of SOX4. Using COBRA assays, increased methylation of miR-203, miR-219-2, miR-596, and miR-618 was detected in endometrial cancer cells relative to those seen in a normal cell line and in normal endometrium. Transfection of a miR-203 mimic decreased SOX4 gene expression. Hypermethylation of miR-203 was detected in 52% of type I endometrioid endometrial carcinomas (n =131) but was not seen in any of 10 uninvolved normal endometria (P <0.001). Methylation status of miR-203 was significantly associated with microsatellite instability and MLH1 methylation in endometrial tumors (P <0.001). Furthermore, hypermethylation of miR-203 was found in endometrioid and clear endometrial subtype tumors, but not in cervical squamous cell and ovarian carcinomas. Conclusions: Hypermethylation of miR-203 is a frequent event in endometrial carcinomas and is strongly associated with microsatellite instability and MLH1 methylation status. Thus, miR-203 methylation level might represent a marker for patients with endometrioid and clear endometrial sub-cancers. [Copyright &y& Elsevier]

Abstract: Objectives: Inherited genetic variability contributes to susceptibility to cervical cancer. We investigated the association of single nucleotide polymorphisms (SNPs) in the human epidermal growth factor receptor (ERBB) family with cervical cancer. Methods: We used the transmission disequilibrium test (TDT) to look for excessive transmission of tag single nucleotide polymorphisms (tSNPs) in ERBB family members EGFR, ERBB2, ERBB3, and ERBB4 in a large sample of women with invasive and in situ cervical cancer and their biological parents (628 trios). The study used a discovery set of trios (244) analyzed by Illumina GoldenGate in which SNPs reaching a P <.05 were re-tested by TaqMan in the combined set of 628. We also explored collaborative effects of different ERBB alleles. Results: Based on single SNP TDT tests we identified 16 significant SNPs in the discover stage and six of 14 SNPs that could be assayed by TaqMan were significantly overtransmitted in women with cervical cancer in the combined replication set. Four SNPs were located in intron 1 of EGFR and two SNPs in intron 24 of ERBB4. The EGFR variants are located near multiple enhancers, silencers, and the previously identified functional common polymorphisms in intron 1. Conclusions: Our data provide evidence for the involvement of intron 1 EGFR variants and intron 24 ERBB4 variants in modulating risk for the development of in situ and invasive cervical cancer. These variants should be examined in additional populations and functional studies would be needed to confirm this hypothesis. [Copyright &y& Elsevier]

Abstract: Objective: We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. Methods: Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50mg/m2 day 1, topotecan 0.75mg/m2 days 1, 2 and 3 and bevacizumab 15mg/kgday 1 every 21days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6months. We explored PET/CT as a potential early indicator of response to therapy. Results: Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1–19). Median follow-up was 10months (range, 1.7–33.4). The 6-month PFS was 59% (80% CI: 46–70%). In 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4–14%) and 8 PR (31%; 80% CI: 19–45%) lasting a median of 4.4months. Ten patients had SD (39%; 80% CI: 25–53%) with median duration of 2.2months. Median PFS was 7.1months (80% CI: 4.7–10.1) and median OS was 13.2months (80% CI: 8.0–15.4). All patients were evaluated for toxicity. Grade 3–4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. Conclusion: The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity. [Copyright &y& Elsevier]

Abstract: Objective: Heritable polymorphisms modulate metastatic efficiency in Cancer Single nucleotide polymorphisms (SNPs) in MMP9 (rs17576) and SIPA1 (rs746429, rs931127) have been associated with nodal metastases in multiple cancers. We investigated the association of these SNPs with nodal metastases in early-stage cervical cancer. Methods: Consecutive patients with stage IB cervical cancer who underwent a pelvic lymph node (LN) dissection were included. Cases (>1 positive LN, n =101) were compared with controls (negative LN pathology, n =273). Genotyping was performed on genomic DNA in the 3 SNPs using a TaqMan assay and correlated with clinical variables. Results: The G allele at SIPA1 rs931127 was associated with an increased risk of nodal disease (OR 1.9, P =0.03) and approached significance at SIPA 1 rs746429 (OR 2.2, P =0.09) and MMP9 rs17576 (OR 1.5, 0.08). In patients with stage Ib1 lesions (n =304), the G allele at both SIPA1 SNPs was associated with LN metastases (rs746429 OR 10.1, P =0.01; rs931127 OR 2.4, P =0.01). In patients with no lymph vascular space invasion, SIPA1 SNPs were again associated with LN metastases, and all patients with nodal disease had at least one G allele at SIPA1 rs746429. Conclusions: In this case–control study, SNPs in SIPA1 varied statistically in cervical cancer patients with and without nodal metastases and in MMP9 after controlling for stage and lymphvascular space invasion. Further work is needed to characterize inherited polymorphisms that provide a permissive background for the metastatic cascade. [Copyright &y& Elsevier]

Abstract: Objectives: The aim of this study was to evaluate the effect of number of chemotherapy cycles and other clinical and pathologic factors on progression-free (PFS) and overall survival (OS) in patients with newly diagnosed cervical cancer. Methods: We identified 118 patients with locally advanced cervical cancer (stages IB2–IVA) treated with combination weekly cisplatin (40 mg/m2) and radiation therapy (RT) between 2003 and 2007. Kaplan–Meier and Cox proportional hazard models were utilized to evaluate PFS and OS for associations with number of chemotherapy cycles and other factors. Results: The majority of patients had stage IB2 or II disease (70%), squamous histology (91%), and size <6 cm (65%). Median RT duration was 50 days and 95% received brachytherapy. Thirty percent of patients completed <6 cycles of chemotherapy, and estimated PFS and OS were 63% and 75%, respectively. In multivariate analyses, the number of chemotherapy cycles was independently predictive of PFS and OS. Patients who received <6 cycles of cisplatin had a worse PFS (HR 2.65; 95% CI 1.35–5.17; p =0.0045) and OS (HR 4.47; 95% CI 1.83–10.9; p =0.001). Advanced stage, longer time to RT completion, and absence of brachytherapy were also associated with decreased OS and PFS (p <0.05). Similar results were found when analysis was conducted using a breakpoint of at least five but not less than five chemotherapy cycles. Higher grade was associated with decreased PFS (p =0.03) but not OS. Age, race, BMI, tumor size, smoking, histology, and IMRT were not statistically significant for OS or PFS. Conclusions: Aggressive supportive care to minimize missed chemotherapy treatments may improve survival after chemoradiation. [Copyright &y& Elsevier]

Abstract: Objective: A 10-point “Surgical Apgar Score” (SAS) for predicting postoperative complications after general and vascular operations has recently been developed and validated. We sought to estimate the ability of this metric to predict major postoperative complications in women undergoing ovarian cancer cytoreductive procedures. Methods: All eligible patients with stage III and IV epithelial ovarian, fallopian tube and primary peritoneal cancer undergoing surgical cytoreduction at our institution between 1999 and 2005 were included. Medical records were reviewed and demographic data, clinicopathologic characteristics, comorbidities and intra and postoperative complications were analyzed. The surgical score was calculated from intraoperative blood loss, lowest mean arterial pressure and lowest heart rate as previously described. Descriptive statistics, univariable and multivariable analyses were used as appropriate. Occurrence of major postoperative complications represented the primary outcome. Results: A total of 232 cases were analyzed. Mean age was 62 years. Most patients were Caucasian (92%) and diagnosed with stage III disease (83%). Mean duration of surgical procedure was 171 (70–350) minutes. Median SAS was 6 points (range 1–9). On multivariable analyses, occurrence of major postoperative complications was associated with multiple comorbidities (OR 2.2; 95% CI:1.5–3.1; p <0.0001), stage IV disease (OR 2.5; 95% CI:1.1–5.7; p =0.03), ASA class (OR 2.4; 95% CI:1.2–4.7; p =0.01) and SAS≤4 (OR 7.4; 95% CI:2.9–18.8; p <0.0001). Conclusions: Lower SAS (≤4) is the most powerful predictor of postoperative complications in patients undergoing cytoreductive surgery for advanced epithelial ovarian cancer. This prognostic tool may prove helpful for triaging such patients to optimal postoperative levels of care and directing counseling, monitoring and management in the postoperative period. [Copyright &y& Elsevier]

Abstract: Objective: To explore the yield and impact of perioperative imaging on management among patients undergoing surgical resection and treatment of uterine sarcomas. Methods: A retrospective chart review was done for women with histologically confirmed uterine sarcomas treated at Barnes Jewish Hospital/Washington University from 2001 to 2007. Descriptive statistics, Cox multivariate models, and Kaplan–Meier plots were used to evaluate associations and survival. Results: A total of 92 patients were identified and 55 (60%) were diagnosed with stage III–IV disease. Perioperative imaging was obtained in 84 (91%) cases, including chest X-ray in 66 (72%), computerized tomography (CT) of the abdomen and pelvis in 59 (64%), chest CT in 33 (36%), positron emission tomography (PET) in 8 (9%), and CT of the head, pelvic magnetic resonance imaging (MRI), or bone scan in a total of 2 (2.2%). Imaging identified abnormalities concerning for metastases in 30 (32%) studies. Thirty-four recurrences have been documented, and 21 (62%) of these treatment failures were extrapelvic. Multivariate analysis of this series noted that tomographic evidence of extrauterine disease predicted recurrence (p =0.028) and incomplete surgical resection (p =0.003, HR 6.0 95% CI 1.9–19.9) predicted disease-free survival. Imaging contributed to change in surgical and post-surgical treatment decisions in 8 (9%) patients. Conclusion: Pretreatment imaging studies change management in a minority of patients with newly diagnosed uterine sarcomas. [Copyright &y& Elsevier]

Abstract: Objective: To determine the long-term effects of radical hysterectomy on bladder and bowel function. Methods: Subjects included women who underwent radical hysterectomy for early stage cervical cancer between 1993 and 2003. Two contemporary controls who underwent extrafascial abdominal hysterectomy for benign disease were identified for each subject. Identified subjects and controls were surveyed. The Urogenital Distress Inventory (UDI) was used to assess symptoms of incontinence, and the Incontinence Impact Questionnaire (IIQ) was used to examine the impact of incontinence on quality of life. The Manchester Health Questionnaire and Fecal Incontinence Quality of Life Scale (FIQL) were used to assess anorectal symptoms. Results: Surveys were returned by 66 of 209 (32%) subjects and 152 of 428 (36%) controls. Overall, 50% of subjects and 42% of controls reported mild incontinence symptoms; 34% of subjects and 35% of controls reported moderate–severe symptoms (p =0.72). Incontinence was associated with moderate–severe impairment in 18% of subjects and 14% of controls (p =0.74). Fecal incontinence symptoms were uncommon, not differing between subjects and controls. Conclusion: Urinary incontinence is relatively common after radical hysterectomy, but severe anorectal dysfunction is uncommon. Radical hysterectomy does not appear to be associated with more long-term bladder or anorectal dysfunction than simple hysterectomy. [Copyright &y& Elsevier]

Abstract: Objectives: The optimal treatment regimen for advanced stage endometrial carcinoma (EC) is yet to be established. The objective of this study was to evaluate the feasibility and toxicity of delivering sequential doxorubicin–cisplatin (AC) followed by whole abdomen irradiation (WAI). Methods: Patients with stage III/IV EC with <2 cm residual disease were eligible. The treatment regimen included 3 cycles of AC (50 mg/m2 each) followed by WAI plus para-aortic and/or true pelvic boost. Outcome objectives were feasibility of the regimen, acute toxicity and chronic irradiation toxicity monitored for at least one year after completing treatment. Results: Thirty-one patients were entered onto the study. Twenty-nine were evaluable for feasibility of the regimen, and 22 patients were evaluable for chronic radiation toxicity with a median follow-up of 21 months. Three patients (14%) experienced severe chronic toxicity including one treatment-related death. The five-year progression-free survival (PFS) and overall survival (OS) was 52.5% and 60.1% respectively. Conclusions: The results from the first stage of this study found this regimen of sequential AC followed by WAI eligible for further study. Although toxicity was not excessive at the time of completion of the first stage, there was insufficient interest by the Gynecologic Oncology Group to continue study of this regimen; therefore, a conclusion regarding feasibility and chronic toxicity in an expanded cohort as initially intended is not possible. The risk of recurrence in advanced EC is sufficiently high that may warrant further investigation of sequential chemotherapy and WAI. [Copyright &y& Elsevier]

Abstract: Objective. : Studies of cervical cancer and its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3), have identified genes that often show aberrant DNA methylation and therefore represent candidate early detection markers. We used quantitative PCR assays to evaluate methylation in five candidate genes (TNFRSF10C, DAPK1, SOCS3, HS3ST2 and CDH1) previously demonstrated as methylated in cervical cancer. Methods. : In this analysis, we performed methylation assays for the five candidate genes in 45 invasive cervical cancers, 12 histologically normal cervical specimens, and 23 liquid-based cervical cytology specimens confirmed by expert review as unequivocal demonstrating cytologic high-grade squamous intraepithelial lesions, thus representing the counterparts of histologic CIN3. Results. : We found hypermethylation of HS3ST2 in 93% of cancer tissues and 70% of cytology specimens interpreted as CIN3; hypermethylation of CDH1 was found in 89% of cancers and 26% of CIN3 cytology specimens. Methylation of either HS3ST2 or CDH1 was observed in 100% of cervical cancer tissues and 83% of CIN3 cytology specimens. None of the five genes showed detectable methylation in normal cervical tissues. Conclusion. : Our data support further evaluation of HS3ST2 and CDH1 methylation as potential markers of cervical cancer and its precursor lesions. [Copyright &y& Elsevier]

Abstract: Objectives. : There is a well known association between obesity and endometrial cancer. We sought to examine the relationships between body mass index (BMI), as a measure of obesity, and known demographic, clinical, and molecular characteristics of microsatellite instability and MLH1 promoter methylation in a cohort of patients with endometrial cancer. Methods. : Corpus cancer specimens were prospectively obtained from 473 consecutively enrolled patients between 1992 and 2004. Clinical and pathologic data were extracted from review of the medical record. Microsatellite instability (MSI) was evaluated in all tumors, and methylation of the MLH1 promoter was determined for MSI positive tumors. Results. : The median (SD) age and BMI were 64.8 years (11.9) and 33.5 (9.4), respectively. Histology included 376 endometrioid (79%), 69 serous/clear cell or mixed (15%), and 28 sarcomas (6%). Median BMI was 32.4 for endometrioid, 31.0 for serous/clear cell or mixed, and 27.8 for sarcomas (p =0.14). BMI was negatively associated with age at surgery (p <0.01). The remainder of analyses excluded sarcoma histology. BMI was associated with stage of disease; patients with stage I/II disease had significantly higher BMI than those with stage III/IV disease (32.6 vs. 30.6; p =0.02). In relation to molecular features of endometrial cancer, BMI was significantly different between MSI positive tumors compared to MSI negative tumors (30.3 vs. 32.7; p =0.02). MSI was also significantly different between tumor histology, occurring with a higher frequency in Type I than Type II tumors (p <0.01). Conclusions. : The majority of endometrial cancer patients are obese. Those with higher BMI are more likely to be younger, present with early stage disease, and have MSI negative tumors. [Copyright &y& Elsevier]

Abstract: Objective. : To report the utility of the monoclonal, anti-vascular endothelial growth factor antibody bevacizumab in combination with cytotoxic chemotherapy for women with recurrent cervical cancer. Methods. : A retrospective analysis of women with recurrent cervical cancer treated with bevacizumab combination therapy was performed. Results. : Six patients were identified. The patients had a median of 3 prior regimens. All of the patients had multisite, metastatic disease. The combination regimen included IV 5-fluorouracil in 5 (83%) patients and capecitabine in one (17%) subject. Treatment was well tolerated. Grade 4 toxicity occurred in one patient who developed neutropenic sepsis. Clinical benefit (CR, PR, or SD) was noted in 67% of the subjects. This included 1 (17%) complete response, 1 (17%) partial response and two (33%) patients with stable disease. The median time to progression for the four women who demonstrated clinical benefit was 4.3 months. Conclusions. : Combination bevacizumab is well tolerated and displayed encouraging anti-tumor activity in heavily pretreated recurrent cervical cancer. [Copyright &y& Elsevier]

Abstract: Objective.: To use microarray data to reveal regions of potential chromosomal loss or gain important in cervical intraepithelial neoplasia (CIN) and invasive cervical cancer by identifying mRNA expression biases in contiguous chromosomal regions. Methods.: Data from three RNA expression microarray experiments were used: one primary experiment using cDNA arrays profiling gene expression in cervical epithelium from viral cytopathic effect to invasive cancer, one experiment using Affymetrix arrays profiling gene expression in invasive cancerous cervical epithelium, and one experiment using Affymetrix arrays profiling gene expression in CIN cervical biopsy specimens. Gene expression was aligned along chromosomes to reveal regions of significant chromosomal imbalance. Regions showing significant gain or loss and verified in more than one experiment are presented here. RT-PCR was performed to validate expression of one gene in a region. Results.: Gain of 3q was detected from the CIN II (P =0.018), CIN III (P =0.005), and invasive cancer (P =0.0002) cDNA arrays, and gain of 12q was detected from the CIN (P =0.05) and invasive cancer (P =0.05) Affymetrix arrays. Loss of 6p was detected from the CIN III (P =0.004) cDNA arrays and invasive cancer (P =0.05) Affymetrix arrays. Loss of 4q was detected from the invasive cancer (P =0.04) cDNA arrays and invasive cancer (P =0.05) Affymetrix arrays. RAN, located in the region of gain on 12q24.3, was overexpressed in CIN and invasive cancer. Conclusions. : Alignment of microarray expression data by chromosomes can be used to estimate regions of potential chromosomal aberration and identify differentially expressed genes important in the development of CIN and invasive cancer. [Copyright &y& Elsevier]

Abstract: Objective. : Recent additions of novel chemotherapeutics, such as pegylated liposomal doxorubicin (PLD) and topotecan (TPT), have provided clinicians with multiple options for treating recurrent ovarian cancer. Evaluating treatment response in patients without radiographic or physically measurable disease is problematic, thereby CA-125 values may be the only available objective criteria. It has been advocated that several cycles of novel agents are required prior to an observed CA-125 response. In this study, we sought to gain insight into response patterns regarding CA-125 in responders vs. non-responders and to determine whether specific “cut-off” values could help predict ultimate clinical response. Methods. : Patients with recurrent ovarian cancer who received either single agent PLD, TPT, or both were included. CA-125 levels were evaluated prior to initiation of chemotherapy and thereafter for each additional cycle. The Rustin criteria were utilized to evaluate CA-125 response. Results. : Fifty-four of 120 patients were judged to be responders. When comparing responders to non-responders, as expected, the majority of responders demonstrated a decrease after each of the first 4 cycles. However, nearly 50% of responders who received PLD demonstrated an increase in CA-125 after cycle 1. There were no responders who demonstrated two successive rises in CA-125. Conclusion. : The majority of patients with recurrent ovarian cancer who will ultimately manifest a CA-125 response to novel agents, such as TPT or PLD, will demonstrate a decrease following each cycle. An initial increase in CA-125 should not mandate discontinuation of current therapy, but a successive rise over two or more cycles reliably predicts that a treatment response ultimately is unlikely. [Copyright &y& Elsevier]

Abstract: Objective: : The recent approval of a vaccine to prevent HPV infection is an important advance in cervical cancer prevention. This article is intended to provide gynecologic oncologists with a comprehensive background in modern cervical cancer prevention strategies. Methods: : We describe and contrast the quadrivalent and bivalent vaccines. More established cervical cancer prevention strategies are reviewed, with comments on the impact of HPV vaccination. Clinical guidance is provided for use of the approved quadrivalent vaccine. Safety and side effects of both vaccines are reviewed and future questions and challenges are explored. Results: : It is vitally important that both vaccinated and unvaccinated women continue to fully engage in cervical cancer prevention, including cervical cancer screening, follow-up of abnormal screens, and treatment of premalignant lesions. A quadrivalent virus-like particle vaccine has now been approved for use in girls and women ages 9 to 26. A bivalent vaccine may be available soon. Vaccine efficacy in clinical trials has been outstanding, with 100% protection against HPV-type-specific cervical intraepithelial neoplasia (CIN) II and III. Conclusions: : Comprehensive cervical cancer protection now includes prophylactic vaccination for girls and young women in addition to screening and treatment of premalignant changes. Gynecologic oncologists will continue to play an important role in promoting optimal prevention practices. [Copyright &y& Elsevier]

Abstract: Objective. : While panniculectomy has been shown to be a useful technique in obese women undergoing gynecologic surgery, the long-term outcome of these patients has been poorly described. The goal of this study was to determine the long-term outcomes and patient satisfaction of women who underwent panniculectomy at the time of pelvic surgery. Methods. : A retrospective review of patients who underwent panniculectomy at the time of pelvic surgery between 1996 and 2004 was performed. Postoperative complications and long-term trends in weight were evaluated. Patient satisfaction was assessed by telephone survey. Results. : Forty-two patients were identified. The mean EBL was 522 ml, the mean operating time was just over 4 h. Wound complications were noted in 36% of the subjects. Two weeks after the procedure, 86% of the women had a weight that was lower than their preoperative weight. Weight loss peaked 3 months postoperatively, 97% of the subjects had a net lower weight, with a mean loss of nearly 20 lb. Over the ensuing 2 years, weight loss gradually declined. After 2 years of follow-up, 62% of the women were below their preoperative body weights. The mean weight loss at 24 months was 7 lb. Overall patient satisfaction with the procedure was high. Eighty-six percent of the subjects responded that they would undergo the procedure again given their outcome. Conclusions. : Panniculectomy is well tolerated and associated with a high rate of patient satisfaction. Panniculectomy is a valuable component of gynecologic surgery in morbidly obese women. [Copyright &y& Elsevier]

Abstract: Objective. : Cervical sarcomas are exceedingly rare neoplasms associated with a poor prognosis. The objective of this study was to examine the treatment and outcome of women with cervical sarcomas. Methods. : A hospital-based tumor registry was searched to identify all patients with cervical sarcomas treated between 1986 and 2003. The medical records of all patients were reviewed. All pathologic specimens were reviewed by a single pathologist. Results. : Among 1583 with cervical malignancies, 8 cervical sarcomas were identified. All patients presented with vaginal bleeding. The lesions were clinically staged as IB1 (2), IB2 (4), IIIA (1), and IIIB (1). Five of the tumors were carcinosarcomas. Other histologies included sarcoma NOS (12.5%), leiomyosarcoma (12.5%), and endometrial stromal sarcoma (12.5%). Initial treatment included surgery in 5 patients, radiation in 2, and chemoradiation in 1. Six patients were treated with curative intent, 5 received adjuvant therapy. While both patients treated palliatively died from progressive disease, the other 6 patients remain alive after a mean follow-up of 2.5 years. Two patients have recurred. One patient underwent a thoracotomy for an isolated pulmonary metastasis and is alive with no evidence of disease. The second patient developed pulmonary metastases and is alive 8 months after recurrence. Conclusions. : Cervical sarcomas are rare neoplasms. Most patients present with vaginal bleeding and a palpable cervical mass. While the optimal management of these tumors is uncertain, aggressive primary therapy can result in prolonged survival and cure. [Copyright &y& Elsevier]

Abstract: Objective.: End-of-life (EOL) medical care consumes 10–12% of national health care expenditures and 27% of Medicare dollars annually. Studies suggest that hospice services decrease EOL expenditures by 25–40%. The goal of this study was to compare the total cost of hospital-based resources utilized in ovarian cancer patients during their last 60 days of life for those enrolled in hospice versus those not on hospice. Methods.: Study eligibility included patients who expired from ovarian cancer from 1999 to 2003. Medical records were reviewed for demographic data as well as treatment, response and recurrence rates, histologic type, grade and stage. Billing records were analyzed for costs of inpatient and outpatients visits, including radiologic, laboratory and pharmacy charges. Total cost of hospital resources was compared between patients managed on hospice for >10 days (hospice group) versus <10 days (non-hospice group) using the following methods: Mann–Whitney U, Kruskal–Wallis and Student''s t tests. Overall survival was compared using Kaplan–Meier statistics. Results.: Of the 84 patients analyzed, 67 (79.8%) were in the non-hospice group and 17 (20.2%) were in the hospice group. Demographic, histologic and staging characteristics as well as platinum sensitivity were similar between the two groups before the last 60 days of life. Mean number of chemotherapy cycles before the study period was also similar (20.4 and 21.0, respectively). However, during the study period, the mean total cost per patient in the non-hospice group was $59,319 versus $15,164 in the hospice group (P = 0.0001). A significant difference in cost was noted for mean inpatient days ($6584 vs. $1629, P = 0.0007), radiology ($6063 vs. $2343, P = 0.003), laboratory ($12,281 vs. $2026, P = 0.0004) and pharmacy charges ($13,650 vs. $4465, P = 0.0017) as well as for treating physician per patient ($112,707 vs. $34,677, P = 0.04). Overall survival for the two groups was the same. Conclusions.: Our findings demonstrate that there is a significant cost difference with no appreciable improvement in survival between ovarian cancer patients treated aggressively versus those enrolled in hospice at the EOL. These data suggest that earlier hospice enrollment is beneficial. Furthermore, cost variations between physicians and patients imply that education may be an important variable. [Copyright &y& Elsevier]

Abstract: Objective.: Molecular and environmental co-factors are known risk factors for cervical cancer. The aim of this study was to define the prognostic significance of HPV 18 and its phylogenetically related viruses and smoking on survival in patients with early stage cervical cancer. Methods.: HPV typing was performed on stage IB–IIB cervical tumors. Subjects positive for HPV 18 or 45 were compared to the remainder of the cohort and to women with tumors containing HPV 16, 31, or 52. Tobacco use was ascertained by patient questionnaire. Results.: Tumors of 255 women were evaluated. The presence of HPV 18 or 45 was associated with decreased survival. In a multivariable Cox proportional hazards analysis comparing patients with HPV 18 or 45 containing tumors to the rest of the cohort, the hazard ratio for death from cervical cancer was 2.08 (95% CI, 1.07–4.04). The hazard ratio for death from cervical cancer was 2.41 (95% CI, 1.17–4.96) when the HPV 18 and 45 group was compared to women with HPV 16 or its related viruses, 31 and 52. Smoking was associated with a decreased survival for women with HPV 18 or 45, even after adjusting for other known prognostic factors (P = 0.031). Conclusions.: In addition to pathologic indicators, molecular and environmental co-factors are important determinates of outcome in early stage cervical cancer. The presence of HPV 18 or 45 is associated with a decreased survival. The adverse effect of HPV 18 and 45 on survival is compounded by tobacco use. [Copyright &y& Elsevier]

Abstract: Objectives: Functional assays of tumor suppression and loss of heterozygosity point to a tumor suppressor gene (TSG) for cervical cancer (CC) on chromosome 11q23. We evaluated IGSF4, a putative TSG located in the region, for promoter methylation and gene silencing in CC cell lines and cervical tissues. Methods: IGSF4 expression was detected by both RT-PCR and Northern blot analysis. Methylation maps of the IGSF4 promoter region were generated for 11 CC cell lines based upon bisulfite-genomic sequencing, using seven nested-PCR primer sets covering 97 CpG sites. Methylation fingerprints in primary cervical tissues were evaluated by denaturing high performance liquid chromatography. Results: A 4.4-kb mRNA was seen in cell lines, consistent with the RT-PCR results for both cell lines and primary cervical tissue. IGSF4 was expressed in 6/11 cell lines, 6/8 CC tissues and in all seven normal cervical epithelia. In the cell lines, IGSF4 silencing was associated with promoter hypermethylation. The methylation status in the region covering the −18 to −2 CpG sites correlated most strongly with expression, pointing to the existence of an unmethylated core in the IGSF4 promoter in cell lines expressing IGSF4. This unmethylated core spans approximately 180 bp and is immediately upstream of the ATG site. In primary tissues, methylation was detected in 15/23 (65%) CC specimens but in none of seven normal cervical epithelia. Conclusions: Our data strongly suggest that IGSF4 is a TSG and that gene silencing by aberrant hypermethylation may contribute to the development of CC. [Copyright &y& Elsevier]

Abstract: Objectives: To estimate the sensitivity and specificity of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-d-glucose (FDG) for detecting pelvic and para-aortic lymph node metastasis in patients with uterine corpus carcinoma before surgical staging. Methods: Patients with newly diagnosed FIGO grade 2 or 3 endometrioid, papillary serous, or clear cell adenocarcinoma or uterine corpus sarcoma scheduled for surgical staging, including bilateral pelvic and para-aortic lymphadenectomy, were eligible. PET was performed within 30 days of surgery and interpreted independently by two nuclear medicine physicians. The imaging, operative, and pathologic findings for each patient and each nodal site were compared, and the sensitivity and specificity of FDG-PET in predicting nodal metastasis were determined. Results: Twenty patients underwent FDG-PET before surgical staging. One patient found to have ovarian carcinoma on final pathology was excluded. Of the 19 primary intrauterine tumors, 16 (84%) exhibited increased FDG uptake. One patient did not undergo lymphadenectomy; her chest CT was suspicious for metastatic disease and FDG-PET showed uptake in multiple nodal and pulmonary foci. Metastatic disease was confirmed by percutaneous nodal biopsy. A total of three pathologically positive nodes were found in 2 of the 18 patients (11%). FDG-PET predicted that 3 patients would have positive lymph nodes (2 true positive and 1 false positive). Analyzed by lymph node regions, FDG-PET had 60% sensitivity and 98% specificity. The sensitivity and specificity by individual patient were 67% and 94%, respectively. Conclusions: FDG-PET is only moderately sensitive in predicting lymph node metastasis pre-operatively in patients with endometrial cancer. This imaging modality should not replace lymphadenectomy, but may be helpful for patients in whom lymphadenectomy cannot be, or was not, performed. [Copyright &y& Elsevier]

To compare stages IB1 and IB2 cervical cancers treated with radical hysterectomy (RH) and to define predictors of nodal status and recurrence.Patients with stage IB cervical cancers undergoing RH between 1990 and 2000 were evaluated and clinicopathological variables were abstracted. The perioperative complication rate, estimated blood loss (EBL), and OR time were also tabulated. Variables were analyzed using X2 and t tests. Disease-free survival (DFS) was calculated by Kaplan–Meier method. Multivariate analysis was performed via stepwise logistic regression. Cox-proportional hazards were used to identify independent predictors of recurrence.RH was performed on 109 stage IB1 and 86 stage IB2 patients. Mean age, EBL, and perioperative complication rates were similar. Overall, 38 patients (14 IB1 vs. 24 IB2) had positive nodes (P = 0.01) including 9 patients with positive para-aortic nodes (2 IB1 and 7 IB2). Parametrial involvement (PI) and outer 2/3 depth of invasion (DOI) were significantly more common in the IB2 tumors as well. Patients with IB2 disease received adjuvant radiation more frequently than IB1 patients (52% vs. 37%, P = 0.04). Univariate predictors of nodal status included lymphovascular space involvement (LVSI) (P = 0.001), DOI (P = 0.011), PI (P = 0.001), and stage (P = 0.011). Multivariate analysis identified only LVSI (OR 6.4, CI 2.4–17, P = 0. 0002) and PI (OR 8, CI 3.1–20, P = 0. 0001) as independent predictors of positive nodes. With a median follow-up of 35 months, estimates of DFS revealed tumor size (P = 0.008), nodal status (P = 0.0004), LVSI (P = 0.002), PI (P = 0.004), and DOI (P = 0.0004) as significant univariate predictors. Neoadjuvant chemotherapy, age, grade, histology, and adjuvant radiation were not associated with recurrence. The significant independent predictors of DFS were LVSI (ROR 5.7, CI 2–16, P = 0.0064) and outer 2/3 DOI (OR 5.8, CI 2–20, P = 0.0029). Neither tumor size nor nodal status was a significant predictor of DFS.The prognosis in stage IB cervical cancer seems to be most influenced by presence of LVSI and DOI and not by tumor size as the staging criteria would suggest. These factors are best determined pathologically after radical hysterectomy. This report contains the largest comparison of IB1 and IB2 patients managed by RH. Tumor size failed to predict recurrence or nodal status when stratified by LVSI, DOI, and PI. Treatment decisions based on tumor size alone should be reconsidered. [Copyright &y& Elsevier]

Objective. Panniculectomy has been used to facilitate pelvic surgery in obese women. The goal of this study was to determine the effect of panniculectomy on staging adequacy and lymph node yield in obese women with endometrial carcinoma undergoing staging laparotomy.Methods. A retrospective review of patients with endometrial neoplasms who underwent panniculectomy at the time of hysterectomy was performed. For each subject, two control patients were matched by body mass index (BMI).Results. Twenty-seven endometrial cancer patients who underwent panniculectomy at the time of staging were identified. Panniculectomy was successfully performed in all 27 patients. While the mean number of pelvic nodes was statistically similar between the two groups (16.2 vs. 13.7) (P = 0.199), the paraaortic node count was higher in patients who underwent panniculectomy (4.3 vs. 2.9) (P = 0.032). A paraaortic node dissection was not feasible in 3 (11.1%) of the panniculectomy patients and in 11 (20.4%) of the controls (P = 0.365). There were no differences in intraoperative or postoperative complications or in survival between the two groups.Conclusion. Among obese women with endometrial cancer, panniculectomy is well tolerated, feasible, and associated with acceptable morbidity. While the clinical significance of an increased paraaortic node count is uncertain, our findings suggest that panniculectomy may enhance operative exposure and facilitate endometrial cancer staging. [Copyright &y& Elsevier]

Objective. To evaluate how the independent predictors of recurrence for stage IB2 cervical cancers treated with up-front radical hysterectomy apply to established risk models.Methods. Patients with IB2 cervical cancers diagnosed from 1990 to 2000 were identified from tumor registries of two institutions. Patients were classified into risk groups: high-risk (HR) (positive nodes, parametria, or margins), intermediate-risk (IR) (positive lymph vascular space involvement (LVSI) with any cervical stromal invasion (CSI), or (-) LVSI and > middle- CSI), or low-risk (LR) (absence of HR or IR characteristics). Disease-free survival (DFS) was estimated by Kaplan–Meier method and comparisons between subgroups were studied by log rank. A Cox proportional hazards model was used to determine independent predictors of recurrence.Results. We identified 86 patients with stage IB2 tumors treated by RH. We found 34% of patients to be HR, 60% IR, and 6% LR. Of the 52 IR patients, 28 had (+) LVSI with superficial, middle, and outer 1/3 CSI, and 24 had (-) LVSI with middle or outer 1/3 invasion. Overall, postoperative adjuvant radiation (PRT) was used in 52% of the 86 patients, including 0/5 LR, 16/52 IR, and 29/29 HR patients. Univariate predictors of recurrence were pelvic nodal disease, (+) LVSI, (+) parametria, outer 1/3 CSI, and tumor size > 6 cm. Age, grade, histology, and the use of postoperative radiation were not associated with recurrence. Multivariate analysis identified LVSI as the only independent predictor of recurrence (RR 5.2, P = 0.03). Two-year DFS for LR, IR, and HR patients was 100%, 83%, and 60%, respectively. Only 4/24 (17%) IR patients with (-) LVSI got PRT compared with 12/28 (43%) of IR patients with (+) LVSI. The 2-year DFS for IR patients with (-) LVSI was 96%. IR (+) patients recurred more frequently with a 2-year DFS of 71%.Conclusions. Overall, 66% of patients with IB2 disease were classified as having low or intermediate-risk disease. IR patients with (-) LVSI and all LR patients did well with surgery alone. This study defines the independent importance of LVSI and questions the utility of published IR models when applied to stage IB2 cervical cancer. [Copyright &y& Elsevier]

Objective. The aim of the study was to identify clinical features, define prognostic factors and optimize treatment in patients with colorectal cancer with synchronous ovarian metastases at the time of initial diagnosis.Methods. A retrospective analysis of patients treated by the gynecologic oncology service at Barnes Jewish Hospital between 1990 and 2001 was performed. Twenty-eight patients with colorectal carcinomas with synchronous ovarian metastases at the time of diagnosis were identified. Clinical and pathological characteristics were evaluated, and survival was analyzed by the method of Kaplan and Meier.Results. Abdominal pain was the most common symptom at presentation. Only 14% of the patients presented with gastrointestinal bleeding. Fifty-four percent of patients who underwent barium enema had intrinsic colonic lesions, while 40% of patients who had endoscopies performed had their colonic tumors identified. Preoperatively colon cancer was considered in the differential diagnosis of 71% of the patients. At exploration, the ovarian metastases were significantly larger than the primary colon tumors. Overall, 68% of patients had intraperitoneal nodal metastasis and 86% had transmural extension of their tumors. The only pathological variable associated with survival was tumor grade. The median disease-free survival was 10.3 months while the median overall survival was 18.4 months.Conclusion. Most patients with colon cancer with synchronous ovarian metastases present with vague symptoms. At exploration, locally advanced tumors and other distant metastases such as in the liver are common. Surgical management should include extirpation of the primary tumor and any bulky ovarian metastases. Cytoreduction may be considered in highly selected patients. [Copyright &y& Elsevier]

: ObjectiveTo determine the performance of liquid-based cytology using ThinPrep in the postirradiation surveillance of women with gynecologic malignancies.: MethodsPatients with endometrial and cervical cancer treated with primary or adjuvant radiotherapy between 2000 and 2002 were identified. Details regarding tumor characteristics, treatment, and cytologic and histologic results were abstracted. Binomial variables were compared with the chi-square test. The performance characteristics of liquid-based cytology were evaluated.: ResultsA total of 302 liquid-based cytologic samples from 121 women were evaluated. Overall, 294 (97.4%) of the specimens were adequate for interpretation and 132 (44.9%) were within normal limits. Benign cellular changes, including benign radiation changes, were identified in 141 (47.6%). Atypical squamous cells (ASCUS) were found in 15 (5.1%), recurrent dysplasia in 4 (1.3%), and recurrent carcinoma in 2 (0.7%). Follow-up of the 15 ASCUS smears revealed 13 (86.7%) normal smears and 2 cases of squamous intraepithelial lesions. Benign findings were noted in three of the four smears with SIL. The sensitivity for the detection of SIL was 33%, the specificity 99%, and the positive predictive value (PPV) 25%. Of the 4 patients with local recurrences, 2 were detected by cytology. The sensitivity for the detection of recurrent carcinoma was 50%, with a specificity and PPV of 100%.: ConclusionThinPrep for the surveillance of women with gynecologic malignancies treated with radiotherapy is associated with a high rate of satisfactory samples and a low rate of equivocal and ASCUS cytology. [Copyright &y& Elsevier]

Objectives. The objectives of this study were to evaluate the clinical significance and outcome of pneumatosis intestinalis or bowel perforation in patients with gynecologic malignancies.Methods. A retrospective review of all gynecologic oncology patients at our institution from 1996 to the present was performed to identify computed tomography examinations showing pneumatosis, free air, or the presence of portal venous gas. Admission symptoms, laboratory testing, radiographic and operative findings, and overall survival were evaluated. At the discretion of the attending gynecologic oncologist, patients were managed either surgically or conservatively. Statistical analysis was performed with Fisher''s exact test.Results. Twenty-eight patients met study criteria. Thirteen patients were excluded as a result of radiographic free air immediately following surgery, thus leaving 15 patients for analysis. Sixty percent (n = 9) of patients were managed surgically while 40% (n = 6) were managed conservatively. Pain and tenderness at presentation prompted surgical intervention in a statistically significant number of patients (P = 0.04). No other sign or symptom was significant. Of the 6 patients managed conservatively, 3 (50%) died within 1 week of diagnosis. Survival for the others was 2, 4, and 6 months. Of the 9 patients managed surgically 6 (67%) patients died, 4 within 2 weeks of surgery and the remainder at 2 and 12 months postoperatively. The 3 patients who survived all had surgical intervention and none had radiographic or pathologic evidence of cancer at the time of presentation (P = 0.01). Overall mortality at 6 months was 73% (11/15). Surgical management was associated with prolonged ICU care, mechanical ventilation, and sepsis.Conclusions. Pneumatosis intestinalis and bowel perforation carry a grave prognosis for patients with gynecologic malignancies. These data suggest that patients explored for radiographic evidence of pneumatosis or perforation with preoperative evidence of active malignancy do not survive the immediate postoperative period. The balance between quality and quantity of life must be considered when weighing the options for the management of this condition. [Copyright &y& Elsevier]

Objective. We set out to determine the ability of positron emission tomography with fluorodeoxyglucose to detect groin lymph node metastases from vulvar cancer.Methods. From January 2000 to August 2001, patients with squamous cell cancer of the vulva undergoing radical excision and lymphadenectomy were offered preoperative positron emission tomography. The imaging and pathologic status of each patient and groin were compared, and the sensitivity, specificity, and predictive value of positron emission tomography in predicting nodal metastasis were determined.Results. Fifteen patients underwent positron emission tomography prior to exploration of 29 groins. Six patients had positive scans, suggesting metastases in 8 groins. Pathologically, 5 patients had metastases in 9 groins, with positron emission tomography demonstrating metastases in 4 of 5 patients and 6 of 9 groins with disease. On a patient-by-patients basis, positron emission tomography had a sensitivity of 80%, specificity of 90%, positive predictive value of 80%, and negative predictive value of 90% in demonstrating metastases. On a groin-by-groin basis, positron emission tomography had a sensitivity of 67%, specificity of 95%, positive predictive value of 86%, and negative predictive value of 86%. Positron emission tomography was more accurate in detecting extranodal metastases than disease confined within the groin nodes (P = 0.048).Conclusions. Positron emission tomography is relatively insensitive in predicting lymph node metastasis, and a negative study is not a reliable surrogate for a pathologically negative groin. However, the high specificity suggests that positron emission tomography is useful in planning radiation therapy and as an adjunct to lymphatic mapping and sentinel lymph node dissection. [Copyright &y& Elsevier]

Objective. The aim of this study was to determine the prevalence and types of complementary and alternative medicine (CAM) usage by women with gynecologic cancer in an outpatient midwestern university practice.Methods. Any patient with a gynecologic cancer seen in the outpatient clinic of the gynecologic oncology division at Washington University over a 3-month period was eligible, excluding those patients with a new cancer diagnosis. Subjects completed a questionnaire anonymously. Two by two comparisons were made using the Fisher exact test and P was considered significant at P < 0.05.Results. Nearly half (49.6%) of 113 respondents had used CAM since being diagnosed with cancer. Characteristics significantly associated with CAM use include annual income greater than $30,000, cancer site of origin other than the cervix, and use of CAM prior to cancer diagnosis. Users with annual incomes greater than $30,000 were significantly more likely to use CAM in the “other” category that included acupuncture, reflexology, and electromagnetic therapy. Fewer than 25% of CAM users received information regarding CAM from a physician, nurse, or practitioner of CAM. Women used CAM in hopes of achieving a wide range of potential benefits including both improved well-being and anti-cancer effects. The most common actual benefit these women perceived was an improvement in psychosocial well-being, including increased hope or optimism.Conclusions. American patients with gynecologic cancer frequently use CAM in addition to standard medical therapy. Oncologists caring for women with gynecologic cancer should initiate a dialogue about usage of CAM, discussing the potential adverse effects of CAM and the patient''s therapeutic goals. [Copyright &y& Elsevier]

Objectives. The aims of this study were to determine the response rate of pyrazoloacridine (PZA) in patients with recurrent or persistent endometrial carcinoma and to describe the nature and degree of toxicity in this population.Methods. PZA was initially administered at a dose of 750 mg/m2 intravenously over 3 h every 3 weeks but, due to toxicity, was subsequently reduced to 560 mg/m2 at the same schedule.Results. Among 23 evaluable patients, 11 of whom had had prior chemotherapy, there was 1 (4.3%) partial response and no complete responses. Forty-eight percent of patients had grade 4 neutropenia. There was 1 treatment-related death, in a patient who had prior chemotherapy and radiotherapy.Conclusion. This dose and schedule of PZA has insignificant activity in this population. The optimal PZA dose appears to vary between different populations and may be related to prior therapy. [Copyright &y& Elsevier]

To determine impact and cost savings of a quality intervention involving enhanced patient, provider, and staff education focused on same day discharge after robotic assisted total hysterectomy, and/or bilateral salpingo-oophorectomy with sentinel and/or additional lymph node dissection. A quality project was undertaken at our institution to improve the rate of same day discharge after robotic assisted hysterectomy and to assess the resource utilization savings of such an intervention. Literature supports feasibility and safety of same day discharge for robotic assisted hysterectomies alone or with other procedures for benign and malignant indications. Complex robotic assisted hysterectomies include bilateral salpingo-oophorectomy plus sentinel or additional lymph node resection. We collected historical data via chart review for the 12 months of 2018 (Group A) to determine our baseline same day discharge rate for complex robotic hysterectomies. Faculty, outpatient clinic and perioperative clinic staff were provided with education regarding the same day discharge goal for complex robotic assisted hysterectomies for patients from a single institution in our gynecologic oncology practice. We then prospectively collected the outcome data on patients undergoing complex robotic hysterectomies for the subsequent 12 months in 2019 (Group B). We compared demographic, clinical factors, and factors of resource utilization such as time in surgery and recovery and length of admission. Descriptive statistics and t-test were utilized to compare the groups. One hundred three patients underwent complex robotic assisted hysterectomy in 2018, and 5% (5 patients) were discharged home on the day of surgery (Group A). One hundred twelve patients underwent complex robotic assisted hysterectomy in 2019 (Group B), and 32% (36 patients) were discharged home on the day of surgery. There was no significant difference between mean age (62 vs 64) or BMI (37 vs 36) in the two cohorts, respectively. Median length of stay was 21 hours for patients that were not discharged on day of surgery and 3.5 hours for patients discharged day of surgery. Of the 41 total patients undergoing same day discharge (Group A + Group B), there was one urgent care visit, one ER visit and and no readmissions in 30 days post procedure. A savings of approximately $1975 per case when patient discharged day of surgery. By promoting same day discharge after robotic assisted hysterectomy, 648 in-patient care hours were saved during the 12 months post intervention. A low cost patient and provider education initiative to increase same day discharge after robotic hysterectomy in gynecologic oncology patients positively impacted cost and resource utilization without negatively impacting readmission rates and ER utilization. In 12 months, the same day discharge rate in one facility was increased from 5% to 32% of robotic hysterectomy cases. [ABSTRACT FROM AUTHOR]