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issn:1048-891
1.  Pathologic Ultrastaging Improves Micrometastasis Detection in Sentinel Lymph Nodes during Endometrial Cancer Staging 
Objective
To describe the incidence of low-volume, ultrastage-detected metastases in sentinel lymph nodes (SLNs) identified at surgical staging for endometrial carcinoma and to correlate it with depth of myoinvasion (DMI) and tumor grade.
Methods
We reviewed all patients who underwent primary surgery for endometrial carcinoma with successful mapping of at least one SLN at our institution from 9/2005-12/2011. All patients underwent a cervical injection for mapping. The SLN ultrastaging protocol involved cutting an additional two adjacent 5-μm sections at each of two levels, 50-μm apart, from each paraffin block lacking metastatic carcinoma on routine H&E. At each level, one slide was stained with H&E and with immunohistochemistry (IHC) using anti-cytokeratin AE1:AE3.
Micrometastases (tumor deposits <0.2mm and ≤2mm) and isolated tumor cells (≤0.2mm) were classified as low-volume, ultrastage-detected metastases if pathologic ultrastaging was the only method allowing detection of such nodal disease.
Results
Of 508 patients with successful mapping, 413(81.3%) had endometrioid carcinoma. Sixty-four(12.6%) of 508 patients had positive nodes: routine H&E detected 35 patients(6.9%), ultrastaging detected an additional 23 patients(4.5%) who would have otherwise been missed (4 micrometastases, 19 isolated tumor cells), and 6 patients(1.2%) had metastatic disease in their non-SLNs. The incidence of low-volume, ultrastagedetected nodal metastases in grade 1, 2, and 3 patients was 3.8%, 3.4%, and 6.9%, respectively. The frequency of low-volume, ultrastage-detected metastases in patients with a DMI of 0, <50%, and ≥50% was 0.8%, 8.0%, and 7.4%, respectively. Lymphovascular invasion was present in 20(87%) of the cases containing low-volume, ultrastage-detected metastases in the lymph nodes.
Conclusions
SLN mapping with pathologic ultrastaging in endometrial carcinoma detects additional low-volume metastases(4.5%) that would otherwise go undetected with routine evaluations. Our data support the incorporation of pathologic ultrastaging of SLNs in endometrial carcinoma with any degree of myoinvasion. The oncologic significance of lowvolume nodal metastases requires long-term follow-up.
doi:10.1097/IGC.0b013e3182954da8
PMCID: PMC4079038  PMID: 23694985
sentinel lymph node; endometrial carcinoma; ultrastaging; micrometastasis; low-volume metastasis
2.  Inhibition of Enhancer of Zeste Homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration and invasion in endometrial cancer cell lines 
Objective
To investigate the impact of Enhancer of Zeste Homolog 2 (EZH2) expression on endometrial cancer cell line behavior.
Methods/materials
EZH2 expression levels were compared between the non-malignant endometrial cell line T-HESC, and 3 endometrial cancer cell lines, ECC-1, RL95-2 and HEC1-A. Stable EZH2 knockdown cell lines were created and the impact on cellular proliferation, migration and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. EZH2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and shEZH2 cell lines was performed using student's t test and Fischer's exact test.
Results
EZH2 protein expression was increased in all 3 cancer cell lines, and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration and invasion. Down regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in G2/M. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3, and a concomitant decrease in β-catenin. EZH2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion and nodal metastasis.
Conclusions
EZH2 expression is associated with tumor cell proliferation, migration and invasion in 3 endometrial cancer cell lines, as well as increased stage, grade, depth of invasion and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted.
doi:10.1097/IGC.0b013e318296a265
PMCID: PMC3694282  PMID: 23792601
EZH2; endometrial cancer; pathology
3.  The Impact of Maximum Rectal Distention and Tandem Angle on Rectal Dose in 3D Planned Gynecologic High-Dose-Rate Brachytherapy for Locally Advanced Cervical Cancer 
Objective
Computed tomography (CT)-based treatment planning for cervical cancer has allowed investigation into the volumetric radiation dose delivered to the rectum. The goal of intracavitary brachytherapy is to maximize the tumor dose while decreasing the dose to normal tissue like the rectum. We investigated the effects of tandem angle and maximum rectal distention on rectal dose delivered in HDR brachytherapy for locally advanced cervical cancer.
Methods and Materials
Between July 2007 and January 2010, 97 brachytherapy treatment planning CT scans from the first and last implant of 51 patients with locally advanced cervical cancer were reviewed. The rectum was manually contoured from the ischial tuberosity to the bottom of the sacroiliac joint. The maximum rectal distention was determined by measuring the largest anterior-posterior diameter of the rectum superior to the tandem ring and inferior to the end of the applicator. A volumetric measurement of the maximum and mean rectal dose, dose to 2cc (D2cc), dose to 1cc (D1cc) of the rectum was calculated. The tandem angle and the ICRU rectal point were recorded, and a dose volume histogram was referenced.
Results
The mean maximum rectal distention was 3.01cm. The mean D1cc, D2cc, mean rectal dose, maximum rectal dose, and ICRU rectal dose were 3.03 Gy, 2.78 Gy, 4.19 cGy, 1.40 cGy, and 2.99 Gy per treatment, respectively. In a multivariate analysis controlling for surface area, tandem angle, and body mass index (BMI), there was a significant increase in D2cc with increasing rectal distention (P=.016). There were no significant findings when observing the effects of tandem angle on D2cc.
Conclusion
Rectal distention significantly impacts D2cc delivered in HDR brachytherapy. In contrast, tandem angle does not. Concerted efforts to decrease rectal distention should be considered during treatment planning and delivery.
doi:10.1097/IGC.0b013e3182959030
PMCID: PMC3706279  PMID: 23792603
Tandem angle; Brachytherapy; Rectal Distention; CT; Cervical Cancer
4.  Risk Factors for Ovarian Cancers with and without Microsatellite Instability 
Objective
In a population-based sample of epithelial ovarian cancers, to evaluate the association between microsatellite instability status and: 1) Ovarian cancer risk factors and 2) The distribution of the specific histologic subtypes.
Patients and methods
Participants were drawn from three population-based studies of primary epithelial ovarian cancer: Tumor DNA was analyzed using five standardized microsatellite markers to assess microsatellite instability (MSI) status. Patients were divided into three groups (MSI-high, MSI-low and MSI-stable) according to NCI criteria. We compared the prevalence of specific known risk and protective factors among the three subgroups, including BMI, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the three subgroups.
Results
A total of 917 ovarian cancer patients were included. One hundred twenty seven (13.8%) cancers were MSI-high. Subgroup analyses according to smoking, BMI, parity, past oral contraceptive use and past tubal ligation did not reveal any statistically significance differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 BRCA2-mutation patients. The proportions of different ovarian cancer histologies among the various microsatellite instability subgroups were similar.
Conclusions
The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without microsatellite instability. The distributions of microsatellite instability do not differ significantly among ovarian cancers with different histologies. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors, compared to 6% among patients with BRCA2 mutations, but this difference was not statistically significant.
doi:10.1097/IGC.0b013e31829a5527
PMCID: PMC3740723  PMID: 23748177
5.  CA125 Level Association with Chemotherapy Toxicity and Functional Status in Older Women with Ovarian Cancer 
Objective
Older women with ovarian cancer have increased cancer-related mortality and chemotherapy toxicity. CA125 is a sensitive biomarker for tumor burden. The study evaluates the association between CA125, geriatric assessment (GA), and treatment toxicity.
Methods
This is a secondary subset analysis of patients age ≥65 with ovarian cancer accrued to a multicenter prospective study that developed a predictive toxicity score for older adults with cancer. Clinical and geriatric covariates included sociodemographics, GA (comorbidity, social support, functional, nutritional, psychological, cognitive status), treatment, and labs. Utilizing bivariate analyses, we determined the association of abnormal CA125 (≥35 U/mL) with baseline GA, grade 3–5 toxicity (CTCAE v.3), dose adjustments, and hospitalization. Logistic regression analysis was used to check for potential confounder for association between CA125 and chemotherapy toxicity.
Results
Fifty-one (10%) of 500 patients accrued to the primary study had a diagnosis of ovarian (92%), peritoneal (4%), or fallopian tube (4%) cancer. Median age was 72 (range, 65–86). Forty-six patients (90%) had stage III–IV disease. Twenty-three patients (45%) received first-line chemotherapy, and 34 (67%) received platinum-doublet therapy. Thirty-six (71%) had an abnormal CA125. Grade 3–5 toxicity occurred in 19 patients (37%). Abnormal CA125 was associated with assistance with instrumental activities of daily living (IADL) (p<0.05), lower performance status (p=0.05), grade 3–5 toxicity (p=0.03), non-heme toxicity (p=0.04), and dose reductions (p=0.01). No association between CA125 level and total toxicity score was observed.
Conclusions
Among older women with ovarian cancer, abnormal CA125 was associated with poor pre-treatment functional status and an increased probability of chemotherapy toxicity and dose reduction.
doi:10.1097/IGC.0b013e318299438a
PMCID: PMC3772622  PMID: 23765208
CA125; older women; ovarian cancer; chemotherapy toxicity; functional status
6.  Brief Report: Knowledge, attitudes, practices and perceived risk of cervical cancer among Kenyan women 
OBJECTIVES
Eastern Africa has the highest incidence and mortality rates from cervical cancer worldwide. It is important to describe the differences among women and their perceived risk of cervical cancer in order to determine target groups to increase cervical cancer screening.
METHOD
In this cross-sectional study we surveyed women seeking reproductive health services in Kisumu, Kenya to assess their perceived risk of cervical cancer and risk factors influencing cervical cancer screening uptake. Chi-square statistics and t-tests were used to determine significant factors, which were incorporated into a logistic model to determine factors independently associated with cervical cancer risk perception.
RESULTS
While 91% of the surveyed women had heard of cancer, only 29% of the 388 surveyed women had previously heard of cervical cancer. The majority had received their information from healthcare workers. Few women (6%) had ever been screened for cervical cancer and cited barriers such as fear, time, and lacking knowledge about cervical cancer. Nearly all previously screened women (22/24, 92%) believed that cervical cancer was curable if detected early, and that screening should be conducted annually (86%). Most women (254/388, 65%) felt they were at risk for cervical cancer. Women with perceived risk of cervical cancer were older (OR=1.06, 95% CI 1.02, 1.10), reported a history of marriage (OR=2.08, CI 1.00, 4.30), were less likely to feel adequately informed about cervical cancer by healthcare providers (OR= 0.76, CI 0.18, 0.83) and more likely to intend to have cervical cancer screening in the future (OR= 10.59, CI 3.96, 28.30). Only 5% of women reported that they would not be willing to undergo screening, regardless of cost.
Conclusions
Cervical cancer is a major health burden for women in sub-Saharan Africa, yet only one-third of women had ever heard of cervical cancer in Kisumu, Kenya. Understanding factors associated with women’s perceived risk of cervical cancer could guide future educational and clinical interventions to increase cervical cancer screening.
doi:10.1097/IGC.0b013e31828e425c
PMCID: PMC3662490  PMID: 23694983
Screening; Barriers; Cervical Cancer; Africa
7.  CA-125 Level as a Prognostic Indicator in Type I and Type II Epithelial Ovarian Cancer 
Objective
The majority of patients with epithelial ovarian cancer achieved a complete clinical remission with normal CA-125 will still relapse and die from their disease. The present study was to determine whether CA-125 levels before, during and after primary treatment provided prognostic information for both Type I and Type II ovarian cancer.
Methods
In this retrospective study, we identified 410 epithelial ovarian cancer patients who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis.
Results
The baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I (p < 0.001). The nadir CA-125 was an independent predictor of PFS (p < 0.001) and OS (p = 0.035) duration. The PFS and OS durations were 21.7 and 79.4 months in patients with CA-125 ≤ 10 U/ml and 13.6 and 64.6 months in those with 11-35 U/ml (p = 0.01 and 0.002, respectively). Histotype was an independent predictor of PFS (p = 0.041): the PFS and OS durations of type I patients were longer than those in type II (p < 0.001 and < 0.001, respectively).
Conclusions
The nadir CA-125 and the histotype are predictive of PFS and OS duration in ovarian cancers experienced a CCR. PFS and OS durations were shorter in patients with CA-125 levels of 11-35 U/ml and type II disease than in those with ≤ 10 U/ml and type I.
doi:10.1097/IGC.0b013e31828f7a24
PMCID: PMC3760786  PMID: 23669443
ovarian cancer; CA-125; prognosis factors; tumor marker; pathological type
8.  Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity 
Objective
The majority of women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemo-resistant, recurrent disease. Therefore, a great need exists to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents.
Methods
In this study, we investigated the activity of Avemar®, a natural, non-toxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy, and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level.
Results
We found that FWGE exhibited significant anti-proliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson’s correlation of FWGE sensitivity and gene expression data identified 2,142 genes (FDR<0.2) representing 27 biological pathways (p<0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemo-sensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity.
Conclusions
Our findings confirm the value of FWGE as a natural product with anti-cancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE’s effect on human cancer cells.
doi:10.1097/IGC.0b013e318258509d
PMCID: PMC4036555  PMID: 22740002
Fermented wheat germ extract; Avemar; ovarian cancer; apoptosis; cisplatin
9.  SIX-YEAR REGRESSION AND PROGRESSION OF CERVICAL LESIONS OF DIFFERENT HPV VIRAL LOADS IN VARIED HISTOLOGICAL DIAGNOSES 
Objective
This study aims to evaluate HPV viral load as a biomarker for triage into colposcopy and CIN2 therapy, in order to reduce the colposcopy referral rate and CIN2 over treatment in low resource settings.
Methods
In 1999, 1997 women aged 35–45 in Shanxi, China, received six cervical screenings with pathological confirmation. In 2005, 1461 histologically normal women, 99 with cervical intraepithelial neoplasia (CIN) grade 1 (CIN1), and 30 with CIN grade 2 or worse (CIN2+) were rescreened in a follow-up study. HPV was detected by Hybrid Capture 2. Viral load, estimated by the ratio of relative light units to standard positive control, was categorized into four groups: negative (<1.0), low (≥1.0, <10.0), moderate (≥10.0, <100.0) and high (≥100.0). We estimated cumulative incidence of CIN2+ by viral load subgroups and calculated adjusted hazard ratios (aHR) for CIN2+ using Cox proportional hazards regression.
Results
Cumulative incidence of CIN2+ increased with baseline HPV viral load among normal women and women with CIN1 at baseline (P-trend<0.001). Repeat moderate-high viral load was associated with the highest risk for CIN2+ (aHR=188.8, 95% confidence interval: 41.2–864.1). Raising the RLU/PC cutoff from 1.0 to 10.0 for colposcopy greatly reduced the referral rate from 18.1% to 12.9%. It also increased the specificity (84.8% vs. 90.4%), the positive predictive value (22.5% vs. 28.9%), and the positive likelihood ratio (6.4 vs. 8.9), yet with loss of the sensitivity by 12% (97.6% vs. 85.7%). Among women with CIN2 at baseline, 56% regressed to normal, 24% regressed to CIN1, 4% remained CIN2, and 16% progressed to CIN3+.
Conclusions
Locales using HPV testing as the primary screening method, and lacking high-quality cytology-based screening, should consider viral load as an alternative to colposcopy triage for women over age 35. Viral load may also predict CIN2 progression until additional biomarkers become available.
doi:10.1097/IGC.0b013e318286a95d
PMCID: PMC3636161  PMID: 23455757
Cervical Intraepithelial Neoplasia (CIN); Hazard Ratios (HR); Human Papillomavirus (HPV) viral load; Regression; Progression
10.  Ribonucleotide Reductase Expression in Cervix Cancer: a Radiation Therapy Oncology Group Translational Science Analysis 
Objective
To evaluate pretherapy ribonucleotide reductase (RNR) expression and its effect upon radiochemotherapeutic outcome in women with cervical cancer.
Methods/Materials
Pretherapy RNR M1, M2, M2b immunohistochemistry was done on cervical cancer specimens retrieved from women treated on Radiation Therapy Oncology Group (RTOG) 0116 and 0128 clinical trials. RTOG 0116 enrollees (node-positive stage IA-IVA) received weekly cisplatin (40mg/m2) with amifostine (500mg) and extended-field radiation then brachytherapy (85Gy). RTOG 0128 enrollees (node-positive or bulky ≥ 5cm stage IB-IIA, or stage IIB-IVA) received day 1, 23, 43 cisplatin (75mg/m2), 5-FU (4-day 1gm/m2) during pelvic radiation then brachytherapy (85Gy), plus celecoxib (400mg twice daily, day 1 through 1 year). Disease-free survival (DFS) was estimated univariately by the Kaplan-Meier method. Cox proportional hazards models evaluated the impact of RNR immunoreactivity on DFS.
Results
51 tissue samples were analyzed; 13 from RTOG 0116 and 38 from RTOG 0128. M1, M2, and M2b overexpression (3+) frequencies were 2%, 80%, and 47%, respectively. Low-level (0–1+, n=44/51) expression of the regulatory subunit M1 did not associate with DFS (p=0.38). High (3+) M2 expression occurred in most (n=41/51), but without impact alone upon DFS (hazard ratio (HR): 0.54, 95% confidence interval [CI]: 0.2–1.4; p=0.20). After adjusting for M2b status, pelvic node-positive women had increased hazard for relapse or death (HR: 5.5, 95% CI: 2.2–13.8; p=0.0003).
Conclusions
These results suggest that RNR subunit expression may discriminate cervical cancer phenotype and radiochemotherapy outcome. Future RNR biomarker studies are warranted.
doi:10.1097/IGC.0b013e31828b4eb5
PMCID: PMC3662019  PMID: 23552804
ribonucleotide reductase; radiosensitivity; cervical cancer
11.  The Risk of Lymph-Node Metastasis with Positive Peritoneal Cytology in Endometrial Cancer 
Objective
To determine the correlation between positive peritoneal cytology (PPC) and lymph node metastasis in patients with endometrial cancer grossly confined to the uterus.
Methods
Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with endometrial cancer grossly confined to the uterus who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analysis used Chi-square test and logistic regression models.
Results
A total of 22,947 patients were identified. PPC was present in 3.5% of patients. The incidence of lymph node metastasis was significantly higher among patients with PPC compared to those with negative peritoneal cytology for all histologic types examined (p<0.0001): endometrioid adenocarcinoma; 28.7% vs. 6.9%, adenocarcinoma not otherwise specified; 35.4% vs. 5.8%, clear cell/serous carcinoma; 41.4% vs. 19.0%, and carcinosarcoma; 38.4% vs. 14.4%. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of lymph node metastasis (p<0.0001).
Conclusion
Our data indicates that patients with positive washings are at significant risk of nodal metastasis and adverse prognosis. Although, no longer a part of the current FIGO staging criteria, peritoneal cytology status should continue to inform clinical decision-making in endometrial cancer.
doi:10.1097/IGC.0b013e318275afd2
PMCID: PMC3992285  PMID: 23196758
Peritoneal cytology; Lymph node; Metastasis; Endometrial cancer
12.  A New Diagnostic Test for Endometrial Cancer? 
Objective
During saline-infused sonohysterography (SIS), the distension fluid is typically discarded. If cytology analysis could identify those patients with endometrial cancer, many women would be spared from further procedures.
Methods
Thirty consecutive patients with clinical stage I or II endometrial adenocarcinoma were prospectively recruited preoperatively. Saline-infused sonohysterography was performed by instilling 5 mL of saline, withdrawing and sending for analysis. Saline was reinfused until complete SIS images were obtained and sent separately for cytology.
Results
Of the 30 women enrolled, SIS was technically successful in 29. Demographics included mean age (60.5 ± 6.99 years), body mass index (35.55 ± 8.18 kg/m2), endometrioid histology (76%), and grade (grade 1, 67%). Prestudy diagnostic method included biopsy (70%), dilatation and curettage (17%), and hysteroscopy (10%). Adequate cytology specimens were obtained in 66% of the 5mL flushes and 72% of the complete SIS collections. Of adequate specimens, the sensitivities to detect endometrial cancer for the 5-mL, complete, and combined fluid samples were 26% (95% confidence interval, 9%–51%), 36% (17%–59%), and 42% (22%–63%). Sensitivity based on the whole study sample (N = 30) was 33% (17%–53%). Statistical significance was not found in the association between a positive test and age, body mass index, grade, diagnostic method, or volume instilled or aspirated.
Conclusions
Most patients with early endometrial cancer can undergo SIS procedures with adequate cytology specimens obtained from distention media. However, the sensitivity is low, and refinements are necessary before utilizing as a diagnostic test. In cases with positive results, the patient may be able to avoid other costly and painful procedures.
doi:10.1097/IGC.0b013e31829fe8f6
PMCID: PMC3976997  PMID: 23881100
Saline-infused sonohysterography; Endometrial cancer; Cytopathology
13.  Lithium and inhibition of GSK3β as a potential therapy for serous ovarian cancer 
Objective
Lithium chloride has been shown to demonstrate anti-cancer properties at supratherapeutic doses. This study was designed to determine whether lithium chloride, as a single agent or in combination with cytotoxic agents reduces ovarian cancer cell growth and metabolic activity at clinically achievable levels.
Materials and Methods
We studied the effects of lithium chloride on two high-grade serous ovarian cancer cell lines, SKOV3 and OVCA 433, and primary cultures developed from ascitic fluid collected from patients with metastatic high-grade serous ovarian cancer. We assessed proliferation and metabolism using cell cycle analysis, MTT assays and cellular proliferation and clonogenic potential assays.
Results
Treatment with 1mM LiCl had no effect on the cell cycle distribution or metabolic activity of the SKOV3 and OVCA 433 cell lines. Combination treatment with cisplatin or paclitaxel led to statistically significant decreases in metabolic activity in the OVCA 433 cell line and 50% of cultures investigated. The decreased metabolic activity was not, however, associated with decreased cell growth or clonogenic potential.
Conclusions
Combination treatment with LiCl and cytotoxic agents at physiologically achievable drug concentrations reduces ovarian cancer cell metabolism but does not appear to effect cellular proliferation. The potential for combined lithium/cytoxic therapies appears to be limited based on our analysis of both established cell lines and short term ovarian cancer cultures.
doi:10.1097/IGC.0b013e31827cfecb
PMCID: PMC3972899  PMID: 23295942
14.  A POPULATION-BASED STUDY OF VISUAL INSPECTION WITH ACETIC ACID (VIA) FOR CERVICAL SCREENING IN RURAL NIGERIA 
OBJECTIVE
Cervical cancer is the most common gynaecological cancer in developing countries. Visual Inspection with Acetic Acid (VIA) was introduced to screen for cervical premalignant lesions in developing countries due to the inability of many countries to implement high quality cytologic services. We sought to compare VIA performance among different health workers in Nigeria.
METHODS
In a population-based project, seven health workers working who had been screening women with VIA for about two years at local government health centers in rural Nigeria were retrained in a two-week program using the IARC training manual. Women from a rural village who had never had cervical cancer screening were recruited into the study. Each woman had cervical cancer screening by VIA, liquid-based cytology and oncogenic human Papillomavirus (HPV) DNA testing.
RESULTS
Despite similar participant characteristics, across all age groups, providers had wide ranges of VIA results; 0–21% suspect cancer and 0–25% VIA positive. VIA was insensitive compared to a combination of cytology and HPV testing.
CONCLUSION
In our study, VIA was not reproducible nor was it sensitive compared to cytology and HPV testing.
doi:10.1097/IGC.0b013e318280f395
PMCID: PMC3580031  PMID: 23354369
Cervical cancer; VIA; Liquid-based cytology; HPV DNA; Health workers
15.  End-of-Life Care of Women with Gynecologic Malignancies - A Pilot Study 
Objective
There is limited data regarding the end-of-life care for women with gynecologic malignancies. We set out to generate pilot data describing the care that women with gynecologic malignancies received in last six months of life. Patient demographics, patterns of care and utilization of palliative medicine consultation services were evaluated.
Methods
100 patients who died from gynecologic malignancies were identified in our institutional database. Only patients who had received treatment with a gynecologic oncologist within one year of death were included. Medical records were reviewed for relevant information. Data were abstracted from the electronic medical record and analyses were made using Students T, and Mann-Whitney testing with SPSS software.
Results
The mean age of patients was 60 years (range 30–94 years). Racial/ethnic distribution was 38% Caucasian, 34% Black, and 15% Hispanic. 75% of patients received chemotherapy within the last six months of life, 30% received chemotherapy within the last six weeks of life. The median number of days hospitalized during the last six months of life was 24 (range 0–183 days). During the last six months of life, 19% were admitted to the Intensive Care unit, 17% were intubated, 5% had terminal extubation, and 13% had cardio-pulmonary resuscitative efforts. 64% had a family meeting, 50% utilized hospice care, and 49% had palliative medicine consultations. There was a significant difference in hospice utilization when comparison was made between patients who had ≥ 14 days from consultation until death versus patients who had ≤ 14 days or no consultation, 21 (72%) versus 29 (41%), p =0.004. Patients who were single were less likely to have a palliative medicine consultation, p=0.005.
Conclusions
End-of-life care for patients with gynecologic malignancies often includes futile, aggressive treatments and invasive procedures. It is unknown whether these measures contribute to longevity or quality-of-life. These pilot data suggest that factors for implementation of timely hospice referral, family support and legacy building should include specialists trained in palliative medicine.
doi:10.1097/IGC.0b013e3182842efa
PMCID: PMC3746978  PMID: 23429487
Palliative medicine; gynecologic malignancies; quality-of-life; death and dying; hospice
16.  Risk Factors for Developing Multiple Malignancies in Endometrial Cancer Patients 
Objective
The purpose of this study was to investigate the clinical and pathologic characteristics of patients with endometrial cancer (EC) and associated breast, colorectal, or ovarian cancer and to define the risk of developing an associated malignancy during follow-up after EC treatment.
Methods/Materials
During a 13-year period, 1,028 women had a hysterectomy for EC at our institution and available clinical information. An associated malignancy was defined as diagnosis of another malignant disease before or at the time of operation for EC or during follow-up.
Results
Of these 1,028 patients, 208 (20%) had a history of another malignancy besides EC. Most frequent were carcinomas of the breast (10%), colon-rectum (3%), and ovary (4%). Patients with a family history of hereditary nonpolyposis colorectal cancer (HNPCC)–related cancers and presence of EC in the lower uterine segment (LUS) had a higher risk of developing colorectal cancer within 5 years after hysterectomy (2% and 6%, respectively). After multivariate analysis, only LUS involvement remained significantly associated with this risk. Patients with EC and associated ovarian cancer were more likely to be younger and have superficially invasive EC, family history of HNPCC-related tumors, and family history of breast or ovarian cancer. After multivariate analysis, only age younger than 50 years (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.49–12.21) and family history of breast or ovarian cancer (OR, 3.95; 95% CI, 1.60–9.72) were significantly related to risk of having ovarian cancer associated with EC. No significant risk factors were identified for development of an associated breast cancer after EC.
Conclusions
Young age, family history of malignancy, and LUS involvement may indicate the need for more intensive preventive strategies for colorectal cancer as well as for evaluating the risk of synchronous ovarian cancer in EC patients.
doi:10.1097/IGC.0b013e318219711f
PMCID: PMC3929041  PMID: 21666488
breast cancer; colorectal cancer; endometrial cancer; multiple tumors; ovarian cancer
17.  Evaluation of Pegylated Liposomal Doxorubicin Dose on the Adverse Drug Event Profile and Outcomes in Treatment of Recurrent Endometrial Cancer 
Objective
To determine factors which may increase the likelihood of adverse drug events (ADEs) in recurrent endometrial cancer patients treated with pegylated liposomal doxorubicin (PLD) as well as this agent’s impact on clinical outcomes.
Methods
The treatment records of endometrial cancer patients who received PLD at The University of Texas, M.D. Anderson Cancer Center from 1996 to 2006 were reviewed. Patient demographics, PLD dose, ADEs, use of supportive care interventions, disease progression and survival were extracted. Logistical regression analysis was used to identify factors which were associated with higher incidence of ADEs and which influenced survival.
Results
A total of 60 recurrent endometrial cancer patients were identified who experienced 122 ADEs. The most commonly reported ADEs were nausea (18.9%), palmar-plantar erythrodysesthesia (PPE) (16.4%), muscle weakness (12.3%), mucositis (10.7%), and peripheral neuropathy (9.8%). Seventeen patients (28%) required a dose reductiondue to ADEs. However, only five (8.3%) patients discontinued therapy because of toxicity. Cooling mechanisms were used in 19 patients to prevent PPE, although nine of these patients still experienced PPE. Treatment with six or more cycles of PLD was associated with increased incidence of neutropenia (p=0.045), peripheral neuropathy (p=0.004), and PPE (p<0.001). No differences in PFS or TTP was found between the doses of PLD, however there was an assessable trend toward increased survival with doses of 40mg/m2.
Conclusions
While there was no association with dose level and ADEs, more cycles received increased the incidence of toxicities, including PPE and neuropathy. There was no association between different doses of PLD and PFS or TTP.
doi:10.1097/IGC.0b013e31827c18f3
PMCID: PMC3899886  PMID: 23295941
Doxil; endometrial cancer; adverse effects; dose intensity
18.  Gemcitabine for Advanced Endometrial Cancer: A Review of the MSKCC Experience 
Background
Gemcitabine has been used in an off-label setting for treatment of advanced endometrial cancer (EMC), but there is a lack of published data showing its efficacy in treating this disease. We performed a retrospective review to determine the progression-free survival (PFS) and response rate (RR) of EMC patients treated with gemcitabine at Memorial Sloan-Kettering Cancer Center (MSKCC).
Methods
Eligible patients had histologically confirmed advanced (stage IV or recurrent) EMC that was treated with single-agent gemcitabine at MSKCC between 1999 and 2009. Response to therapy was determined by review of CT imaging by RECIST 1.1 criteria.
Results
We identified 46 eligible patients for our review. The median age was 66 years (range, 52-87).The median dose of gemcitabine administered was 800mg/m2 infused on day 1 and 8 of a 21-day cycle. The predominant histology was endometrioid (48%, n=22), followed by serous (35%, n=16), clear cell (15%, n=7), and undifferentiated (2%, n=1). The overall RR was 10.9% (95% CI,1.9 -19.9); 4 patients (9%) achieved a partial response (PR) and 1 patient (2%) achieved a PR that became a complete response after surgical removal of a site of residual disease. Thirteen patients (28%) displayed stable disease (SD) lasting at least 3 months. Of note, 5 of the 7 (71%) patients with clear cell histology displayed SD or PR (n=5).The median PFS was 3.0 months (95% CI, 2.1-3.3).
Conclusion
In a mixed population of patients with previously treated advanced EMC, gemcitabine was well tolerated and showed modest activity. Patients with clear cell histology appeared to have greater likelihood of benefit.
doi:10.1097/IGC.0b013e31824a33a2
PMCID: PMC3904291  PMID: 22635030
19.  The Peru Cervical Cancer Prevention Study (PERCAPS): Community Based Participatory Research in Manchay, Peru 
Objective
Cervical cancer is a preventable disease which causes significant morbidity and mortality, particularly in developing countries. While technology for early detection continues to improve, prevention programs suffer from significant barriers. Community Based Participatory Research is an approach to research which focuses on collaboration with the community to surmount these barriers. The objective of this study was to evaluate the utility of Community Based Participatory Research techniques in a mother-child screen/treat and vaccinate program for cervical cancer prevention in Manchay, Peru.
Methods/materials
HPV self-sampling and cryotherapy were utilized for the screen/treat intervention, and the Gardasil vaccine was utilized for the vaccine intervention. Community health workers from Manchay participated in a 3-day educational course, designed by the research team. The community health workers then decided how to implement the interventions in their community. The success of the program was measured by: 1) the ability of the community health workers to determine an implementation plan, 2) the successful use of research forms provided, 3) participation and retention rates, and 4) satisfaction of the participants.
Results
1) The community health workers used a door-to-door approach through which participants were successfully registered and both interventions were successfully carried out; 2) registration forms, consent forms, and result forms were utilized correctly with minimal error; 3) screen/treat intervention: 97% of registered participants gave an HPV sample, 94% of HPV positive women were treated, and 90% returned for 6-month follow-up; vaccine intervention: 95% of registered girls received the 1st vaccine, 97% of those received the 2nd vaccine, and 93% the 3rd; 4) 96% of participants in the screen/treat intervention reported high satisfaction.
Conclusion
Community Based Participatory Research techniques successfully helped to implement a screen/treat and vaccinate cervical cancer prevention program in Manchay, Peru. These techniques may help overcome barriers to large-scale preventive health-care interventions.
doi:10.1097/IGC.0b013e318275b007
PMCID: PMC3529758  PMID: 23165314
cervical cancer; prevention; community based participatory research
20.  The Revised 2009 FIGO Staging System for Endometrial Cancer: Should the 1988 FIGO Stage IA and IB be Altered? 
Objectives
The revised 2009 FIGO staging system for endometrial cancer included many changes over the 1988 system, particularly for stage I subgroups. We sought to describe the overall survival (OS) of women with stage I endometrial cancer and examine how the estimated stage-specific OS is altered in the 2009 system.
Methods
A prospectively maintained institutional endometrial database was analyzed. All patients underwent primary surgery between 1/93 - 6/09.
Results
Data from 1658 women were analyzed, including 1307 patients with FIGO 1988 stage I disease. The 5-year OS for the 1988 stage IA (92.4%), IB (87.3%), and IC (75.7%) significantly differed (P<0.001). When patients were restaged using the 2009 system, we identified 1411 stage I patients with 5-year OS for 2009 stage IA of 89.2%, vs. OS of 75.1% for IB (P=0.001). The adjusted concordance probabilities for the 1988 stage I group and 2009 stage I group were 0.612 ± 0.0014 and 0.536 ± 0.0111, respectively.
Conclusions
The 1988 FIGO classification of stage I endometrial cancer correctly identified 3 subgroups of patients that had significantly different OS. Specifically, 1988 FIGO stage IA and IB had distinct oncologic outcomes. The revised 2009 system eliminates the most favorable group from the new classification system, and estimates of stage-specific OS for stage IB are substantially altered by the changes made in 2009. The revised system for stage I did not improve its predictive ability over the 1988 system. These data highlight the importance of developing individualized risk-prediction models and nomograms in endometrial cancer.
doi:10.1097/IGC.0b013e31820cc305
PMCID: PMC3870338  PMID: 21436699
21.  Sexual Morbidity Associated With Poorer Psychological Adjustment Among Gynecological Cancer Survivors 
Objectives
Sexual morbidity is a distressing and undertreated problem in gynecological cancer survivorship known to occur early and persist well beyond the period of physical recovery. Although often studied as a separate domain, sexuality represents an integral component of psychological adjustment and quality of life (QoL) that is adversely affected by cancer treatments. The present study tests the association between sexual morbidity, and adverse psychological adjustment and QoL outcomes.
Methods
A cross-sectional design was used. The participants were gynecological (cervical, endometrial, ovarian, and vulvar) cancer survivors who were partnered (N = 186), whose cancer was diagnosed 2 to 10 years previously, and who were at least 6 months post any cancer therapy. Most had been found to have early-stage disease (70%) and were treated with hysterectomy (77%), chemotherapy (43%), and/or radiotherapy (23%). Sexual morbidity was operationalized as a multidimensional construct including sexual behavior, sexual functioning, and subjective sexual satisfaction, assessed by patient self-report. Outcomes included self-reported depressive symptoms, traumatic stress symptoms, cancer-specific stress, stress about body changes, and QoL. Nurse-rated of performance status and disruptive signs/symptoms of treatment toxicity, as well as relevant sociodemographic and disease variables were collected as potential controls.
Results
Hierarchical multiple regression analyses tested sexual morbidity as a predictor of poor outcomes. All statistical models were significant, accounting for 12% to 53% of the variance in psychological adjustment/QoL. Sexual morbidity covaried with worsened depressive symptoms, body change stress, and psychological QoL beyond the negative contributions of (older) age, (poorer) performance status, and (greater) fatigue. Notably, disease and treatment variables were not statistically significant correlates of psychological adjustment or QoL.
Conclusions
These findings suggest that prevention or treatment of sexual morbidity might foster improved psychological adjustment/QoL. Given the high rates of sexual morbidity in this population and the connection between sexuality and broader psychological adjustment/QoL, there is a clear need for better integration of sexuality rehabilitation into routine clinical care.
doi:10.1111/IGC.0b013e3181d24ce0
PMCID: PMC3869624  PMID: 20375814
Sexual morbidity; Gynecological cancers; Survivorship; Quality of life; Psychological adjustment
22.  Timing of Referral for Genetic Counseling and Genetic Testing in Patients with Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma 
Objective
To assess patients' preferences of the timing of referral for genetic counseling and testing in relation to the diagnosis, treatment and recurrence of ovarian, tubal, or primary peritoneal cancers.
Methods/Materials
Ninety-two patients who underwent counseling and testing by one certified genetic counselor were identified. Introductory letter, consent form and questionnaire were mailed to gather information regarding factors influencing the decision to undergo genetic counseling and testing and opinions regarding optimal timing. Medical records were reviewed for demographic and clinical data.
Results
Of 47 consenting women, 45 underwent testing. Eight (18%) were found to have a genetic mutation. Women lacked consensus about the optimal time for referral for and to undergo genetic testing, though women with stage I disease preferred testing after completion of chemotherapy. Most women were comfortable receiving the results by phone, but 1/3 preferred an office visit.
Conclusions
Patients' views regarding the best time to be referred for and undergo counseling and testing varied greatly. Due to the high mortality of this disease, clinicians should discuss referral early and personalize the timing to each patient. The subset of patients who prefer results disclosure during an office visit should be identified at the time of their initial counseling.
doi:10.1097/IGC.0b013e3182994365
PMCID: PMC3864646  PMID: 23748176
genetic counseling; genetic testing; BRCA mutation; timing; ovarian/fallopian tube/primary peritoneal cancer
23.  Comparison of Survival Outcomes Between Patients With Malignant Mixed Mullerian Tumors and High-Grade Endometrioid, Clear Cell, and Papillary Serous Endometrial Cancers 
Introduction
Malignant mixed mullerian tumors (MMMTs) are an aggressive subtype of endometrial cancer (EC). Previous studies compare survival between high-grade endometrioid (EM), clear cell (CC), and papillary serous (PS) ECs; yet few studies compare MMMTs to these aggressive subtypes. The goal of this study was to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) among EC subtypes.
Methods
We conducted a retrospective cohort study of EC cases treated at Magee-Women’s Hospital between 1996 and 2008. Kaplan-Meier estimates of RFS, DSS, and OS as well as and log-rank tests were used to compare survival distributions between histologic subtypes. Cox regression was used to estimate hazard ratios for histologic subtypes, adjusted for other significant prognostic factors. Interactions between histologic subtype and prognostic factors were examined to assess effect modification.
Results
This cohort included 81 MMMT (15%), 254 high-grade EM (46%), 73 CC (13%), and 147 PS (26%) cases. Compared to high-grade EM (6%) and CC (7%) cases, relatively more MMMT (12%) and PS (12%) cases were nonwhite. Stage differed significantly among the subtypes, with 36%, 34%, 37%, and 51% of MMMT, high-grade EM, CC, and PS cases, respectively, diagnosed at advanced late stage (P < 0.001). Kaplan-Meier curves and log-rank tests showed similar RFS, DSS, and OS between MMMT, high-grade EM, CC, and PS cases stratified by stage. In adjusted Cox regression models, RFS and DSS were not significantly different between MMMT and other subtypes. High-grade EM cases had a significantly better OS compared to MMMT cases (HR, 0.63; 95% confidence interval [CI], 0.41–0.98).
Conclusions
This is the first retrospective study to suggest that certain survival outcomes are similar among MMMT, high-grade EM, CC, and PS subtypes. Other large-scale studies are needed to confirm these findings.
doi:10.1097/IGC.0b013e31821a62dd
PMCID: PMC3827731  PMID: 21666484
Mortality; Aggressive endometrial cancers; Carcinosarcoma
24.  Elevated ribonucleotide reductase levels associate with suppressed radiochemotherapy response in human cervical cancers 
Objective
Ribonucleotide reductase (RNR) supplies deoxyribonucleotide diphosphates demanded by cells to repair radiation-induced DNA damage. Here, we investigate the impact of pretherapy RNR M1, M2, and M2b (p53R3) subunit level upon human cervical cancer radiochemosensitivity.
Methods/Materials
Immunohistochemistry was performed on a tissue array comprised of 18 paired benign uterine cervix and stage 1B2 cervical cancers to evaluate the relationship between cytosolic RNR M1, M2, and M2b staining intensity and radiochemotherapy cancer response. Patients underwent surgical hysterectomy (n = 8), or daily radiation (45 Gy), co-administered once weekly cisplatin (40 mg/m2), then low-dose-rate brachytherapy (30 Gy), followed by adjuvant hysterectomy (n = 10). Radiochemotherapy response was determined by RECIST v1.0 criteria at the time of brachytherapy. Cancer relapse rates and disease-free survival were calculated.
Results
M1, M2, and M2b antibody staining intensity was low (0–1+) in benign uterine cervix tissue. M1 and M2b immunoreactivity was 2+ or 3+ in the majority of cervical cancers (13 of 18). M2 immunoreactivity was 3+ in nearly all cervical cancers (16 of 18). Cervical cancers overexpressing M1 and M2b had an increased hazard for incomplete radiochemotherapy response, relapse, and shortened disease-free survival.
Conclusions
RNR subunit levels may predict human cervical cancer radiochemosensitivity and subsequent posttherapy cancer outcome. Further validation testing of RNR subunits as biomarkers for radiochemotherapy response is warranted.
doi:10.1097/IGC.0b013e318270577f
PMCID: PMC3481180  PMID: 23051959
ribonucleotide reductase; radiosensitivity; cervical cancer
25.  Sexual Function of Endometrial Cancer Patients Enrolled on the Gynecologic Oncology Group LAP2 Study 
Objectives
To present responses to sexual function items contained within the quality of life (QOL) survey of the Gynecologic Oncology Group (GOG) LAP2 study, to investigate associations between sexual function and other factors such as relationship quality and body image), and to explore patterns of response in endometrial cancer patients.
Methods
Participants enrolled on the LAP2 QOL study arm completed a self-report QOL survey, which contained sexual function items, before surgery, and at 1, 3, 6-weeks and 6-months post surgery. Responses to sexual function questions were classified into three patterns—responder, intermittent responder and non-responder—based on whether the sexual function items were answered when the QOL survey was completed.
Results
Of 752 patients who completed the QOL survey, 225 completed the sexual function items within the QOL survey, 224 responded intermittently, and 303 did not respond at all. No significant differences of sexual function were found between the patients randomized to laparoscopy compared to laparotomy. Among those who responded completely or intermittently, sexual function scores declined after surgery and recovered to pre-surgery levels at 6 months. Sexual function was positively associated with better quality of relationship (P<0.001), body image (P<0.001), and QOL (P<0.001), and negatively associated with fear of sex (P<0.001).
Conclusion
Our findings suggest that younger patients, those who were married, and those who had quality relationships were more likely to answer the sexual function items and have better quality of sexual function. Factors such as age, relationship quality, body image, and pain may place women with endometrial cancer at risk for sexual difficulties in the immediate recovery period; however, sexual function improved by 6-months postoperatively in our cohort of early-stage endometrial cancer patients.
doi:10.1097/IGC.0b013e31827277fa
PMCID: PMC3536465  PMID: 23095778
sexual function; endometrial cancer; gynecologic cancer treatment; laparoscopy; laparotomy

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