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1.  Cell-type-specific level of DNA nucleotide excision repair in primary human mammary and ovarian epithelial cell cultures 
Cell and tissue research  2008;333(3):461-467.
DNA repair, a fundamental function of cellular metabolism, has long been presumed to be constitutive and equivalent in all cells. However, we have previously shown that normal levels of nucleotide excision repair (NER) can vary by 20-fold in a tissue-specific pattern. We have now successfully established primary cultures of normal ovarian tissue from seven women by using a novel culture system originally developed for breast epithelial cells. Epithelial cells in these cultures aggregated to form three-dimensional structures called “attached ovarian epispheres”. The availability of these actively proliferating cell cultures allowed us to measure NER functionally and quantitatively by the unscheduled DNA synthesis (UDS) assay, a clinical test used to diagnose constitutive deficiencies in NER capacity. We determined that ovarian epithelial cells manifested an intermediate level of NER capacity in humans, viz., only 25% of that of foreskin fibroblasts, but still 2.5-fold higher than that of peripheral blood lymphocytes. This level of DNA repair capacity was indistinguishable from that of normal breast epithelial cells, suggesting that it might be characteristic of the epithelial cell type. Similar levels of NER activity were observed in cultures established from a disease-free known carrier of a BRCA1 truncation mutation, consistent with previous normal results shown in breast epithelium and blood lymphocytes. These results establish that at least three “normal” levels of such DNA repair occur in human tissues, and that NER capacity is epigenetically regulated during cell differentiation and development.
PMCID: PMC4301738  PMID: 18575893
Primary ovarian epithelial culture; Nucleotide excision repair; Unscheduled DNA synthesis; Xeroderma pigmentosum; BRCA1; Human
2.  IL-18-primed helper NK cells collaborate with dendritic cells to promote recruitment of effector CD8+ T cells to the tumor microenvironment 
Cancer research  2013;73(15):4653-4662.
Chemokine-driven interactions of immune cells are essential for effective anti-tumor immunity. Human natural killer (NK) cells can be primed by the IL1-related pro-inflammatory cytokine IL-18 for unique helper activity, which promotes dendritic cell (DC) activation and DC-mediated induction of type-1 immune responses against cancer. Here we show that such IL-18-primed ‘helper’ NK cells produce high levels of the immature DC (iDC)-attracting chemokines CCL3 and CCL4 upon exposure to tumor cells or the additional inflammatory signals IFNα, IL-15, IL-12, or IL-2. These ‘helper’ NK cells potently attract iDCs in a CCR5-dependent mechanism and induce high DC production of CXCR3 and CCR5 ligands (CXCL9, CXCL10, and CCL5), facilitating the subsequent recruitment of type-1 effector CD8+ T (Teff) cells. Using cells isolated from the malignant ascites of patients with advanced ovarian cancer, we show that ‘helper’ NK cell-inducing factors can be used to enhance local production of Teff cell-recruiting chemokines. Our findings reveal the unique chemokine expression profile of ‘helper’ NK cells and highlight the potential for utilizing two-signal-activated NK cells to promote homing of type-1 immune effectors to the human tumor environment.
PMCID: PMC3780558  PMID: 23761327
natural killer cells; dendritic cells; chemokines; IL-18; ovarian cancer
3.  MUC1 Positive, Kras and Pten Driven Mouse Gynecologic Tumors Replicate Human Tumors and Vary in Survival and Nuclear Grade Based on Anatomical Location 
PLoS ONE  2014;9(7):e102409.
Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.
PMCID: PMC4117479  PMID: 25078979
4.  Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells 
Oncotarget  2014;5(12):4180-4194.
Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplatin-refractory endstage ovarian cancer patients. However, through study of the combination effect on Drp1 (the reported target of mdivi-1) knockout MEF cells and the functional analysis of mdivi-1 analogs, we revealed that the synergism between mdivi-1 and cisplatin is Drp1-independent. Mdivi-1 impairs DNA replication and its combination with cisplatin induces a synergistic increase of replication stress and DNA damage, causing a preferential upregulation of a BH3-only protein Noxa. Mdivi-1 also represses mitochondrial respiration independent of Drp1, and the combination of mdivi-1 and cisplatin triggers substantial mitochondrial uncoupling and swelling. Upregulation of Noxa and simultaneous mitochondrial swelling causes synergistic induction of mitochondrial outer membrane permeabilization (MOMP), proceeding robust mitochondrial apoptotic signaling independent of Bax/Bak. Thus, the novel mode of MOMP induction by the combination through the “dual-targeting” potential of mdivi-1 on DNA replication and mitochondrial respiration suggests a novel class of compounds for platinum-based combination option in the treatment of platinum as well as multidrug resistant tumors.
PMCID: PMC4147315  PMID: 24952704
Platinum resistance; mdivi-1; replication stress; Noxa; mitochondrial swelling
5.  Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case–control studies 
Cancer causes & control : CCC  2013;24(5):10.1007/s10552-013-0174-4.
The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.
We used data from 21 case–control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model.
Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03–1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39–2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12–1.50). For these histological types, consistent dose– response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer.
Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.
PMCID: PMC3818570  PMID: 23456270
Case–control studies; Histological type; Ovarian neoplasms; Smoking
6.  Plasma microRNAs as novel biomarkers for endometriosis and endometriosis-associated ovarian cancer 
Endometriosis, a largely benign, chronic inflammatory disease, is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors. We aimed to identify plasma miRNAs that can be used to differentiate endometriosis and ovarian cancer patients from healthy individuals.
Experimental design
We conducted a two-stage exploratory study to investigate the utility of plasma miRNA profiling to differentiate between endometriosis, endometriosis-associated ovarian cancer (EAOC) and healthy individuals. In the first stage, using global profiling of more than 1,000 miRNAs via reverse transcriptase quantitative PCR (RT-qPCR) in a 20-patient initial screening cohort, we identified 23 candidate miRNAs, which are differentially expressed between healthy controls (n=6), endometriosis (n=7), and EAOC (n=7) patients based on the fold changes. In the second stage, the 23 miRNAs were further tested in an expanded cohort (n=88) of healthy individuals (n =20), endometriosis (n = 33), EAOC (n = 14), and serous ovarian cancer cases (SOC, n= 21, included as controls).
We identified three distinct miRNA signatures with reliable differential expression between healthy individuals, endometriosis, and EAOC patients. When profiled against the control SOC category, our results revealed different miRNAs, suggesting that the identified signatures are reflective of disease-specific pathogenic mechanisms. This was further supported by the fact that the majority of miRNAs differentially expressed in human EAOC were mirrored in a double transgenic mouse EAOC model.
Our study reports for the first time that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and EAOC cases.
PMCID: PMC3596045  PMID: 23362326
Endometriosis; endometriosis-associated ovarian cancer; microRNA; plasma
7.  Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling 
The Journal of Experimental Medicine  2013;210(7):1433-1445.
MDSC-derived nitric oxide supports the development of Th17 cells in ovarian cancer dependent on the induction of endogenous NOS2 and the cGMP–cGK pathway in Th17 cells.
Nitric oxide (NO) is a ubiquitous mediator of inflammation and immunity, involved in the pathogenesis and control of infectious diseases, autoimmunity, and cancer. We observed that the expression of nitric oxide synthase-2 (NOS2/iNOS) positively correlates with Th17 responses in patients with ovarian cancer (OvCa). Although high concentrations of exogenous NO indiscriminately suppress the proliferation and differentiation of Th1, Th2, and Th17 cells, the physiological NO concentrations produced by patients’ myeloid-derived suppressor cells (MDSCs) support the development of RORγt(Rorc)+IL-23R+IL-17+ Th17 cells. Moreover, the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1β/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1β/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity and the canonical cyclic guanosine monophosphate (cGMP)–cGMP-dependent protein kinase (cGK) pathway of NO signaling within CD4+ T cells. Inhibition of NOS2 or cGMP–cGK signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. Our data indicate that, apart from its previously recognized role as an effector mediator of Th17-associated inflammation, NO is also critically required for the induction and stability of human Th17 responses, providing new targets to manipulate Th17 responses in cancer, autoimmunity, and inflammatory diseases.
PMCID: PMC3698515  PMID: 23797095
8.  Placental site trophoblastic tumor: Immunohistochemistry algorithm key to diagnosis and review of literature☆ 
•Histologic morphology is frequently equivocal for PSTTs.•Histology combined with immunohistochemical staining was necessary to make the diagnosis.•PSTT confined to the uterus was successfully treated with surgery alone.
PMCID: PMC3895280  PMID: 24624322
Placental site trophoblastic tumor; Gestational trophoblastic neoplasm; hPL; Chemoresistant
9.  Comparison of Survival Outcomes Between Patients With Malignant Mixed Mullerian Tumors and High-Grade Endometrioid, Clear Cell, and Papillary Serous Endometrial Cancers 
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.
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.
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).
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.
PMCID: PMC3827731  PMID: 21666484
Mortality; Aggressive endometrial cancers; Carcinosarcoma
11.  Ovarian Cancer: Prevention, Detection and Treatment of the Disease and Its Recurrence. Molecular Mechanisms and Personalized Medicine Meeting Report 
To review the current understanding of the underlying molecular, biologic and genetic mechanisms involved in ovarian cancer development and how these mechanisms can be targets for prevention, detection and treatment of the disease and its recurrence.
In May 2012, we convened a meeting of researchers, clinicians and consumer advocates to review the state of current knowledge on molecular mechanisms and identify fruitful areas for further investigations.
The meeting consisted of seven scientific sessions, ranging from Epidemiology, Early Detection, and Biology to Therapeutics and Quality of Life. Sessions consisted of talks and panel discussions by international leaders in ovarian cancer research. A special career-development session by the CDMRP Department of Defense Ovarian Cancer Academy as well as an oral abstract and poster session showcased promising new research by junior scientists.
Technological advances in the last decade have increased our knowledge of the molecular mechanisms involved in a host of biological activities related to ovarian cancer. Understanding the role these mechanisms play in cancer initiation and progression will help lead to the development of prevention and treatment modalities that can be personalized to each patient, thereby helping to overcome this highly-fatal malignancy.
PMCID: PMC3460381  PMID: 23013733
ovarian neoplasms; epidemiology; etiology; screening; biomarkers; proteomics; genomics; metabalomics; BRCA1/2; cancer stem cells; micro RNA; nuclear receptors; individualized medicine; cancer vaccines; quality of life; patient reportable outcomes; therapeutics; clinical trials; survival
12.  Use of fertility drugs and risk of ovarian cancer: results from a US-based case-control study 
Previous studies examining associations between use of fertility drugs and ovarian cancer risk have provided conflicting results. We used data from a large case-control study to determine whether fertility drug use significantly impacts ovarian cancer risk when taking into account parity, gravidity, and cause of infertility.
Data from the Hormones and Ovarian Cancer Prediction (HOPE) study were used (902 cases, 1802 controls). Medical and reproductive histories were collected via in-person interviews. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Models were adjusted for age, race, education, age at menarche, parity, oral contraceptive use, breastfeeding, talc use, tubal ligation, and family history of breast/ovarian cancer.
Ever use of fertility drugs was not significantly associated with ovarian cancer within the total HOPE population (OR: 0.93, 95%CI: 0.65–1.35) or among women who reported seeking medical attention for infertility (OR: 0.87, 95%CI 0.54–1.40). We did observe a statistically significant increased risk of ovarian cancer for ever use of fertility drugs among women who, despite seeking medical attention for problems getting pregnant, remained nulligravid (OR: 3.13, 95%CI 1.01–9.67).
These results provide further evidence that fertility drug use does not significantly contribute to ovarian cancer risk among the majority of women; however, women who despite infertility evaluation and fertility drug use remain nulligravid, may have an elevated risk for ovarian cancer.
Our results suggest that fertility drug use does not significantly contribute to overall risk of ovarian cancer when adjusting for known confounding factors.
PMCID: PMC3415595  PMID: 22707710
ovarian cancer; fertility drugs; infertility; case-control
13.  Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression 
CXCL12 is a chemotactic cytokine that has pro-metastatic functions in several malignancies through interactions with its receptor, CXCR4. CXCL12 is an estrogen-regulated gene, and notably, estrogen is a major risk factor for endometrial cancer (EC) development. As few studies examine concurrent CXCL12, CXCR4, and estrogen receptor (ER) expression in EC patients, we examined this pathway in 199 EC patients with data from the University of Pittsburgh Medical Center Cancer Registry. Immunohistochemistry (IHC) was used to detect CXCR4, CXCL12, and ER protein expression. As CXCR4 expression was positive in all cases, this investigation focused on associations between CXCL12 and ER expression, clinicopathologic factors, and survival outcomes using chi-square tests, Kaplan-Meier graphs, and log-rank tests. CXCL12 expression was negative in 63 cases (32%) and positive in 136 cases (68%). Negative CXCL12 expression was borderline significantly associated with metastasis (χ2 p=0.07). ER expression was negative in 75 cases (38%) and positive in 124 cases (62%). Positive ER expression was significantly associated with low grade and early stage tumors (χ2 p<0.001). CXCL12 and ER were not significantly associated (χ2 p=0.11). Positive CXCL12 expression was associated with longer overall survival (OS) (log-rank p=0.006) and longer recurrence-free survival (RFS) (log-rank p=0.01) in ER negative patients, but not in ER positive patients. We identified a unique molecular signature associated with better OS and RFS in EC patients. In addition to pathological characteristics of the tumor, expression of CXCL12 and ER may be clinically useful for assigning adjuvant treatment to EC cases.
PMCID: PMC3291748  PMID: 22025313
clear cell; papillary serous; prognostic biomarkers; chemokines; metastasis
14.  Aspirin, Non-Aspirin Nonsteroidal Anti-inflammatory Drugs, or Acetaminophen and risk of ovarian cancer 
Epidemiology (Cambridge, Mass.)  2012;23(2):311-319.
Aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) and acetaminophen all have biologic effects that might reduce the risk of ovarian cancer. However, epidemiologic data on this question are mixed.
A population-based, case-control study in western Pennsylvania, eastern Ohio, and western New York State included 902 women with incident epithelial ovarian cancer who were diagnosed between February 2003 to November 2008 and 1,802 matched controls. Regular use (at least 2 tablets per week for 6 months or more) of aspirin, NA-NSAIDs, and acetaminophen before the reference date (9 months before interview date) was assessed by in-person interview. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
The OR for aspirin use was 0.81 (95% CI= 0.63–1.03). Decreased risks were found among women who used aspirin continuously (0.71 [0.54–0.94]) or at a low-standardized daily dose (0.72 [0.53–0.97]), who used aspirin for the prevention of cardiovascular disease (0.72 [0.57–0.97]), who used aspirin more recently, or who used selective COX-2 inhibitors (0.60 [0.39–0.94]). No associations were observed among women using non-selective NA-NSAIDs or acetaminophen.
Risk reductions of ovarian cancer were observed with use of aspirin or selective COX-2 inhibitors. However, the results should be interpreted with caution due to the inherent study limitations and biases.
PMCID: PMC3454462  PMID: 22252409
15.  Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients 
S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic–pharmacodynamic (PK–PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK–PD models were developed and fit simultaneously to the PK–PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis–Menten kinetics in the myelosuppression-based model. The mechanism-based PK–PD model characterized the nonlinear PK disposition, and the bidirectional PK–PD interaction between S-CKD602 and monocytes.
PMCID: PMC3480239  PMID: 23112576
population pharmacokinetics; pharmacodynamics; PEGylated liposome; nonlinear kinetics
16.  Phase I and Pharmacokinetic Study of Pegylated Liposomal CKD-602 (S-CKD602) in Patients with Advanced Malignancies 
S-CKD602 is a pegylated liposomal formulation of CKD-602, a semi-synthetic camptothecin analogue. Pegylated (STEALTH®) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was performed in patients (pts) with refractory solid tumors.
Experimental Design
S-CKD602 was administered IV every 3 weeks. Modified Fibonacci escalation was used (3–6 pts/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over two weeks and total (lactone + hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated + released) CKD602 measured by LC-MS/MS.
45 pts (21 male) were treated: median age 62 years (range: 33–79 years); ECOG status: 0 to 1 (43 pts) and 2 (2 pts). Dose-limiting toxicities of grade 3 mucositis occurred in 1/6 pts at 0.3 mg/m2, grade 3/4 bone marrow suppression in 2/3 pts at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in 1/6 pts at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in 2 pts with refractory ovarian cancer (1.7 and 2.1 mg/m2). High inter-patient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD-602.
S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 IV once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 wks is consistent with STEALTH® liposomes and provides extended exposure compared with single doses of non-liposomal camptothecins.
PMCID: PMC3428134  PMID: 19190127
17.  Contraception Methods, beyond Oral Contraceptives and Tubal Ligation, and Risk of Ovarian Cancer 
Annals of epidemiology  2010;21(3):188-196.
Few studies have examined methods of contraception, beyond oral contraceptives (OCs) and tubal ligation, in relation to ovarian cancer risk.
Nine hundred two cases with incident ovarian/peritoneal/tubal cancer were compared to 1800 population-based controls. Women self-reported all methods of contraception using life calendars.
Each of the contraceptive methods examined reduced the risk of ovarian cancer as compared to use of no artificial contraception. Comparing ever versus never use, after adjustment for potentially confounding factors and all other methods of contraception, the methods of contraception that emerged as protective were OCs (adj OR 0.75, 95% CI 0.61–0.93); tubal ligation (adj OR 0.63, 95% CI 0.51–0.77); intrauterine devices (IUDs) (adj OR 0.75, 95% CI 0.59–0.95); and vasectomy (adj OR 0.77, 95% CI 0.61–0.99). While for oral contraceptives and tubal ligation, the longer the duration of use, the greater the effect, for IUDs the pattern was reversed: significant protection occurred with short duration and progressively greater risk (albeit non-significant) was seen with longer duration of use.
In the largest case-control study to date, a range of effective methods of contraception reduced the risk for ovarian cancer. OCs and tubal ligation reduced ovarian cancer risk with lower odds ratios with longer duration of use, whereas IUDs reduced risk overall, having the greatest impact with short duration of use.
PMCID: PMC3052991  PMID: 21109450
contraception; contraceptive methods; oral contraceptives; tubal ligation; IUDs; ovarian cancer
18.  Proteomic Analysis of Ovarian Cancer Proximal Fluids: Validation of Elevated Peroxiredoxin 1 in Patient Peripheral Circulation 
PLoS ONE  2011;6(9):e25056.
Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy in the United States. Unfortunately, a validated protein biomarker-screening test to detect early stage disease from peripheral blood has not yet been developed. The present investigation assesses the ability to identify tumor relevant proteins from ovarian cancer proximal fluids, including tissue interstitial fluid (TIF) and corresponding ascites, from patients with papillary serous EOC and translates these findings to targeted blood-based immunoassays.
Methodology/Principal Findings
Paired TIF and ascites collected from four papillary serous EOC patients at the time of surgery underwent immunodepletion, resolution by 1D gel electrophoresis and in-gel digestion for analysis by liquid chromatography-tandem mass spectrometry, which resulted in an aggregate identification of 569 and 171 proteins from TIF and ascites, respectively. Of these, peroxiredoxin I (PRDX1) was selected for validation in serum by ELISA and demonstrated to be present and significantly elevated (p = 0.0188) in 20 EOC patients with a mean level of 26.0 ng/mL (±9.27 SEM) as compared to 4.19 ng/mL (±2.58 SEM) from 16 patients with normal/benign ovarian pathology.
We have utilized a workflow for harvesting EOC-relevant proximal biofluids, including TIF and ascites, for proteomic analysis. Among the differentially abundant proteins identified from these proximal fluids, PRDX1 was demonstrated to be present in serum and shown by ELISA to be elevated by nearly 6-fold in papillary serous EOC patients relative to normal/benign patients. Our findings demonstrate the facile ability to discover potential EOC-relevant proteins in proximal fluids and confirm their presence in peripheral blood serum. In addition, our finding of elevated levels of PRDX1 in the serum of EOC patients versus normal/benign patients warrants further evaluation as a tumor specific biomarker for EOC.
PMCID: PMC3184097  PMID: 21980378
19.  Common variants at 19p13 are associated with susceptibility to ovarian cancer 
Bolton, Kelly L. | Tyrer, Jonathan | Song, Honglin | Ramus, Susan J. | Notaridou, Maria | Jones, Chris | Sher, Tanya | Gentry-Maharaj, Aleksandra | Wozniak, Eva | Tsai, Ya-Yu | Weidhaas, Joanne | Paik, Daniel | Van Den Berg, David J. | Stram, Daniel O. | Pearce, Celeste Leigh | Wu, Anna H. | Brewster, Wendy | Anton-Culver, Hoda | Ziogas, Argyrios | Narod, Steven A. | Levine, Douglas A. | Kaye, Stanley B. | Brown, Robert | Paul, Jim | Flanagan, James | Sieh, Weiva | McGuire, Valerie | Whittemore, Alice S. | Campbell, Ian | Gore, Martin E. | Lissowska, Jolanta | Yang, Hannah | Medrek, Krzysztof | Gronwald, Jacek | Lubinski, Jan | Jakubowska, Anna | Le, Nhu D. | Cook, Linda S. | Kelemen, Linda E. | Brook-Wilson, Angela | Massuger, Leon F.A.G. | Kiemeney, Lambertus A. | Aben, Katja K.H. | van Altena, Anne M. | Houlston, Richard | Tomlinson, Ian | Palmieri, Rachel T. | Moorman, Patricia G. | Schildkraut, Joellen | Iversen, Edwin S. | Phelan, Catherine | Vierkant, Robert A. | Cunningham, Julie M. | Goode, Ellen L. | Fridley, Brooke L. | Kruger-Kjaer, Susan | Blaeker, Jan | Hogdall, Estrid | Hogdall, Claus | Gross, Jenny | Karlan, Beth Y. | Ness, Roberta B. | Edwards, Robert P. | Odunsi, Kunle | Moyisch, Kirsten B. | Baker, Julie A. | Modugno, Francesmary | Heikkinenen, Tuomas | Butzow, Ralf | Nevanlinna, Heli | Leminen, Arto | Bogdanova, Natalia | Antonenkova, Natalia | Doerk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Thompson, Pamela J. | Carney, Michael E. | Goodman, Marc T. | Lurie, Galina | Wang-Gohrke, Shan | Hein, Rebecca | Chang-Claude, Jenny | Rossing, Mary Anne | Cushing-Haugen, Kara L. | Doherty, Jennifer | Chen, Chu | Rafnar, Thorunn | Besenbacher, Soren | Sulem, Patrick | Stefansson, Kari | Birrer, Michael J. | Terry, Kathryn L. | Hernandez, Dena | Cramer, Daniel W. | Vergote, Ignace | Amant, Frederic | Lambrechts, Diether | Despierre, Evelyn | Fasching, Peter A. | Beckmann, Matthias W. | Thiel, Falk C. | Ekici, Arif B. | Chen, Xiaoqing | Johnatty, Sharon E. | Webb, Penelope M. | Beesley, Jonathan | Chanock, Stephen | Garcia-Closas, Montserrat | Sellers, Tom | Easton, Douglas F. | Berchuck, Andrew | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A.
Nature genetics  2010;42(10):880-884.
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world accounting for 4 percent of deaths from cancer in women1. We performed a three-phase genome-wide association study of EOC survival in 8,951 EOC cases with available survival time data, and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P=5×10−4 and 6×10−4), but did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P=3×10−9 and 4×10−11 respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1 interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
PMCID: PMC3125495  PMID: 20852633
20.  Cancer and Chronic Diseases in Minority Populations: The Need for More Educational Materials in Spanish for Healthcare Providers 
This short communication piece provides an overview of the Latin American Supercourse, a collection of public health lectures in Spanish targeting educators in Mexico, US, and Spanish speaking countries.
PMCID: PMC3204105  PMID: 21559967
Internet; Prevention; Cancer;  Education; Communications;  Public health
21.  Radical Hysterectomy for Early Stage Cervical Cancer: Laparoscopy Versus Laparotomy 
Laparoscopic radical hysterectomy appears to be a feasible alternative to laparotomy for early stage cervical cancer with similar surgical outcomes and lessened morbidity.
Gynecologic oncologists have recently begun using laparoscopic techniques to treat early stage cervical cancer. We evaluated a single institution's experience of laparoscopic radical hysterectomy and staging compared with laparotomy.
A retrospective chart review identified stage IA2 and IB1 cervical cancer patients who underwent laparoscopic radical hysterectomy and pelvic lymph node dissection from July 2003 to April 2009. A 2:1 cohort of patients treated with laparotomy were matched by stage.
Nine laparoscopic patients (3 stage IA2, 6 stage IB1) with 18 matched controls (6 and 12) were identified. Demographics for each group were similar. None had positive margins or lymph nodes. An average of 11.2 vs.13.9 pelvic lymph nodes (P=0.237) were removed. Average operating time was 231.7 vs. 207.2 minutes (P=0.434), and average estimated blood loss was 161.1 vs. 394.4mL (P=0.059). Average length of stay was 2.9 vs. 5.5 days (P=0.012). No transfusions or operative complications were noted in the laparoscopic group vs. 3 each in the open group (P=0.194). No laparoscopic patients and 5 open patients had a postoperative wound infection (P=0.079). No recurrences were noted.
Laparoscopic radical hysterectomy is a feasible alternative to laparotomy for early stage cervical cancer. Similar surgical outcomes are achieved with significantly less morbidity.
PMCID: PMC3148874  PMID: 21902978
Laparoscopic radical hysterectomy; Cervical cancer
22.  Polymorphism in the GALNT1 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women: The Ovarian Cancer Association Consortium 
Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92–1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies.
PMCID: PMC2880167  PMID: 20142253
23.  Targeted treatment of recurrent platinum-resistant ovarian cancer: current and emerging therapies 
With advances in surgical techniques and chemotherapeutic agents, mortality rates from epithelial ovarian cancer (EOC) have slightly decreased over the last 30 years. However, EOC still ranks as the most deadly gynecologic cancer with an overall 5-year survival rate of 45%. Prognosis is especially disappointing for women with platinum-resistant disease, where 80% of patients will fail to respond to available therapies. Emerging treatment strategies have sub-sequently focused on targets which are integral to tumor growth and metastasis. In this review, we will focus on those innovative agents currently under investigation in clinical trials.
PMCID: PMC3130354  PMID: 21734812
platinum-resistant; ovarian cancer; targeted therapy; immunotherapy; angiogenesis; growth factors
24.  Factors associated with Type I and Type II endometrial cancer 
Cancer causes & control : CCC  2010;21(11):1851-1856.
We investigated risk factors for Type II (n = 176) vs. Type I (n = 1,576) endometrial cancer (EC) in cases treated at Magee-Womens Hospital between 1996 and 2008.
Clinical data were available from the University of Pittsburgh Medical Center (UPMC) Network Cancer Registry. Logistic regression was used to estimate the adjusted odds of having Type II EC vs. Type I EC. Risk factors of interest in this analysis were age, race, body mass index (BMI), year of diagnosis, parity, menopausal status, and history of additional primary tumors.
Relative to women with Type I EC, women with Type II EC were more likely to be older at diagnosis (OR: 1.03 per 1 year increase in age, 95% CI 1.01–1.05), of non-white race (OR: 2.95, 95% CI 1.66–5.27), have a history of additional primary tumors (OR: 1.56, 95% CI 1.05–2.32), and less likely to be obese (OR: 0.45, 95% CI 0.29–0.70).
In this large retrospective cohort of patients with EC, the striking difference in risk factors associated with Type II vs. Type I tumors suggests that these subtypes represent different disease entities that require different treatment modalities. Currently, Type II cases have a significantly worse prognosis compared to Type I. Further characterization of risk factors associated with developing Type II tumors is needed to prevent this aggressive malignancy.
PMCID: PMC2962676  PMID: 20628804
Endometrial cancer; Epidemiology; Type I; Type II

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