Publications by authors named "Robert P Edwards"

192 Publications

Same-day discharge after minimal invasive hysterectomy: Applications for improved value of care.

Eur J Obstet Gynecol Reprod Biol 2021 Apr 24;259:140-145. Epub 2021 Feb 24.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States; Magee-Womens Research Institute, Pittsburgh, PA 15213, United States; UPMC Hillman Cancer Center, Pittsburgh, PA 15232, United States; Department of Health Administration and Public Health, John G. Rangos Sr. School of Health Sciences, Duquesne University, Pittsburgh, PA 15219, United States.

Objective: Hysterectomy is one of the most common surgical procedures. Same-day discharge (SDD) is increasingly utilized for minimally invasive hysterectomies, but its uptake varies across healthcare systems and surgical specialties. An evidence-based initiative was developed to aid in the incorporation of SDD into the practice of minimally invasive hysterectomy (MIH) in the UPMC Health System. The objective of this study was to identify trends of SDD utilization across various gynecologic specialties at UPMC, as well as evaluate the impact of SDD on length of stay (LOS) and complications after the implementation of SDD initiative.

Study Design: We retrospectively identified 5554 patients who underwent MIH between 2014 and 2017 and were eligible for SDD, as determined by physicians and authorized by patients' insurance plans. Multivariable logistic regression models evaluated the trend of SDD utilization among four specialty types (general gynecologists, urogynecologists, specialized minimally invasive surgeons, and oncologists) and trends in complications. Multivariable logistic and linear regression models were applied to compare complications and LOS between patients with SDD vs. those with overnight admissions.

Results: SDD utilization increased from 28.55% to 74.99% during the study period. SDD significantly increased over the study period for all specialty types, with urogynecologists having the highest uptake from 3.9% in 2014 to 95.8% in 2017 (p<.01). After adjusting for year, specialty types, MIH procedure type, and total case time, SDD utilization was associated with shorter mean LOS (p<.01); such that mean LOS was 764.43 min (95% CI: 735.46-793.40) for SDD patients and 2041.84 min (95% CI: 2015.99-2067.70) for patients with overnight admissions. SDD was also associated with 42% lower odds (95% CI: 0.37-0.93, p=.02) of complications compared with patients with overnight admissions.

Conclusion: Same-day discharge uptake increased over years and was associated with lower odds of complications and decreased length of stay. More studies are needed to explore same-day discharge process to improve patient outcomes, patient satisfaction, and value of care.
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http://dx.doi.org/10.1016/j.ejogrb.2021.02.020DOI Listing
April 2021

What is driving the decreased incidence of preterm birth during the coronavirus disease 2019 pandemic?

Am J Obstet Gynecol MFM 2021 05 19;3(3):100330. Epub 2021 Feb 19.

Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA (Drs Lemon, Edwards and Simhan); Department of Clinical Analytics, University of Pittsburgh Medical Center, Pittsburgh, PA (Dr Lemon).

Background: Institutions across the world have observed a decrease in the incidence of preterm births during the coronavirus disease 2019 pandemic. The reason for this reduction remains unknown.

Objective: We sought to explore potential causes for the decrease in preterm births by exploring the following 3 hypotheses: (1) do women who are more likely to be able to work from home incur less physical/or emotional stress resulting in longer gestation? (2) Does the effect of the coronavirus disease 2019 pandemic on the incidence of preterm births vary by race? (3) Is this change provider driven?

Study Design: Using a retrospective cohort of all singleton deliveries at a single tertiary care center, we compared the deliveries for the period before the coronavirus disease 2019 pandemic (January 1, 2018-January 31, 2020) with those occurring during the pandemic (April 1, 2020-October 27, 2020). Comparisons between the period before and during the pandemic were made using Pearson chi-square or t tests as appropriate. The overall incidence of preterm birth, defined as delivery at <37 weeks' gestation, was analyzed and then further classified into spontaneous or indicated preterm births. The population was then stratified by the following categories: (1) insurance type and neighborhood disadvantage; (2) race; and (3) provider type. The provider type was classified as delivery occurring within an outpatient care facility, a clinic that provides prenatal care to those eligible for medical assistance, or a nonoutpatient care facility.

Results: In a population of 17,687 pre-coronavirus disease 2019 deliveries, and 5396 deliveries occurring during the coronavirus disease 2019 pandemic, there was a significant decrease in the overall incidence of preterm births (11.1 vs 10.1%; P=.039). Both spontaneous and indicated preterm deliveries decreased across the entire population. When stratified, decreases in the incidence of spontaneous preterm birth before vs during the coronavirus disease 2019 pandemic were limited to deliveries to women from more advantaged neighborhoods (most advantaged, 4.4 vs 3.8%; least advantaged, 7.2 vs 7.4%), white mothers (white, 5.6 vs 4.7%; black, 6.6 vs 7.1%), and those receiving care from nonoutpatient care providers (nonoutpatient care providers, 5.5 vs 4.8%; outpatient care providers, 6.3 vs 6.7%).

Conclusion: The incidence of preterm births has decreased during the coronavirus disease 2019 pandemic. Decreases in the rate of spontaneous preterm births were limited to deliveries to white women, living in more advantaged neighborhoods, and deliveries at nonoutpatient care facilities. The coronavirus disease 2019 response regulations may have benefited women with more indicators of advantage disproportionately more.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100330DOI Listing
May 2021

Gestational weight gain and risk of epithelial ovarian cancer.

Cancer Causes Control 2021 May 22;32(5):537-545. Epub 2021 Feb 22.

Womens Cancer Research Program, Magee-Womens Research Institute and UPMC Hillman Cancer Center, and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Objective: To examine the association between (GWG) and epithelial ovarian cancer (EOC).

Methods: We compared GWG between 670 incident EOC cases and 1,551 community controls from a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003 to 2008. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with GWG adjusting for potential confounders. To explore the potential effect of maternal long-term weight retention after childbearing, we restricted analyses to women who began their childbearing years as normal/underweight and examined differences in EOC risk between those who were normal/underweight versus those who were overweight/obese at study baseline reference date.

Results: Average GWG per full-term pregnancy did not differ between cases and controls. Among women who were normal/underweight at study baseline, greater average GWG was not associated with EOC (OR = 0.9, 0.8, 0.7 for quartiles 2, 3 and 4 of GWG gain, respectively, compared to quartile 1). In contrast, among women who were overweight/obese at study baseline, greater average GWG was positively associated with EOC (OR = 1.4, 1.8, 1.2, for quartiles 2, 3, and 4 compared to quartile 1; interaction p = 0.04).

Conclusion: We posit that maternal post-partum weight retention and not gestational weight gain itself among normal/underweight women may impact subsequent risk of EOC. If our hypothesis is supported in other studies designed to assess this question directly, then counseling women on the importance of healthy weight management after a pregnancy could provide another means to help women reduce their risk of this often-fatal malignancy.
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http://dx.doi.org/10.1007/s10552-021-01405-5DOI Listing
May 2021

Immunotherapy Advances for Epithelial Ovarian Cancer.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Obstetrics and Gynecology and Reproductive Sciences, Magee-Womens Research Institute and Foundation and Magee-Womens Hospital of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

New treatment modalities are needed in order to improve the prognosis of women diagnosed with epithelial ovarian cancer (EOC), the most aggressive gynecologic cancer type. Most ovarian tumors are infiltrated by immune effector cells, providing the rationale for targeted approaches that boost the existing or trigger new anti-tumor immune mechanisms. The field of immuno-oncology has experienced remarkable progress in recent years, although the results seen with single agent immunotherapies in several categories of solid tumors have yet to extend to ovarian cancer. The challenge remains to determine what treatment combinations are most suitable for this disease and which patients are likely to benefit and to identify how immunotherapy should be incorporated into EOC standard of care. We review here some of the most promising immune therapies for EOC and focus on those currently tested in clinical trials.
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http://dx.doi.org/10.3390/cancers12123733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764119PMC
December 2020

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Circulating CD14 HLA-DR monocytic cells as a biomarker for epithelial ovarian cancer progression.

Am J Reprod Immunol 2021 03 21;85(3):e13343. Epub 2020 Sep 21.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Problem: Previous studies identified circulating CD14 HLA-DR monocytic cells as an immune suppressive subset in solid malignancies, such as prostate, renal cell carcinoma, and pancreatic cancer. Such monocytic cells have been implicated not only in tumour progression but also as a potential barrier for immunotherapy. This study examined the relationship between the frequency of circulating monocytic cells and epithelial ovarian cancer (EOC) progression pre- and post-frontline chemotherapy, defined by disease stage, which is a leading prognostic factor for this malignancy.

Method Of Study: Incident cases of 236 women with EOC were recruited and comprehensive flow cytometry was utilized to assess the frequency of peripheral blood CD33 CD11b HLA-DR CD14 CD15 monocytic cells, henceforth termed CD14 HLA-DR monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14 HLA-DR monocytic cell percentages and disease stage. Wilcoxon signed-rank tests evaluated changes in these monocytic cell levels pre- and post-chemotherapy in a patient subset (n = 70).

Results: Patients with elevated frequencies of circulating CD14 HLA-DR monocytic cells at diagnosis were at 3.33-fold greater odds of having advanced stage (III/IV) EOC (CI: 1.04-10.64), with a significant trend in increasing CD14 HLA-DR monocytic cell levels (P = .04). There was a 2.02% median decrease of these monocytic cells post-chemotherapy among a subset of patients with advanced stage disease (P < .0001).

Conclusion: These findings support the potential clinical relevance of CD14 HLA-DR monocytic cells in EOC for prognosis and may indicate a non-invasive biomarker to measure disease progression.
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http://dx.doi.org/10.1111/aji.13343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897210PMC
March 2021

Impact of Ki-67 Labeling Index on Prognostic Significance of the Chemotherapy Response Score in Women With Tubo-ovarian Cancer Treated With Neoadjuvant Chemotherapy.

Int J Gynecol Pathol 2021 May;40(3):278-285

The chemotherapy response score (CRS) proposed by Bohm and colleagues in 2015 has been validated as a reproducible method for determining histopathologic response of tubo-ovarian carcinoma to neoadjuvant chemotherapy and stratifies tumor response into 3 groups: CRS1 is defined as minimal/no response, CRS2 as moderate response, and CRS3 as marked response. Although described as a 3-tiered system, it essentially works as a 2-tiered system (CRS1/CRS2 vs. CRS3) for assessing prognosis. Here, we analyzed the prognostic value of CRS in a large cohort of tubo-ovarian carcinomas at a tertiary care center and evaluated the potential for Ki-67 labeling index on post-neoadjuvant chemotherapy samples to provide additional prognostic information. We included 170 patients with tubo-ovarian carcinoma treated with neoadjuvant chemotherapy followed by interval debulking surgery. We determined CRS for each case by reviewing slides from the interval debulking surgery resection specimen and calculated progression-free survival and overall survival. For each case with residual disease (CRS1 and CRS2, n=123, 72%), we also performed Ki-67 antibody staining and determined both average and highest Ki-67 labeling index. Consistent with prior studies, patients in our cohort with CRS1 and CRS2 showed significantly shorter progression-free survival and overall survival compared with CRS3. Further, in the subset of cases with CRS1 and CRS2, Ki-67 labeling index was predictive of OS at multiple cutoff points. An average Ki-67 labeling index of 20% (log rank test P-value: 0.0004) or a highest Ki-67 labeling index of 50% (log rank test P-value: 0.0002) could provide a practically useful cutoff. Multivariable cox proportional hazard model showed worse overall survival with both, average Ki-67 >20% (hazard ratios: 2.02, P-value: 0.00422, confidence interval: 1.25-3.28) and highest Ki-67 >50% (hazard ratios: 1.88, P-value: 0.0205, confidence interval: 1.1-3.2). We propose adding Ki-67 labeling index to CRS to provide additional prognostic separation between patients with CRS1 and CRS2.
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http://dx.doi.org/10.1097/PGP.0000000000000706DOI Listing
May 2021

Survival and recurrence after intraperitoneal chemotherapy use: Retrospective review of ovarian cancer hospital registry data.

Cancer Med 2020 10 19;9(20):7388-7397. Epub 2020 Aug 19.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Intraperitoneal/intravenous chemotherapy (IP/IV) was associated with improved survival for ovarian cancer (OC) patients in several randomized clinical trials. However, the uptake of IP/IV in clinical practice is varied due to conflicting evidence about its impact on survival and recurrence. The aim of this study was to explore the uptake of IP/IV treatment and to evaluate its impact on survival and recurrence in OC patients.

Methods: Demographic and clinical information on OC patients (N = 2916) who underwent treatment for OC between 2000 and 2017 was obtained from the large healthcare system cancer registry. Duplicate records, grade 1, rare (eg, gelatinous carcinoma), and non-epithelial (eg, granulosa cell carcinoma) tumors were excluded. Kaplan-Meier survival curves were constructed to compare 5- and 10-year survival based on the chemotherapy type, surgery type, and stage. Multivariable Gray's piecewise constant time-varying coefficient models were fitted to evaluate the effect of IP/IV on adjusted hazard ratio (AHR) of OC survival and recurrence adjusting for potential confounders.

Results: The final sample consisted of 1846 OC patients, 14% (250/1846) of which received IP/IV chemotherapy. IP/IV was significantly associated with improved 10-year survival (P < .001). Multivariable Gray's model demonstrated that IP/IV therapy significantly reduced the AHR of death (AHR = 0.39-1.07, P < .001) with the beneficial effect gradually declining over time. Use of IP/IV chemotherapy had no impact on OC recurrence.

Conclusions: These findings demonstrated that only a small fraction of eligible patients underwent IP/IV chemotherapy. We report a significant 10-year survival, but not necessarily recurrence benefit is associated with IP/IV chemotherapy compared to IV only, suggesting the need for novel ways of identifying patients who may benefit from IP/IV chemotherapy.
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http://dx.doi.org/10.1002/cam4.3340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571805PMC
October 2020

Phase II study of everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer.

Gynecol Oncol 2020 01 15;156(1):32-37. Epub 2019 Nov 15.

University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Background: Recurrent ovarian, fallopian tube, and peritoneal cancers have limited potential for cure with traditional therapies. Preliminary results from a phase I study of everolimus and bevacizumab in advanced solid tumors showed it to be a promising combination. The primary objective of this study was to evaluate the 6-month progression-free survival for everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer. Secondary objectives included evaluation of efficacy and safety.

Methods: In this open-label, single-institution, phase II trial, patients received everolimus 10 mg/day by mouth and bevacizumab 10 mg/kg intravenously every 14 days on a 28-day cycle. Treatment continued until disease progression or adverse event.

Results: Fifty patients were enrolled. Median age was 60.5 years (range 28-82). Forty-six (92%) subjects had measurable disease. Thirteen (26%) (24% adjusted) were progression-free at 6 months (95% CI 16.67-42.71%). One patient had a complete response, while six had a partial response and 35 had stable disease as their best response. Patients with both platinum-sensitive and -resistant disease demonstrated responses, as did some prior bevacizumab exposure. There were two grade 4 and 31 grade 3 toxicities noted in 25 distinct patients. The most common reported toxicities included oral mucositis, fatigue, diarrhea, hypertension, pain, nausea and anorexia. Thirty-eight (76%) patients came off study because of disease progression. Unique molecular profiles were identified in long-term responders.

Conclusions: Combining everolimus and bevacizumab does not distinctly improve response compared to bevacizumab alone, but further study of selected patients with alterations in the PI3K/mTOR pathway may document benefit.
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http://dx.doi.org/10.1016/j.ygyno.2019.10.029DOI Listing
January 2020

Relationships Between a History of Abuse, Changes in Body Mass Index, Physical Health, and Self-Reported Depression in Female Bariatric Surgery Patients.

Bariatr Surg Pract Patient Care 2019 Sep 24;14(3):113-119. Epub 2019 Sep 24.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

A history of physical and sexual abuse has been implicated in weight gain. Although bariatric surgery is effective for weight loss in severely obese individuals, we investigated whether bariatric surgery patients who self-report a history of physical and/or sexual abuse have differential outcomes regarding weight loss, body mass index (BMI), quality of life (SF-36), and depressive symptoms (Center for Epidemiologic Studies Depression [CESD]) compared with nonabused patients. Standardized assessments at baseline and follow-up visits were performed on 103 obese (BMI >35) female bariatric surgery patients (mean age: 44.11 years, standard deviation: 11.67 years). In total 49.5% of participants reported abuse. Abused group had significantly higher BMI ( < 0.01) and depression scores ( < 0.01). After surgery, the BMI between the two groups was no longer significantly different, although the abused group remained significantly more depressed. Mixed models showed that abuse was associated with CESD scores ( < 0.01) and SF-36 mental composite scores ( = 0.03) after adjusting for smoking history. Bariatric surgery leads to a better weight loss in abused patients. Abuse history might be an additional factor for clinicians to consider when advising bariatric surgery, as our study suggests that women with history of abuse may have a higher weight loss benefit but less mental health improvement from the intervention.
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http://dx.doi.org/10.1089/bari.2018.0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763960PMC
September 2019

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Mod Pathol 2019 12 25;32(12):1834-1846. Epub 2019 Jun 25.

Department of Obstetrics and Gynecology, Sahlgrenska Cancer Center, Inst Clinical Scienses, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7/CK20/CDX2/PAX8. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
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http://dx.doi.org/10.1038/s41379-019-0302-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207534PMC
December 2019

Metabolic Syndrome in Endometrial Cancer Patients: Systematic Review.

Metab Syndr Relat Disord 2019 06 30;17(5):241-249. Epub 2019 Mar 30.

1 Department of Epidemiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania.

Large numbers of previously published studies show the importance of Metabolic syndrome (MetS) in the development of endometrial cancer (EC), the most common gynecologic malignancy in the United States. Defining the association between EC and MetS is complicated by inconsistencies among the MetS definitions used in EC. The aim of this study was to identify the MetS definition that is most practical for EC patients, as well as to estimate the prevalence of MetS using each definition in EC patients. A systematic literature search of PubMed and Embase was conducted to identify studies published between 1988 and 2018 and reporting the components of MetS in EC patients. Relevant studies were selected based on the presence of key MetS components, including central obesity, dyslipidemia, elevated blood pressure, and impaired glucose metabolism. Two independent reviewers extracted information from these articles. Our literature search has identified 400 articles, 8 of which were used for the final analyses. In this systematic review, the prevalence of MetS in EC patients varied based on the definition used, ranging from 6% for International Diabetes Federation (IDF) to 62% for Harmonized. IDF and Harmonized of MetS were the most practical definitions for women with EC. While our review included different approaches to diagnosing MetS and linking it to EC, we argue that there is a need for single and practical MetS definition criteria to improve diagnostics, decrease the inconsistencies across the future EC studies, and foster a cohesive understanding of the evidence regarding the association between MetS and EC.
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http://dx.doi.org/10.1089/met.2018.0106DOI Listing
June 2019

Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference.

Cancer 2019 06 5;125(12):1963-1972. Epub 2019 Mar 5.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5-year survival has been achieved through cytoreductive surgery, combination platinum-based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long-term survival in late-stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug-resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on "Critical Questions in Ovarian Cancer Research and Treatment" was held in Pittsburgh, Pennsylvania, on October 1-3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.
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http://dx.doi.org/10.1002/cncr.32004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557260PMC
June 2019

Neoadjuvant Chemoradiation Therapy Followed by Extrafascial Hysterectomy in Locally Advanced Type II Endometrial Cancer Clinically Extending to Cervix.

Pract Radiat Oncol 2019 Jul - Aug;9(4):248-256. Epub 2019 Feb 22.

Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. Electronic address:

Purpose: The role of neoadjuvant chemoradiation therapy in locally advanced type II endometrial cancer is controversial. We thus aimed to present our experience with the hypothesis that neoadjuvant chemoradiation therapy is associated with similarly high rates of downstaging and locoregional control for type II endometrial cancer and type I endometrial cancer.

Methods And Materials: Thirty-four patients with type II endometrial cancer with clinical evidence of cervical ± parametrium involvement treated with neoadjuvant external beam radiation therapy (45-50.4 Gy in 25-28 fractions) and high-dose-rate brachytherapy with a median total dose of 20 Gy (range, 15-27.5) in 4 fractions (range, 3-5) and concurrent platinum chemotherapy ± adjuvant chemotherapy from 2008 to 2018 were retrospectively reviewed. Patients with type I pathologic diagnoses and those treated with definitive (rather than preoperative) intent were excluded.

Results: Pathologic characteristics were as follows: 38% were carcinosarcoma, 18% serous, and 24% clear cell. Ninety-four percent of patients were downstaged to an extrafascial hysterectomy, and 94% had negative surgical margins. The 2-year local control, regional control, distant control, disease-free survival, and overall survival were 87.8%, 81.3%, 76.3%, 52.5%, and 63.7%, respectively. There was 1 subacute grade 3 and 1 late grade 3 small bowel obstruction, directly attributable to radiation therapy.

Conclusions: Neoadjuvant chemoradiation therapy effectively downstages the majority of locally advanced type II endometrial cancers, thereby increasing the likelihood of achieving complete resection with negative margins.
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http://dx.doi.org/10.1016/j.prro.2019.02.007DOI Listing
December 2019

Breastfeeding factors and risk of epithelial ovarian cancer.

Gynecol Oncol 2019 04 25;153(1):116-122. Epub 2019 Jan 25.

Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. Electronic address:

Objective: Previous studies suggest that breastfeeding reduces epithelial ovarian cancer (EOC) risk. However, the effects of age, timing and episode details on the EOC-breastfeeding relationship have not been examined. The objective of this study was to examine the association between breastfeeding factors and epithelial ovarian cancer.

Methods: We examined breastfeeding factors among parous women in a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003 to 2008. We compared 689 incident EOC cases to 1572 community controls. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with breastfeeding patterns adjusting for potential confounders.

Results: Compared to never breastfeeding, breastfeeding any offspring was associated with a 30% reduction in EOC risk (OR = 0.70; 95%CI = 0.58-0.85). That association lasted more than 30 years (OR = 0.69, 95%CI = 0.53-0.88). An average breastfeeding episode of 3 months was also associated with reduced risk (OR = 0.73, 95%CI = 0.58-0.80). A greater number of breastfeeding episodes was associated with greater risk reduction (OR = 0.78, 95%CI = 0.64-0.96 and OR = 0.49, 95%CI = 0.36-0.68 1-2 and 3+ episodes, respectively, compared to never breastfed, trend p = 0.01). Longer breastfeeding duration was also associated with reduced risk (OR = 0.75 and 0.62 for less than and greater than 1-year total duration, respectively, compared to never breastfed). An earlier age at first breastfeeding was further associated with increased protection (OR = 0.50-0.80, for first episode at age <25, 25-29, and 30+, respectively, trend p = 0.001).

Conclusions: Breastfeeding for as few as 3 months is associated with reduced EOC risk. Although this association decreases over time, it persists for more than 30 years. Longer cumulative duration, increasing number of breastfeeding episodes, and earlier age at first breastfeeding episode are each associated with increased benefit.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558958PMC
April 2019

Phase I study of intravenous oxaliplatin and intraperitoneal docetaxel in recurrent ovarian cancer.

Int J Gynecol Cancer 2019 01;29(1):147-152

University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Introduction: Intraperitoneal (IP) chemotherapy improves survival in ovarian cancer but its use has been limited by toxicity with cisplatin-based regimens. The primary objective of this study was to define the maximum tolerated dose and dose-limiting toxicity of intravenous (IV) oxaliplatin and IP docetaxel in women with recurrent ovarian, fallopian tube or peritoneal cancer. Secondary objectives were response rate, time to progression, symptom interference with quality of life, and pharmacokinetics.

Methods: Patients received a constant dose of oxaliplatin 75 mg/m IV on day 1 and docetaxel escalating from 50 mg/m IP on day 2 every 3 weeks using a 3 + 3 design. Treatment continued until disease progression, remission, or intolerable toxicity occurred. Plasma and IP samples were taken to determine drug concentrations. Patients completed the MD Anderson Symptom Inventory weekly.

Results: Twelve patients were included. The median number of cycles was 4 (range 2-6) with a median time to progression of 4.5 months. Among eight patients with measurable disease, the best responses were partial response in two patients, stable disease in five, and progressive disease in one. A total of 14 grade 3-4 toxicities were noted, most commonly hematologic. Four patients, all dose level 3, had six dose-limiting toxicities: two with prolonged neutropenia, one with infection, one with hyponatremia, and two with abdominal pain. Dose level 3 was therefore considered intolerable. The mean±SD ratio of docetaxel area under the curve (AUC) in IP fluid to AUC in plasma was 229±111. Symptom interference with life activities steadily decreased from cycle 1 to 5.

Conclusions: Oxaliplatin 75 mg/m IV on day 1 and docetaxel 75 mg/m IP on day 2 was the maximum tolerated dose. Most patients had partial response or stable disease, even in a heavily pre-treated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in quality of life.
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http://dx.doi.org/10.1136/ijgc-2018-000055DOI Listing
January 2019

Single-Institution Experience in 3D MRI-Based Brachytherapy for Cervical Cancer for 239 Women: Can Dose Overcome Poor Response?

Int J Radiat Oncol Biol Phys 2019 05 31;104(1):157-164. Epub 2018 Dec 31.

Department of Radiation Oncology, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address:

Purpose: Recent Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology guidelines recommend that the dose to 90% (D90) of the high-risk clinical target volume (HRCTV) in cervical cancer be at least 85 Gy, with higher doses for poor response to radiation therapy.

Methods And Materials: A retrospective review of brachytherapy delivered at a single institution was evaluated for dosimetry and outcomes. Significance of tumor parameters on local control was evaluated with Kaplan-Meier and univariable and multivariable Cox regression analysis. Correlations were determined with a linear regression model.

Results: A total of 239 women underwent high-dose-rate brachytherapy for cervical cancer between 2007 and 2018 with evaluable dosimetry. Median follow-up was 28.6 months. The median prescribed dose was 27.5 Gy in 5 fractions, with a median HRCTV D90 of 83.9 Gy (range, 81.9-85.7 Gy), HRCTV volume of 31 cm (range, 14.9-121.9 cm), and treatment time of 51 days (range, 36-83 days). Local control for the entire cohort at 5 years was 90.8%. Local control was worse with adenocarcinomas, HRCTV >40 cm at brachytherapy, requirement for a higher brachytherapy dose, and treatment >51 days. On multivariable analysis, local control was worse with adenocarcinoma (hazard ratio, 4.141; 95% confidence interval, 1.498-11.444; P = .006) and HRCTV >40 cm (hazard ratio, 3.640; 95% confidence interval, 1.316-10.069; P = .013). HRCTV EQD2 D90 > 85 Gy did not statistically improve outcomes for any subset. The 2-year progression-free survival for HRCTV >40 cm was 66.2% versus 84.1% if ≤40 cm (P < .001). Overall survival was predicted by HRCTV and overall treatment time in multivariable analysis. For women with HRCTV ≤40 cm, overall survival at 2 years was 90.4% versus 68.5% if >40 cm (P < .001).

Conclusion: Local control was excellent with magnetic resonance imaging-based planning in the entire cohort of patients. A poor response to external beam radiation (larger HRCTV) and adenocarcinoma histology predicted for worse local control despite association with higher brachytherapy prescription. Women with these risk factors face higher rates of extrapelvic progression and poorer overall survival.
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http://dx.doi.org/10.1016/j.ijrobp.2018.12.042DOI Listing
May 2019

Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles.

Oncogene 2019 03 5;38(13):2380-2393. Epub 2018 Dec 5.

Magee Womens Research Institute, Pittsburgh, Pennsylvania, USA.

The backbone of ovarian cancer treatment is platinum-based chemotherapy and aggressive surgical debulking. New therapeutic approaches using immunotherapy via immune checkpoint blockade, which have demonstrated clinical efficacy in other tumor types, have been less promising in ovarian cancer. To increase their clinical efficacy, checkpoint inhibitors are now being tested in clinical trials in combination with chemotherapy. Here, we evaluated the impact of cisplatin on tumor immunogenicity and its in vivo roles when used alone or in combination with anti-PD-L1, in two novel murine ovarian cancer cell models. The 2F8 and its platinum-resistant derivative 2F8cis model, display distinct inflammatory profiles and chemotherapy sensitivities, and mirror the primary and recurrent human disease, respectively. Acute and chronic exposure to cisplatin enhances tumor immunogenicity by increasing calreticulin, MHC class I, antigen presentation and T-cell infiltration. Cisplatin also upregulates PD-L1 expression in vitro and in vivo, demonstrating a dual, paradoxical immune modulatory effect and supporting the rationale for combination with immune checkpoint blockade. One of the pathways activated by cisplatin treatment is the cGAS/STING pathway. Chronic cisplatin treatment led to upregulation of cGAS and STING proteins in 2F8cis compared to parental 2F8 cells, while acute exposure to cisplatin further increases cGAS and STING levels in both 2F8 and 2F8cis cells. Overexpression of cGAS/STING modifies tumor immunogenicity by upregulating PD-L1, MHC I and calreticulin in tumor cells. Anti-PD-L1 alone in a platinum-sensitive model or with cisplatin in a platinum-resistant model increases survival. These studies have high translational potential in ovarian cancer.
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http://dx.doi.org/10.1038/s41388-018-0581-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440870PMC
March 2019

Diagnosis and Treatment of Ovarian Cancer.

Hematol Oncol Clin North Am 2018 12;32(6):943-964

Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, 300 Halket Street, Pittsburgh, PA 15213, USA. Electronic address:

Epithelial ovarian cancer classically presents with vague persistent gastrointestinal, urologic, or nonacute abdominal/pelvic symptoms (bloating, early satiety, discomfort). Ultimately, a pelvic examination or imaging identifies an adnexal mass typically with accompanied advanced peritoneal dissemination. Management involves aggressive cytoreductive surgery in combination with platinum and taxane chemotherapy. Over the last 20 years, optimal resection and mode and timing of chemotherapy have evolved. The authors review the initial diagnosis and management and present the available data and recommendations to guide the decision tree of when to use neoadjuvant, intraperitoneal, HIPEC, dose-dense, and maintenance chemotherapy in the front-line treatment of epithelial ovarian cancer.
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http://dx.doi.org/10.1016/j.hoc.2018.07.010DOI Listing
December 2018

The Evolution of Estrogen Receptor Signaling in the Progression of Endometriosis to Endometriosis-Associated Ovarian Cancer.

Horm Cancer 2018 12 9;9(6):399-407. Epub 2018 Oct 9.

Deptartment of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

To investigate changes in estrogen receptor alpha (ERα) signaling during progression of endometriosis to endometriosis-associated ovarian cancer (EAOC) as a driver of malignant transformation. We procured tissue samples of normal endometrium, endometriosis (benign, atypical, concurrent with EAOC), and EAOC. We evaluated expression of a 236-gene signature of estrogen signaling. ANOVA and unsupervised clustering were used to identify gene expression profiles across disease states. These profiles were compared to profiles of estrogen regulation in cancer models from the Gene Expression Omnibus (GEO). Gene Set Enrichment Analysis (GSEA) was performed to determine whether gene expression in EAOC was consistent with ERα activity. ANOVA revealed 158 differentially expressed genes (q < 0.05) and unsupervised clustering identified five distinct gene clusters. The estrogen signaling profile of EAOC was not consistent with activated ERα in pre-clinical models. Gene set enrichment analysis did not identify signatures of activated ERα in EAOC but instead identified expression patterns consistent with loss of ERα function and development of endocrine resistance. Gene expression data suggest that ERα signaling becomes inactivated throughout the progression of endometriosis to EAOC. The gene expression pattern in EAOC is more consistent with profiles of endocrine resistance.
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http://dx.doi.org/10.1007/s12672-018-0350-9DOI Listing
December 2018

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Int J Mol Sci 2018 Aug 21;19(9). Epub 2018 Aug 21.

Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena 07743, Germany.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed ( = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa ( = 0.51, = 1.7 × 10), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
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http://dx.doi.org/10.3390/ijms19092473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163881PMC
August 2018

The Prognostic Significance of p16 Status in Patients With Vulvar Cancer Treated With Vulvectomy and Adjuvant Radiation.

Int J Radiat Oncol Biol Phys 2019 01 16;103(1):152-160. Epub 2018 Aug 16.

Department of Radiation Oncology, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania. Electronic address:

Purpose: Vulvar squamous cell carcinoma (VSCC) is a relatively rare malignancy. Human papillomavirus has been implicated as a causative factor for a subset of these patients. The purpose of this study was to evaluate whether p16-positivity (a human papillomavirus surrogate) predicts for better response rates in women who undergo surgery followed by adjuvant radiation therapy (RT).

Methods And Materials: We retrospectively analyzed data from women with VSCC who were treated with adjuvant RT. p16-Positivity was defined as diffuse strong immunoreactivity within the tumor. Time to event outcomes was performed with Kaplan-Meier and cumulative incidence methodologies.

Results: Thirty-nine women were identified. Ten had positive results for p16 (p16+), and 29 had negative results (p16-). The median follow-up was 25.7 months. The median age at diagnosis was 59 years for women with p16+ tumors and 74 years for women with p16- tumors (P = .022). The distribution of stage did not differ by p16 status. The indications for adjuvant RT were close/positive margins in 19 women, positive nodes in 9 women, and both in 11 women. There were 21 recurrences: 15 vulvar, 3 isolated nodal, 2 synchronous vulvar/nodal, and 1 distant metastasis. In-field relapse rates at 3 years were lower in p16+ patients (32.5%) than in p16- patients (59.1%, P = .072). This trend was also observed in progression-free survival (P = .062). A p16+ status and a lower International Federation of Gynecology and Obstetrics stage were associated with fewer in-field relapses and improved progression-free survival in multivariable analyses. The p16 status was not a predictor of overall survival.

Conclusions: p16-Positivity appears to be a prognostic factor for in-field relapse rates in patients with VSCC appropriately treated with adjuvant RT.
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http://dx.doi.org/10.1016/j.ijrobp.2018.08.014DOI Listing
January 2019

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

J Pathol Clin Res 2018 10 21;4(4):250-261. Epub 2018 Sep 21.

Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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http://dx.doi.org/10.1002/cjp2.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174617PMC
October 2018

Inflammatory biomarker in adipose stem cells of women with endometrial cancer.

Biomark Med 2018 09 25;12(9):945-952. Epub 2018 Jul 25.

Department of Obstetrics, Gynecology, & Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, 3380 Blvd of the Allies, Pittsburgh, PA 15213, USA.

Aim: To explore inflammatory biomarkers secreted by adipose stem cells (ASCs) in omental, retroperitoneal and subcutaneous adipose tissues of women with endometrial cancer.

Patients & Methods: ASCs were collected from 22 women, aged 35-83 years, undergoing hysterectomy for endometrial cancer. Angiopoietin-2, EGF, IL-8, leptin, VEGFA, VEGFC and VEFGD levels in the ASC-conditioned media were analyzed by Luminex.

Results: We found a significant difference between the three depots for IL-8 (p < 0.0001), with the highest levels of IL-8 in the omental depot. VEGFA levels were highest in the retroperitoneal depot.

Conclusion: This is one of the first studies to explore biomarker expression in ASC-conditioned media in adipose tissue. ASC characteristics may be important to evaluate in relation to cancer risk.
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http://dx.doi.org/10.2217/bmm-2017-0355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439519PMC
September 2018

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

PLoS One 2018 6;13(7):e0197561. Epub 2018 Jul 6.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197561PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034790PMC
December 2018

Image-based multichannel vaginal cylinder brachytherapy for the definitive treatment of gynecologic malignancies in the vagina.

Gynecol Oncol 2018 08;150(2):293-299

Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address:

Purpose: Brachytherapy is integral to vaginal cancer treatment and is typically delivered using an intracavitary single-channel vaginal cylinder (SCVC) or an interstitial brachytherapy (ISBT) applicator. Multi-channel vaginal cylinder (MCVC) applicators allow for improved organ-at-risk (OAR) sparing compared to SCVC while maintaining target coverage. We present clinical outcomes of patients treated with image-based high dose-rate (HDR) brachytherapy using a MCVC.

Methods And Materials: Sixty patients with vaginal cancer (27% primary vaginal and 73% recurrence from other primaries) were treated with combination external beam radiotherapy (EBRT) and image-based HDR brachytherapy utilizing a MCVC if residual disease thickness was 7 mm or less after EBRT. All pts received 3D image-based BT to a total equivalent dose of 70-80 Gy.

Results: The median high-risk clinical target volume was 24.4 cm (interquartile range [IQR], 14.1), with a median dose to 90% of 77.2 Gy (IQR, 2.8). After a median follow-up of 45 months (range, 11-78), the 4-year local-regional control, distant control, DFS, and OS rates were 92.6%, 76.1%, 64.0%, and 67.2%, respectively. The 4-year LRC rates were similar between the primary vaginal (92%) and recurrent (93%) groups (p = 0.290). Pts with lymph node positive disease had a lower rate of distant control at 4 years (22.7% vs. 89.0%, p < 0.001). There were no Grade 3 or higher acute complications. The 4-year rate of late Grade 3 or higher toxicity was 2.7%.

Conclusions: Clinical outcomes of pts with primary and recurrent vaginal cancer treated definitively in a systematic manner with combination EBRT with image-guided HDR BT utilizing a MCVC applicator demonstrate high rates of local control and low rates of severe morbidity. The MCVC technique allows interstitial implantation to be avoided in select pts with ≤7 mm residual disease thickness following EBRT while maintaining excellent clinical outcomes with extended 4-year follow-up in this rare malignancy.
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http://dx.doi.org/10.1016/j.ygyno.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409556PMC
August 2018

Unplanned postoperative intensive care unit admission for ovarian cancer cytoreduction is associated with significant decrease in overall survival.

Gynecol Oncol 2018 08 19;150(2):306-310. Epub 2018 Jun 19.

Department of Obstetrics and Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objectives: Previous studies have identified age, nutritional status, and hematocrit as risk factors for unplanned ICU admission in gynecologic oncology patients. We sought to identify additional perioperative factors that can be predictive of unplanned ICU admission and its impact on outcomes in women with ovarian cancer undergoing ovarian cancer cytoreductive procedures.

Methods: This was a case-control study of patients with unplanned ICU admission after primary surgery for ovarian cancer from January 2007 to December 2013. Controls were selected in a 2:1 ratio matching for primary surgeon and date of surgery. Clinical data was abstracted and compared between cases and controls using conditional logistic regression.

Results: The dataset consisted of 324 patients (108 ICU admissions, 216 controls). On multivariable analysis, failure to optimally cytoreduce (p = 0.001, OR 3.76) and higher EBL (p < 0.001, OR 1.20 per 100 cm) remained significant predictors of unplanned ICU admission. On multivariable analysis of outcomes, ICU admission was independently associated with increased length of stay (12 days vs. 6 days, p < 0.001), increased number of postop complications (2 vs. 0, p < 0.001), and increased risk of readmission within 30 days (p = 0.041, OR 2.46). Even controlling for debulking status, ICU admission remained associated with a worse median OS (27.3 vs 57.9 months, p < 0.001).

Conclusions: ICU admission for women undergoing cytoreductive surgery for ovarian cancer is associated with a significant decrease in OS and increase in number of postoperative complications. For this inherently high-risk population, this information is critical when counseling patients about peri-operative risks in primary cytoreductive surgery.
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http://dx.doi.org/10.1016/j.ygyno.2018.06.008DOI Listing
August 2018

Helicase-Driven Activation of NFκB-COX2 Pathway Mediates the Immunosuppressive Component of dsRNA-Driven Inflammation in the Human Tumor Microenvironment.

Cancer Res 2018 08 31;78(15):4292-4302. Epub 2018 May 31.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Presence of cytotoxic CD8 T cells (CTL) in tumor microenvironments (TME) is critical for the effectiveness of immune therapies and patients' outcome, whereas regulatory T(reg) cells promote cancer progression. Immune adjuvants, including double-stranded (ds)RNAs, which signal via Toll-like receptor-3 (TLR3) and helicase (RIG-I/MDA5) pathways, all induce intratumoral production of CTL-attractants, but also Treg attractants and suppressive factors, raising the question of whether induction of these opposing groups of immune mediators can be separated. Here, we use human tumor explant cultures and cell culture models to show that the (ds) RNA Sendai Virus (SeV), poly-I:C, and rintatolimod (poly-I:CU) all activate the TLR3 pathway involving TRAF3 and IRF3, and induce IFNα, ISG-60, and CXCL10 to promote CTL chemotaxis to -treated tumors. However, in contrast with SeV and poly I:C, rintatolimod did not activate the MAVS/helicase pathway, thus avoiding NFκB- and TNFα-dependent induction of COX2, COX2/PGE2-dependent induction of IDO, IL10, CCL22, and CXCL12, and eliminating Treg attraction. Induction of CTL-attractants by either poly I:C or rintatolimod was further enhanced by exogenous IFNα (enhancer of TLR3 expression), whereas COX2 inhibition enhanced the response to poly-I:C only. Our data identify the helicase/NFκB/TNFα/COX2 axis as the key suppressive pathway of dsRNA signaling in human TME and suggest that selective targeting of TLR3 or elimination of NFκB/TNFα/COX2-driven suppression may allow for selective enhancement of type-1 immunity. This study characterizes two different poly-I:C-induced signaling pathways in their induction of immunostimulatory and suppressive factors and suggests improved ways to reprogram the TME to enhance the antitumor efficacy of immunotherapies. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636317PMC
August 2018

Cost-effectiveness analysis of biopsy strategies for endometrial cancer diagnosis in women with postmenopausal bleeding: Pipelle sampling curette versus dilatation & curettage.

Gynecol Oncol 2018 07 7;150(1):112-118. Epub 2018 May 7.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 3380 Boulevard of the Allies, 300 Halket Street, Pittsburgh, PA 15213, United States.

Background: Endometrial sampling is widely used for accurate diagnosis of endometrial cancer (EC), which is the most common gynecologic cancer in US women. The objective of this study was to explore the cost-effectiveness of two endometrial sampling procedures for diagnosing EC: (1) Pipelle endometrial sampling (Pipelle), and (2) dilatation & curettage (D&C), while accounting for sampling procedure failure rates and diagnostic accuracy in women with postmenopausal bleeding (PMB).

Method: The decision analytic model was built to compare the cost-effectiveness of Pipelle and D&C strategies in a hypothetical cohort of PMB women. The analysis was performed from the perspective of a public healthcare payer (Medicare, US). We used 2017 Medicare reimbursement data for cost estimation. The effectiveness of these two diagnostic strategies was measured by analyzing the remaining life expectancy after EC diagnosis and subsequent treatment.

Results: The base case analysis suggested that Pipelle was not only equally effective (32.11 vs. 32.11 years of life), but also less costly ($1897.80 vs. $2999.11) based on Medicare reimbursement when compared to D&C. In one-way sensitivity analyses and Monte Carlo probabilistic sensitivity analysis, the Pipelle remained the more cost-effective sampling strategy even after accounting for sampling failure rate associated with each sampling strategy.

Conclusion: The Pipelle is the more cost-effective sampling strategy compared to D&C for EC diagnosis in women with PMB. From the cost-effectiveness perspective, the higher sampling failure rate of Pipelle should not be regarded as a limitation in its clinical application.
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http://dx.doi.org/10.1016/j.ygyno.2018.04.565DOI Listing
July 2018

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

Br J Cancer 2018 04 20;118(8):1123-1129. Epub 2018 Mar 20.

Radiation Oncology Research Unit, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany.

Background: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.

Methods: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.

Results: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.

Conclusions: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
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http://dx.doi.org/10.1038/s41416-018-0011-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931085PMC
April 2018
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