Browsing by Subject "Ovarian neoplasms"
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Item A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO(Springer Nature, 2021) Blackford, Amanda L.; Childs, Erica J.; Porter, Nancy; Petersen, Gloria M.; Rabe, Kari G.; Gallinger, Steven; Borgida, Ayelet; Syngal, Sapna; Cote, Michele L.; Schwartz, Ann G.; Goggins, Michael G.; Hruban, Ralph H.; Parmigiani, Giovanni; Klein, Alison P.; Epidemiology, Richard M. Fairbanks School of Public HealthIntroduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. Methods: We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations. Results: BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73-0.84 and 0.70, 95% CI: 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]). Discussion: The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.Item Claudin-4 Stabilizes the Genome via Nuclear and Cell-Cycle Remodeling to Support Ovarian Cancer Cell Survival(American Association for Cancer Research, 2025) Villagomez, Fabian R.; Lang, Julie; Nunez-Avellaneda, Daniel; Behbakht, Kian; Dimmick, Hannah L.; Webb, Patricia G.; Nephew, Kenneth P.; Neville, Margaret; Woodruff, Elizabeth R.; Bitler, Benjamin G.; Anatomy, Cell Biology and Physiology, School of MedicineHigh-grade serous ovarian carcinoma is marked by chromosomal instability, which can serve to promote disease progression and allow cancer to evade therapeutic insults. The report highlights the role of claudin-4 in regulating genomic instability and proposes a novel therapeutic approach to exploit claudin-4-mediated regulation.Item Effects of the WRITE Symptoms Interventions on Symptoms and Quality of Life Among Patients With Recurrent Ovarian Cancers: An NRG Oncology/GOG Study (GOG-0259)(American Society of Clinical Oncology, 2022) Donovan, Heidi S.; Sereika, Susan M.; Wenzel, Lari B.; Edwards, Robert P.; Knapp, Judith E.; Hughes, Susan H.; Roberge, Mary C.; Thomas, Teresa H.; Klein, Sara Jo; Spring, Michael B.; Nolte, Susan; Landrum, Lisa M.; Casey, A. Catherine; Mutch, David G.; DeBernardo, Robert L.; Muller, Carolyn Y.; Sullivan, Stephanie A.; Ward, Sandra E.; Obstetrics and Gynecology, School of MedicinePurpose: GOG-259 was a 3-arm randomized controlled trial of two web-based symptom management interventions for patients with recurrent ovarian cancer. Primary aims were to compare the efficacy of the nurse-guided (Nurse-WRITE) and self-directed (SD-WRITE) interventions to Enhanced Usual Care (EUC) in improving symptoms (burden and controllability) and quality of life (QOL). Methods: Patients with recurrent or persistent ovarian, fallopian, or primary peritoneal cancer with 3+ symptoms were eligible for the study. Participants completed baseline (BL) surveys (symptom burden and controllability and QOL) before random assignment. WRITE interventions lasted 8 weeks to develop symptom management plans for three target symptoms. All women received EUC: monthly online symptom assessment with provider reports; online resources; and every 2-week e-mails. Outcomes were evaluated at 8 and 12 weeks after BL. Repeated-measures modeling with linear contrasts evaluated group by time effects on symptom burden, controllability, and QOL, controlling for key covariates. Results: Participants (N = 497) reported mean age of 59.3 ± 9.2 years. At BL, 84% were receiving chemotherapy and reported a mean of 14.2 ± 4.9 concurrent symptoms, most commonly fatigue, constipation, and peripheral neuropathy. Symptom burden and QOL improved significantly over time (P < .001) for all three groups. A group by time interaction (P < .001) for symptom controllability was noted whereby both WRITE intervention groups had similar improvements from BL to 8 and 12 weeks, whereas EUC did not improve over time. Conclusion: Both WRITE Intervention groups showed significantly greater improvements in symptom controllability from BL to 8 and BL to 12 weeks compared with EUC. There were no significant differences between Nurse-WRITE and SD-WRITE. SD-WRITE has potential as a scalable intervention for a future implementation study.Item Physician Influence on Variation in Receipt of Aggressive End-of-Life Care Among Women Dying of Ovarian Cancer(American Society of Clinical Oncology, 2022) Mullins, Megan A.; Uppal, Shitanshu; Ruterbusch, Julie J.; Cote, Michele L.; Clarke, Philippa; Wallner, Lauren P.; Epidemiology, Richard M. Fairbanks School of Public HealthPurpose: End-of-life care for women with ovarian cancer is persistently aggressive, but factors associated with overuse are not well understood. We evaluated physician-level variation in receipt of aggressive end-of-life care and examined physician-level factors contributing to this variation in the SEER-Medicare data set. Methods: Medicare beneficiaries with ovarian cancer who died between 2000 and 2016 were included if they were diagnosed after age 66 years, had complete Medicare coverage between diagnosis and death, and had outpatient physician evaluation and management for their ovarian cancer. Using multilevel logistic regression, we examined physician variation in no hospice enrollment, late hospice enrollment (≤ 3 days), > 1 emergency department visit, an intensive care unit stay, terminal hospitalization, > 1 hospitalization, receiving a life-extending or invasive procedure, and chemotherapy (in the last 2 weeks). Results: In this sample of 6,288 women, 51% of women received at least one form of aggressive end-of-life care. Most common were no hospice enrollment (28.9%), an intensive care unit stay (18.6%), and receipt of an invasive procedure (20.7%). For not enrolling in hospice, 9.9% of variation was accounted for by physician clustering (P < .01). Chemotherapy had the highest physician variation (12.4%), with no meaningful portion of the variation explained by physician specialty, volume, region, or patient characteristics. Conclusion: In this study, a meaningful amount of variation in aggressive end-of-life care among women dying of ovarian cancer was at the physician level, suggesting that efforts to improve the quality of this care should include interventions aimed at physician practices and decision making in end-of-life care.Item Prediagnostic BMI trajectories in relation to pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial(Wiley, 2022) Hoyt, Margaret; Song, Yiqing; Gao, Sujuan; O’Palka, Jacquelynn; Zhang, Jianjun; Epidemiology, School of Public HealthObjective: It remains elusive whether prediagnostic BMI trajectory is associated with pancreatic cancer. Methods: This study investigated this question among 145,489 participants who gave rise to 696 incident cases of pancreatic cancer over a median follow-up of 12 years in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. At baseline, participants were asked to recall their weight at ages 20, 50, and 55 to 74 years (at enrollment), as well as their height. Results: At age 50 years, people with obesity had a significantly increased risk of pancreatic cancer compared with those with a normal weight after adjustment for confounders (hazard ratio [95% CI]: 1.27 [1.01-1.60]). Individuals who had overweight at age 20 years experienced a marginally significant elevated risk of pancreatic cancer (hazard ratio [95% CI]: 1.22 [0.99-1.50]). Compared with individuals who maintained a steady normal weight during follow-up, no significantly altered risk of pancreatic cancer was observed for those whose weight status changed from normal weight to overweight, from normal weight to obesity, and from overweight to obesity. Conclusions: The present study revealed that prediagnostic adulthood BMI trajectory was not associated with pancreatic cancer risk, but overweight at young adulthood and obesity at middle adulthood may confer an elevated risk of this malignancy.Item Quality of Life and Adverse Events: Prognostic Relationships in Long-Term Ovarian Cancer Survival(Oxford University Press, 2021) Wenzel, Lari; Osann, Kathryn; McKinney, Chelsea; Cella, David; Fulci, Giulia; Scroggins, Mary J.; Lankes, Heather A.; Wang, Victoria; Nephew, Kenneth P.; Maxwell, George L.; Mok, Samuel C.; Conrads, Thomas P.; Miller, Austin; Mannel, Robert S.; Gray, Heidi J.; Hanjani, Parviz; Huh, Warner K.; Spirtos, Nick; Leitao, Mario M., Jr.; Glaser, Gretchen; Sharma, Sudarshan K.; Santin, Alessandro D.; Sperduto, Paul; Lele, Shashikant B.; Burger, Robert A.; Monk, Bradley J.; Birrer, Michael; Medicine, School of MedicineBackground: There is a critical need to identify patient characteristics associated with long-term ovarian cancer survival. Methods: Quality of life (QOL), measured by the Functional Assessment of Cancer Therapy-Ovarian-Trial Outcome Index (FACT-O-TOI), including physical, functional, and ovarian-specific subscales, was compared between long-term survivors (LTS) (8+ years) and short-term survivors (STS) (<5 years) of GOG 218 at baseline; before cycles 4, 7, 13, 21; and 6 months post-treatment using linear and longitudinal mixed models adjusted for covariates. Adverse events (AEs) were compared between survivor groups at each assessment using generalized linear models. All P values are 2-sided. Results: QOL differed statistically significantly between STS (N = 1115) and LTS (N = 260) (P < .001). Baseline FACT-O-TOI and FACT-O-TOI change were independently associated with long-term survival (odds ratio = 1.05, 95% confidence interval = 1.03 to 1.06 and odds ratio = 1.06, 95% confidence interval = 1.05 to 1.07, respectively). A 7-point increase in baseline QOL was associated with a 38.0% increase in probability of LTS, and a 9-point increase in QOL change was associated with a 67.0% increase in odds for LTS. QOL decreased statistically significantly with increasing AE quartiles (cycle 4 quartiles: 0-5 vs 6-8 vs 9-11 vs ≥12 AEs, P = .01; cycle 21 quartiles: 0-2 vs 3 vs 4-5 vs ≥6 AEs, P = .001). Further, LTS reported statistically significantly better QOL compared with STS (P = .03 and P = .01, cycles 4 and 21, respectively), with similar findings across higher AE grades. Conclusions: Baseline and longitudinal QOL change scores distinguished LTS vs STS and are robust prognosticators for long-term survival. Results have trial design and supportive care implications, providing meaningful prognostic value in this understudied population.Item Racial Differences in the Tumor Immune Landscape and Survival of Women with High-Grade Serous Ovarian Carcinoma(American Association for Cancer Research, 2022) Peres, Lauren C.; Colin-Leitzinger, Christelle; Sinha, Sweta; Marks, Jeffrey R.; Conejo-Garcia, Jose R.; Alberg, Anthony J.; Bandera, Elisa V.; Berchuck, Andrew; Bondy, Melissa L.; Christensen, Brock C.; Cote, Michele L.; Doherty, Jennifer Anne; Moorman, Patricia G.; Peters, Edward S.; Segura, Carlos Moran; Nguyen, Jonathan V.; Schwartz, Ann G.; Terry, Paul D.; Wilson, Christopher M.; Fridley, Brooke L.; Schildkraut, Joellen M.; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts. Methods: The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race. Results: Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant. Conclusions: Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC. Impact: This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.Item The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer(American Association for Cancer Research, 2021) Patel, Monal; Wang, Yinu; Bartom, Elizabeth T.; Dhir, Rohin; Nephew, Kenneth P.; Matei, Daniela; Murmann, Andrea E.; Lengyel, Ernst; Peter, Marcus E.; Anatomy, Cell Biology and Physiology, School of MedicineOvarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2-7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3' untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses. SIGNIFICANCE: These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.Item Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women(American Association for Cancer Research, 2024) Sah, Samyukta; Bifarin, Olatomiwa O.; Moore, Samuel G.; Gaul, David A.; Chung, Hyewon; Kwon, Sun Young; Cho, Hanbyoul; Cho, Chi-Heum; Kim, Jae-Hoon; Kim, Jaeyeon; Fernández, Facundo M.; Biochemistry and Molecular Biology, School of MedicineBackground: Distinguishing ovarian cancer from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of ovarian cancer pathogenesis. Accumulating evidence suggests a link between ovarian cancer and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved ovarian cancer diagnosis and prevention. Methods: Here, we profiled the serum lipidome of 208 ovarian cancer, including 93 early-stage patients with ovarian cancer and 117 nonovarian cancer (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning (ML) approaches. Results: We found that lipidome alterations unique to ovarian cancer were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in ovarian cancer in comparison with other gynecological diseases. ML methods selected a panel of 17 lipids that discriminated ovarian cancer from nonovarian cancer cases with an AUC value of 0.85 for an independent test set. Conclusions: This study provides a systemic analysis of lipidome alterations in human ovarian cancer, specifically in Korean women.Item Single-cell analysis of a high-grade serous ovarian cancer cell line reveals transcriptomic changes and cell subpopulations sensitive to epigenetic combination treatment(Public Library of Science, 2022-08-03) Sriramkumar, Shruthi; Metcalfe, Tara X.; Lai, Tim; Zong, Xingyue; Fang, Fang; O'Hagan, Heather M.; Nephew, Kenneth M.; Medical and Molecular Genetics, School of MedicineOvarian cancer (OC) is a lethal gynecological malignancy with a five-year survival rate of only 46%. Development of resistance to platinum-based chemotherapy is a common cause of high mortality rates among OC patients. Tumor and transcriptomic heterogeneity are drivers of platinum resistance in OC. Platinum-based chemotherapy enriches for ovarian cancer stem cells (OCSCs) that are chemoresistant and contribute to disease recurrence and relapse. Studies examining the effect of different treatments on subpopulations of HGSOC cell lines are limited. Having previously demonstrated that combined treatment with an enhancer of zeste homolog 2 inhibitor (EZH2i) and a RAC1 GTPase inhibitor (RAC1i) inhibited survival of OCSCs, we investigated EZH2i and RAC1i combination effects on HGSOC heterogeneity using single cell RNA sequencing. We demonstrated that RAC1i reduced expression of stemness and early secretory marker genes, increased expression of an intermediate secretory marker gene and induced inflammatory gene expression. Importantly, RAC1i alone and in combination with EZH2i significantly reduced oxidative phosphorylation and upregulated Sirtuin signaling pathways. Altogether, we demonstrated that combining a RAC1i with an EZH2i promoted differentiation of subpopulations of HGSOC cells, supporting the future development of epigenetic drug combinations as therapeutic approaches in OC.