The Genomic Landscape of Vulvar Squamous Cell Carcinoma.

Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup.

Randomized trial of exercise on depressive symptomatology and brain derived neurotrophic factor (BDNF) in ovarian cancer survivors: The Women's Activity and Lifestyle Study in Connecticut (WALC).

OBJECTIVES: Depression is one of the most prevalent mental disorders, and rates are higher among cancer survivors than the general population, and higher in ovarian cancer patients compared to cohorts of other cancer survivors. Physical activity has been associated with lower depressive symptoms in cancer survivors, yet no trial has examined this association in women with ovarian cancer. We examined the effect of exercise on depression symptomatology and serum brain derived neurotrophin factor (BDNF) which has been associated with depression, in women with ovarian cancer. METHODS: We conducted a 6-month home-based randomized trial of exercise vs. attention-control (AC) in 144 ovarian cancer survivors. Depressive symptomatology was measured via the Center for Epidemiologic Studies Depression Scale (CES-D). Serum total and free BDNF was measured at baseline and 6-months. Student's t-statistic and mixed-model repeated measures analysis was used to evaluate six-month change between arms in CES-D scores and BDNF. RESULTS: Women were 57.3 ±â€¯8.6 (mean ±â€¯SD) years old, 1.7 ±â€¯1.0 years post-diagnosis with a baseline CES-D score of 11.79 ±â€¯10.21. The majority (55%) were diagnosed with stage III/IV ovarian cancer. CES-D scores decreased in the exercise arm by 2.7 points (95% CI: -4.4, -0.9) or a 21% decrease compared to a 0.3 point decrease (-2.2, 1.5) (3% decrease) in the AC arm (P = 0.05). There was no difference in change in total or free BDNF between the exercise and AC arms. CONCLUSIONS: Ovarian cancer survivors are able to exercise at recommended levels, and exercise was associated with a significant reduction in depressive symptomatology.

Synergistic enhancement of efficacy of platinum drugs with verteporfin in ovarian cancer cells.

BACKGROUND: Epithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells. METHODS: The efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array. RESULTS: Treatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment. CONCLUSIONS: Either in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients.

Cervical Cancer Patients' Willingness and Ability to Serve as Health Care Educators to Advocate for Human Papillomavirus Vaccine Uptake.

Human papillomavirus (HPV) causes nearly all cervical cancer. Only half of females and less than half of males receive the recommended HPV vaccine dose. This study explores whether cervical cancer patients may serve as health advocates to adolescents and their parents in encouraging the uptake of the HPV vaccine. The study targeted an opportunity sample of women seen in the gynecology oncology clinic with a diagnosis of cervical cancer. During interviews, patients were asked about the following: provider conversations regarding cervical cancer, knowledge of HPV and the vaccine, discussions with family or friends about the causes or prevention of cervical cancer, and whether they would be willing to talk with others about the HPV vaccine. Twenty-three interviews were conducted in 2016-2017. Patients ranged from 28 to 61 years of age. Four team members developed a coding list, then used these themes to code the interviews. Six themes resulted from the analysis of the transcripts: (1) Expressions of fears, questioning effectiveness of vaccine; (2) Low level of health literacy; (3) Acquiring health information from television, internet; (4) Provider conversations (with patients regarding HPV and the vaccine); (5) Patient stigma surrounding cervical cancer; (6) Patients' willingness to serve as a health care educator. While cervical cancer patients overall expressed a willingness to serve as health care educators, barriers remain. Low health literacy and a lack of understanding of the causes of cervical cancer persist. These issues will need to be addressed in order for cervical cancer patients to be effective advocates.

Implementing universal Lynch syndrome screening (IMPULSS): protocol for a multi-site study to identify strategies to implement, adapt, and sustain genomic medicine programs in different organizational contexts.

BACKGROUND: Systematic screening of all colorectal tumors for Lynch Syndrome (LS) has been recommended since 2009. Currently, implementation of LS screening in healthcare systems remains variable, likely because LS screening involves the complex coordination of multiple departments and individuals across the healthcare system. Our specific aims are to (1) describe variation in LS screening implementation across multiple healthcare systems; (2) identify conditions associated with both practice variation and optimal implementation; (3) determine the relative effectiveness, efficiency, and costs of different LS screening protocols by healthcare system; and (4) develop and test in a real-world setting an organizational toolkit for LS screening program implementation and improvement. This toolkit will promote effective implementation of LS screening in various complex health systems. METHODS: This study includes eight healthcare systems with 22 clinical sites at varied stages of implementing LS screening programs. Guided by the Consolidated Framework for Implementation Research (CFIR), we will conduct in-depth semi-structured interviews with patients and organizational stakeholders and perform economic evaluation of site-specific implementation costs. These processes will result in a comprehensive cross-case analysis of different organizational contexts. We will utilize qualitative data analysis and configurational comparative methodology to identify facilitators and barriers at the organizational level that are minimally sufficient and necessary for optimal LS screening implementation. DISCUSSION: The overarching goal of this project is to combine our data with theories and tools from implementation science to create an organizational toolkit to facilitate implementation of LS screening in various real-world settings. Our organizational toolkit will account for issues of complex coordination of care involving multiple stakeholders to enhance implementation, sustainability, and ongoing improvement of evidence-based LS screening programs. Successful implementation of such programs will ultimately reduce suffering of patients and their family members from preventable cancers, decrease waste in healthcare system costs, and inform strategies to facilitate the promise of precision medicine. TRIAL REGISTRATION: N/A.

What do cervical cancer patients know, how do they learn, and who do they tell? A pilot study.

BACKGROUND: This study explored what patients identified with cervical cancer know about the link between human papillomavirus (HPV) and cervical cancer and where they learned this information. Patients share a great deal of information with family, friends and colleagues and we were interested in the accuracy and sources of information they are sharing. METHODS: Patients identified through the EHR of a health system who had a history of cervical cancer were invited to participate in a brief survey of their experience. The sample represents an opportunity sample of patients who responded. RESULTS: Generally, these patients, drawn from the Geisinger Health System in central Pennsylvania, were older (mean 57.5 years), White, and about half had annual household income of $35 K. Among all respondents about 17% had not heard of HPV, 21% did not know about an HPV vaccine, and about 38% did not know about the link between HPV and cervical cancer. Most frequently patients reported obtaining their information about HPV from television advertisements. About half received information from their oncologist. Patients reported having conversations with families about their own cancer, the cause of their cancer and HPV vaccination. It is important to note that these conversations were supported by information from many sources. CONCLUSIONS: Patients may serve as a conduit for information about their condition and may be informal 'educators' in the community. It is important to make certain that these opportunities are informed by information obtained from trusted and accurate sources.

Adipose microenvironment promotes hypersialylation of ovarian cancer cells.

Sialylation, the addition of negatively charged sialic acid sugars to terminal ends of glycans, is upregulated in most cancers. Hypersialylation supports multiple pro-tumor mechanisms such as enhanced migration and invasion, resistance to apoptosis and immune evasion. A current gap in knowledge is the lack of understanding on how the tumor microenvironment regulates cancer cell sialylation. The adipose niche is a main component of most peritoneal cancers' microenvironment. This includes ovarian cancer (OC), which causes most deaths from all gynecologic cancers. In this report, we demonstrate that the adipose microenvironment is a critical regulator of OC cell sialylation. In vitro adipose conditioning led to an increase in both ⍺2,3- and ⍺2,6-linked cell surface sialic acids in both human and mouse models of OC. Adipose-induced sialylation reprogramming was also observed in vivo from intra-peritoneal OC tumors seeded in the adipose-rich omentum. Mechanistically, we observed upregulation of at least three sialyltransferases, ST3GAL1, ST6GAL1 and ST3GALNAC3. Hypersialylated OC cells consistently formed intra-peritoneal tumors in both immune-competent mice and immune-compromised athymic nude mice. In contrast, hyposiaylated OC cells persistently formed tumors only in athymic nude mice demonstrating that sialylation impacts OC tumor formation in an immune dependent manner. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancers.

Correlation between steroid receptor expression and response to progestational therapy in patients with atypical endometrial hyperplasia or cancer.

Background: Conservative management of atypical endometrial hyperplasia (AEH) or endometrial cancer (EMCA) often relies on the treatment of synthetic progestins, which show varied success and response rates. We evaluate the correlation between steroid receptor expression and response to progestin therapy in patients with AEH and EMCA. Methods: Retrospective cohort study collected data for patients with AEH or EMCA who had an endometrial sample after receiving conservative therapy utilizing either Megestrol acetate or Levonorgestrel Intrauterine device (IUD). Immunohistochemistry (IHC) was performed on pre- and post- treatment biopsy samples to assess androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) expression. IHC scores (1-12) were calculated based on staining intensity and percentage of positive cells. Results and analysis: We identified 15 patients with AEH and EMCA between 2015 and 2023 with the majority of African American ethnicity (53 %). Fourteen patients (93 %) received Megestrol acetate, and 1 patient received Levonorgestrel IUD alone. Three patients ultimately underwent hysterectomy. Seven (46.6 %) endometrial samples had strong positivity for AR, PR and ER expression on pre-treatment biopsies, and only 3 (20 %) of them maintained strong positivity for the 3 receptors in the post-treatment. Patients who successfully responded to the treatment demonstrated a significantly greater decrease in IHC scores after the treatment compared to those who did not respond (p = 0.009). Conclusion: Steroid receptor expression could be used as a possible biomarker for response to progestin therapy in patients undergoing conservative management for AEH and EMCA.

Immune Modulation of Innate and Adaptive Responses Restores Immune Surveillance and Establishes Antitumor Immunologic Memory.

Current immunotherapies have proven effective in strengthening antitumor immune responses, but constant opposing signals from tumor cells and the surrounding microenvironment eventually lead to immune escape. We hypothesized that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system would provide a robust and long-term antitumor effect by creating immunologic memory against tumors. To achieve this, we developed CARG-2020, a genetically modified virus-like vesicle (VLV) that is a self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three immune modulators: (i) the pleiotropic antitumor cytokine IL12, in which the subunits (p35 and p40) are tethered together; (ii) the extracellular domain (ECD) of the protumor IL17RA, which serves as a dominant-negative antagonist; and (iii) a shRNA targeting PD-L1. Using a mouse model of ovarian cancer, we demonstrated the oncolytic effect and immune-modulatory capacities of CARG-2020. By enhancing IL12 and blocking IL17 and PD-L1, CARG-2020 successfully reactivated immune surveillance by promoting M1, instead of M2, macrophage differentiation, inhibiting MDSC expansion and establishing a potent CD8+ T cell-mediated antitumoral response. Furthermore, we demonstrated that this therapeutic approach provided tumor-specific and long-term protection against the establishment of new tumors. Our results provide a rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance antitumor responses and prevent a recurrence.

BRCA status dictates Wnt responsiveness in epithelial ovarian cancer.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2 mutant (BRCA2mt) patients are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 function in ovarian cancer. Transcriptomic and pathway analysis comparing BRCA1 mutant (BRCA1mt), BRCA2mt and homologous recombination wild-type (HRwt) ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type (BRCAwt), BRCA1null and BRCA2null mouse ovarian cancer cells, we observed preferential activation of the canonical Wnt/ß-catenin signaling in BRCAwt ovarian cancer cells while the non-canonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1null cells. Interestingly, BRCA2null mouse ovarian cancer cells, demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor, Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival.

DNA nanotherapy for pre-neoplastic cervical lesions.

OBJECTIVE: This study aims to test the hypothesis that targeted nanoparticle delivery of DNA encoding HPV16-regulated diphtheria toxin (DT-A) will result in the death of HPV16-infected cells. MATERIALS AND METHODS: Plasmid constructs containing a HPV16 Long Control Region (LCR) DNA sequence upstream of DT-A or luciferase reporter (Luc) DNA sequences were used to formulate poly(ß-amino ester) nanoparticles. The effect on tumor growth of HPV/DT-A-nanoparticle injection directly into HPV16(+) CaSki human cervical cancer cell-derived xenografts in mice was determined. To evaluate the ability of the HPV16 LCR regulatory sequence to activate gene expression specifically in HPV16-infected cells, mice underwent bioluminescent optical imaging following intraperitoneal injection of HPV/Luc-nanoparticles. The use of Lutrol F127, a thermal-sensitive gel, to target delivery of nanoparticles and subsequent gene expression to cervical epithelial cells was evaluated in ex vivo cultures of mouse cervix and following intravaginal delivery of nanoparticle/gel in mice, as well as in ex vivo cultures of surgical LEEP samples. RESULTS: The selected HPV16 LCR regulatory sequence activates gene expression in both HPV16-infected cells and non-infected cells. However, in the cervix, it is specifically active in epithelial cells. Following exposure of cervical cells to HPV/DT-A-nanoparticles mixed with Lutrol F127 gel, DT-A is expressed and cells die. CONCLUSIONS: An HPV16 DNA sequence that targets gene expression specifically to HPV16-infected cells remains to be discovered. Topical application of a Lutrol F127 thermal gel/nanoparticle mix is illustrative of how to restrict exposure of cells to therapeutic nanoparticles, thereby allowing for targeted DNA delivery to cervical pre-cancerous lesions.

A rare case of ovarian hemangioma in a 30-year-old nulligravid woman.

A 30-year-old nulligravid woman with a history of polycystic ovarian syndrome presented for evaluation of left adnexal mass. The patient was referred to the gynecologic oncology clinic after endorsing signs of abdominal pain for a month and the pelvis ultrasound demonstrated hypoechoic solid mass in the left ovary. Magnetic resonance imaging with T1- and T2-weighted images demonstrated progressive centripetal "filling-in" of the mass suggesting a unique variation of malignant ovarian mass, similar to what is seen in hepatic hemangioma. Upon resection of the ovarian mass, pathology reported that the mass was filled with numerous small blood vessels with single later of endothelial cells confirming the diagnosis of ovarian hemangioma, capillary-type-a rare finding.

Generation of Stable Epithelial-Mesenchymal Hybrid Cancer Cells with Tumorigenic Potential.

PURPOSE: Cancer progression, invasiveness, and metastatic potential have been associated with the activation of the cellular development program known as epithelial-to-mesenchymal transition (EMT). This process is known to yield not only mesenchymal cells, but instead an array of cells with different degrees of epithelial and mesenchymal phenotypes with high plasticity, usually referred to as E/M hybrid cells. The characteristics of E/M hybrid cells, their importance in tumor progression, and the key regulators in the tumor microenvironment that support this phenotype are still poorly understood. METHODS: In this study, we established an in vitro model of EMT and characterized the different stages of differentiation, allowing us to identify the main genomic signature associated with the E/M hybrid state. RESULTS: We report that once the cells enter the E/M hybrid state, they acquire stable anoikis resistance, invasive capacity, and tumorigenic potential. We identified the hepatocyte growth factor (HGF)/c-MET pathway as a major driver that pushes cells in the E/M hybrid state. CONCLUSIONS: Herein, we provide a detailed characterization of the signaling pathway(s) promoting and the genes associated with the E/M hybrid state.

Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory.

Current immunotherapies have proven effective in strengthening anti-tumor immune responses but constant opposing signals from tumor cells and surrounding microenvironment eventually lead to immune escape. We hypothesize that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system will provide a robust and long-term anti-tumor effect by creating immunological memory against the tumor. To achieve this, we developed CARG-2020, a virus-like-vesicle (VLV). It is a genetically modified and self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three transgenes: 1 ) the pleiotropic antitumor cytokine IL-12 in which the subunits (p35 and p40) are tethered together; 2) the extracellular domain (ECD) of the pro- tumor IL-17RA, which can serve as a dominant negative antagonist; and 3) shRNA for PD-L1. Using a mouse model of ovarian cancer, we demonstrate the oncolytic effect and immune modulatory capacities of CARG-2020. By enhancing IL-12 and blocking IL-17 and PD-L1, CARG-2020 successfully reactivates immune surveillance by promoting M1 instead of M2 macrophage differentiation, inhibiting MDSC expansion, and establishing a potent CD8+ T cell mediated anti-tumoral response. Furthermore, we demonstrate that this therapeutic approach provides tumor-specific and long-term protection preventing the establishment of new tumors. Our results provide rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance the anti-tumor response and to prevent recurrence.

MNRR1 is a driver of ovarian cancer progression.

Cancer progression requires the acquisition of mechanisms that support proliferative potential and metastatic capacity. MNRR1 (also CHCHD2, PARK22, AAG10) is a bi-organellar protein that in the mitochondria can bind to Bcl-xL to enhance its anti-apoptotic function, or to respiratory chain complex IV (COX IV) to increase mitochondrial respiration. In the nucleus, it can act as a transcription factor and promote the expression of genes involved in mitochondrial biogenesis, migration, and cellular stress response. Given that MNRR1 can regulate both apoptosis and mitochondrial respiration, as well as migration, we hypothesize that it can modulate metastatic spread. Using ovarian cancer models, we show heterogeneous protein expression levels of MNRR1 across samples tested and cell-dependent control of its stability and binding partners. In addition to its anti-apoptotic and bioenergetic functions, MNRR1 is both necessary and sufficient for a focal adhesion and ECM repertoire that can support spheroid formation. Its ectopic expression is sufficient to induce the adhesive glycoprotein THBS4 and the type 1 collagen, COL1A1. Conversely, its deletion leads to significant downregulation of these genes. Furthermore, loss of MNRR1 leads to delay in tumor growth, curtailed carcinomatosis, and improved survival in a syngeneic ovarian cancer mouse model. These results suggest targeting MNRR1 may improve survival in ovarian cancer patients.

Exercise adherence in a randomized controlled trial of exercise on quality of life in ovarian cancer survivors.

PURPOSE: Factors associated with improving exercise in ovarian cancer survivors remain unknown. We explored characteristics associated with exercise adherence among women treated for ovarian cancer in the Women's Activity and Lifestyle Study in Connecticut (WALC) randomized controlled trial. METHODS: We evaluated adherence among women randomized to the WALC exercise intervention (N = 74). Women had to be exercising ≤ 90 min/week and post-treatment. The intervention included 25 telephone-based exercise counseling sessions over 6 months. Adherence was defined as 150 min/week of moderate/vigorous-intensity exercise. We evaluated factors associated with exercise adherence and duration using multivariate logistic and linear regression. The number of sessions sufficient to achieve 150 min/week was modeled with an unadjusted receiver operating characteristic (ROC) curve. RESULTS: Women were 57.3 ± 8.8 years old and 1.7 ± 1.0 years since diagnosis. The mean exercise time over 6 months was 166.0 ± 66.1 min/week, and 64.9% of women met the 150 min/week goal. Women attended 22.8 ± 3.6 (92%) counseling sessions. No cancer recurrence during the study (OR = 9.15, 95% CI: 1.09-44.02) and greater session attendance (OR = 1.21, 95% CI: 1.02-1.43) were related to meeting the exercise goal. Greater session attendance (P < 0.01) and higher baseline activity level (P = 0.02) were associated with greater average weekly exercise duration. The ROC curve suggested attending 18 counseling sessions was optimal to meet the exercise goal. CONCLUSIONS: Women attending more counseling sessions or with no cancer recurrence during the study were more likely to meet the exercise goal. More research is needed to understand ideal counseling intensity for ovarian cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Eighteen counseling sessions are sufficient for ovarian cancer survivors to achieve 150 min/week exercise.

Effect of exercise on body composition among women with ovarian cancer.

PURPOSE: Obesity is associated with a higher risk of mortality in women with ovarian cancer. Exercise has improved body composition among cancer survivors, yet no randomized controlled trial has explored the effect of exercise on body composition in women with ovarian cancer. In this analysis, we examined the effect of a six-month aerobic exercise intervention on body composition among ovarian cancer survivors in the Women's Activity and Lifestyle Study in Connecticut (WALC). METHODS: Women with ovarian cancer (N = 144) were randomized in a 1:1 ratio to 6 months of an aerobic exercise intervention or attention-control, and body composition was measured as a secondary outcome at baseline and 6 months via dual-energy X-ray absorptiometry (DEXA). Women with at least one DEXA scan were included in the analysis (N = 103). RESULTS: On average, participants were 57.1 (± 8.7) years old and 1.6 (± 0.9) years since diagnosis. Women randomized to exercise maintained weight during the trial (- 0.11 kg, P = 0.82), while women in attention-control gained weight (+ 1.40 kg, P = 0.03); however, the between-group difference did not reach statistical significance (P = 0.09). We found no statistically significant differences by study arm for changes in body fat percentage, bone mineral density, or lean body mass. CONCLUSIONS: Weight was maintained as a result of a 6-month aerobic exercise intervention among post-treatment ovarian cancer survivors. Future exercise and healthy eating interventions should consider additional measures (e.g., computer tomography scans, D3-creatinine) to more accurately assess changes in body composition. IMPLICATIONS FOR CANCER SURVIVORS: Moderate-intensity aerobic exercise may help ovarian cancer survivors maintain weight.

Intermittent Fasting induced ketogenesis inhibits mouse epithelial ovarian tumors by promoting anti-tumor T cell response.

Epithelial Ovarian Cancer (EOC) is the most lethal gynecologic cancer with limited genetic alterations identified that can be therapeutically targeted. In tumor bearing mice, short-term fasting, fasting mimicking diet and calorie restriction enhance the activity of antineoplastic treatment by modulating systemic metabolism and boosting anti-tumor immunity. We tested the outcome of sixteen-hour intermittent fasting (IF) on mouse EOC progression with focus on fasting driven antitumor immune responses. IF resulted in consistent decrease of tumor promoting metabolic growth factors and cytokines, recapitulating changes that creates a tumor antagonizing environment. Immune profiling revealed that IF profoundly reshapes anti-cancer immunity by inducing increase in CD4+ and CD8+ cells, paralleled by enhanced antitumor Th1 and cytotoxic responses, by enhancing their metabolic fitness. Metabolic studies revealed that IF generated bioactive metabolite BHB which can be a potential substitute for simulating the antitumor benefits of IF. However, in a direct comparison, IF surpassed exogenous BHB therapy in improving survival and activating anti-tumor immune response. Thus, our data provides strong evidence for IF and its metabolic mediator BHB for ameliorating EOC progression and as a viable approach in maintaining and sustaining an effective anti-tumor T cell response.

A Novel Role of Connective Tissue Growth Factor in the Regulation of the Epithelial Phenotype.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between the epithelial and mesenchymal stage is essential for tissue homeostasis. Many of the genes promoting mesenchymal transformation have been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify the genes responsible for maintaining the epithelial phenotype and inhibiting EMT. METHODS: RNA seq was performed using an vitro model of EMT. CTGF expression was determined via qPCR and Western blot analysis. The knockout of CTGF was completed using the CTGF sgRNA CRISPR/CAS9. The tumorigenic potential was determined using NCG mice. RESULTS: The knockout of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as anoikis resistance, cytoskeleton remodeling, increased cell stiffness, and the acquisition of invasion and tumorigenic capacity. CONCLUSIONS: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with the early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for the conservation of epithelial structure and function. These findings provide a new window into understanding the early stages of mesenchymal transformation.

Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response.

In various cancer models, dietary interventions have been shown to inhibit tumor growth, improve anticancer drug efficacy, and enhance immunity, but no such evidence exists for epithelial ovarian cancer (EOC), the most lethal gynecologic cancer. The anticancer immune responses induced by 16-h intermittent fasting (IF) were studied in mice with EOC. IF consistently reduced metabolic growth factors and cytokines that stimulate tumor growth, creating a tumor-hostile environment. Immune profiling showed that IF dramatically alters anti-cancer immunity by increasing CD4+ and CD8+ cells, Th1 and cytotoxic responses, and metabolic fitness. ß-hydroxy butyrate (BHB), a bioactive metabolite produced by IF, partially imitates its anticancer effects by inducing CD8+ effector function. In a direct comparison, IF outperformed exogenous BHB treatment in survival and anti-tumor immune response, probably due to increased ketogenesis. Thus, IF and one of its metabolic mediators BHB suppress EOC growth and sustain a potent anti-tumor T cell response.