Vaginal Recurrence More than 17 Years after Hysterectomy and Adjuvant Treatment for Uterine Carcinoma with Successful Salvage Brachytherapy: A Case Report

Purpose: Although the majority of recurrences occur within the first 3 years of hysterectomy for endometrioid carcinoma, we report herein a successful salvage vaginal brachytherapy in a patient with endometrioid uterine carcinoma which recurred more than 17 years after initial treatment. Materials and Methods: A 61-year-old female was diagnosed with endometrioid adenocarcinoma of the uterus and treated with TAH-BSO, followed by adjuvant external beam radiation therapy (EBRT) to the whole pelvis. After remaining free of any recurrent or metastatic disease for more than 17 years, she was diagnosed with isolated vaginal cuff recurrence and successfully treated with a salvage high-dose-rate intracavitary vaginal brachytherapy. Results: The patient remained disease free until her death from unrelated causes 7 years later. Conclusion: To the best of our knowledge, this case represents the longest time to recurrence of endometrial cancer in someone who had been treated with TAH-BSO and adjuvant pelvic EBRT. This case highlights that even with adjuvant therapy, late recurrences may occur, and successful salvage brachytherapy is very effective

Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB

<p>Abstract</p> <p>Background</p> <p>Platinum-resistance (PR) continues to be a major problem in the management of epithelial ovarian cancer (EOC). Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells <it>in vitro </it>and <it>in vivo </it>by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS) and resistant EOC cells.</p> <p>Methods</p> <p>The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA) was used to evaluate NF-κB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP.</p> <p>Results</p> <p>Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-κB DNA binding activity were all found to be down-regulated in the combination groups.</p> <p>Conclusion</p> <p>This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.</p

A patient perspective on applying intermittent fasting in gynecologic cancer

OBJECTIVE: Researchers sought patient feedback on a proposed randomized controlled trial (RCT) in which gynecological cancer patients would modify their diets with intermittent fasting to gain insight into patients\u27 perspectives, receptivity, and potential obstacles. A convenience sample of 47 patients who met the inclusion criteria of the proposed RCT provided their feedback on the feasibility and protocols of the RCT using a multi-method approach consisting of focus groups (n = 8 patients) and surveys (n = 36 patients). RESULTS: Patients were generally receptive to the concept of intermittent fasting, and many expressed an interest in attempting it themselves. Patients agreed that the study design was feasible in terms of study assessments, clinic visits, and biospecimen collection. Feedback on what could facilitate adherence included convenient appointment scheduling times and the availability of the research team to answer questions. Regarding recruitment, patients offered suggestions for study advertisements, with the majority concurring that a medical professional approaching them would increase their likelihood of participation

Bioenergetic Adaptations in Chemoresistant Ovarian Cancer Cells.

Earlier investigations have revealed that tumor cells undergo metabolic reprogramming and mainly derive their cellular energy from aerobic glycolysis rather than oxidative phosphorylation even in the presence of oxygen. However, recent studies have shown that certain cancer cells display increased oxidative phosphorylation or high metabolically active phenotype. Cellular bioenergetic profiling of 13 established and 12 patient derived ovarian cancer cell lines revealed significant bioenergetics diversity. The bioenergetics phenotype of ovarian cancer cell lines correlated with functional phenotypes of doubling time and oxidative stress. Interestingly, chemosensitive cancer cell lines (A2780 and PEO1) displayed a glycolytic phenotype while their chemoresistant counterparts (C200 and PEO4) exhibited a high metabolically active phenotype with the ability to switch between oxidative phosphorylation or glycolysis. The chemosensitive cancer cells could not survive glucose deprivation, while the chemoresistant cells displayed adaptability. In the patient derived ovarian cancer cells, a similar correlation was observed between a high metabolically active phenotype and chemoresistance. Thus, ovarian cancer cells seem to display heterogeneity in using glycolysis or oxidative phosphorylation as an energy source. The flexibility in using different energy pathways may indicate a survival adaptation to achieve a higher \u27cellular fitness\u27 that may be also associated with chemoresistance

Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR\u27s tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

BACKGROUND: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. METHODS: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. RESULTS: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. CONCLUSION: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin\u27s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers

Onward and Upward: The Legacy of Black Urologists in America

In partnership with the American Urological Association\u27s William P. Didusch Center for Urologic History, Henry Ford Health hosted a Grand Rounds event from 7 – 9 a.m. Wednesday, June 14, in the Buerki Auditorium at Henry Ford Hospital. The event highlights the contributions of Black urologists to the history of medicine despite systemic racism in the medical field and across the country. Covering the impact of exclusion and segregation in the past, as well as present day issues such as microaggressions and cultural insensitivity, the lecture and discussion calls for a future of successfully integrating medicine to achieve better outcomes for physicians and their patients. The schedule of the event is as follows: 7 a.m.: Welcome by Craig Rogers, M.D., Chair, Department of Urology, Vattikuti Urology Institute. Introductory remarks by Adnan Munkarah, M.D., President, Care Delivery System and Chief Clinical Officer and Steven Kalkanis, M.D., CEO of Henry Ford Medical Group and CEO of Henry Ford Hospital. 7:10 a.m.: Keynote speaker Arthur L. Burnett II, M.D., MBA., FACS., professor of urology, Johns Hopkins University School of Medicine will present “Onward and Upward: The Legacy of Black Urologists in America. 7:30 a.m.: Panel discussion moderated by Linda McIntire, M.D., President, R. Frank Jones Urological Society, and graduate of Henry Ford urology program, featuring the panelists listed below. Melvin Hollowell, M.D., FACS Dr. Hollowell earned his medical degree in 1959 and has practiced in Detroit for 64 years. At 93 years young, he is still practicing today. Isaac Powell, M.D. Dr. Powell graduated with his medical degree in 1969 and became the first African American graduate from the Henry Ford Hospital urology program in 1974. Conrad Maitland, M.D. Dr. Maitland has been practicing for 40 years and is himself a survivor of prostate cancer - a disease that disproportionately affects Black men. Ray Littleton, M.D. Dr. Littleton joined the senior staff at Henry Ford Hospital in 1980 and helped pioneer minimally invasive surgery by performing the first percutaneous kidney stone removal in Michigan in 1983

The impact of a wireless audio system on communication in robotic-assisted laparoscopic surgery: A prospective controlled trial.

BACKGROUND: Robotic surgery presents a challenge to effective teamwork and communication in the operating theatre (OR). Our objective was to evaluate the effect of using a wireless audio headset device on communication, efficiency and patient outcome in robotic surgery. METHODS AND FINDINGS: A prospective controlled trial of team members participating in gynecologic and urologic robotic procedures between January and March 2015. In the first phase, all surgeries were performed without headsets (control), followed by the intervention phase where all team members used the wireless headsets. Noise levels were measured during both phases. After each case, all team members evaluated the quality of communication, performance, teamwork and mental load using a validated 14-point questionnaire graded on a 1-10 scale. Higher overall scores indicated better communication and efficiency. Clinical and surgical data of all patients in the study were retrieved, analyzed and correlated with the survey results. The study included 137 procedures, yielding 843 questionnaires with an overall response rate of 89% (843/943). Self-reported communication quality was better in cases where headsets were used (113.0 ± 1.6 vs. 101.4 ± 1.6; p \u3c .001). Use of headsets reduced the percentage of time with a noise level above 70 dB at the console (8.2% ± 0.6 vs. 5.3% ± 0.6, p \u3c .001), but had no significant effect on length of surgery nor postoperative complications. CONCLUSIONS: The use of wireless headset devices improved quality of communication between team members and reduced the peak noise level in the robotic OR

Ovarian cancer modulates the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells via glutamine metabolism

OBJECTIVE: Immature CD11b(+)Gr1(+) myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study\u27s objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells. METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti PD1 mAb. The treatment effect was assessed by survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. RESULTS: Depletion of Gr1(+) immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. These findings, in addition to the adoptive transfer studies, validated the role of immunosuppressive CD11b(+)Gr1(+) myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironment produced both recruitment and regulatory factors for immunosuppressive CD11b(+)Gr1(+) myeloid cells. CD11b(+)Gr1(+) myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted mainly by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found be the most significantly elevated gene in tumor primed myeloid cells. Inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression, and function in myeloid cells. CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b(+)Gr1(+) myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in those immunosuppressive myeloid decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer