Clinicopathologic Characteristics of a Single-institution Cohort of Ovarian Adult Granulosa Cell Tumors, With Biomarker and Therapeutic Implications Utilizing the Detection of Androgen, Estrogen, and Progesterone Hormone Receptor Expression by Immunohistochemistry.

Adult granulosa cell tumors (AGCTs) are rare ovarian tumors with generally good prognosis after surgical resection; however, they do have recurrence potential. Therapeutic and management options for recurrences are currently limited, and the need for expanded adjuvant therapies is increasingly recognized. Anti-hormonal therapy is being explored as an option, which relies on the detection and assessment of hormone receptor expression (androgen, estrogen, and progesterone receptors) as a biomarker and therapeutic target. Our study identifies several clinicopathologic characteristics with significant associations for recurrence of AGCT, which were younger age, higher stage, and larger tumor size. Our study also demonstrates that androgen receptor (AR) expression may be utilized as a potential biomarker for hormonal therapy and that detection of AR expression in AGCT by immunohistochemistry (IHC) varies depending on the antibody clone used for testing. AR was detected in 95% of samples tested with antibodies derived from clone AR27. This detection rate is much higher than previously reported.

Virtual visits among gynecologic oncology patients during the COVID-19 pandemic are accessible across the social vulnerability spectrum.

OBJECTIVE: The COVID-19 pandemic has quickly transformed healthcare systems with expansion of telemedicine. The past year has highlighted risks to immunosuppressed cancer patients and shown the need for health equity among vulnerable groups. In this study, we describe the utilization of virtual visits by patients with gynecologic malignancies and assess their social vulnerability. METHODS: Virtual visit data of 270 gynecology oncology patients at a single institution from March 1, 2020 to August 31, 2020 was obtained by querying a cohort discovery tool. Through geocoding, the CDC Social Vulnerability Index (SVI) was utilized to assign social vulnerability indices to each patient and the results were analyzed for trends and statistical significance. RESULTS: African American patients were the most vulnerable with a median SVI of 0.71, Asian 0.60, Hispanic 0.41, and Caucasian 0.21. Eighty-seven percent of patients in this study were Caucasian, 8.9% African American, 3.3% Hispanic, and 1.1% Asian, which is comparable to the baseline institutional gynecologic cancer population. The mean census tract SVI variable when comparing patients to all census tracts in the United States was 0.31 (range 0.00 least vulnerable to 0.98 most vulnerable). CONCLUSIONS: Virtual visits were utilized by patients of all ages and gynecologic cancer types. African Americans were the most socially vulnerable patients of the cohort. Telemedicine is a useful platform for cancer care across the social vulnerability spectrum during the pandemic and beyond. To ensure continued access, further research and outreach efforts are needed.

Sucrose Non-Fermenting Related Kinase Expression in Ovarian Cancer and Correlation with Clinical Features.

Sucrose non-fermenting related kinase (SNRK) is a serine/threonine kinase known to regulate cellular metabolism and adipocyte inflammation. Since alterations in adipocyte metabolism play a role in ovarian cancer metastasis, we investigated the expression of SNRK in benign and malignant human ovarian tissue using immunohistochemistry and qPCR. The number of SNRK positive (+) nuclei is increased in malignant tissue compared to benign tissue (21.03% versus 14.90%, p < .0431). The most strongly stained malignant SNRK+ nuclei were stage 1 compared to stage 2-4 disease. Differential expression of SNRK in early versus late stage disease suggests specific roles for SNRK in ovarian cancer metastasis.

Landscape of potential germline pathogenic variants in select cancer susceptibility genes in patients with adult-type ovarian granulosa cell tumors.

OBJECTIVE: The objective of this study was to assess the frequency of potential germline pathogenic variants that may contribute to risk of development of adult granulosa cell tumors (AGCT) given the paucity of germline testing guidelines for these patients. METHODS: This was a retrospective cross-sectional study analyzing comprehensive genomic profiling (CGP) results of AGCT with the FOXL2 p.C134W mutation submitted to Foundation Medicine between 2012 and 2022. Cases with a potential germline pathogenic variant were identified by filtering single nucleotide variants and short indels by variant allele frequency (VAF) and presence in ClinVar for select cancer susceptibility genes. Odds ratios for AGCT risk were calculated compared to a healthy population. RESULTS: Prior to analysis, 595 patients were screened and 516 with a somatic FOXL2 p.C134W mutation were included. Potential germline pathogenic variants in a DNA repair-related gene (ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, RAD51C, or RAD51D) were found in 6.6% of FOXL2-mutated AGCT. Potential germline pathogenic CHEK2 variants were found in 3.5% (18/516) of AGCT patients, a rate that was 2.8-fold higher than Genome Aggregation Database non-cancer subjects (95% CI 1.8-4.6, p < 0.001). The founder variants p.I157T (38.9%, 7/18) and p.T367fs*15 (c.1100delC; 27.8%, 5/18) were most commonly observed. CHEK2 VAF indicated frequent loss of the wildtype copy of the gene. CONCLUSIONS: These results support ongoing utilization of genomic tumor profiling and confirmatory germline testing for potential germline pathogenic variants. Further prospective investigation into the biology of germline variants in this population is warranted.

Carboplatin, paclitaxel, and pembrolizumab followed by pembrolizumab maintenance for primary treatment of incompletely resected epithelial ovarian cancer.

Objective: Incompletely resected epithelial ovarian cancer represents a poor prognostic subset of patients. Novel treatment strategies are needed to improve outcomes for this population. We evaluated a treatment strategy combining platinum-based chemotherapy with pembrolizumab followed by pembrolizumab maintenance therapy in the first-line treatment after incomplete resection of epithelial ovarian cancer patients. Methods: This was a single-arm, non-randomized pilot study of carboplatin, taxane, and immune checkpoint inhibitor, pembrolizumab, followed by 12 months of maintenance pembrolizumab in patients with incompletely resected epithelial ovarian cancer (EOC). Results: A total of 29 patients were enrolled and evaluated for efficacy and safety. The best response to therapy was complete response in 16 (55%) patients, partial response in 9 (31%) patients, and 3 (10%) patients with progression of disease. The median progression-free survival (PFS) was 13.2 months. Grade 3 and 4 toxicities occurred in 20% of patients. In all, 7 patients discontinued therapy due to adverse events. Quality-of-life scores remained high during therapy. Response to therapy did not correlate with PD-L1 tumor expression. Conclusions: Combination platinum-taxane therapy with pembrolizumab did not increase median progression-free survival in this cohort of patients. Key message: EOC is an immunogenic disease, but immune checkpoint inhibitor therapy has yet to impact outcomes. The current study utilized pembrolizumab in combination with standard chemotherapy followed by a maintenance treatment strategy in incompletely resected EOC. Progression-free survival was not extended in this poor prognostic group with combined chemotherapy and immunotherapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT 027766582.

A case series of triplet anti-hormonal therapy in androgen receptor-positive recurrent adult ovarian granulosa cell tumor.

Therapeutic options for recurrent adult granulosa cell tumors (AGCT) are limited. After examining the hormonal pathways involved in FOXL2-mutated granulosa cell tumor development, a novel treatment regimen was utilized for recurrent AGCT: a combination of an androgen receptor antagonist, a gonadotropin-releasing hormone receptor agonist, and an aromatase inhibitor for hormonal blockade. In this case series, seven patients at our institution were treated with bicalutamide 50 mg orally once daily, Leuprolide acetate 7.5 mg intramuscular (IM) injection every 4 weeks, and a daily oral aromatase inhibitor. These patients had recurrent AGCT with androgen receptor positive tumors and had failed prior aromatase inhibitor therapy. All patients had undergone multiple surgical resections and many cycles of chemotherapy. Patients were monitored for toxicities and for response to treatment. Of the seven patients receiving the triple therapy, six saw clinical benefit. Two patients demonstrated a partial response and four patients had stable disease. One patient had progressive disease on the regimen. For the two patients who had a partial response to the triple therapy, there was strong expression of the androgen receptor (AR) noted on tumor immunohistochemistry. This drug combination was well-tolerated except for severe hot flashes in one patient. In conclusion, the triple therapy combination of an androgen receptor antagonist, aromatase inhibitor, and GnRH agonist demonstrated measurable responses in patients with recurrent AGCTs after multiple previous treatments. A prospective clinical trial is planned to further investigate these findings.

Same-Day Discharge After Robotic Hysterectomy: A Resource Utilization and Quality Improvement Project.

BACKGROUND: We implemented a low-cost education initiative to improve the rate of same-day discharge following hysterectomy performed for malignancy and assessed feasibility and impact on resource utilization. METHODS: Development and implementation of faculty, patient, clinical, and perioperative staff education regarding the goal of same-day discharge for patients undergoing robotic hysterectomy and staging by gynecologic oncologists was started in July 2019. Chart review of 103 patients prior to the intervention and 112 patients after the start of the intervention was completed. RESULTS: The rate of same-day discharge increased from 5% to 32% following the low-cost process change initiative, and a total of approximately 682 inpatient care hours were saved per 31 patients. DISCUSSION: The rate of same-day discharges after hysterectomy and staging performed by gynecologic oncologists can be safely increased with a simple educational intervention, which can save significant patient care resources.

Correction: Parashar et al. Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance. Cancers 2022, 14, 958.

The authors would like to correct the author byline to include Dr [...].

Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance.

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named 'MCW-OV-SL-3' from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21-q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer.

Improving Value-Based Care Education in a Fellowship by Incorporating ACGME Competencies.

BACKGROUND: Most value-based care educational interventions teach knowledge of cost but fail to recognize the interrelatedness of the Accreditation Council for Graduate Medical Education (ACGME) competencies of medical knowledge, patient care, practice-based learning and improvement, and systems-based practice. OBJECTIVE: We analyzed the impact on clinical decision-making of an educational curriculum that incorporated the spectrum of ACGME competencies. METHODS: Five didactic sessions for a gynecologic oncology fellowship were modified to incorporate cost- and value-based care considerations for each clinical topic addressed. After discussion, the group of fellows identified 1 high-value and 5 low-value practices to target for improvement. The fellows then undertook a chart audit of clinical decisions occurring for patients seen in the outpatient clinics. The frequency of low- and high-value practices was compared before and after the educational intervention. RESULTS: A total of 126 patients with a cervical cancer diagnosis were seen by participants in the outpatient setting during the entire observation period. After the intervention, the occurrence of 3 identified low-value practices was reduced by 13% to 33%, demonstrating modest effect sizes (effect size ϕ = 0.2-0.3). One high-value practice (smoking cessation counseling) increased 100% after a fellow-initiated quality improvement project was undertaken. Two low-value practices, including routine surveillance imaging, remained unchanged. CONCLUSIONS: Overlaying value-based concepts in didactic conference teaching resulted in measurable changes in decision-making behavior. Engaging learners in a subsequent, focused quality practice review served as a vital part of their educational experience and allowed us to assess learner competency in its practical application.

Non-uniform weighting of local motion inputs underlies dendritic computation in the fly visual system.

The fly visual system offers a unique opportunity to explore computations performed by single neurons. Two previous studies characterized, in vivo, the receptive field (RF) of the vertical system (VS) cells of the blowfly (calliphora vicina), both intracellularly in the axon, and, independently using Ca2+ imaging, in hundreds of distal dendritic branchlets. We integrated this information into detailed passive cable and compartmental models of 3D reconstructed VS cells. Within a given VS cell type, the transfer resistance (TR) from different branchlets to the axon differs substantially, suggesting that they contribute unequally to the shaping of the axonal RF. Weighting the local RFs of all dendritic branchlets by their respective TR yielded a faithful reproduction of the axonal RF. The model also predicted that the various dendritic branchlets are electrically decoupled from each other, thus acting as independent local functional subunits. The study suggests that single neurons in the fly visual system filter dendritic noise and compute the weighted average of their inputs.

Targeted, Deep Sequencing Reveals Full Methylation Profiles of Multiple HPV Types and Potential Biomarkers for Cervical Cancer Progression.

Background: Invasive cervical cancer (ICC) and its premalignant phase (cervical intraepithelial neoplasia; CIN1-3) are distinguished by gynecologic and pathologic examination, yet no current methodologies can predict precancerous lesions that are destined to progress to ICC. Thus, development of reliable assays to assess patient prognosis is much needed.Methods: Human papillomavirus (HPV) DNA methylation is significantly altered in cervical disease. Using an HPV enrichment approach and next-generation DNA sequencing, methylation status was characterized in a case-case comparison of CIN (n = 2 CIN1; n = 2 CIN2; n = 20 CIN3) and ICC (n = 37) samples. Pyrosequencing validated methylation changes at CpGs of interest in a larger sample cohort (n = 61 CIN3; 50 ICC).Results: Global viral methylation, across HPV types, was significantly higher in ICC than CIN3. Average L1 gene methylation in 13 different HPV types best distinguished CIN3 from ICC. Methylation levels at individual CpG sites as a quantitative classifier achieved a sensitivity and specificity of >95% for detecting ICC in HPV 16 samples. Pyrosequencing confirmed significantly higher methylation of these CpGs in E1 of HPV 16 in ICC compared with CIN3.Conclusions: Global HPV methylation is significantly higher in ICC than CIN3, with L1 gene methylation levels performing best for distinguishing CIN3 from ICC. Methylation levels at CpGs in the E1 gene of HPV 16 (972, 978, 1870, and 1958) can distinguish between CIN3 and ICC.Impact: Higher methylation at specific E1 CpGs may associate with increased likelihood of progression to ICC in HPV 16-positive CIN3 lesions. Cancer Epidemiol Biomarkers Prev; 26(4); 642-50. ©2017 AACR.

A prospective pilot study on the incidence of post-operative lymphedema in women with endometrial cancer.

To determine the incidence of lower-extremity lymphedema after surgical therapy including lymphadenectomy in endometrial cancer patients using standardized leg measurements. Also, to determine additional risk factors for the development of lymphedema and to study the effect of lymphedema on one's quality of life. In this prospective cohort study, patients with the diagnosis of endometrial cancer who were to undergo definitive surgical management were evaluated pre-operatively and followed post-operatively over the course of two years. Standardized leg measurements were performed by the same individuals at six time-points. Subjects also completed a standardized quality-of-life survey at each time-point. The incidence of lymphedema in 39 women with endometrial cancer using a standardized leg measurement protocol was 12.8% with lymphedema defined as a 20% increase in post-operative leg measurements. There was no significant association between the development of lymphedema and the number of pelvic or para-aortic lymph nodes removed, medical comorbidities, or surgical approach (p > 0.05). Of the five patients who met criteria for lymphedema, only one had worsening quality-of-life concerns post-operatively on the FACT-En, version 4, survey. This is the first prospective study using standardized leg measurements to calculate the incidence of post-operative lymphedema in endometrial cancer. Medical comorbidities, surgical approach, number of lymph nodes removed, and location of lymph nodes removed did not appear to affect the development of lymphedema in this cohort. A prospective, multicenter trial is needed to confirm these findings and to further assess the impact of lymphedema on one's quality of life.

Effect of a best-practice alert on the rate of influenza vaccination of pregnant women.

OBJECTIVE: To estimate the effect of a best-practice alert, a reminder within the electronic medical record on the rate of vaccination of pregnant women against influenza. METHODS: Beginning on October 1, 2008, at the Medical College of Wisconsin Obstetrics and Gynecology Clinic, we added a best-practice alert to our electronic prenatal record. The best-practice alert let the health care provider know at each prenatal visit if the patient had not yet either received vaccination against influenza or voiced an informed refusal. We then compared our 2008-2009 vaccination rate with our 2007-2008 rate. If a patient went unvaccinated, we reviewed her record to determine whether a discussion regarding vaccination was held and, if so, the reason she went unvaccinated. RESULTS: Our 2008-2009 vaccination rate exceeded our 2007-2008 rate, 61% compared with 42%, respectively (P<.001; confidence interval [CI] for the difference in proportions 0.14-0.25). Health care providers documented a higher rate of discussions regarding influenza vaccination in 2008-2009 compared with 2007-2008, 89.5% compared with 49.5%, respectively (P<.001, CI for the difference in proportions 0.35-0.45). In 2008-2009, the most common reason for going without vaccination was an informed refusal. In 2007-2008, most of the medical records of unvaccinated women contained no documented discussion. In 2008-2009, 68.1% of the women whose health care providers documented a discussion accepted vaccination. CONCLUSION: Both our rate of vaccination of pregnant women against influenza and the rate of a documented discussion regarding vaccination increased after implementation of the best-practice alert. We recommend that users of electronic medical records add a best-practice alert to improve influenza vaccination rates. LEVEL OF EVIDENCE: II.