Learning to lead: The evolution of a pilot leadership curriculum for gynecologic oncology fellows at the Ohio State University.

•Leadership training is under-emphasized in traditional medical education.•An effective leadership curriculum must be dynamic and requires genuine investment from participants.•Through didactic education, self-reflection, and real-world perspective we can actively mold future leaders in gynecologic oncology.

Prevalence of type 2 diabetes diagnoses in the perioperative and survivorship periods following surgical management of endometrial cancer: An opportunity for screening and intervention?

OBJECTIVE: To determine the prevalence of Type 2 diabetes mellitus (T2DM) diagnoses during the peri-operative and survivorship periods in patients following surgical management of endometrial cancer (EC). METHODS: An IRB-approved, retrospective single-institution cohort study was performed in patients who underwent surgical management of EC from 2014 to 2020. The perioperative period was defined as the 30 days before and after surgery. T2DM diagnoses occurring during survivorship were recorded. T2DM diagnoses were defined by a HgbA1c ≥6.5% or a random blood glucose ≥200 mg/dL. Sequelae of peri-operative T2DM and predictors of future T2DM were examined utilizing univariate analysis. RESULTS: Of 519 patients meeting inclusion criteria, 37 (7.1%) were diagnosed with T2DM in the perioperative period. Patients diagnosed with T2DM in the perioperative period had significantly higher BMI (p = 0.006) compared to no T2DM, but there were no significant differences in age (p = 0.20), ethnicity/race (p > 0.05) or ECOG score (p = 0.19). The rates of intraoperative complications between groups did not significantly differ, except for vascular complications (p = 0.005), and the incidence of any postoperative complication was higher in the perioperative T2DM group (p = 0.01). With a median follow-up of 29 months [range 11.6-49.0 months], an additional 18.3% (n = 88) of the cohort met diagnostic criteria for T2DM. BMI (p < 0.001), perioperative glucose (p < 0.001), and HgbA1c (p = 0.002) demonstrate risk for a T2DM diagnosis during survivorship. CONCLUSION(S): In this retrospective cohort of EC patients, 25.4% were diagnosed with T2DM, with the majority diagnosed in the survivorship period. Surgical management and subsequent surveillance of EC presents an opportunity to diagnose at-risk patients with T2DM.

Tissue factor as a novel diagnostic target for early detection of ovarian cancer using ultrasound microbubbles.

INTRODUCTION: Ovarian cancer (OC) is the deadliest gynecologic malignancy, with an overall 5-year survival rate of less than 30%. The existing paradigm for OC detection involves a serum marker, CA125, and ultrasound examination, neither of which is sufficiently specific for OC. This study addresses this deficiency through the use of a targeted ultrasound microbubble directed against tissue factor (TF). METHODS: TF expression was examined in both OC cell lines and patient-derived tumor samples via western blotting and IHC. In vivo microbubble ultrasound imaging was analyzed using high grade serous ovarian carcinoma orthotopic mouse models. RESULTS: While TF expression has previously been described on angiogenic, tumor-associated vascular endothelial cells (VECs) of several tumor types, this is first study to show TF expression on both murine and patient-derived ovarian tumor-associated VECs. Biotinylated anti-TF antibody was conjugated to streptavidin-coated microbubbles and in vitro binding assays were performed to assess the binding efficacy of these agents. TF-targeted microbubbles successfully bound to TF-expressing OC cells, as well as an in vitro model of angiogenic endothelium. In vivo, these microbubbles bound to the tumor-associated VECs of a clinically relevant orthotopic OC mouse model. CONCLUSION: Development of a TF-targeted microbubble capable of successfully detecting ovarian tumor neovasculature could have significant implications towards increasing the number of early-stage OC diagnoses. This preclinical study shows potential for translation to clinical use, which could ultimately help increase the number of early OC detections and decrease the mortality associated with this disease.

Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series.

Effective second-line treatment options for patients with recurrent ovarian clear cell carcinoma (OCCC) are limited. This case series sought to report tumor characteristics and oncologic outcomes in a small group of patients treated with combination lenvatinib and pembrolizumab. A retrospective analysis of patients with ovarian clear cell carcinoma treated with combination lenvatinib and pembrolizumab at a single institution was performed. Patient and tumor characteristics were collected including demographics and germline/somatic testing. Clinical outcomes were also evaluated and reported. Three patients with recurrent OCCC were included in the study. The median age of patients was 48 years old. All patients had platinum-resistant disease and had received 1-3 prior lines of therapy. The overall response rate was 100% (3/3). Progression-free survival ranged from 10 months to not-yet-reached. One patient remains on treatment, while the other two died of disease with overall survival of 14 and 27 months. Combination lenvatinib-pembrolizumab demonstrated favorable clinical response in these patients with platinum-resistant, recurrent, ovarian clear cell carcinoma.

Less is more: clinical utility of postoperative laboratory testing following minimally invasive hysterectomy for endometrial cancer.

BACKGROUND: With the increasing rates of same-day discharge following minimally invasive surgery for endometrial cancer, the need for and value of routine postoperative testing is unclear. OBJECTIVE: This study aimed to determine whether routine postoperative laboratory testing following minimally invasive hysterectomy for endometrial cancer leads to clinically significant changes in postoperative care. STUDY DESIGN: This was a single-institution retrospective cohort study of patients undergoing minimally invasive hysterectomy for endometrial cancer by a gynecologic oncologist between June 2014 and June 2017. Patient demographics, preoperative comorbidities, operative and postoperative data, and pathologic findings were manually extracted from the patients' medical records. The financial burden of laboratory testing was computed using hospital-level cost data. RESULTS: Of the 649 women included in the analysis, most (91.4%) were White, with a mean age of 61 years, and mean body mass index of 38.0 kg/m2. The most common comorbidities were diabetes mellitus (31.9%, n=207), chronic pulmonary disease (7.9%, n=51), and congestive heart failure (3.2%, n=21). Median operative time was 151 minutes (range, 61-278), and median estimated blood loss was 100 mL (range, 10-1500). Most patients (68.6%, n=445) underwent lymphadenectomy. All patients had postoperative laboratory tests ordered: 100% complete blood count, 99.7% chemistry, 62.9% magnesium, 46.8% phosphate, 37.4% calcium, and 1.2% liver function tests. Twenty-six patients (4.0%) had a change in management owing to postoperative laboratory test results. Of these 26 women, 88% experienced a change in clinical status that would have otherwise prompted testing. Only 3 (0.5% of entire cohort) were asymptomatic: 1 received a blood transfusion for asymptomatic anemia, and the other 2, who did not carry a diagnosis of diabetes mellitus, had interventions for hyperglycemia. On univariable analysis, peripheral and cerebrovascular disease, diabetes mellitus with end-organ damage, and a Charlson Comorbidity Index of ≥3 were associated with increased odds of change in management; these were not significant on multivariable analysis. Routine postoperative laboratory evaluation in this cohort increased hospital costs by $292,000. CONCLUSION: Routine postoperative laboratory tests are unlikely to lead to significant changes in management for women undergoing minimally invasive hysterectomy for endometrial cancer, and may increase cost without providing a discernible clinical benefit. In the setting of strict postoperative guidelines, laboratory tests should be ordered when clinically indicated rather than as part of routine postoperative management for women undergoing minimally invasive hysterectomy for endometrial cancer.

Help wanted: low provider density is associated with advanced stage cervical cancer.

BACKGROUND: Patients in rural areas have a higher incidence of cervical cancer with increased rates of metastatic disease than their urban counterparts. OBJECTIVE: To evaluate whether medical provider density, acting as a surrogate for screening availability, is associated with the incidence of cervical cancer or proportion diagnosed with advanced stage disease. METHODS: Cervical cancer cases by county from 2015 were retrieved from the SEER database. The numbers of primary obstetric-gynecologists (OB-GYN), family practice, and internal medicine providers were obtained from the Area Health Resource File, and population estimates for each county were used to calculate provider to resident ratios. Spearman rank correlations were used to compare the number of providers per 100 000 residents with the overall incidence of cervical cancer as well as the proportion diagnosed at an advanced stage. Multivariable logistic regression was performed to assess factors independently associated with advanced stage disease, accounting for county of residence. Mortality was compared across different OB-GYN provider density categories. RESULTS: A total of 3505 cases of cervical cancer from 405 counties were included. Spearman correlation demonstrated a significant inverse association between the number of OB-GYN providers per 100 000 residents and the incidence of cervical cancer (p<0.0001) as well as the proportion diagnosed at an advanced stage (p=0.003). Compared with those living in counties with ≤5 OB-GYN providers per 100 000 residents, those living in counties with >10 providers had a 29% reduction in the odds of presenting with advanced stage disease (OR=0.71; 95% CI 0.55 to 0.91). An inverse association between cervical cancer-related mortality and OB-GYN provider density was also noted. CONCLUSION: A significant inverse correlation between provider density and incidence of cervical cancer, proportion with advanced stage disease, and cervical cancer-related mortality was observed. Increasing provider density in these underserved, high-risk areas may improve timely cancer detection.

Beyond mismatch repair deficiency? Pre-treatment neutrophil-to-lymphocyte ratio is associated with improved overall survival in patients with recurrent endometrial cancer treated with immunotherapy.

OBJECTIVE: To determine the association of pre-treatment neutrophil-to-lymphocyte ratio (NLR) with progression-free survival (PFS) and overall survival (OS) for patients with recurrent endometrial cancer (EC) treated with immunotherapy. METHODS: Recurrent EC patients treated with immunotherapy alone or in combination from 2016 to 2021 were included. Demographics, pre-treatment laboratory results, pathologic data, response at first radiographic assessment, and cancer outcomes were obtained from the medical record. Kaplan-Meier curves were generated to compare PFS and OS stratified by NLR. RESULTS: The 106 patients included in the study were stratified by NLR <6 (n = 77, 72.6%) or NLR ≥6 (n = 29, 27.3%). Most had endometrioid pathology (59%), widely metastatic disease, and 36.8% had received ≥2 treatment lines before initiating immunotherapy. Mismatch repair deficiency (dMMR) was noted in 52 (49.1%) tumors. Most dMMR patients (94.3%) were treated with single-agent pembrolizumab, and most MMR proficient patients (78.7%) were treated with lenvatinb plus pembrolizumab. In the overall cohort, 40.2% (partial response (PR) 29.9%, complete response (CR) 10.4%) of patients with a NLR <6 responded at first radiographic assessment, compared to 31% (PR 27.5%, CR 3.4%) of patients with NLR ≥6 (p 0.691). Kaplan-Meier curves stratified by NLR <6 vs. ≥6 showed no difference in PFS. However, NLR <6 was associated with improved OS (p < 0.05). In the NLR < 6 group, the probability of survival at one year was 69% (95% CI: 58%, 82%), compared to 41% (95% CI: 26%, 67%) for the NLR > 6 group. CONCLUSIONS: Pre-treatment NLR <6 was associated with improved OS for recurrent EC patients treated with immunotherapy. NLR holds promise as a predictive biomarker for survival after immunotherapy treatment for patients with recurrent EC.

High pre-treatment neutrophil-to-lymphocyte ratio as a prognostic marker for worse survival in patients with recurrent/metastatic cervical cancer treated with immune checkpoint inhibitors.

Objective: To evaluate the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and survival outcomes among patients with recurrent/metastatic cervical cancer treated with PD-1/PD-L1 inhibitors. Methods: A retrospective analysis of patients with recurrent/metastatic cervical cancer treated with PD-1/PD-L1 inhibitors from 2016 to 2021 was conducted. Progression free survival (PFS) and overall survival (OS) outcomes were assessed for patients stratified by NLR (<8 vs ≥ 8) utilizing Kaplan-Meier method. Univariable analysis was performed to compare baseline characteristics between the two groups. Results: A total of 49 patients were included in analysis. A majority of patients had squamous cell histology (57%), were PD-L1 positive (55%), received ≤ 1 prior lines of systemic therapy (57%), and had distant metastatic disease at the time of treatment (69%). The groups were well-balanced with respect to age, race, histology, smoking status, PD-L1 positivity, prior lines of treatment (≤1 vs > 1), prior radiation therapy, ECOG performance status, and disease distribution for patients with a NLR < 8 (n = 35) compared to those with a NLR ≥ 8 (n = 14). A pre-treatment NLR of < 8 was associated with improved survival (p < 0.01), with 57% (95% CI: 41%, 78%) probability of survival at one year compared to 26% (95% CI: 10%, 66%) for those with NLR ≥ 8. No statistically significant differences in probability of PFS at 1 year were seen between NLR < 8 compared to those with NLR ≥ 8 (p = 0.70). Conclusions: Pre-treatment NLR may hold prognostic value for patients with metastatic/recurrent cervical cancer treated with PD-1/PD-L1 inhibitors, with NLR < 8 associated with improved survival.

Aberrant expression of TMEM205 signaling promotes platinum resistance in ovarian cancer: An implication for the antitumor potential of DAP compound.

INTRODUCTION: TMEM205 is a novel transmembrane protein associated with platinum resistance (PR) in epithelial ovarian carcinoma (OC), however, the specific mechanisms associated with this resistance remain to be elucidated. METHODS: TMEM205 expression was evaluated in platinum-sensitive (PS) versus platinum resistant (PR) ovarian cancer cell lines and patient serum/tissues. Exosomal efflux of platinum was evaluated with inductively coupled plasma mass spectrometry (ICP-MS) after pre-treatment with small molecule inhibitors (L-2663/L-2797) of TMEM205 prior to treatment with platinum. Cytotoxicity of combination treatment was confirmed in vitro and in an in vivo model. RESULTS: TMEM205 expression was 10-20 fold higher in PR compared to PS ovarian cancer cell lines, serum samples, and tissues. Co-localization with CD1B was confirmed by in-situ proximity ligation assay suggesting that TMEM205 may mediate PR via the exosomal pathway. Exosomal secretion was significantly increased 5-10 fold in PR cell lines after treatment with carboplatin compared to PS cell lines. Pre-treatment with L-2663 prior to carboplatin resulted in significantly increased intracellular concentration of fluorescently-labeled cisplatin and decreased exosomal efflux of platinum. Decreased cell survival and tumor growth in vitro and in vivo was observed when PR cells were treated with a combination of L-2663 with carboplatin compared to carboplatin alone. CONCLUSION: TMEM205 appears to be involved in the development of PR in ovarian cancer through the exosomal efflux of platinum agents. This study provides pre-clinical evidence that TMEM205 could serve as a possible biomarker for PR as well as a therapeutic target in combination with platinum agents.

Progress in Gynecologic Cancers with Antibody Drug Conjugates.

PURPOSE OF REVIEW: This article provides a comprehensive review of antibody-drug conjugates (ADCs) under investigation in gynecologic cancers. The structure and function of ADCs are reviewed with a focus on clinical benefit as well as toxicity profiles. RECENT FINDINGS: Several ADCs with various target antigens have been investigated in ovarian, cervical, and endometrial cancer. ADCs have consistently demonstrated favorable safety/tolerability profiles both as monotherapy and in combination therapy. In ovarian cancer, response rates have ranged from 9 to 46% for monotherapy with response rates as high as 83% in combination therapy. In patients with cervical cancer with progressive disease despite doublet therapy and bevacizumab, response rates as high as 24% have been observed. ADCs represent a rapidly evolving field of targeted therapy which have demonstrated notable clinical benefit both as monotherapy but also in combination therapy with an overall favorable toxicity profile. With continued refinement of the target biomarkers utilized, improved clinical benefit is likely to be observed.

An ecological evaluation of the increasing incidence of endometrial cancer and the obesity epidemic.

BACKGROUND: The prevalence of obesity has increased significantly in recent decades, particularly among younger women, and is a known risk factor for endometrial cancer. OBJECTIVE: This study aimed to evaluate the trend in the prevalence of obesity and the incidence of type I endometrial cancer over time in various age categories to determine whether an ecological relationship exists. STUDY DESIGN: Data from the Surveillance, Epidemiology, and End Results Program and the National Health and Nutrition Examination Survey were used. The overall trend in the incidence of type 1 endometrial cancer and prevalence of obesity were observed over time from 1988 to 2016 and further categorized by age group (<45, 45-54, and ≥55 years). RESULTS: The prevalence of obesity has increased for all women, but most significantly for women younger than 45 years with a 16.3% increase among women aged 20 to 34 years and a 17.9% increase for women aged 35 to 44 years. The incidence of endometrial cancer has also increased across all age categories, and although it has increased in patients younger than 45 years by more than 14-fold (from <0.1 per 100,000 in 1988 to 1.4 per 100,000 in 2016), a more pronounced increase of 63-fold and 50-fold was observed among women aged 45 to 54 years (0.2 per 100,000 in 1988 to 12.6 per 100,000 in 2016) and women aged 55 years and older (from 0.6 per 100,000 in 1988 to 30 per 100,000 in 2016), respectively. The mean age of women diagnosed as having endometrial cancer also decreased from 64.1 years from 1988 to 1990 to 61.0 years from 2014 to 2016. CONCLUSION: The prevalence of obesity has increased significantly in women of all ages. This increase, particularly among women aged <45 years, occurred simultaneously with an increase in the incidence of endometrial cancer in young women, with an even more pronounced increase among women aged ≥45 years.

Antibody-drug conjugates for the treatment of ovarian cancer.

INTRODUCTION: Ovarian cancer typically presents at an advanced stage and while initial chemotherapy response rates are favorable, a majority of patients experience recurrence with the subsequent development of chemoresistance. Recurrent, platinum-resistant disease is associated with a very poor prognosis as treatment in this setting is often limited by systemic toxicity. Antibody-drug conjugates (ADCs) are novel therapeutic agents designed to target antigens specific to ovarian tumor cells with direct delivery of cytotoxic agents to combat recurrent, platinum-resistant disease while limiting systemic toxicity. AREAS COVERED: The basic structure and function of ADCs will be reviewed as well as the current data on ADCs under investigation in ovarian cancer. EXPERT OPINION: ADCs represent a promising class of targeted therapy in recurrent ovarian cancer with excellent response rates particularly when utilized as combination therapy. While mirvetuximab soravtansine is the only ADC that has been evaluated in a phase 3 trial, many other ADCs and trials are on the horizon. As the field of targeted therapy continues to evolve, continued development of target antigens and ADCs are likely to represent a key development in treatment of recurrent, platinum-resistant disease.

Where you live matters: A National Cancer Database study of Medicaid expansion and endometrial cancer outcomes.

OBJECTIVE: To determine associations between adoption of Medicaid expansion (ME) and changes in insurance status, early stage diagnosis, and cancer survival among women with endometrial carcinoma (EC). METHODS: The National Cancer Database (NCDB) was queried for patients diagnosed with EC between the age 40-64 from 2004 to 2015. Difference-in-differences analysis quantified the impact of ME on the proportion of new EC diagnoses with insurance (vs. uninsured), the proportion diagnosed with stage I (vs. II-IV), and overall survival. RESULTS: 156,253 patients were included. Among 65,019 women living in ME states, ME is associated with an increase in the percent of EC cases who are insured of 1.4% (95% CI 0.9-2.0%, p < 0.0001), with strongest effects among Hispanic women, women in the lowest income quartile, and women in the second age quartile (age 53-57). There was no overall impact of ME on stage, though an increase of early stage diagnoses by 2.4% (95% CI 0.3-4.5%, p = 0.022) was observed among women age 53-57. There was a trend towards improved overall survival with ME, which was strongest in women age 53-57 (HR = 0.83, 95% CI 0.70-0.99, p = 0.037). CONCLUSIONS: Among women with EC, ME positively impacted insurance coverage, an important hurdle in accessing health care. In women aged 53-57, ME was associated with earlier stage at diagnosis and improved survival, suggesting that the magnitude of the improvement in insurance coverage may correlate with important clinical outcomes. Efforts should continue to understand the complexity of barriers to health care access and to develop effective strategies to surmount them.

Cervical cancer radiation therapy compliance rates based on location of radiation therapy.

OBJECTIVE: Completion of radiation therapy (RT) within 60 days has been proposed as a national quality measure for patients with carcinoma of the cervix as protracted RT has been associated with worse oncologic outcomes. The objective of this study was to compare compliance rates based on location of RT administration. METHODS: This was a retrospective chart review of patients diagnosed with cervical cancer between January of 2000 to December of 2016 who were planned to undergo primary treatment with sensitizing chemotherapy and RT. Patients who completed both external beam radiation therapy (EBRT) and brachytherapy (BT) at the primary institution were compared to patients who completed a portion or all of their RT elsewhere. The primary outcome measured was completion of RT within 60 days. Secondary outcomes included compliance with sensitizing chemotherapy, total radiation dose, recurrence rate, progression free survival (PFS) and overall survival (OS). The groups were compared using standard statistical analysis. RESULTS: This study included 100 patients, 75 of which received all of their RT at the primary institution. These patients were more likely to complete RT within 60 days when compared to patients who underwent RT at different facilities (58.7% vs 24%, respectively; p = 0.005). Patients who underwent all of their RT at the primary institution completed their therapy an average of 16.4 days sooner (75.1 ±â€¯21.3 days versus 58.7 ±â€¯13.2 days; p = 0.001). Overall survival was significantly improved in this group (p = 0.03). CONCLUSION: Women who complete EBRT and BT at different institutions are more likely to have a protracted RT course (>60 days). These patients should be identified at diagnosis and efforts made to coordinate their care to avoid delays in treatment.