Multiplex serum immune profiling reveals circulating LAG-3 is associated with improved patient survival in high grade serous ovarian cancer.

OBJECTIVE: High grade serous ovarian cancer (HGSOC) exhibits low response rates to clinically available immunotherapies. Nevertheless, emerging research has demonstrated that certain immune factors are predictive for HGSOC patient clinical outcomes, with our own groups previous work demonstrating that intratumoral levels of the immune checkpoint receptor LAG-3 is associated with improved patient survival. In this current study we sought to uncover non-invasive circulating immune prognostic and predictive signatures in HGSOC. METHODS: A multiplex approach was employed that examined circulating levels of immune checkpoint receptors LAG-3 and PD-1 along with 48 common cytokine and chemokines in a cohort of 75 HGSOC treatment naïve patient serum samples. RESULTS: Elevated serum LAG-3 was significantly associated with improved progression-free survival (PFS) and overall survival (OS) in HGSOC, while circulating PD-1 levels were largely unrelated with patient clinical outcomes. Cytokine and chemokine analysis revealed lower IL-15 expression correlated with improved PFS and OS, while increased IL-1α, IL-1Ra, IL-6, IL8 and VEGF were significantly associated with preoperative CA-125 levels. ROC analysis demonstrated that serum LAG-3 levels exhibited consistent reasonable predictability as a single agent. CONCLUSIONS: Serum-derived LAG-3 was identified out of a diverse array of chemokine and cytokines as the immune-based factor most significantly associated with improved HGSOC survival. These findings suggest that LAG-3 could be implemented as a non-invasive patient predictive marker for improved HGSOC clinical outcomes.

Predictive Value of an Alternative Strategy for Measuring Depth and Size of Stage 1 Vulvar Squamous Cell Carcinoma.

OBJECTIVES: Despite poor reproducibility for measuring vulvar cancer depth, 1-mm or greater invasion triggers lymphadenectomy for small tumors. Previous literature suggests that measuring depth from the nearest dysplastic rete peg (alternative method) rather than highest dermal papilla (conventional method) may be acceptable. METHODS: Pathologic staging and follow-up information were recorded for 100 pT1 vulvar squamous cell carcinoma (SCC) resected from 1990 to 2019. Conventional depth, alternative depth, gross/clinical size, and size of the invasive component were measured for each tumor. In this retrospective study, we evaluated which clinicopathologic factors were most predictive of lymph node involvement and recurrence. RESULTS: Depending on the measurements used (conventional vs alternative depth, clinical lesion size vs cumulative extent of invasive component), between 1 and 18 cases were downstaged to pT1a. All such cases were pN0, without lymphovascular or perineural invasion. Infiltrative cords (hazard ratio [HR] = 5.15; 95% CI = 1.63-16.2; p = .005) and perineural invasion (HR = 3.16; 1.18-8.45; p = .022) were most strongly associated with groin recurrence. Of staging criteria evaluated, only cumulative extent of the invasive component 2 cm or greater was significantly associated with groin recurrence (HR = 2.87; 1.01-8.17; p = .048). The Kaplan-Meier curves for local recurrence-free survival by stage did not show significant separation regardless of method. CONCLUSIONS: Patients downstaged using alternative measurement techniques lacked nodal disease/recurrence; one-third of those with nodal sampling experienced postoperative morbidity. Our data suggest that the use of alternative depth and cumulative extent of invasion could safely allow some conventional stage IB vulvar SCC patients to avoid groin surgery, thereby reducing treatment-related morbidity.

Trends in surgical complexity and treatment modalities utilized in the management of ovarian cancer in an era of neoadjuvant chemotherapy.

OBJECTIVES: To investigate the impact of the increased use of neoadjuvant chemotherapy on the complexity of cytoreductive surgeries for ovarian cancer. METHODS: Using the National Cancer Database, we performed a retrospective cohort study of women diagnosed between 2004 and 2015 with stage III or IV epithelial ovarian cancer who underwent either primary cytoreductive surgery (PDS) followed by adjuvant chemotherapy, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery. Cases were assigned a surgical complexity category as 1) Inadequate, 2) Low, 3) Moderate and, 4) High complexity. The primary outcome was the trend in surgical complexity over time. Secondary outcomes included temporal trends in treatment modality, perioperative mortality, and survival. RESULTS: At total of 52,582 (76.3%) underwent PDS and 16,307 (23.7%) underwent NACT. The utilization of NACT increased from 7.7% in 2004 to 27.8% in 2015 (p-trend < 0.001). Patients undergoing moderate complexity surgeries increased from 28.9% to 33.5% and high complexity surgeries from 26.3% to 30% (p-trend < 0.001, for both). Trends in increasing surgical complexity were seen in both NACT and PDS cohorts. This increase in surgical complexity was seen most profoundly at the high-volume centers. Overall 30-day mortality decreased from 3.4% in 2004 to 1.4% in 2015; and 90-day mortality decreased from 7.6% to 4%. During the same time, 5-year survival increased from 39.7% to 49%. CONCLUSIONS: Increase in the utilization of NACT is associated with decreased 30- and 90-day mortality and increase in five-year survival. Moreover, the overall complexity of ovarian cancer surgery has increased in both PDS and NACT cohorts.

Bowel Resection Outcomes in Ovarian Cancer Cytoreductive Surgery by Surgeon Specialty.

Importance: Extensive bowel surgery is often necessary to achieve complete cytoreduction in patients with epithelial ovarian cancer. Regardless of who performs the surgery, it has been well documented that bowel resections are a high-risk procedure and an anastomotic leak is a severe complication that can occur. There are few studies addressing whether surgeon type impacts surgical outcomes in this patient population. Objective: To compare surgical outcomes between gynecologic oncologist, general surgeons, and a 2-surgeon team approach for patients with advanced epithelial ovarian cancer who underwent bowel surgery during cytoreductive debulking. Design, Setting, Participants: This retrospective cohort study used the American College of Surgeons' National Surgical Quality Improvement Program datasets from 2012 through 2020. The aforementioned years of the dataset were analyzed from March 2022 to March 2023 and reanalyzed in May 2024 for quality assurance. Analysis of cytoreductive surgeries performed by a gynecologic oncologist, a general surgeon, or a 2-surgeon team approach for patients with ovarian cancer recorded in National Surgical Quality Improvement Program datasets was included. The 2-surgeon team approach included any combination of the aforementioned surgical specialties. Main outcome and measure: The primary outcome of interest was anastomotic leak after bowel surgery during ovarian cancer debulking. Results: A total of 1810 patients were included in the study; in the general surgery cohort, mean (SD) patient age was 65.1 (11.1) years and mean (SD) body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was 26.9 (7.4); in the gynecologic oncology cohort, mean (SD) patient age was 63.5 (11.7) years and mean BMI (SD) was 27.7 (6.5); and in the 2-surgeon team cohort, mean (SD) patient age 62.4 (12.1) years and mean (SD) BMI was 28.1 (7.0). Gynecologic oncologists performed 1217 cases (67.2%), general surgery performed 97 cases (5.4%), and 496 cases had 2-surgeon teams involved (27.4%). Bivariate analysis revealed an anastomotic leak rate of 3.6% for gynecologic oncologists, 5.2% for general surgeons, and 0.4% for cases that had 2 surgical teams involved (P < .001). By multivariable analysis, the adjusted odds ratio for anastomotic leak was 1.53 (95% CI, 0.59-3.96) for the general surgeon group (P = .38) vs an adjusted odds ratio of 0.11 (95% CI, 0.03-0.47) for the 2-surgeon team approach (P = .003) with the referent being gynecologic oncology. Conclusion and Relevance: In this study, the anastomotic leak rate was found to be lower when 2 surgeons participated in the case, regardless of the surgical specialty. These results suggest that team-based care improves surgical outcomes.

Enhanced amphiregulin exposure promotes modulation of the high grade serous ovarian cancer tumor immune microenvironment.

High grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy in which chemoresistant recurrence rates remain high. Furthermore, HGSOC patients have demonstrated overall low response rates to clinically available immunotherapies. Amphiregulin (AREG), a low affinity epidermal growth factor receptor ligand is known to be significantly upregulated in HGSOC patient tumors following neoadjuvant chemotherapy exposure. While much is known about AREG's role in oncogenesis and classical immunity, it is function in tumor immunology has been comparatively understudied. Therefore, the objective of this present study was to elucidate how increased AREG exposure impacts the ovarian tumor immune microenvironment (OTIME). Using NanoString IO 360 and protein analysis, it was revealed that treatment with recombinant AREG led to prominent upregulation of genes associated with ovarian pathogenesis and immune evasion (CXCL8, CXCL1, CXCL2) along with increased STAT3 activation in HGSOC cells. In vitro co-culture assays consisting of HGSOC cells and peripheral blood mononuclear cells (PBMCs) stimulated with recombinant AREG (rAREG) led to significantly enhanced tumor cell viability. Moreover, PBMCs stimulated with rAREG exhibited significantly lower levels of IFNy and IL-2. In vivo rAREG treatment promoted significant reductions in circulating levels of IL-2 and IL-5. Intratumoral analysis of rAREG treated mice revealed a significant reduction in CD8+ T cells coupled with an upregulation of PD-L1. Finally, combinatorial treatment with an AREG neutralizing antibody and carboplatin led to a synergistic reduction of cell viability in HGSOC cell lines OVCAR8 and PEA2. Overall, this study demonstrates AREG's ability to modulate cytotoxic responses within the OTIME and highlights its role as a novel HGSOC immune target.

A Genetic Revolution: Cancer Genetic Testing and Counseling.

Genetic counseling is a relatively young profession that has advanced rapidly over the last 50 years. The term "genetic counseling" was first coined by Sheldon Reed in 1947 to describe the advice he would give to physicians regarding their patient's genetic conditions. Today, more than 5,000 genetic counselors are licensed through the American Board of Genetic Counselors. Clinically, genetic counselors practice in a variety of specialties, including pediatrics, prenatal, neurology and psychiatry; however, oncology remains the most common.1 This article is centered on the most common areas of genetic counseling and addresses the topics of cancer genetic testing, genetic counseling, and explores past and current practices.

The gender authorship gap in gynecologic oncology research.

Female first authorship and senior authorship in academic obstetrics and gynecology has increased over time but gender-specific publishing data are lacking within gynecologic oncology. We examined contribution by gender to the subspecialty's flagship journal, Gynecologic Oncology, over five decades, from 1972 to 2014, to identify trends in gender representation. Chi-square tests were used to compare gender distributions within and between the first and last years studied (1972-73 and 2014) as well as linear regression to model trends over time. Female first and senior authorship increased significantly from 1972 to 2014 (first: χ2 = 20.9, p < .01; senior: χ2 = 9.9, p < .01). The number of female first authors increased markedly after 2000. Male senior authors still outnumber female senior authors. Papers with senior female authors were more likely to have female first authors, suggesting a mentorship role. Subspecialty-wide gender equity initiatives should encourage continued mentorship of women by female colleagues.