Immunological modifications following chemotherapy are associated with delayed recurrence of ovarian cancer.

Introduction: Ovarian cancer recurs in most High Grade Serous Ovarian Cancer (HGSOC) patients, including initial responders, after standard of care. To improve patient survival, we need to identify and understand the factors contributing to early or late recurrence and therapeutically target these mechanisms. We hypothesized that in HGSOC, the response to chemotherapy is associated with a specific gene expression signature determined by the tumor microenvironment. In this study, we sought to determine the differences in gene expression and the tumor immune microenvironment between patients who show early recurrence (within 6 months) compared to those who show late recurrence following chemotherapy. Methods: Paired tumor samples were obtained before and after Carboplatin and Taxol chemotherapy from 24 patients with HGSOC. Bioinformatic transcriptomic analysis was performed on the tumor samples to determine the gene expression signature associated with differences in recurrence pattern. Gene Ontology and Pathway analysis was performed using AdvaitaBio's iPathwayGuide software. Tumor immune cell fractions were imputed using CIBERSORTx. Results were compared between late recurrence and early recurrence patients, and between paired pre-chemotherapy and post-chemotherapy samples. Results: There was no statistically significant difference between early recurrence or late recurrence ovarian tumors pre-chemotherapy. However, chemotherapy induced significant immunological changes in tumors from late recurrence patients but had no impact on tumors from early recurrence patients. The key immunological change induced by chemotherapy in late recurrence patients was the reversal of pro-tumor immune signature. Discussion: We report for the first time, the association between immunological modifications in response to chemotherapy and the time of recurrence. Our findings provide novel opportunities to ultimately improve ovarian cancer patient survival.

Trends in surgical approach to hysterectomy and perioperative outcomes in Michigan hospitals from 2010 through 2020.

The objective of this study was to determine the trends in surgical approach to hysterectomy over the last decade and compare perioperative outcomes and complications. This retrospective cohort study used clinical registry data from the Michigan Hospitals that participated in Michigan Surgical Quality Collaborative (MSQC) from January 1st, 2010 through December 30th, 2020. A multigroup time series analysis was performed to determine how surgical approach to hysterectomy [open/TAH, laparoscopic (TLH/LAVH), and robotic-assisted (RA)] has changed over the last decade. Abnormal uterine bleeding, uterine fibroids, chronic pelvic pain, pelvic organ prolapse, endometriosis, pelvic mass, and endometrial cancer were the most common indications for hysterectomy. The open approach to hysterectomy declined from 32.6 to 16.9%, a 1.9-fold decrease, with an average decline of 1.6% per year (95% CI - 2.3 to - 0.9%). Laparoscopic-assisted hysterectomies decreased from 27.2 to 23.8%, a 1.5-fold decrease, with an average decrease of 0.1% per year (95% CI - 0.7 to 0.6%). Finally, the robotic-assisted approach increased from 38.3 to 49.3%, a 1.25-fold increase, with an average of 1.1% per year (95% CI 0.5 to 1.7%). For malignant cases, open procedures decreased from 71.4 to 26.6%, a 2.7-fold decrease, while RA-hysterectomy increased from 19.0 to 58.7%, a 3.1-fold increase. After controlling for the confounding variables age, race, and gynecologic malignancy, RA hysterectomy was found to have the lowest rate of complications when compared to the vaginal, laparoscopic and open approaches. Finally, after controlling for uterine weight, black patients were twice as likely to undergo an open hysterectomy compared to white patients.

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.

Concurrent Surgery for Locoregional Gynecologic Cancers and Pelvic Floor Disorders in a Population of Patients With Medicare Insurance.

OBJECTIVE: To estimate the rate of concurrent surgery for locoregional gynecologic cancer and pelvic organ prolapse-urinary incontinence (POP-UI) and to assess the rate of surgery for POP-UI within 5 years for those who did not undergo concurrent surgery. METHODS: This is a retrospective cohort study. The SEER-Medicare data set was used to identify cases of local or regional endometrial, cervical, and ovarian cancer diagnosed from 2000 to 2017. Patients were followed up for 5 years from diagnosis. We used χ 2 tests to identify categorical variables associated with having a concurrent POP-UI procedure with hysterectomy or within 5 years of hysterectomy. Logistic regression was used to calculate odds ratios and 95% CIs adjusted for variables statistically significant (α=.05) in the univariate analyses. RESULTS: Of 30,862 patients with locoregional gynecologic cancer, only 5.5% underwent concurrent POP-UI surgery. Of those with a preexisting diagnosis related to POP-UI, however, 21.1% had concurrent surgery. Of the patients who had a diagnosis of POP-UI at the time of initial surgery for cancer and who did not undergo concurrent surgery, an additional 5.5% had a second surgery for POP-UI within 5 years. The rate of concurrent surgery remained constant over the time period (5.7% in 2000 and 2017) despite an increase in the frequency of POP-UI diagnosis in the same time frame. CONCLUSION: The rate of concurrent surgery for patients with an early-stage gynecologic cancer and POP-UI-associated diagnosis in women older than age 65 years was 21.1%. Of women who did not undergo concurrent surgery but had a diagnosis of POP-UI, 1 in 18 underwent surgery for POP-UI within 5 years of their index cancer surgery. Dedicated efforts must be made to identify patients who would most benefit from concurrent cancer and POP-UI surgery in those with locoregional gynecologic cancers and pelvic floor disorders.

Decreased incidence of febrile neutropenia in Michigan following masking and social distancing orders for the COVID-19 pandemic: A population based cohort study.

BACKGROUND: It has been theorized that 75%-80% of febrile neutropenia (FN) is caused by endogenous pathogens, while up to 20% of cases are thought to be caused by a viral infection. It is unknown if precautions such as masking and social distancing reduce the risk of FN in susceptible populations. AIM: To determine whether coronavirus disease 2019 (COVID-19) infection mitigation efforts, namely masking and social distancing, were associated with a reduction in the incidence of FN. METHODS: This was a retrospective population based cohort study comparing the incidence of FN in the 13 mo prior to (Year 0) and 13 mo following (Year 1) the public health executive orders (PHEO) in Michigan. Data was queried for all emergency department (ED) visits from April 1, 2019 to March 31, 2021 from the National Syndromic Surveillance Program, a program which collects data that is voluntarily submitted by approximately 89% of Michigan EDs. The primary study outcome was the incidence of FN as a proportion of ED visits in the 13-mo before and 13-mo after COVID-19 mitigations efforts, namely masking and social distancing. We hypothesized that there would be a significant decrease in the incidence of FN in the period following the PHEO aimed at reducing the spread of the severe acute respiratory syndrome coronavirus 2 virus. RESULTS: There was a total of 8979221 total ED visits captured during the study period. In Year 0 there were 5073081 recorded ED visits and 3906140 in Year 1. There was a significant reduction in the proportion of total ED visits with a diagnosis of FN, decreasing 13.3% across periods (0.15% vs 0.13%, P = 0.036). In patients with a hematologic malignancy a more impressive reduction in the incidence of FN was evident following PHEO (22% vs 17%, P = 0.02). CONCLUSION: We found a significant association between social distancing and mask guidelines implemented on a large public scale with decreased rates of FN, particularly in those with a hematologic malignancy. These findings may be useful in the design of future research and recommendations regarding the prevention of FN.

Incidence and Survival of Multiple Primary Cancers in US Women With a Gynecologic Cancer.

Objectives: To evaluate risk of a second cancer and associated survival times in United States women with diagnosis of cancer. Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for 2 cohorts of women aged 18 - 89 with either an index gynecologic or non-gynecologic cancer diagnosed between 1992 - 2017. Index cases were followed to determine if a second primary cancer was subsequently diagnosed; defined according to SEER multiple primary and histology coding rules. Standard Incident Ratios (SIR) and latency intervals between index diagnosis and second primary diagnosis were evaluated. Among those who developed a second primary cancer, median survival times from diagnosis of second primary cancer were also calculated. Results: Between 1992 - 2017, 227,313 US women were diagnosed with an index gynecological cancer and 1,483,016 were diagnosed with an index non-gynecologic cancer. Among patients with index gynecologic cancer, 7.78% developed a non-gynecologic subsequent primary cancer. The risk of developing any non-gynecologic cancer following an index gynecologic cancer was higher than the risk in the general population (SIR 1.05, 95% CI 1.04 - 1.07). Organs especially at risk were Thyroid (SIR 1.45), Colon and Rectum (SIR 1.23), and Urinary System (SIR 1.33). Among women diagnosed with an index non-gynecologic cancer, 0.99% were diagnosed with a subsequent gynecologic cancer. The risk of developing a gynecologic cancer following a non-gynecologic cancer was also elevated compared to the average risk of the general population (SIR 1.05, 1.03 - 1.07), with uterine cancer having the highest SIR of 1.13. Conclusion: The risk of a developing a second primary cancer and the corresponding survival time is based on the order and site of the index and subsequent cancer. Surveillance guidelines should be examined further to optimize survivorship programs.

Does origin of article impact citation metrics in Gynecologic Oncology?

Objectives: To determine if the origin of article published in Gynecologic Oncology ("Journal") is correlated with quality of the article when measured per US institution and per country, using an index of citation (IOC) metric as a stand-in for article quality. Methods: PubMed was used to query the Journal from 2005 to 2020. Articles not deemed original research were excluded. A US-only cohort ("US-Only") was evaluated separately from the entire cohort ("Whole"). The IOC for each article was calculated by dividing the number of citations listed in PubMed by the days from the publication date to 9/1/2021. The IOC per US institution was summarized by the median value. All articles were hand reviewed for correctness. The Whole cohort included all countries with 3 or more publications (including all of the US-Only cohort) and underwent similar analysis. Correlation coefficients were estimated using Pearson's correlation after log-transformation. Results: In the US-only cohort, 2733 articles from 276 institutions within the US contributed original articles to the Journal. The association between the number of publications per institution and the median IOC was not well correlated (Pearson's Correlation coeffeicient r = 0.16, p = 0.009). In the Whole cohort, 5,848 original research articles were published from 40 countries. There was no difference between median IOC for articles from US compared to non-US institutions was (0.0026 vs 0.0027, p = 0.287). The US median IOC was ranked 17/40. The US accounted for just over half (51.2%) of publications, and there was a trend of decreasing Non-US publications over time (p = 0.0004). Conclusions: The Journal was fairly consistent in the quality of articles published over the 15-year study period when using the IOC as a surrogate for quality, regardless of the article's country or US institution of origin.

Minimally invasive hysterectomy for benign indications-surgical volume matters: a retrospective cohort study comparing complications of robotic-assisted and conventional laparoscopic hysterectomies.

The objective of this study was to evaluate the incidence of perioperative complications in robotic-assisted hysterectomies performed by high-volume robotic surgeons compared to conventional laparoscopic hysterectomies performed by all gynecologic surgeons. This retrospective cohort study was performed at a single-center community based hospital and medical center. A total of 332 patients who underwent hysterectomy for benign indications were included in this study. Half of these patients (n = 166) underwent conventional laparoscopic hysterectomy and the other half underwent a robotic-assisted laparoscopic hysterectomy. The main outcome measures included composite complication rate, estimated blood loss (EBL), and hospital length of stay (LOS). Median (IQR) EBL was significantly lower for robotic hysterectomy [22.5 (30) mL] compared to laparoscopic hysterectomy [100 (150) mL, p < 0.0001]. LOS was significantly shorter for robotic hysterectomy (1.0 ± 0.2 day) compared to laparoscopic hysterectomy (1.2 ± 0.7 days, p = 0.04). Despite averaging 3.0 (IQR 1.0) concomitant procedures compared to 0 (IQR 1.0) for the conventional laparoscopic hysterectomies, the incidence of any type of complication was lower in the robotic hysterectomy group (2 vs. 6%, p = 0.05). Finally, in a logistic regression model controlling for multiple confounders, robotic-assisted hysterectomy was less likely to result in a perioperative complication compared to traditional laparoscopic hysterectomy [odds ratio (95% CI) = 0.2 (0.1, 0.90), p = 0.04]. In conclusion, robotic-assisted hysterectomy may reduce complications compared with conventional laparoscopic hysterectomy when performed by high volume surgeons, especially in the setting of other concomitant gynecologic surgeries.

Disparities in adjuvant treatment of high-grade endometrial cancer in the Medicare population.

BACKGROUND: Black women experience worse survival effects with high-grade endometrial cancer. Differences in adjuvant treatment have been proposed to be major contributors to this disparity. However, little is known about the differences in type or timing of adjuvant treatment as it relates to race and ethnicity in the Medicare population. OBJECTIVE: This study aimed to examine patterns of adjuvant therapy and survival for non-Hispanic Black women vs non-Hispanic White women and Hispanic women who have undergone surgery for high-grade endometrial cancer in the Medicare population. STUDY DESIGN: We used the Medicare-linked Surveillance, Epidemiology, and End Results database to identify women who underwent surgery as a primary treatment for uterine grade 3 endometrioid adenocarcinoma, carcinosarcoma, clear-cell carcinoma, or serous carcinoma between the years 2000 and 2015. Women who did not identify as White or Black race or Hispanic ethnicity were excluded. Multinomial logistic regression was used to estimate odds ratios and 95% confidence intervals for receiving a treatment delay or not receiving adjuvant treatment (compared with those who received adjuvant treatment within 12 weeks) adjusted for clinical and demographic characteristics. Overall survival was stratified by race and ethnicity, route of surgery, operative complications, and type and timing of adjuvant therapy, which were analyzed using the Kaplan-Meier method. Cox proportional-hazards regression was used to estimate the hazard ratio of death by race and ethnicity adjusted for known predictors and surgical outcomes and adjuvant therapy patterns. RESULTS: A total of 12,201 women met the study inclusion criteria. Non-Hispanic Black patients had a significantly worse 5-year overall survival than Hispanic and non-Hispanic White patients (30.9 months vs 51.0 months vs 53.6 months, respectively). Approximately 632 of 7282 patients (8.6%) who received adjuvant treatment experienced a treatment delay. Delay in treatment of ≥12 weeks was significantly different by race and ethnicity (P=.034), with 12% of Hispanic, 9% of non-Hispanic Black, and 8% of non-Hispanic White women experiencing a delay. After adjustment for the number of complications, age, histology (endometrioid vs nonendometroid), International Federation of Gynecology and Obstetrics stage, marital status, comorbidity count, surgical approach, lymph node dissection, and urban-rural code, Hispanic women had a 71% increased risk of treatment delay (odds ratio, 1.71; 95% confidence interval, 1.23-2.38) for all stages of disease. In the same model, non-Hispanic Black race was independently predictive of decreased use of adjuvant treatment for the International Federation of Gynecology and Obstetrics stage II and higher (odds ratio, 1.32; 95% confidence interval, 1.04-1.68). Non-Hispanic Black race, number of perioperative complications, and nonendometrioid histology were predictive of worse survival in univariate models. Treatment delay was not independently predictive of worse 1- or 5-year survival at any stage. CONCLUSION: Non-Hispanic Black race was predictive of worse 5-year survival across all stages and was associated with omission of adjuvant treatment in International Federation of Gynecology and Obstetrics stage II or higher high-grade endometrial cancer. In unadjusted analyses, patients who experience treatment omission or delay experienced poorer overall survival, but these factors were not independently associated in multivariate analyses. This study suggests that race and ethnicity are independently associated with the type and timing of adjuvant treatment in patients with high-grade endometrial cancer. Further efforts to identify specific causes of barriers to care and timely treatment are imperative.

Impact of positive cytology in uterine serous carcinoma: A reassessment.

OBJECTIVES: The aim of this study was to evaluate the prognostic value of peritoneal cytology status among other clinicopathological parameters in uterine serous carcinoma (USC). METHODS: A retrospective study of 148 patients diagnosed with uterine serous carcinoma from 1997 to 2016 at two academic medical centers in the Detroit metropolitan area was done. A central gynecologic pathologist reviewed all available slides and confirmed the histologic diagnosis of each case of USC. We assessed the prognostic impact of various clinicopathological parameters on overall survival (OS) and endometrial cancer-specific survival (ECSS). Those parameters included race, body mass index (BMI), stage at diagnosis, tumor size, lymphovascular invasion (LVSI), peritoneal cytology status, receipt of adjuvant treatment, and comorbidity count using the Charlson Comorbidity Index (CCI). We used Cox proportional hazards models and 95% confidence intervals for statistical analysis. RESULTS: Positive peritoneal cytology had a statistically significant effect on OS (HR: 2.09, 95% CI: [1.19, 3.68]) and on ECSS (HR: 2.02, 95% CI: [1.06 - 3.82]). LVSI had a statistically significant effect on both OS (HR: 2.27, 95% CI: [1.14, 4.53]) and ECSS (HR: 3.45, 95% CI: [1.49, 7.99]). Black or African American (AA) race was also found to have a significant effect on both OS (HR: 1.92, 95% CI: [1.07, 3.47]) and ECSS (HR: 2.01, 95% CI: [1.02, 3.98]). Other factors including BMI and tumor size > 1 cm did not show a statistically significant impact on OS or ECSS. CONCLUSIONS: Peritoneal washings with positive cytology and LVSI are important prognostic tools that may have a significant impact on overall survival in USC and can be used as independent negative prognosticators to help guide adjuvant treatment.

Using Technology to Improve Women's Health Care.

Background: Technology is being integrated into all aspects of health care. While many applications offer novel experiences, the evidence supporting translation to improved education or care is evolving. Methods: We review ways that technology is affecting a variety of fields pertinent to women's health, including patient communication, physician education, and health care performance. Results: In the Ochsner Health Department of Obstetrics and Gynecology, we have developed a platform known as Connected Maternity Online Monitoring-Connected MOM-to encourage remote monitoring during the prenatal course. We are also assessing improvements in quality and safety through a centralized fetal heart rate monitoring bunker known as TeleStork. Conclusion: Through systematic integration of technology into the delivery of women's health care at Ochsner, we hope to demonstrate sustainable improvements in physician skills, patient access, and quality and safety.

Personalized Medicine in Gynecologic Cancer: Fact or Fiction?

Personalized medicine in gynecologic oncology is an evolving field. In recent years, tumor profiling and large databases such as TCGA and NCI-Match have provided us with enormous amounts of molecular data. Several therapies that capitalize on novel genetic and immune discoveries including VEGF inhibitors, PARP inhibitors, and cancer vaccinations are discussed in this article. Additionally, we have seen direct to consumer marketing play an important role in cancer care and prevention as patients have increased ability to access genetic testing. This presents a unique challenge to gynecologic oncology providers as we learn to navigate the world of personalized medicine.

Personalized Medicine in Gynecologic Cancer: Fact or Fiction?

Personalized medicine in gynecologic oncology is an evolving field. In recent years, tumor profiling and large databases such as TCGA and NCI-Match have provided us with enormous amounts of molecular data. Several therapies that capitalize on novel genetic and immune discoveries including VEGF inhibitors, PARP inhibitors, and cancer vaccinations are discussed in this article. Additionally, we have seen direct to consumer marketing play an important role in cancer care and prevention as patients have increased ability to access genetic testing. This presents a unique challenge to gynecologic oncology providers as we learn to navigate the world of personalized medicine.