Cervical Cancer Screening Recommendations: Now and for the Future.

Cervical cancer is the fourth most common cancer worldwide, with over 600,000 new cases annually and approximately 350,000 cancer-related deaths per year. The disease burden is disproportionately distributed, with cancer-related mortality ranging from 5.2 deaths per 100,000 individuals in highly-developed countries, to 12.4 deaths per 100,000 in less-developed countries. This article is a review of the current screening recommendations and potential future recommendations.

Cost-Conscious Colposcopy: A Single-Institution Review of Biopsy Submission Practices and Outcomes.

OBJECTIVE: Distribution of cervical dysplasia may influence approach for excisional procedures. Separating colposcopy biopsies into multiple specimen cups for pathologic evaluation incurs additional costs. The authors aimed to determine whether the practice of separating biopsy specimens impacts patient outcomes. METHODS: A retrospective review of all colposcopy cases from a single institution was performed. A total of 1,331 cases were reviewed from January 1, 2017, to December 31, 2019. Multibiopsy cohorts were separated by number of specimen cups received by pathology (single or multiple). Cohorts were compared for histology, need for excisional procedure, and final excisional pathology results. Specimen processing fees were acquired from the Department of Pathology ($70/specimen). Statistical analysis performed on MINITAB using Pearson chi-square and Fisher exact tests. RESULTS: Excisional procedures were required by 30.4% (86/283) of multiple specimen submissions compared with 28.2% (154/547) of single specimen cup submissions ( p = .50). There was a higher, although not statistically significant, rate of additional procedures in the multiple specimen cup cohort (8.8 vs 2.9% [ p = .08]). Malignancy diagnosis was equivalent in each cohort. Cost analysis revealed adopting a single specimen cup model would reduce costs up to approximately $30,000/year. CONCLUSIONS: Patient outcomes were not improved by the practice of submitting multiple specimen cups. Given the additional cost associated with separating specimens, the authors recommend during routine colposcopy that all cervical biopsies be sent for evaluation as a single pathology specimen unless a lesion of concern is identified in an area not normally excised during traditional excisional procedures.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology.

Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options.

Analysis of executional and procedural errors in dry-lab robotic surgery experiments.

BACKGROUND: Analysing kinematic and video data can help identify potentially erroneous motions that lead to sub-optimal surgeon performance and safety-critical events in robot-assisted surgery. METHODS: We develop a rubric for identifying task and gesture-specific executional and procedural errors and evaluate dry-lab demonstrations of suturing and needle passing tasks from the JIGSAWS dataset. We characterise erroneous parts of demonstrations by labelling video data, and use distribution similarity analysis and trajectory averaging on kinematic data to identify parameters that distinguish erroneous gestures. RESULTS: Executional error frequency varies by task and gesture, and correlates with skill level. Some predominant error modes in each gesture are distinguishable by analysing error-specific kinematic parameters. Procedural errors could lead to lower performance scores and increased demonstration times but also depend on surgical style. CONCLUSIONS: This study provides insights into context-dependent errors that can be used to design automated error detection mechanisms and improve training and skill assessment.

Robot-assisted kidney transplantation is a safe alternative approach for morbidly obese patients with end-stage renal disease.

BACKGROUND: Many centres deny obese patients with a body mass index (BMI) >35 access to kidney transplantation due to increased intraoperative and postoperative complications. METHODS: From August 2017 to December 2019, 73 consecutive cases of kidney transplantation in morbidly obese patients were enrolled at a single university at the initiation of a robotic transplant surgery program. Outcomes of patients who underwent robotic assisted kidney transplant (RAKT) were compared to frequency-matched patients undergoing open kidney transplant (OKT). RESULTS: A total of 24 morbidly obese patients successfully underwent RAKT, and 49 obese patients received an OKT. The RAKT group developed fewer surgical site infections (SSI) than the OKT group. Graft function, creatinine, and glomerular filtration rate (GFR) were similar between groups 1 year after surgery. Graft and patient survival were 100% for both groups. CONCLUSIONS: RAKT offers a safe alternative for morbidly obese patients, who may otherwise be denied access to OKT.

PD-L1 and Mismatch Repair Status in Uterine Carcinosarcomas.

Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ≥1 or a TPS score of ≥1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ≥10 or a TPS score of ≥10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas.

Mismatch Repair Deficiency in Uterine Carcinosarcoma: A Multi-institution Retrospective Review.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended in endometrial carcinomas as a screening test for Lynch syndrome, and mismatch repair deficiency (MMRd) is reported in ∼30% of cases. However, few studies have evaluated the rate of MMR loss in uterine carcinosarcomas. A 5-year retrospective database search of uterine carcinosarcomas was performed at 3 academic institutions. The histologic diagnoses, type of carcinoma present, and MMR IHC interpretations were confirmed by a gynecologic pathologist. One hundred three cases of uterine carcinosarcomas with available MMR IHC results were identified. Ninety-nine cases (96%) showed intact expression and 4 cases (4%) showed loss of MLH1/PMS2. All MMRd carcinosarcomas identified in this series had an endometrioid carcinomatous component and wild-type p53 expression. In contrast, the majority of MMR intact carcinosarcomas had a serous morphology and aberrant p53 expression. Three additional cases initially diagnosed as carcinosarcoma also revealed MMRd; however, given the lack of clear mesenchymal differentiation, these cases were reclassified as dedifferentiated endometrial carcinomas and were subsequently excluded from the carcinosarcoma category. No cases of Lynch syndrome were identified among carcinosarcoma patients, as all 4 MMRd cases were due to somatic MLH1 hypermethylation. In summary, we found that the rate of MMRd is markedly lower in uterine carcinosarcoma when compared with endometrial carcinoma. In the setting of MMR loss, a diagnosis of dedifferentiated carcinoma should be considered as almost half of the MMRd tumors which were called carcinosarcomas initially were reclassified as dedifferentiated on review. However, given the interobserver variability in the classification of carcinosarcoma versus dedifferentiated carcinoma a universal screening approach that includes uterine carcinosarcoma is still recommended.

Predictors of quality of care and survival in a three-state cohort of locally advanced cervical cancer patients and development of a predictive model to identify women at risk of incomplete treatment.

To expand our prior statewide analysis of care distribution for locally advanced cervical cancer in Virginia to include 2 more states and to develop a tool for predicting quality of care. Complete treatment was defined as receiving chemotherapy (CT), brachytherapy (BT), and external beam radiotherapy.State cancer registry databases yielded a three-state cohort of 3197 women diagnosed with locally advanced cervical cancer from 2000 to 2013. A logistic regression evaluated predictors for receipt of BT, CT, and high (2-3 modalities received) versus low (0-1 modalities received) quality care. A Cox proportional hazards models determined predictors of survival. Finally, a predictive model was developed and preliminarily validated using our cohort.Only 35.3% of the cohort received complete treatment and only 57.3% received BT. Significant predictors of lower odds of receiving high quality care varied by state but included: 66+ age at diagnosis as compared to 18 to 42, 42 to 53, or 53 to 66; cancer stage IVA as compared to IIIx, IIx, or IB2; public insurance with supplement as compared to private; treatment at a low volume facility; and closer distance quintiles to a high volume treatment center as compared to the furthest quintile. Significant predictors of worse survival varied by state but included: low quality score (0-1 modalities received); 2000 to 2004 or 2005 to 2009 year of diagnosis as compared to 2010 to 2013; 66+ age at diagnosis as compared to 18 to 42, 42 to 53, or 53 to 66; cancer stage IVA as compared to IIIx, IIx, or IB2; treatment at a low volume facility; and unmarried/unknown marital status as compared to married. Our treatment quality prediction tool included age, age, treatment at high volume facility, and cancer stage and demonstrated 78.2% sensitivity and a 62.9% specificity.Only 35.3% of patients received complete guidelines-concordant treatment. Additionally, in 2/3 states it appeared that BT usage may have decreased during the study period. Our predictive model may help identify patients/regions at risk of receiving low quality care to target interventions aimed at improving cervical cancer treatment quality and survival.

Quality Initiative to Improve Compliance With Perioperative Anticoagulation.

PURPOSE: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in gynecologic oncology surgical patients. Many centers use neuraxial analgesia (NA), which affects the timing of prophylactic anticoagulation. In 2012, we determined that the rate of VTE in patients undergoing laparotomy with NA was higher than in those who received alternative pain control. In addition, compliance with preoperative anticoagulation guidelines was only 40%. We undertook a quality initiative (QI) project to increase compliance to 80% in NA cases and maintain 90% in non-NA cases. METHODS: A multidisciplinary working group designed and deployed a QI intervention bundle. Compliance was defined as the receipt of a prophylactic dose of anticoagulant within 1 hour after NA or before skin incision regardless of anesthesia type. Data were abstracted from the medical record after the study period. Cases from the year before QI were used for comparison. Primary outcome was compliance and secondary outcome was the rate of VTE. RESULTS: One hundred women were treated under the QI project and 182 historical cases (HCs) were used for comparison. Overall compliance improved (96% QI v 73% HC; P < .001). This difference was marked in cases with NA (95% QI v 40% HC; P < .001) and remained stable in non-NA cases (97% QI v 91% HC; P = .29). The overall rate of VTE, independent of anesthesia type, remained unchanged (2.1% HC v 0% QI; P = .3). CONCLUSION: Relatively simple and inexpensive initiatives to improve routine processes within the surgical pathway are feasible and attract staff participation. Such efforts are likely to translate into greater levels of patient safety.

Interpreting Randomized Clinical Trials in Gynecologic Oncology Surgery: Does One Size Fit All?

Randomized clinical trials (RCTs) are considered the gold standard of clinical research. They are designed to eliminate bias and to produce objective and generalizable results about new treatment paradigms. Although RCTs have recognized limitations, including long completion time and high cost, they also have transformed clinical research and improved the quality of health care by rigorously evaluating countless new treatment options. Surgical RCTs present their own unique set of limitations including an inability to standardize surgical technique and expertise; an inability to overcome enrollment bias by enrolling surgeons; and a lack of generalizability with respect to institutional resources and abilities. Here, we discuss surgical RCTs in two domains: upfront management of advanced ovarian cancer and surgical management of early-stage cervical cancer. Familiarity with the abundant retrospective data available for both of these clinical scenarios as well as recognition of the strengths and limitations of surgical RCTs are critical to determine the best treatment for an individual patient.

Robotic pancreas transplantation: the state of the art.

PURPOSE OF REVIEW: Robotic pancreas transplantation is a novel procedure that aims to reduce surgical invasiveness, and thereby limit complications related to the surgical access. Given that few centers are providing robotic transplantation, this review serves as a state of the science article to outline early experiences and highlight areas for future research. RECENT FINDINGS: Pancreas transplantation results in relatively high rates of wound and other surgical complications that are known to deleteriously impact outcomes. The minimally invasive, robotic-assisted approach decreases wound complications. Because of the obesity epidemic, overweight and obese status is encountered in an increasing number of transplant candidates. These candidates are subject to increased wound-related complications and most benefit from a robotic approach. The first clinical reports on laparoscopic, robotic-assisted kidney and pancreas transplantation indicate a significant decrease in wound complications and excellent outcomes in obese patients otherwise denied access to transplantation. SUMMARY: With excellent results achieved in surgically challenging patients and further accumulation of experience, laparoscopic, robotic-assisted pancreas and kidney transplantation may evolve to a new standard approach.

Thrombosis and Thromboprophylaxis in Gynecology Surgery.

Gynecologic surgery offers unique challenges, as pelvic surgery places patients at an increased risk of venous thromboembolism (VTE). Prevention of VTE is a goal of patients, policy makers, and surgeons. In this review, we address the current research and recommendations for VTE prophylaxis.

Utilization of Postoperative Chemoradiotherapy Among Women in the United States With High-risk Cervical Cancer.

OBJECTIVE: Prospective randomized data demonstrates that chemoradiotherapy (CRT) improves overall survival in women with high-risk pathologic features following radical hysterectomy. Despite this, not all high-risk patients receive adjuvant CRT and the patterns of care in this patient population are unknown. We sought to investigate the rates of adjuvant therapy utilization through analysis of the National Cancer Database. MATERIALS AND METHODS: The National Cancer Database was queried for women with cervical cancer treated initially with hysterectomy from 2002 to 2012. Patients without high-risk pathologic features were excluded: pN, positive surgical margins, and parametrial invasion (Peters' criteria). Among the 5947 evaluable patients, univariable analysis and multivariable analysis were performed to investigate potential factors associated with CRT utilization and overall survival following diagnosis. RESULTS: Adjuvant CRT was performed in 41.8% of women and adjuvant radiotherapy, chemotherapy, and no adjuvant therapy was utilized in 9.8%, 23.6%, and 24.8% of women, respectively. On multivariable analysis, CRT utilization was associated with younger age, race, lower facility volume, pN, parametrial invasion, and a negative surgical margin. Residence distance to treating facility, year of diagnosis, household income, insurance status, and facility type did not predict for CRT utilization. CONCLUSIONS: Despite level I evidence supporting its use, less than half of women in this large US cohort with high-risk cervical cancer received adjuvant CRT. Use of adjuvant CRT for women did not significantly increase between 2002 and 2012. Patient age, race, and pathologic risk factors were associated with use of adjuvant CRT.

Malignant Brenner tumor of the ovary: Review and case report.

Ovarian neoplasms are a heterogeneous group of tumors with varying incidence in the general population. The most common are the surface epithelial tumors which include transitional cell tumors. Transitional cell tumors include both transitional cell carcinoma and Brenner tumor. The vast majority of Brenner tumors are benign, often incidental findings; however, malignant Brenner tumors (MBT) do occasionally occur. MBT present similarly to other ovarian neoplasms with abdominal pain and bulk symptoms. On imaging, these tumors demonstrate nonspecific findings. Microscopically, they demonstrate areas of conventional benign Brenner tumor juxtaposed with regions of frank malignancy showing marked cytologic atypia and infiltration. There is no consistent tumor marker for these tumors, but CA-125, CA 72-4 and SCC have been reported in singular instances. Tumors express several immunohistochemical markers of urothelial differentiation including uroplakin III, thrombomodulin, GATA3, p63, as well as cytokeratin 7. The primary treatment modality is surgical excision. Due to their rarity, the precise role and regimen of adjuvant chemo-radiation therapy for MBT has not been established. We herein review a case of MBT with emphasis on primary treatment and treatment of recurrent disease, including the use of adjuvant pelvic radiation, discuss the current state of the literature and standards of practice regarding this malignancy.

Hormone replacement therapy after treatment for cervical cancer: Are we adhering to standard of care?

OBJECTIVE: The aim of this study was to assess hormone replacement therapy (HRT) and bone care health maintenance practices for cervical cancer patients with iatrogenic menopause, and, secondarily, to investigate the potential impact of specific demographic and clinical factors. METHODS: Women diagnosed with iatrogenic menopause due to cervical cancer treatment between January 1, 2005 and December 31, 2015 were identified from the University of Virginia's tumor registry. Univariable data were analyzed using Wilcoxon rank sum, Chi square, and Fisher's exact test; multivariable analysis was conducted using logistic regression. RESULTS: Two hundred and two women were included for analysis. Ninety-seven of these women (48.0%) received counseling and/or a prescription for HRT. After multivariable analysis, older age at diagnosis (adjusted OR 0.940, 95% CI 0.890-0.993, p=0.0270) and uninsured payer status (adjusted OR 0.455, 95% CI 0.212-0.977, p=0.0435) were associated with a decreased likelihood of receiving counseling or a prescription for HRT. A longer duration of follow-up was associated with the primary outcome with an adjusted OR of 1.011 (95% CI 1.001-1.020, p=value 0.0252). Dual-energy X-ray absorptiometry scans (DEXA) were infrequent and received by only 17/197 (8.6%) of all women. CONCLUSIONS: Fewer than half of all women received counseling and/or a prescription for HRT after diagnoses of iatrogenic menopause, and disparities were noted based on insurance status. These findings reflect a need for clearer guidelines on HRT during survivorship and improved efforts to reduce disparities in the distribution of survivorship care.

A SEER-Medicare analysis of the impact of metformin on overall survival in ovarian cancer.

OBJECTIVE: Determine whether metformin use is associated with improved survival in patients with ovarian, fallopian tube or primary peritoneal cancer. METHODS: All patients with a diagnosis of first epithelial ovarian cancer from 2007 to 2011 in the combined SEER-Medicare database were identified from the SEER registry primary site codes. Comorbidities, procedures and cancer treatment ICD-9 and HCPCS codes were used to search the Medicare claims files. Medication use was determined with National Drug Codes using the Medicare Part D event files. The primary outcome, overall survival, was assessed between metformin users and non-users using a Cox Proportional Hazards survival model. To control for confounding, metformin users were matched to non-metformin users using propensity scores. Effect of dosage on survival was assessed using discrete time survival analysis with pooled logistic regression (PLR). RESULTS: There were 2291 cases that met our inclusion criteria. Of these, 180 (7.9%) had been on metformin. The median age was 73years, with the majority of the population being White (83.5%) and treated with primary surgery (74.1%). Metformin use was not associated with overall survival in the entire cohort (HR 0.96, 95% CI 0.75-1.23) or in the matched sample cohort (HR 0.88, 95% CI 0.66-1.17). However, exploratory regression with time-varying coefficients suggests a protective metformin effect for women alive after 30months follow-up (HR=0.37, 95% 0.16-0.87). CONCLUSION: No statistically significant association was observed between metformin use and overall survival in a matched cohort of 360 ovarian cancer patients. However, exploratory modeling suggests metformin use may be protective in a certain subgroup of patients.

Cutting costs and standardizing care: Once-per-cycle complete blood count monitoring may be safe for patients undergoing platinum-based chemotherapy.

AIM: The aim of this study was to evaluate whether frequency of complete blood count (CBC) testing during chemotherapy for gynecologic cancer impacts hospital admissions or rates of neutropenic fever. METHODS: A retrospective cohort study was performed at a single academic institution. Patients undergoing platinum-based chemotherapy for endometrial or ovarian cancer from January 2010 to December 2014 were identified from a clinical database. Patients receiving dose-dense chemotherapy or on a clinical trial were excluded. Electronic chart review collected demographic and clinical characteristics. The primary outcome was the rate of febrile neutropenia or hospital admission. RESULTS: A total of 174 patients were identified, 63 (36%) with endometrial and 111 (64%) with ovarian cancer. Fifty-four percent of patients received multiple CBC per cycle compared with 46% who only had one CBC per cycle. The majority of patients were treated with a platinum-based doublet (85%). Dose reductions, addition of granulocyte colony stimulating factor, and rates of grade 3 or 4 anemia and neutropenia were significantly associated with more frequent testing. There was no difference in rates of neutropenic fever (5.3 vs 3.8%, P = 0.45) or hospital admission (22.3 vs 21.3%, P = 0.86) for multiple versus single CBC monitoring. CONCLUSION: More frequent laboratory testing detected more cases of grade 3 or 4 hematopoietic toxicities and was associated with more interventions. There were no differences in number of hospitalizations or cases of neutropenic fever by frequency of laboratory testing, suggesting that it may be appropriate to decrease routine laboratory tests for select patients.