Adnexal Lesion Imaging: Past, Present, and Future.

Currently, imaging is part of the standard of care for patients with adnexal lesions prior to definitive management. Imaging can identify a physiologic finding or classic benign lesion that can be followed up conservatively. When one of these entities is not present, imaging is used to determine the probability of ovarian cancer prior to surgical consultation. Since the inclusion of imaging in the evaluation of adnexal lesions in the 1970s, the rate of surgery for benign lesions has decreased. More recently, data-driven Ovarian-Adnexal Reporting and Data System (O-RADS) scoring systems for US and MRI with standardized lexicons have been developed to allow for assignment of a cancer risk score, with the goal of further decreasing unnecessary interventions while expediting the care of patients with ovarian cancer. US is used as the initial modality for the assessment of adnexal lesions, while MRI is used when there is a clinical need for increased specificity and positive predictive value for the diagnosis of cancer. This article will review how the treatment of adnexal lesions has changed due to imaging over the decades; the current data supporting the use of US, CT, and MRI to determine the likelihood of cancer; and future directions of adnexal imaging for the early detection of ovarian cancer.

Oxidative phosphorylation inhibitors inhibit proliferation of endometriosis cells.

In brief: Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study suggest that inhibitors of oxidative phosphorylation may serve as novel agents for the treatment of endometriosis. Abstract: Current therapeutic strategies for endometriosis focus on symptom management and are not curative. Here, we provide evidence supporting the inhibition of oxidative phosphorylation (OXPHOS) as a novel treatment strategy for endometriosis. Additionally, we report an organotypic organ-on-a-chip luminal model for endometriosis. The OXPHOS inhibitors, curcumin, plumbagin, and the FDA-approved anti-malarial agent, atovaquone, were tested against the endometriosis cell line, 12Z, in conventional as well as the new organotypic model. The results suggest that all three compounds inhibit proliferation and cause cell death of the endometriotic cells by inhibiting OXPHOS and causing an increase in intracellular oxygen radicals. The oxidative stress mediated by curcumin, plumbagin, and atovaquone causes DNA double-strand breaks as indicated by the elevation of phospho-γH2Ax. Mitochondrial energetics shows a significant decrease in oxygen consumption in 12Z cells. These experiments also highlight differences in the mechanism of action as curcumin and plumbagin inhibit complex I whereas atovaquone blocks complexes I, II, and III. Real-time assessment of cells in the lumen model showed inhibition of migration in response to the test compounds. Additionally, using two-photon lifetime imaging, we demonstrate that the 12Z cells in the lumen show decreased redox ratio (NAD(P)H/FAD) and lower fluorescence lifetime of NAD(P)H in the treated cells confirming major metabolic changes in response to inhibition of mitochondrial electron transport. The robust chemotoxic responses observed with atovaquone suggest that this anti-malarial agent may be repurposed for the effective treatment of endometriosis.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

Beyond post-operative readmissions: analysis of the impact of unplanned readmissions during primary treatment of advanced-stage epithelial ovarian cancer on long-term oncology outcome.

BACKGROUND: Multiple studies have assessed post-operative readmissions in advanced ovarian cancer. OBJECTIVE: To evaluate all unplanned readmissions during the primary treatment period of advanced epithelial ovarian cancer, and the impact of readmission on progression-free survival. METHODS: This was a single institution retrospective study from January 2008 to October 2018. Χ2/Fisher's exact and t-test, or Kruskal-Wallis test were used. Multivariable Cox proportional hazard models were used to assess the effect of covariates in progression-free survival analysis. RESULTS: A total of 484 patients (279 primary cytoreductive surgery, 205 neoadjuvant chemotherapy) were analyzed. In total, 272 of 484 (56%; 37% primary cytoreductive surgery, 32% neoadjuvant chemotherapy, p=0.29) patients were readmitted during the primary treatment period. Overall, 42.3% of the readmissions were surgery related, 47.8% were chemotherapy related, and 59.6% were cancer related but not related to surgery or chemotherapy, and each readmission could qualify for more than one reason. Readmitted patients had a higher rate of chronic kidney disease (4.1% vs 1.0%, p=0.038). Post-operative, chemotherapy, and cancer-related readmissions were similar between the two groups. However, the percentage of inpatient treatment days due to unplanned readmission was twice as high for primary cytoreductive surgery at 2.2% vs 1.3% for neoadjuvant chemotherapy (p<0.001). Despite longer readmissions in the primary cytoreductive surgery group, Cox regression analysis demonstrated that readmissions did not affect progression-free survival (HR=1.22, 95% CI 0.98 to 1.51; p=0.08). Primary cytoreductive surgery, higher modified Frailty Index, grade 3 disease, and optimal cytoreduction were associated with longer progression-free survival. CONCLUSIONS: In this study, 35% of the women with advanced ovarian cancer had at least one unplanned readmission during the entire treatment time. Patients treated by primary cytoreductive surgery spent more days during readmission than those with neoadjuvant chemotherapy. Readmissions did not affect progression-free survival and may not be valuable as a quality metric.

Molecular classification in endometrial cancer: Opportunities for precision oncology in a changing landscape.

Endometrial carcinoma (EC) classification and risk stratification have undergone a global transformation in the last decade, shifting from a reliance on poorly reproducible histomorphological parameters such as grade and histotype, toward a molecular classification that is consistent and biologically informative. Molecular classification enables reliable categorization of ECs, provides prognostic information, and is now beginning to drive clinical management, including surgery and adjuvant therapy. Within this framework, we now have the ability to further refine both the prognostic and predictive value of molecular classification. As we move toward the routine implementation of this classification system as a stratification tool for research, clinical trials, and patient care, it is imperative that access to these tests be equitable. Furthermore, continued education will be critical for patients and providers to understand the value that this molecular information provides.

Ovarian Cancer Detection in Average-Risk Women: Classic- versus Nonclassic-appearing Adnexal Lesions at US.

Background Several US risk stratification schemas for assessing adnexal lesions exist. These multiple-subcategory systems may be more multifaceted than necessary for isolated adnexal lesions in average-risk women. Purpose To explore whether a US-based classification scheme of classic versus nonclassic appearance can be used to help appropriately triage women at average risk of ovarian cancer without compromising diagnostic performance. Materials and Methods This retrospective multicenter study included isolated ovarian lesions identified at pelvic US performed between January 2011 and June 2014, reviewed between September 2019 and September 2020. Lesions were considered isolated in the absence of ascites or peritoneal implants. Lesions were classified as classic or nonclassic based on sonographic appearance. Classic lesions included simple cysts, hemorrhagic cysts, endometriomas, and dermoids. Otherwise, lesions were considered nonclassic. Outcomes based on histopathologic results or clinical or imaging follow-up were recorded. Diagnostic performance and frequency of malignancy were calculated. Frequency of malignancy between age groups was compared using the χ2 test, and Poisson regression was used to explore relationships between imaging features and malignancy. Results A total of 970 isolated lesions in 878 women (mean age, 42 years ± 14 [SD]) were included. The malignancy rate for classic lesions was less than 1%. Of 970 lesions, 53 (6%) were malignant. The malignancy rate for nonclassic lesions was 32% (33 of 103) when blood flow was present and 8% (16 of 194) without blood flow (P < .001). For women older than 60 years, the malignancy rate was 50% (10 of 20 lesions) when blood flow was present and 13% (five of 38) without blood flow (P = .004). The sensitivity, specificity, positive predictive value, and negative predictive value of the classic-versus-nonclassic schema was 93% (49 of 53 lesions), 73% (669 of 917 lesions), 17% (49 of 297 lesions), and 99% (669 of 673 lesions), respectively, for detection of malignancy. Conclusion Using a US classification schema of classic- or nonclassic-appearing adnexal lesions resulted in high sensitivity and specificity in the diagnosis of malignancy in ovarian cancer. The highest risk of cancer was in isolated nonclassic lesions with blood flow in women older than 60 years. © RSNA, 2022 See also the editorial by Baumgarten in this issue.

Racial and ethnic enrollment disparities in clinical trials of poly(ADP-ribose) polymerase inhibitors for gynecologic cancers.

OBJECTIVES: Disparities persist in the enrollment of racial/ethnic groups in clinical trials for ovarian cancers. We sought to analyze the enrollment rates of patients by race/ethnicity in phase II/III clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancers and compare these to the racial/ethnic prevalence of ovarian cancers in the United States. METHODS: This study was a retrospective review of clinical trials registered with ClinicalTrials.gov. Studies included evaluated PARP inhibitors for the treatment of ovarian, fallopian tube, and primary peritoneal cancers. Enrollment rates for clinical trials were stratified by race/ethnicity and type of cancer. Enrollment fractions (EFs) were calculated using prevalence data from the Surveillance, Epidemiology, and End Results Program. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare racial/ethnic group enrollment rates to Non-Hispanic (NH) White enrollment rates. RESULTS: Forty-eight trials were identified, 15 of which met inclusion criteria. The EFs for included trials, were 1.5% for NH-White, 0.47% for NH-Black, 0.33% for Hispanic, and 2.38% for Asian/Pacific Islander. Patients who identified as NH-Black and Hispanic were significantly underrepresented compared to those who identified as NH-White (OR 0.23, 95% CI [0.18-0.29] and OR 0.3, 95% CI [0.25-0.38] respectively, p < 0.001). CONCLUSIONS: NH-Black and Hispanic patients are significantly underrepresented in clinical trials evaluating PARP inhibitors for ovarian cancers compared to NH-White cohorts. Phase II/III trials assessing PARP inhibitors for ovarian cancers do not accurately represent the populations diagnosed with these malignancies. Enrollment strategies are needed to increase diversity in PARP inhibitor clinical trials for women's cancers.

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Opportunistic osteoporosis screening using routine computed tomography images to identify bone loss in gynecologic cancer survivors.

OBJECTIVE: Cancer treatment-induced bone loss is a known side effect of cancer therapy. Computed tomography (CT) bone mineral density screening is a novel tool for identifying bone loss. This study aims to use routine CT images to determine long-term bone mineral density changes and osteoporosis risk among women with gynecologic cancers. METHODS: Bone loss was evaluated in a retrospective cohort of women ≤65 years old with gynecologic cancer who underwent oophorectomy from January 2010 to December 2014. Opportunistic CT-based bone mineral density measurements (Hounsfield units, HU) were performed at baseline and intervals up to 5 years after cancer diagnosis. Osteoporosis risk was categorized by HU. Bivariate and multivariate analyses were performed to compare baseline to follow-up bone mineral density at 1, 3, and 5 years and to identify predictors of bone loss following diagnosis. RESULTS: A total of 185 patients (median age 53 years, range 23-65 years, 78.1% ovarian cancer) were included. Bone mineral density significantly decreased between baseline and 1 year (p<0.001), 3 years (p<0.001), and 5 years (p<0.001). Half with normal bone mineral density at baseline had risk for osteopenia or osteoporosis at 5 years. Four percent had osteoporosis risk at baseline compared with 1 year (7.4%), 3 years (15.7%), and 5 years (18.0%). Pre-treatment bone mineral density was a significant predictor at 1 and 5 years (1 year: p<0.01; 5 years: p<0.01). History of chemotherapy predicted bone loss at 1 year (p=0.03). More lifetime chemotherapy cycles were associated with increased risk of osteoporosis at 1 year (p=0.03) and 5 years (p=0.01). CONCLUSIONS: Women with gynecologic cancers may experience accelerated cancer treatment-induced bone loss. Routine CT imaging is a convenient screening modality to identify those at highest risk for osteoporosis who warrant further evaluation with dual-energy X-ray absorptiometry. Routine bone mineral density assessments 1 year following oophorectomy for cancer treatment may be warranted in this population.

An open-label phase I dose-escalation study of the safety and pharmacokinetics of DMUC4064A in patients with platinum-resistant ovarian cancer.

OBJECTIVES: MUC16 is overexpressed in the majority of human epithelial ovarian cancers (OC). DMUC4064A is a humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. This trial assessed the safety, tolerability, pharmacokinetics, and preliminary activity of DMUC4064A in patients with platinum-resistant OC. METHODS: DMUC4064A was administered once every 3 weeks to patients in 1.0-5.6 mg/kg dose escalation cohorts, followed by cohort expansion at the recommended Phase II dose (RP2D). RESULTS: Sixty-five patients were enrolled and received a median of 5 cycles (range 1-20) of DMUC4064A. The maximum tolerated dose was not reached; 5.2 mg/kg was the RP2D based on the overall tolerability profile. The most common adverse events were fatigue, nausea, abdominal pain, constipation, blurred vision, diarrhea, and anemia. Sixteen patients (25%) experienced related grade ≥ 3 toxicities. Twenty-six patients (40%) experienced ocular toxicities. The exposure of acMMAE was dose proportional, with a half-life of ~6 days. Sixteen patients (25%) experienced confirmed objective partial response (PR or CR) starting at ≥3.2 mg/kg dose levels, while 23 (35%) patients had best responses of PR or CR. Overall, the clinical benefit rate was 42% (27 patients with a best response [confirmed and unconfirmed] of CR, or PR or SD lasting ≥6 months). Among the 54 patients with high MUC16 immunohistochemistry scores, the clinical benefit rate was 46% (25 patients). Median progression-free survival was 3.9 months overall. CONCLUSIONS: In this Phase I study, DMUC4064A demonstrated a tolerable safety profile along with encouraging efficacy in the indication of platinum-resistant OC.

Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. METHODS: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. INTERPRETATION: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. FUNDING: US National Cancer Institute.

Comparison of International Ovarian Tumor Analysis Simple Rules to Society of Radiologists in Ultrasound Guidelines for Detection of Malignancy in Adnexal Cysts.

OBJECTIVE. The purpose of this study was to evaluate the International Ovarian Tumor Analysis (IOTA) simple rules and the Society of Radiologists in Ultrasound (SRU) guidelines for detecting ovarian malignancy in a general population of women presenting to radiology departments with adnexal cystic lesions. MATERIALS AND METHODS. A retrospective multicenter study of ultrasound-detected adnexal cystic lesions with appropriate follow-up was conducted. Lesions were classified into benign, indeterminate, or malignant categories according to criteria based on the IOTA simple rules and the SRU guidelines. The prevalence of nonneoplastic cysts, neoplasms, and malignant tumors was calculated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated, and ROC analysis for the diagnosis of malignancy was performed. RESULTS. A total of 697 women with 764 cystic lesions were included; 85.2% (651/764) of the lesions were nonneoplastic, 12.2% (93/764) were benign neoplasms, and 2.6% (20/764) were malignant neoplasms. Nearly all malignancies were classified into indeterminate and malignant categories. The prevalence of malignancy in the indeterminate category was 4.8% (7/145) (SRU) to 10.7% (7/65) (IOTA) and in the malignant category was 18.1% (13/72) (SRU) to 34.3% (12/35) (IOTA). Only one malignancy was misclassified as benign by the IOTA simple rules. The sensitivity of the IOTA simple rules for malignancy was 90.0%; specificity, 96.5%; PPV, 29.0%; NPV, 99.8%; and accuracy, 96.4%. The corresponding values for the SRU guidelines were 100%, 89.6%, 14.9%, 100%, and 89.8%. In ROC analysis, the IOTA simple rules were slightly more accurate than the SRU guidelines (AUC, 0.9805 versus 0.9713; p = 0.0003). CONCLUSION. Both imaging characterization methods were sensitive for identifying ovarian malignancies, but the PPV was low among women presenting to radiology departments, and the indeterminate classification harbored one-third of the total malignancies. Exploration of varied clinical settings and inclusion of secondary tests may help to refine these systems.

BRCA Mutation Carriers: Breast and Ovarian Cancer Screening Guidelines and Imaging Considerations.

Patients who carry the BRCA1 and BRCA2 gene mutations have an underlying genetic predisposition for breast and ovarian cancers. These deleterious genetic mutations are the most common genes implicated in hereditary breast and ovarian cancers. This monograph summarizes the evidence behind current screening recommendations, reviews imaging protocols specific to this patient population, and illustrates some of the imaging nuances of breast and ovarian cancers in this clinical setting.

Paternal uniparental isodisomy of tyrosine hydroxylase locus at chromosome 11p15.4: spectrum of phenotypical presentations simulating hydatidiform moles.

Uniparental disomy is an abnormal genetic condition in which both homologous chromosomes or part of the chromosome are inherited from one parent and the other parent's homologous chromosome is lost. We report three cases of gestations with paternal uniparental isodisomy at tyrosine hydroxylase or TH01 locus on chromosome 11p15.4 identified by DNA genotyping. The patients' age ranged from 32 to 35 years and all patients presented with missed abortion during the first trimester. Abnormal chorionic villi were seen in all cases with histomorphological and/or p57 immunohistochemical features simulating either partial or complete mole. While two patients had an uneventful clinical course, one patient presented with clinical complications simulating persistent gestational trophoblastic disease/neoplasia that required multiagent chemotherapy with etoposide, methotrexate, actinomycin D, vincristine, and cyclophosphamide (EMA-CO). In summary, paternal uniparental isodisomy of tyrosine hydroxylase locus at chromosome 11p15.4 may result in an abnormal gestation that simulates a hydatidiform mole both clinically and histologically. The presence of abnormal trophoblastic proliferation combined with loss of p57 expression in villous cytotrophoblast and stromal cells may be associated with an aggressive clinical behavior.

NCCN Guidelines Insights: Ovarian Cancer, Version 1.2019.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Anti-programmed Death-1 Immunotherapy for Endometrial Cancer with Microsatellite Instability-High Tumors.

OPINION STATEMENT: Among gynecologic malignancies, mismatch repair-deficient endometrial cancers show the greatest response to anti-programmed cell death-1 (PD-1) antibodies, such as pembrolizumab. Routine immunohistochemical (IHC) and molecular testing should be performed on all endometrial cancers at the time of diagnosis in order to identify endometrial cancers with mismatch repair deficiency that may show improved response to anti-PD-1 therapy in the progressive or metastatic setting. Institutional effort to enroll patients in clinical trials investigating the use of immune checkpoint inhibitors in endometrial cancer should be prioritized.

Using simple radiologic measurements to anticipate surgical challenge in endometrial cancer: a prospective study.

OBJECTIVES: To determine if linear measurements of adiposity from pre-operative imaging can improve anticipation of surgical difficulty among endometrial cancer patients. METHODS: Eighty patients with newly diagnosed endometrial cancer were enrolled. Routine pre-operative imaging (MRI or CT) was performed. Radiologic linear measurements of the following were obtained: anterior-to-posterior skin distance; anterior skin to anterior edge of L5 distance (total anterior); anterior peritoneum to anterior edge of L5 distance (visceral obesity); and posterior edge of L5 to posterior skin distance (total posterior). Surgeons completed questionnaires quantifying preoperative anticipated operative difficulty and postoperative reported operative difficulty. The primary objective was to assess for a correlation between linear measurements of visceral fat and reported operative difficulty. RESULTS: Seventy-nine patients had questionnaires completed, preoperative imaging obtained, and surgery performed. Univariate analysis showed all four linear measurements, body mass index, weight, and anticipated operative difficulty were associated with increased reported operative difficulty (P< 0.05). Multivariate analysis demonstrated that body mass index and linear measurements visceral obesity and total posterior were independently associated with increased reported operative difficulty (P< 0.05). Compared with body mass index, the visceral obesity measurement was more sensitive and specific for predicting increased reported operative difficulty (visceral obesity; sensitivity 54%, specificity 91 %; body mass index; sensitivity 38%, specificity 89%). A difficulty risk model combining body mass index, visceral obesity, and total posterior demonstrated better predictive performance than any individual preoperative variable. CONCLUSIONS: Simple linear measurements of visceral fat obtained from preoperative imaging are more predictive than body mass index alone in anticipating surgeon-reported operative difficulty. These easily obtained measurements may assist in preoperative decision making in this challenging patient population.

Indeterminate Adnexal Cysts at US: Prevalence and Characteristics of Ovarian Cancer.

Purpose To assess the prevalence of indeterminate adnexal cysts in women presenting to academic medical centers for pelvic ultrasonography (US), determine the incidence of malignancy, and identify cyst and patient characteristics that are predictive of malignancy. Materials and Methods A multicenter study of US-detected adnexal cysts with appropriate follow-up (surgical pathologic examination, imaging and/or clinical examination) was conducted from January 2008 to June 2012. Indeterminate cysts were classified as category 1 (typical benign appearing cysts >5 cm) or category 2 (cysts with avascular solid components) on the basis of a combination of definitions in the existing literature. The incidence of neoplasms and malignant tumors was calculated. Patient and cyst characteristics associated with neoplasm and malignant tumors were evaluated with the χ2 test or Fisher exact test for categorical variables and the t test for continuous variables. A backward stepwise logistic regression model was performed for two outcomes: (a) the presence of any neoplasm (benign or malignant) and (b) the presence of a malignant tumor. Results There were 1637 women with an adnexal cyst at US; 391 (mean age = 41.8 years ± 13.5.1; range = 17-91 years) had an indeterminate adnexal cyst at US. The prevalence of indeterminate adnexal cysts was 23.9% (391 of 1637; 95% confidence interval [CI]: 0.22, 0.26). Three hundred three indeterminate cysts in 280 women (mean age = 42.9 years ± 14.1; range = 17-88 years) had adequate follow-up. The incidence of ovarian neoplasms (benign and malignant) was 24.8% (75 of 303 cysts; 95% CI: 0.20, 0.30), and the incidence of malignant tumors was 3.6% (11 of 303 cysts; 95% CI: 0.02, 0.06). The proportion of ovarian neoplasms differed between category 1 and category 2 cysts (17.5% [25 of 143 cysts; 95% CI: 0.12, 0.25] vs 31.3% [50 of 160 cysts; 95% CI: 0.24, 0.39], respectively; P = .001). The proportion of malignant tumors differed between categories 1 and 2 cysts (0% [0 of 143 cysts] vs 6.9% [11 of 160 cysts; 95% CI: 0.03, 0.12]; P < .001). The presence of an avascular nodular component was a significant predictor of malignancy at stepwise logistic regression analysis (odds ratio = 2.83; P ≤ .0001; 95% CI: 1.69, 4.70). Conclusion The presence of an avascular nodular component was the most significant predictor of the presence of malignancy in indeterminate adnexal cysts. The risk of malignancy is higher with category 2 cysts than with category 1 cysts. © RSNA, 2018.

Neoadjuvant chemotherapy is associated with a high rate of perioperative blood transfusion at the time of interval cytoreductive surgery.

BACKGROUND: The oncologic safety of allogeneic blood transfusion in ovarian cancer patients is unknow. We sought to determine the prevalence and oncologic safety of perioperative allogeneic blood transfusion during interval cytoreduction surgery among women receiving neoadjuvant chemotherapy for ovarian cancer. METHODS: We utilized retrospective chart review to identify a cohort of patients undergoing interval cytoreduction at a large academic tertiary referral center. We compared outcomes in patients who were exposed to perioperative blood transfusion compared with patients who were not exposed. Our primary endpoint was progression free survival; our secondary endpoint was overall survival. Baseline clinical characteristics were collected for patients in each group. RESULTS: Sixty-six women were included in the final cohort of women undergoing interval cytoreductive surgery after NACT. A total of 51 women (77%) were exposed to allogeneic perioperative pRBC transfusion. Fifteen women (23%) were not exposed to transfusion. The baseline characteristics were generally well matched. Women who were not exposed to a perioperative blood transfusion were more likely to have a normalized CA125 prior to undergoing cytoreductive surgery. Preoperative hemoglobin concentration was lower in the transfusion group (10.5 g/dLvs 11.5 g/dL, p < 0.009). Perioperative transfusion was not associated with a significant difference in progression free survival (PFS = 7.6 months for transfused, 9.4 months for not transfused; log-rank test p = 0.4617). Similarly, there was no observed difference between groups for overall survival (OS = 23.6 months for transfused, 22.5 months for not transfused; log-rank test p = 0.1723). CONCLUSIONS: Women undergoing neoadjuvant chemotherapy for ovarian cancer are at high risk of exposure to blood transfusion at the time of interval cytoreductive surgery. Future studies will continue to evaluate the safety and impact of transfusion on ovarian cancer survival in this at risk population.