PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1.

Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is thought to recruit canonical PRC1 (cPRC1) via chromodomain-containing CBX proteins to promote stable repression of developmental genes. PRC2 forms two major subcomplexes, PRC2.1 and PRC2.2, but their specific roles remain unclear. Through genetic knockout (KO) and replacement of PRC2 subcomplex-specific subunits in naïve and primed pluripotent cells, we uncover distinct roles for PRC2.1 and PRC2.2 in mediating the recruitment of different forms of cPRC1. PRC2.1 catalyzes the majority of H3K27me3 at Polycomb target genes and is sufficient to promote recruitment of CBX2/4-cPRC1 but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at catalyzing H3K27me3, we find that its accessory protein JARID2 is essential for recruitment of CBX7-cPRC1 and the consequent 3D chromatin interactions at Polycomb target genes. We therefore define distinct contributions of PRC2.1- and PRC2.2-specific accessory proteins to Polycomb-mediated repression and uncover a new mechanism for cPRC1 recruitment.

Evaluating nutrition in advanced ovarian cancer: which biomarker works best?

BACKGROUND: Advanced epithelial ovarian cancer (OC) patients often present with malnutrition; however, the ideal nutritional evaluation tool is unclear. We aimed to evaluate the role of preoperative albumin, Prognostic Nutritional Index [PNI], neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR] as independent predictors of severe postoperative complications and 90-day mortality in OC patients who underwent primary cytoreductive surgery to identify the ideal tool. METHODS: OC patients who underwent surgery at Mayo Clinic (2003-2018) were included; biomarkers were retrospectively retrieved and established cut-offs were utilized. Outcomes included severe complications (Accordion grade ≥ 3) and 90-day mortality. Univariate and multivariable logistic regression models were performed. Biomarkers were evaluated in separate models adjusted for age and American Society of Anesthesiologists (ASA) score for 90-day mortality, and adjusted for age, ASA score, stage, and surgical complexity for severe complications. RESULTS: Albumin <3.5 g/dL, PNI < 45, NLR > 6 and PLR ≥ 200 were univariately associated with 90-day mortality (all p < 0.05) in 627 patients that met inclusion criteria. Each marker remained significant in adjusted models with albumin having the highest OR: 6.04 [95% CI:2.80-13.03] and AUC (0.83). Univariately, PNI <45, NLR >6, and PLR ≥200 were significant predictors of severe complications(all p < 0.05), however failed to reach significance in adjusted models. Albumin was not associated with severe complications. CONCLUSION: All biomarkers were associated with 90-day mortality in adjusted models, with albumin being the easiest predictor to attain clinically; none with severe complications. Future research should focus less on methods of nutritional assessment and more on strategies to improve nutrition during OC tumor-directed therapy.

Uterine perivascular epithelioid cell tumors (PEComa) and the accuracy of proposed classification systems in predicting the malignant versus non-malignant behavior.

OBJECTIVE: To compare the accuracy of available classification systems (Folpe, modified Folpe, Bennet, and Schoolmester) in predicting the behavior of uterine Perivascular Epithelioid Cell tumors (PEComas). METHODS: We reviewed the pathology registry to identify all uterine PEComas treated at our center. We conducted a systematic literature review searching electronic databases from inception to November 2023. We included all references reporting at least one case of uterine PEComa; cases associated with tuberous sclerosis complex were excluded. Patient-level data were extracted by identified records. Survival analysis was used to assess the accuracy of all proposed classification systems to classify uterine PEComas as malignant versus non-malignant. RESULTS: Six uterine PEComas were treated at our center. The literature search identified 101 uterine PEComas from 32 studies. Eighty-five out of 107 PEComas (28 studies and our series) reported enough follow-up data and details to apply all four classifications. The modified Folpe classification demonstrated the highest hazard ratio (HR) for relapse (HR:8.63; 95% confidence interval [CI] 2.06-36.1) and death due to PEComa (HR:6.8, 95%CI:0.89-51.6) for malignant versus non-malignant PEComas. Changing the cut-off of PEComa size to ≥8 cm and mitotic figures per 50 high power fields to ≥5, the HR for recurrence lowered (HR:6.26; 95% CI 2.20-17.80), but HR for death increased (HR:10.3; 95% CI 1.35-77.80). CONCLUSIONS: The modified Folpe classification was the most accurate in predicting the PEComa behavior. Changing the cut-off of PEComa size and number of mitotic figures may improve the accuracy in predicting death due to disease.

Practice patterns and complications of hysterectomy for invasive cervical cancer after the Laparoscopic Approach to Cervical Cancer trial.

BACKGROUND: After the publication of the Laparoscopic Approach to Cervical Cancer trial, the standard surgical approach for early-stage cervical cancer is open radical hysterectomy. Only limited data were available regarding whether the change to open abdominal hysterectomy observed after the Laparoscopic Approach to Cervical Cancer trial led to an increase in postoperative complication rates as a consequence of the decrease in the use of the minimally invasive approach. OBJECTIVE: This study aimed to analyze whether there was a correlation between the publication of the Laparoscopic Approach to Cervical Cancer trial and an increase in the 30-day complications associated with surgical treatment of invasive cervical cancer. STUDY DESIGN: Data from the American College of Surgeons National Surgical Quality Improvement Program were used to compare the results in the pre-Laparoscopic Approach to Cervical Cancer period (January 2016 to December 2017) vs the results in the post-Laparoscopic Approach to Cervical Cancer period (January 2019 to December 2020). The rates of each surgical approach (open abdominal or minimally invasive) hysterectomy for invasive cervical cancer during the 2 periods were assessed. Subsequently, 30-day major complication, minor complication, unplanned hospital readmission, and intra- or postoperative transfusion rates before and after the publication of the Laparoscopic Approach to Cervical Cancer trial were compared. RESULTS: Overall, 3024 patients undergoing either open abdominal hysterectomy or minimally invasive hysterectomy for invasive cervical cancer were included in the study. Of the patients, 1515 (50.1%) were treated in the pre-Laparoscopic Approach to Cervical Cancer period, and 1509 (49.9%) were treated in the post-Laparoscopic Approach to Cervical Cancer period. The rate of minimally invasive approaches decreased significantly from 75.6% (1145/1515) in the pre-Laparoscopic Approach to Cervical Cancer period to 41.1% (620/1509) in the post-Laparoscopic Approach to Cervical Cancer period, whereas the rate of open abdominal approach increased from 24.4% (370/1515) in the pre-Laparoscopic Approach to Cervical Cancer period to 58.9% (889/1509) in the post-Laparoscopic Approach to Cervical Cancer period (P<.001). The overall 30-day major complications remained stable between the pre-Laparoscopic Approach to Cervical Cancer period (85/1515 [5.6%]) and the post-Laparoscopic Approach to Cervical Cancer period (74/1509 [4.9%]) (adjusted odds ratio, 0.85; 95% confidence interval, 0.61-1.17). The overall 30-day minor complications were similar in the pre-Laparoscopic Approach to Cervical Cancer period (103/1515 [6.8%]) vs the post-Laparoscopic Approach to Cervical Cancer period (120/1509 [8.0%]) (adjusted odds ratio, 1.17; 95% confidence interval, 0.89-1.55). The unplanned hospital readmission rate remained stable during the pre-Laparoscopic Approach to Cervical Cancer period (7.9% per 30 person-days) and during the post-Laparoscopic Approach to Cervical Cancer period (6.3% per 30 person-days) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.58-1.04)]. The intra- and postoperative transfusion rates increased significantly from 3.8% (58/1515) in the pre-Laparoscopic Approach to Cervical Cancer period to 6.7% (101/1509) in the post-Laparoscopic Approach to Cervical Cancer period (adjusted odds ratio, 1.79; 95% confidence interval, 1.27-2.53). CONCLUSION: This study observed a significant shift in the surgical approach for invasive cervical cancer after the publication of the Laparoscopic Approach to Cervical Cancer trial, with a reduction in the minimally invasive abdominal approach and an increase in the open abdominal approach. The change in surgical approach was not associated with an increase in the rate of 30-day major or minor complications and unplanned hospital readmission, although it was associated with an increase in the transfusion rate.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Measuring the impact of specific surgical complications after ovarian cancer cytoreductive surgery on short-term outcomes.

OBJECTIVE: We sought to measure the impact of specific peri-operative complications after primary cytoreductive surgery on relevant patient outcomes and use of resources. METHODS: A cohort of patients with advanced ovarian cancer who underwent primary cytoreductive surgery at two institutions (2006-2016) were studied. Specific known complications ('exposures') within 30 days of surgery were evaluated to determine the impact on outcomes. Exposures included bowel leak, superficial surgical site infection, deep surgical site infection, venous thromboembolic event, and cardiac event. Outcomes were prolonged lengths of stay, readmission or non-home discharge, reoperation, organ failure, delay to adjuvant chemotherapy, and 90-day mortality. Population attributable risk (PAR) was used to estimate the proportion of adverse outcomes that could be prevented by elimination of a causal exposure and considers both the strength of the association and the prevalence of the complication; adjusted PARs (aPAR) were calculated using adjusted relative risks (aRR) adjusted for stage (IIIC vs IV) and American Society of Anesthesiology score (<3 vs ≥3). RESULTS: A cohort of 892 patients was included. Each of the evaluated exposures had an impact on readmission/non-home discharge (aPAR range 5.3 to 13.5). A venous thromboembolic event was significantly associated with 90-day mortality (aRR=2.9 (95% CI 1.3 to 6.7); aPAR=8.6 (95% CI -1.8 to 19.1)) and organ failure (aRR=4.7 (95% CI 2.3 to 9.5); aPAR=13.9 (95% CI 2.8 to 25.1)). Similarly, a cardiac event was most strongly associated with organ failure and was very impactful (aPAR=19.0 (95% CI 6.8 to 31.1)).Bowel leak was a major contributor to poor outcome, including reoperation (aPAR=45.5 (95% CI 34.3 to 56.6)), organ failure (aPAR=13.6 (95% CI 2.6 to 24.6)), readmission/non-home discharge (aPAR=5.3 (95% CI 1.6 to 9.0)), delay to adjuvant chemotherapy (aPAR=5.9 (95% CI 2.3 to 9.4)), and prolonged lengths of stay (aPAR=13.0 (95% CI 9.1 to 16.9)). CONCLUSION: Going beyond reporting complications using common scales to measure their genuine impact provides important information for providers, patients, and payers. We report that less frequent exposures, including a venous thromboembolic event, cardiac events, and bowel leaks, have a high impact on patients and use of resources.

How deep is too deep? Assessing myometrial invasion as a predictor of distant recurrence in stage I endometrioid endometrial cancer.

OBJECTIVES: The goal of this study was to evaluate the depth of myometrial invasion as a predictor of distant recurrence in patients with node-negative stage IB endometrioid endometrial cancer. METHODS: A retrospective multicenter study, including surgically staged endometrial cancer patients at Mayo Clinic, Rochester (MN, USA) between January 1999 and December 2017, and Fondazione Policlinico Universitario A. Gemelli (Rome, Italy) between March 2002 and March 2017, was conducted. Patients without lymph node assessment were excluded. The follow-up was restricted to the first 5 years following surgery. Recurrence-free survival was estimated using the Kaplan-Meier method. Cox proportional hazards models were fit to evaluate the association of clinical and pathologic characteristics with the risk of recurrence. RESULTS: Of 386 patients, the mean (SD) depth of myometrial invasion was 70.4 (13.2)%. We identified 51 recurrences (14 isolated vaginal, 37 non-vaginal); the median follow-up of the remaining patients was 4.5 (IQR 2.3-7.0) years. At univariate analysis, the risk of non-vaginal recurrence increased by 64% (95% CI 1.28 to 2.12) for every 10-unit increase in the depth of myometrial invasion. International Federation of Gynecology and Obstetrics (FIGO) grade and myometrial invasion were independent predictors of non-vaginal recurrence. The 5-year non-vaginal recurrence-free survival was 95.2% (95% CI 92.0% to 98.6%), 84.0% (95% CI 76.6% to 92.1%), and 67.1% (95% CI 54.2% to 83.0%) for subsets of patients with myometrial invasion <71% (n=207), myometrial invasion ≥71% and grade 1-2 (n=132), and myometrial invasion ≥71% and grade 3 (n=47), respectively. A total of 256 (66.3%) patients received either vaginal brachytherapy only or no adjuvant therapy. Patients who received adjuvant chemotherapy, regardless of receipt of external beam radiotherapy or vaginal brachytherapy, had an approximately 70% lower risk of any recurrence (HR adjusted for age, grade, myometrial invasion 0.31, 95% CI 0.12 to 0.85) and of non-vaginal recurrence (adjusted HR 0.32, 95% CI 0.10 to 0.99). CONCLUSION: The invasion of the outer third of the myometrium and histologic grade were found to be independent predictors of distant recurrence among patients with endometrioid, node-negative stage IB endometrial cancer. Future studies should investigate if systemic adjuvant therapy for patients with myometrial invasion of the outer third would improve outcomes.

Endometrial cancer with positive sentinel lymph nodes: pathologic characteristics of metastases as predictors of extent of lymphatic dissemination and prognosis.

OBJECTIVES: To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models. RESULTS: A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy. CONCLUSION: Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study.

OBJECTIVE: Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted. METHODS: We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3). RESULTS: Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%. CONCLUSIONS: Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified.

Acute advanced aortic stenosis.

Acute decompensation often represents the onset of symptoms associated with severe degenerative aortic stenosis (AS) and usually complicates the clinical course of the disease with a dismal impact on survival and quality of life. Several factors may derange the faint balance between left ventricular preload and afterload and precipitate the occurrence of symptoms and signs of acute heart failure (HF). A standardized approach for the management of this condition is currently lacking. Medical therapy finds very limited application in this setting, as drugs usually indicated for the control of acute HF might worsen hemodynamics in the presence of AS. Urgent aortic valve replacement is usually performed by transcatheter than surgical approach whereas, over the last decades, percutaneous balloon valvuloplasty gained renewed space as bridge to definitive therapy. This review focuses on the pathophysiological aspects of acute advanced AS and summarizes current evidence on its management.

Intraluminal tumor cells and prognostic accuracy of endometrial cancer stage criteria: A multi-institution study.

OBJECTIVE: Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. METHODS: We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. RESULTS: In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69-1.32) or OS (HR = 0.97, 95% CI = 0.72-1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06-5.05) and OS (HR = 2.16, 95% CI = 1.14-4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. CONCLUSION: While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

Comparison of the Contracted Accordion, Expanded Accordion, and Clavien-Dindo complication grading scales after ovarian cancer cytoreduction.

OBJECTIVE: To compare the ability of current complication reporting scales (Contracted Accordion Scale, Expanded Accordion Scale, Clavien-Dindo Scale) to reflect the severity of patient outcomes after cytoreductive surgery for ovarian cancer. METHODS: We included all patients undergoing primary debulking surgery for stage IIIC/IV ovarian cancer from 2006 to 2016 at two expert centers for ovarian cancer. Complications within 30 days of surgery were graded according to three scales. Outcomes included length of stay, mortality (90-day), and delayed initiation of chemotherapy (>42 days after surgery). Correlations were assessed using the Spearman rank correlation, and comparisons between groups were evaluated using the Wilcoxon rank-sum test and the χ2 test. RESULTS: Among the 892 patients, 185 (20.7%) patients had a grade 3 or higher complication per all scales. Patients with grade 3 or higher complications (compared with those with none, grade 1 or grade 2) had longer length of stay, higher 90-day mortality, and delayed initiation of chemotherapy. The expanded scales (Expanded Accordion Scale and Clavien Dindo Scale) provided a more refined characterization of outcome compared with the Contracted Accordion Scale. However, mortality was actually found to be as high as 25.0% for grade 5 complications using the Expanded Accordion Scale. Patients with organ failure or requiring an invasive procedure had significantly worse outcomes than those without either complication, highlighting the importance of separating these events. CONCLUSIONS: All three scales demonstrated general correlation with important outcomes after ovarian cancer surgery. However, the expanded scales (Clavien Dindo Scale and Expanded Accordion Scale) used important events commonly encountered after cytoreductive surgery, provided a more refined view of the severity of complications, and should be used in reporting outcomes in ovarian cancer.

Impact of comorbidities and extent of lymphadenectomy on quality of life in endometrial cancer patients treated with minimally invasive surgery in the era of sentinel lymph nodes.

OBJECTIVE: To identify predictors of quality of life (QoL) among patients who undergo surgical staging with sentinel lymph node (SLN) biopsy or lymphadenectomy for endometrial cancer. METHODS: Patients who underwent minimally invasive surgery for primary endometrial cancer at the Mayo Clinic from October 2013 to June 2016 were mailed a 30-item QoL in Cancer survey (QLQ-C30) and a validated 13-item lower extremity lymphedema screening questionnaire. Patients who answered <50% of the items or had a pre-operative history of lymphedema were excluded. Multivariable linear regression models were fit to evaluate predictors of QoL using inverse-probability of treatment weighting to adjust for differences at the time of the surgery between the lymphadenectomy and SLN groups. RESULTS: The 221 patients included in the analysis were stratified into two groups: patients who underwent (1) bilateral lymphadenectomy as 'backup' after SLN mapping (lymphadenectomy group; n=101) or (2) SLN removal with or without side-specific lymphadenectomy (SLN group; n=120). On multivariable analysis, obesity, lower extremity lymphedema, and kidney disease had significant (p<0.05) and clinically meaningful negative impacts on global QoL. Declines in average adjusted global QoL scores were marked (19.7 points lower) in patients with BMI ≥40 kg/m2 and lower extremity lymphedema compared with non-obese patients without lower extremity lymphedema. In contrast, there was only a 2.9 point difference in the adjusted average global QoL score between the SLN and lymphadenectomy groups. CONCLUSIONS: Lower extremity lymphedema coupled with obesity predicts poorer QoL in patients who undergo surgical staging for endometrial cancer. In this population, reduction of lower extremity lymphedema by performing SLN instead of lymphadenectomy and earlier targeted interventions may improve patients' QoL. Future research focusing on targeted interventions is needed.

Let go of the myth: safety of indocyanine green for sentinel lymph node mapping in endometrial cancer.

OBJECTIVE: Sentinel lymph node mapping by intracervical indocyanine green injection is the preferred method for surgical staging in endometrial cancer. Adverse reactions to indocyanine green are extremely rare, and information about the safety of this tracer in patients with a history of other allergies, asthma, or comorbidities is limited. We aim to evaluate the rate of adverse reactions to indocyanine green injected during sentinel lymph node mapping in patients with endometrial cancer and review the etiology of such reactions. METHODS: All patients with endometrial cancer undergoing sentinel lymph node mapping with indocyanine green cervical stroma injection at the Mayo Clinic in Rochester, Minnesota between June 2014 and December 2018 were retrospectively evaluated. Any adverse reaction occurring intra-operatively or within 7 days after surgery was identified. A thorough chart review was performed by an allergy specialist physician for any patient with an allergic-type reaction. RESULTS: We included 923 patients of which 565 (61.2%) had a history of allergy to antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), other medications, and/or environmental exposures. Of 490 patients who had previously received contrast media, 25 (5.1%) had a history of an adverse reaction. No immediate anaphylaxis or other allergic reactions were observed after indocyanine green injection. 10 (1.1%) patients developed a transient skin reaction within 7 days after surgery. None of these patients had a history of contrast media reaction. Based on timing and clinical/peri-operative history of affected patients, it was determined that skin reactions were likely induced by other newly prescribed medications or contact sensitivity, not administration of indocyanine green. CONCLUSION: Indocyanine green injection for sentinel lymph node mapping in patients with endometrial cancer caused no immediate/delayed anaphylactic or other severe allergic reactions. This included patients with a history of other allergies, asthma, and comorbidities. The myth of iodine's relationship to allergic reactions must be refuted to allow indocyanine green use in patients with a history of contrast media or shellfish allergy.

Prognostic factors in patients with endometrial cancer with isolated lymphatic recurrence.

OBJECTIVE: To analyze the clinicopathological features and outcomes in patients with endometrial cancer with isolated lymphatic recurrence after lymphadenectomy, stratified by different isolated lymphatic recurrence sites and treatment approaches. METHODS: We retrospectively reviewed all surgically treated patients with endometrial cancer, identifying those with recurrence. We defined primary isolated lymphatic recurrence as the first and unique evidence of recurrence in lymph node-bearing areas, without concomitant vaginal, hematogenous, or peritoneal recurrence. Isolated lymphatic recurrences were classified as pelvic, para-aortic, distant, or multiple sites. Our primary outcome was cause-specific survival after diagnosis of the recurrence. RESULTS: Among 4216 patients with surgically staged endometrial cancer, we identified 66 (1.6%) women with isolated lymphatic recurrence. The overall median cause-specific survival for patients with isolated lymphatic recurrence was 24 months. Although cause-specific survival was not significantly different between the four isolated lymphatic recurrence groups (p=0.21), 7 of 15 (47%) patients with isolated lymphatic recurrence in the para-aortic area were long-term survivors. At multivariate Cox regression, the absence of lymphovascular space invasion and grade 1 histology in the primary tumor were significantly associated with improved cause-specific survival. In addition, patients with isolated lymphatic recurrence who underwent surgery for recurrence (with/without other associated therapies) had improved cause-specific survival compared with patients who did not undergo surgery, also after adjusting for age. CONCLUSIONS: Low-grade histology and absence of lymphovascular space invasion in the primary tumor were predictors of improved prognosis in patients with endometrial cancer with isolated lymphatic recurrence. In addition, in this retrospective cohort, patients with isolated lymphatic recurrence who were selected for eradicative surgical treatment had improved cause-specific survival.

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review.

BACKGROUND: Endometrial cancers with more than one molecular feature-POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'. OBJECTIVE: To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. METHODS: Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. RESULTS: Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%. CONCLUSIONS: The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing.

Endometrial carcinosarcoma.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

Gestational choriocarcinoma.

Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.