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Background: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. Methods: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. Results: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for ‘copy-number’ status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined ‘high-risk’ group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. Conclusions: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

Endometrial carcinoma (EC) is the fourth most common cancer in women in the developed world. Classification of ECs by histomorphologic criteria has limited reproducibility and better tools are needed to distinguish these tumors and enable a subtype-specific approach to research and clinical care. Based on the Cancer Genome Atlas, two research teams have developed pragmatic molecular classifiers that identify four prognostically distinct molecular subgroups. These methods can be applied to diagnostic specimens (e.g., endometrial biopsy) with the potential to completely change the current risk stratification systems and enable earlier informed decision making. The evolution of genomic classification in ECs is shared herein, as well as potential applications and discussion of the essential research still needed in order to optimally integrate molecular classification in to current standard of care.

Introduction/Background*Vulvar squamous cell carcinoma (VSCC) is subclassified into three prognostically relevant groups: i) HPV-Associated (HPV-A), ii) HPV-Independent TP53 mutated (HPV-I p53abn), and iii) HPV-Independent TP53 wild type (HPV-I p53wt). Immunohistochemistry (IHC) for p16 and p53 are used as surrogate markers for HPV viral integration and TP53 mutational status, respectively.We assessed the reproducibility of subclassification based on p16 and p53 IHC and evaluated the prognostic significance of VSCC molecular subgroups in a patient cohort treated by vulvar field resection (VFR) surgery.MethodologyVSCC formalin-fixed paraffin-embedded tumour tissue and patient clinicopathologic data from 68 cases treated by vulvar field resection (VFR) were collected from the Leipzig School of Radical Pelvic Surgery. Immunohistochemistry for p16 and p53 was performed at three different institutions and evaluated independently by seven pathologists and two pathology research fellows. Tumors were classified into one of four groups: HPV-A, HPV-I p53wt, HPV-I p53abn, and Indeterminate (requiring additional investigation). Selected cases were further interrogated by HPV RNA in situ hybridisation (ISH) and TP53 sequencing.Result(s)*Final VSCC subclassification yielded 22 tumors (32.4%) were HPV-A, 41 (60.3%) were HPV-I p53abn, and 5 (7.3%) were HPV-I p53wt; the clinicopathologic data is summarised in table 1. Interobserver agreement (overall Fleiss’ kappa statistic) for the four-category classification was 0.74. No statistically significant differences in clinical outcomes between HPV-A and HPV-I VSCC were observed (figure 1).Abstract 231 Table 1Clinicopathologic features of vulvar squamous cell carcinoma stratified by HPV statusAbstract 231 Table 2Summary of the clinicopathologic features by ProMisE molecular subtypeConclusion*Interobserver reproducibility of VSCC subclassification based on p16 and p53 IHC is very good, supporting their routine use in clinical practice. VSCCs treated by VFR surgery showed no significant difference in clinical outcomes when stratified based on HPV status. This contrasts with the significant prognostic differences between HPV-A and HPV-I VSCC demonstrated in cohorts treated by conventional conservative surgical approaches and suggests that a change in surgical approach can improve outcomes in patients with HPV-I VSCC.

ObjectivesMolecular classification of endometrial carcinoma (EC) enables consistent classification of tumours and provides valuable prognostic and predictive information. Herein we describe molecular subtype distribution and histomorphologic correlates in recently diagnosed (2016) ECs from across Canada.MethodsMolecular classification was performed on representative tumour specimens from participating centres. Clinicopathologic, management and outcome data were collected (REDCap).Results1453 ECs from 30 centres have been identified. Complete molecular (ProMisE) and outcome data is reportable for 862 patients. Histologic and clinicopathologic parameters associated with molecular subtype and are summarised in table 1. Amongst participating centres, routine testing of MMR and p53 immunohistochemistry (IHC) was performed in only 23.5% (range 3.5–80.0% per centre) and 15% (2.2–45.7%) of cases respectively. We found p53 abn ECs across a range of histotypes, including low grade endometrioid EC. Subclonal p53 staining was observed in 3.9% of cases and significantly associated with the presence of pathogenic POLE mutations (p≤0.001). Subclonal MMR IHC expression was seen in 3.5% of cases and has previously been shown to occur predominantly in the context of MLH1 hypermethylation. MMRd was significantly associated with LVI (p <0.001). ProMisE subtype was significantly associated with clinical outcomes (p<0.001) even in low stage disease [OS p=0.045, DSS p=0.009, PFS p=0.005 for stage I].Abstract 4 Table 1Univariable association of clinicopathologic characteristics by proactive molecular risk classifier for endometrial cancer (ProMisE) subtypeConclusionsObservation of unusual or unexpected p53 and MMR IHC staining patterns and associated clinical implications highlight the importance of routine testing of these parameters in ECs.

BackgroundThe endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer.Primary Objective(s)The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation.Study HypothesisMolecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation.Trial DesignThe RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I–III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. The POLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I–III POLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility.Major Inclusion/Exclusion CriteriaInclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm.Primary Endpoint(s)Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in the POLEmut-BLUE trial.Sample SizeThe p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and the POLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600.Estimated Dates for Completing Accrual and Presenting ResultsThe four clinical trials will have different completion dates; main results are expected from 2028.Trial Registration NumberThe RAINBO program is registered at clinicaltrials.gov (NCT05255653).

IntroductionThe benefit of systematic lymphadenectomy (LNE) in low-stage, low-grade ovarian carcinoma is unknown. However, most guidelines still recommend LNE in these patients. Prior studies examining the benefit of this invasive procedure have been hampered small numbers, and large-scale studies that consider modern classification are needed.MethodsA cohort of 666 pathology-reviewed and immunohistochemistry-validated endometrioid ovarian carcinomas has recently been evaluated using endometrial carcinoma-inspired molecular subtyping. This molecularly characterized series is now being used to assess the value of LNE. Contributing centers are performing detailed chart reviews, so that surgical procedures and lymph node status can be correlated with molecular subtype and outcomes.Results349 stage I, 181 stage II, 85 stage III, and 22 stage IV cases with a median OS follow-up of 6.11 years (RevKM) were collected from 17 centres across Canada and Europe. Analysis of the first 70/666 cases revealed positive nodes in only a single presumed low stage patient after systematic pelvic and paraaortic LNE (n=1/44). LNE was not performed in 3/44 and restricted to pelvic nodes in 6/44 low-stage cases, all of which were pN0. Tumor spread beyond the Uterus and/or Adnexa was associated with positive nodes in 33%.ConclusionPreliminary results indicate that abandonment of LNE in low-stage, low-grade endometrioid ovarian carcinoma may reduce morbidity without worsening prognosis for these patients. Completion and expansion of our international team initiative stands to provide a powerful statement on the value of LNE, and influence of molecular subtype on disease spread, possibly improving precision care for ovarian carcinoma patients.

BackgroundQuality of life (QoL) in endometrial cancer (EC) is understudied. Incorporation of QoL questionnaires and patient-reported outcomes in clinical trials has been inconsistent, and the tools and interpretation of these measures are unfamiliar to most practitioners. In 2012, the Gynecologic Cancer InterGroup Symptom Benefit Working Group convened for a brainstorming collaborative session to address deficiencies and work toward improving the quality and quantity of QoL research in women with EC.MethodsThrough literature review and international expert contributions, we compiled a comprehensive appraisal of current generic and disease site–specific QoL assessment tools, strengths and weaknesses of these measures, assessment of sexual health, statistical considerations, and an exploration of the unique array of histopathologic and clinical factors that may influence QoL outcomes in women with EC.ResultsThis collaborative composition is the first publication specific to EC that addresses methodology in QoL research and the components necessary to achieve high quality QoL data in clinical trials. Future recommendations regarding (1) the incorporation of patient-reported outcomes in all clinical trials in EC, (2) definition of an a priori hypothesis, (3) utilization of validated tools and consideration of new tools corresponding to new therapies or specific symptoms, (4) publication within the same time frame as clinical outcome data, and (5) attempt to correct for disease site–specific potential confounders are presented.ConclusionsImproved understanding of methodology in QoL research and an increased undertaking of EC-specific QoL research in clinical trials are imperative if we are to improve outcomes in women with EC.

Surgical staging of endometrial carcinoma includes the collection of peritoneal washings in the abdomen and pelvis. A positive finding upstages patients to International Federation of Gynecology and Obstetrics stage IIIA. However, the prognostic significance of such an upstaging, and thus the justification for the routine performance of this procedure, is unclear. This 5-year retrospective study was conducted to determine the frequency and prognostic significance of upstaging of endometrial carcinoma based solely on positive washings. The cohort for the study was collected by review of pathology reports of all washings that were performed prior to hysterectomies for suspected endometrial carcinomas over a 5-year period (01/1995–12/1999). Cases with positive cytology were selected if there was no grossly apparent intraperitoneal disease, no histologic evidence of extra-uterine tumor and the cases would otherwise have been considered stage I or II (case group). An age-matched control group was selected of stage I and II patients with the same histologic subtypes and negative washings (n=19). Of 220 endometrial carcinomas, peritoneal washing cytology was abnormal in 19 (8.6%) and was solely responsible for upstaging only 10 patients (4.5% of all cases, eight—endometrioid, one–serous, one–mixed; nine stage IA or IB and one stage IIB). Adjuvant therapy was administered in 90% of the case group and 74% of the control group. After a median follow-up of 51 months (case group) and 63 months (control group), we found only a single patient with progression of disease (recurrence, metastases or death) in the control group. It is concluded that abnormal cytology without other evidence of extrauterine disease leads to upstaging of a minority of endometrial carcinoma patients (4.5%), but does not appear to affect their overall outcome. Although this is a small single site study, it raises questions about the value of this procedure in patients with endometrial cancer.

Endometrial cancer is the most common gynaecological cancer in high income countries and its incidence is rising globally. Although an ageing population and fewer benign hysterectomies have contributed to this trend, the growing prevalence of obesity is the major underlying cause. Obesity poses challenges for diagnosis and treatment and more research is needed to offer primary prevention to high-risk women and to optimise endometrial cancer survivorship. Early presentation with postmenopausal bleeding ensures most endometrial cancers are cured by hysterectomy but those with advanced disease have a poor prognosis. Minimally invasive surgical staging and sentinel-lymph-node biopsy provides a low morbidity alternative to historical surgical management without compromising oncological outcomes. Adjuvant radiotherapy reduces loco-regional recurrence in intermediate-risk and high-risk cases. Advances in our understanding of the molecular biology of endometrial cancer have paved the way for targeted chemotherapeutic strategies, and clinical trials will establish their benefit in adjuvant, advanced, and recurrent disease settings in the coming years.

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration 1 . The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus 2 – 4 , yet little is known about the factors and mechanisms that mediate these effects. Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer’s disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. Plasma from voluntarily running mice reduces baseline expression of neuroinflammatory genes and experimentally induced brain inflammation when infused into sedentary mice.