The pathological classification of endometrial carcinomas, one of the cornerstones in patient clinical management, has traditionally been based on morphologic features. However, this classification ...system does not fully reflect the biological diversity of endometrial carcinomas and has limited reproducibility. In the last decade, several studies have reported the strong prognostic value of the molecular endometrial carcinoma subgroups and, more recently, its potential to inform adjuvant treatment decisions. This has in turn resulted in a transition from a purely morphological classification towards an integrated histological and molecular system in the latest World Health Organization (WHO) classification of tumors of female reproductive organs. The new European treatment guidelines combine the molecular subgroups with traditional clinicopathological features in order to guide treatment decision-making. Accurate molecular subgroup assignment is therefore essential for adequate patient management. This review aims to address caveats and evolution of molecular techniques relevant in the implementation of the molecular endometrial carcinoma classification, as well as challenges in the integration of the molecular subgroups with traditional clinicopathological features.
This paper explores the impact of COVID-19 restrictions on gender biases in a STEM Faculty in an Irish University. For the purposes of this research, gender bias was understood as gender-based ...inclinations or prejudices which affect researchers' personal and professional opportunities as described by fifteen interviewees (nine women, six men). We used thematic interviews to explore participants' perspectives. Analyzing interviews with an inductive approach showed that gender biases experienced before COVID-19 restrictions were different from biases during restrictions. In discussing gender biases prior to the pandemic, interviewees mentioned institutional disparities, discrimination, implicit biases, stereotypes and gender roles. When discussing gender issues during COVID restrictions, interviewees mentioned disparities at home, challenges involved in parenting, support from colleagues and the University, as well as negative and positive impacts of restrictions on existing gender issues. Our results show that while COVID-19 restrictions and the associated consequences constrained all gender groups, they most negatively affected women researchers with caring responsibilities. Moving forward, reducing gender disparities requires promoting a horizontal organizational structure, and adjusting policies and work arrangements to cater for vulnerable cohorts such as parents, and international and early-career researchers. Offering a hybrid working model that grants more flexibility to those with caring responsibilities and which accommodates personal circumstances would help improve the working conditions for all researchers and nurture an organizational culture of care for the employees; thereby also fostering gender equity and tolerance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and ...radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.
Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for
exonuclease domain were done to classify tumors as p53 abnormal (p53abn),
ultramutated (
mut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis.
Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%),
mut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for
mut EC, 72% for MMRd EC, and 74% for NSMP EC (
< .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (
= .019); 100% versus 97% for patients with
mut EC (
= .637); 68% versus 76% (
= .428) for MMRd EC; and 80% versus 68% (
= .243) for NSMP EC.
Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with
mut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.
PURPOSE OF REVIEWChanges in molecular classification together with a deeper knowledge of both immune disregulation and phosphatidylinositol-3 kinase (PI3K) pathway alterations are leading to a new ...endometrial cancer treatment paradigm. This review will address the cutting-edge data in this field.
RECENT FINDINGSThis article will cover the updated data in endometrial cancer molecular classification and its correlation with the outcomes in randomized clinical trials (e.g., PORTEC-3). Moreover, we will review the latest data regarding checkpoint blockade molecules (CPB) in the recurrent setting and how they are changing the treatment landscape. In addition, the role of the PI3K inhibitors, their activity, and toxicity profile will be described.
SUMMARYAs result of the incorporation of molecular classification in our daily practice, the adjuvant treatment in endometrial cancer is rapidly evolving and leading to a new paradigm. The promising data observed with CPB in the recurrent setting have led to the food and drug administration approval of pembrolizumab as monotherapy and in combination with lenvatinib. Additionally, the current outcomes achieved with PI3K inhibitor agents encourage us to continue our clinical research to identify those patients who may benefit the most.
B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single ...cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.
Given the environmental problems humanity is currently facing, and considering that the future of the planet lies in the hands of children and their actions, research on the determinants of ...sustainable behaviors in children has become more relevant; nonetheless, studies on this topic focusing on children are scarce. Previous research on adults suggests, in an isolated manner, the relationship between connectedness to nature, the development of behaviors in favor of the environment, and positive results derived from them, such as happiness and well-being. In the present research, connectedness to nature was considered as a determinant of sustainable behaviors, and happiness was considered as a positive consequence of the latter. This research aimed to demonstrate the relationship between these variables in children. Two hundred and ninety-six children with an average age of 10.42 years old participated in the study, in which they responded to a research instrument that measured connectedness to nature, sustainable behaviors (
, and
), and happiness. To analyze the relationships between these variables, a model of structural equations was specified and tested. The results revealed a significant relationship between connectedness to nature and sustainable behaviors, which, in turn, impact happiness. This suggests that children who perceive themselves as more connected to nature tend to perform more sustainable behaviors; also, the more pro-ecological, frugal, altruistic, and equitable the children are, the greater their perceived happiness will be. The implications for studying and promoting sustainable behaviors are discussed within the framework of positive psychology.
Aims
Human epidermal growth factor receptor 2 (HER2) amplification in endometrial cancer (EC) is almost completely confined to the p53‐abnormal (p53abn) molecular subtype and independent of ...histological subtype. HER2 testing should therefore be molecular subtype‐directed. However, the most optimal approach for HER2 testing in EC has not been fully established. Therefore, we developed an EC‐specific HER2 immunohistochemistry (IHC) scoring method and evaluated its reproducibility and performance to establish an optimal diagnostic HER2 testing algorithm for p53abn EC.
Methods and results
HER2 IHC slides of 78 p53abn EC were scored by six gynaecopathologists according to predefined EC‐specific IHC scoring criteria. Interobserver agreement was calculated using Fleiss’ kappa and the first‐order agreement coefficient (AC1). The consensus IHC score was compared with HER2 dual in‐situ hybridisation (DISH) results. Sensitivity and specificity were calculated. A substantial interobserver agreement was found using three‐ or two‐tiered scoring κ = 0.675, 95% confidence interval (CI) = 0.633–0.717; AC1 = 0.723, 95% CI = 0.643–0.804 and κ = 0.771, 95% CI = 0.714–0.828; AC1 = 0.774, 95% CI = 0.684–0.865, respectively. Sensitivity and specificity for the identification of HER2‐positive EC was 100 and 97%, respectively, using a HER2 testing algorithm that recommends DISH in all cases with moderate membranous staining in >10% of the tumour (IHC+). Performing DISH on all IHC‐2+ and ‐3+ cases yields a sensitivity and specificity of 100%.
Conclusions
Our EC‐specific HER2 IHC scoring method is reproducible. A screening strategy based on IHC scoring on all cases with subsequent DISH testing on IHC‐2+/‐3+ cases has perfect test accuracy for identifying HER2‐positive EC.
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