Reproducibility of lymphovascular space invasion (LVSI) assessment in endometrial cancer

Aims Lymphovascular space invasion (LVSI) in endometrial cancer (EC) is an important prognostic variable impacting on a patient's individual recurrence risk and adjuvant treatment recommendations. Recent work has shown that grading the extent of LVSI further improves its prognostic strength in patients with stage I endometrioid EC. Despite this, there is little information on the reproducibility of LVSI assessment in EC. Therefore, we designed a study to evaluate interobserver agreement in discriminating true LVSI from LVSI mimics (Phase I) and reproducibility of grading extent of LVSI (Phase II). Methods and results Scanned haematoxylin and eosin (H&E) slides of endometrioid EC (EEC) with a predefined possible LVSI focus were hosted on a website and assessed by a panel of six European gynaecological pathologists. In Phase I, 48 H&E slides were included for LVSI assessment and in Phase II, 42 H&E slides for LVSI grading. Each observer was instructed to apply the criteria for LVSI used in daily practice. The degree of agreement was measured using the two-way absolute agreement average-measures intraclass correlation coefficient (ICC). Reproducibility of LVSI assessment (ICC = 0.64, P < 0.001) and LVSI grading (ICC = 0.62, P < 0.001) in EEC was substantial among the observers. Conclusions Given the good reproducibility of LVSI, this study further supports the important role of LVSI in decision algorithms for adjuvant treatment

Massive right atrial myxoma presenting as syncope and exertional dyspnea: case report

Primary heart neoplasms are rare occurring with an estimated incidence of 0.0017-0.19%. Myxoma is the most prevalent primary heart tumor. The right atrium is an unusual localization, occurring only in 15-20% of myxoma cases. We report a rare case of a massive right atrial myxoma causing tricuspid valve obstruction and presenting as syncope and exertional dyspnea. This case illustrates the influence of myxoma's size, position and mobility as well as patient's body posture and respiration to the development of signs and symptoms. Three-dimensional echocardiography proved useful in surgery planning, allowing a better definition of the tumor outline and attachment

Influence of EPICardial adipose tissue in HEART diseases (EPICHEART) study: Protocol for a translational study in coronary atherosclerosis

Accumulation of epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD) and increased risk of coronary events in asymptomatic subjects and low-risk patients, suggesting that EAT promotes atherosclerosis in its early stage. Recent studies have shown that the presence of CAD affects the properties of adjacent EAT, leading to dynamic changes in the molecular players involved in the interplay between EAT and the coronary arteries over the history of the disease. The role of EAT in late-stage CAD has not been investigated.coronárioResumoIntroduc¸ão:Acumulac¸ão de tecido adiposo epicárdico (TAE) tem sido associado a doenc¸acoronária aterosclerótica (DC) e aumento do risco de eventos coronários em indivíduos ass-intomáticos e doentes de baixo risco, sugerindo que o TAE pode promover fases precoces daDC. Estudo recentes mostraram que a presenc¸a de DC afeta as características do TAE adja-cente levando a modificac¸ões dinâmicas nos mediadores envolvidos na comunicac¸ão entre oTAE e as artérias coronárias ao longo da história da DC. O papel doTAE nas fases avanc¸adas daaterosclerose coronária não foi investigado.Objetivos: Através de análise comparativa com o tecido adiposo mediastínico e subcutâneo,pretendemos investigar se o volume do TAE, avaliado por tomografia computadorizada (TC), eo seu proteoma, avaliado por espectrometria de massa técnica de SWATH, estão associados aestadios avanc¸ados da DC numa coorte de estenose aórtica grave.Métodos: O estudo EPICHEART (NCT03280433) é um estudo prospetivo que inclui doentescom estenose aórtica grave referenciados para substituic¸ão eletiva da válvula aórtica, cujoprotocolo envolve avaliac¸ão pré-operatória clínica, nutricional, ecocardiográfica, por TC eangiografia coronária invasiva. Durante a cirurgia cardíaca, colhemos amostras de tecido adi-poso epicárdico, mediastínico e subcutâneo para análise do seu proteoma por espectrometriade massa técnica de SWATH. Adicionalmente, colhemos líquido pericárdico, sangue venoso per-iférico e do seio coronário para investigar mediadores de DC derivados do TAE na circulac¸ãosistémica e local.Conclusão: Desenhámos um estudo de translac¸ão para explorar a associac¸ão da quantidade equalidade do TAE com a DC tardia. Esperamos identificar mediadores da comunicac¸ão recíprocaentre o TAE e as artérias coronárias que estão envolvidos na patogénese das fases avanc¸adas daDC, especialmente, calcificac¸ão coronária, os quais podem servir como novos alvos terapêuticose soluc¸ões de engenharia biomédica para visualizac¸ão da DC

Expert pathology for GTD : towards an international multidisciplinary team meeting (MDT)

Background: Gestational trophoblastic disease, comprising hydatidiform moles and gestational trophoblastic tumours, is extremely rare. Exact diagnosis is crucial to indicate the appropriate treatment and to prevent complications. The scarcity and variability in the number of cases available for reporting, lack of specialized training in GTD and non-existence of refresher courses available implies that the pathologist dealing with these rare and at times extremely challenging cases are not completely confident in their diagnosis. Objectives: To explores the benefits of implementation of an international multidisciplinary conference (virtual) to aid diagnosis of difficult cases and support clinical management of GTD. Methods: A short survey was circulated to all 46 members of the EOTTD pathology and genetics working party, and further spread to other colleagues who practice GTD. This showed that the pathologists and geneticists working with GTD patients do not feel adequately supported and equipped with dealing with these rare diseases. Outcome: Virtual cross-border MDTs were initiated in April 2022, bringing together participants from 11 European countries on a bi-yearly basis. Mean numbers of 3 patients are discussed during the MDTs followed by 3-4 QA cases. A participant survey was conducted at the end of virtual meeting with an average satisfaction rate of 9.5. The pathologists felt supported and benefited from networking and clinical collaboration. Conclusions and outlook: This international multidisciplinary team meeting (MDT) continues to provide support in managing the uncertainty with difficult and rare cases and enhances the pathologists training and experience. The frequency of meetings and the number of cases discussed per meeting will be increased in 2023 given the positive response. This will empower individuals and organisations to work together and improve diagnosis and the prognosis for these young patients.</p

Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants

Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets

Endometrial Endometrioid Carcinoma Metastases Show Decreased ER-Alpha and PR-A Expression Compared to Matched Primary Tumors.

Patients with endometrial endometrioid carcinoma (EEC) that present with advanced primary disease and develop recurrences have a poor outcome. The phenotype of EEC metastases and recurrences is poorly studied. We evaluated the morphological features and ER-alpha/PRA/p53 immunohistochemical expression of a sample of 45 EEC metastases compared to matched primary tumors. Additionally, we studied methylation levels of ER-alpha/PRA gene promoters. The distribution of histological FIGO grade was significantly different in metastases, which disclosed higher grade than primary tumors (p = 0.005). Mitotic index was significantly lower in metastases compared to matched primary tumors (p<0.001). ER-alpha (p = 0.002) and PRA (p<0.001) median H-scores were significantly lower in metastases than in matched primary EECs, but there was no significant difference concerning p53 expression (p = 0.056). ER-alpha/PRA expression differences did not correlate with differences in metastases morphology. ER-alpha/PRA gene promoter levels were globally low (range: 0% to 11.9%). One case showed higher ER-alpha gene promoter methylation in metastasis compared to matched EEC primary tumor. Regarding PRA, there was a significant higher frequency of its promotor methylation in metastases compared to primary tumors (51.6% vs. 22.7%, p = 0.022). In conclusion, EEC metastatic disease displays phenotypic changes along with ER-alpha and PRA decreased expression compared to primary tumors. ER-alpha and PRA gene promoter methylation seems to play a limited role in the etiology of these alterations. PR expression assessment for hormonal treatment decision of patients with advanced tumors, may be more adequate in metastases than in EEC primary tumors