Aus Fehlern Lernen: Potenziale Fùr Die Stiftungsarbeit

Study exploring how German foundations deal with mistakes in practical terms, the culture among German foundations for addressing errors, and the particular challenges foundations face in this area

Prognostic biomarkers in uveal melanoma: the status quo, recent advances and future directions

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.N.J.L. would like to thank all members of the Laboratory of Clinical and Experi-mental Pathology (LPCE), Centre Hospitalier Universitaire de Nice, Nice, France; and all members of the Anatomic Pathology Service, Pathology Department, Centro Hospitalar e Universitario do Porto,Porto, Portugal, especially to JoseRamon Vizcaino (Head of Service), Joana Raposo Alves (Advisor ofPathology Training), Andre Coelho, David Tente and Francisca Emanuel Costa for their continuous support and help in the developmen

ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

<p>Abstract</p> <p>Background</p> <p>ASPM (<it>Abnormal Spindle-like Microcephaly associated</it>) over-expression was recently implicated in the development of malignant gliomas.</p> <p>Results</p> <p>To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. <it>Aspm </it>expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres <it>in vitro </it>and in mouse xenografts <it>in vivo</it>. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models.</p> <p>Conclusion</p> <p>These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme.</p

Current and Future Implications of COVID-19 among Youth Wheelchair Users: 24-Hour Activity Behavior.

Preventative measures taken worldwide to decrease the transmission of COVID-19 have had a tremendous impact on youth. Following social restrictions, youth with and without physical disabilities are engaging in less physical activity, more increased sedentary behavior, and poor sleep habits. Specifically, youth wheelchair users (YWU) are likely disproportionately affected by COVID- 19 and have a higher risk of contraction due to underlying comorbidities. While we cannot control all of the negative long-term implications of COVID-19 for YWU, participation in positive 24-h activity behaviors can decrease chronic disease risk and the likelihood of long-term complications resulting from infection. This commentary is to extend the discourse on the importance of 24-h activity behaviors by focusing on YWU. Specifically, we discuss the importance of chronic disease prevention, provide a brief overview of 24-h activity behaviors, and outline some of the lessons that can be learned from the COVID-19 pandemic.N/

A Multicenter Study Validates the WHO 2022 Classification for Conjunctival Melanocytic Intraepithelial Lesions With Clinical and Prognostic Relevance

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth WHO Classification of Eye Tumors (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility

PD-L1 Expression in 65 Conjunctival Melanomas and Its Association with Clinical Outcome

Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed. PD-L1 expression in IC correlated with a higher pTNM stage and PD-L1 expression in TC with worse disease-specific survival. PD-L1 expression is a potential prognostic biomarker that correlates with poor prognosis in CM patients

Biopathologie des tumeurs épithéliales de la thyroïde (place de la pathologie moléculaire et des signatures microRNAs)

Les carcinomes thyroïdiens les plus fréquents développés à partir des cellules folliculaires sont les carcinomes papillaires (80%) et les carcinomes vésiculaires. Une nouvelle entité appelée tumeurs de potentiel de malignité incertain (TPMI), correspondant à des tumeurs difficiles à classer histologiquement, a été récemment proposée. Après recensement et analyse qualitative des collections d échantillons thyroïde stockés dans le Centre de Ressources Biologiques du CHU de Nice et destinés à la recherche translationnelle, nous avons montré que certains fixateurs non formolés permettaient d obtenir des acides nucléiques de meilleure qualité qu avec le formol, sur des échantillons thyroïdiens fixés. Nous avons ensuite montré que la recherche de différents marqueurs immunohistochimiques et moléculaires n apportaient pas d aide diagnostique ou pronostique dans le cadre des TPMI. Dans le but de mieux connaître la physiopathologie, et de définir une signature de ces tumeurs, nous avons voulu caractériser, à l aide de puces microRNA, le profil microRNA des TPMI. Leur profil s est avéré être différent de celui des adénomes et des carcinomes thyroïdiens, mais nous n avons pas pu individualiser un set de microRNA suffisamment significatif pour distinguer de façon très précise les TPMI des autres tumeurs thyroïdiennes. Notre travail s est poursuivi par une analyse in vitro à partir de lignées cellulaires thyroïdiennes en étudiant les microRNAs modulés lors d utilisation d agents anti-cancéreux (inhibiteurs d histones déacétylase). Nous avons pu mettre en évidence le rôle de certains microRNAs pouvant présenter un potentiel prédictif pour la réponse aux chimiothérapies.NICE-BU Sciences (060882101) / SudocSudocFranceF

The Desire to Better Understand Older Adults with Solid Tumors to Improve Management: Assessment and Guided Interventions—The French PACA EST Cohort Experience

Todays challenge in geriatric oncology is to screen patients who need geriatric follow-up. The main goal of this study was to analyze factors that identify patients, in a large cohort of patients with solid tumors, who need more geriatric interventions and therefore specific follow-up. Between April 2012 and May 2018, 3530 consecutive patients were enrolled in the PACA EST cohort (France). A total of 3140 patients were finally enrolled in the study. A Comprehensive Geriatric Assessment (CGA) was performed at baseline. We analyzed the associations between factors at baseline (geriatric and oncologic factors) and the need to perform more than three geriatric interventions. The mean age of the population was 82 years old with 59% of patients aged older than 80 years old. A total of 8819 geriatric interventions were implemented for the 3140 patients. The percentage of patients with three or more geriatric interventions represented 31.8% (n = 999) of the population. In multivariate analyses, a Mini Nutritional assessment (MNA) &lt;17, an MNA &#8804;23&#183;5 and &#8805;17, a performans status (PS) &gt;2, a dependence on Instrumental Activities of Daily Living (IADL), a Geriatric Depression Scale (GDS) &#8805;5, a Mini Mental State Examination (MMSE) &lt;24, and a Screening tool G8 &#8804;14 were independent risk factors associated with more geriatric interventions. Factors associated with more geriatric interventions could assist practitioners in selecting patients for specific geriatric follow-up