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The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

Energetic metabolism reprogramming is critical for cancer and immune responses. Current methods to functionally profile the global metabolic capacities and dependencies of cells are performed in bulk. We designed a simple method for complex metabolic profiling called SCENITH, for single-cell energetic metabolism by profiling translation inhibition. SCENITH allows for the study of metabolic responses in multiple cell types in parallel by flow cytometry. SCENITH is designed to perform metabolic studies ex vivo, particularly for rare cells in whole blood samples, avoiding metabolic biases introduced by culture media. We analyzed myeloid cells in solid tumors from patients and identified variable metabolic profiles, in ways that are not linked to their lineage or their activation phenotype. SCENITH's ability to reveal global metabolic functions and determine complex and linked immune-phenotypes in rare cell subpopulations will contribute to the information needed for evaluating therapeutic responses or patient stratification.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M-mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH-wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH-wildtype/H3-wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAFV600E mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary.

There exist elements apart from uranium and plutonium that could potentially be used to construct the core of a nuclear explosive device. These belong to the so-called minor actinides (MAs), which exist in nonnegligible amounts in spent nuclear fuel (SNF) and are in nearly all cases not covered by international safeguards. Future reprocessing of SNF could result in significant separation of these elements, potentially leading to new proliferation concerns. In this work, a methodology for a transparent assessment of the barriers against proliferation of MAs has been developed and applied to the case of neptunium, americium, and curium separated from spent fuel from pressurized water reactors. In this methodology, openly available data and Monte Carlo simulations have been used to assess the barriers posed by a number of parameters relevant to the production of a nuclear explosive device from SNF. The evaluation shows that the properties of neptunium present low barriers to proliferation and that it should be discussed within the context of future nonproliferation treaties and possibly be placed under international safeguards. The properties of americium and curium present higher barriers to proliferation, meaning that these elements require less focus in the nonproliferation context. [ABSTRACT FROM AUTHOR]

Long-lived high-level waste from commercial nuclear power reactors is a problem that concerns stakeholders and scientists working in the back end of the nuclear fuel cycle. Nuclear waste transmutation is under investigation to tackle this problem, transforming nuclides that represent a long-term source of radioactivity, radiotoxicity, and heat into short-lived or stable nuclides. However, the transmutation process will require that several long-lived isotopes be separated from the spent nuclear fuel, which raises proliferation concerns. In this paper, we perform an investigation of the attractiveness characteristics related to the material used in a lead-cooled fast reactor system concept designed to burn minor actinides before and after irradiation. The materials evaluated are separated uranium, neptunium, plutonium, americium, and curium. We also evaluated grouped product materials, neptunium + americium and neptunium + plutonium. Additionally, we present potential safeguards and physical protection implications for the proposed materials. The main conclusion of this paper is that the separated neptunium and plutonium generated by the fast reactor are materials that deserve attention mainly related to physical protection measures. [ABSTRACT FROM AUTHOR]

Mise à jour des recommandations de prise en charge des tumeurs germinales du testicule. Revue exhaustive de la littérature effectuée sur PubMed depuis 2022 concernant le diagnostic, le traitement et le suivi des tumeurs germinales du testicule (TGT), et la tolérance des traitements. Le niveau de preuve des références a été évalué. Le bilan initial d'un patient atteint d'une tumeur germinale du testicule repose sur un examen clinique, une évaluation biologique (par le dosage de marqueurs sériques AFP, hCG totale, LDH) et radiologique (échographie scrotale et tomodensitométrie thoracoabdominopelvienne [TAP]). L'orchidectomie par voie inguinale est la première étape thérapeutique : elle permet le diagnostic histologique, définit le stade local, et les facteurs de risque évolutifs pour les tumeurs germinales non séminomateuses (TGNS) de stades I. Pour les patients atteints d'un séminome pur de stade I, le risque évolutif compris entre 15 et 20 % fait privilégier la surveillance chez des patients compliants ; la chimiothérapie adjuvante par carboplatine AUC 7 est une option ; les indications de radiothérapie lomboaortiques sont limitées. Pour les patients atteints d'une TGNS de stade I, différentes options sont envisageables entre une surveillance ou une stratégie adaptée au risque (surveillance ou 1 cycle de bléomycine étoposide cisplatine [BEP] en fonction de la présence ou non d'emboles vasculaires au sein de la tumeur). Le curage ganglionnaire rétropéritonéal de stadification a une place très limitée. Le traitement des TGT métastatiques est une chimiothérapie par BEP en l'absence de contre-indication à la bléomycine dont le nombre de cycles est défini selon les groupes pronostiques de l'International Germ Cell Cancer Consortium Group (IGCCCG). La radiothérapie lombo-aortique est encore un standard dans les tumeurs germinales séminomateuses (TGS) de stade IIA. À l'issue de la chimiothérapie, l'évaluation de la taille des masses résiduelles doit être réalisée par un scanner TAP pour les TGNS : un curage ganglionnaire rétropéritonéal est recommandé pour toute masse résiduelle supérieure à 1 cm, ainsi que l'exérèse de tous les autres sites métastatiques. Pour les TGS, une réévaluation par TEP-18FDG est nécessaire pour préciser l'indication chirurgicale des masses résiduelles > 3 cm. La chirurgie reste rare dans ces situations. Le respect des recommandations de prise en charge des TGT permet d'obtenir un taux de survie spécifique excellent de 99 % pour les stades I et de plus de 85 % pour les stades métastatiques. To update the guidelines for the management of germ cell tumours of the testis. Comprehensive PubMed review from 2022 on the diagnosis, treatment and follow-up of testicular germ cell tumours (TGT), as well as safety of treatments. The level of evidence of the studies was assessed. The initial assessment of a patient with a germ cell tumour of the testis is based on a clinical examination, biological evaluation (by measuring the serum markers AFP, total hCG, and LDH) and radiological evaluation (scrotal ultrasound and thoraco-abdomino-pelvic computed tomography [TAP]). Inguinal orchiectomy is the first therapeutic step, as it allows histological diagnosis and defines the local stage and risk factors for progression in stage I nonseminomatous germ cell tumours (NSGCTs). For patients with pure stage I seminoma, the risk of progression is between 15 % and 20 %, so surveillance is preferred in compliant patients; adjuvant chemotherapy with carboplatin AUC 7 is an option; and the indications for lumbo-aortic radiotherapy are limited. For patients with stage I NSGCT, various options exist, namely, surveillance or a risk-adapted strategy (surveillance or 1 cycle of BEP [bleomycin etoposide cisplatin] depending on the presence or absence of vascular emboli within the tumour). Retroperitoneal lymph node dissection for staging has a very limited role. Treatment of metastatic GCT consists of chemotherapy with BEP in the absence of contraindication to bleomycin, the number of cycles of which is defined according to the prognostic groups of the International Germ Cell Cancer Consortium Group (IGCCCG). Lumbo-aortic radiotherapy is still the standard treatment for stage IIA seminomatous germ cell tumours (SGCTs). At the end of chemotherapy, the size of any residual mass should be assessed via a TAP scan for NSGCTs, with retroperitoneal lymph node dissection recommended for any residual mass greater than 1 cm, along with removal of all other metastatic sites. For SGCT, reassessment via 18FDG PET scans is necessary to determine the surgical indication for residual masses > 3 cm. Surgery remains rare in these situations. Adherence to the recommendations for the management of GCT results in excellent specific survival rates of 99 % for patients with stage I disease and over 85 % for patients with metastatic disease. [ABSTRACT FROM AUTHOR]

L'objectif de cette publication est de rappeler la conduite à tenir initiale face à un incidentalome surrénalien et le cas échéant d'établir la prise en charge carcinologique d'une tumeur maligne de la surrénale. Le groupe de travail multidisciplinaire a actualisé les recommandations sur la prise en charge carcinologique d'un incidentalome surrénalien, établies par le CCAFU en 2022, en s'appuyant sur une revue exhaustive de la littérature effectuée sur PubMed. Si la majorité des masses surrénaliennes sont bénignes et non fonctionnelles, il est important de les investiguer, du fait du potentiel endocrinien grave et de certains cancers. Les tumeurs malignes de la surrénale (TMS) sont essentiellement des carcinomes corticosurrénaliens (CCS), des phéochromocytomes malins (PCM) et des métastases surrénaliennes (MS). Le bilan de malignité d'un incidentalome surrénalien inclut une anamnèse complète, un examen physique, une évaluation biochimique/hormonale pour rechercher une sécrétion hormonale infraclinique. Des hypothèses diagnostiques sont parfois disponibles dès ce stade mais c'est l'imagerie morphologique et fonctionnelle et l'analyse histologique qui permettront de clore le bilan de malignité et de poser le diagnostic carcinologique. Les CCS et les PCM sont surtout sporadiques mais une origine héréditaire est toujours possible. Un CCS est suspecté en préopératoire mais le diagnostic de certitude est histologique. Le diagnostic de PCM est plus délicat et se base sur la clinique, la biologie et l'imagerie. Le diagnostic de certitude de MS passe par une biopsie percutanée. À l'issue, les dossiers doivent obligatoirement être discutés au sein du réseau COMETE — cancers de la surrénale. The objective of this publication is to recall the initial work-up when faced with an adrenal incidentaloma and, if necessary, to establish the oncological management of an adrenal malignant tumor. The multidisciplinary working group updated French urological guidelines about oncological assessment of the adrenal incidentaloma, established by the CCAFU in 2022, based on an exhaustive literature review carried out on PubMed. Although the majority of the adrenal masses are benign and non-functional, it is important to investigate them, as a percentage of these can cause serious endocrine diseases or be cancers. Malignant adrenal tumors are mainly represented by adrenocortical carcinomas (ACC), malignant pheochromocytomas (MPC) and adrenal metastases (AM). The malignancy assessment of an adrenal incident includes a complete history, a physical examination, a biochemical/hormonal assessment to look for subclinical hormonal secretion. Diagnostic hypotheses are sometimes available at this stage, but it is the morphological and functional imaging and the histological analysis, which will make it possible to close the malignancy assessment and make the oncological diagnosis. ACC and MPC are mainly sporadic but a hereditary origin is always possible. ACC is suspected preoperatively but the diagnosis of certainty is histological. The diagnosis of MPC is more delicate and is based on clinic, biology and imagery. The diagnosis of certainty of AM requires a percutaneous biopsy. At the end, the files must be discussed within the COMETE — adrenal cancer network. [ABSTRACT FROM AUTHOR]

Mise à jour des recommandations de prise en charge du pénis. Revue exhaustive de la littérature effectuée sur PubMed depuis 2022 concernant le diagnostic, le traitement et le suivi des tumeurs du pénis. Le niveau de preuve des références a été évalué. Au total 95 % des cancers du pénis infiltrants sont des carcinomes épidermoïdes, dont un tiers en rapport avec une infection à Human Papillomavirus (HPV). L'examen clinique permet d'identifier la taille de la lésion, sa localisation, sa proximité avec le méat urétral, son infiltration en profondeur. L'interrogatoire doit évaluer les fonctions urinaire et sexuelle. L'IRM est l'imagerie de référence pour le bilan local. Les tumeurs du pénis sont classées en faible risque (≤ pT1a et bien différencié G1), de risque intermédiaire (pT1a G2), à haut risque (≥ pT1b, ou G3, ou contingent sarcomatoïde). L'évaluation ganglionnaire du cancer du pénis est fondamentale. La technique du ganglion sentinelle est recommandée pour l'évaluation des patients cN0 ayant une tumeur de risque intermédiaire ou plus. La TEP 18FDG est recommandée chez le patient cN+. La chirurgie est le traitement de référence localement et est fonction de la taille, de la localisation et du grade de la tumeur. Un traitement topique ou par curiethérapie peut être indiqué dans certains cas. Un curage inguinal radical (CIR) est recommandé pour les stades cN1/cN2. Une chimiothérapie néoadjuvante est recommandée pour les stades cN3, associée à un CIR chez les patients répondeurs. Les formes métastatiques peuvent faire l'objet de chimiothérapie palliative, et d'immunothérapie dans le cadre d'un essai clinique. Le traitement du cancer du pénis est essentiellement chirurgical plus ou moins associé à une chimiothérapie en cas d'extension ganglionnaire. Le facteur pronostique principal est l'atteinte ganglionnaire justifiant une prise en charge diagnostique et thérapeutique précoce des aires inguinales. To update recommendations for the management of penile lesion. Comprehensive review from 2022 of the literature performed on PubMed since 2022 concerning the diagnosis, treatment and follow-up of penile tumors. The level of evidence of the references was assessed. A total of 95 % of invasive infiltrating penile cancers are squamous cell carcinomas, a third of which are related to Human Papillomavirus (HPV) infection. Clinical examination can help identify the size of the lesion, its location, its proximity to the urethral meatus, and its deep infiltration. Questioning should assess urinary and sexual function. MRI is the gold standard reference imaging tool for local assessment. Penile tumors are classified as low-risk (≤ pT1a and well-differentiated G1), intermediate-risk (pT1a G2) and), high-risk (≥ pT1b, or G3, or sarcomatoid contingent). Lymph node assessment in penile cancer is fundamental. The sentinel node technique is recommended for the evaluation of cN0 patients with tumors of intermediate risk or higher. 18FDG PET is recommended for cN+ patients. Surgery is the gold standard for local treatment and depends, depending on the tumour size, location and grade of the tumor. Topical treatment or brachytherapy may be indicated in some certain cases. Topical treatment or brachytherapy may be indicated in certain cases. Radical inguinal lymphadenectomy (RIL curettage (RIC) is recommended for stages cN1/cN2. Neoadjuvant stages. Neo-adjuvant chemotherapy is recommended for cN3 stages, combined with RILRIC in responders. Metastatic forms may be treated with palliative chemotherapy, and immunotherapy as part of a clinical trial. Treatment of penile cancer is essentially surgical, with or without chemotherapy in the case of lymph node involvement extension. The main prognostic factor is lymph node involvement, which justifies early diagnostic and therapeutic management of the inguinal areas. [ABSTRACT FROM AUTHOR]