1,721,005 research outputs found
Adult type diffuse gliomas in the new 2021 WHO Classification
Full text linkAdult-type diffuse gliomas represent a group of highly infiltrative central nervous system tumors with a prognosis that significantly varies depending on the specific subtype and histological grade. Traditionally, adult-type diffuse gliomas have been classified based on their morphological features with a great interobserver variability and discrepancy in patient survival even within the same histological grade. Over the last few decades, advances in molecular profiling have drastically changed the diagnostic approach and classification of brain tumors leading to the development of an integrated morphological and molecular classification endowed with a more clinically relevant value. These concepts were largely anticipated in the revised fourth-edition of WHO classification of central nervous system tumors published in 2016. The fifth-edition (WHO 2021) moved molecular diagnostics forward into a full integration of molecular parameters with the histological features into an integrative diagnostic approach. Diagnosis of adult type diffuse gliomas, IDH mutant and IDH-wildtype has been simplified by introducing revised diagnostic and grading criteria. In this review, we will discuss the most recent updates to the classification of adult-type diffuse gliomas and summarize the essential diagnostic keys providing a practical guidance to pathologists
EBF1 is expressed in pericytes and contributes to pericyte cell commitment
No full textEarly B-cell factor-1 (EBF1) is a transcription factor with an important role in cell lineage specification and commitment during the early stage of cell maturation. Originally described during B-cell maturation, EBF1 was subsequently identified as a crucial molecule for proper cell fate commitment of mesenchymal stem cells into adipocytes, osteoblasts and muscle cells. In vessels, EBF1 expression and function have never been documented. Our data indicate that EBF1 is highly expressed in peri-endothelial cells in both tumor vessels and in physiological conditions. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS) analysis suggest that EBF1-expressing peri-endothelial cells represent bona fide pericytes and selectively express well-recognized markers employed in the identification of the pericyte phenotype (SMA, PDGFRβ, CD146, NG2). This observation was also confirmed in vitro in human placenta-derived pericytes and in human brain vascular pericytes (HBVP). Of note, in accord with the key role of EBF1 in the cell lineage commitment of mesenchymal stem cells, EBF1-silenced HBVP cells showed a significant reduction in PDGFRβ and CD146, but not CD90, a marker mostly associated with a prominent mesenchymal phenotype. Moreover, the expression levels of VEGF, angiopoietin-1, NG2 and TGF-β, cytokines produced by pericytes during angiogenesis and linked to their differentiation and activation, were also significantly reduced. Overall, the data suggest a functional role of EBF1 in the cell fate commitment toward the pericyte phenotype
ζ Chain-associated protein of 70 kDa (ZAP70) deficiency in human subjects is associated with abnormalities of thymic stromal cells: Implications for T-cell tolerance
No full textNew pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)
Full text linkBackground: To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). Subjects and Methods: In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples. Results: Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease-causing VUS (class 3–4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants. Conclusions: Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome
A multimodal staged approach for the resection of a Sylvian aqueduct rosette-forming glioneuronal tumor: A case report and literature review
No full textBackground and importance: The rosette-forming glioneuronal tumor (RGNT) is a rare central nervous system tumor which often arises intraventricularly. We report the first surgical case of an RGNT arising from the Sylvian aqueduct treated through a double approach. Clinical presentation: A 25-year-old female presented with triventricular hydrocephalus on MRI secondary to a 2 cm Sylvian aqueduct mass. Emergent endoscopic third ventriculostomy with biopsy confirmed the diagnosis of RGNT. She was first followed up and due to the rapid tumor's growth a double surgical approach was proposed. The first was a telo-velar approach to the lower third of the aqueduct. The second stage was an endoscopic ultrasound aspirator aided transfrontal transforaminal approach; last postoperative MRI shows a 6 mm residual tumor. Patient leads an active working and social life. Conclusion: Choosing a two stages approach for this rare and complex Sylvian aqueduct RGNT resulted in a positive clinical and radiological outcome
Glioblastoma models driven by different mutations converge to the proneural subtype
Full text linkThe need of reliable syngeneic animal models for gliomas has been addressed in the last decades by reproducing genetic alterations typical of human glioblastoma in the mouse. Since different alterations underlie different molecular glioblastoma subtypes it is commonly expected that tumors induced by specific alterations represent models of the corresponding subtypes. We tested this assumption by a multilevel analysis ranging from a detailed histopathological analysis to a genome-wide expression profiling by microarray and RNA-seq on gliomas induced by two distinct molecular alterations: the overstimulation of the PDGF- and the EGF- pathways. These alterations are landmarks of proneural and classical glioblastoma subtypes respectively. However, our results consistently showed a strong similarity between the two glioma models. The expression profiles of both models converged toward a signature typical of oligodendrocyte progenitor cells, regardless the wide differentiative potential of the cell of origin. A classification based on similarity with human gliomas profiles revealed that both models belong to the proneural subtype. Our results highlight that reproducing a molecular alteration specific of a glioblastoma subtype not necessarily generates a tumor model recapitulating such subtype
Leptomeningeal dissemination of anaplastic medullary cone astrocytoma: An unexpected findings in a patient with leptomeningeal enhancement and clinical history of multiple myeloma
Full text linkWe report a challenging autopsy case with an insidious clinical presentation with diffuse lepto- and pachymeningeal enhancement in a context of a complex clinical history. Clinical features, neuroradiological and anamnestic data were consistent with central nervous system (CNS) dissemination of a previously known lambda restricted multiple myeloma. Autoptic findings allowed to discard this hypothesis. Unexpectedly, CNS sampling revealed an atypical glial cell proliferation within the sacral meningeal layers. No primary intraparenchymal CNS glial lesion was found. Findings supported the final diagnosis of anaplastic astrocytoma IDH1-wild type of the medullary cone with diffuse leptomeningeal and cerebrospinal fluid (CSF) dissemination. This occurrence represents an extremely rare condition itself, further complicated by the clinical history of the patient that led to formulate the most probable diagnosis of localization of the primary known disease. This autopsy case underlines that patients previously diagnosed with a primary tumor are not only at risk of recurrences or progression of the original disease, but they must be always accurately checked for eventual onset of a second tumor, including rare conditions such as gliomatosis
Treatment strategy for vertebral metastases from anal squamous cell carcinoma: a comprehensive literature review and case report
No full textPurpose/aim of the study: Purpose/aim of the study:Central nervous system (CNS), skull, and vertebral metastases from anal squamous cell carcinoma (SCC) are an exceedingly rare entity. We report the first case of multiple vertebral metastases from a primary anal SCC with the aim of define a target therapeutic strategy.Case presentation: We present the case of a 68-year-old male admitted to our hospital for acute exacerbation chronic low back pain and left L2 radiculopathy. His medical history included the diagnosis of a human papilloma virus related, moderately differentiated anal SCC (cT3N0M0-stage IIB), treated with standard chemoradiotherapy regimen two years earlier. Spinal magnetic resonance imaging revealed an isolated solid lesion of the L2 vertebral body. After the surgical removal, histopathological examination confirmed the diagnosis of moderately differentiated SCC. At 1-month radiological follow-up, two new lesions at the level of T7 to T11 were identified. Additional chemotherapy and radiotherapy for metastatic localization of L2, T7, and T11 were administered. Two-year follow-up demonstrated a radiologically and clinically well-controlled disease. To supplement our case, a systematic literature review on the CNS, skull, and vertebral metastases and their treatments has been performed.Conclusion: Despite several proposed guidelines for the management of vertebral metastases, at present, a universally accepted treatment strategy for vertebral metastases from anal SCC has not been defined. Based on our clinical experience and literature review, in case of vertebral metastases from anal SCC, a prompt and aggressive, local and systemic, and multimodal treatment of the vertebral lesions may be paramount to improve the patient outcomes
Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
No full textTuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC
- …
