Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome

: The WHO 2021 classification of central nervous system cancers distinguishes diffuse gliomas that arise in adults (referred to as the "adult type") and those that arise in children (defined as "paediatric") based on clinical and molecular characteristics."). However, paediatric-type gliomas may occasionally be present in younger adults and occasionally adult-type gliomas may occur in children. Diffuse low-grade paediatric glioma includes diffuse astrocytoma altered by MYB or MYBL1, low-grade polymorphic juvenile neuroepithelial tumour, angiocentric glioma, and diffuse low-grade glioma with an altered MAPK pathway. Here, we examine these newly recognised entities according to WHO diagnostic criteria and propose an integrated diagnostic approach that can be used to separate these clinically and biologically distinct tumor groups

Diagnostic and Therapeutic Strategy in Anaplastic (Malignant) Meningioma, CNS WHO Grade 3

Simple Summary Only 1% of all meningioma diagnosis is classified as malignant (anaplastic) meningioma. Due to their rarity, clinical management of these tumors presents several gaps. In this review, we investigate current knowledge of anaplastic meningioma focusing on their pathological and radiological diagnosis, molecular assessment, and loco-regional and systemic management. Despite the current marginal role of systemic therapy, it is possible that the increasing knowledge of molecular altered pathways of the disease will lead to the development of novel effective systemic treatments. Background: Meningiomas are the most common primary central nervous system malignancies accounting for 36% of all intracranial tumors. However, only 1% of meningioma is classified as malignant (anaplastic) meningioma. Due to their rarity, clinical management of these tumors presents several gaps. Methods: We carried out a narrative review aimed to investigate current knowledge of anaplastic meningioma focusing on their pathological and radiological diagnosis, molecular assessment, and loco-regional and systemic management. Results: The most frequent genetic alteration occurring in meningioma is the inactivation in the neurofibromatosis 2 genes (merlin). The accumulation of copy number losses, including 1p, 6p/q, 10q, 14q, and 18p/q, and less frequently 2p/q, 3p, 4p/q, 7p, 8p/q, and 9p, compatible with instability, is restricted to NF2 mutated meningioma. Surgery and different RT approaches represent the milestone of grade 3 meningioma management, while there is a marginal role of systemic therapy. Conclusions: Anaplastic meningiomas are rare tumors, and diagnosis should be suspected and confirmed by trained radiologists and pathologists. Despite the current marginal role of systemic therapy, it is possible that the increasing knowledge of molecular altered pathways of the disease will lead to the development of novel effective systemic treatments

Significance of the Presence of Microscopic Vascular Invasion After Complete Resection of Stage I–II pT1-T2N0 Non-small Cell Lung Cancer and Its Relation with T-Size Categories: Did the 2009 7th Edition of the TNM Staging System Miss Something?

Introduction:The aim of this study was to assess the significance of microscopic vascular invasion (MVI) in a population of resected patients with early-stage non-small cell lung cancer (NSCLC), along with an analysis of the effect of the combination of MVI and tumor size for the T-size categories T1a-T2b according to the 2009 7th edition of the tumor, node, metastasis (TNM) classification.Methods:From January 1993 to August 2008, 746 patients with pT1-T2N0 NSCLC received resection at our institution. MVI was ascertained using histopathological and immunohistochemical techniques.Results:MVI was observed in 257 patients (34%). Prevalence was higher in adenocarcinoma (ADK) than in squamous cell carcinoma (p = 0.002). A significant correlation was found between MVI and ADK (p = 0.03), increased tumor dimension (p = 0.05), and the presence of tumor-infiltrating lymphocytes (p = 0.02). The presence of MVI was associated with a reduced 5-year survival overall (p = 0.003) and in ADK (p = 0.0002). In a multivariate survival analysis, MVI was an indicator of poor survival overall (p = 0.003) and in ADK (p = 0.0005). In each T category (T1a-T2b) of the 2009 TNM staging system, survival of MVI+ patients was significantly lower than the corresponding MVI− patients; T1a and T1b MVI+ patients had a survival similar to MVI− T2 patients.Conclusions:The finding of MVI in pT1-T2N0 NSCLC is frequent. MVI correlates with adenocarcinoma histotype, increased tumor dimensions, and tumor-infiltrating lymphocytes. The presence of MVI is an independent negative prognostic factor. In our experience, MVI was a stronger prognostic indicator than T size in T1a-T2b categories according to the 2009 TNM staging system

Adult Medulloblastoma: Updates on Current Management and Future Perspectives

Simple Summary Adult medulloblastoma is an extremely rare tumor of the central nervous system. Standard multimodal treatment, comprising maximal safe surgical resection followed by craniospinal radiotherapy and multi-agent chemotherapy, can improve the prognosis of this disease, producing, however, important acute and long-term toxicities. Herein, we review the state of the art for adult medulloblastoma diagnosis and treatment, presenting novel molecular advances and their therapeutic implications and discussing the central role of hub centers to guarantee the highest quality of care and a better overall outcome for this rare tumor. Medulloblastoma (MB) is a malignant embryonal tumor of the posterior fossa belonging to the family of primitive neuro-ectodermic tumors (PNET). MB generally occurs in pediatric age, but in 14-30% of cases, it affects the adults, mostly below the age of 40, with an incidence of 0.6 per million per year, representing about 0.4-1% of tumors of the nervous system in adults. Unlike pediatric MB, robust prospective trials are scarce for the post-puberal population, due to the low incidence of MB in adolescent and young adults. Thus, current MB treatments for older patients are largely extrapolated from the pediatric experience, but the transferability and applicability of these paradigms to adults remain an open question. Adult MB is distinct from MB in children from a molecular and clinical perspective. Here, we review the management of adult MB, reporting the recent published literature focusing on the effectiveness of upfront chemotherapy, the development of targeted therapies, and the potential role of a reduced dose of radiotherapy in treating this disease

Intron 4-5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4-5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR\u2009=\u20092.500, p\u2009=\u20090.015) and p63 (HR\u2009=\u20092.659, p\u2009=\u20090.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (-) cases (21 vs 14, p\u2009=\u20090.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p\u2009=\u20090.026), no angioinvasion (40.7% vs 71.0%, p\u2009=\u20090.015), lower Ki67 (50 vs 70%, p\u2009=\u20090.005), and PD-L1 expressions in both tumor (0 vs 3%, p\u2009=\u20090.021) and immune cells (0 vs 10%, p\u2009=\u20090.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients

DNA methylation analysis by bisulfite next-generation sequencing for early detection of oral squamous cell carcinoma and high-grade squamous intraepithelial lesion from oral brushing

open9siOral squamous cell carcinoma (OSCC) is commonly preceded by oral potentially malignant lesions (OPML). The aim of the present study was to assess, by bisulfite next-generation sequencing (NGS), the methylation status of a list of candidate genes obtained from oral brushings to early detect OPML and OSCC.This study was supported by an academic grant (FARB FFBO124539) from the University of Bologna.openMorandi, Luca; Gissi, Davide; Tarsitano, Achille; Asioli, Sofia; Monti, Valentina; Del Corso, Giacomo; Marchetti, Claudio; Montebugnoli, Lucio; Foschini, Maria PiaMorandi, Luca; Gissi, Davide; Tarsitano, Achille; Asioli, Sofia; Monti, Valentina; Del Corso, Giacomo; Marchetti, Claudio; Montebugnoli, Lucio; Foschini, Maria Pi

Epigenomic and somatic mutations of pituitary tumors with clinical and pathological correlations in 111 patients

Objective To profile clinically non-aggressive and aggressive pituitary adenomas (PAs)/pituitary neuroendocrine tumours (PitNETs) and pituitary carcinomas for somatic mutations and epigenetic alterations of genes involved in cell proliferation/differentiation, microRNAs (miRNA)/long noncoding RNA (LncRNA)-post-transcriptional regulators and therapy targets. Design Retrospective observational study. Patients and Measurements A total of 64 non-aggressive and 41 aggressive PAs/PitNETs and 6 pituitary carcinomas treated by endoscopic surgery with >= 1-year follow-up were included. Somatic mutations of 17 genes and DNA methylation of 22 genes were assessed. Ten normal pituitaries were used as control. Results We found at least one mutation in 17 tumours, including 6/64 non-aggressive, 10/41 aggressive PAs/PitNETs, and 1/6 pituitary carcinoma. AIP (N = 6) was the most frequently mutated gene, followed by NOTCH (4), and TP53 (3). Hypermethylation of PARP15, LINC00599, ZAP70 was more common in aggressive than non-aggressive PAs/PITNETs (p < .05). Lower levels of methylation of AIP, GNAS and PDCD1 were detected in aggressive PAs/PITNETs than non-aggressive ones (p < .05). For X-linked genes, males presented higher level of methylation of FLNA, UXT and MAGE family (MAGEA11, MAGEA1, MAGEC2) genes in aggressive vs. non-aggressive PAs/PITNETs (p < .05). In pituitary carcinomas, methylation of autosomal genes PARP15, LINC00599, MIR193 and ZAP70 was higher than in PAs/PITNETs, while X-linked genes methylation level was lower. Conclusions Somatic mutations and methylation levels of genes involved in cell proliferation/differentiation, miRNA/LncRNA-post-transcriptional regulators and targets of antineoplastic therapies are different in non-aggressive and in aggressive PAs/PitNETs. Methylation profile also varies according to gender. Combined genetic-epigenetic analysis, in association with clinico-radiological-pathological data, may be of help in predicting PA/PitNET behaviour

Endoscopic endonasal approach for loco-regional recurrent clivus chordomas

Introduction. Role of surgery for loco-regional recurrences of clivus chordomas (CCs) is still debated. It has been proposed in selected cases with a curative or with palliative intent, eventually followed by radiation or chemo/radiation treatments. Only limited data on the endoscopic endonasal approach (EEA) are available. Research question. To assess the role of EEA for loco-regional recurrent CCs. Materials and Methods. All consecutive loco-regional recurrent CCs operated by EEA at our Institution from 1998 to 2021 were identified. The extension of tumor resection, symptoms control, overall survival (OS), and progression free survival (PFS) were assessed. Results. Series includes 54 patients (53.7% females, mean age 55± 14 years). Surgery was planned with a resective aim in 35 (64.8%) patients, while it was palliative in 19 (35.2%). Gross tumor removal was achieved in 24 cases (44.4%). Main complications consisted of 2 (3.7%) CSF leaks. Further local relapses were observed in 30 (55.5%) patients after 25± 24 months; 29 (53.7%) patients deceased after 34 ± 31 months. OS and PFS were lower in these cases than primary surgeries (p<0.001 and p<0.001), but cases undergone surgery with a resective aim had a significant better OS and PFS than for those treated for palliation (p<0.001). Determinants of recurrences were tumoral size (p=0.48) and previous radiotherapy (p=009). Discussion and Conclusions. EEA has proven to be effective for loco-regional recurrent CCs alleviating patients symptoms and preserving their quality of life with limited morbidities. However, because overall prognosis is poor, EEA should be reserved to selected recurrent cases