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The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for pituitary neuroendocrine tumors (PitNETs) to improve the quality of their histological diagnosis. Each center performed at least 30 histological cases of PitNETs using the EPPG tools and assessed their value using a scorecard with 10 questions. For each center, the histological cases were carried out by pathologists with varying levels of expertise in pituitary pathology defined as junior, intermediate, and expert. Two hundred and ninety histological cases were collected from six French and Italian centers. The three EPPG tools were validated and regarded as helpful for a more accurate and time-efficient diagnosis. The usefulness of level 2 and level 3 of the "EPPG's multi-step approach for immunohistochemistry" including pituitary transcription factors (PIT1, TPIT, and SF1) and chromogranin, SSTRs, and P53 respectively was higher in "other non-functioning" (silent plurihormonal PIT1, silent corticotroph, and null cell): 88% vs 32%, p < 10–6 and 42% vs 14%, p = 0.002, respectively. The diagnostic algorithm proved more useful for junior pathologists (p = 0.0001) and those with intermediate experience. PIT-EASY survey confirmed the importance of a standardized approach to PitNETs for an accurate and reproducible diagnosis and served as validation of the EPPG proposal. The tool appeared to be of practical value to junior participants and staff with intermediate experience for safe routine diagnostic reporting. [ABSTRACT FROM AUTHOR]

Simple Summary: Alterations in the SMARCB1/INI1 expression pattern have been detected in many tumors, including chordomas. We studied a large group of patients with conventional spinal chordomas, and the aims were to assess the differences in the immunohistochemical expression of SMARCB1/INI1 and the underlying alterations in the SMARCB1 gene and to investigate the correlation between clinicopathological features and patient survival. Partial SMARCB1/INI1 loss was identified in several patients, and this pattern correlated with mobile spine location and inadequate surgical margins. Moreover, mobile spine tumor location and inadequate surgical margins negatively impacted disease-free survival. The complete loss of SMARCB1/INI1 is currently ongoing as a target for molecular therapy; therefore, the partial loss of SMARCB1/INI1 in tumors could also have therapeutic implications. The partial loss of SMARCB1/INI1 expression has recently been reported in skull base conventional chordomas, with possible therapeutic implications. We retrospectively analyzed 89 patients with conventional spinal chordomas to investigate the differences in the immunohistochemical expression of SMARCB1/INI1 and the underlying genetic alterations in the SMARCB1 gene. Moreover, we assessed the correlation of clinicopathological features (age, gender, tumor size, tumor location, surgical margins, Ki67 labelling index, SMARCB1/INI1 pattern, previous surgery, previous treatment, type of surgery, and the Charlson Comorbidity Index) with patient survival. Our cohort included 51 males and 38 females, with a median age at diagnosis of 61 years. The median tumor size at presentation was 5.9 cm. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) rates were 90.8% and 54.9%, respectively. Partial SMARCB1/INI1 loss was identified in 37 (41.6%) patients with conventional spinal chordomas (27 mosaic and 10 clonal). The most frequent genetic alteration detected was the monoallelic deletion of a portion of the long arm of chromosome 22, which includes the SMARCB1 gene. Partial loss of SMARCB1/INI1 was correlated with cervical–thoracic–lumbar tumor location (p = 0.033) and inadequate surgical margins (p = 0.007), possibly due to the high degree of tumor invasiveness in this site. Among all the considered clinicopathological features related to patient survival, only tumor location in the sacrococcygeal region and adequate surgical margins positively impacted DFS. In conclusion, partial SMARCB1/INI1 loss, mostly due to 22q deletion, was detected in a significant number of patients with conventional spinal chordomas and was correlated with mobile spine location and inadequate surgical margins. [ABSTRACT FROM AUTHOR]

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, established new approaches to both CNS tumor nomenclature and grading, emphasizing the importance of integrated diagnoses and layered reports. This edition increased the role of molecular diagnostics in CNS tumor classification while still relying on other established approaches such as histology and immunohistochemistry. Moreover, it introduced new tumor types and subtypes based on novel diagnostic technologies such as DNA methylome profiling. Over the past decade, molecular techniques identified numerous key genetic alterations in CSN tumors, with important implications regarding the understanding of pathogenesis but also for prognosis and the development and application of effective molecularly targeted therapies. This review summarizes the major changes in the 2021 fifth edition classification of pediatric CNS tumors, highlighting for each entity the molecular alterations and other information that are relevant for diagnostic, prognostic, or therapeutic purposes and that patients' and oncologists' need from a pathology report. [ABSTRACT FROM AUTHOR]

Background/Objectives: Clivus metastases from distant neoplasms are uncommon occurrences both in clinical practice and the neurosurgical literature. Surgical management is debated, particularly about the role of surgery and the preferable approach. The aim of this study was to report our surgical experience and review the concerning literature. Methods: Our institutional registry was retrospectively reviewed, and patients who underwent surgical treatment for clival metastasis from 1998 to 2023 were included. A PRISMA systematic review of the literature was performed. Results: Four patients were enrolled, and all of them underwent an endoscopic endonasal approach (EEA). Three presented with cranial nerve (CN) VI palsy. The aim of surgery was biopsy in all cases. No complications were reported. Mean overall survival (OS) was 6 ± 1 months. The systematic review retrieved 27 papers reporting 39 patients who underwent the surgical treatment of clivus metastases. Most of them (79.5%) presented with CN palsies, and EEA was the preferred approach in 92.3% of the cases, to perform a biopsy in most patients (59%). Two hemorrhagic complications (5.1%) were reported, and the mean OS was 9.4 ± 5.6 months. Conclusions: Clival metastases are uncommonly observed, in most cases, during advanced stages of oncological disease. The aim of surgery should be the confirmation of diagnosis and symptomatic relief, balancing the risk–benefit ratio in a multidisciplinary context. EEA is the approach of choice, and it should be carried out in experienced tertiary skull base centers. [ABSTRACT FROM AUTHOR]

This article discusses the case of a 57-year-old male with a history of B-cell chronic lymphocytic leukemia who developed multiple intra-axial lesions in the brain. The patient experienced symptoms such as headache, fever, seizures, and coma. Imaging scans revealed edematous lesions with contrast enhancement. A biopsy confirmed the diagnosis of peripheral T-cell lymphoma, Not Otherwise Specified (NOS) consistent with Primary CNS T-cell lymphoma. The article highlights the importance of distinguishing this type of lymphoma from other intra-axial tumors and discusses the prognosis and potential treatment options. [Extracted from the article]

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, established new approaches to both CNS tumor nomenclature and grading, emphasizing the importance of integrated diagnoses and layered reports. This edition increased the role of molecular diagnostics in CNS tumor classification while still relying on other established approaches such as histology and immunohistochemistry. Moreover, it introduced new tumor types and subtypes based on novel diagnostic technologies such as DNA methylome profiling. Over the past decade, molecular techniques identified numerous key genetic alterations in CSN tumors, with important implications regarding the understanding of pathogenesis but also for prognosis and the development and application of effective molecularly targeted therapies. This review summarizes the major changes in the 2021 fifth edition classification of pediatric CNS tumors, highlighting for each entity the molecular alterations and other information that are relevant for diagnostic, prognostic, or therapeutic purposes and that patients' and oncologists' need from a pathology report. [ABSTRACT FROM AUTHOR]

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4Cseq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of firstgeneration somatostatin analogs. [ABSTRACT FROM AUTHOR]

Purpose: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. Methods: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. Results: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1–68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05–0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03–0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1–0.65, p = 0.004). Conclusion: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed. [ABSTRACT FROM AUTHOR]

Glioblastoma IDH-wildtype represents the most lethal and frequent primary tumor of the central nervous system. Thanks to important scientific efforts, we can now investigate its deep genomic assessment, elucidating mutated genes and altered biological mechanisms in addition to its clinical aggressiveness. The telomerase reverse transcriptase gene (TERT) is the most frequently altered gene in solid tumors, including brain tumors and GBM IDH-wildtype. In particular, it can be observed in approximately 80–90% of GBM IDH-wildtype cases. Its clonal distribution on almost all cancer cells makes this gene an optimal target. However, the research of effective TERT inhibitors is complicated by several biological and clinical obstacles which can be only partially surmounted. Very recently, novel immunological approaches leading to TERT inhibition have been investigated, offering the potential to develop an effective target for this altered protein. Here, we perform a narrative review investigating the biological role of TERT alterations on glioblastoma and the principal obstacles associated with TERT inhibitions in this population. Moreover, we discuss possible combination treatment strategies to overcome these limitations. [ABSTRACT FROM AUTHOR]

Background: Brain stroke is a rare, life-threatening condition associated with pituitary apoplexy (PA), resulting from direct arterial occlusion due to mechanical compression secondary to the sudden enlargement of the pituitary adenoma, or to vessel vasospasm, induced by tumor hemorrhage. Case report: We report the case of a 64-year-old woman with PA complicated by bilateral anterior circulation stroke due to critical stenosis of both anterior cerebral arteries (ACA). Despite the quick surgical decompression and consequent blood flow restoration, the neurological conditions of the patient did not improve and she died 18 days later. Ten other cases of anterior circulation stroke due to PA were retrieved in a systematic review of literature. Clinical and neuroradiological features of these patients and treatment outcome were assessed to suggest the most proper management. Conclusion: The onset of neurological symptoms suggestive for brain stroke in patients with PA requires performing an emergency Magnetic Resonance Imaging (MRI), including Diffusion-weighted and angiographic MR-sequences. The role of surgery in these cases is debated, however, transsphenoidal adenomectomy would permit us to decompress the ACA and restore blood flow in their territories. Although the prognosis of PA-induced anterior circulation stroke is generally poor, a timely diagnosis and treatment would be paramount for improving patient outcome. [ABSTRACT FROM AUTHOR]

Introduction: The loss of SMARCB1/INI1 protein has been recently described in poorly differentiated chordoma, an aggressive and rare disease variant typically arising from the skull base. Methods: Retrospective study aimed at 1) examining the differential immunohistochemical expression of SMARCB1/INI1 in conventional skull base chordomas, including the chondroid subtype; 2) evaluating SMARCB1 gene deletions/copy number gain; and 3) analyzing the association of SMARCB1/INI1 expression with clinicopathological parameters and patient survival. Results: 65 patients (35 men and 30 women) affected by conventional skull base chordoma, 15 with chondroid subtype, followed for >48 months after surgery were collected. Median age at surgery was 50 years old (range 9-79). Mean tumor size was 3.6 cm (range 2-9.5). At immunohistochemical evaluation, a partial loss of SMARCB1/INI1 (>10% of neoplastic examined cells) was observed in 21 (32.3%) cases; the remaining 43 showed a strong nuclear expression. Fluorescence in situ hybridization (FISH) analysis was performed in 15/21 (71.4%) cases of the chordomas with partial SMARCB1/INI1 loss of expression. Heterozygous deletion of SMARCB1 was identified in 9/15 (60%) cases and was associated to copy number gain in one case; no deletion was found in the other 6 (40%) cases, 3 of which presenting with a copy number gain. No correlations were found between partial loss of SMARCB1/INI1 and the clinicopathological parameters evaluated (i.e., age, tumor size, gender, tumor size and histotype). Overall 5-year survival and 5-year disease-free rates were 82% and 59%, respectively. According to log-rank test analysis the various clinicopathological parameters and SMARCB1/INI1 expression did not impact on overall and disease free-survival. Discussion: Partial loss of SMARCB1/INI1, secondary to heterozygous deletion and/or copy number gain of SMARCB1, is not peculiar of aggressive forms, but can be identified by immunohistochemistry in a significant portion of conventional skull base chordomas, including the chondroid subtype. The variable protein expression does not appear to correlate with clinicopathological parameters, nor survival outcomes, but still, it could have therapeutic implications. [ABSTRACT FROM AUTHOR]

The role of the endoscopic transplanum–transtuberculum approach (ETTA) in the treatment of pituitary adenomas/PitNETs (PAs) is sparsely analyzed in the literature, and its use is still debated in the current practice. The aim of this study was to report our experience with this approach. Our institutional registry was retrospectively reviewed, and patients who underwent ETTA for a PA from 1998 to 2022 were included. Fifty-seven cases were enrolled over a time span of 25 years, corresponding to 2.4% of our entire PA caseload. Radical resection was achieved in 57.9% of cases, with re-do surgery (p = 0.033) and vessel encasement/engulfment (p < 0.001) as predictors of partial resection. CSF leak incidence stood at 8.8%, with higher BMI (p = 0.038) as its only significant predictor. Partial or full improvement of the visual field deficits was achieved in 73.5% of cases. No surgical mortality was observed. According to our results, ETTA for the treatment of PAs is characterized by a satisfactory surgical outcome but with greater morbidity than the conventional endoscopic approach. Therefore, it should be reserved for the few selected cases otherwise unsuitable for the endoscopic trans-sphenoidal route, representing a valid alternative and an effective complementary route for the transcranial approach for these challenging PAs. [ABSTRACT FROM AUTHOR]

Phospholipases are essential intermediaries that work as hydrolyzing enzymes of phospholipids (PLs), which represent the most abundant species contributing to the biological membranes of nervous cells of the healthy human brain. They generate different lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid, representing key elements of intra- and inter-cellular signaling and being involved in the regulation of several cellular mechanisms that can promote tumor progression and aggressiveness. In this review, it is summarized the current knowledge about the role of phospholipases in brain tumor progression, focusing on low- and high-grade gliomas, representing promising prognostic or therapeutic targets in cancer therapies due to their influential roles in cell proliferation, migration, growth, and survival. A deeper understanding of the phospholipases-related signaling pathways could be necessary to pave the way for new targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Artificial Intelligence (AI) involves several and different techniques able to elaborate a large amount of data responding to a specific planned outcome. There are several possible applications of this technology in neuro-oncology. Methods: We reviewed, according to PRISMA guidelines, available studies adopting AI in different fields of neuro-oncology including neuro-radiology, pathology, surgery, radiation therapy, and systemic treatments. Results: Neuro-radiology presented the major number of studies assessing AI. However, this technology is being successfully tested also in other operative settings including surgery and radiation therapy. In this context, AI shows to significantly reduce resources and costs maintaining an elevated qualitative standard. Pathological diagnosis and development of novel systemic treatments are other two fields in which AI showed promising preliminary data. Conclusion: It is likely that AI will be quickly included in some aspects of daily clinical practice. Possible applications of these techniques are impressive and cover all aspects of neuro-oncology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The current study, conceived with the contribution of the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) and the Epilepsy Study Group of the Italian Neurological Society (SIN), aimed to assess potential physician-related barriers to refer subjects for epilepsy surgery. All the members of SIN and LICE were invited by email to complete a 28-item online questionnaire. The survey items included: (1) individual and medical practice characteristics, (2) knowledge of current indications to select candidates for epilepsy surgery, (3) factors potentially affecting the attitude toward epilepsy surgery. Overall, 210 physicians completed the survey. More than half (63.3%) of the participants showed proper knowledge of the ILAE drug-resistance. Definition and almost two-thirds of them (71.9%) considered themselves adequately informed about indications, risks, and benefits of epilepsy surgery. Surgery was regarded as a valid option to be used as early as possible by 84.8% of the interviewees, and 71% of them estimated its complication rate to be low. However, more than half (63%) of the respondents reportedly referred patients for surgery only after the failure of 3–5 antiseizure medications. Overestimation of risks/complications of surgery and inadequate healthcare resources were identified as the main factor contrasting the patient referral for surgery by 43% and 40.5% of the participants, respectively. In conclusion, this survey confirms the existence of knowledge gap within both physicians and the healthcare system, as well as an educational need regarding epilepsy surgery. Further researches are warranted to define learning outcomes and optimize educational tools. [ABSTRACT FROM AUTHOR]

Background: Pathological brain processes may induce adaptive cortical reorganization, however, the mechanisms underlying neuroplasticity that occurs in the presence of lesions in eloquent areas are not fully explained. The aim of this study was to evaluate functional compensatory cortical activations in patients with frontal brain gliomas during a phonemic fluency task and to explore correlations with cognitive performance, white matter tracts microstructural alterations, and tumor histopathological and molecular characterization. Methods: Fifteen patients with frontal glioma were preoperatively investigated with an MRI study on a 3T scanner and a subgroup underwent an extensive neuropsychological assessment. The hemispheric laterality index (LI) was calculated through phonemic fluency task functional MRI (fMRI) activations in the frontal, parietal, and temporal lobe parcellations. Diffusion-weighted images were acquired for all patients and for a group of 24 matched healthy volunteers. Arcuate Fasciculus (AF) and Frontal Aslant Tract (FAT) tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. All patients were operated on with a resective aim and underwent adjuvant therapies, depending on the final diagnosis. Results: All patients during the phonemic fluency task fMRI showed left hemispheric dominance in temporal and parietal regions. Regarding frontal regions (i.e., frontal operculum) we found right hemispheric dominance that increases when considering only those patients with tumors located on the left side. These latter activations positively correlate with verbal and visuo-spatial short-term memory, and executive functions. No correlations were found between the left frontal operculum and cognitive performance. Furthermore, patients with IDH-1 mutation and without TERT mutation, showed higher rightward frontal operculum fMRI activations and better cognitive performance in tests measuring general cognitive abilities, semantic fluency, verbal short-term memory, and executive functions. As for white matter tracts, we found left and right AF and FAT microstructural alterations in patients with, respectively, left-sided and right-side glioma compared to controls. Conclusions: Compensatory cortical activation of the corresponding region in the non-dominant hemisphere and its association with better cognitive performance and more favorable histopathological and molecular tumor characteristics shed light on the neuroplasticity mechanisms that occur in the presence of a tumor, helping to predict the rate of post-operative deficit, with the final goal of improving patients'quality of life. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the diagnostic accuracy of SSX and SSX::SS18 antibodies in decalcified surgical specimens and outcome of synovial sarcomas (SS) of bone. Methods and results: Twenty‐five cases were classified as bone SS (prevalence 0.32% among malignant primary bone sarcoma). Median age was 34 years (range = 9–79). Twenty‐four of 25 patients presented with non‐metastatic tumours, one with lung metastases. The majority of tumours involved the long bones of extremities with metaphyseal origin. Mean size of the tumour was 7.1 cm. Twenty cases (80%) were monophasic and five (20%) were biphasic. SS18::SSX fusion‐specific antibody had 92% sensitivity and 99% specificity for primary bone SS, whereas SSX C‐terminus antibody had 100% sensitivity and 94% specificity. Fluorescence in‐situ hybridisation (FISH) analysis was feasible in nine (36%) cases and detected SS18 rearrangement in all nine cases. All patients underwent surgical removal of their primary tumour, with adequate margins in 18 (72%) patients. Chemotherapy with metothrexate, cisplatin, doxorubicin and ifosfamide was used in the seven patients. Two patients with inadequate surgical margins received radiotherapy. With a median follow‐up of 80 months (range = 6–428), 5‐ and 10‐year overall survival (OS) was 66.6% and 47.9%, respectively, and 5 and 10 years' disease‐free survival (DFS) was 36.8% [95% confidence interval (CI) = 18.0–55.7%] and 32.2% (95% CI = 14.6–51.2%), respectively. A significant improvement in 10 years' DFS in patients undergoing chemotherapy compared with patients who did not was observed (P = 0.039). Conclusions: Our series highlights the utility of SS18::SSX fusion‐specific and SSX C‐terminus antibodies to support the diagnosis of SS. Adjustment chemotherapy was associated with improved prognosis in this series. [ABSTRACT FROM AUTHOR]

Background: Secondary peripheral chondrosarcomas arising in solitary osteochondromas is an unusual complication, reported in small series. In this study, we aimed to present our experience with this rare variant of chondrosarcoma and compare results with already published data in order to determine prognostic factors for overall and disease-free survival.Methods: The case study includes retrospective data from patients diagnosed at a single institution from 1943 to 2019. Clinical data were collected reviewing all available medical records from first to last follow-up visits. To exclude the presence of the Multiple Osteochondroma Hereditary Syndrome, few patients, with a suspect of a familial form of the disease, were evaluated for the presence of germline heterozygous variants in EXT1 and EXT2 genes. Results were summarized using descriptive statistics and statistical analysis were performed to reveal associations between variables.Results: Two hundred and fourteen secondary peripheral chondrosarcomas that arose exclusively from solitary osteochondromas diagnosed in a multidisciplinary setting at the IRCCS Istituto Ortopedico Rizzoli were retrospectively identified, 66.4% males and 33.6% females with a median age at diagnosis of 38 years. The local recurrence rate was 17.3%, while the metastases one was 5.1%. Besides age, a high histologic grade is the only factor associated with worse 5-year and 10-year overall survival (log-rank p = 0.0005, HR = 3.74; 95% CI 1.69-8.26). Moreover, high histological grade (HR = 3.75; 95% CI = 1.69-8.34; p = 0.001) and surgical debulking (HR = 3.71; 95% CI = 1.57-8.79; p = 0.003) were associated with a significantly worse disease-free survival.Conclusions: Our study confirm the low-grade behavior of secondary peripheral chondrosarcomas and demonstrate that the best choice of treatment for those arising in solitary osteochondromas is the wide surgical excision, when possible. Location per se is not a factor that affects prognosis, while the accurate histological grade assessment is correlated with the tumor aggressiveness and a long term follow up is necessary for this rare variant of chondrosarcoma. [ABSTRACT FROM AUTHOR]

Purpose: Biochemical remission (BR), gross total resection (GTR), and intraoperative cerebrospinal fluid (CSF) leaks are important metrics in transsphenoidal surgery for acromegaly, and prediction of their likelihood using machine learning would be clinically advantageous. We aim to develop and externally validate clinical prediction models for outcomes after transsphenoidal surgery for acromegaly. Methods: Using data from two registries, we develop and externally validate machine learning models for GTR, BR, and CSF leaks after endoscopic transsphenoidal surgery in acromegalic patients. For the model development a registry from Bologna, Italy was used. External validation was then performed using data from Zurich, Switzerland. Gender, age, prior surgery, as well as Hardy and Knosp classification were used as input features. Discrimination and calibration metrics were assessed. Results: The derivation cohort consisted of 307 patients (43.3% male; mean [SD] age, 47.2 [12.7] years). GTR was achieved in 226 (73.6%) and BR in 245 (79.8%) patients. In the external validation cohort with 46 patients, 31 (75.6%) achieved GTR and 31 (77.5%) achieved BR. Area under the curve (AUC) at external validation was 0.75 (95% confidence interval: 0.59–0.88) for GTR, 0.63 (0.40–0.82) for BR, as well as 0.77 (0.62–0.91) for intraoperative CSF leaks. While prior surgery was the most important variable for prediction of GTR, age, and Hardy grading contributed most to the predictions of BR and CSF leaks, respectively. Conclusions: Gross total resection, biochemical remission, and CSF leaks remain hard to predict, but machine learning offers potential in helping to tailor surgical therapy. We demonstrate the feasibility of developing and externally validating clinical prediction models for these outcomes after surgery for acromegaly and lay the groundwork for development of a multicenter model with more robust generalization. [ABSTRACT FROM AUTHOR]

Unlabelled: Tissue transglutaminase 2 (TG2) is ubiquitously expressed in normal tissues and plays an important role in the pathophysiology of wound healing. An increase in periodontal tissues has been previously reported in cyclosporine-induced gingival overgrowth.Purpose: The aim of this study was to explore associations between TG2 expression and the vascularization and maturation processes of peri-implant soft tissues over time.Materials and Methods: Edentulous patients proposed for mandibular implant-retained overdentures were included in the study. Biopsies of the peri-implant mucosa were performed at the first surgical stage and at 4, 8, and 12 months after prosthetic load. A follow-up program was directed to record plaque indexes, bleeding on probing data, and pocket probing depth around implants. An evaluation of the vessels' density was carried out by digital virtual microscopy and using an immunohistochemistry approach (antibodies anti-CD31, anti-TG2). A robust multivariable regression model was implemented.Results: According to model results, blood vessel count and probing (as a marker of gingival overgrowth in absence of plaque) significantly decrease over time and are associated with TG2, particularly for values above the median.Conclusion: The association of an increased TG2 expression in the extracellular matrix might have a significant impact in the development of gingival overgrowth around a loaded implant. [ABSTRACT FROM AUTHOR]

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 = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) 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 = 0.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). 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. [ABSTRACT FROM AUTHOR]

In 2009, the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) conducted an overview about the techniques used for the pre-surgical evaluation and the surgical treatment of epilepsies. The recognition that, in selected cases, surgery can be considered the first-line approach, suggested that the experience gained by the main Italian referral centers should be pooled in order to provide a handy source of reference. In light of the progress made over these past years, some parts of that first report have accordingly been updated. The present revision aims to harmonize the general principles regulating the patient selection and the pre-surgical work-up, as well as to expand the use of epilepsy surgery, that still represents an underutilized resource, regrettably. The objective of this contribution is drawing up a methodological framework within which to integrate the experiences of each group in this complex and dynamic sector of the neurosciences. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to assess the association between clinical and radiological features as well as of isocitrate dehydrogenase 1 and 2 (IDH 1,2) mutations with outcome in head and neck chondrosarcomas.Study Design: Retrospective study.Setting: Tertiary referral center.Methods: Clinical, histological, and molecular data of patients with head and neck chondrosarcomas treated by surgery were collected.Results: Forty-six patients were included. The mean age at diagnosis was 56 years (range, 17-78). The tumor originated from the skull base (52.2%), facial bones (28.2%), or laryngotracheal area (19.6%). At last follow-up (median 52.5 months), 38 patients were alive, 30 of which were disease free, whereas 8 had died, 4 of disease progression and 4 of other causes. Fourteen (30.4%) had local recurrence and 2 (4.3%) had lung metastasis. All cases were negative for cytokeratin AE1/AE3, brachyury, and IDH1 at immunohistochemistry, while Sanger sequencing identified IDH1/2 point mutations, typically IDH1 R132C, in 9 (37.5%) tumors arising from the skull base. Margin infiltration on the surgical specimen negatively affected the outcome, whereas no correlation was identified with IDH mutation status.Conclusions: An adequate margin positively affects survival. IDH mutation status does not affect patient outcome. [ABSTRACT FROM AUTHOR]

Introduction: Sellar/parasellar tumors (SPTs) very rarely become symptomatic during pregnancy. No specific guidelines exist for their management, that is extremely challenging as mother and fetus health can be jeopardized. Materials and methods: Data of patients with SPTs becoming symptomatic during pregnancy treated at two Italian referral Centers were retrospectively collected. Systematic literature review was also performed. Results: Our series consisted of 6 cases, 3 meningiomas, 1 ACTH-secreting adenoma, 1 pituicytoma and 1 craniopharyngioma. Mean age at presentation was 33.6 ± 6.0 years. Five patients complained of visual disturbances, associated with headache in one case, that occurred between gestation week (GW) 22 and 34. In 5 cases, pregnancy was uneventful with the delivery of a healthy baby between GW 33 and 35, followed by endoscopic surgical tumor exeresis (n = 4) or proton bean therapy (n = 1). Another patient presented with stigmata typical of Cushing's syndrome and rapidly worsening pre-eclampsia, that required pregnancy interruption and adenomectomy. Based on personal and literature cases, a practical algorithm was proposed to help clinicians dealing with these patients. Conclusions: SPTs becoming symptomatic in pregnancy deserve careful monitoring and multidisciplinary management. Overall, wait-and-see approach is suggested, reserving surgery to patients with rapidly progressive/life-threatening situations, significant risk of permanent neurological impairment or malignant lesions. [ABSTRACT FROM AUTHOR]

Background: Tractography has been widely adopted to improve brain gliomas' surgical planning and guide their resection. This study aimed to evaluate state-of-the-art of arcuate fasciculus (AF) tractography for surgical planning and explore the role of along-tract analyses in vivo for characterizing tumor histopathology. Methods: High angular resolution diffusion imaging (HARDI) images were acquired for nine patients with tumors located in or near language areas (age: 41 ± 14 years, mean ± standard deviation; five males) and 32 healthy volunteers (age: 39 ± 16 years; 16 males). Phonemic fluency task fMRI was acquired preoperatively for patients. AF tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. Along-tract analyses were performed, dividing the AF into 15 segments along the length of the tract defined using the Laplacian operator. For each AF segment, diffusion tensor imaging (DTI) measures were compared with those obtained in healthy controls (HCs). The hemispheric laterality index (LI) was calculated from language task fMRI activations in the frontal, parietal, and temporal lobe parcellations. Tumors were grouped into low/high grade (LG/HG). Results: Four tumors were LG gliomas (one dysembryoplastic neuroepithelial tumor and three glioma grade II) and five HG gliomas (two grade III and three grade IV). For LG tumors, gross total removal was achieved in all but one case, for HG in two patients. Tractography identified the AF trajectory in all cases. Four along-tract DTI measures potentially discriminated LG and HG tumor patients (false discovery rate < 0.1): the number of abnormal MD and RD segments, median AD, and MD measures. Both a higher number of abnormal AF segments and a higher AD and MD measures were associated with HG tumor patients. Moreover, correlations (unadjusted p < 0.05) were found between the parietal lobe LI and the DTI measures, which discriminated between LG and HG tumor patients. In particular, a more rightward parietal lobe activation (LI < 0) correlated with a higher number of abnormal MD segments (R = −0.732) and RD segments (R = −0.724). Conclusions: AF tractography allows to detect the course of the tract, favoring the safer-as-possible tumor resection. Our preliminary study shows that along-tract DTI metrics can provide useful information for differentiating LG and HG tumors during pre-surgical tumor characterization. [ABSTRACT FROM AUTHOR]

We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Context: DNA methylation has been identified among putative regulatory mechanisms for CYP11B2 expression in primary aldosteronism.Objective: The objective of this work is to investigate DNA methylation and expression of genes encoding steroidogenic enzymes in benign adrenocortical tumors.Design and Setting: This cross-sectional study took place at university hospitals.Patients: We collected fresh-frozen tissues from patients with benign adrenocortical adenomas (n = 48) (nonfunctioning n = 9, autonomous cortisol secretion n = 9, Cushing syndrome n = 17, aldosterone-producing [APA] n = 13) and adrenal cortex adjacent to APA (n = 12). We collected formalin-fixed, paraffin-embedded (FFPE) specimens of paired APA and concurrent aldosterone-producing cell clusters (APCCs) (n = 6).Intervention: DNA methylation levels were evaluated by quantitative bisulfite next-generation sequencing in fresh-frozen tissues (CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B1, HSD3B2, NR5A1, STAR, and TSPO) and FFPE APA/APCC paired samples (CYP11B2). CYP11B1, CYP11B2, CYP17, CYP21, and STAR gene expressions were examined by quantitative real-time polymerase chain reaction.Main Outcome Measure: The main outcome measure was DNA methylation.Results: CYP11B2 methylation levels were significantly lower in APA than in other adrenal tissues (P < .001). Methylation levels of the remaining genes were comparable among groups. Overall, CYP11B2 expression and DNA methylation were negatively correlated (ρ = -0.379; P = .003). In FFPE-paired APA/APCC samples, CYP11B2 methylation level was significantly lower in APA than in concurrent APCCs (P = .028).Conclusions: DNA methylation plays a regulatory role for CYP11B2 expression and may contribute to aldosterone hypersecretion in APA. Lower CYP11B2 methylation levels in APA than in APCCs may suggest an APCC-to-APA switch via progressive CYP11B2 demethylation. Conversely, DNA methylation seems not to be relevant in regulating the expression of genes encoding steroidogenic enzymes other than CYP11B2. [ABSTRACT FROM AUTHOR]

The exact prediction of outcome of patients with Merkel cell carcinoma (MCC) of the skin is difficult to determine, although several attempts have been made to identify clinico-pathologic prognostic factors. The Ki67 proliferative index is a well-known marker routinely used to define the prognosis of patients with neuroendocrine neoplasms. However, its prognostic value has been poorly investigated in MCC, and available published results are often contradictory mainly because restricted to small series in the absence of standardized methods for Ki67 evaluation. For this reason, we explored the potential prognostic role of Ki67 proliferative index in a large series of MCCs using the WHO standardized method of counting positive cells in at least 500 tumor cells in hot spot areas on camera-captured printed images. In addition, since MCC may be considered as the cutaneous counterpart of digestive neuroendocrine carcinomas (NECs), we decided to stratify MCCs using the available and efficient Ki67 threshold of 55%, which was found prognostic in digestive NECs. This choice was also supported by the Youden index analysis. In addition, we analyzed the prognostic value of other clinico-pathologic parameters using both univariate and multivariate analysis. Ki67 index appeared significantly associated with prognosis at univariate analysis together with stage IV, lack of MCPyV, and p63 expression, but not at the multivariate analysis, where survival resulted independently influenced by p63 expression and tumor stage, only. [ABSTRACT FROM AUTHOR]

Objective: Pituitary macroadenomas (PAs) are usually defined as benign intracranial tumors. However, they may present local aggressive course. High Ki67 labelling index (LI) values have been related to an aggressive tumor behavior. A recent clinicopathological classification of PA based on local invasiveness and proliferation indexes, divided them in groups with different prognosis. We evaluated the utility of conventional MRI (cMRI) and diffusion-weighted imaging (DWI), in predicting the Ki67- LI according the clinicopathological classification. Methods: 17 patients (12 M and 5 F) who underwent surgical removal of a PA were studied. cMRI features, quantification of T1 W and T2W signal intensity, degree of contrast uptake (enhancement ratio, ER) and apparent diffusion coefficient (ADC) values were evaluated by using a 3 T scan. Statistics included Mann–Whitney test, Spearman’s test, and receiver operating characteristic analysis. A value of p ≤ 0.05 was considered significant for all the tests. Results: Negative correlations were observed between Ki-67 LI, ADCm (ρ = - 0.67, p value = 0.005) and ER values (ρ = −0.62; p = 0.008). ER values were significantly lower in the proliferative PA group (p = 0.028; p = 0.017). ADCm showed sensitivity and specificity of 90 and 85% respectively into predict Ki67-LI value. A value of ADCm ≤0, 711 x 10–6 mm2 emerged as a cut-off of a value of Ki67-LI ≥ 3%. Conclusion: Adding quantitative measures of ADC values to cMRI could be used routinely as a non-invasive marker of specific predictive biomarker of the proliferative activity of PA. Advances in knowledge: Routinely use of DWI on diagnostic work-up of pituitary adenomas may help in establish the likely biological aggressive lesions. [ABSTRACT FROM AUTHOR]

Aims: A wide range of post‐radiotherapy (RT) vascular lesions can occur, ranging from benign lymphangiomatous papules of the skin (BLAPs), to atypical vascular lesions (AVLs) and post‐RT angiosarcomas (ASs). The relationship between benign and malignant post‐RT breast lesions and their prognostic features are still controversial. The aims of this study were to investigate the relationship between benign and malignant mammary post‐RT vascular lesions and to define post‐RT AS prognostic features. Methods and results: Seventy‐four post‐RT vascular lesion cases were obtained and stained with antibodies against CD34, CD31, D2‐40, Ki67, and c‐Myc. Mutational analysis was performed by deep sequencing for the following genes: KRAS, NRAS, HRAS, BRAF, PIK3CA, TP53, NOTCH1, PTEN, CDKN2A, EGFR, AKT1, CTNNB1, hTERT, and PTPRB. Post‐RT AS cases were graded according to a previously reported breast AS grading system. AVL cases showed a low number of HRAS and hTERT mutations, whereas post‐RT AS cases showed a high frequency of EGFR, TP53, HRAS and hTERT mutations. On follow‐up, all BLAP and AVL patients were alive with no evidence of disease. Post‐RT AS 5‐year overall survival declined with the increase in grade, as follows: 85.7% for grade 1, 83.3% for grade 2, and 40.4% for grade 3. Conclusions: Our findings confirm that BLAP and AVL have a good prognosis, and that post‐RT AS prognosis is strongly related to histological grading. On molecular analysis, AVL and post‐RT AS shared HRAS and hTERT mutations, suggesting a relationship between the two lesions. [ABSTRACT FROM AUTHOR]

BACKGROUND: A non-invasive sampling procedure for the early detection of Oral Squamous Cell Carcinoma (OSCC) based on DNA methylation analysis of a panel of 13 genes was applied in 4 different OSCC risk-group of patients. Aim of the study is to evaluate the between-group differences and the variables related to the methylation profile of each group. METHODS: Oral brushing samples were collected from 54 healthy subjects, 31 Oral Leukoplakia (OL) patients, 18 Oral Lichen Planus (OLP) patients and 26 patients previously treated for OSCC. Each sample was considered positive or negative in relation to a predefined cut-off value. RESULTS: None of the samples from 54 healthy subjects were positive, whereas 22/31 OL, 3/18 OLP and 8/26 surgically treated OSCC samples showed positive values with respect to the cut-off. In OL patients, dysplasia was the only variable significantly related to positive values: 10/10 OLs with high-grade dysplasia were positive with respect to 12/21 OLs without dysplasia (Chi 6.039, p < 0.05). CONCLUSION: DNA methylation analysis in epithelial cells collected by oral brushing seems to be a promising genetic method to distinguish lesions at high risk of developing OSCC. Larger population studies and an adequate follow-up period are necessary to confirm these preliminary data. [ABSTRACT FROM AUTHOR]

Objective: Pituitary neuroendocrine tumours (PitNET)s can be aggressive, thus presenting local invasion, postsurgical recurrence and/or resistance to treatment, responsible for significant morbidity. The study aimed at identifying prognostic factors of postsurgical outcome using data‐driven classification of patients. Design: Retrospective observational study. Methods: Clinicopathological and radiological data of patients with PitNET treated via endoscopic endonasal surgery were collected. Tumour recurrence/progression and progression‐free survival were assessed by classification tree analysis (CTA) and Kaplan‐Meier curves, respectively. Histological subtype, cavernous/sphenoid sinus invasion, mitosis, Ki‐67, p53, Trouillas' grading, degree of tumour exeresis and postsurgery disease activity were also evaluated. Results: A total of 1066 (466 gonadotroph, 287 somatotroph, 148 lactotroph, 157 corticotroph and 8 thyrotroph) tumours were included; 21.7% invaded the cavernous/sphenoid sinus. Based on Trouillas' classification, 64.3% were grade 1a, 14.2% 1b, 16.1% 2a, and 5.4% 2b; 18.3% had >2/10 HPF mitoses, 24.9% had Ki‐67 ≥3%; 15.8% were positive for p53. Exeresis was radical in 81.2% of the cases. Median follow‐up was 59.2 months. At last evaluation, 79.4% of the patients were cured; 20.6% had disease persistence, controlled by medical treatment in 18.3% of them. Disease recurrence/progression was recorded in 10.9% of the cases. CTA identified 5 distinct patient subgroups with different risk of disease recurrence/progression. Grade 2 of the Trouillas' grading, >2/10 HPF mitoses, Ki‐67 ≥3%, p53 protein expression (P <.001), tumour invasion (P =.002) and ACTH‐subtype (P =.003) were identified as risk factors of disease recurrence/progression. Conclusions: The combined evaluation of Trouillas' grading, proliferation indexes and immunohistochemistry appears promising in the prediction of surgical outcome in PitNET. [ABSTRACT FROM AUTHOR]

Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors. [ABSTRACT FROM AUTHOR]

Aims: De‐differentiated chordoma is an uncommon and incompletely characterised aggressive neoplasm. Only a few cases originating from the skull base have been reported. Methods and results: All consecutive cases of skull‐base de‐differentiated chordomas treated surgically in a referral centre from January 1990 to June 2019 were retrospectively evaluated to assess peculiar pathological, radiological and clinical features. Patient data were retrieved from paper and electronic records. Six cases (two male, four female; mean age at surgery = 46 years, range = 35–64), treated surgically at our institution were identified. Transformation to de‐differentiated chordomas occurred after radiation therapy in three cases (mean = 13.6 years after treatment, range = 5–25), two during tumour progression, while one was de‐novo. Magnetic resonance imaging and surgical examination revealed the presence of two different tumour components, corresponding to the conventional and de‐differentiated portion on histological examination. The de‐novo case presented a PIK3CA mutation. DNA methylation analysis revealed consistent epigenetic changes in TERT, MAGEA11 and UXT. Prognosis was poor, as five of six patients died after surgery and radiation therapy, with a mean overall survival of 29 months (range = 11–52). Conclusions: Skull‐base de‐differentiated chordomas are extremely rare and aggressive neoplasms with characteristic magnetic resonance imaging, surgical and histological features. Therefore, an early and accurate histological diagnosis is of paramount relevance. Molecular analysis appears promising to define mechanisms involved in tumour de‐differentiation. [ABSTRACT FROM AUTHOR]

Genetic heterogeneity displayed by tumour cells (intratumoural heterogeneity, ITH) represents a diagnostic challenge when assessing tumour mutational profile. In oral squamous cell carcinoma (OSCC), ITH may be found both in tumour cells and in adjacent mucosa. Genetic heterogeneity of the adjacent mucosa can be interpreted as evidence of the field cancerization (field heterogeneity, FH). The aim of the study was to investigate the impact of intratumoural and intrafield heterogeneity on locoregional control. Ten OSCC patients (5 recurrent and 5 nonrecurrent) were studied. Multiple areas were sampled from the bulk of the tumour and the adjacent nonneoplastic mucosa. A panel of 10 tumour-specific OSCC driver genes was analysed for each sample and was used to calculate heterogeneity. Values were compared among recurrent and nonrecurrent OSCC. Mutational analysis highlighted that a single tumour sample has limited accuracy in assessing the genetic profiles of tumours. High values of ITH considering shared mutations between specimens were found in both recurrent and non-recurrent OSCC (p = 0.095). On the contrary, the intrafield genetic heterogeneity was significantly less frequently in the non-recurrent OSCC group (p = 0.032). Heterogeneity within each specimen calculated with variant allele frequency confirmed that there was better discrimination between recurrent and nonrecurrent groups using nonneoplastic adjacent mucosa than tumour tissue (p value 0.0006 and 0.0048 respectively). In agreement with the theory of field cancerization, intrafield genetic heterogeneity correlates with a higher risk of developing loco-regional recurrences and second primaries. In order to reduce the ITH effects, analysis of multiple tumour areas should be encouraged. [ABSTRACT FROM AUTHOR]