Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

BACKGROUND: Primary sinonasal mucosal melanomas are aggressive tumors with a poor clinical control by current treatments, raising the urgent need of novel strategies. METHODS: By fluorescence in situ hybridization (FISH), direct sequencing, and immunohistochemistry, we investigate the spectrum of molecular abnormalities in a cohort of 32 cases of primary sinonasal mucosal melanomas. RESULTS: We found that all primary sinonasal mucosal melanomas lack BRAF V600E mutation; in addition, they are characterized by somatic mutations of NRAS (22%) and KIT (12.5%), together with amplification of RREB1 (100%) and loss of MYB (76%). The large majority of cases showed KIT protein expression (96.9%). Among tumor suppressor genes, primary sinonasal mucosal melanomas showed loss of PTEN (48.1%) and p16/INK4a (55.2%). All tested cases showed expression of pAkt and pErk, suggesting a combined activation of PI3K/Akt and RAS-mitogen-activated protein kinase (MAPK) pathways. CONCLUSIONS: This molecular fingerprint strongly argues against the clinical efficacy of BRAF-inhibitors, but could candidate primary sinonasal mucosal melanomas to therapeutic strategies targeting RAS and KIT mutations or inhibiting PI3K-Akt-mTOR pathway

MGMT methylation in diffuse large B-cell lymphoma: validation of quantitative methylation-specific PCR and comparison with MGMT protein expression.

AIMS: (1) To validate a quantitative real time methylation specific PCR assay (MethyLight) for the detection of O6-methylguanine-DNA methyltransferase (MGMT) gene methylation status (MS) in diffuse large B-cell lymphoma (DLBCL). (2) To determine the immunohistochemical (IHC) expression of the MGMT protein and correlate it with MS. Both IHC and MethyLight results were compared with patient's outcome. METHODS: 71 patients with primary nodal DLBCL were studied. MGMT immunoreactivity was detected using a specific monoclonal antibody. The MS of MGMT gene was analysed in 52/71 DLBCL using MethyLight. A selected subset of 40 DLBCL was also analysed using qualitative methylation-specific PCR (MSP). Statistical analysis of overall survival (OS), lymphoma-specific survival (LSS) and progression free survival (PFS) was performed according to IHC and MS results. RESULTS: 19/71 DLBCLs (27%) were MGMT-negative at IHC; all were analysed, together with 33/52 MGMT-positive DLBCLs. MethyLight showed a better performance than MSP. There was a good correlation between the presence of MGMT expression and the unmethylated status; the absence of IHC expression was poorly correlated with the presence of methylation. Better OS, LSS and PFS was found in DLBCLs with MGMT gene methylation. DLBCLs not expressing MGMT at IHC showed a longer PFS. CONCLUSIONS: The quantitative real-time methylation-specific PCR assay for the detection of MGMT gene hypermethylation has been validated for the first time in DLBCL. Immunohistochemistry seems to represent an useful preliminary test to identify unmethylated cases; MS analysis may be performed in non-immunoreactive cases to identify truly methylated DLBCLs, which bear a better prognosis

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology

Acinar cell carcinomas (ACCs) of the pancreas are rare pancreatic neoplasms accounting for about 1\u20132% of pancreatic tumors in adults and about 15% in pediatric subjects. They show different clinical symptoms at presentation, different morphological features, different outcomes, and different molecular alterations. This heterogeneous clinicopathological spectrum may give rise to difficulties in the clinical and pathological diagnosis with consequential therapeutic and prognostic implications. The molecular mechanisms involved in the onset and progression of ACCs are still not completely understood, although in recent years, several attempts have been made to clarify the molecular mechanisms involved in ACC biology. In this paper, we will review the main clinicopathological and molecular features of pancreatic ACCs of both adult and pediatric subjects to give the reader a comprehensive overview of this rare tumor typ