Spedali Civili di Brescia

This paper is aimed at synthetizing the conceptual basis of compartmental surgery (CS) for tumours of the anterior (floor of mouth and oral tongue) as well as posterior (base of tongue, superior and inferior gingival-buccal sulcus extending into the masticator space and infratemporal fossa) oral cavity, its indications, and outcomes. In spite of numerous bioendoscopic, radiological, and surgical advancements in management of oral cancer, its oncologic surgical control continues to be hampered by a considerable risk of local recurrence rate. Use of a conventional approach based on an empirical 5 mm safe margin surrounding the lesion in its three-dimensional extension, even when associated to accurate frozen sections techniques, seems inadequate to improve the oncologic outcomes of these patients in the near future. In contrast, application of the CS concepts herein detailed seems to open new opportunities for increasing surgical radicality, while maintaining adequate functional outcomes when proper reconstructive techniques are applied. Even though further multicentric prospective studies are needed to confirm the replicability of the oncological results described by pioneers of the CS approach, as well as to quantify the functional outcomes obtained by its large-scale application, this surgical philosophy confirms its vitality, relentless diffusion, and progressive evolution in the head and neck cancer arena.

No previous study described adolescents and young adults (AYAs) with HIV in Italy. Aims were to investigate the temporal trend of AYAs enrolment in the ICONA cohort over 2014-2023, and to compare their baseline characteristics and antiretroviral therapy (ART) outcomes with adults. All subjects enrolled in ICONA, the Italian cohort enrolling HIV-1 positive individuals from ART-naïve, over 2014-2023 were grouped into: AYAs (18-24 years old) and adults (≥25). Study outcomes were: time to first ART start, time to treatment discontinuation (TD) of first-line regimen, cause-specific TD, virologic failure, and loss-to-follow-up (LTFU). Overall, 9519 participants: 653 AYAs (6.9%) and 8,866 adults (93.1%). Excluding the decline recorded in 2020, the percentage of AYAs enrolled showed a similar trend before- and after-COVID. Compared with adults, AYAs had a milder clinical presentation, a better viro-immunological status, a higher mean change of cluster of differentiation 4 count over 24 months and, after adjusting, a higher risk of TD for patient's choice/adherence-related issues and LTFU. The less advanced clinical presentation and more robust immune recovery of AYAs, might depend upon more recent HIV infection, better thymic function, and lower immune activation. The higher risk of TD due to patient's choice/adherence-related issues and LTFU among AYAs is a major concern and suggests the need to create ad hoc clinical care pathways.

Abstract AdrenoCortical Carcinoma (ACC) is an aggressive, rare and heterogenous malignancy, that requires diverse preclinical models. For this reason, the development of new cell lines is pivotal. Here we describe the development and characterization of two of them, SMAC-2 and SMAC-3, established from surgical specimens of ACC patients. The characterization included their mutational profiling, the evaluation of steroidogenic enzymes expression, secretory activity and the expression of steroid hormone receptors. The proliferative ability of these cells within a zebrafish embryos xenograft was also evaluated. SMAC-2 originated from a metastatic EDP-M-treated ACC in a female patient with Cushing syndrome and hyperandrogenism, while SMAC-3 derived from a male patient with a mitotane-treated local recurrence, with no sign of hypercortisolism. TP53 was mutated in both lines. SMAC-2 cells were characterized by a pathogenic alteration on CTTNB1 gene and a deletion of CDKN2A gene, while SMAC-3 on MSH2 gene. Basal hormonal status analysis showed a cell model-specific fingerprint either in the hormonal secretion and gene and protein expression of steroid hormone receptors. SMAC-2 secreted high levels of cortisol. SMAC-3 secreted low basal level of cortisol. Mitotane displayed in both cell lines a low potency. Under the experimental conditions used, the xenografted area did not increase for both cell models. Experiments were carried out to study the stability of the two cell lines. SMAC-2 and SMAC-3 display unique molecular and functional features, expanding the repertoire of experimental ACC models and representing valuable tools for preclinical research alongside established cell lines.

IntroductionThis study evaluated 6-month effectiveness and safety of automated insulin delivery (AID) in comparison with multiple daily injections (MDI) in pediatric and adult type 1 diabetes (T1D).Materials and methodsIndividuals with T1D, aged 2–80 years, were enrolled across 32 international centers (in the United States, Europe, Canada, and New Zealand) and randomized 1:1 to AID intervention (MiniMed™ 670G or 770G system) or MDI with or without continuous glucose monitoring. Primary endpoints were change in mean HbA1c for participants with a baseline HbA1c >8.0% (Group 1) and percentage of time spent below 70 mg/dL (%TBR <70 mg/dL [<3.9 mmol/L]) for participants with baseline HbA1c ≤8.0% (Group 2), to show superiority of AID intervention versus MDI. Safety endpoints including rates of severe hypoglycemia and diabetic ketoacidosis (DKA), and difference in diabetes treatment satisfaction score were assessed.ResultsFor Group 1, N = 56 participants (aged 29.4 ± 17.0 years) were randomized to AID intervention and N = 54 participants (aged 36.8 ± 19.6 years) were randomized to MDI. For Group 2, N = 73 (aged 37.4 ± 21.0 years) and N = 69 (aged 39.2 ± 19.3 years), respectively, were randomized to AID and MDI. Change in HbA1c (mean [95% CI] difference of −0.7% [−1.1, −0.3], P = 0.0002) and difference in %TBR <70 mg/dL (4.8% [−6.4, −3.1], P<0.001) favored AID intervention versus MDI. Rates of severe hypoglycemia (AID: 1.82/100 patient-years) and DKA (MDI: 3.52/100 patient-years) were low and met preestablished success criteria for safety.DiscussionThis large, international, multicenter randomized controlled trial demonstrates safety of the MiniMed™ 670G/770G systems. AID significantly improved HbA1c and time spent in hypoglycemia when compared with MDI, in both youth and adults living with T1D.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT02748018.

Spitz melanocytoma is a melanocytic neoplasm of intermediate malignant potential. BRAF fusions are rare in Spitz tumors, and AKAP9::BRAF rearrangements are exceptionally uncommon. We describe the clinicopathological and molecular features of a Spitz melanocytoma in a 41-year-old woman, analyzed by next-generation sequencing (NGS). The lesion was a well-circumscribed dermal proliferation of spindle melanocytes within a collagen-rich stroma, lacking cytological atypia, mitoses, or necrosis. Immunohistochemistry demonstrated positivity for S100, SOX10, and MART1, weak HMB45 staining, and a very low proliferative index (<1%) on MART1/Ki-67; preferentially expressed antigen in melanoma protein (PRAME) expression was weak and focal. NGS identified an AKAP9 (exon 32)::BRAF (exon 9) fusion, without TERT promoter mutations or other high-risk alterations. This case highlights a rare molecular subset of Spitz melanocytoma and underscores the importance of integrated molecular and histopathological assessment for accurate diagnosis, prognostic evaluation, and potential targeted therapy.

Ribonucleotide reductase (RR) is the rate-limiting enzyme for NTPs conversion into dNTPs, playing a central role in genome replication and maintenance. It is composed by two catalytic (RRM1) and two regulatory (alternatively RRM2 and p53R2) subunits, of which RRM2's functionality depends on a diferric center in the active site and is one of the most expressed genes in many tumors, among which Rhabdomyosarcoma (RMS), a rare and aggressive pediatric tumor. Didox (3,4-dihydroxy-benzohydroxamic acid) is a highly effective RRM2 inhibitor with iron chelating properties which shows fewer in vivo side effects than classical RR inhibitors. In the present work, we analyzed the impact of didox on RMS cells. Our data clearly showed that didox effectively reduces cell viability, clonogenic capability and motility of both RD and RH30 cells (representative of embryonal named ERMS and alveolar subtype named ARMS), with higher potency in ARMS cells. Interestingly, didox is effective in inhibiting the cell viability of RMS radioresistant. Mechanistically, didox modulates the main iron-related proteins (TfR1 and H-ferritin), confirming its iron chelating properties; it induces mitochondrial ROS formation and caused an increase in double positive annexin-V/PI cells, confirming apoptosis as mechanism of cell death. Moreover, didox also potently reduces in vivo tumor proliferation of RH30 cells, without significant side effects on animals. Finally, the combination of sublethal doses of Actinomycin-D and didox is effective in decreasing cell viability and clonogenicity of RMS cells. Therefore, our data suggests the effectiveness of the RR inhibitor didox on both in vitro and in vivo RMS proliferation.