Ospedale Bellaria

Sinonasal tumours are rare entities presenting with non-specific symptoms, therefore being often misinterpreted. The present study aimed to evaluate if the 13-gene DNA Methylation assay for early cancer detection already assessed in the oral cavity, was also useful in nasal cavity tumours. The case series consisted of 93 patients (63 males/30 females), 49 with malignant tumours, 14 with benign/borderline tumours, 34 as control series with 33 inflammatory polyps and one fungus ball. We collected one flocked swab from the lesion and one from the contralateral nasal cavity. All sinonasal cancer cases were evaluated by bisulfite next generation DNA sequencing, investigating the following genes: ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MIR193, LINC00599, MIR296, TERT, GP1BB. To evaluate the performance of the methylation assay, a specific methylation score was calculated for each sample using linear discriminant analysis, with a predefined positivity threshold of 1.0615547. The association between diagnosis and methylation score positivity was evaluated through Fisher's exact test and calculation of risk ratios with 95% confidence intervals. Additionally, dimensionality reduction techniques were employed to explore the structure of the dataset and assess the ability of methylation profiles to distinguish between different pathological conditions. The 13-gene DNA Methylation scored positive in 42/49 malignant tumours; We included also 14 benign/borderline tumours of which 11 scored positive. Among 33 inflammatory polyps, 24 scored negative, as well as 64/70 normal contralateral mucosa and one fungus ball. Therefore, excluding benign/borderline tumours, the detected sensitivity was 85.7% and specificity 85.6% (AUC: 0.878).

The concept of "HER2-negative" breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which has shown survival benefit in patients with metastatic carcinoma with minimal HER2 protein expression that lack HER2 gene amplification by in situ hybridization. In clinical trials using T-DXd, HER2-low was defined as an immunohistochemistry (IHC) score 1+ or an IHC score 2+ without HER2 gene amplification. HER2-ultralow was defined as faint or barely perceptible, incomplete membrane staining in >0% to ≤10% of tumor cells (IHC score 0+/with membrane staining) and HER2-null as the complete absence of staining (IHC score 0/absent membrane staining). These results now necessitate more detailed evaluation and reporting of traditional "HER2-negative" results to identify patients with metastatic breast cancer who may benefit from T-DXd therapy. Both the US Food and Drug Administration and the European Medicines Agency have extended the regulatory approval of T-DXd to patients with metastatic breast cancer showing HER2-low or HER2-ultralow expressions. Updated clinical management guidelines now, therefore, incorporate the spectrum of HER2 results into treatment selection algorithms in the metastatic setting. To align histopathologic practice with these developments, the College of American Pathologists has issued a new biomarker-reporting template that recommends explicit distinction between IHC 0/absent membrane staining and IHC 0+/with membrane staining. Key concerns among pathologists include assay variability, scoring reproducibility, and quality assurance standards for accurately detecting such low levels of HER2 expression. This manuscript provides expert consensus, evidence-based practical recommendations for identifying and reporting tumors with HER2-low and HER2-ultralow expression. We emphasize standardized testing protocols, validated assays, robust internal and external controls, and focused training for pathologists. A universal structured pathology report is proposed to highlight the accurate distinction between IHC 0 (null), IHC 0+ (ultralow), and HER2-low expressions.

Inverted sinonasal papilloma (ISP) is a benign epithelial neoplasm with potential for malignant transformation into squamous cell carcinoma (ISP-SCC). While high-risk HPV infection has been studied as a possible driver, other factors, including occupational exposures, may play a role. Thirty-two cases (n = 32) of ISP and ISP SCC were retrospectively analysed. These cases had been diagnosed between 2010 and 2022. We assessed their occupational history through the Italian Sino-Nasal Cancer Registry questionnaire and performed p16/p53 immunohistochemistry, HPV DNA and RNA testing. Overall, 41% of ISP and 40% of ISP-SCC cases reported exposure to IARC Group 1–2 A carcinogens, and 69% had a history of smoking. Transcriptionally active HPV was detected in only one case (3.1%). Conventional bivariate analyses did not reveal significant associations between occupational exposure and malignant transformation. However, hierarchical cluster analysis identified three distinct phenotypes. Cluster 1 included predominantly male smokers with high cumulative occupational and non-occupational exposure, with ISP-SCC in 17%. Cluster 2, characterized by the highest occupational exposure and lowest smoking prevalence, consisted exclusively of ISP-SCC cases (100%), suggesting occupational carcinogens as a possible independent driver. Cluster 3 had minimal exposure, inflammatory features, and no malignant transformation. These findings highlight the potential of multidimensional analytical approaches to identify high-risk subgroups and inform targeted preventive and surveillance strategies in exposed populations.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-33299-7.

Background/Objectives: Inflammatory bowel diseases (IBDs) are chronic conditions with significant psychological comorbidities. Research on subclinical psychosomatic syndromes in this category of patients remains limited. This study aimed to identify distinct psychosomatic profiles using the Diagnostic Criteria for Psychosomatic Research-Revised (DCPR-R) framework and to examine their associations with health behaviors. Methods: A total of 111 adult IBD patients in clinical remission or with low disease activity were enrolled and underwent a comprehensive assessment of sociodemographic and clinical variables, psychosomatic syndromes and health behaviors. Hierarchical clustering using complete linkage and Jaccard distance was performed on two subsets of common psychosomatic syndromes in this sample. Associations between psychosomatic syndromes and profiles and health behaviors were examined using multiple regression models, controlling for IBD severity and applying Benjamini-Hochberg correction. Analyses were conducted according to a pre-registered protocol. Results: Six distinct clusters were identified: irritability (9.3%), pure allostatic overload (18.7%), pure alexithymia (26.7%), overwhelmed type A behavior (12%), subclinical depressive mood (13.3%), and alexithymic type A behavior (26.7%). Pure alexithymia patients showed higher smoking odds (OR = 3.85, p = 0.033) and overwhelmed type A behavior patients showed less frequent physical activity (OR = 0.27, p = 0.018). For individual syndromes, irritable mood was associated with lower alcohol consumption (OR = 0.29, p = 0.035) while type A behavior was associated with higher consumption (OR = 1.87, p = 0.030). However, all associations became non-significant after false discovery rate correction. Conclusions: IBD patients with low disease activity exhibit distinct psychosomatic profiles. While specific syndromes and profiles showed trends toward certain health behaviors, associations were not robust to multiple comparison correction. Psychosomatic profiling may inform personalized clinical approaches, though larger studies are needed to establish definitive associations with health behaviors.

2002 Background: The 1st and 2 nd interim analyses of the CATNON trial on anaplastic glioma (NCT00626990) showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) in patients with IDH mutant (mt) tumors, but no benefit of concurrent (conc) TMZ regardless of Isocitrate dehydrogenase 1 and 2 (IDH) mutation (mt) status. We now present the final analysis and the exploratory molecular marker analysis of the study. Methods: The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ. Methylation status including MGMT promoter methylation status were assessed with the Infinium MethylationEPIC Beadchip. IDH mutation (mt) status and glioma specific alterations were assessed with a glioma targeted panel using Agilent SureSelect baits. Results: After a median follow-up of 10.9 years and with 499 events observed, in the intent-to-treat population the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.906 (95%CI 0.760, 1.082; p=0.28) and after adjTMZ 0.647 (95%CI 0.541, 0.773; p <0.0001). In 660 patients IDH status could be determined: IDH was mt in 444 tumors and wild type (wt) in 216 tumors. Median OS was 1.7 yrs in patients with IDHwt tumors and 8.5 years in patients with IDHmt tumors. Benefit to TMZ was limited to patients with anaplastic glioma IDHmt of which 199 were still alive (45%). For patients with IDHmt tumors the HR for concTMZ was 0.81 (95% CI 0.63-1.04; p=0.09) and for adjTMZ 0.54 (95% CI 0.42-0.69,p < 0.0001). No benefit was observed of concTMZ in IDHmt glioma patients that also received adjTMZ (HR 0.92 95% CI 0.63-1.36; p=0.69). In patients with IDHmt tumors that had received any TMZ median OS was 10.3 years, the median OS in patients treated with adjTMZ was 12.5 years (95% CI 9.4-15.0; p<0.0001). In exploratory analysis, high-copy number Amplification of PDGFR and CDK4 ; Homozygous deletion of the CDKN2A/B locus, total copy number alterations, methylation subtype (A_IDH vs A_IDH_HG, G-CIMP high versus low, MGMT -promoter methylation as determined by methylation arrays) were all associated with outcome but none was predictive for benefit to TMZ. Conclusions: Despite more follow-up, concTMZ did not improve OS regardless of IDH status. AdjTMZ increased OS in patients with IDHmt tumors but not in patients with IDHwt tumors. Molecular factors of known prognostic significance for IDHmt 1p/19q intact anaplastic glioma did not predict benefit to TMZ. Median OS in patients with IDHmt glioma having received adjTMZ after RT was 12.5 years. Standard of post-operative care in patients with high grade IDHmt astrocytoma should be RT followed by 12 cycles adjTMZ. Funding Source: MSD. Clinical trial information: NCT00626990 .

To evaluate the risk of hyponatremia during therapy with antidepressant drugs, in particular by investigating whether there is a different risk profile depending on the class or single active principles. A meta-analysis was performed including all studies in which the risk of hyponatremia in subjects with or without antidepressant treatment was assessed. An extensive Medline, Embase and Cochrane search was performed, to retrieve all studies published up to February 5th 2024, using the following words: hyponatremia and antidepressant. Of 409 retrieved articles, 10 studies satisfied the inclusion criteria encompassing a total of 1,026,870 patients with 89,403 hyponatremic subjects. Treatments with selective serotonin reuptake inhibitors (OR = 3.31 [2.41;4.56], p < 0.01), serotonin-noradrenaline reuptake inhibitors (OR = 5.79 [1.27;26.49], p = 0.02) and tricyclic antidepressants (OR = 3.01 [1.27;7.14], p = 0.01) were found to be significantly associated with an increased risk of hyponatremia, whereas treatment with noradrenaline and specific serotonergic antidepressants was not. A network meta-analysis indicated that treatments with venlafaxine (OR = 5.99 [2.39;14.99], p < 0.01), paroxetine (OR = 4.93 [2.01;12.12], p < 0.01), sertraline (OR = 4.15 [1.98;8.70], p < 0.01), citalopram (OR = 3.49 [1.54;7.9], p < 0.01), escitalopram (OR = 3.49 [1.49;8.19], p < 0.01), fluoxetine (OR = 3.40 [1.13;10.21], p = 0.03) and mirtazapine (OR = 2.83 [1.16;6.92], p = 0.02) were found to be significantly associated with an increased risk of hyponatremia with a progressively decreasing OR. Clomipramine (OR = 4.50 [0.97;20.93], p = 0.05) also showed a trend towards a greater risk of hyponatremia. Otherwise, treatments with fluvoxamine, imipramine, maprotiline, amitriptyline and mianserin were not associated with an increased risk of hyponatremia. These data appear useful on clinical grounds, in order to increase the awareness regarding the possibility that antidepressants induce hyponatremia and to encourage regular serum sodium monitoring.

Mucosal melanoma of the head and neck (MM-H&N) is an aggressive disease known for its frequent residual tumours/relapses (RT/R) at the surgical site, as well as eventual metastases. Our understanding of the MM-H&N mutational landscape, together with the correlation of specific mutations with clinical-pathological features, is significantly less comprehensive compared to that of cutaneous melanoma. Additionally, the mutational status of consecutive samples collected from single patients has not been investigated, which limits our ability to characterise the prognosis and treatment options for this patient subset. A total of 53 MM-H&N specimens from 27 patients were analysed using a laboratory-developed multigene next-generation sequencing (NGS) panel. Among these, material from 46 of 53 (86.8%) samples and from 25 of 27 patients (92.6%) was suitable for NGS. The most frequently detected mutations were found in the RAS genes family, specifically KRAS and NRAS (seven of 46, 15.2%), as well as TP53, KIT and BRAF (each in three of 46, 6.5%); 25 of 46 (54.3%) samples exhibited a wild-type (WT) status. A statistically significant association between BRAF/RAS mutations and mucosal lentiginous histology (P = 0.041) was observed. Additionally, four of 11 (36.4%) patients with consecutive specimens, with no pre-/intersurgery systemic therapies administered and all having at least two evaluable NGS results, demonstrated molecular heterogeneity in the analysed samples. MM-H&N shows a significant percentage of WT cases and a limited number of targetable mutations, predominantly involving BRAF/RAS mutations, the latter of which are associated with mucosal lentiginous histology. A subset of patients with consecutive samples demonstrates discordant molecular results, indicating that NGS of all samples may be necessary to determine the most appropriate therapeutic approach.

PurposeTegumentary leishmaniasis (TL) is a neglected disease in Europe, often underdiagnosed or misdiagnosed due to its variable clinical presentation. Mucosal leishmaniasis (ML) is a rare manifestation of TL, and isolated tonsillar leishmaniasis is an even rarer finding, with very few reported cases. This study aims to expand knowledge on this unusual clinical entity by describing five cases of isolated tonsillar leishmaniasis diagnosed in the Emilia-Romagna region (ERR), northeastern Italy, emphasizing diagnostic challenges and treatment outcomes.MethodsBetween January 2014 and December 2024, all consecutive patients presenting with unilateral tonsillar swelling and pharyngodynia were evaluated at otolaryngology units in ERR hospitals. Histopathological analysis, special stains (H&E, Giemsa, PAS, Ziehl-Neelsen), and immunostaining (CD1a) were performed at the referring hospital. Microbiological confirmation was obtained through real-time PCR targeting Leishmania kDNA and rRNA. Treatment was administered according to current TL guidelines.ResultsWe included five patients who presented with unilateral tonsillar swelling mimicking malignancy and with a histological diagnosis of non-necrotizing granulomas. Histology revealed amastigotes in four cases. PCR confirmed Leishmania infection in all cases. Treatment with liposomal amphotericin B or pentamidine led to complete clinical remission.ConclusionIsolated tonsillar leishmaniasis should be considered in the differential diagnosis of head and neck tumors, especially in endemic regions. Histological and molecular tools are essential for accurate diagnosis. Increased awareness among clinicians and pathologists is necessary to improve recognition and management of this rare presentation.