Mariacarmela Santarpia

Cutaneous melanoma is among the most common malignancies in the United States and accounts for ~5% of all cancers. Melanoma preferentially metastasizes to lymph nodes, lungs, liver and brain, while bladder involvement is rare and associated with poor prognosis. The present study reports a 79‑year‑old woman with stage III, operable, BRAF wild‑type melanoma of the back, treated with surgical excision and adjuvant immunotherapy. During adjuvant pembrolizumab treatment, a first solitary pulmonary relapse was observed. The metastasis was amenable to surgical resection, and the patient continued immunotherapy. Subsequently, recurrent haematuria led to the identification of a bladder lesion, which was removed via transurethral resection and the pathological evaluation confirmed metastatic melanoma. Following this second relapse, restaging imaging documented systemic disease progression involving lymph nodes, liver and bone. The patient then initiated first‑line treatment with nivolumab and ipilimumab, achieving an ongoing clinical and radiological partial response. This study highlights several clinically relevant aspects: The potential role of local treatment strategies for oligoprogressive disease in prolonging the benefit of immunotherapy, the rare occurrence of bladder metastasis during adjuvant pembrolizumab, and the activity of combined cytotoxic T‑lymphocyte‑associated protein 4/programmed cell death protein 1 (PD‑1) blockade even after progression on prior anti‑PD‑1 therapy. Early recognition of atypical metastatic sites and multidisciplinary management may contribute to prolonged disease control in selected patients with metastatic melanoma.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma in which Merkel cell polyomavirus (MCPyV) oncoproteins and ultraviolet-induced mutations provide distinct sources of tumor immunogenicity. This narrative review examines the biological determinants, immunohistochemical assessment, and prognostic and therapeutic relevance of programmed death ligand 1 (PD-L1) in MCC, linking tumor immunobiology to pathological interpretation. PD-L1 expression on tumor and immune cells is often concentrated at tumor–immune interfaces, consistent with interferon-γ-driven adaptive immune resistance. Reported associations with survival and treatment response vary across studies, partly reflecting differences in tissue sampling, assays, scoring compartments, and treatment context. Immune checkpoint blockade can produce durable responses in both PD-L1-positive and PD-L1-negative tumors, while baseline PD-L1 expression alone is not a validated criterion for treatment selection. Resistance mechanisms and emerging biomarkers are discussed alongside viral status, T-cell architecture, antigen-presentation defects, and alternative immune checkpoints. A reporting framework should emphasize specimen characteristics, assay documentation, separate assessment of PD-L1 expression in tumor and immune cells, and spatial heterogeneity. Interpreting PD-L1 within this biological and pathological context supports informative reporting and highlights the potential of integrated spatial biomarkers to improve understanding of immune responsiveness in MCC.

1. Lung cancer remains the foremost cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) comprising approximately 85% of all diagnoses [1]Platinum-based chemotherapy has...

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a rising incidence and a poor prognosis that largely reflects late-stage diagnosis. Although most cases are sporadic, approximately 5–10% of PDACs occur in the context of inherited cancer susceptibility, including hereditary pancreatic cancer (HPC) syndromes and familial pancreatic cancer (FPC). Germline pathogenic variants in genes involved in DNA damage repair, cell-cycle regulation, and genomic stability—such as BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11, mismatch repair genes, and TP53—contribute to PDAC risk and may influence disease biology. This review provides an overview of the genetic landscape of hereditary and FPC, focusing on established cancer predisposition syndromes and emerging susceptibility genes. Current evidence regarding the prevalence, penetrance, and clinical relevance of germline pathogenic variants (PGVs) is summarized, together with the challenges associated with identifying individuals at increased risk. Contemporary recommendations for germline genetic testing, including the use of multigene panel approaches and limitations in real-world implementation, are also discussed. In addition, surveillance strategies for PDAC in high-risk individuals (HRI) are reviewed, and the available data on the outcomes and limitations of surveillance programs are examined. Finally, the therapeutic implications of inherited alterations, particularly in DNA repair-deficient PDAC, are outlined with reference to genotype-informed systemic treatment approaches.

Over the past decade, significant achievements in elucidating the molecular pathogenesis of non–small cell lung cancer (NSCLC) have catalyzed a paradigm shift from empiric therapies to precision oncology. In this context, HER2 alterations, including protein overexpression, gene amplification, and activating mutations, constitute distinct molecular subsets within NSCLC. In the past few years, targeted therapeutic modalities such as antibody–drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.

Melanocytic Tumors of Uncertain Malignant Potential (MELTUMPs) remain among the most challenging entities in dermatopathology due to overlapping morphologic features and marked inter-observer variability. This comprehensive review critically assesses the diagnostic and potential prognostic significance of combining p16 and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) as a practical surrogate for genomic alterations involving the 9p21 (CDKN2A/MTAP) locus. We analyzed the molecular underpinnings of the CDKN2A/MTAP axis and systematically reviewed existing literature to define an integrated IHC strategy for ambiguous melanocytic lesions. The combined use of p16, a sensitive marker of CDKN2A inactivation, and MTAP, a highly specific marker for homozygous 9p21 deletion, was assessed for its diagnostic complementarity and potential clinical utility. p16 IHC demonstrates high sensitivity but limited specificity due to heterogeneous staining in borderline lesions. In contrast, MTAP loss exhibits near-absolute specificity for CDKN2A/MTAP co-deletion, albeit with lower sensitivity. Concordant loss of both markers strongly supports melanoma or high-risk melanocytoma, while MTAP retention may predict responsiveness to adjuvant interferon therapy. Combined p16/MTAP IHC provides a synergistic, biologically grounded approach that refines diagnostic accuracy in MELTUMPs. This dual-marker algorithm promotes a shift from purely morphology-based evaluation toward a reproducible, molecularly informed classification, improving both diagnostic confidence and patient management.

Background: Melanoma is a highly heterogeneous neoplasia in which transcriptional profile encodes much of the biological diversity that determines tumor progression and therapeutic response. To refine its molecular stratification and profiles characterization, we conducted an in silico transcriptomic analysis. Methods: Public microarray datasets from the GEO and ArrayExpress were examined, and the E-MTAB-6697 expression dataset was selected. We used a K-Means clustering algorithm to stratify 194 tumor samples into expression-driven subgroups and analyzed each one to define their transcriptional and biological profiles. Differential expression analysis between identified clusters and controls was performed. Additionally, we applied Weighted-Gene correlation analysis to identify coordinated expression hubs in the tumor dataset and tested the resulting modules for correlation with the identified clusters. Results: Unsupervised clustering of melanoma transcriptomic profiles identified three distinct molecular subtypes characterized by divergent biological programs. While all clusters shared the dysregulation of pathways involved in epidermal differentiation, immune response, and lipid metabolism, they diverged in proliferation, phenotypic plasticity, metabolic adaptation, and apoptotic regulation. Cluster A was characterized by enrichment in DNA replication, repair, and mitochondrial metabolism modules, suggesting a proliferative yet genomically stable state. Cluster B showed enrichment in immune and cytokine signaling pathways alongside reduced proliferative activity, consistent with a quiescent or transitional phenotype. Cluster C displayed coordinated enrichment in cell-cycle, DNA-maintenance, and neuroectodermal reprogramming pathways, indicating a highly plastic and proliferative subtype. Despite these molecular distinctions, all clusters retained an “immunologically hot” profile (IPS 7–8), indicating potential responsiveness to immunotherapy. Conclusions: These findings provide an overview of the functional characteristics of melanoma heterogeneity and identify biological processes that could be targeted by drugs for the development of tailored therapies for each subtype. Nevertheless, future studies in independent clinically annotated cohorts would be required.

Immune checkpoint inhibitors (ICIs) have radically changed the therapeutic landscape of several cancers. However, only a limited number of predictive factors are currently available in clinical practice to select patients for immunotherapy. The impact of excess weight on ICI toxicity and efficacy is presently under debate. This study was aimed at evaluating the occurrence of immune-related adverse events (irAEs) among cancer patients on ICI therapy according to baseline body mass index (BMI) and gender. The association with clinical outcomes was also analyzed. Patients and methods: One-hundred thirty patients (93 males, 37 females, median age 67 years) with diverse types of advanced cancer treated with ICIs at a single university hospital were included in the study. Patients with a previously diagnosed thyroid dysfunction were excluded from this analysis. Results: A number of irAEs occurred in 51 patients (39.2%; 33 males, 18 females). Their development significantly correlated to BMI. Overweight/obese patients experienced a higher (59.5% vs 40.5%; pvs 10.6 weeks; p=0.003) occurrence of irAEs than normal weight patients. About 65% of overweight/obese patients had an associated dysmetabolic state (i.e., hypertension, glycemic disturbances and/or dyslipidemia) and displayed higher prevalence of irAEs than those without comorbidities (p=0.019). At multivariate regression analyses, BMI was confirmed as an independent predictor of risk for developing AEs (p<0.001), with an odds ratio (OR) of 3.182 for overweight/obese patients. No differences in BMI or gender emerged in progression-free survival (PFS) and overall survival (OS) rates. Conclusions: irAEs occurred more frequently in overweight/obese patients, mainly with metabolic abnormalities. These data underline the importance of a comprehensive clinical assessment, including weight and dysmetabolic comorbidities, of patients at baseline and during ICI therapy.

Background: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs). However, post-marketing pharmacovigilance is crucial to identify real-world safety signals including sex-specific differences that may not be evident in controlled trial settings. Methods: This analysis reviewed 845 individual case safety reports (ICSRs) from the EudraVigilance (EV) database between 1 January 2021, and 8 April 2025, involving NSCLC patients treated with sotorasib. Adverse drug reactions (ADRs) were assessed by sex, seriousness, outcome, and system organ class (SOC). Disproportionality analyses were conducted to detect sex-specific safety signals, and results were compared with data from the CodeBreaK200 RCT by using a two-proportion z-test. Results: Among the ICSRs, 49.2% involved male and 40.1% female patients. Serious ADRs accounted for 47.5% of cases, with females at higher risk (relative risk [RR] = 1.31; 95% confidence interval (CI): 1.22–1.40; p < 0.0001). The most frequently reported SOCs were neoplasms (15.8%), gastrointestinal disorders (15.3%), and hepatobiliary disorders (11.5%). Four sex-specific safety signals were identified: women had a significantly increased risk of cholestasis (RR = 3.37) and hepatotoxicity (RR = 3.01), while men were less likely to report decreased appetite (RR = 0.20) and rash (RR = 0.14). Real-world data showed lower reporting of diarrhea, fatigue, nausea, and liver enzyme elevations (p < 0.0001). Conclusions: Real-world pharmacovigilance supports the RCT findings and highlights sex-specific risks, thus emphasizing the importance of sex-aware monitoring and personalized toxicity management.