Hepatic Injury Induced by a Single Dose of Nivolumab - a Case Report and Literature Review.

BACKGROUND: The use of nivolumab in the treatment of metastatic melanoma has become well established during past years. Despite its undeniable efficacy, immune-related side effects may occur, including acute liver injury. Liver toxicity caused by nivolumab is usually observed as liver enzyme elevation with mild or no symptoms; further, there is limited information regarding any histopathological findings. CASE: We report a case of a 38-year-old woman with metastatic melanoma who developed unusual nivolumab-induced hepatic injury after a single dose of nivolumab. A liver biopsy was performed to assess the aetiology of hepatic lesions as no other analysis concerning biochemistry, virology, autoantibodies, nor imaging studies revealed any pathology. The histopathological analysis showed an oedema in the portal fields and mixed inflammation consisting of eosinophilic and neutrophilic granulocytes. The major finding was a prominent, predominantly intracellular, cholestasis. CONCLUSION: To our knowledge, no such histopathological pattern of liver injury has been described in relation to nivolumab therapy elsewhere. This type of liver injury shows higher resistance to corticosteroids, which may warrant upfront high-dose corticotherapy combined with other immunosuppressive agents, including mycophenolate mofetil. This case highlights a necessary awareness regarding immunotherapy-related adverse events, which could be severe and potentially life-threatening.

Analysis of DNA methylation and microRNA expression in NUT (nuclear protein in testis) midline carcinoma of the sinonasal tract: a clinicopathological, immunohistochemical and molecular genetic study.

The aim of this study was a detailed clinicopathological investigation of sinonasal NUT midline carcinoma (NMC), including analysis of DNA methylation and microRNA (miRNA) expression. Three (5%) cases of NMC were detected among 56 sinonasal carcinomas using immunohistochemical screening and confirmed by fluorescence in situ hybridization. The series comprised 2 males and 1 female, aged 46, 60, and 65 years. Two tumors arose in the nasal cavity and one in the maxillary sinus. The neoplasms were staged pT1, pT3, and pT4a (all cN0M0). All patients were treated by radical resection with adjuvant radiotherapy. Two patients died 3 and 8 months after operation, but one patient (pT1 stage; R0 resection) experienced no evidence of disease at 108 months. Microscopically, all tumors consisted of infiltrating nests of polygonal cells with vesicular nuclei, prominent nucleoli and basophilic cytoplasm. Abrupt keratinization was present in only one case. Immunohistochemically, there was a diffuse expression of cytokeratin (CK) cocktail, CK7, p40, p63, and SMARCB1/INI1. All NMCs tested negative for EBV and HPV infection. Two NMCs showed methylation of RASSF1 gene. All other genes (APC, ATM, BRCA1, BRCA2, CADM1, CASP8, CD44, CDH13, CDKN1B, CDKN2A, CDKN2B, CHFR, DAPK1, ESR1, FHIT, GSTP1, HIC1, KLLN, MLH1a, MLH1b, RARB, TIMP3, and VHL) were unmethylated. All NMCs showed upregulation of miR-9 and downregulation of miR-99a and miR-145 and two cases featured also upregulation of miR-21, miR-143, and miR-484. In summary, we described three cases of sinonasal NMCs with novel findings on DNA methylation and miRNA expression, which might be important for new therapeutic strategies in the future.