RESUMEN
Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.
RESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is an important disease with a high incidence among patients admitted to intensive care units. Over the last decades, the survival of critically ill patients has improved; however, cognitive deficits are among the long-term sequelae. We hypothesize that acute lung injury leads to upregulation of cerebral cytokine synthesis. METHODS: After approval of the institutional and animal care committee, 20 male pigs were randomized to one of three groups: (1) Lung injury by oleic acid injection (OAI), (2) ventilation only (CTR) or (3) untreated. We compared neuronal numbers, proportion of neurons with markers for apoptosis, activation state of Iba-1 stained microglia cells and cerebral mRNA levels of different cytokines between the groups 18 hours after onset of lung injury. RESULTS: We found an increase in hippocampal TNFalpha (p < 0.05) and IL-6 (p < 0.05) messenger RNA (mRNA) in the OAI compared to untreated group as well as higher hippocampal IL-6 mRNA compared to control (p < 0.05). IL-8 and IL-1beta mRNA showed no differences between the groups. We found histologic markers for beginning apoptosis in OAI compared to untreated (p < 0.05) and more active microglia cells in OAI and CTR compared to untreated (p < 0.001 each). CONCLUSION: Hippocampal cytokine transcription increases within 18 hours after the induction of acute lung injury with histological evidence of neuronal damage. It remains to be elucidated if increased cytokine mRNA synthesis plays a role in the cognitive decline observed in survivors of ARDS.
RESUMEN
BACKGROUND: Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios. CASE PRESENTATION: We present a case of disseminated enterovirus infection resulting from combined rituximab and ibrutinib maintenance treatment in a 57-year-old Caucasian patient. with mantle cell lymphoma. Initially presenting with myositis symptoms, further diagnostic investigation revealed myocarditis, enteritis, myeloencephalitis, and hepatitis. These organ manifestations led to potentially life-threatening complications such as rhabdomyolysis, delirium, and heart rhythm disturbances. After treatment with high-dose intravenous immunoglobulins, virus clearance was achieved and organ functions could be restored. CONCLUSIONS: This case emphasizes the risk of combined therapy with rituximab/ibrutinib for severe immune-related side effects with the necessity of continuous patient monitoring. High-dose intravenous therapy should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we recommend subtyping for the development of efficient preventive and therapeutic strategies.
