Aplastic anemia secondary to nivolumab and ipilimumab in a patient with metastatic melanoma: a case report.

BACKGROUND: Immune checkpoint blockade (ICB) is becoming an increasingly prevalent strategy in the clinical realm of cancer therapeutics. With more patients being administered ICB for a host of tumor types, the scope of adverse events associated with these drugs will likely grow. Here we report a case of aplastic anemia (AA) in a patient with metastatic melanoma secondary to dual ICB therapy. To our knowledge, this is only the second case of AA secondary to dual ICB in the literature, and the first to have a positive patient outcome. CASE PRESENTATION: A 51-year old male with metastatic melanoma was started on dual immune checkpoint blockade, in the form ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Two weeks following the second cycle, he presented to the emergency department with profound polypipsia, polyuria and fatigue. The patient was diagnosed with diabetic ketoacidosis secondary to immune therapy induced type-1 diabetes and was admitted to the ICU. While in hospital the patient developed a symptomatic anemia and neutropenia. A bone marrow biopsy revealed a markedly hypocellular marrow with trinlineage hypoplasia with no evidence of myelodysplasia, neoplasm or excess blasts. Flow cytometry revealed an inverted CD4+:CD8+ ratio and an absence of hematogones. Taken together the presumed etiology was AA secondary to immunotherapy. The patient was subsequently started in IV methylprednisone 70 mg/day for 8 days, followed by a prednisone taper. This intervention rectified the bicytopenia and to date the patient has shown stable blood counts. CONCLUSION: With the use of ICBs becoming increasingly prevalent in the clinical arena, the number of patients presenting with immune-related adverse events will likely increase. The current case illustrates the need to be vigilant when managing cancer patients receiving ICB. The resolution of this patient's AA with corticosteroids highlights the value of early detection and appropriate treatment of these rare immune-mediated adverse events.

RNA-Seq profiling reveals aberrant RNA splicing in patient with adult acute myeloid leukemia during treatment.

BACKGROUND: Multiple genetic alterations that affect the process of acute myeloid leukemia (AML) have been discovered, and more evidence also indicates that aberrant splicing plays an important role in cancer. MATERIALS AND METHODS: We present a RNA-Seq profiling of an AML patient with complete remission after treatment, to analyze the aberrant splicing of genes during treatment. We sequenced 3.97 and 3.32 Gbp clean data of the AML and remission sample, respectively. Firstly, by analyzing biomarkers associated with AML, to assist normal clinical tests, we confirmed that the patient was anormal karyo type, with NPM1 and IDH2 mutations and deregulation patterns of related genes, such as BAALC, ERG, MN1 and HOX family. Then, we performed alternative splicing detection of the AML and remission sample. RESULTS: We detected 91 differentially splicing events in 68 differentially splicing genes (DSGs) by mixture of isoforms (MISO). Considering Psi values (Ψ) and confidence intervals, 25 differentially expressed isoforms were identified as more confident isoforms, which were associated with RNA processing, cellular macromolecule catabolic process and DNA binding according to GO enrichment analysis. An exon2-skipping event in oncogene FOS (FBJ murine osteosarcoma viral oncogene homolog) were detected and validated in this study. FOS has a critical function in regulating cell proliferation, differentiation and transformation. The exon2-skipping isoform of FOS was increased significantly after treatment. CONCLUSIONS: All the data and information of RNA-Seq provides highly accurate and comprehensive supplements to conventional clinical tests of AML. Moreover, the splicing aberrations would be another source for biomarker and even therapeutic target discovery. More information of splicing may also assist the better understanding of leukemogenesis.

Detection of prostate cancer related copy number variations with SNP genotyping array.

AIM: Prostate cancer is characterized by the accumulation of multiple copy number variants (CNVs) across the genome. We aim to identify potential prostate cancer related CNVs. MATERIALS AND METHODS: Whole-genome SNP genotyping data of 18 prostate cancer patients was downloaded from the GEO (Gene Expression Omnibus) database. PennCNV was used to detect CNVs. All genes and miRNAs affected by CNVs were annotated. We also identified biological processes where these genes over-represented to capture the characteristics of prostate cancer. RESULTS: Dominance of deletions was identified in all subjects. A total of 131 genes and 2 miRNAs which were affected by CNVs supported by at least two samples were detected. Over-representations of biological processes related with immune or inflammation response and cell cycle were identified. Two miRNAs, hsa-miR-1302 and hsa-miR-548j, were affected by CNVs and their target genes were reported to be related with prostate cancer according to the Mendelian Inheritance in Man database. CONCLUSIONS: We identified genes known to be affected by prostate cancer associated CNVs in previous studies; we also identified new genes and miRNAs not reported as interesting. The discoveries in this study may advance the knowledge of the prostate cancer pathogenesis.