A Rare Case of Acute Kidney Injury with Central Nervous System Manifestations.

Multiple myeloma (MM) is usually a disease of the elderly and only less than 1% are young individuals below 35 years of age. Central nervous system (CNS) manifestations of MM are even rarer, the most common being leptomeningeal involvement. We report a case of a 35-year-old male who presented with a fever of 3 weeks duration associated with slurring of speech, nasal regurgitation, hearing loss, and decreased urine output. CNS examination showed IX, X, and XII cranial nerve palsies with right otitis media and bilateral mastoiditis with conductive hearing loss. Renal biopsy showed cast nephropathy. The kappa-lambda ratio was 18, with ß2 microglobulin measuring 12 mg/L. Bone marrow showed 90% plasma cells, and skeletal survey had bony lytic lesions. He responded well to dexamethasone, bortezomib, and thalidomide. His renal functions returned to normal, and palsies have improved completely. This report shows that MM should be suspected even in young patients with classical features of myeloma and CNS involvement is very rare in MM.

Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies.

Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures. Immunohistochemical analysis of IBC patient tumor samples with documented tumor emboli revealed high NFκB (p65) staining along with expression of XIAP, a potent anti-apoptotic protein known to interact with NFκB signaling in enhancing survival of malignant cells. Subsequently, the high content assay developed allowed for simultaneous imaging and morphometric analysis, including count and viability of spheroids derived from SUM149, rSUM149 and SUM190 cells and its application to evaluate XIAP and NFκB inhibitory agents. We demonstrate the efficacy of the off-patent drug disulfiram when chelated with copper, which we had previously reported to inhibit NFκB signaling, was highly effective in disrupting both IBC spheroids and emboli grown in vitro. Taken together, these results identify a high-throughput approach to target tumor spheroid formation for drug discovery. Finally, disulfiram is a safe and approved drug for management of alcohol abuse, warranting its evaluation for repurposing in IBC therapy.