Genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma.

BACKGROUND: Urothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology. METHODS: In this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction. RESULTS: Among the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups. CONCLUSION: These findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.

Bortezomib-induced motor neuropathy: A case report.

INTRODUCTION: Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma, Waldenström's macroglobulinemia, mantle cell lymphoma. The most reported adverse effects include fatigue, thrombocytopenia, gastrointestinal symptoms, and peripheral neuropathy, which mostly manifests as sensory neuropathic symptoms. We present a case of a patient who experienced motor neuropathy after initiating treatment with bortezomib. CASE REPORT: An 87-year-old male was diagnosed with multiple myeloma and started on treatment with bortezomib, dexamethasone, and lenalidomide (VRd). After five cycles of therapy, he developed lower extremity weakness, which was severely debilitating, affecting his ability to walk, and this prompted his visit to the emergency department. MANAGEMENT AND OUTCOME: The patient was admitted for further workup and underwent electromyography, which was consistent with demyelinating polyneuropathy with active denervation. His symptoms were attributed to bortezomib, and his VRd regimen was held. His symptoms failed to improve despite discontinuation of bortezomib. He then received steroids and intravenous immunoglobulin (IViG) with a gradual resolution of his symptoms. He was thereafter restarted on only lenalidomide and dexamethasone with no recurrence of his neuropathy. DISCUSSION: Clinicians need to be aware of the likely risk for motor neuropathy associated with bortezomib. Risk factors like older age and pre-existing neuropathy can predispose patients to this adverse effect, and clinicians should monitor for this toxicity and facilitate dose reduction or discontinuation of therapy if warranted. Sometimes, patients may also need further treatment with steroids or IVIG.