Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers. These include ASPSCR1–TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1–TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs. Here we examined the functional properties of the ASPSCR1–TFE3 fusion oncoprotein, defined its target promoters on a genome-wide basis and performed a high-throughput RNA interference screen to identify which of its transcriptional targets contribute to cancer cell proliferation. We first confirmed that ASPSCR1–TFE3 has a predominantly nuclear localization and functions as a stronger transactivator than native TFE3. Genome-wide location analysis performed on the FU-UR-1 cell line, which expresses endogenous ASPSCR1–TFE3, identified 2193 genes bound by ASPSCR1–TFE3. Integration of these data with expression profiles of ASPS tumour samples and inducible cell lines expressing ASPSCR1–TFE3 defined a subset of 332 genes as putative up-regulated direct targets of ASPSCR1–TFE3, including MET (a previously known target gene) and 64 genes as down-regulated targets of ASPSCR1–TFE3. As validation of this approach to identify genuine ASPSCR1–TFE3 target genes, two up-regulated genes bound by ASPSCR1–TFE3, CYP17A1 and UPP1, were shown by multiple lines of evidence to be direct, endogenous targets of transactivation by ASPSCR1–TFE3. As the results indicated that ASPSCR1–TFE3 functions predominantly as a strong transcriptional activator, we hypothesized that a subset of its up-regulated direct targets mediate its oncogenic properties. We therefore chose 130 of these up-regulated direct target genes to study in high-throughput RNAi screens, using FU-UR-1 cells. In addition to MET, we provide evidence that 11 other ASPSCR1–TFE3 target genes contribute to the growth of ASPSCR1–TFE3-positive cells. Our data suggest new therapeutic possibilities for cancers driven by TFE3 fusions. More generally, this work establishes a combined integrated genomics/functional genomics strategy to dissect the biology of oncogenic, chimeric transcription factors.

Background The advent of anti-PD1 therapy for cancer treatment has led to improvements in response rates and overall survival. However, anti-PD1 therapy has the potential to cause immune-related adverse events (irAEs), which can be treated with corticosteroids if severe. The clinical implications of concomitant immunotherapy and systemic steroids remain unclear, as short courses of steroids do not significantly suppress T-cell function. The primary objective of this study is to determine if the use of concomitant steroids impacts the efficacy of anti-PD1 therapy. Methods This retrospective, single-center study reviewed adult patients who received at least four cycles of nivolumab or pembrolizumab for the treatment of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma from November 2014 to February 2016. Patients who received steroids (prednisone equivalent >10 mg) during anti-PD1 therapy were divided into two main cohorts based on the duration of steroid administration of ≤2 weeks or >2 weeks. Time to disease progression, overall response, and overall survival were assessed. Results Twenty-seven of 55 patients (13 melanoma, 11 NSCLC, 3 renal cell carcinoma) required steroids during anti-PD1 therapy. In patients who received steroids, median time to disease progression was 5.6 months for melanoma, 5.8 for NSCLC, and 2.0 for renal cell carcinoma. The overall response rate (ORR) was 3/13 (23%) for melanoma, 6/11 (54%) for NSCLC, and 1/3 (33%) for renal cell carcinoma. Median overall survival was 11.9 months for melanoma, 9.9 for NSCLC, and not reached for renal cell carcinoma. Thirteen patients who had received steroids expired; 11 of these patients had received prednisone >10 mg/day for >2 weeks. Conclusion High-dose steroids for long durations during anti-PD1 therapy may be associated with poorer survival outcomes.

The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P ‫؍‬ 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P ‫؍‬ 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P ‫؍‬ 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died.

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