👤 M A Bilen

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive skeletal dysplasia caused by mutations in the We reported three siblings with DMC syndrome. Two 4-year-old monozygotic male twins, born to consanguineous parents, presented with growth retardation and developmental delay. Radiographs showed generalized platyspondyly, rhizomelic shortening and metaphyseal dysplasia, while biochemical tests excluded MPS IV. Molecular tests revealed a homozygous deletion in exon 16 of the The clinical and radiological features of our patients were consistent with DMC syndrome, with partial overlap with MPS IV. This case series represents the first reported coexistence of DMC and Down syndrome. In addition, we identified a novel homozygous deletion in exon 16 of the Show less

For decades, platinum chemotherapy was the mainstay of treating metastatic urothelial carcinoma (mUC). More recently, checkpoint inhibitors (CPI) were an important addition to the armamentarium capable of inducing durable responses for a minority of patients. Management of mUC has changed significantly with the advent of antibody-drug conjugate (ADC) therapies and fibroblast growth factor receptor inhibitors (FGFRi). Enfortumab vedotin, a Nectin-4 targeting ADC, is now the first line therapy of choice in combination with pembrolizumab. Erdafitinib, a pan FGFR1-4 inhibitor, is approved for patients with susceptible FGFR3 alterations. There are multiple other agents in development within both therapeutic classes that hold promise. But most patients will still succumb to their disease, either via primary or secondary resistance. This review looks critically at the approved and pipeline ADC and FGFR-targeting agents of interest in mUC as well as known mechanisms of resistance by which their efficacy is dampened. We propose strategies for overcoming resistance including combination strategies, tumor microenvironment modification, and drug structure modification to maximize efficacy. The progress to date in mUC has been remarkable, but there is still significant work to do in this deadly disease and this review highlights the gap between current available therapeutics and cure that so desperately needs to be closed. Show less

Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements. Show less