Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Clinicaltrials.gov NCT00126672

Nephrogenic systemic fibrosis: concepts and perspectives Fibrose nefrogênica sistêmica: conceitos e perspectivas

Nephrogenic systemic fibrosis is a chronic, progressive condition that develops in some patients with renal impairment after exposure to gadolinium-based contrast agents used in magnetic resonance imaging. Thickening of the skin is typical, usually affecting the extremities. Visceral organs can also be affected. The diagnosis of the disease requires careful clinicopathological correlation. Treatment aims at restoring renal function, which is associated with delayed progression and, eventually, remission of skin changes. Reduction and prevention of nephrogenic systemic fibrosis cases are based on limiting the use of gadolinium-based contrast agents in patients with kidney disorders (especially in patients with advanced renal failure at stages 4 and 5), and restricting their use to situations in which they are essential to diagnosis/follow-up. Other than limiting exposure to gadolinium based contrast agents, no effective preventive methods have been reported. Due to increased awareness about the disease among radiologists and nephrologists, the incidence of nephrogenic systemic fibrosis is declining.<br>Fibrose nefrogênica sistêmica é condição crônica, progressiva, desenvolvida caracteristicamente em pacientes nefropatas após exposição a contrastes radiológicos que contenham gadolínio. O espessamento cutâneo é aspecto típico, envolvendo predominantemente as extremidades. Envolvimento visceral pode ocorrer. O diagnóstico da doença requer cuidadosa correlação clínico-patológica. O tratamento visa à restauração da função renal, que se associa ao retardo da progressão e, eventualmente, remissão das alterações cutâneas. A prevenção da ocorrência e redução da incidência baseiam-se na limitação do uso de contrastes à base de gadolínio em nefropatas (especialmente na insuficiência renal avançada em estágios 4 e 5), restringindo-os às condições nas quais seja imprescindível ao diagnóstico/acompanhamento. À exceção da restrição de exposição aos agentes de contraste a base de gadolínio, não há métodos preventivos efetivos relatados. Devido à ampla divulgação da doença entre radiologistas e nefrologistas, a incidência da fibrose nefrogênica sistêmica está em declínio