👤 Stefano Cavalieri

Pembrolizumab, alone (monopembro) or with chemotherapy (CT+pembro), is state-of-the-art for recurrent/metastatic head and neck cancers (RM HNSCC). Direct comparisons of progression-free (PFS) and overall survival (OS) lack, but the two options are perceived as equivalent. So, the choice of first-line therapy relies on individual judgment without solid evidence. Inferring patient survivals from published curves may provide data to make inferences. Kaplan-Meier curves from Keynote 048 trial publications were digitized and reconstructed to infer individual patient data for CPS≥ 1, CPS1-19, and CPS≥ 20 subgroups. Restricted mean survival time differences (RMSTD) in PFS and OS at 12 months were estimated to quantify survival benefits. The 12-month RMSTD in PFS was significantly longer in CT+pembro over monopembro: CPS≥ 1 (1.04 months, p = 0.004), CPS1-19 (1.09 months, p = 0.027), and CPS≥ 20 (1.17 months, p = 0.027). No OS differences were observed. The PFS benefits challenge the perception of equivalence between monopembro and CT + pembro in RM HNSCC. These results emphasize the need to reconsider chemo-free approaches in everyday practice and in clinical trial design. The implications of a PFS benefit, including quality of life, in absence of OS gain should be weighed against toxicities in shared decision-making. Show less

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Show less

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. Show less