BACKGROUND:The aim of this study was to investigate the clinical and biological impact of TP53 gain-of-function (GOF) mutations in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Although concurrent TP53 mutations are associated with poor outcomes in EGFR-mutant NSCLC, the specific impact of TP53 GOF mutations on resistance to EGFR tyrosine kinase inhibitors has remained unknown. MATERIALS AND METHODS:Genomic profiling was performed for pretreatment tumor samples from 140 individuals with advanced or recurrent EGFR-mutant NSCLC who received first-line osimertinib monotherapy. TP53 mutations were functionally classified into GOF and non-GOF mutations. Progression-free survival (PFS) was evaluated according to TP53 status. Underlying biological characteristics of tumors positive for TP53 mutations were explored by transcriptome analysis in 53 patients. RESULTS:TP53 mutations were detected in 64 (45.7%) of 140 patients, with GOF and non-GOF mutations being identified in 19 (13.6%) and 45 (32.1%) patients, respectively. PFS was significantly shorter in individuals with TP53 GOF mutations than in those wild type for TP53 (median of 12.0 versus 31.4 months, P = 0.0016) or those with TP53 non-GOF mutations (median of 12.0 versus 21.9 months, P = 0.038). The GOF mutations were not associated with baseline clinical features or a reduced objective response rate, suggestive of a role in early development of osimertinib resistance. Transcriptomic analysis revealed upregulation of the ephrin signaling pathway in TP53 GOF-mutant NSCLC. CONCLUSIONS:TP53 GOF mutations define a biologically and clinically distinct subtype of EGFR-mutant NSCLC characterized by early resistance to osimertinib.
OBJECTIVE:Hyperphosphatemia is a well-established predictor of mortality in hemodialysis patients. However, its impact may vary depending on clinical conditions. We examined whether serum albumin and creatinine (Cr) levels modify the association between hyperphosphatemia and mortality. DESIGN AND METHODS:We conducted a prospective, multicenter cohort study involving 3,050 patients on maintenance hemodialysis, followed for up to 4 years. The primary outcomes were all-cause and cardiovascular mortality. Serum phosphorus levels were the main exposure; serum albumin and Cr levels were evaluated as potential effect modifiers. Sensitivity analyses were performed using the Geriatric Nutritional Risk Index and modified creatinine index. Cox proportional hazards models were used to assess mortality risk. RESULTS:Over a median follow-up of 3.5 years, 639 patients died, including 227 from cardiovascular causes. In multivariable-adjusted models, hyperphosphatemia was significantly associated with higher risks of both all-cause and cardiovascular mortality. Stratified analyses revealed that this association was significant only in patients with higher serum albumin or lower Cr levels. Among patients with lower albumin or higher Cr, the association was not significant. Significant interaction effects were observed between serum phosphorus and both albumin and Cr, highlighting a potential modifying role of nutritional and muscular status in phosphate-related mortality risk. In sensitivity analyses, similar patterns were observed, with the association between hyperphosphatemia and mortality being more evident among patients with higher Geriatric Nutritional Risk Index and lower modified creatinine index. CONCLUSION:The prognostic impact of hyperphosphatemia may differ according to serum albumin and Cr levels in patients undergoing hemodialysis.
Abstract Background Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) are a major cause of antibody-mediated rejection (AMR) after kidney transplantation. Routine pretransplant screening usually focuses on HLA typing and antibodies against HLA-A, -B, -C, -DRB1, and -DQB1. HLA-DPB1 typing is not always included because HLA-DPB1 antigens are expressed at relatively low levels and have historically been considered less immunogenic. However, emerging evidence suggests that anti-HLA-DPB1 antibodies may be sometimes clinically significant. Case presentation A 35-year-old woman with end-stage kidney disease caused by glycogen storage disease type II underwent ABO-compatible(O → A) living kidney transplantation from her mother. Pretransplant immunological evaluation revealed negative complement-dependent cytotoxicity and flow cytometric crossmatch results, and no DSA against HLA-A, -B, -C, -DRB1, or -DQB1 were detected. On postoperative day 2, the patient developed acute pancreatitis. Therapeutic drug monitoring showed trough levels of tacrolimus of 3.5 ng/mL and mycophenolate mofetil of 0.8 μg/mL. Although these levels were within the therapeutic range, drug-induced pancreatitis was suspected on the basis of the clinical course. On postoperative day 4, the patient developed anuria and Doppler ultrasonography demonstrated loss of diastolic blood flow in the transplanted kidney. Despite aggressive fluid resuscitation, graft perfusion did not improve. Graft biopsy could not be performed because cellulitis around the graft region and thrombocytopenia increased the risk of complications. HLA-DPB1 typing and DSA re-evaluation revealed a DSA against HLA-DPw5 (DPB1*05:01) with a normalized mean fluorescence intensity (nMFI) of 10,562. Retrospective analysis of the stored pretransplant serum sample revealed the same antibody with an nMFI of 2,792. Treatment with plasmapheresis and rituximab was initiated, and graft function gradually recovered to creatinine 1.0 mg/dL after approximately 3 weeks of anuria. Conclusions This case suggests that anti-HLA-DP antibodies may be sometimes clinically relevant and could be considered in selected cases, particularly those with a history of pregnancy, blood transfusions or previous transplants, or in cases where unexplained early graft dysfunction is observed.
