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.
BACKGROUND & AIMS:Direct-acting antiviral agents (DAA)-mediated HCV cure correlates with better outcomes, but there are insufficient data on detailed mortality-related risk factors after cure. This study sought to clarify mortality and associated risk factors post-HCV cure. METHODS:The study included HCV patients with sustained virological response following DAA (DAA-SVR) from 39 REAL-C centres in North America, Europe and Asia-Pacific. The primary outcome was all-cause mortality in DAA-SVR patients. Mortality rate per 1000 patient-years (PY) was calculated as the number of deaths divided by total PY multiplied by 1000. RESULTS:A total of 10 034 DAA-SVR patients (stratified by cirrhosis status: 5611 non-cirrhosis, 4153 compensated, 270 decompensated) were included. With a median follow-up of 4.76 PY, 4.9% (491) died. The all-cause mortality rates were 6.2, 13.1, 60.0 and 10.4 per 1000 PY for patients without cirrhosis, compensated and decompensated cirrhosis, and overall patients, respectively. The 5-year cumulative survival was 95.1% (94.5%-95.6%) overall, with the lowest rate of 73.9% (67.0%-79.5%) in decompensated cirrhosis. Non-liver-related death was the main cause in non-cirrhosis (non-liver-related vs. liver: 5.2 vs. 0.8 per 1000 PY)/compensated cirrhosis (8.2 vs. 4.8 per 1000 PY), while liver-related death was dominant in decompensated cirrhosis (24.7 vs. 33.8 per 1000 PY). Risk factors for higher mortality included age > 65 (3.2-fold), male (1.5-fold), cirrhosis (decompensated 7.6-fold) and baseline DM (1.5-fold). CONCLUSION:This study showed significant age, sex, fibrosis stage and DM differences in mortality and causes among DAA-SVR patients. It provided granular subgroup data for precision medicine to support individualised care, future modelling studies and public health planning.
We report on our initial clinical experience with partial breast proton beam therapy (PB-PBT) without tumor resection as an alternative to partial mastectomy for low-risk early-stage breast cancer. This trial commenced in 2015, and eligibility criteria included women with cT1N0M0 invasive ductal carcinoma, estrogen receptor positivity, human epidermal growth factor receptor type-2 negativity, age of 40–70 years, and a performance status of 0 or 1. In Phase I, PB-PBT was administered at 62.4 Gy (RBE) in 26 fractions using the field-in-field technique. After confirming that no serious adverse events occurred, Phase II was conducted using the same dose. Follow-up evaluations were conducted every 3 months for the first year after irradiation and every 6 months thereafter. As of December 2025, 11 patients had completed a follow-up of ≥ 5 years. The median follow-up time was 82 months. Tumors exhibited immediate shrinkage post-PB-PBT, with morphological changes on ultrasonography and magnetic resonance imaging observed within 3–6 months. No recurrence was observed within the irradiated field in patients with > 5 years of follow-up. Dermatitis was Grade 1 in 55
Background:Ipilimumab plus nivolumab (I-N) with or without chemotherapy is an established first-line treatment for advanced non-small cell lung cancer (NSCLC). For patients with a large baseline tumor size (BTS), chemotherapy combined with immune checkpoint inhibitors (ICIs) has shown better outcomes compared with ICI monotherapy. However, the specific radiographic size criteria for determining whether to prioritize the CheckMate227 or CheckMate9LA regimen are undefined. Therefore, we evaluated how BTS impacts the efficacy of I-N-based therapy in our cohort. Methods:This multicenter retrospective study was conducted across 19 institutions in Japan. Adult patients with advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) 1-49% who received I-N-based therapy as first-line systemic treatment between January 2018 and March 2022 were included. We excluded patients with EGFR or ALK mutation. Patients were classified into two groups: the I-N group and the I-N-chemo group. Survival outcomes were evaluated based on BTS (≥50 vs. <50 mm). Baseline covariates were obtained from medical records. Results:A total of 87 patients were included: 25 in the I-N group and 62 in the I-N-chemo group. Among patients with BTS ≥50 mm, median progression-free survival (PFS) was 4.0 months [95% confidence interval (CI): 0.7-6.7] in the I-N group and 5.5 months (95% CI: 3.4-8.1) in the I-N-chemo group (P=0.03). Median overall survival (OS) was 8.3 months (95% CI: 1.0-10.7) for I-N and 17.7 months (95% CI: 10.9-not reached) for I-N-chemo (P=0.005). Among patients with BTS <50 mm, there were no statistically significant differences in PFS or OS between the I-N and I-N-chemo groups. Conclusions:Our findings suggest that I-N combined with chemotherapy may be effective treatment for NSCLC patients with a high tumor burden (BTS ≥50 mm). However, given the retrospective nature of this study and the limited subgroup sample sizes, these results should be interpreted with caution.
To investigate whether preoperative computed tomography (CT)-based tumor–portal/superior mesenteric vein (PV/SMV) contact angle and contact length predict pathological venous invasion and refine prognostic stratification in anatomically resectable pancreatic ductal adenocarcinoma (R-PDAC). We retrospectively reviewed 108 patients who underwent upfront pancreaticoduodenectomy without neoadjuvant chemotherapy for pancreatic head PDAC, including 101 anatomically resectable cases and 7 borderline resectable cases with PV involvement (BR-PV). Tumor–PV/SMV contact angle and contact length were measured on multidetector CT. Their associations with pathological PV/SMV invasion, PV/SMV resection, and overall survival (OS) were analyzed. Both contact angle and contact length predicted pathological venous invasion, with optimal cutoff values of 90° for angle (AUC = 0.86) and 15 mm for length (AUC = 0.84), and both were significantly associated with pathological venous invasion and PV/SMV resection (all p < 0.001). In the subgroup with R-PDAC, however, only contact length provided meaningful prognostic stratification. Patients with contact length ≥ 15 mm had significantly worse OS than those with contact length < 15 mm (p = 0.0032) or no contact (p < 0.001), and their survival was comparable to that of BR-PV patients (p = 0.8548). In multivariable analysis, contact length ≥ 15 mm remained an independent adverse prognostic factor (HR 2.79, 95
