ABSTRACT:The prognostic heterogeneity of multiple myeloma is mainly driven by the genomic features of myeloma cells. The International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) recently proposed a high-risk (HR) genomic model to have a consensus definition of genomic risk. We performed next-generation sequencing in the form of a panel on samples from 6528 patients with newly diagnosed multiple myeloma (NDMM) and 1583 patients at first relapse between 2019 and 2024. We observed that 22.4% of patients at diagnosis and 36.7% of patients at first relapse were classified as high risk according to the Consensus Genomic Staging. Clinical data were available for 2695 patients at diagnosis. After a median follow-up of 35 months, the median progression-free survival (PFS) was 30 months for patients with HR NDMM and 51 months for standard-risk (SR) patients (P< .0001). The HR cytogenetic criteria from the Revised- International Staging System score were not able to differentiate between HR and SR patients based on the IMS/IMWG genomic subgroups. Looking at each criterion independently, we found that the presence of del(17p), TP53 mutation, biallelic del(1p32), or the combination of intermediate-risk cytogenetics (gain 1q, del(1p32), t(4;14), t(14;16), t(14;20)) significantly reduced the PFS when compared with SR patients. Moreover, patients with several cumulating criteria had an even worse prognosis. Among SR patients, classified according to the genomic definition with normal creatinine, the median PFS for those with high β2-microglobulin was not significantly different from that of patients with normal β2-microglobulin level. This study validated the IMS/IMWG genomic definition of HR myeloma in a large cohort of patients diagnosed from 2019 onwards.
Background Artificial intelligence (AI) systems are increasingly deployed in clinical practice, particularly in radiology, pathology, endoscopy, and decision support. While these tools improve efficiency and accuracy, concerns have arisen about deskilling—the erosion of physicians’ expertise due to reliance on automation. Materials and methods We conducted a narrative review of empirical studies, randomized trials, and theoretical analyses published up to August 2025. The focus was on quantitative evidence of decreased performance following AI exposure, automation bias, and structural changes in training environments. Sources included PubMed, Embase, and gray literature. Results Evidence of clinical deskilling, though scarce, is consistent across specialties. In a multicenter randomized trial in colonoscopy, the adenoma detection rate (ADR) dropped significantly from 28.4% to 22.4% when endoscopists reverted to non-AI procedures after repeated AI use, while ADR remained stable with AI assistance (25.3%). In radiology, a controlled study of 27 breast imaging radiologists showed that erroneous AI prompts increased false-positive recalls by up to 12%, even among experienced readers. In computational pathology, experimental web-based tasks revealed that over 30% of participants reversed correct initial diagnoses when exposed to incorrect AI suggestions under time constraints. Structural deskilling has been reported in cytology following the UK’s transition to human papillomavirus primary screening, leading to an 80%-85% reduction in case volumes and consolidation of laboratories from 45 to 8 centers, with major implications for training capacity. Across domains, analyses confirm the presence of automation bias and highlight risks of diminished independent diagnostic reasoning. Conclusions Although limited in number, empirical studies consistently demonstrate that AI can inadvertently impair physicians’ performance or reduce opportunities for skill maintenance. Quantitative evidence of decreased diagnostic accuracy, error propagation, and training erosion underscores the need for longitudinal monitoring, adaptive curricula, and regulatory frameworks to mitigate deskilling. Safeguarding clinical expertise should be considered a central component of AI safety and resilience in medicine.
BACKGROUND:Dual anti-human epidermal growth factor receptor 2 (HER2) therapy plus chemotherapy followed by maintenance treatment with HER2-targeted and endocrine therapies is standard first-line treatment for hormone-receptor-positive, HER2-positive metastatic breast cancer. On the basis of preclinical and clinical data, the addition of palbociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) may overcome resistance to both endocrine and HER2-directed therapies. METHODS:In this phase 3, open-label, randomized trial, we enrolled patients with hormone-receptor-positive, HER2-positive metastatic breast cancer who did not have disease progression after four to eight cycles of chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio to receive maintenance HER2-targeted and endocrine therapies with or without palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included the objective response, clinical benefit, safety, and overall survival. RESULTS:A total of 518 patients underwent randomization: 261 were assigned to receive palbociclib and 257 to receive standard therapy. At a median follow-up of 53.5 months, patients in the palbociclib group had significantly longer progression-free survival than those in the standard-therapy group (median duration, 44.3 months vs. 29.1 months; hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; two-sided P = 0.02). Grade 3 and 4 adverse events, predominantly from neutropenia, occurred in 79.7% and 10.0% of the patients, respectively, in the palbociclib group, as compared with 30.6% and 3.6% of the patients, respectively, in the standard-therapy group. CONCLUSIONS:The addition of palbociclib to maintenance anti-HER2 and endocrine therapies led to a significant improvement in progression-free survival over standard therapy, with increased toxic effects, mainly neutropenia. (Funded by Pfizer and others; PATINA ClinicalTrials.gov number, NCT02947685.).
BACKGROUND:The KRAS p.G12D variant occurs in 5% of patients with non-small-cell lung cancer (NSCLC) and is the most common substitution variant in pancreatic ductal adenocarcinoma, occurring in 40% of patients, but no targeted therapies directed against this variant are currently approved for clinical use. Setidegrasib (ASP3082) is a first-in-class KRAS G12D-targeted protein degrader. METHODS:We conducted this phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. The primary objectives were to evaluate the safety profile, as indicated by dose-limiting toxic effects and adverse events (the primary end points), and to determine the phase 2 dose. Setidegrasib was administered intravenously once weekly at doses of 10 to 800 mg. RESULTS:Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as the phase 2 dose, adverse events occurred during treatment in all the patients, with events of grade 3 or higher in 42%. Treatment-related adverse events occurred in 93% of the patients; the most common were transient infusion-related reactions (in 80%) and nausea (in 30%). Adverse events led to discontinuation in 2 patients. Among the 45 patients with NSCLC who received the 600-mg dose, 36% (95% confidence interval [CI], 22 to 51) had a partial response, the median progression-free survival was 8.3 months (95% CI, 4.1 to could not be estimated), and the estimated 12-month overall survival was 59% (95% CI, 40 to 74). Among the 21 patients with metastatic pancreatic ductal adenocarcinoma who received the 600-mg dose as second- or third-line treatment (of whom 67% received setidegrasib as third-line treatment), 24% (95% CI, 8 to 47) had a response, the median progression-free survival was 3.0 months (95% CI, 1.4 to 6.9), and the median overall survival was 10.3 months (95% CI, 4.2 to 13.0). CONCLUSIONS:Setidegrasib was associated with antitumor activity and a low incidence of treatment discontinuation due to adverse events in patients with previously treated advanced KRAS p.G12D-mutated NSCLC or pancreatic ductal adenocarcinoma. (Funded by Astellas Pharma; ClinicalTrials.gov number, NCT05382559.).
Airborne particulate matter (PM) is a complex mixture of particles thought to be associated with a range of adverse health effects, including female breast cancer. Current evidence on the association between PM and female breast cancer risk is inconsistent. This study investigated the association between long-term exposure to PM and breast cancer risk in a nested case-control study within the French E3N-Generation cohort including 5222 breast cancer cases identified over the 1990–2011 follow-up period and 5222 individually matched controls. Annual mean concentrations of PM10 and PM2.5 at participants’ residential addresses, were estimated using a land use regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models. ORs for each 10 µg/m3 increase in the average of PM2.5 and PM10 were 1.14 (95% CI: 0.99–1.30) and 1.08 (95% CI: 0.98–1.18), respectively. When restricted to invasive ductal and lobular carcinomas, ORs were 2.74 (95% CI: 1.05–7.15) for PM2.5 and 2.05 (95% CI: 1.11–3.78) for PM10. Comparable effects of PM exposure estimated by a chemistry transport model reinforces these findings. This study suggests a potential association between PM2.5 and PM10 exposure and breast cancer risk.
