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.).
PURPOSE:There is no standard second-line therapy for gastroenteropancreatic (GEP) and lung large-cell neuroendocrine carcinoma (NEC) after the failure of platinum-based chemotherapy. This study aimed to investigate the efficacy of nivolumab ± ipilimumab. METHODS:The GCO-001-NIPINEC (ClinicalTrials.gov identifier: NCT03591731) trial was a noncomparative, open-label, phase II trial. The main inclusion criteria were age ≥18 years, performance status (PS) ≤2, advanced large- and small-cell GEP-NEC and large-cell lung NEC, and second- or third-line treatment for NECs refractory to platinum-based chemotherapy. Patients were randomly assigned (1:1) and stratified by age and PS to receive nivolumab (3 mg/kg/once every 2 weeks) ± ipilimumab (1 mg/kg/once every 6 weeks) for 2 years or until progression or unacceptable toxicity. The primary end point was objective response rate (ORR) at 8 weeks, assessed by investigators. RESULTS:A total of 185 patients (91 in the nivolumab arm and 94 in the nivolumab-ipilimumab arm) were enrolled between December 2018 and March 2021; 169 were analyzed (median age of 64.5 years, 71% male, 91% PS 0-1). The main primary tumor locations were lungs (50%), colorectal (15%), gastroesophageal (14%), and pancreatic (13%) regions. The ORR at 8 weeks was 7.2% (95% CI, 2.7 to 15.1]) in the nivolumab arm and 14.0% (95% CI, 7.4 to 23.1) in the nivolumab-ipilimumab arm. The best ORR was 9.6% and 20.9%, respectively, whereas the median progression-free and overall survival were approximately 2 months and 6 months in both arms. One treatment-related death occurred, in the nivolumab arm. The grade 3-4 adverse events (≥5%) were asthenia (13%), gamma-glutamyl transferase increase (10%), alkaline phosphatase increase (9%), dyspnea (7%), and anemia (6%) in the nivolumab-ipilimumab arm. CONCLUSION:Nivolumab-ipilimumab could be a second-/third-line treatment option for patients with NECs. However, given the limited magnitude of benefit, studies are warranted to evaluate its use earlier and/or associated with chemotherapy.
Objective:W0180 is a humanised IgG1κ antagonistic monoclonal antibody against the V domain-containing immunoglobulin suppressor of T-cell activation (VISTA) designed to enhance antitumour activities by inhibiting the immunosuppressive role of VISTA in myeloid cells and T cells in solid tumours. Methods and analysis:Preclinical experiments evaluated the pharmacodynamics and antitumour activity of W0180. A first-in-human phase 1 dose-escalation study investigated the maximum tolerated dose (MTD), safety/tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics of W0180, both as monotherapy and in combination with pembrolizumab (an anti-programmed cell death protein-1 (PD-1) therapy), with the aim of establishing a recommended dose for expansion (RDE). In the monotherapy arm, cohorts of patients with locally advanced/metastatic solid tumours received once-weekly W0180 at increasing doses (from 3.5 to 600 mg). In the combination therapy arm, patients with relapsed/refractory, advanced/metastatic solid tumours and ≥1 prior anti-PD (ligand)-1 therapy line received W0180 (60 or 300 mg)+pembrolizumab. Results:W0180 exhibited pH-independent blockade of the VISTA-ligand interaction in vitro and showed antitumour activity in a syngeneic preclinical murine model expressing human VISTA. In the phase 1 study, of the 33 patients in the monotherapy (n=24) or combination therapy (n=9) arms, 28 contributed to dose determination. Dose-limiting toxicities were Grade 2 cerebral infarction and Grade 3 infusion-related reaction (IRR; n=1 each). The study was terminated prematurely in the dose-escalation phase (due to a business decision by the sponsor) before the MTD/RDE was reached. Common related treatment-emergent adverse events were IRR and fatigue; most were of mild severity. No patients achieved Response Evaluation Criteria in Solid Tumours objective response; two had prolonged stable disease (SD; one from each arm). Biomarker analysis suggested a dose-dependent pharmacodynamic effect of W0180. Conclusion:W0180 demonstrated manageable safety, preliminary signs of clinical activity with prolonged SD and dose-dependent pharmacodynamics consistent with preclinical data (even though MTD was not reached) in patients with locally advanced/metastatic tumours, both as monotherapy and in combination with anti-programmed cell death protein-1 therapy. Trial registration number:NCT04564417.
