782 Background: FOLFIRINOX is a preferred regimen for borderline and locally advanced pancreatic ductal adenocarcinomas (PDAC). Stereotactic body radiotherapy (SBRT) is promising for local disease control, and predictive markers are needed to define when FOLFIRINOX followed by SBRT is of clinical benefit. Methods: Two single-arm, phase 2 trials for borderline resectable PDAC (BRPC) and locally advanced PDAC (LAPC), were conducted at the Yale Smilow Cancer Hospital from 8/2017 – 1/2019 (NCT03099265) and 9/2019 – 9/2023 (NCT03991962). Patients received 8-12 cycles of FOLFIRINOX followed by SBRT (33 Gy in 5 fractions). Radiographic and biochemical responses (CA19-9) were assessed by a multi-disciplinary team for surgical eligibility. Endoscopic ultrasound strain elastography with core biopsies were performed pre-treatment, post-FOLFIRINOX, and post-SBRT to determine the strain ratio (tumor stiffness) and PDAC molecular subtype, respectively. The primary endpoint was 9-month progression-free survival (PFS). Additional endpoints included median PFS, median overall survival (OS), patterns of recurrence, tumor stiffness (assessed by elastography strain ratio), and PDAC molecular subtype (assessed by K17 IHC test). Results: Twenty patients (10F, 10M, median age 64) were enrolled. Thirteen had BRPC and seven had LAPC. Twelve (60%) patients received FOLFIRINOX + SBRT and three (15%) underwent surgery on protocol. Nine-month PFS was 36% (95% CI, 19-68%, expected was 50% based on LAP07). Median PFS was 8 months (95% CI, 5.8-32.4), and median OS was 13.2 months (95% CI, 9-59). The median follow-up was 72.5 months. Overall response rate was 25% with 5 partial responses. Locoregional-only recurrences were rare (10%), with most recurrences occurring at distant sites (40%) or locoregional sites (20%), indicating favorable local disease control. One patient died of oxaliplatin-related pneumonitis. Pre-treatment tumor stiffness was higher in BRPC vs. LAPC (30.5 vs. 11.4, p = 0.04), and stiffer tumors were mainly basal-like molecular subtype ( p = 0.06). Higher pre-treatment tumor stiffness had a non-significant increased risk of death (adjusted for stage, HR 3.85, 95% CI 0.79–18.84, p = 0.09), such that BRPC with higher pre-treatment stiffness exhibited survival outcomes comparable to that of locally advanced tumors. In contrast, among CA19-9 responders, tumors that became stiffer with chemotherapy had a non-statistical improved overall survival relative to tumors that became softer (HR 0.39, 95% CI 0.07-2.04, p = 0.26). Conclusions: FOLFIRINOX followed by SBRT achieved local disease control in PDAC. Tumor stiffness and molecular subtype emerged as potential biomarkers of response and prognosis, warranting validation in larger studies. Early trial closure from the COVID-19 pandemic and censoring of exceptional responders prior to SBRT likely contributed to the inferior observed outcomes. Clinical trial information: NCT03099265 , NCT03991962 .

Objective Anti-Ku antibodies (Abs) are rare and detected in various autoimmune diseases (AIDs), presenting in various phenotypes, potentially affecting different organs including the lungs. This study aimed to describe the characteristics and evolution of interstitial lung disease (ILD) in anti-Ku-positive patients. Methods An observational, multicentre, retrospective study was conducted across 10 French University Hospitals between January 2010 and June 2025, including patients with anti-Ku Abs with ILD. Clinical data and all pulmonary function tests and chest CT scans available were reviewed for this study. ILD progression was defined using criteria inspired by the American Thoracic Society/European Respiratory Society/Japenese Respiratory Society/Asociación Latinoamericana de Tórax Clinical Practice Guidelines, applied across the entire follow-up period rather than within the 12-month timeframe, to capture all clinically meaningful progression events. To account for event timing, time to ILD progression was analysed as a time-to-event outcome using Cox proportional hazards models. Results Among 154 anti-Ku-positive patients (51 with idiopathic inflammatory myopathy, 46 with systemic lupus erythematosus, 30 with Sjögren’s disease, 27 with systemic sclerosis), 60 (39%) had ILD (68% women, median age 56 years). The predominant ILD pattern was fibrotic non-specific interstitial pneumonia (27%, n=16). ILD was already present at AID diagnosis in 48 patients (80%). Forty-five (75%) patients progressed after a median time of 4 (2–11) years. Male sex (adjusted HR (aHR) 2.7; 95% CI 1.4 to 5.2) was associated with ILD progression. When the 12-month cut-off was strictly applied, only six patients fulfilled the progressive fibrosing ILD definition. Baseline pulmonary fibrosis was present in 34 (57%) patients and was associated with a reduced survival when adjusting for age at ILD diagnosis and cardiac involvement (aHR 6.5, 95% CI 1.5 to 28.2). Conclusion ILD occurred in 39% of anti-Ku-positive patients and progressed in 75% of them, underscoring the importance of systematic ILD screening and monitoring in these patients.

Background Sarcoidosis is a chronic granulomatous disease of unknown origin, and the potential involvement of microorganisms has long been debated. We conducted the present study to explore the role of microorganisms at the onset of the disease using shotgun sequencing on lymph node samples. Methods We conducted a prospective cohort study of adult patients admitted for sarcoidosis in the department of internal medicine from a tertiary referral university hospital in France ( ClinicalTrials.gov identifier NCT05916638 ). Plasma and tissue samples were collected from sarcoidosis patients prior to the initiation of treatment. Plasma controls were healthy individuals. Tissue sample controls were patients with metastatic adenocarcinoma who underwent lymph node biopsy procedures for cancer staging. Results Plasma samples were collected from 19 patients with sarcoidosis and 10 control subjects. Of the 45 proteins studied using a multiplex quantification assay, the levels of 29 were significantly higher in the sarcoidosis patients. Of these, C-X-C motif chemokine ligand 9, lymphotoxin-α and tumour necrosis factor were also significantly upregulated at the mRNA level in affected tissues. Unbiased transcriptomic analysis of lymph node tissue revealed enrichment of the interferon (IFN)-γ signalling pathway, the interleukin (IL)-2-STAT5 pathway and the IL-6-JAK-STAT3 pathway in sarcoidosis patients. Shotgun sequencing of the lymph nodes showed no evidence of bacteria, fungi, viruses or parasites in the sarcoidosis samples. Conclusion Our findings challenge the long-held belief that sarcoidosis is caused by a microorganism. The activation of the JAK-STAT and IFN-γ signalling pathways in sarcoidosis tissue indicates that JAK inhibitors could be used to treat the condition.

Cancer remains a leading cause of morbidity and mortality worldwide. Given its substantial burden, quality of life has become a key outcome in cancer care and research. Patient-reported outcome measures (PROMs) are commonly used to assess quality of life. Although qualitative research is essential for establishing PROM content validity, patient narratives are less often collected and analysed systematically once PROMs are implemented. Adding open-ended responses to quantitative PROM data may provide policy-relevant insights into what patients themselves prioritise. This study has aimed to identify the factors that people living with or beyond cancer across Europe perceive as having the greatest impact on their quality of life. Following a pan-European validation study of the newly developed EUonQoL-Kit – a set of questionnaires designed to assess the quality of life of people living with or beyond cancer in Europe – the responses to the final open-ended question “Having completed the questionnaire, what do you feel most impacts your quality of life?” were collected. Responses underwent qualitative thematic analysis using a coding framework iteratively developed and interpreted by researchers and people with lived experience of cancer involved as ‘co-researchers’. Of the 4,284 cancer patients and survivors participating in the EUonQoL-Kit validation study, 3,350 (78.2%) provided a response to the final open-ended question. Factors perceived as having the greatest impact on quality of life were categorised into 23 distinct themes, covering six overarching domains: Physical health, Psychological wellbeing, Social health, Overall health, Healthcare experience and Environment. The most frequently reported factors included physical symptoms, overall health, relationships and connectivity, emotions and feelings, and impact of care pathway. This study provides a comprehensive overview of the factors that impact quality of life most in people living with or beyond cancer across Europe. Combining structured PROMs with open-ended patient input may support more patient-centred quality of life measurement and interpretation and help align care and policy priorities with what matters most to patients.

BACKGROUND:OSE-279 is a high affinity humanized monoclonal bivalent antibody against PD-1 with potent antitumor activity in vivo in syngeneic non-clinical models. METHODS:This phase I study assessed the safety, pharmacokinetics, pharmacodynamics and antitumor activity of OSE-279 in advanced solid tumours. RESULTS:Twenty patients received OSE-279 intravenously at 100 mg q3w (n = 2), 300 mg q3w (n = 7) and 600 mg q6w (n = 11). Median age was 61.5 (range 3-81) years, 50% were female, median number of prior metastatic lines was 2 (range 1-6). Most frequent tumour types were soft tissue sarcoma (n = 4) and anal squamous cell carcinoma (n = 3). OSE-279 monotherapy was safe. Two recommended phase 2 doses were established: 300 mg q3w and 600 mg q6w. The most common (≥10%) related TEAEs were diarrhoea, dry mouth, pruritus, chills, fatigue, headache, dysgeusia and hyperthyroidism. OSE-279 PK exhibited linear dose proportionality and mean receptor occupancy was maintained above 80% in all tested doses. There were 1 CR at 300 mg q3w, 4 PRs at 600 mg q6w and 7 SD with response duration ranging from 6.8 to 18.4 months. CONCLUSION:OSE-279 monotherapy was well tolerated with durable responses in patients with advanced solid tumours. The trial is continuing with OSE-279 combined with OSE2101, a therapeutic cancer vaccine in 1st line HLA-A2 positive PD-L1 ≥ 50% NSCLC. CLINICAL TRIAL REGISTRATION (NCT NUMBER: NCT05751798).

Background: Pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab improves outcomes in high-risk early-stage triple-negative breast cancer (TNBC) in KEYNOTE-522. In France, an Early Access Program (EAP) enabled its use prior to reimbursement, providing real-world evidence on its implementation.Methods: FR-POP was a prospective, multicenter observational cohort including adults with stage II–III TNBC treated with pembrolizumab within the French EAP (April 2022–November 2024). A limited dataset, defined by the French Health Technology Assessment authority, was collected at predefined time points. Analyses were descriptive and assessed patient characteristics, treatment patterns, pathological complete response (pCR), safety, treatment modifications, and quality of life.Results: Overall, 7,687 patients were treated across 427 centers. The cohort included populations underrepresented in trials, including older patients (32.3% ≥60 years) and those with comorbidities. Chemotherapy regimens were consistent with KEYNOTE-522 in 96.1% of patients. The pCR rate was 70.8% among evaluable patients. Temporary pembrolizumab interruptions occurred in 1,105 patients and permanent discontinuations in 1,240, mainly due to suspected adverse events. Immune-related adverse events were reported in 841 patients, including 417 patients with 654 serious events, of which eight were fatal. Quality-of-life scores remained stable over time. Follow-up completion exceeded 50%.Conclusion: This nationwide cohort shows that perioperative pembrolizumab can be implemented at scale in routine practice, with outcomes consistent with clinical trial data. Despite limitations related to observational design and incomplete data, these findings provide complementary evidence on feasibility and safety in a broader, unselected patient population.

Tuberculosis (TB) continues to pose a significant global public health challenge with substantial patient morbidity and mortality. Current TB patient biomarkers lack sufficient resolution to inform treatment response and patient stratification. This necessitates the development of sensitive and reliable host biomarkers. We previously demonstrated the efficacy of TruCulture whole blood stimulation for differentiating asymptomatic TB from active pulmonary TB disease patients in endemic regions. Our systems immunology study expands upon this previous work by evaluating the potential of TruCulture to monitor longitudinal responses to TB treatment in patients from the Predict-TB trial before, during, and after 6 months of antibiotic therapy. We stimulated whole blood from TB patients (n=40) using TruCulture under four conditions (Null, Mycobacterium tuberculosis -antigen, LPS, and IL-1β) at baseline (week 0), during treatment (weeks 16 and 24), and one-year follow-up post- treatment (week 72). 20/25 measured cytokines exhibited significant changes throughout treatment, with several continuing to evolve during post-therapy follow-up. Machine learning based analysis identified Mtb -Ag-induced IL-1RA (AUC = 0.90, 0.92, 0.95 at weeks 16, 24, 72) and LPS-induced NLRP3 (AUC = 0.94 at week 16) as the best protein and transcriptional biomarkers for distinguishing treated from untreated patients, strongly implicating the inflammasome response. Combining these results with the extent of lung disease assessed by FDG PET/CT scans, we showed direct disease relevance for these blood-based biomarkers. The identified biomarker profiles hold promise for improving TB patient care through early prediction of treatment responses, real-time therapy monitoring, and informed development of host-directed therapeutic strategies for clinical decision-making. Graphical abstract:

BACKGROUND:Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. METHODS:Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). RESULTS:Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. CONCLUSIONS:Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.

Objective To determine distinct patterns of patients with autoimmune diseases harbouring anti-Ku antibodies and their respective prognosis.Methods Anti-Ku-positive patients were retrieved through four immunology departments. Clusters were derived from unsupervised multiple correspondence analysis, not including the disease’s diagnosis, followed by hierarchical clustering. Baseline characteristics and risk of disease progression, defined as a composite of new organ involvement or the need for new immunosuppressants, were compared across the retrieved clusters.Results Among 154 anti-Ku-positive patients, three clusters were identified. At disease’s onset, all patients included in cluster 1 (n=42/154, 27%) had muscle involvement, 34% displayed cardiac manifestations. Inflammatory myopathies (n=35/42, 83%) and/or systemic sclerosis (n=17/42, 40%) were the most frequent diagnoses. Cluster 2 (n=69/154, 45%) included the lowest proportion of women (68% vs 83% and 84% in clusters 1 and 3), 54% of patients had lung involvement, and 25% fulfilled Sjögren’s disease criteria. Cluster 3 (n=43/154, 28%) included younger patients (median age 25 years), with 79% of them fulfilling systemic lupus erythematosus criteria. These three clusters have distinct outcomes (p=0.001): cluster 1 developed lung involvement and displayed the higher risk of disease progression, cluster 2 was prone to myositis development and cluster 3 developed various clinical manifestations. The proportion of patients with heart involvement doubled over time in all clusters, with a majority of myocarditis in cluster 1, pulmonary hypertension in cluster 2 and pericarditis in cluster 3.Conclusion Three distinct groups of anti-Ku-positive patients were identified; cardiac involvement should be carefully tracked throughout the follow-up in all of them.

Artificial intelligence (AI) is experiencing considerable growth in medicine, driven by the explosion of available biomedical data and the emergence of new algorithmic architectures. Applications are rapidly multiplying, from diagnostic assistance to disease progression prediction, paving the way for more personalized medicine. The recent advent of large language models, such as ChatGPT, has particularly interested the medical community, thanks to their ease of use, but also raised questions about their reliability in medical contexts. This review presents the fundamental concepts of medical AI, specifically distinguishing traditional discriminative approaches from new generative models. We detail the different exploitable data sources and methodological pitfalls to avoid during the development of these tools. Finally, we address the practical and ethical implications of this technological revolution, emphasizing the importance of the medical community's appropriation of these tools.

Histopathologic evaluation of liver biopsy has played a longstanding role in the diagnosis and management of liver disease. However, the utility of liver biopsy has been questioned by some, given the improved imaging modalities, increased availability of noninvasive serologic tests, and development of artificial intelligence over the past several years. In this review, we discuss the current and future role of liver biopsy in both non-neoplastic and neoplastic liver diseases in the era of improved noninvasive laboratory, radiologic, and digital technologies.