Citations

Abstract Background People living with HIV (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD), but the immunological mechanisms driving plaque formation remain unclear. This study investigated the association between peripheral immune cell subsets and carotid atherosclerotic plaques in PLHIV without prior clinical ASCVD. Methods In this multi-center cross-sectional study, virally suppressed PLHIV receiving antiretroviral therapy were enrolled from two Dutch cohorts: a discovery cohort (n = 994) and a validation cohort (n = 200). Participants underwent carotid ultrasound imaging to assess plaques using standardized criteria. Immune profiling was performed using high-dimensional flow cytometry of 355 immune cell populations. Associations with plaque were analyzed using linear regression adjusted for relevant confounders, and key findings were validated in the second cohort. Transcriptomic profiles of main cell populations were evaluated using deconvoluted bulk RNA sequencing to identify differential expression and pathway enrichment. Results Carotid plaques were present in 584 participants (49%)—502 of 994 (51%) in the discovery and 82 of 200 (41%) in the validation cohort. Plaques were associated with higher counts of several CD8+ T cell subsets, particularly PD-1-expressing cytotoxic T cells with an interferon secretion profile (CD8TC1PD1+). Transcriptomic analysis of CD8+ T cells revealed downregulated mitochondrial function and upregulated type 1 interferon and epidermal growth factor receptor signaling, indicating a senescent phenotype. Conclusions CD8+ T cell senescence may contribute to early atherosclerotic plaque formation in PLHIV. Targeting immune senescence could offer a novel strategy for cardiovascular risk reduction in this population. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT03994835

The success of living donor liver transplantation (LDLT) has bridged the growing gap between organ demand and availability in patients with liver failure or liver cancer. Safety of the living liver donor (LLD) is paramount, and astute intraoperative management plays a critical role in ensuring optimal outcomes for them. Given that intraoperative surgical and anesthesia practices vary widely across centers, the International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a global consensus conference in Toronto in March 2025 to develop guidelines for intraoperative management of the LLD. This manuscript details the recommendations on intraoperative considerations for the safety of LLD developed by Working Group II of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. Working Group II focused on intraoperative monitoring, fluid and ventilation strategies, surgical techniques for vascular and biliary division, surgeon and center-specific experience, and intraoperative crises planning. These guidelines aim to support both established and emerging LDLT teams to ensure high-quality and safe intraoperative care for the LLD.

Abstract Background Liver surgery carries a high risk of complications due to the complex interplay of patient-related factors, disease characteristics, and liver function. Expertise is essential for healthcare professionals managing hepatobiliary patients. This European consensus provides evidence-based guidance on selected aspects of peri- and postoperative care. Methods A modified Delphi process was used to achieve consensus, with a 70% agreement threshold. The expert panel comprised hepatobiliary surgeons, anaesthetists, hepatologists, a specialist nurse, and a physiotherapist. A systematic literature search was conducted in PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases. Six topics were addressed: thromboprophylaxis; perioperative antibiotics; prehabilitation/nutrition/mobilization; bile leak including bilioenteric anastomosis leaks; post-hepatectomy haemorrhage; and post-hepatectomy liver failure (PHLF). Evidence appraisal and statement development followed Scottish Intercollegiate Guidelines Network methodology. A patient representative reviewed the guideline. Results Searching the literature yielded 204 included publications from an initial 6514. Thirty-two statements were formulated with a median evidence level of 2. Evidence strength varied by topic with noticeably lower evidence levels in complex surgery settings and less prevalent conditions. In some topics, study heterogeneity and specific inclusion criteria resulted in conditional recommendations, despite high-level evidence. Notably, the weakest evidence was found for perioperative thromboprophylaxis and PHLF management. Strong recommendations were formulated for prehabilitation, early postoperative mobilization, and avoidance of routine drain use. Several evidence gaps warranting multicentre studies were identified. Conclusion Optimizing peri- and postoperative care after liver resection remains challenging. Standardizing key practices and addressing evidence gaps through collaborative research are vital to improve outcomes.

Autosomal dominant polycystic kidney disease is the most common inherited kidney disorder and a leading monogenic cause of kidney failure. Reduction or loss of polycystin-1 and polycystin-2 function disrupts ciliary calcium signaling, elevates cyclic AMP (cAMP), reprograms cellular metabolism, and activates proliferative cascades that drive cyst expansion. Tolvaptan, a vasopressin V2 receptor antagonist, established cAMP modulation as a disease-modifying strategy but is limited by aquaretic effects and hepatotoxicity risk. This review highlights emerging therapeutic strategies in clinical trial development that extend beyond vasopressin antagonism. Gene-directed therapies aim to restore polycystin dosage, including anti–miR-17 oligonucleotides ( e.g ., farabursen) and pharmacochaperones that rescue misfolded polycystin-1 and restore trafficking in select PKD1 missense variants ( e.g ., VX-407). Paracrine signaling can be modulated with anti–pregnancy-associated plasma protein A antibodies that reduce insulin-like growth factor-1 bioavailability in cystic microenvironments. Metabolic reprogramming is targeted by agents such as metformin, bempedoic acid, glucagon-like peptide-1 receptor agonists, and structured dietary interventions. Sodium-glucose cotransporter 2 inhibitors hold theoretical promise but await definitive results from ongoing trials. A novel cAMP-lowering strategy through phosphodiesterase-4 activation is advancing toward clinical testing. Looking ahead, gene therapy, and genome editing offer the potential to raise polycystin levels above the threshold for cystogenesis, although challenges in vector capacity, kidney-specific delivery, and durability remain. Artificial intelligence–guided discovery, coupled with human organoid platforms, is accelerating therapeutic repurposing and rational combination design. Collectively, these advances signal a transition toward a layered, mechanism-guided framework in which vasopressin blockade is integrated with metabolic, other signaling, and genotype-specific therapies. As biomarkers and risk stratification tools mature, autosomal dominant polycystic kidney disease management is poised to become increasingly precise, tolerable, and effective.

Abstract Pancreatic cancer, projected to become the second-deadliest malignancy in Western societies by 2030, requires urgent innovations in early detection and risk stratification. Intraductal papillary mucinous neoplasms (IPMNs) represent critical precursor lesions, but current clinical guidelines demonstrate suboptimal accuracy in malignancy prediction, leading to either unnecessary surgeries or missed opportunities for early intervention. In this paper, we present Cyst-X, an artificial intelligence (AI) framework that accurately predicts IPMN malignant transformation using multicenter magnetic resonance imaging (MRI) data. Unlike most previous approaches that rely on computed tomography (CT), our method capitalizes on the superior soft tissue contrast of MRI, allowing for more precise identification of subtle imaging biomarkers. We developed and validated deep learning models on 723 T1-weighted and 738 T2-weighted MRI scans from 764 patients among seven international institutions, demonstrating significantly superior performance (AUC=0.82) compared to current clinical (Kyoto) guidelines (AUC=0.75) and expert radiologists. AI-based imaging features correlate strongly with clinically recognized malignancy markers, providing potential biologically relevant insights. This approach holds promise to significantly refine clinical decision-making, reduce unnecessary surgeries, and better identify high-risk IPMN patients for timely intervention. Our approach integrates a novel pancreas segmentation network with robust classification models that identify subtle imaging biomarkers associated with malignancy risk. Importantly, we demonstrate that these models retain high performance in a privacy-preserving federated learning setting, where institutions collaboratively train AI models without exchanging patient data to address key regulatory and ethical barriers. We publicly release the Cyst-X dataset--the first large-scale, multi-center pancreatic cyst MRI collection--to accelerate research in this field. This study addresses a critical clinical need while establishing technical foundations for privacy-preserving AI in radiology that could transform pancreatic cancer management through earlier intervention and reduced unnecessary procedures. The dataset can be accessed at https://osf.io/74vfs/, and the source code for our deep learning segmentation and classification models is available at https://github.com/NUBagciLab/Cyst-X.

Abstract Introduction: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. TRANSFORM (NCT03575351) is a global, randomized, open-label, phase 3 study of liso-cel versus SOC as second-line therapy in adults with R/R LBCL. In the TRANSFORM study, liso-cel showed superior, more durable efficacy versus SOC, with a potential long-term survival benefit and a favorable safety profile, highlighting the curative potential of liso-cel for second-line R/R LBCL. Upon completion of TRANSFORM, patients who received liso-cel could enroll into a separate, long-term follow-up (LTFU) study (NCT03435796). Here, we report results after approximately 4 years of follow-up in patients from TRANSFORM who consented to the LTFU study. Methods The TRANSFORM study compared liso-cel versus SOC (chemotherapy [R-DHAP, R-ICE, or R-GDP] followed by high-dose chemotherapy [HDCT] + ASCT) in adults aged ≤ 75 years with LBCL primary refractory to or relapsed within 12 months of first-line therapy and eligible for ASCT. Patients in the liso-cel arm underwent lymphodepletion followed by liso-cel (100 × 106 CAR+ T cells). Crossover to receive liso-cel was allowed for patients in the SOC arm. The LTFU study enrolled patients who received liso-cel and discontinued early or completed TRANSFORM; liso-cel was not administered during the LTFU study and subsequent therapies were administered at investigator discretion. Selected AEs considered related to liso-cel (malignancies, neurologic, hematologic, or rheumatologic/autoimmune disorders) and OS would be assessed at each visit (month 3 and then every 6 months from years 1 to 5, and then annually) for up to 15 years from liso-cel infusion until study withdrawal or death, whichever occurred first. OS for the combined study was defined as the time from randomization to death due to any cause. PFS for the combined TRANSFORM and LTFU studies incorporated data from TRANSFORM, assessed by an independent review committee, and from LTFU, assessed by investigators, and was defined as the time from randomization to disease progression or death from any cause. For LTFU only, OS and PFS were measured from LTFU consent to event or censoring. In cases where the patient was censored at last assessment date (without receiving new therapy) in TRANSFORM and enrolled in LTFU, LTFU data were used. For patients from the liso-cel arm of TRANSFORM who did not enroll in the LTFU study, the data from TRANSFORM were considered (ie, either an event or censored) at their last adequate assessment date or before starting new therapy. Results are reported descriptively. Results In total, 184 patients were randomized in TRANSFORM (92 per arm); key demographics and baseline characteristics were previously reported (Abramson, et al. Blood 2023). The LTFU study enrolled 67 patients who received liso-cel (liso-cel arm, n = 43; crossover from SOC arm, n = 24). The median follow-up (range) for the liso-cel arm was 16.9 months (1.3–29.7) in the LTFU study and 40.1 months (2.2–61.9) combining the TRANSFORM and LTFU studies. The median follow-ups for OS and PFS for the liso-cel arm in the LTFU study were 17.1 (16.1–21.9) and 16.9 months (16.0–21.8), respectively. In patients from the LTFU study in the liso-cel arm (n = 43), median PFS and OS were both not reached (NR) with 95% CIs of NR–NR. The 24-month rates (95% CI) of PFS and OS were 94.7% (87.4–100.0) and 95.1% (88.4–100.0), respectively. In the 92 patients randomized to the liso-cel arm, using combined data from the TRANSFORM and LTFU studies, median (95% CI) PFS was NR (12.6–NR); 48-month PFS rate was 52.2% (41.5–62.8). Median (95% CI) OS was NR (NR–NR); 48-month OS rate was 61.5% (51.2–71.7). Safety results from the LTFU study in the liso-cel arm showed no new signals compared with previous reports from TRANSFORM. AEs of any grade occurred in 2 patients (hypogammaglobulinemia and dyspnea; n = 1 each), with no second primary malignancies or serious infections. AEs of grade 3 or 4 occurred in 1 patient (dyspnea). No AEs led to death.Conclusions: After a median follow-up of approximately 4 years combining data from the TRANSFORM and LTFU studies, liso-cel continued to demonstrate long-term clinical benefit with high PFS and OS rates in patients with second-line R/R LBCL. The safety profile of liso-cel continued to be manageable with no new safety signals observed during LTFU. These results further support liso-cel as an effective second-line treatment with curative potential for R/R LBCL.

Abstract Background Erdheim-Chester disease (ECD) is a very rare histiocytic/dendritic cell neoplasm driven by mutations in genes of the MAPK pathway, such as BRAFV600E. Its clinical presentation is highly heterogeneous, and data on its natural history and prognosis in large cohorts are limited. Here, we investigated the clinical features and outcomes of a very large international cohort of patients with ECD. Methods We included patients diagnosed with ECD between 1990 and 2024, followed at 13 referral centers in Europe and the Americas, who had available clinical and follow-up data (with a minimal follow-up duration of 6 months). We analyzed the clinical presentation, treatment, and outcomes, and sought to identify predictors of survival. The study was conceived and conducted within the ECD Global Alliance network. Results A total of 1044 patients with ECD were included. The median age at diagnosis was 57 years (IQR 46-66), and the male-to-female ratio was 2.2. The median age at the first ECD manifestation was 55 years (IQR 43-65). Bone pain (20%), kidney and urinary manifestations (18%), and diabetes insipidus (11%) were the most frequently reported initial features. The median number of involved sites was 4 (IQR 3-6), most frequently including the long bones (n=768, 74%), the retroperitoneum, (n=605, 58%), the periaortic space (n=449, 43%), the CNS (n=368, 35%), the facial/orbit area (n=347, 33%), and the heart (n=334, 32%). Among 955 tested patients, 572 (60%) harbored the BRAFV600E mutation, and 86 (9%) a MAP2K1 mutation. Clinical and/or pathology overlap with Langerhans cell histiocytosis and Rosai-Dorfman-Destombes disease was observed in 115 (11%) and 42 (4%) patients, respectively. Clonal hematopoiesis was identified in 217 of 556 tested patients (39%), and a history of second cancer was reported in 272 patients (26%), including both solid (14%) and hematologic (12%) neoplasms. First-line treatment mostly included interferon-alpha (n=342, 33%) and BRAFi/MEKi (n=314, 30%), while second- and third-line treatments mostly consisted of BRAFi/MEKi (55% and 63%, respectively). After a median follow-up of 51 months (IQR 20-89), 222 (21%) patients died; causes of death were related to ECD in almost half of the patients (n=101). A multivariate Cox regression model identified the following factors as significantly associated with increased mortality: older age (HR 1.058, 95%CI 1.033-1.083; p<0.001), pseudo-neurodegenerative lesions (HR 2.280, 95%CI 1.337-3.891; p=0.022), elevated CRP at diagnosis (HR 2.574, 95%CI 1.024-6.467; p=0.044), and second hematologic cancer (HR 2.639, 95%CI 1.602-4.348; p<0.001). Conclusions Despite advances in treatments over the last decade, ECD remains associated with substantial mortality. Age, neurodegenerative lesions, elevated CRP levels, and the presence of a second hematologic cancer are the main predictors of poor survival.

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in >1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are at risk of splanchnic vein thrombosis (SVT). Prior studies failed to demonstrate a benefit of hydroxyurea in preventing SVT extension/recurrence, but these were limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. We therefore investigated the role of cytoreduction as a time-dependent covariate on thrombosis recurrence in a large, international cohort of MPN-SVT patients. Methods We performed a retrospective cohort study of MPN-SVT patients included in the international GASTRO-MPN consortium. Patients diagnosed with MPN at any time before, concurrently with, or up to 60 days after initial SVT were included. Primary outcome was time from initial SVT to first thrombosis recurrence, defined as the composite of SVT extension/recurrence, transjugular intrahepatic portosystemic shunt (TIPS) thrombosis, or venous/arterial thrombosis outside the splanchnic veins. Secondary outcomes included SVT extension/recurrence, TIPS thrombosis or extra-SVT thrombosis individually, clinically relevant bleeding (composite of major and clinically relevant non-major bleeding), MPN progression to myelofibrosis or blast phase, and death. Cytoreductive therapy was treated as a time-dependent covariate to account for discontinuation and therapy changes. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results A total of 757 patients were included for this analysis. Median age was 51 years (IQR 38-62), 59% were female. SVT involved the portomesenteric veins in 558 (77%) patients, hepatic veins in 95 (13%), and both in 54 (7.4%). MPN was known prior to initial SVT in 316 patients (42%) and diagnosed concurrently or up to 60 days after SVT in 441 (58%). Polycythemia vera (PV) was the most common MPN subtype (43%), followed by essential thrombocythemia (ET) in 24%, and primary myelofibrosis in 14%. JAK2V617F mutation was present in 86% and CALR in 2.9%. 13% had prior non-SVT thrombosis. 607 patients (83%) were treated with cytoreduction. At time of SVT, 131 patients (17%) were already on cytoreduction; in those who started after SVT, median time to initiation was 54 days after SVT, and median duration of cytoreduction per patient was 63 months. Cytoreductive therapies used at any point in treatment included hydroxyurea in 504 (69%), ruxolitinib in 182 (25%), and interferon-based in 85 (12%) patients. Anticoagulation (AC) was started within 30 days after SVT in 504 (68%) patients. Median duration of any AC per patient was 24.6 months. During a median follow up of 7.4 years, 245 patients (33%) had thrombosis recurrence; 143 (20%) had SVT extension/recurrence/TIPS thrombosis, 129 (18%) extra-SVT thrombosis (of which 74% venous), 237 patients (32%) experienced clinically relevant bleeding, and 163 (22%) died. After adjusting for age, sex, timing of MPN diagnosis relative to SVT diagnosis, AC within 30 days of SVT, PV/ET vs other MPN, JAK2 mutation, previous thrombosis, non-MPN cancer, and cirrhosis, cytoreductive therapy was associated with a significantly decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). Age was associated with an increased risk of recurrent thrombosis (p=0.01). When considering types of recurrent thrombosis, cytoreduction was associated with a decreased risk of SVT extension/recurrence/TIPS thrombosis (HR 0.62 95%CI 0.42-0.90, p=0.01), but not thrombosis outside the splanchnic veins (HR 0.97 95%CI 0.72-1.30, p=0.82). There was no association between cytoreduction and bleeding (HR 1.10 95%CI 0.82-1.47, p=0.52). Similarly, there was no association between cytoreduction and time to MPN progression (p=0.24) or overall survival (p=0.30). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=271), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.10, p=0.09) for recurrent thrombosis. Limited sample size and low event-rate precluded evaluation of the impact of individual cytoreductive therapies. Conclusions In the largest cohort of MPN-SVT patients to date, we show for the first time that cytoreductive therapy is associated with a decreased risk of thrombosis recurrence, driven largely by decreased SVT extension/recurrence/TIPS thrombosis. Collectively, these findings support use of cytoreductive therapy in individuals with MPN-SVT to prevent recurrent thrombosis.