Citations

Background: Immunotherapy-based regimens have expanded the treatment landscape for unresectable hepatocellular carcinoma (uHCC); however, real-world data are limited. Methods: This retrospective, observational study used data from electronic medical records from Mayo Clinic sites across the United States. Patients with uHCC who initiated a first-line (1L) systemic therapy between June 2020–October 2022 with ≥2 follow-up visits were included. Treatment patterns, overall survival (OS), and post-index gastrointestinal (GI) bleeding were assessed by GI bleeding risk defined by Child–Pugh Class B or C, pre-index GI bleeding, uncontrolled hypertension, or significant varices and band ligation. Results: Of 186 included patients, 68.8% had GI bleeding risk and 31.2% did not. Atezolizumab plus bevacizumab was the most common 1L systemic therapy in patients with or without GI bleeding risk (72.7% and 29.3%, respectively). Median OS (95% confidence interval) with atezolizumab plus bevacizumab was 12.8 (8.0–19.3) months and not reached in patients with and without GI bleeding risk, respectively. OS rates with atezolizumab plus bevacizumab in patients with or without GI bleeding risk, respectively, were 52.3% and 70.6% at 12 months, 41.6% and 57.8% at 18 months, and 34.6% and 51.3% at 24 months. Post-index GI bleeding with atezolizumab plus bevacizumab occurred in 19.4% and 5.9% of patients with and without GI bleeding risk, respectively. Conclusions: During this study period, atezolizumab + bevacizumab was the most common 1L therapy for patients with uHCC, regardless of GI bleeding risk. OS rates with atezolizumab + bevacizumab were lower in patients with versus without GI bleeding risk. Findings highlight the unmet need for guidance on characteristics-driven treatment decisions.

Purpose To compare clinical outcomes between augmented subchondral drilling (aSCD) and nonsubchondral drilling (NoSCD) techniques, both using a cartilage scaffold, in the treatment of isolated patellar cartilage lesions. Methods A retrospective cohort study was conducted on patients who underwent surgical treatment for isolated patellar cartilage using either an aSCD technique (a subchondral drilling augmented with a particulated cartilage allograft scaffold or a flexible osteochondral allograft scaffold) or a NoSCD technique (a particulated juvenile articular cartilage scaffold or a flexible osteochondral allograft scaffold implanted without performing a subchondral drilling). Patients were included if they had a minimum 2‐year follow‐up and excluded if they underwent concomitant meniscal or ligamentous procedures. While tibial tubercle osteotomy (TTO) was commonly performed, it was not a strict inclusion criterion. All procedures were performed through arthrotomy with a standardized postoperative rehabilitation protocol. Clinical outcomes included International Knee Documentation Committee (IKDC) and Lysholm scores, reoperation rates, conversion to total knee arthroplasty, and complications. Results A total of 65 knees were included: 31 in the aSCD group and 34 in the NoSCD group, with a mean follow‐up of 50.4 months (range, 24‐88 months). In the aSCD group, particulated allograft cartilage hydrated with platelet‐rich plasma was used in 80.7% of cases and flexible osteochondral allograft in 19.3%, while the NoSCD group was treated with Cartiform (Arthrex) in 70.6% and particulated juvenile articular cartilage in 29.4% of cases. TTO was performed in 87.0% of aSCD and 91.2% of NoSCD cases. Average defect sizes were 3.7 cm 2 (aSCD) and 4.0 cm 2 (NoSCD). At final follow‐up, the NoSCD group had significantly better outcomes, with higher median IKDC scores (81.0 vs 74.0; P < .001) and median Lysholm scores (83.0 vs 77.0; P < .001). A significantly greater proportion of NoSCD patients exceeded the minimal clinically important difference for IKDC (100% vs 80.6%; P = .024) but not for Lysholm (97.1% vs 93.5%; P = .935) at final follow‐up. In multivariable regression adjusting for scaffold type, TTO, and defect size, aSCD remained a significant independent predictor of lower final IKDC (β = –8.97; P = .001) and Lysholm (β = –12.71; P < .001) scores. The aSCD group had a significantly higher rate of repeat surgery (45.2% vs 14.7%; P = .015). There was no significant difference in conversion to total knee arthroplasty between groups ( P = .432). Conclusions For the treatment of isolated patellar cartilage lesions, a nonsubchondral drilling technique with scaffolding was associated with improved patient‐reported outcomes and fewer complications compared to a subchondral drilling technique with scaffolding, although there was no difference in the rate of conversion to total knee arthroplasty. Level of Evidence Level III, retrospective comparative study.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure with no effective treatment. While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence. Methods and results ZSF1-Obese rats, a cardiometabolic model of HFpEF, were used to investigate systemic and cardiac inflammation, and to characterise the senescent program in immune, circulating endothelial and cardiac cells, before disease onset and onward. Using patient samples, we further evaluated the association between cellular senescence and diagnostic and prognostic markers of HFpEF. Finally, we administered a senolytic - Navitoclax - at two time-points, before and after the appearance of HFpEF. Conclusion ZSF1-Obese rats had increased immune and endothelial senescent cells in their peripheral blood and myocardium, together with exacerbated systemic inflammation and endothelial damage, compared to control ZSF1-Lean rats. Moreover, increased circulating senescent leucocytes were associated with markers of disease severity in patients with HFpEF. Senescent cell clearance decreased circulating B-type natriuretic peptide levels and attenuated inflammation, vascular remodelling, and cardiac fibrosis. Additionally, it improved renal function and reduced pulmonary oedema. Our findings suggest that senotherapeutics may improve the treatment for HFpEF by attenuating systemic effects of the disease whilst reducing cardiac fibrosis and endothelial rarefaction.

Abstract INTRODUCTION M0 images were missing in Siemens ASL data in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, prohibiting cerebral blood flow (CBF) quantification. METHODS A conditional latent diffusion model was trained and evaluated on in‐house datasets, then applied to the Siemens data in ADNI‐3. Regional CBF differences by Alzheimer's disease (AD) stages, their accuracy for AD classification, and CBF trajectory slopes were compared between generated data (Siemens) and acquired data (General Electric). RESULTS The diffusion model generated M0 images with high fidelity (SSIM = 0.918 ± 0.023, PSNR = 31.361 ± 2.537) and minimal CBF bias (mean difference is 0.21 ± 1.58 mL/100 g/min). Both generated and acquired CBF showed similar spatial patterns and decreasing trends with AD progression in specific AD‐related regions. Generated CBF also improved accuracy in classifying AD stages compared to qualitative perfusion images. CONCLUSION This study shows the potential of diffusion models for imputing missing modalities in large‐scale studies exploring the use of ASL as a biomarker of AD. Highlights Using latent diffusion model, we can generate M0 image from control image in arterial spin labeling (ASL) with high fidelity. The generated M0 can be used for cerebral blood flow (CBF) quantification in Alzheimer's Disease Neuroimaging Initiative dataset. The performance of classification between Alzheimer's disease (AD) patients and cognitive normal people is better when using generated CBF maps than using non‐quantitative perfusion images. ASL CBF decreases with AD progression in key AD‐related brain regions.

Abstract Purpose: Mouse models demonstrate a role for RANK and its ligand, RANKL, in osteosarcoma. The primary objective of this single-arm, open-label phase 2 trial was to determine whether denosumab, a RANKL mAb, improved disease control in recurrent osteosarcoma relative to benchmarks derived from historic Children’s Oncology Group clinical trial data. Patients and Methods: Skeletally mature patients ages 11 to 49 years old with measurable disease were eligible for cohort 1, and those with complete surgical resection of all sites of disease were eligible for cohort 2. Patients received denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D supplementation. The primary endpoints were RECIST response and remaining event-free for 4 months for cohort 1 and remaining event-free for 12 months for cohort 2. Toxicity, pharmacokinetics, and pharmacodynamic effects were additional endpoints. Results: Fifteen patients in cohort 1 and 38 in cohort 2 were eligible and evaluable for the primary endpoint. One of 15 cohort 1 patients remained event-free at 4 months. There were no objective responses. Ten of 38 cohort 2 patients were event-free at 12 months. The predefined efficacy criteria were not met in either cohort. The most common ≥ grade 3 adverse events were hypocalcemia and hypophosphatemia (8% and 11%, respectively). At steady state, mean serum denosumab trough concentrations were 23.7 to 31 μg/mL in cycles 2 to 7. Serum c-telopeptide and urine n-telopeptide decreased on treatment. Conclusions: Denosumab was well-tolerated with anticipated side effects and pharmacokinetic and pharmacodynamic parameters but had insufficient activity for further development in osteosarcoma.

Background Immune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs. Methods We carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6–8 weeks after ICI initiation. Findings were validated in two external cohorts. Results We identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8) , OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade ≥2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade ≥2 (OR 3.02; 95% CI 1.83 to 5.02; p<0.001), grade ≥3 (OR 3.59; 95% CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95% CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group. Conclusions Novel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

ABSTRACT Objectives This portion of the Geriatric Emergency Department (GED) Guidelines 2.0 focuses on delirium in the emergency department (ED). Methods A multidisciplinary group applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and develop recommendations related to older ED patients with possible delirium. Results The GED Guidelines 2.0 Delirium Work Group derived six evidence‐based recommendations for risk stratification, diagnosis, and brain imaging. To reduce universal screening, the Delirium Risk Score may be used to identify older adults at low risk for delirium, though the evidence certainty is very low. In adults over 65 admitted to ED observation units, Zucchelli's risk assessment tool (threshold ≥ 4) may stratify delirium risk, also with very low certainty. For adults over 75, the REDEEM Score may be used to identify low‐ or high‐risk individuals, again with very low certainty. For diagnosis, 4AT, bCAM, CAM‐ICU, mCAM, AMT‐4, or RASS may be used to rule delirium in or out, based on very low certainty. The Delirium Triage Screen (DTS) may be used to rule out, but not to rule in, delirium, also with very low certainty. For diagnostic imaging, there is very low certainty of evidence to recommend for or against obtaining a head CT as part of the evaluation for older ED patients with delirium. All recommendations are conditional, reflecting very low certainty of evidence due to the lack of high‐quality ED‐based studies and comparative effectiveness research. Conclusion Rigorous ED‐based research is needed to strengthen evidence and guide delirium care for older adults in geriatric emergency medicine.

Background. Measles, mumps, and rubella (MMR) in solid organ transplant (SOT) recipients is rare. We aim to investigate the pretransplant seroprevalence, MMR infection posttransplant, and whether immediate pretransplant MMR vaccination is associated with MMR infection. Methods. We queried the TriNetX database in December 2024 to assess (1) pretransplant MMR seroprevalence, (2) characteristics and outcomes of posttransplant MMR infections, and (3) outcomes for recipients who received the MMR vaccine within 30 d pretransplant. Only US data were included. MMR infection was identified through International Classification of Diseases (ICD) codes. Results. Among 313 548 SOT recipients identified in the database (from 2009 to 2024), IgG positivity for MMR was 72%, 80%, and 78% when available (~5% each). Based on ICD codes, posttransplant MMR infections occurred in 107 (0.03%), 124 (0.04%), and 38 (0.01%) recipients, respectively. The 90-d rejection rates were 36%, 27%, and 42%, whereas mortality rates were 7%, 8%, and 5%, respectively, in patients with MMR infection. Among 114 recipients vaccinated within 30 d pretransplant, none developed posttransplant MMR infections. Conclusions. Overall, posttransplant MMR infections in adult SOT recipients were uncommon in this data set, and no vaccine-associated infections were documented among those who received the MMR vaccine within 30 d pretransplant in real-world practice. The primary limitation of this study is that most MMR infections were identified using ICD codes without confirmation through serological testing or polymerase chain reaction, and we were unable to further characterize the infections because the de-identified database lacked information on the patient’s ZIP code and transplant hospital. Our study highlights the need for improvement in MMR serology screening and pretransplant MMR vaccination.

Background: Patients with non-English Language Preference are at risk of adverse health outcomes, particularly at end of life and during serious illness. Medical interpreters often feel unprepared to interpret conversations about serious illness. Best practice guidelines recommend a pre-encounter huddle between clinician and interpreter to better prepare both providers. The CHECK-IN (Check in for Exchange of Clinical and Key Information) guide is a simple communication tool designed to facilitate this pre-encounter huddle. We describe the results of a pilot feasibility study of the CHECK-IN guide performed in a simulation environment. The primary objectives of the study were to evaluate the feasibility, acceptability, and preliminary performance of the CHECK-IN guide. Methods: This U.S.-based study is a single-center simulation-based nonblinded randomized pilot feasibility study. Participating clinicians were randomized to usual practice (control) vs. introduction to the CHECK-IN guide (intervention). Clinicians completed pre- and post-session surveys. Participating clinicians were evaluated using the Faculty Observation Rating Scale (FORS), Interpreter Scale (IS), and Interpreter Impact Rating Scale (IIRS). Results: Participants had a highly favorable opinion on the acceptability, appropriateness, and feasibility of the CHECK-IN tool; 91% of participants agreed/strongly agreed on the acceptability of the tool, 91% agreed/strongly agreed on the appropriateness of the tool, and 100% agreed/strongly agreed on the feasibility of the tool. There were no statistical differences between control and intervention groups for the IS, IIRS, and FORS scores. Conclusion: The CHECK-IN guide is a promising tool to guide a pre-encounter huddle between clinician and interpreter, thereby improving interpreter-mediated communication when having conversations about serious illness.