Citations

Abstract Context Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. Objective This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. Methods The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. Results At week 38, lonapegsomatropin significantly reduced trunk percent fat (−1.68% vs +0.37%; least squares [LS] mean difference −2.04%; P < .001), increased total body lean mass (+1.60 kg vs −0.11 kg; LS mean difference 1.70 kg; P < .0001), and reduced trunk fat mass (−0.48 kg vs +0.22 kg; LS mean difference −0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. Conclusion The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

Introduction The safety of operating room extubation (ORE) immediately following cardiac surgery via median sternotomy remains unclear. However, reported outcomes in the setting of parasternal regional analgesia are limited. This study examined the safety of ORE for patients who received postoperative superficial parasternal intercostal plane (SPIP) blocks following median sternotomy for cardiac surgery. Methods Single-center retrospective cohort study from January 2020 to September 2023 compared the outcomes of adult cardiac surgical patients who were either extubated in the operating room immediately after surgery with SPIP blocks (ORE-B), received SPIP blocks and were extubated in the intensive care unit within 6 hours (FTE-B) or did not receive SPIP blocks and were extubated in the intensive care unit within 6 hours (FTE). Assessed outcomes were reintubation, use of non-invasive positive pressure ventilation (NIPPV), intensive care unit (ICU) readmission, return to OR, postoperative transfusion, ICU and hospital length of stay. Results 2294 patients were studied, which included 256 ORE-B patients, 729 FTE-B patients and 1,309 FTE patients. Differences in reintubation rates (1.2% vs 0.7% vs 1.2%, all p≥0.26) and use of NIPPV (4.8% vs 4.8% vs 5.1%, all p≥0.743) did not differ between ORE-B, FTE-B, and FTE groups, respectively. Time to extubation differed between FTE-B and FTE groups (2.5 hours vs 3.8 hours, p=<0.001), respectively. Additionally, hospital length of stay was significantly shorter for groups ORE-B and FTE-B compared with group FTE (5 days vs 5 days vs 6 days), respectively. Conclusions Selective ORE after median sternotomy for cardiac surgery was not associated with an increased risk of reintubation and NIPPV use in the setting of parasternal regional analgesia.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Background: Among the 1.5 million cases of cutaneous squamous cell carcinoma (cSCC) diagnosed annually in the United States, a subset of aggressive tumors recur or metastasize. Treatment options include total margin-controlled surgery, such as Mohs micrographic surgery or other forms of peripheral and deep en face margin assessment (MMS/PDEMA), and standard excision with postoperative vertical section margin assessment (SEVMA). NCCN Guidelines recommend MMS/PDEMA for the management of cSCC classified as very high risk based on NCCN risk stratification criteria. This study aims to validate the recommendation of MMS/PDEMA as the preferred surgical approach for NCCN very high-risk cSCCs, using data from a multicenter, multinational cohort. Methods: A multicenter cohort study was conducted across 12 sites, including 10 in the United States, 1 in Spain, and 1 in Brazil, comprising 2,752 primary NCCN very high-risk cSCCs treated with MMS/PDEMA or SEVMA. Propensity score–weighted analysis was used to balance baseline characteristics. Outcomes included local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Results: After balancing baseline characteristics, SEVMA was associated with a 2-fold higher rate of poor outcomes, including recurrence, metastasis, and DSD, compared with MMS/PDEMA. The 3-year cumulative incidence of poor outcomes was higher for SEVMA: LR (12.5% vs 5.9%), NM (11.6% vs 6.0%), DM (4.3% vs 1.9%), and DSD (6.2% vs 3.3%). Conclusions: This study supports the NCCN recommendation of MMS/PDEMA for NCCN very high-risk cSCC, showing reduced recurrence, metastasis, and cSCC-specific mortality compared with SEVMA.

Importance The potential utility of real-time digital therapeutics that identify impending behavioral outbursts to proactively apply evidence-based interventions for managing children with disruptive behavior disorder has not been tested. Objectives To evaluate feasibility and adherence of a digitally augmented, real-time, proactive behavioral intervention (smartwatch) for children with disruptive behaviors. Design, Setting, and Participants This randomized clinical trial was conducted between March 1, 2022, and December 31, 2023, at Mayo Clinic in Rochester, Minnesota. The study enrolled children aged 3 to 7 years with externalizing behavior problems rated above the clinically significant range (I score ≥120; T score ≥60) on the Eyberg Child Behavior Inventory (ECBI). Interventions Twelve weekly sessions of parent-child interaction therapy (PCIT) (treatment as usual [TAU] arm) vs artificial intelligence (AI)–enhanced PCIT augmented with real-time behavioral outburst alerts (PCIT-AI arm). Main Outcomes and Measures The primary outcome was achieving the a priori feasibility benchmark set at greater than 70% for both completion of PCIT sessions and daily smartwatch wear. Parental reaction time to behavior prompts was measured in seconds. Secondary outcomes were percentage changes in ECBI and Pediatric Sleep Questionnaire scores. Behavioral outburst duration was examined based on parental logs of start and end times of observed tantrums using a smartphone application. Result This study enrolled 50 children (median [IQR] age, 5.0 [4.0-6.0] years; 34 [68%] male and 16 [32%] female; 28 randomized to the PCIT-AI arm and 22 to the PCIT-TAU arm). Of these children, 37 (74%; 21 in the PCIT-AI arm and 16 in the PCIT-TAU arm) completed PCIT, with children wearing the watch a median (IQR) 75.7% (67.8%-82.9%) of the time, thus achieving the feasibility benchmark (primary outcome). Median (IQR) response time to behavior prompts in the PCIT-AI arm was 3.65 (2.07-7.08) seconds. Assessing between-group differences, there was no statistically significantly greater numerical improvement in ECBI-intensity percentage change (13.86%; 95% CI, −1.41% to 29.14%), ECBI-problem percentage change subscale scores (38.59%; 95% CI, −1.22% to 78.40%), or absolute change in Pediatric Sleep Questionnaire scores (−0.16; 95% CI, −1.85 to 1.53) with the PCIT-AI arm than with the PCIT-TAU arm. Children in the PCIT-AI arm had significantly shorter mean (SD) tantrum durations (10.4 [20.8] minutes vs 22.1 [30.0] minutes; P &amp;lt; .001) and lower odds of tantrums lasting for 15 minutes or more (odds ratio, 3.66; 95% CI, 2.72-4.95). Conclusions and Relevance In this randomized clinical trial, both recruitment and technology feasibility benchmarks were achieved. The findings inform the design of fully powered efficacy study of wearable, digitally augmented PCIT for children with disruptive behaviors. Trial Registration ClinicalTrials.gov Identifier: NCT05077722

Key points Staphylococcus aureus showed a significant increase in relative abundance in CRSwNP patients following endoscopic sinus surgery compared to pre‐surgery samples. Other Staphylococcus species were found to correlate positively with S. aureus in patients with nasal polyps; among those, S. caprae correlated strongly while being the most represented in samples. Patients with recurrent nasal polyp growth exhibited a substantially greater postoperative increase in the relative abundance of S. aureus .

Abstract Immune checkpoint inhibitor–associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). How chemotherapy alters the TME, and whether these changes drive chemoresistance, is poorly understood. We examined matched pre- and post-treatment tissue specimens and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAFs) after treatment. These CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrence lesions had the highest prevalence of these CAFs versus primary tumors and untreated metastasis. These CAFs showed elevated non-canonical Wnt mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Our findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising target for this disease. Statement of Significance Therapeutic resistance remains a major challenge in pancreatic cancer. Our findings shed light on the changes in the complex tumor microenvironment in response to chemotherapy and identify fibroblasts high in axonal-guidance genes that may drive tumor progression and chemoresistance, thus uncovering a potential avenue for targeting pancreatic cancer.

Abstract BACKGROUND Children exposed to poverty during frontline therapy for B-lymphoblastic leukemia (B-ALL) experience inferior overall survival (OS), higher relapse rates, and earlier relapse than their peers. Real-world data describing treatment patterns and survival after relapse of B-ALL are lacking and, as a result, the impact of poverty following relapse remains poorly understood. This study evaluated the association of poverty exposure, proxied by insurance status, with post-relapse survival and explored potential explanatory mechanisms, including disease biology and therapy utilization. METHODS Data from Retrospective Study of Contemporary Approaches to First Relapse in B-ALL (ReCALL-1), a multicenter retrospective cohort study of patients &lt; 30 years old with first relapse of B-ALL from 2018-2022, were used. The primary exposure was poverty, proxied by insurance status at relapse, categorized as any private insurance (poverty unexposed), public-only insurance (poverty exposed), no insurance, or unknown; the latter two were not included in comparative analyses due to low numbers. The primary outcome was OS. Secondary outcomes included measurable residual disease (MRD)-negative second complete remission (CR2), relapse after CR2, non-relapse mortality (NRM), with relapse treated as a competing risk, and receipt of cellular and immunotherapies. RESULTS Among 462 patients from 31 U.S. institutions, 41% had private insurance, 47% public-only insurance, 2% no insurance, and 10% unknown. Compared to privately insured patients, those with public insurance were more likely to be Hispanic (56% vs 19%, p&lt;0.001) and have non-English preferred language (30% vs 6%, p&lt;0.001). Non-Hispanic Black patients comprised 9% of those with public insurance and 5% of those with private insurance. Disease characteristics that differed by insurance status at relapse included: Ph-like cytogenetics, more common in publicly insured (23% vs 11%, p=0.002), and infant ALL, more common in privately insured patients (10% vs 5%, p=0.06). Publicly insured patients were more likely to have experienced major organ toxicity during frontline therapy (32% vs 18%, p=0.002) and very early relapse (&lt;18m from diagnosis: 43% vs 32%, p=0.07). Other demographic and disease characteristics, including relapse site and cytomolecular features, were similar by insurance status. With a median follow-up of 51 months from relapse, 4-year OS differed by insurance (log-rank p=0.02): 72% for private vs 56% for public insurance. After adjusting for race/ethnicity and language, public insurance increased the hazard of death by 65% (aHR 1.65 95% CI 1.13-2.42, p=0.004). The association remained, but was attenuated, when unbalanced disease characteristics (time to relapse, infant ALL, Ph-like cytogenetics, prior organ dysfunction) were included (aHR 1.47, 95% CI 1.00-2.16, p=0.05). Rates of MRD-negative CR2 were similar (85% public vs 87% private). However, point estimates suggested publicly insured patients had more relapse after CR2 (44% vs 37%, p=0.42) and higher 4-year NRM (16% vs 10%, Gray's test p=0.12), though neither were significant. Treatment choices for first relapse did not differ by insurance status. Utilization of intensive reinduction (91% vs 95% for public vs private, p=0.18) and clinical trial enrollment (22% for both) were similar. Receipt of cellular therapies did not significantly differ by public vs private insurance: Chimeric Antigen Receptor-T cells (CAR-T: 38% vs 34%, p=0.41), hematopoietic cell transplant (HCT: 42% vs 47%, p=0.32). Use of blinatumomab trended higher in those with private insurance (36% vs 45%, p=0.07), and inotuzumab was similar (11% for both, p=0.87). Median time from relapse to CAR-T or HCT was comparable (to CAR-T 102 vs 100 days, to HCT 117 vs 114 days). CONCLUSION This is the first study to demonstrate differential survival by insurance type, a proxy for poverty exposure, after first relapse of B-ALL. In this large multicenter, real-world cohort, patients with public insurance had worse OS after relapse than those with private insurance. The survival disparity existed independent of other SDOH factors. Adjustment for known high-risk disease features only partially accounted for the observed differences in OS. In contrast, rates of MRD-negative CR2 and receipt of CAR-T and HCT were comparable across insurance types. These findings highlight the urgent need to identify effective interventions that will ensure equitable outcomes after relapse.

Abstract Introduction: CAR-T therapy has transformed cancer therapy. with its first Food and Drug Administration (FDA) approved product in August 2017. Given the expanding indications and growing experience, particularly with management of immediate toxicities requiring specialized expertise such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity syndrome (ICANS), FDA recently removed the Risk Evaluation and Mitigation Strategies (REMS) for CD19 and BCMA targeting CAR-T on June 26th2025. In particular, given that CRS and ICANS typically occur in the first 2 weeks post CAR-T infusion, the minimum required stay near CAR-T treatment center is reduced from one month to 2 weeks. While this could reduce treatment burden for patients (pts) who need to travel away from home to receive CAR-T, there is a need to update the transition of care from CAR-T center to pts' local oncology practice. Pts carry in their rate of recovery and have varying supportive care needs in the second half of the month post CAR-T infusion. To assist with care transition and planning, we examine the use of AI multimodal large language model (LLM) to predict patients' supportive care needs 2 weeks after CAR-T infusion based on the clinical data at the time of CAR-T evaluation, prior to leukapheresis. This timepoint was selected to also maximize travel, lodging and caregiver planning for pts and family as well. Methodology: Pts who were treated with FDA-approved CAR-T at Mayo Clinic Rochester between December 2022 and June 2025 were examined. Based on experiences with referral practices in the Midwest region, we defined patients with high monitoring needs as those who between day 14-30 post CAR-T had either hospital admission due to recurrent CRS or ICANS or required transfusion of more than 1 blood product per week (red blood cell or platelets). Others were classified as low monitoring needs. Clinical notes, labs, vital signs and electrocardiogram at the time of CAR-T evaluation were abstracted and summarized by Gemini LLM for association with patients with high versus low monitoring needs post CAR-T. Model was developed and tested for predicted needs and concordance with actual outcome of these pts. Results: Among the 362 pts who received FDA approved CAR-T in the timeframe, 84 pts had high monitoring needs. An additional 84 pts with low monitoring needs were randomly selected from 278 pts. These were divided into a training cohort and test cohort of 84 pts each, with 42 pts with high and 42 pts with low monitoring needs. Demographics of the two cohorts displayed no statistical difference. LLM analysis of the clinical data at the time of CAR-T eval identified 5 categories associated with risk for high monitoring needs: 1) Disease status (clinical notes about bulky, progressive disease or CNS involvement); 2) inflammatory and tumor burden markers (CRP, LDH); 3) hematologic status (platelet, plt; neutrophil count ANC); 4) renal function; 5) performance status. Using common clinical lab parameter convention (platelets &lt;100, ANC&lt; 1, CrCl&lt; 30ml/min), and prioritizing for not missing pts with high monitoring needs, LLM model was defined to predict patients for high monitoring needs if high risk feature was identified in category 1 or any category combinations; whereas patients with no high risk feature or only 1 category that is not disease status was predicted as low monitoring needs. In this model, the sensitivity was 85.7%, specificity 23.8%, F1 score 65.5%. Applying this model to test cohort 2, the sensitivity was 83.3%, specificity 28.6%, and F1 score 65.4%. Discussion: We demonstrate proof-of-concept that LLM can be used to analyze clinical data at the time of evaluation for CAR-T eligibility to predict for supportive care needs post treatment. Not surprisingly, features identified by LLM to be associated with high monitoring needs are those previously reported by us and others at the time of CAR-T evaluation and or pre-lymphodepletion to be associated with risk for cytopenia, infection, hospitalization and non-relapse mortality. Based on the summary output generated by LLM, additional opportunities for classification methods were identified to improve specificity and balanced accuracy of the LLM model. This is a promising tool for further development to assist clinicians and patients to plan their treatment journey.