Citations

ABSTRACT Background Sentinel lymph node (SLN) biopsy is a critical staging tool in skin and soft tissue cancers. Although technetium lymphoscintigraphy is the most common adjunct, indocyanine green (ICG) demonstrates a promising alternative in pediatric, adolescent, and young adult (AYA) skin and soft tissue cancers. Methods and Objectives Evaluate the safety and efficacy of ICG in SLN biopsy (SLNB) in diverse pediatric and AYA solid cancers in a multi‐institutional environment. This is a prospective, observational study conducted at 13 member institutions in the Pediatric Surgical Oncology Research Collaborative between 2019 and 2023. Eligible patients underwent SLNB for primary or recurrent solid skin and soft tissue tumors. Peritumoral ICG was administered intraoperatively. Outcomes included SLN detection rates, histopathology of excised specimens, and surgeon‐reported assessment of utility. Safety was assessed through adverse event reporting. Results Forty SLNB procedures yielded 84 specimens: 13 melanoma (32.5%), 12 squamous cell carcinoma (30%), 11 non‐rhabdomyosarcoma soft tissue sarcoma (27.5%), two rhabdomyosarcoma (5%), one Ewing sarcoma (2.5%), and one malignant peripheral nerve sheath tumor (2.5%). Histologic evaluation identified 81 lymph nodes, 75 benign (89.3%) and six malignant (7.1%); three specimens were adipose tissue (3.6%). Of 81 lymph nodes, 76% were ICG‐positive. ICG had a sensitivity of 79.5%, a specificity of 33%, and a positive predictive value of 96%. All malignant nodes were ICG‐avid. There were no adverse reactions to ICG at 30 days. Conclusions ICG is a safe and effective adjunct for SLNB in pediatric and AYA soft tissue and skin malignancies.

Abstract Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

Abstract Background Quantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic value in cardiac PET, but their widespread use is limited by the technical demands of dynamic imaging protocols. We evaluated the feasibility of using artificial intelligence (AI) to predict MBF and MFR from static and gated PET images, without the need for dynamic acquisition. Methods A machine learning (XGBoost) model was trained on 82Rb PET multi-center dataset using static perfusion imaging, injected dose, hemodynamic measures, clinical data and CT-derived features (including body composition) from the hybrid CT attenuation scan. Model performance was evaluated externally in an independent cohort. Results In total, 10,566 (derivation-cohort) and 7,842 (external-cohort) patients were included in this multi-center study. On the external-cohort, AI approach achieved an Area under the curve (AUC) of 0.92 (0.92–0.93) for abnormal stress MBF and 0.91 (0.90–0.92) for abnormal MFR; Intra-class correlation (ICC) 0.80 (0.78–0.82) and 0.78 (0.76–0.79), respectively. AI MFR closely mirrored the prognostic performance of measured MFR, showing nearly identical Kaplan–Meier risk stratification (both p<0.0001) and maintaining strong, and independently significant associations with all-cause mortality (HR 3.4 [2.8–4.2] vs. 4.6 [3.6–5.8]; both p<0.001), and demonstrated similar added value to perfusion for mortality prediction. Conclusion AI-predicted virtual stress MBF and MFR assessment using static and gated PET data is feasible and generalizable across cohorts. By removing the dependency on dynamic acquisitions, this approach has the potential to broaden the clinical adoption of flow quantification. STRUCTURED GRAPHICAL ABSTRACT PET: Positron Emission Tomography, CT: Computed Tomography, MFR: Myocardial Flow Reserve Key Question: Can machine learning models trained on dynamic PET datasets accurately predict regional stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) from static image features, physiological parameters, and CT-based anatomical measures? Key Finding: Artificial intelligence can accurately estimate MBF and MFR from non-dynamic PET data, with strong agreement to reference standards. Take-home Message: By eliminating reliance on dynamic PET acquisitions, machine-learning has the potential to broaden clinical adoption of quantitative flow assessment.

OBJECTIVE Chordomas are rare, locally aggressive primary neoplasms. Resection with negative margins is the primary recommended therapeutic approach, while adjuvant radiotherapy and chemotherapy can also play a role in their treatment in certain situations, including lesions with positive margins or those that are poorly differentiated or dedifferentiated. Cervical spine chordomas pose significant surgical challenges given their proximity to critical anatomical structures and the mechanical constraints of the cervical spine. In the current case series, authors aimed to explore the clinical and patient-reported outcomes (PROs) of the surgical treatment of cervical chordomas in a large multicenter cohort. METHODS This multicenter case series analysis utilized data from the prospectively collected Primary Tumor Research and Outcomes Network (PTRON) registry, from its inception (May 16, 2016) to data extraction (February 29, 2024). The study population was restricted to patients with histologically confirmed cervical chordomas involving levels C0–7, who underwent surgical treatment at one of the participating centers, and for whom both the initially planned and postoperatively pathologically confirmed surgical margins were documented. Patient demographics, tumor characteristics, surgical and adjuvant treatments, local recurrence–free survival (LRFS), overall survival (OS), and perioperative adverse events were retrieved. PROs included the Spine Oncology Study Group Outcomes Questionnaire version 2.0 (SOSGOQ2.0), EQ-5D, and SF-36 version 2.0 (SF-36v2). RESULTS Thirty-eight patients were identified, 12 of whom underwent true en bloc resection (EBR), 18 of whom underwent deliberate intralesional resection, and 8 of whom underwent EBR after intralesional surgery or in whom EBR failed. True EBR led to better LRFS (92% vs 83% vs 63%, respectively) and OS (83% vs 39% vs 50%, respectively). Surgical adverse events within 1 year were more frequent with true EBR (100% vs 39% vs 75%, respectively). EQ-5D, SOSGOQ2.0, and SF-36v2 showed improvement with true EBR, whereas the trends for PROs from the other groups were more variable. CONCLUSIONS This multicenter case series analysis provides critical insights into the clinical outcomes and PROs in the largest cohort of surgically treated cervical spine chordomas described to date. It underscores the importance and challenges of wide resection for oncological control. It establishes the associated morbidity and provides an overview of PROs following surgery. These findings contribute valuable evidence to inform shared decision-making and optimize patient care.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1

Autism is a heritable neurodevelopmental condition marked by impaired social interaction, repetitive behavior, and co-occurring conditions. Sleep disturbances are common in autism. This study uses low-cost wearable devices to compare sleep, physical activity, and circadian behavior in autistic adults and their non-autistic relatives. We recruited 318 autistic individuals and 130 family members, collecting accelerometer data over 3 weeks (8249 days). Using a data-driven approach, we identified actimetry-derived features associated with autism. We examined 308 traits using the elastic net algorithm and linear mixed effects regressions. We identified 52 actimetry measures associated with autism (area under the curve: 0.812; confidence interval: 0.761–0.862), validated in a test set (area under the curve: 0.756; confidence interval: 0.700–0.813). Both mean and day-to-day variability in several measures (e.g., time spent sedentary, total light physical activity) were associated with autism. In autistic individuals, reduced physical activity during wake was more strongly associated with shorter sleep time than in non-autistic relatives (likelihood ratio: 41.6; p = 1.13e−10). Reduced physical activity in autistic individuals was linked to increased social impairment, as measured by the Social Responsiveness Scale. Long inactivity periods and lower physical activity levels were associated with autism, correlating with less sleep and later sleep onset. Interventional studies are needed to explore if improving sleep and physical activity can improve the quality of life for autistic individuals. Lay Abstract Autistic individuals frequently report problems with their sleep, though what aspects of sleep are most affected is not well understood. In this study, we recruited 318 adult autistic participants without intellectual disability and 130 of their non-autistic family members to measure their sleep, physical activity, and daily routines. Study participants wore accelerometer-based wrist-worn devices over 3 consecutive weeks to record their movement and activity. In total, 154 distinct physical activity, sleep, and behavioral traits were identified from the recordings, 52 of which were found to associate with autism. Many of these traits were related to physical activity, where autistic individuals were more likely to be less active for longer periods and have lower overall physical activity levels. Long periods of inactivity also associated with less sleep, with a stronger association in those with autism. For example, for every hour of inactivity, autistic participants had on average ~23 min less of sleep compared to ~17 min in their family members. Autistic individuals with lower levels of physical activity showed higher social impairment as measured by the Social Responsiveness Scale. Overall, lower physical activity may impair sleep and worsen the core features of autism. Interventional studies aimed to increase physical activity may improve the quality of life of autistic individuals.

Limited information on the business practices of liver transplant (LT) centers worldwide has been published. Characterizing this data could help identify best practices as well as opportunities for improvement. As such, the International Liver Transplant Society (ILTS) Business Practice Committee conducted a global online survey of LT centers, which was sent to the ILTS membership. Questions focused on 5 main domains: transplant practice and volumes, workforce, finances, quality assessment and performance improvement, and overall program function. Data was compared across program geographic regions and transplant volume. A total of 89 discrete centers were represented, of which 76.4% were academic/university-affiliated, and about one-third each were from Europe (36.0%) and North America (31.5%). The top 3 problems programs reported were finances/funding (60.7%), adequate program support/guidance (48.3%), and transplant volumes (43.8%). In all, 59.6% of respondents felt their salary was undercompensated, consistent across geographic regions. In addition, 69.7% felt their center was not adequately funded to meet program goals, with programs in Europe (N=28/32, 87.5%) and Oceania (N=2/3, 66.7%) most impacted. Transplant surgeon retainment was noted as more difficult for lower volume programs (<50 liver transplants/year, N=13/31). Nearly half (42.7%) of all programs felt under-resourced to provide high-quality care, and the majority (80.9%) felt there was room for growth and improvement under their current model. While international concerns varied widely among LT centers, inadequate salary and center funding, low transplant and referral volumes, and staff retainment were persistent themes. Focusing on adopting region-specific best practices and developing transplant systems of care that focus on these elements is critical to provide optimal care to LT patients worldwide.

PURPOSE Despite evidence of diagnostic accuracy but unclear long-term clinical benefit, national utilization patterns of prostate-specific membrane antigen positron emission tomography (PSMA-PET) are undefined. METHODS We conducted a serial cross-sectional study to evaluate the use of PET imaging among commercial insurance beneficiaries with prostate cancer using administrative claims from deidentified Blue Cross Blue Shield Axis database. Eligible patients included prevalent and incident prostate cancer cases. We calculated the proportions undergoing PET imaging in semiannual periods from January 1, 2016, through December 31, 2024. We examined the association between regional-level contextual sociodemographic and health care characteristics, and regional use of PSMA-PET imaging in 2024. RESULTS A total of 514,750 male beneficiaries age 40-89 years with prostate cancer were identified between 2016 and 2024. The proportion of individuals with prostate cancer undergoing PET imaging increased from 4.5 [95% CI, 4.1 to 4.9] per 1,000 in the first half of 2016 to 77.6 (95% CI, 76.2 to 79.1) per 1,000 in the second half of 2024, P < .001. Increases in PET were driven by uptake of PSMA-PET following approval in 2021, which increased from 0.8 (95% CI, 0.6 to 0.9) per 1,000 in the second half of 2021 to 77.0 (95% CI, 75.5 to 78.5) per 1,000 in the second half of 2024, P < .001. PSMA-PET use in 2024 was higher in regions with greater education (99.3 v 114.6 per 1,000 in lowest [Q1] v highest [Q4] educated) and income (95.4 v 112.3 per 1,000 in Q1 v Q4 income) measures, P < .001. CONCLUSION PSMA-PET was rapidly incorporated into clinical practice among commercial insurance beneficiaries with prostate cancer with higher adoption in geographic regions with higher income and education.

Background and aims: Aberrations in telomere length can have important implications in cancer. Using a cohort of 1007 patients, we investigated whether leukocyte telomere length (LTL) in patients with colorectal cancer (CRC) is associated with survival. We also investigated whether some telomere maintenance genes are associated with survival in these patients. Methods: The Biobank for Gastrointestinal Health Research (BGHR), an ongoing project involving collection of biospecimens at the Mayo Clinic, was utilized to obtain data from patients diagnosed with stage II or III CRC. Blood samples were collected prior to chemotherapy/radiation and DNA was extracted for measuring median LTL. The main outcome measures were overall survival (OS) and disease-free survival (DFS) by disease stage. Results: A significant inverse relationship was observed with patient age and LTL (spearman correlation coefficient (r) = −0.48, 95%; p = 1.13 × 10−58). Females had significantly longer LTL than males (p = 3.97 × 10−5). The rs1317082 SNP in the TERC gene was significantly associated with both OS and DFS in combined stage II and stage III patients (p = 0.017 and p = 0.023, respectively). A statistically significant association of the OBFC1 SNP (rs9419958) was observed for OS for the combined stage II and stage III patients (p = 0.016). Importantly, LTL was significantly associated with both OS and DFS (p = 0.008 and 0.044 respectively) in combined stage II and stage III patients. Conclusions: Our results show that LTL is predictive of OS and DFS for stage II and III CRC patients, particularly over a longer follow-up, extending beyond five years after a diagnosis of CRC, and certain SNPs in genes involved in telomere maintenance are significantly associated with patient outcomes, independent of telomere length.