Contemporary Pediatric Heart Transplant Waitlist Mortality.

BACKGROUND: In 2016, the United Network for Organ Sharing revised its pediatric heart transplant (HT) allocation policy. OBJECTIVES: This study sought to determine whether the 2016 revisions are associated with reduced waitlist mortality and capture patient-specific risks. METHODS: Children listed for HT from 1999 to 2023 were identified using Organ Procurement and Transplantation Network data and grouped into 3 eras (era 1: 1999-2006; era 2: 2006-2016; era 3: 2016-2023) based on when the United Network for Organ Sharing implemented allocation changes. Fine-Gray competing risks modeling was used to identify factors associated with death or delisting for deterioration. Fixed-effects analysis was used to determine whether allocation changes were associated with mortality. RESULTS: Waitlist mortality declined 8 percentage points (PP) across eras (21%, 17%, and 13%, respectively; P < 0.01). At listing, era 3 children were less sick than era 1 children, with 6 PP less ECMO use (P < 0.01), 11 PP less ventilator use (P < 0.01), and 1 PP less dialysis use (P < 0.01). Ventricular assist device (VAD) use was 13 PP higher, and VAD mortality decreased 9 PP (P < 0.01). Non-White mortality declined 10 PP (P < 0.01). ABO-incompatible listings increased 27 PP, and blood group O infant mortality decreased 13 PP (P < 0.01). In multivariable analyses, the 2016 revisions were not associated with lower waitlist mortality, whereas VAD use (in era 3), ABO-incompatible transplant, improved patient selection, and narrowing racial disparities were. Match-run analyses demonstrated poor correlation between individual waitlist mortality risk and the match-run order. CONCLUSIONS: The 2016 allocation revisions were not independently associated with the decline in pediatric HT waitlist mortality. The 3-tier classification system fails to adequately capture patient-specific risks. A more flexible allocation system that accurately reflects patient-specific risks and considers transplant benefit is urgently needed.

Development and Validation of a Novel Pediatric Mechanical Circulatory Support Risk Stratification Tool: The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) Ventricular Assist Device Score.

We sought to develop and validate a new risk stratification score for mortality for children supported with a ventricular assist device (VAD). This retrospective, multicenter study used data from patients undergoing VAD implantation between April 2018 and February 2023 at 44 participating institutions in the Advanced Cardiac Therapies Improving Outcomes (ACTION) network. Multivariable Cox proportional-hazards modeled mortality after VAD implantation. A total of 1,022 patients were enrolled. The 1 year mortality was 19% (95% confidence interval [CI]: 16-23). The multivariable model was used to build the ACTION VADs risk stratification score with four components: ventilation, advanced organ support (dialysis or ECMO), diagnosis, and size (weight ≤5 kg). One point is added for each risk factor. Based on the sum of the risk factors, patients were classified into four classes: class 0-green (4% mortality at 1 year), class 1-yellow (16% mortality at 1 year), class 2-orange (21% mortality at 1 year), and class 3 or higher-red (42% mortality at 1 year). The score performed well, with area under the curve (AUC) of 0.72 and excellent calibration. The ACTION VADs score for mortality can be calculated easily and offers risk stratification and prognostic information for pediatric VAD candidates. This is the first validated risk assessment tool for pediatric mechanical circulatory support.

A prospective cohort study on stereotactic radiotherapy in the management of dural recurrence of olfactory neuroblastoma.

BACKGROUND: Treatment for dural recurrence of olfactory neuroblastoma (ONB) is not standardized. We assess the outcomes of stereotactic body radiotherapy (SBRT) in this population. METHODS: ONB patients with dural recurrences treated between 2013 and 2022 on a prospective registry were included. Tumor control, survival, and patient-reported quality of life were analyzed. RESULTS: Fourteen patients with 32 dural lesions were evaluated. Time to dural recurrence was 58.3 months. Thirty lesions (94%) were treated with SBRT to a median dose of 27 Gy in three fractions. Two patients (3 of 32 lesions; 9%) developed in-field radiographic progression, five patients (38%) experienced progression in non-contiguous dura. Two-year local control was 85% (95% CI: 51-96%). There were no >grade 3 acute toxicities and 1 case of late grade 3 brain radionecrosis. CONCLUSION: In this largest study of SBRT reirradiation for ONB dural recurrence to date, high local control rates with minimal toxicity were attainable.

An intermediate Rb-E2F activity state safeguards proliferation commitment.

Tissue repair, immune defence and cancer progression rely on a vital cellular decision between quiescence and proliferation1,2. Mammalian cells proliferate by triggering a positive feedback mechanism3,4. The transcription factor E2F activates cyclin-dependent kinase 2 (CDK2), which in turn phosphorylates and inactivates the E2F inhibitor protein retinoblastoma (Rb). This action further increases E2F activity to express genes needed for proliferation. Given that positive feedback can inadvertently amplify small signals, understanding how cells keep this positive feedback in check remains a puzzle. Here we measured E2F and CDK2 signal changes in single cells and found that the positive feedback mechanism engages only late in G1 phase. Cells spend variable and often extended times in a reversible state of intermediate E2F activity before committing to proliferate. This intermediate E2F activity is proportional to the amount of phosphorylation of a conserved T373 residue in Rb that is mediated by CDK2 or CDK4/CDK6. Such T373-phosphorylated Rb remains bound on chromatin but dissociates from it once Rb is hyperphosphorylated at many sites, which fully activates E2F. The preferential initial phosphorylation of T373 can be explained by its relatively slower rate of dephosphorylation. Together, our study identifies a primed state of intermediate E2F activation whereby cells sense external and internal signals and decide whether to reverse and exit to quiescence or trigger the positive feedback mechanism that initiates cell proliferation.

A comprehensive, multifaceted strategy to increase pediatric donor heart utilization.

BACKGROUND: In 2016, we initiated a quality improvement endeavor to increase pediatric heart offer acceptance. This study assessed the effect of these interventions at our center. METHODS: We evaluted pre- and postimplementation cohorts (January 1, 2008-December 31, 2016 vs January 1, 2017-July 1, 2023) comparing donor heart utilization. Six interventions were iterated over time to increase offer acceptance ("extended criteria"): ABO-incompatible transplant, ex vivo perfusion for distanced donors, 3-dimensional total cardiac volume (TCV) assessment, acceptance of hepatitis-C or Severe Acute Respiratory Syndrome Coronavirus 2 infected donors, and institutional culture change favoring consideration of donors previously considered unacceptable. Outcomes studied included annual HT volume, median waitlist duration, sequence number at acceptance, and post-transplant clinical outcomes. RESULTS: During the study period, annual transplant volume increased from 16/year to 25/year pre- and postimplementation. Three hundred thirteen of 389 (80%) listed patients were transplanted. Waitlist duration shortened postimplementation (p = 0.01), as did the percentage of accepted heart offers utilizing at least 1 extended criterion (p < 0.001). Institutional culture change and TCV assessment had the largest impact on donor heart utilization (p = 0.04 and p < 0.001). There was no difference in post-HT intubation or intensive care unit days (p = 0.05-0.9), though post-transplant hospitalization duration (p < 0.001) increased. Post-transplant survival was unaffected by the use of extended criteria hearts (p = 0.3). CONCLUSIONS: We report a successful longitudinal, multifaceted effort to increase organ offer utilization, with institutional culture change and TCV assessments most impactful. The use of extended criteria hearts was not associated with inferior survival.

Predicting Stroke for Pediatric Patients Supported With Ventricular Assist Devices: A Pedimacs Report.

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) provides detailed understanding on pediatric patients supported with ventricular assist devices (VADs). We sought to identify important variables affecting the incidence of stroke in pediatric VADs. METHODS: Between 2012 and 2022, 1463 devices in 1219 patients were reported to Pedimacs from 40 centers in patients aged <19 years at their first VAD implantation. Multiphase parametric hazard modeling was used to identify risk factors for stroke among all device types. RESULTS: Of the 1219 patients, the most common devices were implantable continuous (472 [39%]), followed by paracorporeal pulsatile (342 [28%]), and paracorporeal continuous (327 [27%]). Overall freedom from stroke at 6 months was higher in the recent era (2012-2016; 80.2% [95% CI, 77.1%-82.9%] vs 2017-2023; 87.9% [95% CI, 86.2%-89.4%], P = .009). Implantable continuous VADs had the highest freedom from stroke at 3 months (92.7%; 95% CI, 91.1%-93.9%) and 6 months (91.1%; 95% CI, 89.3%-92.6%), followed by paracorporeal pulsatile (87.0% [95% CI, 84.8%-88.9%] and 82.8% [95% CI, 79.8%-85.5%], respectively), and paracorporeal continuous (76.0% [95% CI, 71.8%-79.5%] and 69.5% [95% CI, 63.4%-74.8%], respectively) VADs. Parametric modeling identified risk factors for stoke early after implant and later. Overall, and particularly for paracorporeal pulsatile devices, early stroke risk has decreased in the most recent era (hazard ratio, 5.01). Among implantable continuous devices, cardiogenic shock was the major risk factor. For patients <10 kg, early hazard was only seen in the previous era. For congenital patients, early hazard was seen in nonimplantable device use and use of extracorporeal membrane oxygenation. CONCLUSIONS: The overall stroke rate has decreased from 20% to 15% at 6 months, with particular improvement among paracorporeal pulsatile devices. Risk factor analyses offer insights for identification of higher stroke risk subsets and further management refinements.

Detection of Alteration in Carotid Artery Volumetry Using Standard-of-care Computed Tomography Surveillance Scans Following Unilateral Radiation Therapy for Early-stage Tonsillar Squamous Cell Carcinoma Survivors: A Cross-Sectional Internally-Matched Carotid Isodose Analysis.

Purpose: Radiation induced carotid artery disease (RICAD) is a major cause of morbidity and mortality among survivors of oropharyngeal cancer. This study leveraged standard-of-care CT scans to detect volumetric changes in the carotid arteries of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer, and to determine dose-response relationship between RT and carotid volume changes, which could serve as an early imaging marker of RICAD. Methods and Materials: Disease-free cancer survivors (>3 months since therapy and age >18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Pre- and post-treatment CTs were registered to the planning CT and dose grid. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery subvolumes in 5 Gy increments (i.e. received 50-55 Gy, 55-60 Gy, etc.). The percent-change in sub-volumes across each dose range was statistically examined using the Wilcoxon rank-sum test. Results: Among 46 patients analyzed, 72% received RT alone, 24% induction chemotherapy followed by RT, and 4% concurrent chemoradiation. The median interval from RT completion to the latest, post-RT CT scan was 43 months (IQR 32-57). A decrease in the volume of the irradiated carotid artery was observed in 78% of patients, while there was a statistically significant difference in mean %-change (±SD) between the total irradiated and spared carotid volumes (7.0±9.0 vs. +3.5±7.2, respectively, p<.0001). However, no significant dose-response trend was observed in the carotid artery volume change withing 5 Gy ranges (mean %-changes (±SD) for the 50-55, 55-60, 60-65, and 65-70+ Gy ranges [irradiated minus spared]: -13.1±14.7, -9.8±14.9, -6.9±16.2, -11.7±11.1, respectively). Notably, two patients (4%) had a cerebrovascular accident (CVA), both occurring in patients with a greater decrease in carotid artery volume in the irradiated vs the spared side. Conclusions: Our data show that standard-of-care oncologic surveillance CT scans can effectively detect reductions in carotid volume following RT for oropharyngeal cancer. Changes were equivalent between studied dose ranges, denoting no further dose-response effect beyond 50 Gy. The clinical utility of carotid volume changes for risk stratification and CVA prediction warrants further evaluation.

Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer: A Multicenter Randomized Clinical Trial.

Importance: Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. Objective: To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. Design, Setting, and Participants: A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Interventions: Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Main Outcomes and Measures: Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. Results: A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). Conclusions and Relevance: The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. Trial Registration: ClinicalTrials.gov Identifier: NCT02589938.

Mechanical Ventilation and Outcomes of Children Who Undergo Ventricular Assist Device Placement: 2014-2020 Linked Analysis From the Advanced Cardiac Therapies Improving Outcomes Network and Pediatric Cardiac Critical Care Consortium Registries.

OBJECTIVES: Placement of a ventricular assist device (VAD) improves outcomes in children with advanced heart failure, but adverse events remain important consequences. Preoperative mechanical ventilation (MV) increases mortality, but it is unknown what impact prolonged postoperative MV has. DESIGN: Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Cardiac Critical Care Consortium (PC 4 ) registries were used to identify and link children with initial VAD placement admitted to the cardiac ICU (CICU) from August 2014 to July 2020. Demographics, cardiac diagnosis, preoperative and postoperative CICU courses, and outcomes were compiled. Univariable and multivariable statistics assessed association of patient factors with prolonged postoperative MV. Multivariable logistic regression sought independent associations with outcomes. SETTING: Thirty-five pediatric CICUs across the United States and Canada. PATIENTS: Children on VADs included in both registries. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred forty-eight ACTION subjects were linked to a matching patient in PC 4 . Median (interquartile) age 7.7 years (1.5-15.5 yr), weight 21.3 kg (9.1-58 kg), and 56% male. Primary diagnosis was congenital heart disease (CHD) in 35%. Pre-VAD explanatory variables independently associated with prolonged postoperative MV included: age (incidence rate ratio [IRR], 0.95; 95% CI, 0.93-0.96; p < 0.01); preoperative MV within 48 hours (IRR, 2.76; 95% CI, 1.59-4.79; p < 0.01), 2-7 days (IRR, 1.82; 95% CI, 1.15-2.89; p = 0.011), and greater than 7 days before VAD implant (IRR, 2.35; 95% CI, 1.62-3.4; p < 0.01); and CHD (IRR, 1.96; 95% CI, 1.48-2.59; p < 0.01). Each additional day of postoperative MV was associated with greater odds of mortality (odds ratio [OR], 1.09 per day; p < 0.01) in the full cohort. We identified an associated greater odds of mortality in the 102 patients with intracorporeal devices (OR, 1.24; 95% CI, 1.04-1.48; p = 0.014), but not paracorporeal devices (77 patients; OR, 1.04; 95% CI, 0.99-1.09; p = 0.115). CONCLUSIONS: Prolonged MV after VAD placement is associated with greater odds of mortality in intracorporeal devices, which may indicate inadequacy of cardiopulmonary support in this group. This linkage provides a platform for future analyses in this population.

Dyadic Yoga for Head and Neck Cancer Patients Undergoing Chemoradiation and their Family Caregivers.

OBJECTIVES: Concurrent chemoradiation to treat head and neck cancer (HNC) may result in debilitating toxicities. Targeted exercise such as yoga therapy may buffer against treatment-related sequelae; thus, this pilot RCT examined the feasibility and preliminary efficacy of a yoga intervention. Because family caregivers report low caregiving efficacy and elevated levels of distress, we included them in this trial as active study participants. METHODS: HNC patients and their caregivers were randomized to a 15-session dyadic yoga program or a waitlist control (WLC) group. Prior to randomization, patients completed standard symptom (MDASI-HN) and patients and caregivers completed quality of life (SF-36) assessments. The 15-session program was delivered parallel to patients' treatment schedules. Participants were re-assessed at patients' last day of chemoradiation and again 30 days later. Patients' emergency department visits, unplanned hospital admissions and gastric feeding tube placements were recorded over the treatment course and up to 30 days later. RESULTS: With a consent rate of 76%, 37 dyads were randomized. Participants in the yoga group completed a mean of 12.5 sessions and rated the program as "beneficial." Patients in the yoga group had clinically significantly less symptom interference and HNC symptom severity and better QOL than those in the WLC group. They were also less likely to have a hospital admission (OR = 3.00), emergency department visit (OR = 2.14), and/or a feeding tube placement (OR = 1.78). CONCLUSION: Yoga therapy appears to be a feasible, acceptable, and possibly efficacious behavioral supportive care strategy for HNC patients undergoing chemoradiation. A larger efficacy trial is warranted.

Longitudinal changes in the carotid arteries of head and neck cancer patients following radiation therapy: Results from a prospective serial imaging biomarker characterization study.

INTRODUCTION: We prospectively evaluated morphologic and functional changes in the carotid arteries of patients treated with unilateral neck radiation therapy (RT) for head and neck cancer. METHODS: Bilateral carotid artery duplex studies were performed at 0, 3, 6, 12, 18 months and 2, 3, 4, and 5 years following RT. Intima media thickness (IMT); global and regional circumferential, as well as radial strain, arterial elasticity, stiffness, and distensibility were calculated. RESULTS: Thirty-eight patients were included. A significant difference in the IMT from baseline between irradiated and unirradiated carotid arteries was detected at 18 months (median, 0.073 mm vs -0.003 mm; P = 0.014), which increased at 3 and 4 years (0.128 mm vs 0.013 mm, P = 0.016, and 0.177 mm vs 0.023 mm, P = 0.0002, respectively). A significant transient change was noted in global circumferential strain between the irradiated and unirradiated arteries at 6 months (median difference, -0.89, P = 0.023), which did not persist. No significant differences were detected in the other measures of elasticity, stiffness, and distensibility. CONCLUSIONS: Functional and morphologic changes of the carotid arteries detected by carotid ultrasound, such as changes in global circumferential strain at 6 months and carotid IMT at 18 months, may be useful for the early detection of radiation-induced carotid artery injury, can guide future research aiming to mitigate carotid artery stenosis, and should be considered for clinical surveillance survivorship recommendations after head and neck RT.

Addressing Food Insecurity Through Community Empowerment in a Staten Island (Richmond County) Neighborhood in New York City.

This study investigated community empowerment as a means of addressing food insecurity amongst underserved neighborhoods by increasing available and affordable food choices through Clementine Collective stands in Staten Island, New York (Richmond County), one of the 5 Boroughs of New York City. Given the growing complexity of food insecurity, inclusive and equitable action must be taken that incorporates the voices, perspectives and needs of those most impacted. Through methods of community engagement and empowerment, the Clementine Collective collaborates with local community residents to introduce sustainable solutions that address food insecurity. A survey (N = 132) was administered to customers of a Clementine Collective stand, located in Staten Island, that assessed customers' food habits and attitudes towards their food environment and solutions. The stand was placed in a local meat market grocery store. Descriptive statistics suggested that residents recognized gaps in their food environment and were empowered to advocate for solutions. Engaging residents from their food environment to advocate for local solutions, such as at community bodegas, or small grocery stores, may be an effective method of addressing food insecurity.

MR-guided stereotactic radiation therapy for head and neck cancers.

Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT. Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients. Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality. Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity.

Achieving Consensus: Severity-Graded Definitions of Fontan-Associated Complications to Characterize Fontan Circulatory Failure.

BACKGROUND: Fontan physiology leads to chronic changes in other organ systems that may affect long-term survival and the success of heart transplantation. Inadequate assessment and treatment of the extra-cardiac effects of Fontan may contribute to poor outcomes. Severity-graded/ordinal consensus definitions of Fontan complications are lacking, which limits understanding of how Fontan-specific morbidity affects patients' outcomes. METHODS AND RESULTS: A panel of Fontan patient and physiology experts, including pediatric, adult congenital, heart failure, and critical-care cardiology as well as pediatric nephrology, hepatology and psychology, convened to develop definitions of Fontan complications. Definitions were created by using a severity-graded ordinal scale: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, disabling or life threatening. Following definition creation, a second panel of 21 experts in Fontan circulatory failure used a modified Delphi methodology to modify and vote on definitions until consensus (> 90% agreement without recommended further modification) was reached on final definitions. After 3 rounds of modifications and voting, consensus agreement was achieved on all Fontan-specific definitions. The defined complications and morbidities of Fontan include: anatomic Fontan pathway obstruction, cyanosis, systemic venous abnormalities resulting from venous insufficiency, atrial arrhythmia, ventricular arrhythmia, bradycardia, chronic pleural effusions, chronic ascites, protein-losing enteropathy, plastic bronchitis, hemoptysis and pulmonary hemorrhage, sleep apnea, Fontan-associated liver disease, portal and hepatic variceal disease, acute kidney injury affecting clinical treatment, polycythemia, thrombotic disease, recurrent or severe bacterial infection, skin atrophy, adrenal insufficiency, physical impact of previous stroke, mood/behavior disorder, and neurodevelopmental disorder. CONCLUSION: Consensus and severity-graded definitions of Fontan-specific cardiac and extra-cardiac complications were achieved and are available for use in research. They will allow future robust analyses of Fontan patient outcomes.

Comparison of Machine Leaning Models for Prediction of Acute Pain Severity and On-Treatment Opioid Utilization in Oral Cavity and Oropharyngeal Cancer Patients Receiving Radiation Therapy: Exploratory Analysis from a Large-Scale Retrospective Cohort.

Background: Acute pain is a common and debilitating symptom experienced by oral cavity and oropharyngeal cancer (OC/OPC) patients undergoing radiation therapy (RT). Uncontrolled pain can result in opioid overuse and increased risks of long-term opioid dependence. The specific aim of this exploratory analysis was the prediction of severe acute pain and opioid use in the acute on-treatment setting, to develop risk-stratification models for pragmatic clinical trials. Materials and Methods: A retrospective study was conducted on 900 OC/OPC patients treated with RT during 2017 to 2023. Clinical data including demographics, tumor data, pain scores and medication data were extracted from patient records. On-treatment pain intensity scores were assessed using a numeric rating scale (0-none, 10-worst) and total opioid doses were calculated using morphine equivalent daily dose (MEDD) conversion factors. Analgesics efficacy was assessed based on the combined pain intensity and the total required MEDD. ML models, including Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), and Gradient Boosting Model (GBM) were developed and validated using ten-fold cross-validation. Performance of models were evaluated using discrimination and calibration metrics. Feature importance was investigated using bootstrap and permutation techniques. Results: For predicting acute pain intensity, the GBM demonstrated superior area under the receiver operating curve (AUC) (0.71), recall (0.39), and F1 score (0.48). For predicting the total MEDD, LR outperformed other models in the AUC (0.67). For predicting the analgesics efficacy, SVM achieved the highest specificity (0.97), and best calibration (ECE of 0.06), while RF and GBM achieved the same highest AUC, 0.68. RF model emerged as the best calibrated model with ECE of 0.02 for pain intensity prediction and 0.05 for MEDD prediction. Baseline pain scores and vital signs demonstrated the most contributed features for the different predictive models. Conclusion: These ML models are promising in predicting end-of-treatment acute pain and opioid requirements and analgesics efficacy in OC/OPC patients undergoing RT. Baseline pain score, vital sign changes were identified as crucial predictors. Implementation of these models in clinical practice could facilitate early risk stratification and personalized pain management. Prospective multicentric studies and external validation are essential for further refinement and generalizability.

Clinical acceptability of automatically generated lymph node levels and structures of deglutition and mastication for head and neck radiation therapy.

Background and Purpose: Auto-contouring of complex anatomy in computed tomography (CT) scans is a highly anticipated solution to many problems in radiotherapy. In this study, artificial intelligence (AI)-based auto-contouring models were clinically validated for lymph node levels and structures of swallowing and chewing in the head and neck. Materials and Methods: CT scans of 145 head and neck radiotherapy patients were retrospectively curated. One cohort (n = 47) was used to analyze seven lymph node levels and the other (n = 98) used to analyze 17 swallowing and chewing structures. Separate nnUnet models were trained and validated using the separate cohorts. For the lymph node levels, preference and clinical acceptability of AI vs human contours were scored. For the swallowing and chewing structures, clinical acceptability was scored. Quantitative analyses of the test sets were performed for AI vs human contours for all structures using overlap and distance metrics. Results: Median Dice Similarity Coefficient ranged from 0.77 to 0.89 for lymph node levels and 0.86 to 0.96 for chewing and swallowing structures. The AI contours were superior to or equally preferred to the manual contours at rates ranging from 75% to 91%; there was not a significant difference in clinical acceptability for nodal levels I-V for manual versus AI contours. Across all AI-generated lymph node level contours, 92% were rated as usable with stylistic to no edits. Of the 340 contours in the chewing and swallowing cohort, 4% required minor edits. Conclusions: An accurate approach was developed to auto-contour lymph node levels and chewing and swallowing structures on CT images for patients with intact nodal anatomy. Only a small portion of test set auto-contours required minor edits.

Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis.

BACKGROUND: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. METHODS: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. FINDINGS: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. INTERPRETATION: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. FUNDING: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Multicenter Study of Survival Benefit of Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease.

BACKGROUND: Evidence for the efficacy of cardiac resynchronization therapy (CRT) in pediatric and congenital heart disease (CHD) has been limited to surrogate outcomes. OBJECTIVES: This study aimed to assess the impact of CRT upon the risk of transplantation or death in a retrospective, high-risk, controlled cohort at 5 quaternary referral centers. METHODS: Both CRT patients and control patients were <21 years of age or had CHD; had systemic ventricular ejection fraction <45%; symptomatic heart failure; and significant electrical dyssynchrony (QRS duration z score >3 or single-site ventricular pacing >40%) at enrollment. Patients with CRT were matched with control patients via 1:1 propensity score matching. CRT patients were enrolled at CRT implantation; control patients were enrolled at the outpatient clinical encounter where inclusion criteria were first met. The primary endpoint was transplantation or death. RESULTS: In total, 324 control patients and 167 CRT recipients were identified. Mean follow-up was 4.2 ± 3.7 years. Upon propensity score matching, 139 closely matched pairs were identified (20 baseline indices). Of the 139 matched pairs, 52 (37.0%) control patients and 31 (22.0%) CRT recipients reached the primary endpoint. On both unadjusted and multivariable Cox regression analysis, the risk reduction associated with CRT for the primary endpoint was significant (HR: 0.40; 95% CI: 0.25-0.64; P < 0.001; and HR: 0.44; 95% CI: 0.28-0.71; P = 0.001, respectively). On longitudinal assessment, the CRT group had significantly improved systemic ventricular ejection fraction (P < 0.001) and shorter QRS duration (P = 0.015), sustained to 5 years. CONCLUSIONS: In pediatric and CHD patients with symptomatic systolic heart failure and electrical dyssynchrony, CRT was associated with improved heart transplantation-free survival.

An integrated program to expand donor utilization in pediatric heart transplantation: Case report of successful transplant with multiple donor risk factors.

BACKGROUND: Pediatric heart transplantation (HT) continues to be limited by the shortage of donor organs, distance constraints, and the number of potential donor offers that are declined due to the presence of multiple risk factors. METHODS: We report a case of successful pediatric HT in which multiple risk factors were mitigated through a combination of innovative donor utilization improvement strategies. RESULTS: An 11-year-old, 25-kilogram child with cardiomyopathy and pulmonary hypertension, on chronic milrinone therapy and anticoagulated with apixaban, was transplanted with a heart from a Hepatitis C virus positive donor and an increased donor-to-recipient weight ratio. Due to extended geographic distance, an extracorporeal heart preservation system (TransMedics™ OCS Heart) was used for procurement. No significant bleeding was observed post-operatively, and she was discharged by post-operative day 15 with normal biventricular systolic function. Post-transplant Hepatitis C virus seroconversion was successfully treated. CONCLUSIONS: Heart transplantation in donors with multiple risk factor can be achieved with an integrative team approach and should be taken into consideration when evaluating marginal donors in order to expand the current limited donor pool in pediatric patients.