In adults with classic Hodgkin lymphoma (cHL), metabolic tumour volume (MTV) is valuable for risk stratification. This systematic review explored the role of volumetric parameters in children, adolescents and young adults (CAYA) with cHL. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. Five databases were searched on 16 October 2024. Eligible studies were peer-reviewed manuscripts, written in English, published since database inception that included patients ≤21 years of age with a diagnosis of cHL treated with chemotherapy ± radiotherapy with a baseline 18F-Fluorodeoxyglucose (F-FDG) PET/CT scan for MTV quantification. The search strategy identified 3669 studies, of which 35 were eligible for inclusion. Fifteen studies (43%) evaluated a cohort exclusively ≤21 years of age. All eight studies that explored the association of baseline PET parameters with known risk factors identified a significant correlation. Nine of 12 papers (75%) demonstrated a statistically significant correlation with disease response to therapy on PET/CT. Fifteen of 20 papers (75%) demonstrated an independent statistically significant correlation with clinical outcomes. In the CAYAHL population, volumetric PET parameters are valuable for risk stratification despite heterogeneity in results. Future harmonization of the segmentation approach will facilitate incorporation of MTV into clinical practice.

Pediatric Hodgkin lymphoma (pHL) is a highly curable malignancy in children, adolescents, and young adults, and current treatment strategies aim to minimize adverse late effects. Many patients are enrolled in clinical trials with centralized review for both initial and interim staging. Although academic guidelines provide a structured framework for image interpretation, real-world clinical scenarios sometimes present imaging pitfalls that require nuanced judgment. Morphologic and metabolic imaging pitfalls refer to misinterpretation of findings that occur during staging, disease evaluation, or post-treatment surveillance. In pHL, such pitfalls may result from suboptimal imaging conditions, concurrent inflammatory, infectious, or other findings. These findings do not indicate neoplastic disease but rather are manifestations of other processes specific to each tissue or organ. This Staging, Evaluation and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) initiative represents a transatlantic collaboration among multidisciplinary professionals, aiming to disseminate the insights gained from decades of centralized review experience in North American and European clinical trials. This paper aims to optimize patient care by integrating imaging and clinical expertise in disease staging and surveillance. Although not intended as a comprehensive staging guide, it highlights recurrent imaging pitfalls that may lead to incorrect staging or response assessment. By encouraging interdisciplinary exchange, this work seeks to complement existing literature and serve as a troubleshooting guide for situations where clinical realities diverge from academic paradigms.

Introduction Allogeneic HCT (AlloHCT) offers curative treatment for high-risk and relapsed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoma (T-LLy), but post-HCT relapses remain an obstacle for long-term survival. CD38 is highly expressed in T-ALL/T-LLy, and significant activity of the anti-CD38 antibody, daratumumab (DARA), was seen in a recent clinical trial for relapsed/refractory disease (Bhatla et al., Blood 2024). We developed a phase 1 trial (NCT04972942) to evaluate targeted immunotherapy with DARA after AlloHCT for relapsed T-ALL/T-LLy. Objectives The primary objective is to determine the safety of targeted immunotherapy with DARA after total body irradiation (TBI)-based myeloablative conditioning and AlloHCT for children, adolescents, and young adults (CAYA) with high-risk T-ALL or T-LLy. Additional exploratory objectives will evaluate outcomes of receiving AlloHCT and post-HCT DARA on study and correlate those outcomes with novel biological and immunological studies, including measurable residual or minimal detectable disease (MRD/MDD). Methods Patients 1 (and ≥ 10 kg) to ≤ 39-years, with relapsed T-ALL in second or subsequent remission or relapsed T-LLy with complete response after reinduction therapy are eligible. Participants will undergo myeloablative TBI-based conditioning and AlloHCT with best available donor. Safety of post-HCT DARA will be determined through a phase 1, time-to-event Bayesian optimal interval study design, evaluating 3 dose levels of DARA IV (IND 159396) in 15 participants. If no dose-limiting toxicity (DLT) is observed, an additional 15 participants will be enrolled in a dose expansion cohort (DEC) for additional correlative studies and to guide selection of a recommended phase 2 dose (RP2D) (Figure 1). Participants will have pre- and post-HCT correlative blood, bone marrow, and cerebrospinal fluid studies collected, including NGS-based MRD/MDD. Results Three participants in CR2 enrolled to date, each at dose level 1 (8mg/kg). Participant 1 completed protocol therapy and is alive in CR2 at 27 months post-HCT. Participant 2 received 4 doses of DARA, came off protocol therapy due to moderate chronic GVHD, and is alive in CR2 at 17 months post-HCT. Early tacrolimus taper for EBV pneumonitis and mixed T-cell chimerism likely contributed to their chronic GVHD. Participant 3 completed protocol therapy and is alive in CR2 at 11 months post-HCT. No DLT related to DARA has been observed to date. Conclusions Novel strategies are needed to reduce relapse and improve survival after AlloHCT for relapsed T-ALL/T-LLy. ALLO-T-DART will (1) determine the safety and RP2D of post-HCT DARA and (2) collect data on novel biomarkers of response, MRD/MDD kinetics, and immune reconstitution after DARA treatment for relapsed T-ALL/T-LLy. Supported by DOD USAMRAA #HT94252310686, Johnson & Johnson Innovative Medicine, and Cures Within Reach.

This study aimed to evaluate the prognostic value of conventional and advanced PET metrics for predicting progression-free survival in high-risk pediatric Hodgkin lymphoma (HL), using data from the Children's Oncology Group AHOD1331 trial. Methods: This retrospective analysis included 558 patients from 150 institutions. Conventional PET metrics and radiomics features were extracted from both baseline and interim-therapy PET images. Clinical variables, including demographic characteristics and common risk factors, were also considered. A standardized outcome-modeling pipeline was developed, comprising feature selection and penalized Cox regression with elastic net regularization (CoxNet). Models were trained and evaluated using nested cross-validation stratified by institution, ensuring consistent external testing. We investigated whether conventional PET metrics added prognostic value beyond clinical variables and whether radiomics or interim PET-derived features offered further benefit. Additionally, we compared the prognostic performance of features extracted from automated deep learning (DL) segmentations against those derived from physician annotations. Model performance was assessed using the concordance index (C-index). Results: Among all types of features, the CoxNet model using conventional baseline PET metrics achieved the highest performance (C-index, 0.72 ± 0.01), significantly outperforming the clinical model (C-index, 0.65 ± 0.01). Neither the inclusion of radiomics features nor interim PET-derived features improved performance. Models using DL-generated segmentations achieved comparable prognostic accuracy (C-index, 0.72 ± 0.01) to those using physician-based segmentations. Conclusion: Quantitative PET features provided significant prognostic improvements over clinical variables. Furthermore, DL-based segmentation offered a promising approach for automating feature extraction, supporting more effective risk stratification in pediatric HL.

Congenital heart disease (CHD) patients are at increased risk of developing infective endocarditis, particularly following placement of prosthetic valves, stents, and vascular conduits. As compared to studies of infective endocarditis in adults, there is limited data on use of FDG PET/CT for evaluation of pediatric CHD patients. The primary aim of this study is to determine the value of FDG PET/CT for detecting infective endocarditis in a cohort of pediatric and young adult patients with complex CHD, with a secondary aim of demonstrating the feasibility of obtaining adequate dietary preparation in these complex patients. Single center retrospective review of patients undergoing 18F-FDG PET/CT for suspected endocarditis between April 2014 and October 2025. Patients were identified in a search of the radiology report database. The accuracy of FDG PET/CT was determined based on a combination of clinical outcomes, surgical findings, microbiology and pathology. 67 patients accounted for the 75 examinations meeting inclusion criteria. Median age was 21 (IQR 15–26) years. The most common underlying diagnosis was Tetralogy of Fallot (n = 27). Implanted devices were present in 62/67 patients; 53/67 patients had more than 1 implanted device. RV/PA conduit (n = 48) and Melody valve (n = 27) were the most common implants. 50 of 75 (67

PURPOSE:Individuals with Li-Fraumeni syndrome (LFS) are at risk of developing cancer in multiple organs and therefore require a multimodal screening program. We assessed the performance of annual whole-body noncontrast magnetic resonance imaging (WBMRI) in early cancer detection for individuals with LFS. METHODS:Individuals with a germline pathogenic or likely pathogenic variant in the TP53 gene (defined as LFS) and without cancer diagnosed or treated in the preceding 6 months were eligible to undergo annual noncontrast WBMRI. Clinical findings on WBMRI, follow-up studies, biopsies, and cancer incidence were prospectively assessed. RESULTS:One hundred sixty-two participants with LFS (127 adult, 35 pediatric) underwent 477 WBMRIs; 119 (73%) underwent three or more. The median age at enrollment was 37 years; 75% of participants were female. Classic or Chompret diagnostic criteria for LFS were met for 68.5% of participants. Follow-up studies for findings on WBMRI were pursued for 55.6% of participants. Biopsies were performed in 18% of participants; 39.5% of 38 biopsies confirmed a cancer diagnosis. The rate of follow-up interventions decreased with consecutive WBMRIs. During the study period, of 37 cancers diagnosed in 33 participants, 15 (40.5%) were diagnosed by WBMRI; 86% (13 of 15) were asymptomatic, localized cancers treated with curative intent. The 22 cancers not diagnosed on WBMRI included five sarcomas; one each of adrenocortical, lung, thyroid, and renal cell carcinomas; and 13 cancers that WBMRI would not be expected to detect. CONCLUSION:Annual WBMRI contributes substantially to the detection of asymptomatic localized cancers among individuals with LFS and is best used in conjunction with a multimodality approach endorsed by LFS guidelines. Our study highlights the need for further research to enhance early detection and interception of cancer in LFS.

PURPOSE:Human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in osteosarcoma (OST). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a HER2-targeting monoclonal antibody, trastuzumab, linked to a topoisomerase I inhibitor. We report results of a phase II study of T-DXd in adolescents and young adults with HER2-positive relapsed, unresectable OST (ClinicalTrials.gov identifier: NCT04616560). METHODS:Patients age 12-39 years with relapsed, unresectable OST were eligible for centrally evaluated HER2 expression screening by immunohistochemistry. Patients with >10% of OST cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4 mg/kg intravenously once every 3 weeks for up to 2 years. The study used a 9 + 15 Simon's optimal two-stage design with a primary end point of event-free survival at 24 weeks. RESULTS:Fifty patients were screened for HER2, and 41 met the inclusion criteria of 10% of OST cells having membranous or cytoplasmic HER2 expression. Nine eligible patients, two younger than 18 years, were enrolled and received T-DXd. With a single patient having more than 24 weeks of stable disease (SD) of the nine planned in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1%. The median (range) number of cycles of therapy was 2 (2-12). Grade 3 and 4 possibly related adverse events occurred in three of nine patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. CONCLUSION:T-DXd did not demonstrate sufficient activity to expand enrollment to the planned second stage in patients with OST. No new safety signals were observed.

Hereditary Pheochromocytoma/Paraganglioma Syndromes (HPPS) are a collection of conditions caused by variants in genes producing subunits of the succinate dehydrogenase (SDH) complex or related proteins. These conditions are characterized by substantial lifetime risks for developing pheochromocytomas, paragangliomas, and other tumors. Affected individuals who develop these tumors may experience severe, acute and chronic problems. Indeed, aggressive, malignant, and/or disseminated tumors may result in death. Tumor surveillance enables early intervention, which, in turn, should lead to improved clinical outcomes. However, the desire for intensive surveillance strategies must be balanced against medical and psychosocial risks. In 2017, consensus HPPS surveillance recommendations addressing germline predisposition to SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127 (collectively, SDHx+) related tumors were published after the inaugural AACR Childhood Cancer Predisposition Workshop. Based on the limited available clinical data at that time, these recommendations advocated a uniform approach to tumor surveillance in HPPS. Since then, several other groups have proposed alternative consensus surveillance guidelines. Although these surveillance approaches share some common elements, including recommendations tailored to emerging differences in tumor phenotype based on underlying specific SDHx+ genes, these approaches also vary significantly amongst each other. As clinical data continue to accrue, it is critical that surveillance strategies continue to be refined to address emerging genotype-phenotype differences. In this review, we provide a brief up-to-date clinical overview of HPPS and describe recently proposed tumor surveillance regimens. We then detail our updated consensus pediatric-focused tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.

Perspectives and Understanding of Radiation Risks in CPS: A Practitioner Survey

Abstract Background: Selinexor is a first-in-class, central nervous system (CNS)-penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880). Methods: A rolling-six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics (PK) of selinexor administered once (QW, 35-45 mg/m2) or twice (BIW, 20-35 mg/m2) weekly during a 28-day cycle (Part A). Ten additional patients with high-grade glioma (HGG) were treated at the QW MTD (Part B). Results: In Part A, 49 patients were enrolled. Continuous BIW dosing was limited by extended hematologic toxicity. The MTD on a BIW schedule for three weeks on/one-week off (BIW 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and AST/ALT increase. On a continuous QW schedule, the MTD was 35 mg/m2/dose, DLTs included seizure and thrombocytopenia. In Part B (HGG expansion), there were no additional DLTs observed. Non-dose-limiting toxicity included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range 1-9); Eight of 59 patients (13.5%) received 5-9 cycles, five of whom had HGG. Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic requiring dose or dose-frequency reduction. The MTD and recommended initial phase 2 dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose QW.

Von Hippel-Lindau disease (VHL) is a genetic condition characterized by a high lifetime risk for tumors and cysts throughout the body, including the central nervous system, visual-auditory systems, and intra-abdominal organs. This neoplasia leads to significant morbidity and potential mortality in affected individuals. Tumor surveillance enables early intervention and leads to improved clinical outcomes. Since the 2017 publication of VHL tumor surveillance recommendations from the inaugural American Association for Cancer Research Childhood Cancer Predisposition Workshop, several other groups have proposed alternative consensus surveillance recommendations. Although these screening paradigms share some common elements, they also deviate from each other in some substantial ways. Clinical data continue to accrue in VHL, allowing the condition to be better characterized. Furthermore, surgical techniques have improved over time, and the option of targeted medical therapy has emerged for individuals with VHL. It is critical that surveillance strategies continue to be refined. In this perspective, we provide an up-to-date clinical overview of VHL, describe recently proposed tumor screening regimens, and finally present our updated consensus tumor surveillance recommendations during childhood and adolescence from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop.

Supplementary Figure 1. Nivolumab (A) and Ipilumumab (B) peak and trough concentrations in treatment cycles 1 – 4.

Whole-body MRI (WBMRI) is an integral part of screening infants, children, and adolescents for presymptomatic neoplasms in certain cancer predisposition syndromes, which include Li-Fraumeni and constitutional mismatch repair deficiency syndromes, among others. The list of syndromes in which WBMRI adds value, as part of a comprehensive surveillance protocol, continues to evolve in response to new evidence, growing experience, and more widespread adoption. In July 2023, the AACR reconvened an international, multidisciplinary panel to revise and update recommendations stemming from the 2016 AACR Special Workshop on Childhood Cancer Predisposition. That initial meeting resulted in a series of publications in Clinical Cancer Research in 2017, including "Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI." This 2024 review of WBMRI in cancer predisposition syndrome updates the 2017 WBMRI publication, the revised recommendations derived from the 2023 AACR Childhood Cancer Predisposition Workshop based on available data, societal guidelines, and expert opinion. Different aspects of acquiring and interpreting WBMRI, including diagnostic accuracy, are discussed. The application of WBMRI in resource-poor environments, as well as integration of whole-body imaging techniques with emerging technologies, such as cell-free DNA ("liquid biopsies") and artificial intelligence/machine learning, is also considered.

10501 Background: Individuals with LFS are at risk for developing cancer in multiple organs and therefore require a multimodal cancer screening program. We assessed the performance of annual WBMRI in early cancer detection for individuals with LFS. Methods: Individuals with a germline pathogenic or likely pathogenic variant in the TP53 gene (defined as LFS) and without cancer diagnosed or treated in the preceding 6 months were eligible to undergo annual non-contrast WBMRI. Clinical findings on WBMRI, follow-up studies, and biopsies were prospectively assessed. Cancer incidence during the study period and up to 18 months after WBMRI was evaluated. Results: 162 eligible participants (pts) with LFS (127 adult, 35 pediatric) underwent a total of 477 WBMRIs; 119 (73%) underwent 3 or more. Median age at enrollment was 37 years; 75% of pts were female. Classic or Chompret diagnostic criteria for LFS were met for 66% (84/127) of adult and 77% (27/35) of pediatric pts. Follow-up studies for findings on WBMRI were pursued for 61.4% (78/127) of adult and 34.3% (12/35) of pediatric pts. Biopsies were performed without complication in 18% (29/162) of pts with 39.5% of 38 biopsies confirming a cancer diagnosis. The percentage of pts requiring follow-up studies or biopsies decreased with consecutive WBMRIs (Table 1). During the study period, 37 cancers were diagnosed in 33 pts (27 adults, 6 children); 26 of these pts were alive at the time of data cut off. Fifteen of 37 cancers (40.5%) were asymptomatic cancers diagnosed by WBMRI; 86% (13/15) of these (in 12 patients) were localized and treated with curative intent, including 3 lung cancers and 4 pelvic/abdominal sarcomas. Ten of these 12 pts remain alive at the time of last follow-up. The 22 cancers not diagnosed on WBMRI included five sarcomas, and one each of adrenocortical, lung, thyroid and renal cell carcinoma as well as cancers not likely to be detected on WBMRI (4 breast/chest wall, 3 endoluminal, 3 hematologic, and 3 metastatic recurrences). Conclusions: Annual WBMRI contributes substantially to detection of asymptomatic localized cancers among individuals with LFS but interval cancers remain common. Our study highlights limitations of WBMRI and the need for further research to enhance early detection and interception of cancer in LFS. Sequence of WB-MRI scans and timing of follow-up studies, biopsies, and cancer diagnoses. WB-MRI scan number # pts evaluated # pts with follow-up studies n (%) # pts with biopsiesn (%) # pts dx with ca by WBMRI n (%) # ca dx based on WBMRI n # pts with interval ca dxn (%) # interval ca dx by other means or symptoms (not detected on WBMRI) n 1 162 60 (37.0) 20 (12.3) 6 (3.7) 7 8 (4.9) 8 2 143 38 (26.6) 12 (8.4) 6 (4.2) 6 7 (4.9) 9 3 119 21 (17.6) 3 (2.5) 0 (0) 0 3 (2.5) 3 4 33 5 (15.2) 1 (3.0) 1 (3.0) 1 2 (6.1) 2 5 11 1 (9.1) 0 (0) 1 (9.1) 1 0 (0) 0 6 5 1 (20) 0 (0) 0 (0) 0 0 (0) 0 7 3 1 (33.3) 0 (0) 0 (0) 0 0 (0) 0 pts: participants, ca: cancer, dx: diagnosed.