Cell Rescue Research Articles

B cell-intrinsic IFN-γ promotes excessive CD11c+ age-associated B cell differentiation and compromised germinal center selection in lupus mice

CD11c+ age-associated B cells (ABCs) have emerged as a key component in protective and autoreactive B cell responses. Lupus is an autoimmune disorder linked to reduced efficacy of vaccines and increased susceptibility to infections. Previously, we reported that excessive CD11c+ ABCs not only significantly contribute to autoantibody production but also promote aberrant T cell activation and compromised affinity-based germinal center selection in response to immunization in lupus mice. Yet, the regulation of CD11c+ ABC differentiation is not fully understood. In this study, we show that B cell-intrinsic IFN-γ is required for excessive CD11c+ ABC differentiation in lupus mice. B cell-intrinsic IFN-γ is mainly produced by CD11c+ ABCs. IFN-γ-deficiency leads to decreased expression of ABC characteristic genes. We further show that ablating IFN-γ can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-γ in promoting excessive CD11c+ ABC differentiation, which compromises affinity-based germinal center selection and affinity maturation in lupus, providing a potential strategy to normalize vaccine responses in lupus.

HIF1A/PCDH7 axis mediates fatty acid synthesis and metabolism to inhibit lung adenocarcinoma anoikis.

Aberrantly expressed PCDH7 participates in the malignant progression of many cancers. PCDH7 has been newly discovered as a risk factor in lung cancer, but its functional study in lung adenocarcinoma (LUAD) has not been conducted yet. This study aimed to investigate the functional role of PCDH7 in LUAD. Bioinformatics analyzed the expression of PCDH7 and HIF1A in LUAD tissues, predicted the binding sites between the two, analyzed the clinicopathological relevance of PCDH7 and examined the pathway enrichment of PCDH7. Expression of PCDH7 and HIF1A in LUAD cells was analyzed by RT-qPCR. A nude mouse transplantation tumor model was constructed to analyze the effect of PCDH7 on tumor growth in vivo. The binding relationship between PCDH7 and HIF1A was confirmed by chromatin immunoprecipitation experiments and the dual-luciferase assay. Cell viability was detected with Cell Counting Kit-8. Triglyceride content and Caspase3 activity were measured using corresponding reagent kits. FASN and ACC1 expression was determined utilizing western blot. PCDH7 was highly expressed in LUAD and correlated with patients' overall survival time and N stage. In vitro and in vivo experiments confirmed that PCDH7 could promote LUAD growth and anoikis resistance. Moreover, overexpression of PCDH7 markedly increased the content of triglycerides in cells and promoted the expression of FASN and ACC1 proteins to inhibit LUAD cell anoikis. Cell rescue experiment confirmed that HIF1A activated PCDH7 to suppress LUAD anoikis by promoting fatty acid (FA) synthesis and metabolism. Our findings demonstrated that the HIF1A/PCDH7 axis suppressed LUAD anoikis by promoting FA synthesis and metabolism. The FA synthesis pathway might be a key pathway regulated by PCDH7 in LUAD anoikis.

High dose chemotherapy with autologous stem cell rescue in children and young adults with high-risk Ewing sarcoma: A single institute experience in Taiwan.

A combination treatment of surgery, chemotherapy, and radiotherapy can improve the survivals of pediatric patients with Ewing sarcoma (ES). However, prognosis remains poor for patients with metastatic disease at diagnosis or recurrence. Other high-risk (HR) features include large tumor burden, tumors of the axial skeleton and poor histologic response. Several studies have documented high dose chemotherapy with autologous stem cell rescue (HDC-ASCR) to be effective in such patients. In this retrospective study, we present the results of HDC-ASCR for high-risk Ewing sarcoma in children and young adults in a single institute. From March 2004 to March 2021, patients with ES, Ewing-like sarcoma, or round cell sarcoma received HDC-ASCR as part of treatment were included. The patients' characteristics, disease status, stem cell dose, engraftment status, post-transplant complications, and outcomes were analyzed. Twenty patients receiving HDC-ASCR at complete response (n = 6), partial response (n = 13), and stable disease (n = 1) were enrolled. The male to female ratio was 11:9. Median age at diagnosis and transplant was 15.6 years old (range: 3.3-28.9) and 16.2 (range: 4.2-29.9), respectively. The conditioning regimens included ifosfamide-based in two and melphalan-based in 19. All patients achieved successful engraftment without tansplant-related mortality. The 5-year progression-free and overall survival (OS) rate were 35% and 54.5%, respectively. The causes of death (n = 8) were all contributed to disease progression. Patients in the complete response group or with localized HRES exhibited a higher 5-year OS (p = 0.047 and 0.05, respectively). Compared to the historical cohort without HDC-ASCR as part of primary treatment, the current cohort had a significantly better 5-year OS (p = 0.018). HDC-ASCR seems promising as an alternative treatment for HRES in improving OS in this retrospective study with limited case number.

Management of Busulfan-Induced Lung Injury in Pediatric Patients with High-Risk Neuroblastoma

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities.

High-dose chemotherapy for patients with stage III breast cancer with homologous recombination deficiency: a discrete choice experiment among healthcare providers.

High-dose chemotherapy with autologous stem cell rescue (HDCT) is currently under investigation as a potential therapy for patients with stage III HER2-negative breast cancer with homologous recombination deficiency (HRD). In addition to survival, the impact on short- and long-term side effects might influence the uptake of HDCT by healthcare professionals. As part of the SUBITO trial, we investigated healthcare professionals' treatment (outcome) preferences for patients with HRD stage III HER2-negative breast cancer and established how healthcare professionals make trade-offs between these treatment outcomes. We conducted a discrete choice experiment in which healthcare professionals were asked to choose repeatedly between scenarios with two treatment options (HDCT or standard of care (SOC)) that varied in outcome with respect to 10-year overall survival (OS), short-term toxicity, long-term cognitive impairment, and premature menopause. We analysed treatment preferences, relative importance, and trade-offs using a multinomial logistic model. Thirty-five of the 151 dedicated breast cancer professionals with extensive experience in treating breast cancer patients completed the survey. The 10-year OS and long-term cognitive impairment were the most important attributes. The results indicate a requirement of 10.4% and 25.1% absolute additional improvement in the 10-year survival rate to justify accepting moderate or severe long-term cognitive impairment as a trade-off, respectively. Therefore, we found in our dataset that healthcare professionals expected a large improvement in 10-year OS to accept moderate to severe cognitive impairment. This information calls for further research into chemotherapy-related cognitive impairment, shared decision-making, and treatment preferences for patients with stage III breast cancer.

Preserving insulin function in diabetes: a case report

BackgroundThis case report explores the long-term dynamics of insulin secretion and glycemic control in two patients with diabetes mellitus type 2 over 20 years. The observations underscore the impact of lifestyle interventions, including weight loss and calorie restriction, on insulin secretion patterns and glucose levels during 75 g oral glucose tolerance tests. Additionally, the role of hemoglobin A1c fluctuations, influenced by various factors such as body weight, exercise, and pharmacological interventions, is investigated.Case presentationCase 1 involves a Japanese woman now in her late 70s who successfully maintained her hemoglobin A1c below 7% for over two decades through sustained weight loss and lifestyle changes. Despite a gradual decline in the homeostasis model assessment of β cell function, the patient exhibited remarkable preservation of insulin secretion patterns over the 20-year follow-up. In case 2, a Japanese woman, now in her early 70s, experienced an improvement in hemoglobin A1c to 6.3% after a period of calorie limitation due to a wrist fracture in 2018. This incident seemed to trigger a temporary rescue of pancreatic β cell function, emphasizing the dynamic nature of insulin secretion. Both cases highlight the potential for pancreatic β cell rescue and underscore the persistence of insulin secretion over the 20-year follow-up. Additionally, we have briefly discussed three additional cases with follow-ups ranging from 10 to 17 years, demonstrating similar trends in glucose and insulin ratios.ConclusionsLong-term lifestyle interventions, such as weight loss and calorie restriction, can preserve pancreatic β cell function and maintain glycemic control in type 2 diabetes patients over 20 years. Two patients showed stable or improved insulin secretion and favorable hemoglobin A1c levels, challenging the traditional view of irreversible β cell decline. The findings highlight the importance of personalized, nonpharmacological approaches, suggesting that sustained lifestyle changes can significantly impact diabetes management and potentially rescue β cell function.

LBA14 Intensified alkylating chemotherapy with autologous stem cell rescue (IACT) or conventional chemotherapy followed by olaparib (CCT-O) in stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer (BC): Survival results of the randomized-controlled SUBITO trial

LBA14 Intensified alkylating chemotherapy with autologous stem cell rescue (IACT) or conventional chemotherapy followed by olaparib (CCT-O) in stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer (BC): Survival results of the randomized-controlled SUBITO trial

Craniospinal irradiation and/or intraventricular radioimmunotherapy after high-dose chemotherapy and autologous stem cell rescue in patients with CNS retinoblastoma-Safety and outcomes.

The prognosis for patients with central nervous system (CNS) retinoblastoma (RB) (trilateral or stage 4b metastatic RB) treated with high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT) remains poor. The impact of irradiation when administered as part of upfront therapy post HDC-ASCT on treatment outcomes and survival is unknown. We performed a retrospective review of all patients with CNS RB (seven stage 4b, eight trilateral, one pineal lesion belonging to methylation group RB) who underwent induction chemotherapy with an intent to proceed to HDC-ASCT at two institutions. Twelve of 16 patients (n=75%) achieved an objective response to induction chemotherapy, while four patients had progressive/refractory disease; two patients responded to subsequent therapy and proceeded to ASCT, and two patients did not. Seven of 14 patients who underwent HDC-ASCT, received radiotherapy as part of upfront therapy post HDC-ASCT in the form of craniospinal irradiation (CSI) (n=3), intraventricular radioimmunotherapy (n=3), or both CSI and intraventricular radioimmunotherapy (n=1). The Kaplan-Meier estimate of overall survival for these patients was 62.5% at 5years; no patients developed second malignant neoplasms within the radiation fields. For the seven patients who did not receive radiotherapy, the overall survival was 28.6% at 5years. CSI (23.4Gy) alone or in conjunction with intraventricular RIT may have clinical utility in eliminating persistent MRD post HDC-ASCT, contributing to improved disease-free survival in patients with CNS RB. This treatment strategy merits evaluation in a prospective, multicenter clinical trial for patients with CNS metastatic RB.

Mu opioid receptors gate the locus coeruleus pain generator.

The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic - further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia - providing a functional gate on the LC pain generator.

Consensus recommendations for systemic therapies in the management of relapsed Ewing sarcoma: A report from the National Ewing Sarcoma Tumor Board.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs.

Outcomes of melphalan 140mg/m2 followed by autologous stem cell transplantation in multiple myeloma patients with co-morbidities: Single-centre experience.

High-dose melphalan followed by stem cell rescue is the standard consolidative therapy for transplant-eligible patients with multiple myeloma (MM) in the United Kingdom. A melphalan dose of 200mg/m2 (Mel200) is considered the "gold standard" for autologous stem cell transplant (ASCT) conditioning for fit patients ≤70 years old; however, with a peak diagnosis incidence at 80-89 years old in the UK dose adjustments will be inevitable to limit toxicities. In this single-centre UK-based retrospective analysis, data was collected from patients with plasma cell dyscrasias who underwent a first reduced-intensity, Mel140, ASCT from 2006 to 2019, a total of 81 patients. We found that the procedure was overall safe with seven (9%) of patients requiring ITU admission and a single transplant-related death within the initial autograft admission. The progression-free survival (PFS) and overall survival were comparable with those previously reported in the literature with median PFS for our cohort of 31 months. Univariate analysis of our data showed an inferior PFS for patients aged ≥70 years. In conclusion, although this is a retrospective analysis, it demonstrates that dose-reduced melphalan conditioning is safe and effective in patients deemed unfit for standard-intensity conditioning.

TRIM24 Up-Regulates ORM2 to Alleviate Abnormal Lipid Metabolism, Inflammation, and Oxidative Stress in Mice with Obstructive Sleep Apnea Syndrome and Metabolic Dysfunction–Associated Steatotic Liver Disease

Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Tripartite Motif Containing 24 (TRIM24) deficiency was reported to cause hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of TRIM24 in OSAS & MASLD remain unclear. OSAS & MASLD mouse model was established by intermittent hypoxia (IH) & high-fat diet. IH- & 1% free fatty acid-induced mouse liver cells were served as in vitro model. TRIM24 and HIF-1α were upregulated under IH condition. HIF-1α enhanced the transcriptional activity of TRIM24. Overexpression of TRIM24 reduced hepatic lipid accumulation, decreased serum levels of TC, TG, and LDL-C, and increased serum levels of HDL-C in OSAS & MASLD mice. Additionally, overexpression of TRIM24 alleviated inflammation, oxidative stress, and modulated aberrant lipid metabolism. Mechanically, TRIM24 upregulated the expression of ORM2, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting RAR-alpha to ORM2 promoter. The cell rescue model verified that ORM2 mediated the hepatoprotective effects of TRIM24. Our evidence reveals the important role of TRIM24 as an epigenetic co-regulator of transcription in OSAS & MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS & MASLD.

MicroRNA-486-3p affects cisplatin resistance in high-grade serous ovarian cancer by regulating TMIGD2: An experimental study

Ovarian cancer represents a major public health concern worldwide. High-grade serous ovarian cancer (HGSOC) is a primary epithelial ovarian cancer. Cisplatin resistance poses a substantial obstacle in the management of HGSOC, leading to unfavourable patient outcomes. The primary objective of this study was to investigate the mechanisms underlying cisplatin resistance in patients with HGSOC. TCGA data, GSE65819 dataset, and multiMiR package were used to identify 35 differentially expressed miRNAs (DE-miRNAs). Differentially expressed mRNAs (DE-mRNAs) are indicated using TCGA data. Further, weighted gene co-expression network analysis (WGCNA) was used to determine the correlation coefficients between the DE-mRNAs and DE-miRNAs. A network of miR-486-3p and TMIGD2 was constructed. Molecular biology experiments also indicated that low miR-486-3p or high TMIGD2 expression significantly increased the migratory rate and cisplatin resistance of both SK-OV3 and A2780 cells. In contrast, overexpression of miR-486-3p or downregulation of TMIGD2 decreased the migration rate and enhanced the sensitivity to cisplatin treatment, which provides insights for the development of novel therapeutic approaches. Moreover, RNA-binding protein immunoprecipitation experiment was used to determine the relationship between miR-486-3p and TMIGD2. Cell rescue assays were performed to further investigate these regulatory relationships. In TCGA and GSE65819 datasets, Benjamini and Hochberg false discovery rates (FDR) were selected for P-values. In the molecular biology experiments, one-way analysis of variance was employed to compare different groups, supplemented by Bonferroni post-hoc testing. Statistical significance was set at p < 0.05.

Ovarian function in female survivors of high-risk neuroblastoma.

Data on ovarian function in neuroblastoma survivors are limited. We sought to determine the prevalence of ovarian dysfunction in a cohort of high-risk neuroblastoma survivors and compare outcomes among survivors treated with and without autologous stem cell rescue (ASCR) preceded by myeloablative chemotherapy. Retrospective review of female survivors of high-risk neuroblastoma ≥5 years from diagnosis, diagnosed between 1982 and 2014, and followed in a tertiary cancer center. Participants were divided into two groups: individuals treated with conventional chemotherapy±radiation ("non-ASCR") (n=32) or with chemotherapy±radiation followed by myeloablative chemotherapy with ASCR ("ASCR") (n=51). Ovarian dysfunction was defined as follicle-stimulating hormone ≥15 mU/mL, while premature ovarian insufficiency (POI) was defined as persistent ovarian dysfunction requiring hormone replacement therapy. Poisson models were used to determine prevalence ratios of ovarian dysfunction and POI. Among 83 females (median attained age: 19 years [range, 10-36]; median follow-up: 15 years [range, 7-36]), 49 (59%) had ovarian dysfunction, and 34 (41%) developed POI. Survivors treated with ASCR were 3.2-fold more likely to develop ovarian dysfunction (95% CI: 1.8-6.0; p<0.001) and 4.5-fold more likely to develop POI (95% CI: 1.7-11.7; p=0.002) when compared with those treated with conventional chemotherapy, after adjusting for attained age. Two participants in the non-ASCR group and six in the ASCR group achieved at least one spontaneous pregnancy. Ovarian dysfunction is prevalent in female high-risk neuroblastoma survivors, especially after ASCR. Longitudinal follow-up of larger cohorts is needed to inform counseling about the risk of impaired ovarian function after neuroblastoma therapy.

ETMR-06. PNOC031 - INTERNATIONAL TRIAL FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES

Abstract Embryonal tumors with multilayered rosettes (ETMR) are aggressive central nervous system neoplasms with unfavorable prognosis, exhibiting rapid disease progression and frequent post-therapeutic relapse. The rarity of ETMR necessitates global collaboration to advance therapies. Radiotherapy (RT) has been associated with improved survival outcomes in ETMR with case series revealing that nearly half of ETMR patients treated without RT relapse within six months of diagnosis. However, RT is often withheld due to young patient age and neurodevelopmental considerations. This high-rate of on-treatment relapse is unique to ETMR and suggests that radiation-sparing regimens may be suboptimal. PNOC031 is an international collaboration, establishing a global clinical trial to innovate and improve therapeutic interventions for children with ETMR. Eligible patients with newly-diagnosed ETMR are stratified into three cohorts: Cohort 1 - gross total resection/RT-eligible patients to receive early focal radiotherapy (RT); Cohort 2 – gross total resection/not RT-eligible to receive high-dose chemotherapy with autologous stem cell rescue; and Cohort 3 – less than gross total resection or with metastatic disease to receive RT or high-dose chemotherapy per RT eligibility, based on age and tumor location. Cohort 1 will test the hypothesis if early RT improves outcomes in a pilot cohort of 20 patients. Patients will receive six weeks of induction chemotherapy, followed by focal irradiation and an additional six weeks of chemotherapy. Six-month progression-free survival will be assessed to determine the impact of radiotherapy on the rate of early relapse. Cohorts 2 and 3 will allow collection of uniform prospective clinical data using a common treatment backbone, to inform future clinical trial design for ETMR. Incorporating a myriad of correlative studies, including next-generation sequencing, cerebrospinal fluid analyses, microbiome profiles, and evaluations of social determinants of health alongside cognitive outcomes, will enhance comprehensive understanding of clinical responses and advance therapeutic options for this high risk disease.

LMIC-03. BRAINSTEM RADIATION NECROSIS IN A PATIENT WITH RECURRENT MEDULLOBLASTOMA. SUCCESFULL TREATMENT OF A HIGHLY FEARED COMPLICATION

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in pediatric population. Standard treatment combines surgery, risk-adapted craniospinal irradiation and chemotherapy. Given the well-known cognitive sequelae in young children associated to radiation, strategies in infants try to avoid upfront radiation. A significant number of patients treated during infancy will ultimately relapse. Re-irradition in relapse setting has proven to be effective in disease control (survival depending on several factors) although there is a concern in exceeding radiation tolerance and risk of toxicity. METHODS Herein, we describe the case of male patient that presented at 1 year of age with a non-metastatic anaplastic medulloblastoma that was completely resected. He received 3 cycles of adjuvant chemotherapy (as per Head Start II), local relapse was detected in tumor bed during evaluation and was completely resected, afterwards he received myeloablative chemotherapy with stem cell rescue and posterior fossa radiation therapy (54 Gy). At 8 months off therapy patient developed spinal relapse in imaging with negative cytology, then treated with spinal irradiation 36Gy without adjuvant chemotherapy. He remained disease free during 12 months, then tumor recur at the right cerebellopontine angle, surgery was complete and there was no evidence of distant disease. Patient received adjuvant local radiation with 30.6Gy followed by chemotherapy (bi weekly bevacizumab + irinotecan). Cumulative maximal dose to brainstem was 84Gy. 2 months after radiation patient presented with extreme sleepiness and imaging findings compatible with brainstem radiation necrosis, symptoms resolved promptly after scheduled bevacizumab. Patient is currently 6-year-old and remains free of disease after 3 years off therapy. CONCLUSION Medulloblastoma treatment in infants is challenging because survival is not the only goal. Future clinical trials will help to better tailored treatment based on molecular biology. Re-irradiation in medulloblastoma has been described as well tolerated but clinician should be aware of its complications and management.

GCT-21. MULTINATIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS

Abstract BACKGROUND Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor prognosis. We explored prognostic factors to guide the management of these patients. METHODS We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. Data were summarized using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS We identified 31 patients from eight centers. The median age at initial diagnosis was 11 years (interquartile range (IQR): 9-15.3). Twenty patients (64.5%) suffered a relapse, and 11 patients (35.5%) had refractory disease. The median follow-up time since relapse/progression was 17.5 months (range:1-295). The median time to relapse/progression was 12.1 months (IQR: 5.5-27.5). Ten patients (32.3%) received high-dose chemotherapy (HDCx) with stem cell rescue. Sixteen patients (51.6%) received re-irradiation at relapse/progression. Nine patients (29%) achieved complete remission (CR). Ten patients (32.3%) were alive at the time of the last follow-up. Among the ten survivors, the median serum and cerebrospinal fluid (CSF) alpha-fetoprotein levels were 2.3 ng/dl (range: 0-17) and 2.1 ng/dl (range: 0-55), respectively, the median serum and CSF beta-human chorionic gonadotropin were 23 IU/L (0-168) and 139 IU/L(0-601), none underwent gross total resection, eight received HDCx, and seven received radiotherapy (craniospinal irradiation (n=6), abdominal radiotherapy (n=1)). HDCx (OR=19.8, 95%CI: 2.7-145.7; p=0.01) and achieving CR at the end of relapse treatment (OR=160, 95%CI: 8.9-2880.5; p=&amp;lt;0.001) were associated with a survival benefit. Re-irradiation (OR=3.3 95%CI: 0.53-20.9; p=0.24) was not associated with a survival benefit. CONCLUSIONS A subset of patients with relapsed NGGCTs are salvageable at relapse. HDCx and achieving CR at the end of relapse therapy were associated with a survival benefit. More studies are required to identify these patients who would benefit from salvage therapy.

MDB-43. SHARED DECISION-MAKING (SDM) REGARDING RADIATION-AVOIDING (RA) THERAPY IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB)

Abstract BACKGROUND Standard treatment for MB in patients age ≥ 3 years includes craniospinal radiation with tumor bed boost and chemotherapy. Radiation carries substantial risk of long-term issues, particularly in the youngest patients: second malignancy, neurocognitive issues, vasculopathy and endocrinopathies. Numerous trials have attempted to decrease or avoid the use of radiation by intensifying chemotherapy, some using high dose chemotherapy with autologous hematopoietic stem cell rescue (HDC). One of the most successful RA protocols, Children’s Oncology Group ACNS0334 enrolled children age &amp;lt; 36 months and treated with 3 cycles of induction (+/- high dose methotrexate) and 3 cycles HDC without planned radiation. Since 2012, we offer SDM with caregivers regarding treatment of their children ages 3-7 years with MB. Caregivers may choose standard radiation and chemotherapy (SRC) or the RA treatment above. OBJECTIVE Describe patient and disease characteristics and outcomes in patients aged 3-7 years treated for MB with SDM regarding the use of radiation. METHODS Retrospective analysis of diagnosis, treatment and clinical outcomes in all children &amp;lt;8 y.o. who completed treatment for MB between 2012 and 2023. RESULTS There were 16 patients offered SDM (all gross total resection without metastases) 7 chose RA and 9 SRC. The SRC group was enriched with molecularly high-risk patients (4 MYC or MYCN amplification, 1 SHH with P53 mutation). In the RA group, relapse occurred in 14% (n=1 of 7). In the SRC group, 44% relapsed (n=4 of 9). One patient developed high-grade glioma in the radiation boost field 10 years later. There was 1 death in the RA group due to disease progression and 5 deaths in the SRC group, 1 due to second malignancy. CONCLUSIONS We report excellent survival with RA therapy for appropriately selected young children (age 3-7 years) when SDM is used with families to determine the best treatment for their child.

MDB-82. TRANSFUSION-RELATED IRON OVERLOAD MIMICKING METASTATIC DISEASE IN A PEDIATRIC PATIENT WITH MEDULLOBLASTOMA ON A RADIATION-DELAYING CHEMOTHERAPY REGIMEN

Abstract BACKGROUND Transfusion-related iron overload (TRIO) is a known complication of administering numerous packed red blood cell (pRBC) transfusions in pediatric oncology patients undergoing myelosuppressive therapy. Infant medulloblastoma regimens attempt to avoid or delay radiation and its adverse effects in this population, with intensive myelosuppressive chemotherapy. We report a case of TRIO first suspected as hepatic metastatic disease at time of CNS recurrence in a young patient with medulloblastoma after completion of a high-dose chemotherapy protocol. METHODS Case Report RESULTS A five-year-old male presented with four months of headaches, dizziness, imbalance, and emesis. MRI revealed a posterior fossa mass with near total resection of the mass confirming classic medulloblastoma, non-WNT, non-SHH. The patient received five cycles of induction chemotherapy. This was followed by a single cycle of high-dose chemotherapy (HDCSCR) with autologous stem cell rescue. During therapy, he received 26 pRBC transfusions to correct severe anemia. CNS recurrence occurred 19 months after therapy. Abdominal imaging revealed enlarging hepatic lesions concerning for metastases. Ferritin was 1,268 ng/mL (normal: 7-142 ng/mL) and MRI of liver revealed severe iron load with LIC of 11 mg Fe/g dry weight (dw) (normal: 0.4-2.2 mg Fe/g dw). Ultimately, hepatic lesions were thought to be non-cancerous, and he proceeded with craniospinal irradiation. He was diagnosed with TRIO. He underwent phlebotomy for 33 months with ferritin and MRI liver LIC within normal limits. CONCLUSION This case illustrates an occurrence of TRIO presenting as hepatic lesions concerning for metastatic disease during CNS recurrence in a patient who underwent an infant medulloblastoma regimen with HDCSCR. Our patient required phlebotomy for nearly 3 years to return ferritin and LIC to normal limits. Further investigation on the prevalence of TRIO in medulloblastoma survivors treated with radiation delaying/sparing protocols is necessary to improve outcomes and avoid end organ damage due to iron overload.

ATRT-08. ATYPICAL TERATOID RHABDOID TUMOR IN AN ADULT PATIENT WITH DOWN SYNDROME

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant, highly aggressive embryonal tumor of the central nervous system. Long-term survival remains dismal despite aggressive multimodal therapy, including a maximal safe surgical resection and intensive systemic chemotherapy +/- radiation therapy. While these tumors typically present in infancy or early childhood, there are scattered case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. CASE REPORT A 25-year-old female with Down syndrome presented with nausea, vomiting, dysphagia, and facial droop and was found to have an avidly enhancing, left cerebellopontine angle mass. There was initial clinical suspicion for leukemic chloroma given the patient’s Down syndrome status and known association with higher rates of hematologic malignancy concurrent with a dramatic scarcity of solid tumors in the Down syndrome population. However, histology demonstrated sheets of high-grade rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing defined a frameshift mutation in SMARCB1 (p.C298), and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton radiation, followed by chemotherapy on a modified regimen based on the Children’s Oncology Group protocol, ACNS0333. Systemic methotrexate and all consolidative high-dose chemotherapy with stem cell rescue were omitted due to concern for heightened risk of treatment-related toxicity. The patient remains alive and clinically asymptomatic 19 months from diagnosis. CONCLUSION This report represents the first known case of ATRT in an adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Adult ATRT is a rare entity without standardized treatment or established prognostic understanding. Further studies are needed to define an appropriate risk-adapted therapeutic approach for this patient population.