Background: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) belongs to a group of conditions called the PIK3CA-related overgrowth spectrum (PROS). The varying phenotypes and low frequencies of each somatic mosaic variant make confirmative diagnosis difficult. We present 12 patients who were diagnosed clinically and genetically with MCAP. Genomic DNA was extracted mainly from the skin of affected lesions, also from peripheral blood leukocytes and buccal epithelial cells, and target panel sequencing using high-depth next-generation sequencing technology was performed. Results: Macrocephaly was present in 11/12 patients (92%). All patients had normal body asymmetry. Cutaneous vascular malformation was found in 10/12 patients (83%). Megalencephaly or hemimegalencephaly was noted in all 11 patients who underwent brain magnetic resonance imaging. Arnold–Chiari type I malformation was also seen in 10 patients. Every patient was identified as having pathogenic or likely pathogenic variants of the PIK3CA gene. The variant allele frequency (VAF) ranged from 6.3 to 35.3%, however, there was no direct correlation between VAF and the severity of associated anomalies. c.2740G > A (p.Gly914Arg) was most commonly found, in four patients (33%). No malignancies developed during follow-up periods. Conclusions: This is the first and largest cohort of molecularly diagnosed patients with MCAP in Korea. Targeted therapy with a PI3K-specific inhibitor, alpelisib, has shown successful outcomes in patients with PROS in a pilot clinical study, so early diagnosis for genetic counseling and timely introduction of emerging treatments might be achieved in the future through optimal genetic testing.

Busulfan's narrow therapeutic index and high pharmacokinetic (PK) variability warrant investigation of its exposure–toxicity relationship. We retrospectively analyzed 334 pediatric and young adult patients who underwent allogeneic hematopoietic stem cell transplantation at Seoul National University Children's Hospital between 2009 and 2020 and received once‐daily intravenous busulfan over four days (3‐hour infusion, n = 122; 6‐hour infusion, n = 212). Factors associated with toxicities were identified using multivariable logistic regression, and overall survival (OS) was evaluated by Kaplan–Meier and Cox regression analyses. Despite comparable exposures, the 3‐hour infusion group showed higher C _max (4,260.2 vs 3,028.6 μg/L, P < 0.0001) and more frequent liver function test elevations (13.1% vs 0.5%, P < 0.0001). Receiver operating characteristic analysis identified a C _max cut‐off of 4269.6 μg/L as a factor for hepatotoxicity. The 4‐year OS was superior in the 6‐hour infusion group (82.3% vs 71.9%, P = 0.02) and in the low C _max group (80.8% vs 66.5%, P = 0.01). Cox regression revealed C _max as an independent predictor of OS. A population PK model was developed using NONMEM. A 1‐compartment model incorporating enzyme turnover auto‐inhibition successfully described the busulfan PK profile. Simulations of published once‐daily dosing regimens showed that extending the infusion to 6 hours successfully maintained C _max below the cut‐off threshold. These results show that maintaining busulfan C _max below 4269.6 μg/L is associated with improved safety and survival. Prolonged infusion should be considered when adopting the busulfan once‐daily regimen.

Background: The optimal conditioning regimen of tandem high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for high-risk neuroblastoma (HR-NBL) has not been established. The efficacy of ¹³¹I-MIBG therapy is under exploration in newly diagnosed HR-NBL patients. Here, we compared the outcomes of tandem HDC/ASCT between the ¹³¹I-MIBG combination and non-MIBG groups. Methods: We retrospectively analyzed the clinical data of 33 HR-NBL patients who underwent tandem HDC/ASCT between 2007 and 2021 at the Seoul National University Children’s Hospital. Results: The median age at diagnosis was 3.6 years. ¹³¹I-MIBG was administered to 13 (39.4%) of the patients. Thirty patients (90.9%) received maintenance therapy after tandem HDC/ASCT, twenty-two were treated with isotretinoin ± interleukin-2, and eight received salvage chemotherapy. The five-year overall survival (OS) and event-free survival (EFS) rates of all patients were 80.4% and 69.4%, respectively. Comparing the ¹³¹I-MIBG combined group and other groups, the five-year OS rates were 82.1% and 79.7% (p = 0.655), and the five-year EFS rates were 69.2% and 69.6% (p = 0.922), respectively. Among the adverse effects of grade 3 or 4, the incidence of liver enzyme elevation was significantly higher in the non-¹³¹I-MIBG group. Conclusions: Although tandem HDC/ASCT showed promising outcomes, the ¹³¹I-MIBG combination did not improve survival rates.

Inherited bone marrow failure syndromes are genetic hematologic disorders with increased cancer risk. Accurate diagnosis is crucial for appropriate management. This study assessed the clinical usefulness of next-generation sequencing (NGS)-based target gene sequencing in pediatric and AYA (adolescent and young adult) patients with hematologic abnormalities. From December 2019 to June 2023, 93 patients with suspected congenital hematologic diseases at a single institution underwent NGS-based testing. Medical records were retrospectively reviewed. The median age at diagnosis was 9.3 years (range 0.2–31.4), with 59.1% males. Indications for testing included specific medical histories (28 patients), persistent cytopenia or recurrent neutropenic fever (22 patients), changes in cytopenia patterns (11 patients), and other reasons (32 patients). Pathogenic variants were identified in 9/28 (32.1%), 3/22 (13.6%), 4/11 (36.4%), and 0/32 (0%). Overall, 16 patients (17.2%) had pathogenic variants, including FANCA, BRCA2, PMS2, ELANE, G6PC3 and VPS13B in patients with idiopathic neutropenia, and GATA2 in patients with suspected myelodysplastic syndrome. Genetic findings led to diagnostic revisions in 12 patients (12.9%), including reclassification of aplastic anemia (AA) as Fanconi anemia, Diamond-Blackfan anemia, or Shwachman-Diamond syndrome, prompting hematopoietic stem cell transplantation and altering cancer surveillance. Pathogenic variants were more frequently observed in patients with a specific medical history or changes in cytopenia, and in those with additional clinical features (cytogenetic abnormalities or non-severe AA). This study demonstrated the diagnostic usefulness of NGS-based target gene sequencing for pediatric and AYA patients with suspected genetic hematologic disorders, supporting the need for multicenter studies and standardized guideline development.

It is complicated to establish a consensus on the management and diagnosis of malignancy-triggered hemophagocytic lymphohistiocytosis (M-HLH) in children, as an initial presentation of malignancy is complicated. In this paper, we analyze the clinical characteristics and outcomes of eight pediatric patients in which M-HLH was the initial presentation of malignancy. All patients had hematologic malignancies: three subcutaneous panniculitis-like T-cell lymphomas, two acute lymphoblastic leukemias, two anaplastic large cell lymphomas, and a systemic EBV + T-cell lymphoma of childhood. The incidence rate of M-HLH among leukemia and malignant lymphoma patients in our institution was 1.9%. From the initial diagnosis of HLH, the median time taken to be diagnosed as a malignancy was about 1.3 months. The majority of patients received HLH-targeted immunosuppression and/or etoposide at first. The patients’ clinical response to treatment for HLH and malignancies were varied. Five out of the eight patients died, one of whom died due to HLH-related cerebral edema after the initiation of chemotherapy. The median overall survival was 1.6 years. In order to improve the survival rate, the early detection of M-HLH, rapid screening for malignancy, and complete control of M-HLH with HLH-directed therapy followed by a thorough response monitoring are required.