Comparable outcomes of allogeneic peripheral blood versus bone marrow hematopoietic stem cell transplantation from a sibling donor for pediatric patients.

Traditionally, bone marrow (BM) has been preferred as a source of stem cells (SCs) in pediatric hematopoietic SC transplantation (HSCT); however, the use of peripheral blood SCs (PBSC) has recently increased. With advancing graft-versus-host disease (GVHD) prophylaxis, whether the BM is still a better SC source than PB in sibling donor HSCT remains controversial. Here, we compared the results of BM transplantation (BMT) and PBSC transplantation (PBSCT) in pediatric patients with malignant or non-malignant diseases receiving sibling HSCT using a total of 7.5 mg/kg of anti-thymocyte globulin (ATG). We retrospectively reviewed children who received HSCT from a sibling donor between 2005 and 2020 at Seoul National University Children's Hospital. Of the 86 patients, 40 underwent BMT, and 46 underwent PBSCT. Fifty- six patients had malignant diseases, whereas thirty patients had non-malignant diseases. All conditioning regimens comprised ATG. Busulfan-based myeloablative conditioning regimens were administered to patients with malignant diseases and approximately half of those with non-malignant diseases. The remaining half of the patients with non-malignant diseases were administered cyclophosphamide-based reduced- intensity conditioning regimens. According to studies conducted at our center, all BM donors received G-CSF before harvest to achieve early engraftment. In all 86 patients (47 males and 39 females), the median age at the time of HSCT was 11.4 (range, 0.7 - 24.6) years. The median follow-up period was 57.9 (range, 0.9-228.6) months, and the corresponding values for those with BM and PBSC were 77 (range, 2.4-228.6) months and 48.7 (range, 0.9-213.2) months, respectively. Engraftment failure occurred in one patient with BM and no patient with PBSC. The cumulative incidence of acute GVHD with grades II-IV was higher in PBSC (BM 2.5%, PBSC 26.1%, p = 0.002), but there was no significant difference in those with grades III-IV acute GVHD (BM 0%, PBSC 6.5%, p = 0.3703) and extensive chronic GVHD (BM 2.5%, PBSC 11.6%, p = 0.1004). There were no significant differences in treatment-related mortality (TRM) (BM 14.2%, PBSC 6.8%, p = 0.453), 5-year event-free survival (EFS) (BM 71.5%, PBSC 76.2%, p = 0.874), and overall survival (OS) rates (BM 80.8%, PBSC 80.3%, p = 0.867) between BM and PBSC in the univariate analysis. In the multivariate analysis, which included all factors with p < 0.50 in the univariate analysis, there was no significant prognostic factor for EFS or OS. There was no significant difference in the relapse incidence between BM and PBSC among patients with malignant diseases (BM 14.2%, PBSC 6.8%, p = 0.453). Additionally, there were no significant differences in the TRM, 5-year EFS, and OS rates between malignant and non-malignant diseases nor between the busulfan-based myeloablative regimen and reduced-intensity chemotherapy using cyclophosphamide. In this study, we showed no significant differences in EFS, OS, TRM, and GVHD, except for acute GVHD grades II-IV, between BMT and PBSCT from sibling donors, using ATG (a total of 7.5 mg/kg). Therefore, PB collection, which is less invasive for donors and less labor-intensive for doctors, could also be considered an acceptable SC source for sibling donor HSCT in children.

High-dose chemotherapy followed by autologous stem cell transplantation in pediatric patients with relapsed osteosarcoma.

BACKGROUND: Patients with relapsed osteosarcoma have poor treatment outcomes. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) has been used in several high-risk malignant solid tumors; however, few studies have evaluated their role in treating osteosarcoma. We evaluated the effectiveness of HDCT/ASCT in relapsed pediatric osteosarcoma cases. PROCEDURE: We retrospectively reviewed the medical records of 40 patients diagnosed with and treated for relapsed osteosarcoma at Asan Medical Center and Samsung Medical Center from January 1996 to July 2019. RESULTS: The median age of this cohort was 13.4 years (range: 6.1-18.2). The cohort's 5-year overall survival (OS) was 51.0% ± 0.1% during a median follow-up period of 67.5 months. Twenty-five patients (62.5%) achieved complete remission (CR) with salvage treatment, and the 5-year OS was 82.4% ± 0.1%, whereas none of the remaining 15 patients who did not achieve CR survived (p < .0001). Of the 25 CR cases, 15 underwent subsequent HDCT/ASCT. We compared the effect of HDCT/ASCT among patients who achieved CR. There were no significant differences in the 5-year OS outcomes between patients who did and did not receive HDCT/ASCT (83.9% ± 0.1%, 13/15 vs. 80.0% ± 0.1%, 8/10, respectively; p = .923). CONCLUSION: To our knowledge, we report the first comparative cohort study that proved HDCT/ASCT does not significantly improve survival outcomes in relapsed osteosarcoma. Achievement of CR remains the most crucial factor for good survival outcomes.

Outcome of staging chest CT and identification of factors associated with lung metastasis in children with hepatoblastoma.

OBJECTIVES: To evaluate the outcome of staging chest CT and to identify clinicoradiological factors predictive of lung metastasis in patients with hepatoblastoma based on the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system. METHODS: This bi-center study retrospectively identified patients diagnosed with hepatoblastoma between January 1998 and September 2019 in two tertiary hospitals. The primary outcome was the proportion of the patients who had lung metastasis at staging chest CT. The diagnostic accuracy of staging chest CT was calculated based on the 2017 PRETEXT criteria. The secondary outcome was the identification of factors predictive of lung metastasis using multivariable logistic regression. RESULTS: In total, 123 patients (median age, 1 year; interquartile range, 0-4 years; 59 female) were included. Among those, 28% (35/123; 95% confidence interval [CI], 21-37%) had lung metastasis at staging chest CT. The overall accuracy of staging chest CT was 96.8%. The proportion of lung metastasis in patients with stage I, II, III, and IV was 0%, 24% (12 of 49; 95% CI, 14-38%), 23% (9 of 40; 95% CI, 12-38%), and 56% (14 of 25; 95% CI, 37-73%), respectively. Multifocality (adjusted odds ratio, 6.7; 95% CI, 2.7-17.5; p < .001) and male sex (adjusted odds ratio, 3.1; 95% CI, 1.2-8.6; p = .02) were associated with the presence of lung metastasis. CONCLUSIONS: Twenty-eight percent of the patients with hepatoblastoma had lung metastasis at staging chest CT. Multifocality and male sex were predictive factors for lung metastasis on staging chest CT. KEY POINTS: • The proportion of lung metastasis in patients with hepatoblastoma was 28%. • The overall accuracy of staging chest CT was 97% based on the 2017 PRETEXT system. • Hepatic tumor multifocality and male sex were predictors of lung metastasis.

Erratum: Correction of Affiliations in the Article "Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study".

This corrects the article on p. e393 in vol. 35, PMID: 33258329.

Physeal Abnormalities in Children With High-risk Neuroblastoma Intensively Treated With/Without 13-Cis-Retinoic Acid.

BACKGROUND: This study aimed to investigate the presence of physeal abnormality and its effect on growth in children with high-risk neuroblastoma treated by intensive multimodal treatment with/without 13-cis-retinoic acid (13-CRA). METHODS: Fifteen patients diagnosed with high-risk neuroblastomas at the age of 1 to 10 years, who received treatment such as high-dose chemotherapy and autologous stem cell transplantation with/without 13-CRA, and with complete data during their >2-year follow-up were retrospectively reviewed. The physeal abnormalities were investigated by whole-body magnetic resonance imaging, serially performed every 3 to 6 months. The patients' height growth was also investigated and compared with that of age-and-sex-matched patients with brain tumors who also underwent high-dose chemotherapy and autologous stem cell transplantation. RESULTS: Six of 15 patients presented multifocal physeal abnormalities during follow-up, and all lesions occurred in patients with 13-CRA use. The lesions in 3 patients completely resolved spontaneously without any adverse effect on growth, but some lesions in the other 3 patients progressed to disturb the bony growth. Height growth of matched patients with brain tumors were not significantly different, and none of the matched controls showed definite bony deformity during the follow-up. CONCLUSIONS: Some children who were treated for high-risk neuroblastomas experienced multifocal physeal insults, probably due to the use of 13-CRA. Most lesions resolved spontaneously, but some led to bony deformity. If the lesions are not followed by premature physeal closure, there seems to be no further adverse effect of 13-CRA on leg length growth. Routine periodic screening for physeal status is needed for the patients with high-risk neuroblastomas using 13-CRA. LEVEL OF EVIDENCE: Level IV-prognostic study.

Homozygote CRIM1 variant is associated with thiopurine-induced neutropenia in leukemic patients with both wildtype NUDT15 and TPMT.

BACKGROUND: NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure. METHODS: Whole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age- and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p < 0.01, N = 188 for discovery) and validate (p < 0.05, N = 52 for replication) candidate variants for the tolerated last-cycle 6-mercaptopurine (6-MP) dose intensity percentage (DIP). Both independent and additive effects of the candidate variants on well-known NUDT15 and TPMT were evaluated by multigene prediction models. RESULTS: Among the 12 candidate variants from the discovery phase, the rs3821169 variant of the gene encoding Cysteine-Rich Transmembrane BMP Regulator 1 (CRIM1) was successfully replicated (p < 0.05). It showed high interethnic variability with an impressively high allele frequency in East Asians (T = 0.255) compared to Africans (0.001), Americans (0.02), Europeans (0.009), and South Asians (0.05). Homozygote carriers of the CRIM1 rs3821169 variant (N = 12, 5%) showed significantly lower last-cycle 6-MP DIPs in the discovery, replication, and combined cohorts (p = 0.025, 0.013, and 0.001, respectively). The traditional two-gene model (NUDT15 and TPMT) for predicting 6-MP DIP < 25% was outperformed by the three-gene model that included CRIM1, in terms of the area under the receiver operating characteristic curve (0.734 vs. 0.665), prediction accuracy (0.759 vs. 0.756), sensitivity (0.636 vs. 0.523), positive predictive value (0.315 vs. 0.288), and negative predictive value (0.931 vs. 0.913). CONCLUSIONS: The CRIM1 rs3821169 variant is suggested to be an independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

Feasibility and effectiveness of treatment strategy of tandem high-dose chemotherapy and autologous stem cell transplantation in combination with 131 I-MIBG therapy for high-risk neuroblastoma.

This study was performed to evaluate the safety and effectiveness of tandem HDCT/ASCT combined with targeted radiotherapy using 131 I-MIBG for high-risk neuroblastoma. Patients with high-risk neuroblastoma were treated with 8 to 10 cycles of induction chemotherapy before tandem HDCT/ASCT. Patients received 131 I-MIBG treatment before the second HDCT/ASCT. Local radiotherapy and maintenance therapy were performed after tandem HDCT/ASCT. Between 2012 and 2016, 19 patients were diagnosed with high-risk neuroblastoma in our institution and 18 of them received tandem HDCT/ASCT combined with 131 I-MIBG therapy. For the first HDCT/ASCT regimen, 12 patients received busulfan/melphalan and six patients received melphalan/etoposide/carboplatin. The second HDCT included ThioCy. The median dose of 131 I-MIBG was 17.2 mCi/kg for the first eight patients, while 12 patients in the latter period of the study received reduced dose of 10.7 mCi/kg. The 5-year OS and EFS rates were 79% and 61%, respectively, for all 19 patients with high-risk neuroblastoma, and 83% and 64%, respectively, for 18 patients who completed tandem HDCT/ASCT combined with 131 I-MIBG therapy. Six patients experienced disease relapse and five patients died. Treatment-related mortality was not observed. Among 15 evaluable patients, 11 patients (73%) developed hypothyroidism, six patients (40%) had CKD, and six patients (40%) had growth failure. Hypothyroidism and growth failure were less frequent in patients who received reduced doses of 131 I-MIBG therapy. Tandem HDCT/ASCT combined with HD 131 I-MIBG therapy could be feasible for patients with high-risk neuroblastoma with acceptable toxicity profiles and favorable outcomes.

Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study.

BACKGROUND: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea. METHODS: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016. RESULTS: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively (P = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively. CONCLUSION: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL.

Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia.

Haploidentical family donors have been used as an alternative source in hematopoietic cell transplantation for patients with severe aplastic anemia. We evaluated and compared the outcomes of transplantation in pediatric acquired severe aplastic anemia based on donor type. Sixty-seven patients who underwent transplantation between 1998 and 2017 were included. Fourteen patients received grafts from matched sibling donors, 21 from suitable unrelated donors, and 32 from haploidentical family donors. Ex vivo CD3+ or αß+ T cell-depleted grafts were used for haploidentical transplantation. Sixty-five patients (97.0%) achieved neutrophil engraftment at a median of 11 days. Haploidentical transplantation resulted in significantly faster neutrophil engraftment at a median of 10 days, compared with 14 days in cases of matched sibling donors and 12 days in cases of unrelated donor recipients. Nine patients experienced graft failure, and 5 of 7 who underwent a second transplantation are alive. There was no difference in the incidence of acute or chronic graft-versus-host disease based on donor type. The 5-year overall survival and failure-free survival rates were 93.8% ± 3.0% and 83.3% ± 4.6%, respectively, and there was no significant survival difference based on donor type. The survival outcomes of haploidentical transplantation in patients were comparable with those of matched sibling or unrelated donor transplantation. Optimized haploidentical transplantation using selective T cell depletion and conditioning regimens including low-dose total body irradiation for enhancing engraftment may be a realistic therapeutic option for pediatric patients with severe aplastic anemia.

Quantification of Thiopurine Nucleotides in Erythrocytes and Clinical Application to Pediatric Acute Lymphoblastic Leukemia.

BACKGROUND: Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP). METHODS: RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MS/MS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institution's established LC-MS/MS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated. RESULTS: The imprecision coefficient of variations of 6TG and 6MMP were 5.7%-8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ng/mL for 6TG and 1036 ng/mL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol/8 × 10 RBCs and that of 6MMP from 55 to 20,937 pmol/8 × 10 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase. CONCLUSIONS: In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.

Depletion of αß+ T cells for a haploidentical hematopoietic stem cell transplantation in children.

A consistent and reproducible depletion technique is crucial for the successful transplantation of an ex vivo depleted graft. Our aim was to evaluate the efficacy of an ex vivo technique for depletion of αß+ T cells using a biotinylated anti-TCRαß monoclonal antibody, which was performed by one clinical nurse specialist. Between 2012 and 2017, 119 depletion procedures from 216 apheresis using the anti-TCRαß monoclonal antibody were performed on 105 pediatric patients. The median log depletion of αß+ T cells was 4.0 (range, 2.5-5.0). The median recovery rates of CD34+ , NK, and γδ+ T cells were 90.4%, 74.9%, and 75.9%, respectively. The efficacy of depletion of αß+ T cells significantly improved over time and the duration of the depletion procedure significantly decreased over time. Our study demonstrated that this procedure for depletion of αß+ T cells by skilled staff is highly effective at depleting target cells and obtaining CD34+ progenitor cells.

Outcome of Reinduction Chemotherapy with a Modified Dose of Idarubicin for Children with Marrow-Relapsed Acute Lymphoblastic Leukemia: Results of the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 Study.

This multicenter, prospective trial was conducted to develop an effective and safe reinduction regimen for marrow-relapsed pediatric acute lymphoblastic leukemia (ALL) by modifying the dose of idarubicin. Between 2006 and 2009, the trial accrued 44 patients, 1 to 21 years old with first marrow-relapsed ALL. The reinduction regimen comprised prednisolone, vincristine, L-asparaginase, and idarubicin (10 mg/m²/week). The idarubicin dose was adjusted according to the degree of myelosuppression. The second complete remission (CR2) rate was 72.7%, obtained by 54.2% of patients with early relapse < 24 months after initial diagnosis and 95.0% of those with late relapse (P = 0.002). Five patients entered remission with extended treatment, resulting in a final CR2 rate of 84.1%. The CR2 rate was not significantly different according to the idarubicin dose. The induction death rate was 2.3% (1/44). The 5-year event-free and overall survival rates were 22.2% ± 6.4% and 27.3% ± 6.7% for all patients, 4.2% ± 4.1% and 8.3% ± 5.6% for early relapsers, and 43.8% ± 11.4% and 50.0% ± 11.2% for late relapsers, respectively. Early relapse and slow response to reinduction chemotherapy were predictors of poor outcomes. In conclusion, a modified dose of idarubicin was effectively incorporated into the reinduction regimen for late marrow-relapsed ALL with a low toxic death rate. However, the CR2 rate for early relapsers was suboptimal, and the second remission was not durable in most patients.

Improved Outcome of a Reduced Toxicity-Fludarabine, Cyclophosphamide, plus Antithymocyte Globulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of 2 Multicenter Prospective Studies.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for severe aplastic anemia (SAA); however, the optimal conditioning regimen for HSCT with an unrelated donor has not yet been defined. A previous study using a fludarabine (FLU), cyclophosphamide (Cy), and antithymocyte globulin (ATG) conditioning regimen (study A: 50 mg/kg Cy once daily i.v. on days -9, -8, -7, and -6; 30 mg/m(2) FLU once daily i.v. on days -5, -4, -3, and -2; and 2.5 mg/kg of ATG once daily i.v. on days -3, -2, and -1) demonstrated successful engraftment (100%) but had a high treatment-related mortality rate (32.1%). Therefore, given that Cy is more toxic than FLU, we performed a new phase II prospective study with a reduced-toxicity regimen (study B: 60 mg/kg Cy once daily i.v. on days -8 and -7; 40 mg/m(2) FLU once daily i.v. on days -6, -5, -4, -3, and -2; and 2.5 mg/kg ATG once daily i.v. on 3 days). Fifty-seven patients were enrolled in studies A (n = 28) and B (n = 29), and donor type hematologic recovery was achieved in all patients in both studies. The overall survival (OS) and event-free survival (EFS) rates of patients in study B was markedly improved compared with those in study A (OS: 96.7% versus 67.9%, respectively, P = .004; EFS: 93.3% versus 64.3%, respectively, P = .008). These data show that a reduced-toxicity conditioning regimen with FLU, Cy, and ATG may be an optimal regimen for SAA patients receiving unrelated donor HSCT.

Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma.

The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.

Favorable outcome of hematopoietic stem cell transplantation using a targeted once-daily intravenous busulfan-fludarabine-etoposide regimen in pediatric and infant acute lymphoblastic leukemia patients.

Conditioning regimens for pediatric acute lymphoblastic leukemia (ALL) usually include total body irradiation (TBI), but TBI may result in serious sequelae. Busulfan and cyclophosphamide have been used as an alternative to TBI. Etoposide also has been widely used to enhance antileukemic effect. However, toxicities have been reported in some studies using busulfan, cyclophosphamide, and etoposide regimen. A reduced toxicity myeloablative regimen using busulfan and fludarabine showed promising results. Also, therapeutic drug monitoring (TDM) and administration of targeted doses of busulfan have been recommended to improve the outcome of hematopoietic stem cell transplantation (HSCT). In this study, we evaluated the outcome of HSCT using a targeted once-daily i.v. busulfan-fludarabine-etoposide (BuFluVP) regimen in pediatric and infant ALL. Busulfan (age ≥ 1 year, 120 mg/m(2); age < 1 year, 80 mg/m(2)) was administered once daily as the first dose on day -8, and a targeted dose of busulfan was used according to the TDM results on days -7 to -5. Forty-four patients were evaluated. Donor-type neutrophil engraftment was achieved in all patients. Veno-occlusive disease occurred in 7 patients (15.9%), but all patients were successfully treated. Cumulative incidence of treatment-related mortality and relapse were 9.1% and 9.9%, respectively. One-year overall survival and event-free survival rates of all patients were 86.2% and 83.8%, respectively. Twelve patients (27.3%) were infants at diagnosis, and their 1-year overall survival rate was 83.3%. Our study demonstrated that HSCT using a targeted once-daily i.v. BuFluVP regimen showed favorable outcomes and could be an option for HSCT in pediatric and infant ALL.

Very late relapse of bilateral retinoblastoma.

Retinoblastoma usually recurs within the first few years after treatment completion. We report a rare case of very late relapse in a 6-month-old girl who was diagnosed with bilateral retinoblastoma. The patient achieved first remission after treatment with neoadjuvant chemotherapy, enucleation of the right eye, local laser therapy of the left eye, and adjuvant chemotherapy. Extraocular relapse with multiple metastases occurred 13 years and 8 months after treatment. The patient is currently in second complete remission after receiving high-dose chemotherapy and autologous stem cell transplantation. In conclusion, long-term follow-up is needed for early detection of recurrent retinoblastoma.

Ewing sarcoma/peripheral primitive neuroectodermal tumor in the adrenal gland of an adolescent: a case report and review of the literature.

Ewing sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNETs) typically occur in the long or flat bones, the chest wall, extraskeletal soft tissue, or less frequently, in solid organs. They can arise from anywhere in the body; however, ES/pPNETs arising from the adrenal gland are very rare, especially in children and adolescents. Herein, the authors report a case of an ES/pPNET in the adrenal gland of a 17-year-old girl, who was successfully treated with a multimodal treatment, with a brief review of the pertinent literature.

Clinical characteristics and treatment outcome of Langerhans cell histiocytosis: 22 years' experience of 154 patients at a single center.

Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology. Large studies by single institutions have been infrequent because of the rarity of the disease and the diversity of clinical manifestations. In this study, the clinical characteristics, prognostic factors, and treatment outcomes were analyzed. Medical records were analyzed retrospectively for the 154 patients diagnosed and treated with LCH at Seoul National University Children's Hospital from January 1986 to December 2007. A total of 154 patients were evaluated. One hundred and six patients (68.8%) had single system disease, 48 patients (31.2%) had multisystem disease. Twenty-nine patients (18.8%) had risk organ involvement. Twenty-nine patients (18.8%) relapsed and the overall survival (OS) of the total study population was 97.1% with a median follow-up period of 7.0 years. Patients less than 4 years old, with involvement more than 2 organs and with risk organ involvement showed lower progression free survival (PFS) (P = .001, <.001, and <.001, respectively). Estimated 10-year PFS of patients with and without risk organ involvement were 52.6% and 83.8%, respectively. Patients with single system LCH had excellent prognosis showing 89.6% of PFS and 100% of OS. Patients with multisystem LCH also had a high survival rate, although the incidences of relapse remain to be solved. A new strategy to decrease the incidence of relapse is needed.

Advancements in the understanding and management of histiocytic neoplasms.

Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma. Histiocytic neoplasms are characterized by varied clinical courses and prognoses, necessitating a nuanced understanding of their classification, epidemiology, and clinical manifestations. Genetic studies have revealed somatic mutations, predominantly in the MAPK pathway, suggesting a clonal neoplastic nature. This review covers the current understanding of histiocytic neoplasms, molecular pathophysiology, with a particular focus on mutations in genes such as BRAF, MAP2K1, and the PI3K-AKT signaling pathways, and evolving treatment strategies, especially focusing on LCH, ECD, RDD, and JXG. The treatment landscape has evolved with advancements in targeted therapies. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults. Further research is required to determine the optimal treatment duration and strategies for managing therapy interruptions. Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes.

Ten-Year Trends of Hematopoietic Stem Cell Transplantation in Korean Pediatric Cancer from the National Health Insurance Claims Data.

PURPOSE: We aimed to determine the current application and survival trends of hematopoietic stem cell transplantation (HSCT) among Korean children and adolescents with cancer. MATERIALS AND METHODS: Data of patients aged < 20 years with KCD-10 (Korean Classifications of Diseases, 10th revision) C codes and specific designation codes were collected from the National Health Insurance Service database. Thirty claim codes for HSCT were included, and data from 2009 to 2019 were analyzed. RESULTS: The operational definition of pediatric cancer yielded an annual average of 2,000, with annual cases decreasing. In 2019, 221 HSCTs were performed, a decrease from the ten-year average of 276. Allografts outnumbered autografts with a ratio of 1.5:1. The source of allograft was bone marrow in 15% of patients in 2009; however, it substantially decreased to 3.3% in 2019. Furthermore, 70.5% of allogeneic HSCT used peripheral blood stem cell (PBSC) grafts, which increased to 89.3% by 2015. Cord blood utilization markedly decreased to 2.7% in 2018. The 5-year overall survival (OS) rate of all patients was 85.1%. Overall mortality decreased among patients who underwent recent HSCT, and they exhibited a higher 5-year OS rate. CONCLUSION: In Korea, the number of pediatric patients with cancer is declining; however, the ratio of transplants to all patients remains constant. Patients who recently underwent transplantation showed better survival rates, possibly due to HSCT optimization. Korea showed a substantially greater PBSC utilization in pediatric HSCT. An in-depth examination encompassing donor relations and cause of death with a prospective registry is required in future studies.