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.

Outcomes of intracranial non-germinomatous germ cell tumors: a retrospective Asian multinational study on treatment strategies and prognostic factors.

PURPOSE: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs. METHODS: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan). RESULTS: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or ß-human chorionic gonadotropin (ß-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated ß-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum ß-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS. CONCLUSION: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

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.

Initial Characteristics and Clinical Severity of Hemophagocytic Lymphohistiocytosis in Pediatric Patients Admitted in the Emergency Department.

OBJECTIVES: The diagnosis and management of children with hemophagocytic lymphohistiocytosis (HLH) admitted in the emergency department (ED) are challenging. The present study aimed at describing the initial characteristics of pediatric patients with HLH upon admission in the ED. Moreover, the clinical severity of the condition was assessed. METHODS: We performed a retrospective study of patients who visited the pediatric ED and were newly diagnosed with HLH during hospitalization between February 2012 and January 2017. The patients were classified in the clinically unstable group if at least 1 of the following conditions was observed upon admission in the ED: hypoxia requiring oxygen supplementation, hypotension requiring inotropic support, coagulopathy with prothrombin time (international normalized ratio, ≥1.5), and seizures or altered consciousness. RESULTS: We enrolled 31 pediatric patients with HLH, with a median age of 6.53 years (interquartile range, 1.35-13.24 years). Abdominal discomfort along with fever (74.2%) was the most common presenting symptom in patients admitted in the ED. Based on the HLH-2004 diagnostic criteria, fever (96.8%), hyperferritinemia (96.8%), splenomegaly (74.2%), hypertriglyceridemia and/or hypofibrinogenemia (67.7%), and bicytopenia (41.9%) were observed in the patients. However, only 8 patients (25.8%) met the criteria. Nineteen patients (61.3%) were included in the clinically unstable group. This group had lower albumin (2.3 vs 3.3 g/dL, P = 0.002) and fibrinogen levels and higher ferritin level and neutrophil count than the clinically stable group. Meanwhile, the number of clinical findings that met the diagnostic criteria was not different between the 2 groups. Lower albumin level was a significant risk factor in the clinically unstable group (odds ratio, 0.040; P = 0.004). CONCLUSIONS: Pediatric patients with HLH often have clinically unstable conditions upon admission in the ED. However, only few patients meet the HLH-2004 diagnostic criteria. Lower albumin level may be useful in assessing clinically unstable patients and preparing for possible deterioration.

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.

Epidemiological Study of Hereditary Hemolytic Anemia in the Korean Pediatric Population during 1997-2016: a Nationwide Retrospective Cohort Study.

BACKGROUND: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA. METHODS: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey. RESULTS: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased (P < 0.001 and P = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia. CONCLUSION: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.

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.

Coronary artery involvement in chronic graft-versus-host disease presenting as sudden cardiac arrest.

Graft-versus-host disease (GVHD) is related to considerable morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Cardiac complications associated with GVHD are uncommon, and coronary artery involvement is even more unusual. We report on a male pediatric patient with chronic GVHD who developed a fatal ventricular arrhythmia caused by coronary artery obstruction after HSCT. At 30 months after HSCT, he suddenly collapsed with ventricular fibrillation. After resuscitation, electrocardiography showed abnormal q-wave and ST changes in the inferior leads, suggesting a coronary event. Coronary angiography revealed complete obstruction of the proximal left anterior descending artery, subtotal obstruction of the mid left circumflex artery, and mild narrowing at the right coronary artery. This boy had none of the risk factors for coronary artery disease, and the only possible explanation for the cardiac event is GVHD. Coronary artery disease only rarely occurs as a cardiac event in children. However, coronary artery involvement should be recognized as one of the important manifestations of chronic GVHD in children.

Bone marrow recovery of hematopoietic stem cells and microenvironment after chemotherapy in childhood acute lymphoblastic leukemia: consecutive observations according to chemotherapy schedule.

We investigated bone marrow (BM) recovery of hematopoietic stem cells (HSC) and hematopoietic microenvironment after chemotherapy in childhood acute lymphoblastic leukemia (ALL). Twenty-nine de novo childhood ALL patients were enrolled and BM biopsy sections at diagnosis (BM0), after induction (BM1), consolidation (BM3), interim maintenance (BM5) and delayed intensification (BM7) chemotherapy were obtained. Expressions of CD133, CD34, CD117, osteopontin, osteonectin, CXCL12, and CXCR4 were evaluated by semiquantitative immunohistochemical stains. All markers recovered significantly following chemotherapy while highest values at BM3 (for CD133/CD117/CXCL12/CXCR4), BM5 (for CXCL12/CD34/osteonectin), and BM7 (for osteopontin). Patients with cytogenetic good risk expressed significantly more CD133+/CD34+ cells than those with standard and poor risk in BM5. Patients without aberrant immunophenotype expressed significantly more CD133+ cells in BM1, and more CD117+ cells in BM5 than those with aberrant immunophenotype. Patients treated with standard risk-average chemotherapeutic protocol expressed significantly more CXCR4+ cells than those treated with other protocols in BM7. Patients who showed lowest ANC ≥ 200/µL during induction chemotherapy expressed significantly more CXCR4+ cells at from BM1 to BM5, and more CD133+ cells in BM3 than those who did not. Early and full recovery of BM HSC is most vigorous at BM3 and BM5, respectively. Reconstruction of BM niche and stromal cell recovery is mostly active at BM5, and hematopoietic activity of BM niche recovers mostly at BM7. Patients with cytogenetic good risk, nonaberrant immunophenotype, standard risk-average chemotherapeutic protocol and less BM suppression during induction chemotherapy show prompt recovery of some BM HSC and microenvironment markers compared to others.

Long-term endocrine effects and trends in body mass index changes in patients with childhood-onset brain tumors.

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P < 0.001). The prevalence of combined pituitary hormone deficiencies was higher among patients with SE/SUP-SE tumors than in those with ST/IT tumors (81.7 vs. 36.1%, P < 0.001). Among 98 non-obese patients with SE/SUP-SE tumors, 36.7% developed obesity. The prevalence of combined pituitary hormone deficiencies and obesity was higher in patients with SE/SUP-SE tumors than in those with tumors in other locations; growth impairment was more severe in patients with ST/IT tumors.

Reconstitution of T and NK cells after haploidentical hematopoietic cell transplantation using αß T cell-depleted grafts and the clinical implication of γδ T cells.

To investigate reconstitution of T and NK cells after αß T lymphocyte-depleted haploidentical hematopoietic cell transplantation (HHCT) and the clinical implications of γδ T cells, we analyzed 50 pediatric patients who received 55 HHCTs using αß T cell-depleted grafts. The number of CD3+ T cells and CD8+ T cells recovered rapidly and reached donor levels at days 180 and 60, respectively. Recovery of NK cells was rapid, and the median of NK cells at day 14 was comparable to the donor level. At day 14, median percentage of γδ T lymphocytes was 70.5%. After day 14, the percentage of γδ T cells gradually decreased, while the percentage of αß T cells gradually increased. Patients with a low percentage (≤21%) of γδ T cells at day 30 had significantly higher incidence of cytomegalovirus (CMV) reactivation compared to patients with a high percentage (>70%) of γδ T cells (P < .01). In patients with acute leukemia, patients with high percentage of γδ T cells at day 30 showed significantly higher relapse-free survival compared to those with low percentage of γδ T cells (P = .02). Data suggest that early recovery of γδ T cells decreases the risk of CMV reactivation and leukemia relapse.

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.

Influence of Musculoskeletal Manifestations as the Only Presenting Symptom in B-Cell Acute Lymphoblastic Leukemia.

OBJECTIVE: To evaluate the clinical and prognostic impact of musculoskeletal manifestations as the only initial presenting symptom in childhood acute lymphoblastic leukemia (ALL). STUDY DESIGN: We retrospectively reviewed 158 children with precursor B-cell type ALL who were followed up for >2 years. The patients were assigned to the groups musculoskeletal manifestations (n = 24) or nonmusculoskeletal manifestations (n = 134) based on initial presenting symptom. The symptom duration (regarding any initial presenting symptom) and the leukemic symptom duration (regarding symptoms of systemic manifestation, such as fever, bleeding, or pallor) were assessed, along with other clinical characteristics. RESULTS: The musculoskeletal manifestations group exhibited a longer symptom duration than the nonmusculoskeletal manifestations group (43 days vs 22 days, P = .006), but overall survival did not significantly differ between the groups. Multivariate analysis indicated that a longer symptom duration did not affect prognosis but that a longer leukemic symptom duration was associated with a poorer prognosis (hazard ratio, 7.720; P = .048). CONCLUSION: Musculoskeletal manifestations are associated significantly with diagnostic delay, but this delay does not affect the prognosis. Diagnostic delay after the onset of leukemic symptoms, however, does appear to affect the prognosis. Intensive evaluations for hematologic malignancies may be unnecessary in children who complain of limb pain without any definite cause, unless they also present with accompanying leukemic symptoms.

Hematopoietic stem cell transplantation in pediatric patients with acute myeloid leukemia without favorable cytogenetics.

Intensified chemotherapy, HSCT, and supportive care improve the survival of pediatric patients with AML. However, no consensus has been reached regarding the role of HSCT in patients without favorable cytogenetics. We evaluated OS and EFS according to prognostic factors that affect clinical outcomes, including cytogenetics risk group, conditioning regimen, donor type, disease status at the time of HSCT, and number of chemotherapy cycles prior to HSCT in 65 pediatric patients with AML without favorable cytogenetics who underwent HSCT. Fifteen of the 65 patients died: three of TRM and 12 of disease-related mortality. The 5-year OS and EFS were 78.0% and 72.0%, respectively, and the 5-year cumulative relapse and TRM rates were 26.9% and 5.1%, respectively. Survival rates were not influenced by cytogenetic group (intermediated vs. poor), donor type (related vs. unrelated), transplant type (myeloablative vs. reduced-intensity conditioning), or number of pretransplant chemotherapy cycles (≤3 vs. >3 cycles). The low TRM rate and encouraging outcomes suggest that HSCT may be a feasible treatment for pediatric patients with AML without favorable cytogenetics.

Clinical Characteristics of Transplant-associated Encephalopathy in Children.

We aimed to analyze characteristics of encephalopathy after both hematopoietic stem cell and solid organ pediatric transplantation. We retrospectively reviewed medical records of 662 pediatric transplant recipients (201 with liver transplantation [LT], 55 with heart transplantation [HT], and 67 with kidney transplantation [KT], 339 with allogeneic hematopoietic stem cell transplantation [HSCT]) who received their graft organs at Asan Medical Center between January 2000 and July 2014. Of the 662 patients, 50 (7.6%) experienced encephalopathy after transplantation. The incidence of encephalopathy was significantly different according to the type of organ transplant: LT, 16/201 (8.0%), HT, 13/55 (23.6%), KT, 5/67 (7.5%), and HSCT, 16/339 (4.7%) (P < 0.001). Drug-induced encephalopathy (n = 14) was the most common encephalopathy for all transplant types, but particularly after HSCT. Hypertensive encephalopathy was the most common after KT and HT, whereas metabolic encephalopathy was the most common after LT. The median time to encephalopathy onset also differed according to the transplant type: 5 days after KT (range 0-491 days), 10 days after HT (1-296 days), 49.5 days after HSCT (9-1,405 days), and 39 days after LT (1-1,092 days) (P = 0.018). The mortality rate among patients with encephalopathy was 42.0% (n = 21/50). Only 5 patients died of neurologic complications. Transplant-associated encephalopathy presented different characteristics according to the type of transplant. Specialized diagnostic approach for neurologic complications specific to the type of transplant may improve survival and quality of life in children after transplantation.

The Different Clinical Aspects of Pediatric Primary Airway Tumors in the Larynx, Trachea, and Bronchi.

Primary airway tumors are rare in children and no literature reviewed their characteristics each location. We evaluate the clinical characteristics and outcomes of Korean children with primary airway tumors, from the larynx to bronchi. A retrospective chart review of children with primary tumors of the larynx, trachea, and bronchi at Asan Medical Center from January 2000 to July 2016 was conducted. Nineteen children were diagnosed with primary airway tumors of the larynx (47.4%), trachea (10.5%), and bronchi (42.1%). Median follow-up duration was 2.8 years and there were recurrences in 21.1%. Laryngeal tumors were associated with a younger median age at onset (2 months) and diagnosis (4 months), and most were relatively small (median size = 5.3 mm) and symptomatic. Tracheal and bronchial tumors were found in older children (age at onset and diagnosis > 11 years) and large (> 15.0 mm). Most (75%) patients with bronchial tumors were asymptomatic and all the patients with tracheal tumors were symptomatic. This study suggests that we should consider different the locations in primary airway tumor based on the age at onset and diagnosis, initial symptoms or signs, and size of tumor.

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.