Clonal Hematopoiesis Without Malignant Transformation Lasting Over 2 Years in a 9-Year-old Boy, Following Treatment for Acute Lymphocytic Leukemia.

Children with acute lymphocytic leukemia rarely develop secondary hematological neoplasms. A 5-year-old boy was diagnosed with standard-risk precursor B-cell acute lymphocytic leukemia. The patient exhibited aberrant chromosomal changes in the bone marrow at 6 months postchemotherapy: 46,XY,der(6) t(1;6)(q12;p22) dup(6)(p22p12)[15]. Clinically, the patient has sustained complete remission and has not developed myeloid malignancy over the subsequent period (27 mo). The cytogenetic aberration was observed in 11% of CD34+ cells isolated from the bone marrow. We infer that the abnormal clone acquires self-renewal potency, differentiation, and growth advantage. Further long-term observation is needed to determine the nature of this cytogenetic aberration.

Malignant melanoma in a 12-year-old boy 17 months after completing hepatoblastoma treatment.

BACKGROUND: Melanoma is rare as a secondary malignant neoplasm among childhood cancer survivors. CASE: We report a case of a 12-year-old boy who developed malignant melanoma with systemic metastases 17 months after completing treatment for hepatoblastoma. The diagnosis was made unexpectedly based on a bone marrow examination. The patient did not respond to immune checkpoint inhibitor therapy and died 6 weeks after being diagnosed with melanoma. Whole-exome sequencing to examine 103 genes associated with cancer predisposition did not identify any germ-line variants. CONCLUSION: This case study provides a unique example of melanoma in a childhood cancer survivor following hepatoblastoma treatment but does not identify any candidate variant to link hepatoblastoma and melanoma.

Six Years of Disease-free Survival After a Second Cord Blood Transplantation for Recurrent Acute Lymphocytic Leukemia in a Child With Down Syndrome.

Outcomes are extremely poor in Down syndrome-associated acute lymphocytic leukemia, particularly in recurrent cases. A 2-year-old boy with Down syndrome-associated acute lymphocytic leukemia achieved complete remission after standard chemotherapy. However, he experienced recurrence twice in the bone marrow and central nervous system. Salvage treatments included whole-brain/whole-spine irradiation. Thereafter, the patient received a second cord blood transplantation after the reduced-intensity conditioning. The graft was characterized by killer cell immunoglobulin-like receptor ligands mismatch. The patient has subsequently survived for 6.5 years without recurrence. We speculate that killer cell immunoglobulin-like receptor ligand-mismatched cord blood transplantation enhanced the graft-versus-leukemia effect through natural killer cells, and conferred long-term remission.

Cord Blood Transplantation in 2 Infants Presenting Monosomy 7 Clonal Hematopoiesis: SAMD9 / SAMD9L Germline Mutation.

Recently, germline mutations in SAMD9 and SAMD9L were increasingly found in children with monosomy 7. We report the outcomes in 2 infants with the SAMD9/SAMD9L variant, who presented with anemia and thrombocytopenia (patient 1), and neutropenia and nonsymptomatic white-matter-encephalopathy (patient 2). Both patients received cord blood transplantation and experienced critical post-cord blood transplantation adverse events; patients 1 and 2 developed fulminant engraftment syndrome and life-threatening graft-versus-host disease, respectively. Of note, selective loss of chromosome 7 in bone marrow-derived CD34 + cells was inferred.

Case Report: Successful Treatment With Anti-C5 Monoclonal Antibody in a Japanese Adolescent Who Developed Thrombotic Microangiopathy After Autologous Bone Marrow Transplantation for Malignant Lymphoma.

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of bone marrow transplantation (BMT). Recently, abnormalities in the complement system have been identified in the pathogenesis of TA-TMA, and there are series of reports stating that anti-C5 monoclonal antibody (eculizumab) is effective in patients with high levels of the membrane attack complex (C5b-9). Case Presentation: A 12-year-old boy underwent autologous BMT after receiving high-dose chemotherapy for malignant lymphoma. The patient was engrafted on day 19 after transplantation; however, hemolytic anemia and non-immune thrombocytopenia persisted, and haptoglobin decreased on day 46. Moreover, on day 83, the patient developed pulmonary hemorrhage, hypertension, severe proteinuria, hematuria, and acute kidney injury (AKI). Pulmonary bleeding stopped with daily platelet transfusion and hemostatic agents, but reappeared on day 100. Based on the presence of destruction of red blood cells, elevated lactate dehydrogenase levels, negative direct and indirect Coombs tests, normal ADAMTS13 levels, hemolytic anemia, non-immune thrombocytopenia, and AKI, the patient was diagnosed with systemic TA-TMA and we initiated plasma exchange (PE) and continuous hemodialysis for AKI. High C5b-9 levels were identified at the start of the series of PE, therefore we decided to administer eculizumab. After three courses of eculizumab, no pulmonary hemorrhage was observed, and anemia, thrombocytopenia, renal dysfunction, hematuria, and proteinuria all tended to improve. Three years after transplantation, the patient is alive and does not require eculizumab. Discussion: Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage C5 and the formation of C5b-9. In this case, TA-TMA could not be controlled with PE alone. We therefore decided to use eculizumab relatively early based on the high C5b-9 level and could resolve the momentum of TA-TMA. Conclusion: In previous reports, TA-TMA typically occurred in early post-allogeneic BMT of patients with lymphoma or in post-autologous BMT of patients with neuroblastoma and was treated with eculizumab. We here reported that eculizumab could be successful treatment for TA-TMA in post-autologous BMT of patient with lymphoma.

Characteristics of Kawasaki Disease Patients during the COVID-19 Pandemic in Japan: A Single-Center, Observational Study.

BACKGROUND: Under the Coronavirus disease 2019 (COVID-19) pandemic, manifestations in children with Kawasaki disease (KD) are different between the Western and the Eastern countries. Particularly, there has not been a report comparing a series of KD in Japan, where KD was originally discovered and has a large number of registered cases. METHODS: We compared patients with KD under the period of the COVID-19 pandemic in Japan with the report from Italy during its reported period by a retrospective, cohort, observational study in a Japanese single center. RESULTS: Thirty-two patients with typical KD were treated during the study period, while the Italian study reported 10 patients with the signs of KD. Concerning the proof of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, none (0%) of our KD cases showed a positive result and one and no patients developed the macrophage activation syndrome (MAS) and Kawasaki disease shock syndrome (KDSS), respectively; however, eight (80%) patients in the Italian series were confirmed with SARS-CoV-2 infection. MAS and KDSS developed in six and five patients, respectively. CONCLUSIONS: Cases reported as COVID-19 pandemic-related KD in Italy showed significantly different clinical characteristics from the typical KD symptoms known in Japan. Although they show KD-like manifestations, we cannot conclude that SARS-CoV-2 has the same etiology of our 'classic' KD at the present stage.

Incidence and outcomes of refractory immune thrombocytopenic purpura in children: a retrospective study in a single institution.

Treatment of children with refractory immune thrombocytopenic purpura (ITP) is challenging and poorly established. We retrospectively reviewed the clinical data of 87 patients under the age of 16 years who were diagnosed with ITP from April 1998 to March 2017 in our institution. Refractory ITP was defined as a platelet count of < 50 × 109/L at 14 days after receiving intravenous immunoglobulin (IVIG) and prednisolone. We presumed that there was a pathophysiological overlap between refractory ITP and refractory thrombocytopenia (RT): a subtype of refractory cytopenia of childhood (RCC). Immunosuppressive therapies including anti-thymocyte globulin and cyclosporine (CsA) have been adopted for children with RCC in Japan. Thus, from 2009 onwards, we changed the diagnosis from refractory ITP to RT and introduced CsA for refractory ITP/RT. Nine of 42 patients developed refractory ITP in the 1998-2008 group, who received conventional treatments such as IVIG and steroid therapy. Eight of 45 patients developed refractory ITP in the 2009-2017 group, who received CsA with or without IVIG therapy. The response rate at three years after diagnosis was significantly higher in the 2009-2017 group (98%) than in the 1998-2008 group (83%) (p = 0.019). In conclusion, our strategy of introducing CsA for refractory ITP/RT contributed to better outcomes.

Severe olfactory and gustatory dysfunctions in a Japanese pediatric patient with coronavirus disease (COVID-19).

Coronavirus disease (COVID-19) is often characterized by abnormal olfactory and gustatory symptoms in adults; however, detailed studies on pediatric patients with COVID-19 are extremely limited. A 13-year-old Japanese girl presented with fever and cough, and after 2 days, her olfactory and taste sensations suddenly disappeared. A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was performed using a nasopharyngeal swab. Because a positive result was seen, she was admitted on the 7th day of illness. On admission, the visual analogue scale (VAS) score for smell and taste was 0 of 100%. An intravenous olfaction test using prosultiamine (Alinamin test) was performed on the 15th day of illness to evaluate olfaction, and an increase in latency (33 seconds) and a decrease in duration (55 seconds) were observed. In the odor identification test using 12 different odor cards, only 7 odors were correctly identified. On the 18th day of illness, SARS-CoV-2 tested negative in the RT-PCR test; simultaneously, the VAS score for smell and taste fully improved to 100 of 100%. On the 77th day of illness, full recovery was confirmed in the Alinamin test (latency, 7 seconds; duration, 82 seconds). In this present case, an improvement in olfactory and gustatory dysfunctions was observed with negative results in RT-PCR test for SARS-CoV-2.

Impact of persistent left ventricular regional wall motion abnormalities in childhood cancer survivors after anthracycline therapy: Assessment of global left ventricular myocardial performance by 3D speckle-tracking echocardiography.

AIMS: To identify left ventricular (LV) mechanical impairment by 3D speckle-tracking echocardiography (3DSTE) in long-term childhood cancer survivors after anthracycline therapy with or without persistent LV regional diastolic wall motion abnormalities (WMA) and a preserved LV ejection fraction (EF >53%). METHODS AND RESULTS: Thirty-two patients (median: 14.6 years) and 12 age-matched controls were studied. The patients were divided into two groups according to the existence of WMA: Group 1 (with WMA: n=14), Group 2 (without WMA: n=18). 3DSTE was performed to assess LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), global area strain (GAS), LV torsion, LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV). LV systolic dyssynchrony index (SDI) was calculated as the percentage of the standard deviation of time to peak strain of the 16 segments divided by the RR interval. There was no significant difference in LVEDV, LVESV, GLS, torsion, or SDI derived from LS, CS, or AS among the 3 groups. In contrast, there were significant differences in GRS, GCS, and GAS, and SDI derived from RS among the 3 groups. Compared with group 2, group 1 had significantly reduced GRS (p<0.001), GCS (p<0.01), GAS (p<0.01), and greater SDI derived from GRS (p<0.01). Moreover, the existence of WMA was correlated with GRS (p<0.001), SDI derived from GRS (p<0.001), and LVEF (p=0.036). Multiple linear regression analysis identified GRS as a significant determinant of the existence of WMA (ß=0.751, p=0.001). CONCLUSION: Childhood cancer survivors with persistent LV regional WMA show a reduced LV myocardial performance compared with those without WMA, despite a preserved LVEF.