Successful treatment of young childhood standard-risk hepatoblastoma with cisplatin monotherapy using a central review system.

BACKGROUND: The JPLT3-S (Japanese Study Group for Pediatric Liver Tumors-3) study, conducted cisplatin (CDDP) monotherapy for young children (<3 years old) with standard-risk hepatoblastoma (HB) using a central review system in Japan. In the previous JPLT2 study, cases with resectable tumors without any annotation factors in the PRETEXT (PRETreatment EXTent of disease) classification (standard-risk HB) showed favorable outcomes with treatment consisting of CDDP and pirarubicin, but showed toxicities and late complications. In the JPLT3-S trial, a less intense regimen consisting of CDDP alone was evaluated. METHODS: Patients who were less than 3 years of age and with PRETEXT I, II, or III HB without any annotation factors (e.g., E1, E1a, E2, E2a, H1, N1, P2, P2a, V3, and V3a) were eligible for inclusion in this study. In this trial, the central radiological and pathological features of all patients were reviewed. The primary outcome was the 3-year progression-free survival (PFS). RESULTS: A total of 38 patients (23 female) were included. The median patient age was 12 months (range: 2-34). Two patients discontinued treatment because of progressive disease, and five patients discontinued treatment for other reasons. The 3-year PFS rate was 93.9% (95% confidence interval [CI]: 86.4%-100%). All 38 patients survived (follow-up period 38-98 months), and the OS rate was 100% (CI: 100). Eighteen of the 38 patients (47.4%) experienced ototoxicity as a late complication. CONCLUSION: CDDP monotherapy regimen is feasible in young patients with localized HB, as classified by a central review.

Successful Bone Marrow Transplantation in a Patient with Acute Myeloid Leukemia Developed from Severe Congenital Neutropenia Using Modified Chemotherapy and Conditioning Regimen for Leukemia.

Severe congenital neutropenia (SCN) is characterized by chronic neutropenia with recurrent infections from early infancy and a predisposition to myelodysplastic syndrome/acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with SCN who develop myelodysplastic syndrome/AML. We report an 8-year-old girl with SCN carrying an ELANE mutation that had been refractory to granulocyte colony-stimulating factor. The patient experienced recurrent infections and then developed AML. The counts of leukemic blasts that harbored both CSF3R and RUNX1 mutations spontaneously decreased with antimicrobial therapy, leading to partial remission. After AML recurrence, HSCT was successfully performed using modified chemotherapy and a conditioning regimen. Serial donor lymphocyte infusions against mixed chimerism induced complete donor chimerism over 4 years without any infections or AML relapse. This case suggests the importance of carefully managing neutropenia-related infections, leukemia progression, and HSCT in patients with SCN developing AML.

Bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor in a case with C1q deficiency associated with refractory systemic lupus erythematosus.

Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.

Enhanced DNA repair by DNA photolyase bearing an artificial light-harvesting chromophore.

Photolyases are flavoenzymes responsible for the repair of carcinogenic DNA damage caused by ultraviolet radiation. They harbor the catalytic cofactor flavin adenine dinucleotide (FAD). The light-driven electron transfer from the excited state of the fully-reduced form of FAD to the DNA lesions causes rearrangement of the covalent bonds, leading to the restoration of intact nucleobases. In addition to the catalytic chromophore, some photolyases bear a secondary chromophore with better light absorption capability than FAD, acting as a light-harvesting chromophore that harvests photons in sunlight efficiently and transfers light energy to the catalytic center, as observed in natural photoreceptor proteins. Inspired by nature, we covalently and site-specifically attached a synthetic chromophore to the surface of photolyase using oligonucleotides containing a modified nucleoside and a cyclobutane-type DNA lesion, and successfully enhanced its enzymatic activity in the light-driven DNA repair. Peptide mapping in combination with theoretical calculations identified the amino acid residue that binds to the chromophore, working as an artificial light-harvesting chromophore. Our results broaden the strategies for protein engineering and provide a guideline for tuning of the light perception abilities and enzymatic activity of the photoreceptor proteins.

Clinical features of children with polycythemia vera, essential thrombocythemia, and primary myelofibrosis in Japan: A retrospective nationwide survey.

Background: Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are exceptionally rare during childhood. Thus, clinical features of pediatric Ph-negative MPNs remain largely unknown. This study was therefore performed to address this. Methods: We performed a retrospective study to collect clinical information of children diagnosed with Ph-negative MPNs from 2000 to 2016 using questionnaires in qualified institutions in Japan. The results obtained from the questionnaire survey were then combined with those from the national registry data. Results: Among 50 children identified, five had PV, 44 had ET, and one had PMF. Median age at diagnosis was 14.0, 9.0, and 0 years, respectively. Male to female ratio was 4:1, 21:23, and 1:0, respectively. Detection rates of the JAK2 V617F variant were 0/5 in PV and 9/39 in ET. Frequencies of complications, such as thrombosis and subsequent leukemia, were lower than complication frequencies in adults. We identified two children who developed subsequent leukemia, which has not been reported previously, and one of them died. Conclusion: This is the first nationally representative survey of pediatric Ph-negative MPNs. Given its rarity, an international collaboration with comprehensive genetic analyses might be needed to fully elucidate the clinical and genetic features.

Hematopoietic stem cell transplantation with reduced intensity conditioning from a family haploidentical donor in an infant with familial hemophagocytic lymphohistocytosis.

Allogeneic hematopoietic stem cell transplantation is the only curative method for patients with familial hemophagocytic lymphohistiocytosis (FHL). We present a case of a 3-month-old girl with Munc13-4 mutation (FHL3), who underwent bone marrow transplantation (BMT) from her human leukocyte antigen-haploidentical mother following reduced intensity conditioning (RIC) with fludarabine, melphalan, and busulfan. Engraftment after BMT was generally uneventful, with only mild acute graft versus host disease. Munc13-4 protein was restored following BMT, and she is well and free of disease 14 months after BMT. These results suggest that BMT with RIC from a family haploidentical donor may sufficiently restore immune regulation in infants, while lessening treatment-related mortality and long-term sequelae.

Anthracyclines for acute lymphoblastic leukemia in a child with congenital long QT syndrome.

Anthracyclines are key drugs for the treatment of children with acute lymphoblastic leukemia (ALL). However, anthracyclines are known to induce QT prolongation, and life-threatening complications, such as torsades de pointe may also occur. To date, there have been no reports on the use of anthracyclines in patients with congenital long QT syndrome (LQTS). We report a child with ALL complicated by congenital LQTS who was treated with anthracyclines. The administration of anthracyclines caused QT-interval prolongation, but this was uneventful with the concomitant administration of magnesium sulfate.

Retropharyngeal neuroblastoma in an infant: management without surgery.

SUMMARY: Retropharyngeal neuroblastoma is rare. We report a 3-month-old infant with retropharyngeal neuroblastoma presenting with airway compression, which had an unresectable localized tumor without N-myc amplification. He was promptly treated with chemotherapy, resulting in a dramatic resolution. Subsequently, he received no surgical intervention and is well without evidence of recurrence 10 months after completion of chemotherapy. A review of the literature reveals that retropharyngeal neuroblastoma in infants has a good prognosis, but with some risk of surgical complication. Thus, it might be better to treat unresectable, localized disease accompanied by life-threatening symptoms with chemotherapy alone.