Recurrent spinal atypical teratoid/rhabdoid tumor with pulmonary metastasis.

BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are aggressive pediatric central nervous system malignancies that predominantly affect the brain and have poor survival outcomes. However, spinal ATRT is an uncommon subset of ATRT, and its clinical course and management are poorly understood. CASE: We describe a case of spinal ATRT in a previously healthy 5-year-old girl who initially presented with rapid-onset gait disturbance. Magnetic resonance imaging (MRI) revealed an extramedullary tumor at thoracic level 5 (T5) without bony destruction or metastasis. The patient partially recovered after surgical resection. One month was required for a definitive diagnosis, and the pathology confirmed ATRT characterized by the loss of INI-1 protein expression. Chemoradiotherapy with local irradiation and high-dose chemotherapy with autologous peripheral blood stem cell transplantation led to complete remission and functional recovery for 5 months. However, the condition exhibited progression in the cerebrospinal fluid (CSF) region, resulting in cerebellar, cerebral, and spinal tumor development. Eventually, the disease metastasized to the lungs and disseminated to the entire cerebrospinal cord and fluid. The patient died 15 months after the initial diagnosis. CONCLUSION: This case emphasizes the importance of considering ATRT as a potential diagnostic modality for pediatric spinal cord tumors, enabling prompt multidisciplinary intervention. The heterogeneous appearance of spinal ATRT may make distinguishing it from other spinal tumors difficult, resulting in delayed diagnosis and treatment. The treatment approach for ATRT remains challenging with no established standards. Local irradiation may be preferable to minimize neurodevelopmental effects, and initial craniospinal irradiation may potentially prevent recurrence. Our case emphasizes the likelihood of extracranial metastasis in ATRT, thereby highlighting the importance of a comprehensive assessment of both genetic and epigenetic profiles to identify any factors that may influence the clinical course of this disease. Prompt diagnosis and comprehensive therapeutic strategies are critical for improving outcomes in spinal ATRT patients.

Assessment of anthracycline-induced cardiotoxicity in childhood cancer survivors during long-term follow-up using strain analysis and intraventricular pressure gradient measurements.

BACKGROUND: Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in childhood cancer survivors (CCS), and the cumulative incidence of cardiac events has continued to increase. This study identifies an adequate indicator of cardiac dysfunction during long-term follow-up. PROCEDURE: In total, 116 patients (median age: 15.5 [range: 4.7-40.2] years) with childhood cancer who were treated with anthracycline were divided into three age groups for analysis (C1: 4-12 years of age, C2: 13-18 years of age, C3: 19-40 years of age), and 116 control patients of similar ages were divided into three corresponding groups (N1, N2, and N3). Layer-specific strains were assessed for longitudinal strain (LS) and circumferential strain (CS). The total and segmental intraventricular pressure gradients (IVPG) were also calculated based on Doppler imaging of the mitral inflow using Euler's equation. RESULTS: Conventional echocardiographic parameters were not significantly different between the patients and controls. All layers of the LS and inner and middle layers of the basal and papillary CS in all ages and all IVPGs in C2 and C3 decreased compared to those of corresponding age groups. Interestingly, basal CS and basal IVPG in CCS showed moderate correlation and both tended to rapidly decrease with aging. Furthermore, basal IVPG and anthracycline dose showed significant correlations. CONCLUSIONS: Basal CS and total and basal IVPGs may be particularly useful indicators of cardiotoxicity in long-term follow-up.

[Thrombopoietin receptor agonists for pediatric refractory chronic immune thrombocytopenia].

Various treatments have been used to treat chronic immune thrombocytopenic purpura in children; however, none of it has been established as the standard of care. The administration of thrombopoietin receptor agonists (TPO-RAs) has been approved as a new treatment option in Japan. In this case series, TPO-RAs were administered to 16 patients (eltrombopag, n=9; romiplostim, n=7). Excluding the data of two patients who underwent splenectomy immediately after starting treatment with these medicines, platelet counts increased to ≥50,000/µl in seven patients. The adverse events recorded were grade 2 liver dysfunction (n=1), according to the common terminology criteria for adverse events version 4, and myelofibrosis (classified as MF1 or mild reticulin fibrosis), as observed on bone marrow biopsy (n=2). We continued the administration of TPO-RAs at the same dose in these patients because the complications they experienced were mild. The risk of adverse events associated with long-term use of TPO-RAs in this pediatric population remains unclear, and a prospective evaluation is needed.

Trigenic ADH5/ALDH2/ADGRV1 mutations in myelodysplasia with Usher syndrome.

Trio-next generation sequencing is useful to identify undiagnosed inherited diseases. We have attended a patient with trigenic ADH5/ALDH2/ADGRV1 pathogenic variants, which caused two distinct diseases, myelodysplastic syndrome and Usher syndrome. Whole genome sequencing of peripheral blood from the patient and his parents were applied to identify disease-causing genes. Sanger sequencing was performed to validate the identified ADH5/ALDH2/ADGRV1 variants. Our results identified disease-associated variants in ADGRV1 (disease inheritance autosomal recessive) and in ADH5 (disease inheritance also autosomal recessive) and a variant in ALDH2 (disease inheritance autosomal dominant). Although the variants identified in ADH5 and ALDH2 have been reported, their co-existence in association with disease-causing variation in a third gene has not. They broaden the spectrum of ADGRV1 in Usher syndrome. Findings on next generation sequencing guided rapid and accurate diagnosis, resulting in patient-tailored therapeutic intervention.

[Gilteritinib for pediatric FLT3 internal tandem duplication-positive recurrent acute myeloid leukemia].

Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown efficacy in patients with refractory or recurrent adult acute myeloid leukemia (AML) with FLT3 mutations. However, there are limited data for pediatric patients treated with this drug. Herein, we report the clinical courses of two children with FLT3-mutated recurrent AML who received gilteritinib. Case 1: An 11-year-old boy with secondary relapsed AML presented with an FLT3 internal tandem duplication (ITD) since the first recurrence. One week after gilteritinib initiation, blasts, which had comprised 90% of the white blood cells before treatment, almost disappeared from the peripheral blood without tumor lysis syndrome. The patient developed multiple adverse effects and died from the disease 2.5 months after gilteritinib initiation. Case 2: A 12-year-old girl diagnosed with AML was positive for FLT3 ITD. She received gilteritinib during her first relapse post-stem cell transplantation. After the drug was administered, the recipient cell counts increased, as determined by molecular tests (i.e., FISH), whereas microscopically, there was a complete response for 5 months with good performance status. Gilteritinib treatment in children with FLT3-mutated recurrent AML is feasible and effective. As a patient experienced several adverse effects with gilteritinib treatment, clinical trials are required to determine the appropriate pediatric dose of this medication.

HLA haploidentical hematopoietic cell transplantation using clofarabine and busulfan for refractory pediatric hematological malignancy.

Haploidentical hematopoietic cell transplantation (HCT) conditioning with clofarabine and target area under the blood concentration-time curve (AUC)-based busulfan adjustment was performed in three patients with refractory pediatric leukemia. The target AUC for two patients who had already received multiple transplantations was 3600 and 4000 µmol min/L, and that for the patient with Down's syndrome was 3000 µmol min/L. Regimen-related toxicity was well tolerated in all cases. All three maintained cytological remission throughout the follow-up period (between 31 and 167 weeks). Thus, haploidentical HCT conditioning with clofarabine and target AUC-based busulfan adjustment may be a preferable option for children with recurrent or refractory pediatric leukemia.

Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells.

ATF7IP-PDGFRB is a novel PDGFRB-related fusion gene identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with a signature similar to that of Ph1 ALL, so-called Ph-like ALL. When we introduced ATF7IP-PDGFRB, murine Ba/F3 cells acquired the ability to proliferate in an interleukin (IL)-3-independent manner. On the contrary, the expression of wild-type PDGFRB is not sufficient to acquire the ability for IL-3-independent proliferation in Ba/F3 cells. The introduction of ATF7IP-PDGFRB also induces a typical gene expression profile for Ph1-ALL in Ba/F3 cells. A series of biochemical and cell biological experiments revealed the constitutive activation of ATF7IP-PDGFRB as well as downstream signaling molecules, including AKT and MAPK. Although the phosphoinositide 3-kinase inhibitor led to cell death in both cells into which ATF7IP-PDGFRB had been introduced and IL-3-maintained Mock cells, MEK inhibitor selectively led to cell death into which ATF7IP-PDGFRB had been introduced. The introduction of tyrosine to phenylalanine mutations at binding sites of adaptor molecules important in the MAPK pathway located in the PDGFRB portion abolished ATF7IP-PDGFRB-mediated cell transformation, suggesting that MAPK-mediated signals are critical in ATF7IP-PDGFRB-mediated cell transformation. On treatment with tyrosine kinase inhibitors, ATF7IP-PDGFRB-expressing, but not Mock, Ba/F3 cells underwent rapid apoptosis accompanied by reduced phosphorylation of MAPK. Importantly, the sensitivity of ATF7IP-PDGFRB-expressing Ba/F3 cells to imatinib is significantly higher than that of BCR-ABL1-transformed Ba/F3 cells, as assessed by the IC50. Taken together, ATF7IP-PDGFRB has transforming potential via the constitutive activation of MAPK and participates in the pathogenesis of Ph-like ALL. Our observations suggest the therapeutic importance of tyrosine kinase inhibitors and possibly MEK inhibitor for a subset of BCP-ALL harboring PDGFRB-related fusion kinases.

Significance of CD66c expression in childhood acute lymphoblastic leukemia.

Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p<0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL.

Poor responses to tyrosine kinase inhibitors in a child with precursor B-cell acute lymphoblastic leukemia with SNX2-ABL1 chimeric transcript.

In addition to BCR, various rare fusion partners for the ABL1 gene have been reported in leukemia. We have identified the fusion gene SNX2-ABL1 in a pediatric case of acute lymphoblastic leukemia (ALL), which has only once previously been reported in an adult patient. Cytogenetic analysis detected this fusion gene arising from a t(5;9)(q22;q34) translocation. ALL cells carrying a SNX2-ABL1 fusion exhibited a BCR-ABL1+ ALL-like gene expression profile. The patient poorly responded to dasatinib but partially responded to imatinib. Treatment using tyrosine kinase inhibitors requires further investigation to optimize the genotype-based treatment stratification for patients with SNX2-ABL1 fusion.

Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1.

We introduced SNX2-ABL1, a novel ABL1-related chimeric transcript lacks SH3 and SH2 domains, into murine Ba/F3 cells and compared their function with that of BCR-ABL1. After the expression of SNX2-ABL1 proteins, Ba/F3 cells acquired an ability to proliferate in an IL-3-independent manner. Upon treatment with both imatinib and dasatinib, BCR-ABL1-expressing Ba/F3 cells underwent rapid apoptosis, whereas SNX2-ABL1-expressing Ba/F3 cells showed poorer sensitivity toward these TKIs and could proliferate in the presence of a low dose of dasatinib. Therefore, other TKIs with a more selective effect against this chimeric kinase should be used for the treatment of patients with SNX2-ABL1+ ALL.

Effects of insulin-like growth factor-1 on B-cell precursor acute lymphoblastic leukemia.

Insulin-like growth factor-1 (IGF-1) is known to be a major growth factor with effects on various cell types, including hematopoietic cells, as well as neoplasms, and is regulated by IGF-binding proteins (IGFBPs). In this study, we investigated the effects of IGF-1 on B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. When the expression of IGF-1R in clinical samples of BCP-ALL was examined, five of thirty-two cases showed IGF-1R expression, whereas IGF-1R was expressed in most BCP-ALL cell lines. We observed that IGF-1 enhanced the proliferation of BCP-ALL cell lines that can be partially inhibited by IGFBP-1, -3, and -4, but not other IGFBPs. IGF-1 also partially inhibited dexamethasone-induced apoptosis, but not apoptosis mediated by VP-16 and irradiation. Interestingly, the proliferative effect of IGF-1 was partially blocked by inhibitors of MAPK and AKT, whereas the inhibition of dexamethasone-induced apoptosis was completely blocked by both inhibitors. Our data indicate that IGF-1 is involved in cell proliferation and apoptosis regulation in BCP-ALL cells. Since some BCP-ALL cases express IGF-1R, it appears to be a plausible target for prognostic evaluation and may represent a new therapeutic strategy.