Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Killer-cell immunoglobulin-like receptor ligand mismatch cord blood transplantation in high-risk neuroblastoma.

BACKGROUND: The prognosis of high-risk neuroblastoma stage 4 with bone marrow metastasis, MYCN amplified, or refractory neuroblastoma is poor. To date, no standard treatment has been established. In four selected cases, we challenged the killer-cell immunoglobulin-like receptor ligand mismatch cord blood transplantation in graft-versus-host disease (GVHD) with reduced-intensity conditioning. METHODS: Prior to this study, conventional chemotherapy, autologous peripheral blood stem cell transplantation with high-dose chemotherapy (busulfan and melphalan), surgery and radiation therapy were completed in every case. The status before cord blood transplantation in two cases was not complete remission (CR) and in the others it was CR. The primary site was the mediastinum, two adrenal glands and a retroperitoneum, respectively. Three patients had bone and bone marrow metastasis and one had MYCN amplification. In all cases, international neuroblastoma pathology classification was unfavorable histology. All patients were >2 years of age. RESULTS: Relapse occurred only in one patient 17 months after the last transplantation, and the other three patients maintained disease-free survival for 74, 36, and 24 months, respectively. In one case of relapse the disease could be controlled by conventional chemotherapy. Except one, all patients had no severe complications, such as acute or chronic GVHD. One patient had gastric antral vascular ectasia and hemorrhagic cystitis. CONCLUSION: This strategy might be feasible and should be investigated for efficacy in the future. No definite conclusion can be made, however, due to the very small number of patients. Further prospective studies are required to determine its efficacy.

Prophylactic recombinant thrombomodulin treatment prevents hepatic sinusoidal obstruction syndrome in high-risk pediatric patients that undergo hematopoietic stem cell transplants.

Hepatic SOS is a potentially life-threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high-risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post-HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI-1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS.

[Initial presentation of lymphoblastic crisis in a pediatric chronic myelogenous leukemia patient].

A 9-year-old girl was referred to our hospital because of facial palsy. Both physical and blood examination revealed hepatosplenomegaly and leukocytosis, respectively. A bone marrow examination demonstrated marked hypercellularity involving myeloblasts and lymphoblasts. Based on these results, we suspected mixed phenotype acute leukemia. However, her leukemic blasts expressed B-cell antigens, and a chromosomal analysis of her bone marrow cells revealed the following karyotype: 46, XX, t (9;22) (q34;q11.2). All her neutrophils were positive for the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein. Based on these findings, she was diagnosed with a lymphoblastic crisis of chronic myelogenous leukemia (CML). Combined chemotherapy, involving imatinib, resulted in complete molecular remission. She received cord blood transplant (CBT) during the first complete remission; she is alive and has not suffered a relapse since two years after the CBT. The sudden onset of a blastic crisis in pediatric CML is rare, and it may be difficult to distinguish such cases from de novo Ph-positive leukemia. For diagnostic purposes, it is essential to consider a patient's clinical course and blood test results.

Successful low-dose radiotherapy treatment for Kasabach-Merritt syndrome.

Kasabach-Merritt syndrome (KMS) is characterized by hemangioma associated with life-threatening thrombocytopenia, and is a consumptive coagulopathy. Although treatments available include corticosteroids, α-interferon, vincristine, and surgery, response may be unsatisfactory, and the mortality rate remains at approximately 30%. Although radiotherapy has been used effectively for KMS, it may cause growth retardation and secondary malignancy. We report a case of KMS in which hemangioma of the left thigh was successfully treated with low-dose radiotherapy (6 Gy in six fractions, weekly) after failure of corticosteroid therapy. No significant late effects due to the radiotherapy were noted at 5 year follow up. Thus, low-dose radiotherapy remains an important treatment method for KMS when patients fail to respond to other treatments.

Subcutaneous Panniculitis-like T Cell Lymphoma Diagnosed with a Slowly Progressive Course: A Case Report.

Panniculitis is an inflammation that occurs in subcutaneous adipose tissue. Panniculitis includes physical panniculitis (e.g., traumatic) and infectious panniculitis (e.g., bacterial, fungal, subcutaneous panniculitis-like T cell lymphoma [SPCTL], etc.). Accurate diagnosis is crucial due to similar clinical presentation of all types of panniculitis. Here, we report a case of SPCTL which was initially diagnosed with traumatic panniculitis. A 15-year-old male patient was admitted to a previous hospital due to a progressively enlarged right flank and inguinal mass after an abdominal bruise. He was initially diagnosed with traumatic panniculitis, but the mass expanded throughout the chest and abdomen accompanied by a fever of over 11 months. Computed tomography (CT) revealed a subcutaneous mass in the anterior chest and abdominal wall. Fludeoxyglucose F18 (FDG) uptake was observed at those lesions using FDG-positron emission tomography (PET). A biopsy of the mass lesion was performed, during which SPCTL was diagnosed based on pathological examination. He was initially treated with prednisolone and cyclosporine A for two weeks. His fever went down, but subcutaneous mass in the chest and abdominal wall persisted. Therefore, he received a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen. After 6 courses of CHOP, CT revealed no disease evidence. He remained in complete remission at 30 months of therapy.

Allogeneic stem cell transplantation for inherited metabolic disorders: 35 years' experience at a single institution.

Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.

Successful Emergency Decompressive Laminectomy for Burkitt Lymphoma with Metastatic Spinal Lesions: A Case Report.

Although Burkitt lymphoma (BL) usually arises in the abdomen or pelvis, it can also arise in the epidural space as a primary or secondary site and present with back pain or limb weakness. Emergency management is necessary to relieve spinal cord compression (SCC). Herein, we report a case of BL with metastatic spinal lesions in a 16-year-old female who presented with sudden-onset progressive walking difficulty. She was admitted to a previous hospital where she presented with abdominal pain and vomiting and was diagnosed with intussusception via a computed tomography scan. Laparoscopic small bowel resection was performed, during which a diagnosis of BL was made on the basis of pathological examination. Sudden numbness in the extremities and the complete inability to walk occurred ten days after surgery. Thoracolumbar MRI revealed a metastatic mass extending from C7 to T6 with evidence of SCC. Emergency decompressive laminectomies (from C7 to T6) and partial debulking of the tumor were performed 12 hours after the onset of her neurologic symptoms. She was subsequently treated with chemotherapy, and she made a complete neurologic recovery. Emergency decompressive laminectomies for BL with spinal lesions could effectively lead to the recovery of neurologic symptoms.

Invasive Pulmonary Aspergillosis Successfully Treated with Granulocyte Transfusions Followed by Hematopoietic Stem Cell Transplantation in a Patient with Severe Childhood Aplastic Anemia.

Granulocyte transfusions (GTX) have been used in patients with neutropenia or neutropenia associated with invasive fungal infection. An 11-year-old girl with severe aplastic anemia (SAA) received immunosuppressive therapy (IST) with rabbit antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor. However, IST was not effective and her condition became complicated with life-threatening invasive pulmonary aspergillosis. Owing to the necessity for early neutrophil recovery to resolve the infection, GTX were performed, followed by bone marrow transplantation (BMT) from her mother with human leukocyte antigen-B locus mismatch. Her dyspnea improved and she eventually became afebrile after the initiation of GTX. Despite engraftment failure following BMT, successful engraftment was achieved by salvage therapy with peripheral blood stem cell transplantation. Chest computed tomography scan obtained 4 months after BMT revealed marked improvement in pneumonia. The current case illustrates that GTX may be useful in controlling invasive fungal infections before hematopoietic stem cell transplantation in patients with SAA.

Breath sound analyses of infants with respiratory syncytial virus acute bronchiolitis.

INTRODUCTION: The reliability of a breath sound analysis using an objective method in infants has been reported. OBJECTIVE: Breath sounds of infants with respiratory syncytial virus (RSV) acute bronchiolitis were analyzed via a breath sound spectrogram to evaluate their characteristics and examine their relationship with the severity. SUBJECTS AND METHODS: We evaluated the inspiratory and expiratory breath sound parameters of 33 infants diagnosed with RSV acute bronchiolitis. The sound powers of inspiration and expiration were evaluated at the acute phase and recovery phase of infection. Furthermore, the relationship between the breath sound parameters and the clinical severity of acute bronchiolitis was examined. RESULTS: Analyses of the breath sound spectrogram showed that the power of expiration as well as the expiration-to-inspiration sound ratio in the mid-frequency (E/I MF) was increased in the acute phase and decreased during the recovery phase. The E/I MF was inversely correlated with the SpO2 and positively correlated with the severity score. CONCLUSION: In infants with RSV acute bronchiolitis, the sound power of respiration was large at the acute phase, significantly decreasing in the recovery phase. In 61% of participants, nonuniform, granular bands were shown in the low-pitched region of the expiratory spectrogram.

A Boy Presenting with a Fever and Pancytopenia Diagnosed with Systemic Lupus Erythematosus without a Positive Anti-ds-DNA Antibody Result or Hypocomplementemia: A Case Report.

BACKGROUND: Hematological involvement, including anemia, leukopenia, lymphopenia, and thrombocytopenia, is one of the most common manifestations of childhood-onset systemic lupus erythematosus (cSLE). Specifically, relatively severe forms of hematological involvement, such as macrophage activation syndrome (MAS) and thrombotic microangiopathy, occur in the course of the disease. Positivity for anti-double stranded-DNA (ds-DNA) antibody and hypocomplementemia are important as not only criteria of diagnosing cSLE but also in the determination of the disease activity. CASE REPORT: A 13-year-old boy without pre-existing disease was referred to our hospital chiefly complaining of a fever for > 7 days, long-lasting malaise, nausea, and non-malar face rash. His blood examination showed pancytopenia and hyperferritinemia, but positive results for anti-ds-DNA antibody and hypocomplementemia were not recognized. Bone marrow aspiration revealed no evidence of malignant diseases, hemophagocytic lymphohistiocytosis, or MAS. A renal biopsy for the differential diagnosis of proteinuria and hematuria revealed class IIIa +V lupus nephritis, leading to the diagnosis of cSLE. CONCLUSIONS: It is important for cSLE to be considered in patients with pancytopenia, even those without positive anti-ds-DNA antibody findings or hypocomplementemia, and for aggressive approaches to be adopted for the differential diagnosis, including a renal biopsy.

Successful combination chemotherapy involving clofarabine, cyclophosphamide, and etoposide for pediatric relapsed acute myeloid leukemia: A case report.

Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.

Anticoagulation treatment and prophylactic edoxaban for cerebral sinus venous thrombosis in an adolescent with acute lymphoblastic leukemia.

Pediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient's symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.

Acute megakaryocytic leukemia (AMKL,FAB;M7) with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is characterized by an accumulation of multiple congenital anomalies. Although patients with BWS are known to have a higher incidence of embryonal tumors, there has been no reports associated with acute leukemia. This report describes the case of a patient with BWS who developed Acute Megakaryocytic Leukemia (AMKL,FAB;M7). Because most patients with BWS present gigantism, the therapy-related toxicity of chemotherapy can be a very serious problem. This patient exhibited no therapy-related toxicity after chemotherapy, suggesting that acute leukemia with BWS may not require a reduction in dosage.

Successful Treatment of Pediatric Refractory/Relapsed AML with KIR-Ligand-Mismatched Cord Blood Transplant after FLAG-IDA Reinduction Therapy with or without the GO Regimen.

Prognosis in pediatric patients with refractory/relapsed acute myeloid leukemia (AML) is grim, and there is no standard treatment for such patients. Combined treatment with intensive chemotherapy and gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is useful as reinduction therapy in refractory/relapsed AML. Here, we describe three cases of pediatric refractory/relapsed AML that were successfully managed with FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), with or without GO, as reinduction therapy before a KIR-ligand-mismatched cord blood transplant. This strategy relies on the fact that killer cell immunoglobulin-like receptors (KIR) on cord blood natural killer (NK) cells recognize human leukocyte antigen (HLA) class I alleles, and that donor KIR-ligand incompatibility may be associated with lower incidence of relapse and improved survival in AML, as cells that lack these inhibitory HLA ligands can activate NK cells. All three patients are currently alive and have been disease-free for 24-65 months, although one patient developed severe sinusoidal obstructive syndrome (SOS). Thus, our strategy can result in excellent outcomes in pediatric patients with refractory/relapsed AML.

Peperomins as anti-inflammatory agents that inhibit the NF-kappaB signaling pathway.

The transcription factor nuclear factor kappaB (NF-kappaB) induces the expression of various inflammatory genes. In the common NF-kappaB signaling pathway, peperomin E and 2,6-didehydropeperomin B inhibited IkappaB degradation upon stimulation with TNF-alpha or interleukin-1. Consistent with these results, peperomin E and 2,6-didehydropeperomin B blocked the TNF-alpha-induced activation of IkappaB kinase, while they had no direct effect on the IkappaB kinase activity. Our present results clearly demonstrate that peperomins inhibit the NF-kappaB signaling pathway by blocking IkappaB kinase activation.

Gastric antral vascular ectasia in a pediatric patient with neuroblastoma who underwent tandem stem cell transplantation.

Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder, which causes severe and prolonged gastric bleeding. Although GAVE has been described in adult patients treated with hematopoietic stem cell transplantation (HSCT), a few cases involving pediatric patients have also been reported. A 5-year-old boy with neuroblastoma (NB) developed severe hematemesis after undergoing tandem HSCT, i.e. autologous peripheral blood stem cell transplantation (auto-PBSCT), followed by allogeneic cord blood transplantation (allo-CBT). The patient suffered oral feeding difficulties because of the effects of chemotherapy and an unbalanced diet. Intravenous Busulfan (ivBU) was used as a conditioning regimen for the auto-PBSCT. The diagnosis of GAVE was made based on endoscopy of the upper gastrointestinal tract on day 31 after the allo-CBT. Argon plasma coagulation (APC) was performed twice, and the complete resolution of GAVE was confirmed by an endoscopic re-evaluation, conducted on day 87. GAVE in this case might have been associated with ivBU treatment. Atrophy of the gastric mucosa due to loss of appetite might also have contributed to GAVE. NB was treated using high-doses of alkylating agents, such as BU. Such treatment can cause significant mucositis of the oral cavity as well as vascular lesions and is associated with GAVE. Therefore, GAVE should be considered when gastrointestinal bleeding occurs in NB patients treated with HSCT. APC might be effective against HSCT-GAVE.