Impact of prophylactic echinocandin on the development of neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation: A single-center retrospective study.

BACKGROUND: Although neurotoxicity is a major adverse event associated with busulfan, little information is available regarding the association between drug interactions and neurological symptoms during busulfan-based regimens. This study evaluated the association between prophylactic echinocandins and neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation. METHODS: We retrospectively included consecutive patients who administered intravenous busulfan as a conditioning regimen at our facility between 2007 and 2022. Prophylactic echinocandin use was defined as the use of an echinocandin antifungal drug to prevent invasive fungal disease in SCT recipients. The primary outcome was the incidence of neurological complications within 7 days of busulfan initiation and was compared between the echinocandin group (patients received prophylactic echinocandin) and nonechinocandin group (patients received prophylactic antifungal drugs other than echinocandin and those without antifungal prophylaxis). RESULTS: Among the 59 patients included in this study, the incidence of neurological complications in the echinocandin (n = 26) and nonechinocandin groups (n = 33) was 30.8% and 63.6%, respectively. We observed a negative association between prophylactic echinocandin use and the development of neurological complications after adjusting for the propensity score for receiving prophylactic echinocandins (adjusted odds ratio 0.294, 95% confidence interval 0.090 to 0.959). We observed a lower incidence of neurological complications in the echinocandin group than in the nonechinocandin group. CONCLUSION: Our results suggested that the choice of antifungal prophylaxis is associated with busulfan neurotoxicity.

Nosocomial meningitis caused by Staphylococcus haemolyticus in a child with neutropenia in the absence of intracranial devices: a case report.

BACKGROUND: Coagulase-negative staphylococci can cause hospital-acquired infections, especially in immunocompromised hosts. Bacterial meningitis is a potentially fatal infection of the central nervous system, causing high mortality and morbidity. In general, the causative agents of meningitis, coagulase-negative staphylococci, are associated with direct implantation of a foreign body and the presence of a cerebrospinal fluid (CSF) shunt. Here, we describe a case of nosocomial meningitis caused by Staphylococcus haemolyticus in a child with neutropenia who had no intracranial foreign devices. CASE PRESENTATION: A 15-year-old boy with relapsed acute myeloid leukemia undergoing chemotherapy through a central venous catheter developed fever on Day 13 post-initiation of chemotherapy. There was no history of implantation of neurosurgical devices. Two blood cultures obtained on Day 14 were positive for Staphylococcus haemolyticus. Clinical improvement was noted, and treatment with vancomycin and removal of the central venous catheter resulted in negative repeat blood cultures on Day 18. However, the patient developed a tendency for somnolence and improper speech, along with persistent fever on Day 26. A lumber puncture was performed on Day 27, resulting in positive culture of Staphylococcus haemolyticus. He was diagnosed with meningitis and the dosage of vancomycin was increased. A repeat CSF culture was positive for Staphylococcus haemolyticus on Day 40, so oral rifampicin was added. CSF findings on Day 46 revealed a low concentration of vancomycin, and treatment was switched from vancomycin plus rifampicin to linezolid. After Day 46, four subsequent cerebrospinal fluid tests of the CSF showed no growth of Staphylococcus haemolyticus. The patient's symptoms were improved on Day 52. Brain and spinal magnetic resonance images was taken and it showed no abnormalities. Linezolid was continued until Day 72. The patient was discharged without any complications on Day 72. CONCLUSIONS: To the best of our knowledge, this is the first reported case of Staphylococcus haemolyticus meningitis in a patient without a neurosurgical device. Typical symptoms or signs may be absent in a patient with meningitis who also has neutropenia. Repeated tests of the CSF, and prolonged duration of antibiotics should be considered if atypical pathogens are detected in immunocompromised hosts.

The incidence of symptomatic osteonecrosis is similar between Japanese children and children in Western countries with acute lymphoblastic leukaemia treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol.

In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.

Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in RPS19.

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM_001022.4]. Nearly 180 RPS19 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in vitro functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four RPS19 deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.

Retrospective analysis of high-dose chemotherapy followed by autologous stem cell transplantation for high-risk pediatric osteosarcoma.

The outcomes of osteosarcoma with poor prognostic factors, such as poor responders, metastatic disease at diagnosis, and relapsed or refractory disease, are poor. We reviewed the clinical records of the patients diagnosed with osteosarcoma at our institute between 2004 and 2018 who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in our institute. Ten patients of osteosarcoma with poor responder, refractory status, and metastatic disease at diagnosis received high-dose chemotherapy followed by ASCT. Four patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of thiotepa and melphalan (MEL). Five patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of intravenous busulfan (BU) and MEL. One patient underwent tandem high-dose chemotherapy followed by ASCT with BU and MEL followed by carboplatin and etoposide. None of the ten patients died of regimen related toxicities. None of the five patients with poor responders who underwent high-dose chemotherapy followed by ASCT as part of consolidation therapy died of disease after ASCT. High-dose chemotherapy followed by ASCT might be effective for poor responders in osteosarcoma.

Presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation.

We report two malignant sacrococcygeal tumors in infants that were associated with pathogenic DICER1 variation. These tumors were composed of primitive neuroepithelium, embryonal rhabdomyosarcoma, and cartilage and initially diagnosed as immature teratomas. One child developed intracranial metastasis and died. The second child underwent surgery and chemotherapy and achieved complete remission. This child subsequently developed five additional DICER1-associated neoplasms by age nine. Genetic analysis revealed that both tumors harbored biallelic pathogenic DICER1 variation. We believe these cases represent another novel subtype of DICER1-associated tumor. This new entity, which we propose to call DICER1-associated presacral malignant teratoid neoplasm, may be difficult initially to distinguish from immature teratoma, but recognizing it as an entity can prompt appropriate classification as an aggressive malignancy and facilitate appropriate genetic counseling, DICER1 germline variant testing, screening, and education.

Low-dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high-risk pediatric acute myeloid leukemia.

The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high-risk AML post HSCT who were treated with low-dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13-41 months despite their high-risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low-dose AZA maintenance therapy post HSCT for pediatric patients with high-risk AML.

Successful Treatment of Transplantation-associated Atypical Hemolytic Uremic Syndrome With Eculizumab.

We herein reported a 4-month-old boy with transplantation-associated atypical hemolytic uremic syndrome (TA-aHUS) who was successfully treated with eculizumab. The patient diagnosed with type 3 of familial hemophagocytic lymphohistiocytosis underwent cord blood transplantation. After transplantation, he developed TA-aHUS, but plasma exchanges were unsuccessful. We identified deletions in CFH-related gene 1 (del-CFHR1) by the multiplex ligation-dependent probe amplification testing procedure and CFH autoantibodies. Eculizumab has been administered to the patient, with a marked improvement being achieved in thrombocytopenia. He has been well except for the persistent microhematuria for a year after transplantation. Uncontrolled complement activation might be involved in the pathophysiology of TA-aHUS.

Refractory double-hit lymphoma/leukemia in childhood mimicking B-precursor acute lymphoblastic leukemia at initial presentation.

A 10-year-old girl was referred to our hospital with left preauricular adenopathy and gingival swelling. She was diagnosed with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on being positive for expressions of CD10, CD19, TdT and HLA-DR. She showed no CD20 expression at the time of diagnosis. Based on the initial diagnosis of BCP-ALL, induction chemotherapy for BCP-ALL was initiated. However, the blasts did not disappear from her peripheral blood. Bone marrow examination on day 33 identified 81.3% residual blasts with positive expressions of CD19, 20 and HLA-DR and negative CD10 and TdT expressions; these cells were morphologically and phenotypically different from those at the initial diagnosis. Based on cytogenetic studies, the final diagnosis was double-hit lymphoma/leukemia (DHL) with IgH-BCL2 and Igλ-MYC. Although dose intensive chemotherapy, including rituximab, led to complete remission, bone marrow and central nervous system relapse occurred. At relapse, blasts expressed CD10, CD19 and HLA-DR, but not CD20, findings the same as those at the onset. The patient died of the disease 44 days after cord blood transplantation with non-remission status. DHL in childhood is extremely rare and its prognosis is poor. The establishment of an effective treatment for DHL is highly anticipated.

Successful non-myeloablative allogenic bone marrow transplantation in a child with severe congenital neutropenia complicated by chronic pulmonary infection.

We herein describe a 2-year-old boy with severe congenital neutropenia (SCN) who was successfully treated with reduced-intensity bone marrow transplantation (HSCT). He had suffered recurrent episodes of bacterial pneumonia from 12 months of age, and was found to have severe neutropenia with white blood cell counts below 100/µl. The patient harbored a heterozygous missense mutation in ELANE exon 4 (p.Gln134Pro, NM_001972.2: c.401A>C). This was a novel mutation. Due to intractable pneumonia and severe persistent neutropenia, reduced-intensity HSCT was performed from an HLA-matched sibling donor. The preparative regimen consisted of melphalan, fludarabine, and 4 Gy of total body irradiation. Hematopoietic engraftment was rapidly obtained, i.e., by day +14, and complete donor chimerism was subsequently achieved. The lung complications observed pre-transplantation markedly improved after neutrophil recovery, i.e., by day +60. We concluded that HSCT is a useful treatment for SCN patients, especially for those at high risk of leukemic transformation. Fludarabine-based reduced-intensity HSCT may represent a safe and effective therapeutic option for patients with SCN who need HSCT even if they have intractable infectious complications.

An endobronchial inflammatory myofibroblastic tumor in a 10-yr-old child after allogeneic hematopoietic cell transplantation.

IMTs belong to the group of soft tissue tumor and could occur at any anatomical site; however, the causes and growth feature remain unclear. This case report documents a 10-yr-old male suffering from slowly developing dyspnea on exertion and cough around seven months post-HCT. He was diagnosed with an endobronchial tumor based on imaging, and histology confirmed ALK-positive submucosal spindle-shaped cells with infiltrative cells, compatible with IMT. We should be aware that IMT is a potential complication of pediatric allogeneic HCT and can cause sudden airway obstruction.

A novel NFKB1 variant in a Japanese pedigree with common variable immunodeficiency.

Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant.

Distinct Expression Profiles of Neuroblastoma-Associated mRNAs in Peripheral Blood and Bone Marrow of Non-High-Risk and High-Risk Neuroblastoma Patients.

Non-high-risk (non-HR) neuroblastoma (NB) patients have excellent outcomes, with more than a 90% survival rate, whereas HR NB patients expect less than a 50% survival rate. Metastatic disease is the principal cause of death among both non-HR and HR NB patients. Previous studies have reported the significant but limited prognostic value of quantitative PCR (qPCR)-based assays, measuring overlapping but different sets of neuroblastoma-associated mRNAs (NB-mRNAs), to detect metastatic disease in both non-HR and HR patient samples. A droplet digital PCR (ddPCR)-based assay measuring seven NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was recently developed and exhibited a better prognostic value for HR patient samples than qPCR-based assays. However, it remained to be tested on non-HR patient samples. In the present study, we employed the ddPCR-based assay to study peripheral blood (PB) and bone marrow (BM) samples collected at diagnosis from eight non-HR and eleven HR cases and characterized the expression profiles of NB-mRNAs. The most highly expressed NB-mRNAs in PB and BM differed between non-HR and HR cases, with the CRMP1 mRNA being predominant in non-HR cases and the GAP43 mRNA in HR cases. The levels of NB-mRNAs in PB and BM were 5 to 1000 times lower in non-HR cases than in HR cases. The PB to BM ratio of NB-mRNAs was 10 to 100 times higher in non-HR cases compared to HR cases. The present case series suggests that non-HR and HR NB patients have the distinct expression profiles of NB-mRNAs in their PB and BM.

Association between conditioning intensity and height growth after allogeneic hematopoietic stem cell transplantation in children.

BACKGROUND: The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We reviewed the clinical records of 89 children with malignant diseases who underwent initial allo-HSCT between 2003 and 2021. Height measurements were standardized using standard height charts prepared by the Japanese Society for Pediatric Endocrinology to calculate standard deviation score (SDS). We defined short stature as a height SDS less than -2.0 in that reference. Myeloablative conditioning (MAC) comprised total-body irradiation at more than 8 Gy and busulfan administration at more than 8 mg/kg (more than 280 mg/m2 ). Other conditioning regimens were defined as reduced intensity conditioning (RIC). RESULTS: A total of 58 patients underwent allo-HSCT with MAC, and 31 patients received allo-HSCT with RIC. There were significant differences in the height SDS at 2 and 3 years after allo-HSCT between MAC and RIC group (-1.33 ± 1.20 vs. -0.76 ± 1.12, p = 0.047, -1.55 ± 1.28 vs. -0.75 ± 1.11, p = 0.022, respectively). Multivariate logistic regression analysis with the adjustments for potential confounding factors of patients less than 10 years of age at allo-HSCT and chronic graft-versus host disease demonstrated that MAC regimen was associated with a markedly increased risk of a short stature at 3 years after allo-HSCT (adjusted odds ratio, 5.61; 95% confidence interval, 1.07-29.4; p = 0.041). CONCLUSION: The intensity of conditioning regimen may be associated with short statures after allo-HSCT.

Epidural Spinal Cord Compression as the Presenting Manifestation of Acute Myeloid Leukemia: A Case Report and Literature Review.

We herein report a rare case of spinal cord compression due to epidural involvement of acute myeloid leukemia (AML). A 14-year-old boy presented with a 7-day history of back pain, paraplegia and hypoesthesia. Contrast-enhanced computed tomography revealed an epidural mass. Emergency laminectomy and resection of the mass were performed. Histopathologically, the resected mass was comparable to an extramedullary mass of AML. Chemotherapy was initiated, and complete remission was achieved. Neurological sequelae remained after the treatment. Based on the present and previous reports, spinal cord compression from epidural AML involvement may progress rapidly.

Higher levels of minimal residual disease in peripheral blood than bone marrow before 1st and 2nd relapse/regrowth in a patient with high­risk neuroblastoma: A case report.

More than half of patients with high-risk neuroblastoma (HR-NB) experience relapse/regrowth due to the activation of chemoresistant minimal residual disease (MRD). MRD in patients with HR-NB can be evaluated by quantitating neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow (BM) and peripheral blood (PB) samples. Although several sets of NB-mRNAs have been shown to possess a prognostic value for MRD in BM samples (BM-MRD), MRD in PB samples (PB-MRD) is considered to be low and difficult to evaluate. The present report describes an HR-NB case presenting higher PB-MRD than BM-MRD before 1st and 2nd relapse/regrowth. A 3-year-old female presented with an abdominal mass, was diagnosed with HR-NB, and treated according to the nationwide standard protocol for HR-NB. Following systemic induction and consolidation therapy with local therapy, the patient achieved complete remission but experienced a 1st relapse/regrowth 6 months after maintenance therapy. The patient partially responded to salvage chemotherapy and anti-GD2 immunotherapy but had a 2nd relapse/regrowth 14 months after the 1st relapse/regrowth. Consecutive PB-MRD and BM-MRD monitoring revealed that PB-MRD was lower than BM-MRD at diagnosis (100 times) and 1st and 2nd relapse/regrowth (1,000 and 3 times) but became higher than BM-MRD before 1st and 2nd relapse/regrowth. The present case highlights that PB-MRD can become higher than BM-MRD before relapse/regrowth of patients with HR-NB.