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.

Prevention of chemotherapy-induced vomiting in children receiving multiple-day cisplatin chemotherapy: A hospital-based, retrospective cohort study.

BACKGROUND: Optimal prevention of chemotherapy-induced vomiting (CIV) has not been established for patients receiving cisplatin in divided doses. The aim of this study was to describe the incidence and risk factors of CIV in children who received multiple-day cisplatin chemotherapy. PROCEDURE: A total of 24 consecutive pediatric patients (age 0-19 years) who received multiple-day cisplatin chemotherapy in our hospital were enrolled. Patients with relapsed disease or primary intracranial tumor and those who received concurrent radiation therapy were excluded. The number of chemotherapy cycles reviewed was 107, with a median of five per patient. All patients received granisetron. Dexamethasone and NK-1 receptor antagonists (NK1RA) were used as additional antiemetics for prophylaxis of CIV. RESULTS: CIV was observed in 22 of 24 (92%) patients, and 61 of 107 (57%) cycles. Patients who developed CIV had a higher incidence of other chemotherapy-related adverse events (87 vs. 41%, P < 0.001). The incidence of CIV was lower in patients administered with NK1RA than those without (32 vs. 68%, P < 0.001). Multivariate logistic regression identified age less than or equal to 2 years (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.10-0.63) and administration of NK1RA (OR = 0.16, 95% CI = 0.06-0.43) as independent factors for CIV. CONCLUSIONS: These results suggest that NK1RA is crucial to reduce CIV in children who receive multiple-day cisplatin chemotherapy.

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.

Association between Factor XIII Activity and Clinical Course in Pediatric Patients with Immunoglobulin A Vasculitis.

BACKGROUND: Immunoglobulin A vasculitis is a systemic form of vasculitis that predominantly affects children. Factor XIII activity is decreased in some cases, and several reports have shown an association between abdominal pain and decreased factor XIII activity. However, the clinical significance of decreased factor XIII activity in pediatric immunoglobulin A vasculitis has not been fully elucidated. This study aimed to identify the association between factor XIII activity and the clinical course of pediatric patients with immunoglobulin A vasculitis. METHODS: Forty-four pediatric patients, admitted to Kita-Harima Medical Center with a clinical diagnosis of immunoglobulin A vasculitis between October 1, 2013 and September 30, 2022, were retrospectively reviewed, and 22 patients were analyzed. The patients' background characteristics and clinical course were compared between the normal and decreased factor XIII activity (<70%) groups. RESULTS: The group with decreased factor XIII activity showed a significantly increased duration of hospitalization (14 [6-36] vs. 7 [5-13] days, p = 0.01), total glucocorticoid dose (prednisolone 22.7 [4.9-55.5] vs. 10.1 [3.4-19.6] mg/kg, p = 0.02), and duration of glucocorticoid administration (19 [4-85] vs. 10 [3-15] days, p = 0.03). Correlational analyses showed that these three parameters were negatively correlated with factor XIII activity. CONCLUSIONS: Factor XIII activity was negatively correlated with the duration of hospitalization, total glucocorticoid dose, and duration of glucocorticoid administration. Factor XIII activity is not only associated with abdominal symptoms but also may be a marker to predict the overall trajectory of acute-phase treatment in pediatric patients with immunoglobulin A vasculitis.

Epigallocatechin gallate inhibits sphere formation of neuroblastoma BE(2)-C cells.

OBJECTIVES: A growing number of epidemiological studies have demonstrated that the consumption of green tea inhibits the growth of a variety of cancers. Epigallocatechin gallate (EGCG), the most abundant catechin in green tea, has been shown to have an anti-cancer effect against many cancers. Most cancers are believed to be initiated from and maintained by a small population of tumor-initiating cells (TICs) that are responsible for chemotherapeutic resistance and tumor relapse. In neuroblastoma, an aggressive pediatric tumor that often relapses and has a poor prognosis, TICs were recently identified as spheres grown in a serum-free non-adherent culture used for neural crest stem cell growth. Although EGCG has been reported to induce growth arrest and apoptosis in neuroblastoma cells, its effect on neuroblastoma TICs remains to be defined. METHODS: Gene expression was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). The effects of EGCG on cell proliferation, apoptosis, and sphere formation were determined by cell counting, propidium iodide staining, and sphere (>100 µm in diameter) counting, respectively. RESULTS: Neuroblastoma BE(2)-C cells showed increased expression of stem cell markers (nanog homeobox [NANOG] and octamer-binding transcription factor 4 [OCT4]), as well as decreased expression of neuronal differentiation markers (Cu(2+)-transporting ATPase alpha polypeptide [ATP7A] and dickkopf homolog 2 [DKK2]) in spheres grown in serum-free non-adherent culture, compared to parental cells grown in conventional culture. Although EGCG induced growth arrest and apoptosis in the parental cells in a dose-dependent manner, it was not effective against spheres. However, EGCG potently inhibited sphere formation in the BE(2)-C cells. CONCLUSIONS: The present results suggest that EGCG may inhibit the development of TICs in BE(2)-C cells.

Quantitative assessment of PTPN11 or RAS mutations at the neonatal period and during the clinical course in patients with juvenile myelomonocytic leukaemia.

To evaluate minimal residual disease (MRD) after chemotherapy and haematopoietic stem cell transplantation in juvenile myelomonocytic leukaemia (JMML), a locked nucleic acid-allele specific quantitative polymerase chain reaction (LNA-AS-qPCR) was developed for 13 patients (four types of PTPN11 mutation and four types of RAS mutation). The post-transplant MRD detected by LNA-AS-qPCR analysis was well correlated with chimerism assessed by short tandem repeat PCR analysis. Non-intensive chemotherapy exerted no substantial reduction of the tumour burden in three patients. There was no significant difference in the quantity of RAS mutant DNA after spontaneous haematological improvement in 4 patients with NRAS or KRAS 34G > A during a 2- to 5-year follow-up. PTPN11, NRAS, or KRAS mutant DNA was detected from Guthrie card dried blood in five of seven patients (who were aged <2 years at diagnosis) at a level of 1.0-6.5 x 10(-1) of the values at diagnosis. Accordingly, these five patients might have already reached a subclinical status at birth. Considering the negative correlation between mutant DNA level in neonatal blood spots and age at diagnosis, JMML patients with a larger tumour burden at birth appeared to show earlier onset.

Kawasaki Disease with an Initial Manifestation Mimicking Bacterial Inguinal Cellulitis.

BACKGROUND: Kawasaki disease (KD) is typically characterized by fever, oral cavity erythematous changes, bilateral bulbar conjunctival injection, skin rash, erythema and edema of the hands and feet, and cervical lymphadenopathy. Some atypical patients with KD initially develop cervical and pharyngeal cellulitis; however, an initial presentation with inguinal cellulitis is extremely rare. In addition, to our knowledge, no report has documented the cytokine profile in a KD patient with cellulitis. Case presentation. A previously healthy 8-year-old Japanese girl was hospitalized following a 2-day history of fever and a 5-day history of pain and erythema in the left inguinal region. She was diagnosed with bacterial inguinal cellulitis and was administered antibiotics. The next day, a polymorphous rash emerged on her trunk. After 3 days of antibiotics, however, her fever continued and the cellulitis had spread over the entire lower abdomen. Simultaneously, the bilateral bulbar conjunctival injection without exudate became more prominent and her lips became erythematous. In addition, erythematous changes on her palms appeared a few hours later, which led to the diagnosis of KD. Since she had a high risk score that predicted no response to initial intravenous immunoglobulin (IVIG) at the initiation of treatment, she was treated with IVIG, intravenous prednisolone (PSL), and oral aspirin. The KD symptoms improved the next day, but the cellulitis did not completely resolve until 2 months after discharge. The patient's serum cytokine profile at admission had an IL-6 dominant pattern which was consistent with that of patients with KD despite her initial lack of KD symptoms, and the pattern observed at admission was sustained until IVIG and PSL administration. CONCLUSION: KD should be included in the differential diagnosis for patients presenting with inguinal cellulitis who are unresponsive to initial empiric antibiotics.

Clinical features in proven and probable invasive fungal disease in children and adolescents at a pediatric referral center: a 5-year experience.

BACKGROUND: There is limited information concerning the overall epidemiology of invasive fungal disease (IFD) in children. The aim of this study was to clarify the clinical features of IFD in a tertiary pediatric care hospital. METHODS: Patients diagnosed with proven or probable IFD at our hospital between 2011 and 2015 were retrospectively reviewed. Proven and probable IFD were defined according to the European Organization for Research and Treatment of Cancer/Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group consensus. Patients with possible IFD were excluded. RESULTS: The incidence of proven or probable IFD was 26 of 20,079 hospitalized patients (0.13%). The predominant underlying disease was malignancy (54%) and congenital anomaly (27%). The most common diagnosis was candidemia among the patients with proven IFD (8 of 13, 62%). All the isolated pathogens in the candidemia patients were non-albicans Candida spp. The most common site of infection was the lungs in patients with probable IFD (11 of 13 patients, 85%). In probable IFD episodes, positive ß-D-glucan and galactomannan were found in 12 of 13 (92%) and 5 of 13 (38%) patients, respectively. All but one patient (96%) received empirical antifungal therapy. No patients underwent surgical resection of residual lesions. The overall mortality was 23% and the attributable mortality of IFD was 12%. CONCLUSION: Our results suggest the emergence of non-albicans Candida species as important pathogens in childhood IFD.

Successful treatment of chronic granulomatous disease with fludarabine-based reduced-intensity conditioning and unrelated bone marrow transplantation.

Allogeneic hematopoietic stem-cell transplantation (HSCT) for chronic granulomatous disease (CGD) with a reduced-intensity conditioning regimen can be expected to lead to less therapy-related mortality and late-onset impairment, whereas it has also been reported to increase the risk of unsustained mixed donor chimerism and late rejection after transplantation. Herein, we report a 4-year-old boy with CGD who was successfully treated with unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (RIC). Fludarabine-based RIC, 4 Gy of total body irradiation, 120 mg/kg of cyclophosphamide, and 125 mg/m(2) of fludarabine, was adopted for transplantation, followed with 8.9 x 10(8)/kg mononucleated donor cells infused without T-cell depletion. Although hematopoietic engraftment was rapidly obtained by day +17, he developed unstable donor chimerism. After tacrolimus withdrawal, the patient showed grade III acute graft-versus-host disease (GVHD), and subsequently reached full donor chimerism by day +61. Twelve months post-transplant, the patient has remained well with stable and durable engraftment, 100% donor chimerism, and normal superoxide production, without the requirement of donor lymphocyte infusions (DLI).

Congenital immature pure erythroid leukemia with E-cadherin expression.

Congenital pure erythroid leukemia is exceedingly rare and poses a diagnostic challenge. We report an atypical case of congenital pure erythroid leukemia that did not express typical erythroid markers. The patient presented with a high white blood cell count with blastic cells at birth. Although flow cytometric analyses of peripheral blood and bone marrow showed a large CD45-negative cell population, we did not identify any evidence of monoclonality. While the circulating blasts decreased with only supportive care, hepatomegaly with multiple nodules was accompanied by liver failure, disseminated intravascular coagulation, and development of hemophagocytic lymphohistiocytosis. Pathological examination of the liver biopsy specimen revealed a small round cell tumor that was negative for nearly all hematopoietic cell markers, including classical erythroid cell markers, and positive for CD43, CD71, and E-cadherin, an early erythroid marker epithelial calcium-dependent adhesion protein, suggesting that these tumor cells originated from an immature erythroblast. We found high ß-catenin and c-Myc protein expression, which were not previously described in pure erythroid leukemia. Cytosine arabinoside temporarily alleviated clinical symptoms; however, the patient died of progressive disease at 8 months of age. This case indicates that E-cadherin is useful for diagnosing pure erythroid leukemia, even in immature cases.

Reemergence of translocation t(11;19)(q23;p13.1) in the absence of clinically overt leukemia.

We report the case of a 10-year-old female with acute myeloid leukemia (AML) FAB M0 carrying a novel t(11;19)(q23;p13.1) MLL-ELL variant, in which intron 8 of MLL is fused to exon 6 of ELL. Complete remission, judged by morphology and cytogenetic analysis, was achieved after the conventional chemotherapy. Eight months after completion of therapy, the level of WT-1 in peripheral blood and the number of cells with the MLL-ELL fusion transcript resurged. However, the patient remained overtly healthy and the morphology in the bone-marrow smear was innocuous, with no sign of relapse or secondary leukemia. Without any evidence of relapse, the patient has been closely observed without any therapeutic intervention. For approximately 2 years after the completion of therapy, despite clonal proliferation of pre-leukemic cells with an MLL-ELL fusion gene, she has maintained complete remission. In this case, the rare variant form of MLL-ELL fusion that has been identified may be related to diminished leukemogenic capacity, resulting in the persistence of pre-leukemic status; an additional genetic abnormality may thus be necessary for full transformation of pre-leukemic cells.

Early detection of tumor relapse/regrowth by consecutive minimal residual disease monitoring in high-risk neuroblastoma patients.

Neuroblastoma is an aggressive pediatric tumor accounting for ~15% of cancer-associated mortalities in children. Despite the current intensive therapy, >50% of high-risk patients experience tumor relapse or regrowth caused by the activation of minimal residual disease (MRD). Although several MRD detection protocols using various reverse transcription-quantitative polymerase chain reaction (RT-qPCR) markers have been reported to evaluate the therapeutic response and disease status of neuroblastoma patients, their clinical significance remains elusive. The present study reports two high-risk neuroblastoma patients, whose MRD was consecutively monitored using 11 RT-qPCR markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) during their course of treatment. The two patients initially responded to the induction therapy and reached MRD-negative status. The patients' MRD subsequently became positive with no elevation of their urinary homovanillic acid, urinary vanillylmandelic acid and serum neuron-specific enolase levels at 13 or 19 weeks prior to the clinical diagnosis of tumor relapse or regrowth. The present cases highlight the possibility of consecutive MRD monitoring using 11 markers to enable an early detection of tumor relapse or regrowth in high-risk neuroblastoma patients.

Familial Hemophagocytic Lymphohistiocytosis Presenting as Hydrops Fetalis.

Background Familial hemophagocytic lymphohistiocytosis (FLH) is an autosomal recessive disorder of immune regulation that leads to a hyperinflammatory syndrome. Fetal onset FHL is extremely rare and is considered to be the most severe form of FHL. Case We report a preterm case of FHL that presented as hydrops fetalis. The infant was treated with a chemotherapy regimen based on the HLH-2004 protocol from the third day of life. However, he had persistent cytopenia and died on the 18th day of life due to bacteremia. The detection of defective perforin expression in the patient's natural killer cells and mutations in the PRF1 gene resulted in a molecular diagnosis of FHL. Conclusion We suggest that early diagnosis and the development of an appropriate immunosuppressive strategy that can induce and maintain remission until hematopoietic stem cell transplantation can be performed are required to improve the outcomes of fetal onset FHL.

Differential expression of minimal residual disease markers in peripheral blood and bone marrow samples from high-risk neuroblastoma patients.

Neuroblastoma is an aggressive solid tumor that leads to tumor relapse in more than half of high-risk patients. Minimal residual disease (MRD) is primarily responsible for tumor relapses and may be detected in peripheral blood (PB) and bone marrow (BM) samples. To evaluate the disease status and treatment response, a number of MRD detection protocols based on either common or distinct markers for PB and BM samples have been reported. However, the correlation between the expression of MRD markers in PB and BM samples remains elusive in the clinical samples. In the present study, the expression of 11 previously validated MRD markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) was determined in 23 pairs of PB and BM samples collected from seven high-risk neuroblastoma patients at the same time point, and the sample was scored as MRD-positive if one of the MRD markers exceeded the normal range. Although the number of MRD-positive samples was not significantly different between PB and BM samples, the two most sensitive markers for PB samples (CRMP1 and KIF1A) were different from those for BM samples (PHOX2B and DBH). There was no statistically significant correlation between the expression of MRD markers in the PB and BM samples. These results suggest that MRD markers were differentially expressed in PB and BM samples from high-risk neuroblastoma patients.

Absolute lymphocyte count at the end of induction therapy is a prognostic factor in childhood acute lymphoblastic leukemia.

Recent studies have reported that the absolute lymphocyte count (ALC) during induction therapy is predictive of treatment outcome in de novo acute lymphoblastic leukemia (ALL); however, the significance of ALC on outcomes remains controversial. In the present study, we assessed the significance of ALC at day 29 (ALC-29), the end of induction therapy, on outcomes in our Japanese cohort. The outcomes of 141 patients aged ≤18 years with newly diagnosed ALL who were enrolled on the JACLS ALL-02 at our hospitals were analyzed in terms of ALC-29. Patients with ALC-29 ≥750/µL (n = 81) had a superior 5-year EFS (95.2 ± 2.7 vs 84.3 ± 4.8 %, P = 0.016) and OS (100 vs 87.0 ± 4.7 %, P = 0.0062). A multivariate analysis identified ALC-29 ≥750/µL as a significant predictor of improved EFS and OS after controlling for confounding factors. A multiple linear regression model revealed a significant inverse relationship between the percentage of blasts in bone marrow on day 15 and ALC-29 (P = 0.005). These results indicate that ALC is a simple prognostic factor in childhood ALL, and, thus, has the potential to refine current risk algorithms.

Clinical features of 62 allogeneic stem cell transplantations; the evaluation of prognostic factor in a single institution.

A retrospective analysis of the clinical features of 62 patients with various hematological or other diseases who received allogeneic stem cell transplantation (SCT) between April 1990 and July 2002 in the Department of Pediatrics, Kobe University Hospital was conducted to investigate prognostic factors of allo-SCT. Among 62 allo-SCT, 51 (82%) were bone marrow transplantation (BMT), 5 (8%) were peripheral blood stem cell transplantation and 6 (10%) were cord blood transplantation. Disease-free survival rate (DFS) estimated according to the diagnosis group did not show any significant difference. For hematological malignant diseases, DFS estimated according to the disease stage was 66.7% for the patients in the standard stage and 30.0% for the patients in the advanced stage (p=0.0249). Of 47 evaluable patients receiving allo-BMT, DFS of patients receiving the last transfusion of platelets on or before day 21 was significantly higher than that of patients receiving the last transfusion after day 21 (66.7% vs 34.8%, p=0.0111). These results demonstrate that more appropriate indications and points for SCT should be applied to patients in the advanced stage, and that whether the last transfusion of platelet is on or before or after day 21 is an important prognostic factor for allo-BMT because the necessity for platelet transfusion was vividly reflected in the status of the patients.