Pediatric leukemia and maternal occupational exposure to anticancer drugs: the Japan Environment and Children's Study.

ABSTRACT: Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

The immunoreactive signature of monocyte-derived dendritic cells from patients with Down syndrome.

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2~47 years, 12 males) and 22 controls (age 4~40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, p = 0.00731) and oxidative phosphorylation (hsa00190, p = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.

Rituximab with standard LMB chemotherapy in pediatric high-risk mature B-cell non-Hodgkin lymphoma: A report from the JPLSG B-NHL14 trial.

BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

Heterogeneity and mitochondrial vulnerability configurate the divergent immunoreactivity of human induced microglia-like cells.

Microglia play versatile roles in progression of and protection against neuroinflammatory diseases. Little is known, however, about the mechanisms underlying the diverse reactivity of microglia to inflammatory conditions. We investigated how human induced microglia-like (iMG) cells respond to innate immune ligands. Quantitative PCR showed that poly-I:C and lipopolysaccharide (LPS) activated the expression of IL1B and TNF. Immunoreactivity of iMG did not differ between controls (n = 11) and patients with neuroinflammatory diseases (n = 24). Flow cytometry revealed that CD14high cells expressed interleukin (IL) -1ß after LPS treatment. Immunoblotting showed that poly-I:C and LPS differentially activated inflammatory pathways but commonly induced mitochondrial instability and the expression of pyruvate kinase isoform M2 (PKM2). Furthermore, a potent stimulator of PKM2 (DASA-58) alleviated IL-1ß production after LPS treatment. These data indicate that heterogeneous cell populations and mitochondrial stability underlie the divergent immunoreactivity of human iMG in environments.

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial.

The prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Postchemotherapy immune status in infants with acute lymphoblastic leukemia: A report from the JPLSG MLL-10 trial.

The MLL-10 trial (UMIN000004801) modified a Children's Oncology Group (COG) AALL0631 therapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL). In 2016, one registered case developed secondary immunodeficiency during maintenance therapy and eventually died due to cytomegalovirus infection. Around the same time, fatal secondary immunodeficiencies were reported in five infants with ALL in North America who had received COG-based chemotherapy between 1996 and 2015. Given these cases, we decided to conduct a retrospective study on the postchemotherapy immune status of infants with ALL. A questionnaire collected data on posttreatment immune function, frequency of infections, and supportive care for the 34 infants in the MLL-10 trial. Patients receiving allogeneic hematopoietic stem cell transplantation in first remission were excluded. Responses to the survey were obtained in 28 cases (85%). Most patients were immunocompetent after the completion of chemotherapy (median follow-up duration from the day of chemotherapy completion was 431 days), except for the aforementioned case. There were seven patients with nonsevere viral infection, all of whom recovered. In conclusion, severe chemotherapy-induced immunodeficiency in infants with ALL appears to be rare, but prospective data collection of immune function is necessary to clarify this finding.

Discontinuation of tyrosine kinase inhibitors in pediatric chronic myeloid leukemia.

BACKGROUND: The feasibility of tyrosine kinase inhibitor (TKI) discontinuation in pediatric chronic myeloid leukemia (CML) remains to be fully elucidated. PROCEDURES: TKI was prospectively discontinued in patients who were diagnosed with CML at <20 years of age, treated with TKI for ≥3 years, and sustained molecular response 4.0 (MR4.0) for ≥2 years. Molecular relapse was defined as a single loss of major molecular response (MMR) (BCR-ABL1IS >0.1%). Relapsed patients resumed the same TKI therapy administered before discontinuation. RESULTS: Twenty-two patients with chronic-phase CML were enrolled, and the median ages at diagnosis and at TKI discontinuation were 9 (range: 1-14) years and 16 (5-26) years, respectively. The median follow-up time after TKI discontinuation was 37 months (range: 24-41 months). The median duration of TKI treatment before discontinuation was 100 (42-178) months, and that of MR4.0 was 53.5 (25-148) months. The treatment-free remission (TFR) rate at 12 months was 50.0% (90% confidence interval: 31.7%-65.8%). Eleven patients experienced loss of MMR within 4 months after TKI discontinuation and resumed TKI as originally prescribed. No progression was observed, and all 11 patients regained MR4.0 after TKI resumption. No patient had a withdrawal syndrome. The quality-of-life analysis suggested that successful TFR may improve academic performance in some patients. In patients who discontinued TKI therapy before puberty, the possibility of improvement in growth velocity upon TKI discontinuation was observed. CONCLUSIONS: TKI could be discontinued safely in patients with pediatric CML showing a sustained deep MR.

The utility of core-needle tumor biopsy for pediatric patients.

BACKGROUND: Core-needle biopsy (CNB) is used less frequently for the diagnosis of tumors in pediatric patients. In this report, the utility and safety of CNB for pediatric patients are described. METHODS: The medical records of patients who underwent CNB at the Department of Pediatric Surgery, Kyushu University Hospital from April 2020 to November 2021 were retrospectively reviewed. A 14 G or 16 G BARDMISSION Disposable Needle Instrument was used. For the diagnosis of neuroblastoma, a 14 G needle was selected; for the diagnosis of other tumors a 16 G needle was selected. RESULTS: During the above period 17 CNBs were performed in 17 patients, and the median patient age was 8 years (range, 15 days-19 years). The pathological diagnoses of the tumors were as follows: neuroblastoma, n = 6; lymphoma, n = 3; hepatoblastoma, n = 2; and others, n = 6. The quantity and quality of all tumor samples obtained by CNB was sufficient to make a diagnosis. The postoperative course after CNB was uneventful in most cases, with the exception of one case of hepatoblastoma (pseudoaneurysm). CONCLUSIONS: Core-needle biopsy is useful for pediatric patients. Sufficient tumor specimens were able to be obtained in all cases, irrespective of the type of tumor, and an accurate diagnosis could be made.

[Treatment strategy for pediatric Hodgkin lymphoma].

Pediatric Hodgkin lymphoma (HL) is a malignant disease that arises from lymphoid reticulum cells, which can metastasize to the spleen, liver, and bone marrow, including the lymph nodes. Classic HL is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg (HRS) cell proliferation. Its symptoms include fever, night sweats, weight loss, itching, splenomegaly, and hepatomegaly, along with painless lymphadenopathy. Although HL has long achieved a high cure rate, late complications such as cardiac complications, infertility, and secondary cancers still pose a threat. The current treatment standard includes a combination of multiagent chemotherapy and low-dose radiation therapy, and attempts have been made to establish a regimen that omits radiation therapy in patients who respond well to initial therapy. The introduction of new molecular-targeted agents is expected to result in further treatment reduction.

Infantile neuroblastoma and maternal occupational exposure to medical agents.

BACKGROUND: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study aimed to examine whether such occupational exposure increased the risk of childhood cancer in offspring. METHODS: We used the dataset of the Japan Environment and Children's Study, a nationwide birth cohort involving over 100,000 mother-child pairs. Information was obtained via successive questionnaires that were completed until the child turned 1 year of age. The parents were asked whether they occupationally handled medical agents during pregnancy. RESULTS: A total of 26 infants developed neoplasms: neuroblastoma, leukemia, and brain tumor. The incidence of neuroblastoma was significantly higher in infants whose mothers were exposed to radiation (3/2142: 140.1 per 100,000 population) than in those who were not (12/90,384: 13.3 per 100,000 population). Multivariable regression analyses revealed a close association between maternal irradiation and the development of neuroblastoma (adjusted incident rate ratio: 10.68 [95% confidence interval: 2.98‒38.27]). CONCLUSIONS: The present study demonstrated, for the first time, a potential association between maternal occupational exposure and the occurrence of neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results. IMPACT: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study examined the association between such occupational exposure and offspring's cancers that developed until the age of 1 year. Maternal exposure to ionizing radiation was associated with infantile neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results.

Phase III study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients.

BACKGROUND: Palonosetron has demonstrated non-inferiority to ondansetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients in the United States and Europe. We conducted a single-arm registration study to evaluate the efficacy, safety and pharmacokinetics of palonosetron in pediatric patients in Japan. METHODS: Key inclusion criteria were age of 28 days to 18 years and malignant disease for which initial highly emetogenic chemotherapy or moderately emetogenic chemotherapy was planned. Patients received palonosetron at 20 µg/kg over at least 30 s intravenously before the start of highly emetogenic chemotherapy or moderately emetogenic chemotherapy and received dexamethasone on Days 1-3. The primary endpoint was the proportion of patients achieving a complete response in the overall phase (0-120 h) in Course 1, and its threshold was set at 30%. RESULTS: From December 2016 to June 2019, 60 patients were enrolled, and 58 received at least one dose of palonosetron. The proportion of patients achieving a complete response during the overall phase was 58.6% (95% confidence interval, 44.9%-71.4%), showing the primary endpoint was met (P < 0.0001). Treatment-related adverse events occurred in two patients (3.4%). Regarding the pharmacokinetics of palonosetron, neither the plasma concentration immediately after administration nor the area under the plasma concentration-time curve from time 0 to infinity differed significantly among the age groups. CONCLUSION: We demonstrated the efficacy of palonosetron in pediatric patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy and confirmed the appropriateness of the 20 µg/kg dose, regardless of age, considering the safety and pharmacokinetic profiles. TRIAL REGISTRATION: JapicCTI-163305, registered 6 June 2016.

[Environmental factors for the development of hematopoietic neoplasms in children].

Parental age at birth has been investigated in patients diagnosed with pediatric cancer. The Japan Children's Cancer Registry1985-2007 recruited 5,510 patients with leukemia and 8,782 with other cancers. The proportion of patients born to mother and father aged >40 years showed a higher trend in leukemia than that in other cancers (odds ratio [OR] 1.41, p=0.057), especially in <12-month-old infants born to mother aged >40 years (OR 2.55, p=0.031). We then divided 27,335 patients diagnosed in 1969-2006 into every 8-year birth cohorts to compare proportions of mothers with prenatal medical irradiation. The OR of leukemia was higher than that of other cancers in 1969-1976 (1.25) or 1977-1984 (1.39), which reached statistical significance. We have also studied caregiver's exposure to anticancer drugs. In 15 pediatric patients with cancer who received cyclophosphamide (CPM), the concentration was measured using mothers and medical staff's urine. Five of 7 infants' and 2 of 8 adolescent's mothers showed increased urine CPM levels. CPM was not detected in any medical staff's samples. Maternal exposure to anticancer drugs should also be considered. Efforts of reducing the genotoxicity in both infants and mothers are crucial for pediatric cancer prevention.

Long-term outcomes of children with extracutaneous juvenile xanthogranulomas in Japan.

BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. METHODS: Data of patients aged < 18 years who were diagnosed with JXG between 2001 and 2010 were retrospectively collected through a nationwide survey. RESULTS: Twenty patients (11 male and nine female) had extracutaneous lesions. The median observation time was 10 years (range, 0-17). Six patients presented with symptoms at birth. The median age at diagnosis was 8.5 months (range, 0 month-13 years). Fifteen patients underwent treatment for JXG, including chemotherapy (n = 11), and five did not receive treatment. All patients except one survived; 17 were disease-free and two survived with disease. One newborn-onset patient with liver, spleen, and bone marrow involvement died of the disease. Permanent sequelae included central diabetes insipidus, growth hormone deficiency, and panhypopituitarism detected at diagnosis in three, one, and two patients, respectively. Four patients had visual impairment (optic nerve compression and intraocular invasion in two each), three had epilepsy, one had mental retardation, and one had a skin scar. Eight patients who had intracranial lesions were older at diagnosis, and had a higher frequency of disease-related comorbidities and permanent sequelae than those without intracranial involvement. CONCLUSIONS: Patients with extracutaneous JXG had good outcomes, although those with intracranial lesions had serious permanent sequelae. Effective and safe treatment regimens for patients with intracranial JXG need to be developed.

Multimodal treatment including standard chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for the Ewing sarcoma family of tumors in Japan: Results of the Japan Ewing Sarcoma Study 04.

BACKGROUND: The survival rate in patients with Ewing sarcoma family of tumors (ESFT) in Japan was reported to be < 50% in the 1990s. The Japan Ewing Sarcoma Study Group was established to improve the prognosis of ESFT in Japan. The aim of this phase II trial was to determine the efficacy and safety of multimodal treatment for nonmetastatic ESFT. PROCEDURE: Patients with ESFT aged < 30 years were eligible for participation. The chemotherapy regimen consisted of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) repeating every 21 days for 52 weeks. Local treatment included surgery and/or radiation therapy (0-55.8 Gy) based on the margin of resection and histologic response. The primary endpoint was progression-free survival (PFS) at three years. The study was designed to test whether the lower limit of the 90% confidence interval for PFS would exceed the threshold of 60%. The planned sample size was 53 patients, allowing for 10% of patients being ineligible. RESULTS: Of the 53 patients screened for entry, seven were deemed ineligible. Forty-six patients were considered as the per-protocol set and were used for the efficacy analysis. Three-year PFS was 71.7% (0.59-0.81). Estimated five-year PFS and overall survival were both 69.6%. Although no previously unknown adverse event was reported, three patients developed secondary malignancies (acute lymphoblastic leukemia, myelodysplastic syndrome, and osteosarcoma, one patient each). CONCLUSIONS: Multimodal treatment with standard VDC-IE chemotherapy improved the prognosis for patients with ESFT in Japan, although statistical confirmation of efficacy compared to historical control was not achieved.

The effect of graft-versus-host disease on outcomes after allogeneic stem cell transplantation for refractory lymphoblastic lymphoma in children and young adults.

BACKGROUND: Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation-related toxicity. Acute and chronic graft-versus-host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft-versus-lymphoma effect. METHODS: To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan. RESULTS: The five-year overall survival (OS) and event-free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2-56.9) and 47.8% (95% CI, 40.8-54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five-year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five-year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42-0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five-year OS: 65.6%). CONCLUSION: Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.

Hyperferritinemia and acute kidney injury in pediatric patients receiving allogeneic hematopoietic cell transplantation.

BACKGROUND: Acute kidney injury (AKI) often occurs in pediatric patients who received allogeneic hematopoietic cell transplantation (HCT). We evaluated the risk and effect of HCT-related AKI in pediatric patients. METHODS: We retrospectively studied the survival and renal outcome of 69 children 100 days and 1-year posttransplant in our institution in 2004-2016. Stage-3 AKI developed in 34 patients (49%) until 100 days posttransplant. RESULTS: The 100-day overall survival (OS) rates of patients with stage-3 AKI were lower than those without it (76.5% vs. 94.3%, P = 0.035). The 1-year OS rates did not differ markedly between 21 post-100-day survivors with stage-3 AKI and 29 without it (80.8% vs. 87.9%, P = 0.444). The causes of 19 deaths included the relapse of underlying disease or graft failure (n = 11), treatment-related events (4), and second HCT-related events (4). Underlying disease of malignancy (crude hazard ratio (HR) 5.7; 95% confidence interval (CI), 2.20 to 14.96), > 1000 ng/mL ferritinemia (crude HR 4.29; 95% CI, 2.11 to 8.71), stem cell source of peripheral (crude HR 2.96; 95% CI, 1.22 to 7.20) or cord blood (crude HR 2.29; 95% CI, 1.03 to 5.06), and myeloablative regimen (crude HR 2.56; 95% CI, 1.24 to 5.26), were identified as risk factors for stage-3 AKI until 100 days posttransplant. Hyperferritinemia alone was significant (adjusted HR 5.52; 95% CI, 2.21 to 13.76) on multivariable analyses. CONCLUSIONS: Hyperferritinemia was associated with stage-3 AKI and early mortality posttransplant. Pretransplant iron control may protect the kidney of pediatric HCT survivors.

Autologous Stem Cell Transplantation for Children With Renal Tumors, and Adults With Wilms Tumor: Retrospective Analysis of the Japanese Transplant Registry Unified Management Program.

BACKGROUND: Almost all pediatric patients with renal tumors are diagnosed with nephroblastoma (Wilms tumor), clear cell sarcoma, or malignant rhabdoid tumor. The choice of treatment is important for relapsed and refractory patients with nephroblastoma. Furthermore, clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) have a poor prognosis compared with nephroblastoma. Thus, stem cell transplantation (SCT) is sometimes selected to treat these tumors. PATIENTS AND METHODS: The authors targeted a total of 84 patients with nephroblastoma, CCSK, and MRTK who underwent a first autologous SCT between 1992 and 2014, and were registered in the Japanese Transplant Registry Unified Management Program system. The authors retrospectively analyzed the SCT data for survival rate. RESULTS: Five-year overall survival rates for nephroblastoma, CCSK, and MRTK were 72.4%±6.3%, 46.8%±13.8%, and 36.4%±14.5%, respectively. The event-free survival rates at 5 years were 64.9%±6.7%, 35.7%±12.8%, and 27.3%±13.4%, respectively. The relapse rates at 5 years were 25.3%±11.4%, 46.2%±28.4%, and 60.0%±43.1%, respectively. CONCLUSION: Although the survival rate for nephroblastoma was relatively high, those of CCSK and MRTK were poor.

Acute isolated Aspergillus appendicitis in pediatric leukemia.

Aspergillus is a widespread fungus in the environment, usually invades through the respiratory tract. Invasive aspergillosis is a fatal disseminated infection in immunocompromised hosts. Appendicitis occurs scarcely in patients with leukemia. We report a case of Aspergillus appendicitis that underwent an urgent appendectomy. An 11-year-old boy received the diagnosis of acute myeloid leukemia, because of the bone pain and results of the bone marrow study. He obtained a complete remission after cancer chemotherapy and received peripheral blood stem cell transplantation from a histocompatible sibling. Leukemia relapsed 5 months post-transplant. Induction therapy with etoposide, cytarabine and mitoxantrone was started on Candida prophylaxis. Fifteen days after the end of chemotherapy, he presented with febrile neutropenia and abdominal pain, that did not respond to broad-spectrum antibiotics. Serum levels of C-reactive protein, ß-D-glucan and procalcitonin were unremarkable. Computed tomography scan revealed a swollen appendix and the adjacent tissue inflammation. An urgent appendectomy led to a tentative diagnosis of Aspergillus appendicitis based on the histopathological findings of many fungal hyphal forms. Panfungal polymerase chain reaction using DNA extracted from the lesion determined the pathogen of Aspergillus niger. There was no evidence of invasive aspergillosis. During the prolonged anti-fungal therapy, he achieved a remission of leukemia and underwent the second hematopoietic cell transplantation. To our knowledge, Aspergillus appendicitis was reported to occur in 5 leukemia patients. Four of them survived after appendectomy and one died from intestinal perforation. Early surgical intervention is mandatory for a cure of Aspergillus appendicitis in neutropenic patients on Candida prophylaxis.

Survival and ocular preservation in a long-term cohort of Japanese patients with retinoblastoma.

BACKGROUND: Retinoblastoma is an ocular tumor in infants with cancer predisposition. Treatment of the rare tumor needs to be optimized for ocular preserved survival without second primary malignancy (SPM). METHODS: We studied the outcomes of all patients with retinoblastoma at a tertiary center in 1984-2016, when preservation method changed from radiotherapy (1984-2001) to systemic chemotherapy (2002-2016). RESULTS: One-hundred sixteen infants developed unilateral- (n = 77), bilateral- (n = 38), or trilateral-onset (n = 1) tumor. Ten (8.6%) had a positive family history, despite a few studies on RB1 gene. Contralateral disease occurred in one unilateral-onset case. One-hundred eight of 155 eyes (70%) were enucleated. Nine binocular survivors were from 5 bilateral- and 4 unilateral-onset cases. Two survivors received bilateral enucleation. Six deaths occurred; brain involvement (including 3 trilateral diseases) in 4 bilateral-onset, systemic invasion in a unilateral-onset, and SPM (osteosarcoma) in a bilateral-onset case(s). Two others survived SPM of osteosarcoma or lymphoma. The 10-year overall survival (OS: 98.5% vs. 91.3%, p = 0.068) and binocular survivors (13.2% vs. 5.2%, p = 0.154) between bilateral- and unilateral-onsets did not differ statistically. The 10-year OS and cancer (retinoblastoma/SPM)-free survival (CFS) rates of all patients were 94.9 and 88.5%, respectively. The proportion of preserved eyes did not differ between radiotherapy and chemotherapy eras. The CFS rate of bilateral-onset cases in systemic chemotherapy era was higher than that in radiotherapy era (p = 0.042). The CFS rates of bilateral-onset patients with neoadjuvant chemotherapy (upfront systemic therapy for preservation) was higher than those without it (p = 0.030). CONCLUSIONS: Systemic chemotherapy and local therapy raised OS and binocular survival rates of bilateral-onset patients similarly to those of unilateral-onset patients. All but one death was associated with a probable germline defect of the RB1 gene. Neoadjuvant stratified chemotherapy may support the long-term binocular life with minimized risk of SPM.