A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Minimal Residual Disease Detected by the 7NB-mRNAs ddPCR Assay Is Associated with Disease Progression in High-Risk Neuroblastoma Patients: A Prospective Multicenter Observational Study in Japan.

High-risk neuroblastoma (HR-NB) patients remain far from obtaining optimal outcomes, with more than 50% relapse/regrowth rate despite current intensive multimodal therapy. This originated from the activation/proliferation of chemoresistant minimal residual disease (MRD). MRD with a significant prognostic was reported by several quantitative PCR (qPCR) or droplet digital PCR (ddPCR) assays quantitating different sets of NB-associated mRNAs (NB-mRNAs). The 7NB-mRNAs ddPCR assay quantitating CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs was reported to outperform other qPCR assays by a retrospective in-house observational study. In the present study, the Japan Children's Cancer Group (JCCG) Neuroblastoma Committee conducted a prospective multicenter observational study aimed at evaluating a prognostic value of MRD in bone marrow (BM-MRD) and peripheral blood (PB-MRD) detected by 7NB-mRNAs ddPCR assay. Between August 2018 and August 2022, 7 HR-NB patients who registered for JCCG clinical trials (JN-H-11 and JN-H-15) were enrolled. A total of 19 BM and 19 PB samples were collected, and 4/15 BM and 4/15 PB samples were classified as progressive disease (PD)/non-PD samples. BM-MRD and PB-MRD estimated area under curve (AUC) of 0.767 and 0.800 with a significant accuracy (AUC > 0.7). The present study validated a prognostic value of BM-MRD obtained by a previous study (AUC 0.723) and revealed the significant accuracy of PB-MRD as well as BM-MRD.

The First Case of a Child Infected with SARS-CoV-2 Omicron Variant in Japan, December 2021.

We report the first pediatric patient infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Japan. The patient was a one-year-old boy who resided in Japan. He went abroad with his parents from November 12, 2021 to November 28, 2021 and had no known contact with coronavirus disease (COVID-19) patients there. Upon arrival at the Narita International Airport on November 28, 2021, his father tested positive for SARS-CoV-2 via a quantitative antigen test. Because the boy and his mother tested negative for SARS-CoV-2, they quarantined together at a hotel separately from his father. On December 4, 2021, the boy tested positive by reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2, without symptoms, and was hospitalized with his mother; he and his father were both found to be infected with the SARS-CoV-2 Omicron variant. The boy was not vaccinated against COVID-19. RT-PCR results were negative starting on December 20, 2021. The incubation period and required period for negative conversion of SARS-CoV-2 RNA of the Omicron variant case were similar to those of the cases of conventional strains. We should carefully consider the potential of the SARS-CoV-2 Omicron variant to spread widely among unvaccinated children.

Drug-induced crystalluria attributable to tosufloxacin in children.

BACKGROUND: Drug-induced crystalluria is reportedly caused by a large number of drugs. Tosufloxacin (TFLX), a second-generation fluoroquinolone antibiotic, is reported to cause kidney injury and crystalluria. We retrospectively analyzed patients with crystalluria caused by TFLX to clarify the clinical course of TFLX-induced crystalluria in children. METHODS: This study was designed as a retrospective case series using the database of the National Center for Global Medicine covering the period from January 1, 2020 to March 31, 2021. We enrolled pediatric patients aged 15 years or younger with crystalluria attributable to TFLX treated in our pediatric department and collected clinical data. RESULTS: Thirteen patients were diagnosed with crystalluria attributable to TFLX. The median age of the patients at diagnosis was 4.0 years (range, 0.8-15 years; interquartile range = 1.2-8.8 years), and five patients (38%) were male. Six patients (46%) had gastrointestinal symptoms such as vomiting and abdominal pain, and 12 patients (92%) had decreased oral intake. The median time to diagnosis after TFLX administration was 4 days (range, 2-7 days; interquartile range = 3-6 days). All patients received TFLX at the appropriate dose. Two patients (17%) were diagnosed with acute kidney injury, and both had gastrointestinal symptoms such as vomiting and abdominal pain. CONCLUSIONS: Crystalluria induced by TFLX occurred despite administration of the appropriate dose of TFLX. Physicians should recognize crystalluria and renal injury attributable to TFLX. It may be possible to prevent renal injury by discontinuing drug therapy.

Adapting pediatric health care responses to the COVID-19 pandemic in Japan: A clinical perspective.

The COVID-19 pandemic required our pediatric health care staff to adjust to many irregularities and solve serious issues in our routine clinical practice. In outpatient clinics, many children exhibited common cold symptoms that mimic COVID-19, thus we initially screened patients via an interview form, then later via SARS-CoV-2 antigen test. Cluster infections were entirely avoided by following systematic, everyday precautions. Patientsquality of life has been difficult to maintain during the pandemic, due to social and staffing restrictions. Other unexpected repercussions - such as an unexpected lack of seasonal virus infections, then a respiratory syncytial (RS) virus outbreak - required agile management of hospital resources. While we must continue to adapt our treatment programs in response to the evolving COVID-19 crisis, it remains essential to support the well-being of children through regular health check-ups, mental health support, educational opportunities, proper socialization, and close communication with parents and families.

Successful Treatment with Antibiotics Alone for Infant Rib Osteomyelitis.

Pediatric rib osteomyelitis is a rare disease occurring predominantly in the neonatal period and early childhood and accounting for about 1% of all pediatric osteomyelitis. Compared to osteomyelitis in other parts of the body, pediatric rib osteomyelitis shows few localized findings (such as redness and swelling) and often an indolent lesion as well either of which may delay diagnosis and thus make treatment more difficult. A previously healthy one-year-old girl came to our department with a chief complaint of fever lasting for three days. She was admitted to our department to investigate her fever. At the time of admission, radiographs showed decreased permeability in the left lung field; so, we started antimicrobial therapy on the assumption of pneumonia. On the second day of admission, methicillin-susceptible Staphylococcus aureus was detected in the blood culture. A further, more detailed physical examination revealed some slight left anterior chest swelling. We performed a contrast-enhanced CT scan and an MRI and diagnosed her with rib osteomyelitis complicated with a chest wall abscess. She was given intravenous cefazolin for two weeks, switched to oral cephalexin for four weeks, and then recovered completely. She was treated without surgical intervention, having showed a good response to antimicrobial therapy. Osteomyelitis of the ribs in children is reported to be more common in the lower ribs and to occur more frequently in infants. In many cases, the earliest symptoms are nonspecific, so careful examination to detect any subtle abnormalities-such as swelling or mass-is of key importance for early diagnosis in infants. Regarding treatment, most cases of hematogenous osteomyelitis resolve with antimicrobial therapy alone-although surgical intervention may be required in cases of poor response to antimicrobial therapy. Therefore, early diagnosis of rib osteomyelitis through careful physical examination may reduce the chances of requiring surgical intervention.

Outcome of children with relapsed high-risk neuroblastoma in Japan and analysis of the role of allogeneic hematopoietic stem cell transplantation.

BACKGROUND: In Japan, allogeneic hematopoietic stem cell transplantation is widely performed for recurrent neuroblastomas. This retrospective study aimed to investigate the prognosis of recurrent neuroblastoma in Japan and explore the effectiveness of allogeneic hematopoietic stem cell transplantation. METHODS: Clinical characteristics and data on the treatment of patients with high-risk neuroblastoma who experienced first progression between 2003 and 2010 after attaining complete remission or partial remission were collected from hospitals participating in the Japanese Neuroblastoma Research Group. RESULTS: Data from 61 patients who fulfilled these criteria were collected. The median interval from disease onset to first progression was 19 months (range, 7-65 months), whereas the median observation time of the surviving patients was 18 months (range, 1-69 months). All patients were treated with chemotherapy, where 22 and 3 patients received allogeneic and autologous hematopoietic stem cell transplantation, respectively. Seven patients were alive in second complete remission, and 39 died, including two in complete remission. The 3-year progression-free survival and overall survival rates were 15.3% (SE: 6.1%) and 16.9% (SE: 6.5%), respectively. For patients with allogeneic hematopoietic stem cell transplantation, the 3-year progression-free survival and overall survival were 28.3% (standard error, 12.0%) and 24.3% (standard error, 11.5%), respectively, and for patients without allogeneic hematopoietic stem cell transplantation, the 3-year progression-free survival and overall survival were 6.0% (standard error 5.5%) and 12.0% (standard error 7.6%), respectively. The duration of initial remission (≥ 18 months) and implementation of allogeneic hematopoietic stem cell transplantation were independently predictive of progression-free survival (P = 0.002 and P = 0.017), whereas for overall survival, only allogeneic hematopoietic stem cell transplantation was predictive (P = 0.012). CONCLUSION: Although allogeneic hematopoietic stem cell transplantation contributed to some improvement in prognosis, it was insufficient.

Infantile Stage M Neuroblastoma With 11q Deletion, Mimicking Stage MS.

A 4-month-old boy with abdominal distension was diagnosed with adrenal neuroblastoma with numerous metastases to the liver and nodules in the skin and muscles. Marked hepatomegaly spontaneously regressed with decreasing tumor marker levels, and the final diagnosis was stage M based on radiologic findings confirming metastasis to the pancreas. The neuroblastoma did not have the MYCN amplification but had an 11q aberration. Chemotherapy was initiated at age 6 months with a successful response. Our case reflects the heterogenous clinical behavior of neuroblastoma and highlights the challenging issue of the difference between stage M and stage MS neuroblastoma in infants.

[Hematological neoplasia associated with primary mediastinal germ-cell tumor treated with hematopoietic stem cell transplantation].

The occurrence of a primary mediastinal germ cell tumor and hematological neoplasia provides a poor prognosis that is known to be fatal at a median of 6 months after onset. We report the case of a 15-year-old male who was treated with chemotherapy and hematopoietic cell transplantation based on a report of a surviving case. At diagnosis, the patient had an unresectable mediastinal tumor with elevated alpha-fetoprotein and human chorionic gonadotropin levels and acute megakaryoblastic leukemia. We prioritized treatment with chemotherapy for the tumor owing to the oncological emergency. We then performed leukemia induction therapy and achieved complete remission. Although we used CDDP in combination with intensive therapy, the mediastinal tumor grew too large for it to be safely resected. We transplanted bone marrow from the patient's human leukocyte antigen-haploidentical sibling upon conditioning with busulfan-melphalan. After 44 days, the leukemia recurred in the patient's central nervous system. This was followed by various post-transplant complications, and the patient died of organ failure that was associated with infectious diseases. At necropsy, a poorly engrafted bone marrow was observed. The mediastinal tumor was primarily necrotic, although some immature teratoma components were observed. No leukemic precursor cells were detected. Residual mediastinal tumors may be associated with the recurrence of leukemias. We seek a treatment strategy that enables early tumor resection and high-dose chemotherapy. Further case studies are warranted along with the development of effective treatment methods.

Case Report: Changes in Cytokine Kinetics During the Course of Disease in a Japanese Patient With Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that is reportedly linked to coronavirus disease 2019. Affected patients present with gastrointestinal symptoms and cardiovascular dysfunction, in addition to Kawasaki disease-like features, suggesting the potential for overlapping disease mechanisms. Kawasaki disease has been reported among individuals of East Asian ethnicities, whereas there is minimal clinical literature regarding the occurrence of MIS-C among individuals of Asian ethnicities. A few reports thus far have described changes in cytokine kinetics during the course of disease in patients with MIS-C. We followed the temporal cytokine kinetics in a 9-year-old Japanese girl who exhibited a classical trajectory of MIS-C. The patient exhibited right cervical swelling and pain, abdominal pain, vomiting, and lip reddening, which developed 31 days after she was diagnosed with severe acute respiratory syndrome coronavirus-2 infection. The patient was diagnosed with Kawasaki disease on her fifth day of illness; because she fulfilled the criteria for MIS-C, she was also diagnosed with this disease on her fifth day of illness. Her fever rapidly resolved upon administration of intravenous immunoglobulin, aspirin, and prednisolone. On the patient's sixth day of illness, she developed acute myocarditis, which was treated with two diuretics and one vasodilator; the myocarditis ameliorated within a few days. Analyses of temporal kinetics for 71 serum cytokines revealed several patterns of cytokine changes that were consistent with the patient's clinical course of disease. Importantly, there was a clear distinction between cytokines that did and did not decrease rapidly following post-treatment fever resolution. These findings may be useful for the assessment of disease status and selection of therapy in patients with similar symptoms; they may also provide insights for basic and clinical research regarding MIS-C.

Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1-Related Microglial Activation in Neonatal Hypoxic-Ischemic Encephalopathy: Morphologic Consideration.

Neonatal hypoxic-ischemic encephalopathy (nHIE) is a major neonatal brain injury. Despite therapeutic hypothermia, mortality and sequelae remain severe. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with the pathophysiology of nHIE. In this study, morphologic change and microglial activation under the nHIE condition and LOX-1 treatment were investigated. The microglial activity and proliferation were assessed with a novel morphologic method, immunostaining, and quantitative PCR in the rat brains of both nHIE model and anti-LOX-1 treatment. Circumference ratio, the long diameter ratio, the cell area ratio, and the roundness of microglia were calculated. The correlation of the morphologic metrics and microglial activation in nHIE model and anti-LOX-1 treated brains was evaluated. LOX-1 was expressed in activated ameboid and round microglia in the nHIE model rat brain. In the evaluation of microglial activation, the novel morphologic metrics correlated with all scales of the nHIE-damaged and treated brains. While the circumference and long diameter ratios had a positive correlation, the cell area ratio and roundness had a negative correlation. Anti-LOX-1 treatment attenuated morphologic microglial activation and proliferation, and suppressed the subsequent production of inflammatory mediators by microglia. In human nHIE, round microglia and endothelial cells expressed LOX-1. The results indicate that LOX-1 regulates microglial activation in nHIE and anti-LOX-1 treatment attenuates brain injury by suppressing microglial activation.

Retrospective Analysis of INRG Clinical and Genomic Factors for 605 Neuroblastomas in Japan: A Report from the Japan Children's Cancer Group Neuroblastoma Committee (JCCG-JNBSG).

Neuroblastomas (NBs) exhibit broad and divergent clinical behaviors and tumor risk classification at diagnosis is crucial for the selection of an appropriate therapeutic strategy for each patient. The present study aimed to validate the clinical relevance of International Neuroblastoma Risk Group (INRG) prognostic and genomic markers in a Japanese NB cohort using a retrospective analysis. Follow-up data based on 30 common INRG queries in 605 NB cases diagnosed in Japan between 1990 and 2014 were collected and the genome signature of each tumor sample was integrated. As previously indicated, age, tumor stage, MYCN, DNA ploidy, the adrenals as the primary tumor site, serum ferritin and lactate dehydrogenase (LDH) levels, segmental chromosome aberrations, and the number of chromosome breakpoints (BP) correlated with lower survival rates, while the thorax as the primary tumor site and numerical chromosome aberrations correlated with a favorable prognosis. In the patient group with stage 4, MYCN non-amplified tumors (n = 225), one of the challenging subsets for risk stratification, age ≥ 18 months, LDH ≥ 1400 U/L, and BP ≥ 7 correlated with lower overall and event-free survival rates (p < 0.05). The genome subgroup GG-P2s (partial chromosome gain/loss type with 1p/11q losses and 17q gain, n = 30) was strongly associated with a lower overall survival rate (5-year survival rate: 34%, p < 0.05). Therefore, the combination of the tumor genomic pattern (GG-P2s and BP ≥ 7) with age at diagnosis and LDH will be a promising predictor for MYCN-non-amplified high-risk NBs in patient subsets, in accordance with previous findings from the INRG project.

Sulfadiazine Hypersensitivity and Desensitization in Children With Congenital Toxoplasmosis: A Report on Two Cases.

Combination therapy for toxoplasmosis consists of sulfadiazine, pyrimethamine and leucovorin. Although sulfadiazine can cause hypersensitivity reactions, such as fever, rash and liver dysfunction, there is no consensus on an effective therapy for congenital toxoplasmosis (CTox) without sulfadiazine. We attempted desensitization to sulfadiazine in 2 patients with CTox and sulfadiazine hypersensitivity. Desensitization was achieved for 1 patient.

SARS-CoV-2 infection among returnees on charter flights to Japan from Hubei, China: a report from National Center for Global Health and Medicine.

Due to the significant spread of a new type of coronavirus (SARS-CoV-2) infection (COVID-19) in China, the Chinese government blockaded several cities in Hubei Province. Japanese citizens lost a means of transportation to return back to Japan. The National Center for Global Health and Medicine (NCGM) helped the operation of charter flights for evacuation of Japanese residents from Hubei Province, and this article outlines our experiences. A total of five charter flights were dispatched, and the majority of returnees (793/829 [95.7%]) were handled at NCGM. A large number of personnel from various departments participated in this operation; 107 physicians, 115 nurses, 110 clerical staff, and 45 laboratory technicians in total. Several medical translators were also involved. In this operation, we conducted airborne precautions in addition to contact precautions. Eye shields were also used. The doctors collecting the pharyngeal swab used a coverall to minimize the risk of body surface contamination from secretions and droplets. Enhanced hand hygiene using alcohol hand sanitizer was performed. Forty-eight persons were ultimately hospitalized after the triage at NCGM operation, which was more than the number of persons triaged at the airport (n = 34). Of those hospitalized after NCGM triage, 8.3% (4/48 patients) ultimately tested positive for SARS-CoV-2, significantly higher than the positive rate among subjects not triaged (4/48 [8.3%] vs. 9/745 [1.2%]: p = 0.0057). NCGM participated in a large-scale operation to evacuate Japanese nationals from the COVID-19 epidemic area. We were able to establish a scheme through this experience that can be used in the future.

Correction to: Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG).

In the October 2018 issue of International Journal of Clinical Oncology.

A breathing movement sensor for chest radiography during inspiration in children aged less than 3 years: a prospective randomized controlled study.

Chest radiographs should be obtained at the peak of inspiration so that radiological findings can be precisely interpreted. However, this is not easily achieved, particularly in young children who do not follow the instruction to hold their breath. We developed a sensor that detects the breathing movements and conducted a randomized controlled study to determine whether the sensor would increase the proportion of chest radiographs obtained in the inspiration phase. We recruited 124 infants and children aged less than 3 years, who visited the pediatric department of a general hospital in Tokyo, Japan, and allocated them into one of two groups: with-sensor and without-sensor groups. Overall, 81% of all images were obtained during inspiration. The proportion of chest radiographs taken during inspiration was not statistically different between the two groups (81% vs. 82%). In the with-sensor group, radiologic technologists were able to obtain chest radiographs of the same quality while not observing the chest movement, but the sensor. The use of the sensor did not increase the proportion of chest radiographs taken in the inspiration phase in this study. However, this null result may indicate the possibility of utilizing the sensor for automatizing chest radiography in the future.

A Case of Childhood Blastic Phase Chronic Myeloid Leukemia With Minor BCR-ABL.

Chronic myeloid leukemia (CML) is commonly associated with major BCR-ABL transcript. We present a child with blastic phase CML associated with minor BCR-ABL transcript without prior CML diagnosis. Diagnosis was achieved by fluorescence in situ hybridization of peripheral blood neutrophils, which identified 90% as BCR-ABL positive. The patient received chemotherapy with imatinib followed by dasatinib and underwent reduced-intensity hematopoietic allogeneic stem cell transplantation with prophylactic posttransplant dasatinib for 2 years and has remained in complete molecular remission. Our intensified treatment regimen was effective compared with previous studies on minor BCR-ABL CML describing inferior outcomes with tyrosine kinase inhibitor therapy.