A case of neurodegenerative Langerhans cell histiocytosis exhibiting high osteopontin in cerebrospinal fluid without specific radiological abnormalities.

Neurodegenerative Langerhans cell histiocytosis (ND-LCH) manifests several years after onset of LCH, with progressive neurological symptoms and characteristic brain imaging features. Although ND-LCH has a dismal neurological prognosis, distinct treatment strategies are not available owing to the unknown pathophysiology. We describe the case of a 6-year-old boy who developed left convergent strabismus four years after onset of multisystem LCH (MS-LCH). Although radiological imaging showed no abnormalities, the osteopontin level in the cerebrospinal fluid (CSF-OPN) was highly elevated without other abnormal CSF findings, leading to a diagnosis of ND-LCH. The patient received monthly intravenous immunoglobulin therapy for four years, without symptoms worsening. To investigate the relevance of OPN levels in LCH, we retrospectively analyzed serum and CSF OPN levels in eight LCH patients. Serum OPN levels were markedly elevated in the two MS-LCH patients with macrophage activation (400 and 445 ng/mL) compared to the other six patients (mean: 59 ng/mL). CSF-OPN levels were elevated in the ND-LCH patient (620 ng/mL) compared to the two patients with pituitary involvement (160 and 182 ng/mL), suggesting that the pathophysiology of ND-LCH reflects its inflammatory status. Analysis of CSF-OPN levels would be a useful tool to detect and treat ND-LCH.

Presence of identical B-cell clone in both cerebrospinal fluid and tumor tissue in a patient with opsoclonus-myoclonus syndrome associated with neuroblastoma.

Opsoclonus-myoclonus syndrome associated with neuroblastoma (OMS-NB) is a refractory paraneoplastic syndrome which often remain neurological sequelae, and detailed pathogenesis has remained elusive. We encountered a pediatric patient with OMS-NB treated by immunosuppressed therapy who showed anti-glutamate receptor δ2 antibody and increased B-cells in cerebrospinal fluid (CSF), and multiple lymphoid follicles containing abundant Bcells in tumor tissue. Unbiased B-cell receptor repertoire analysis revealed identical B-cell clone was identified as the dominant clone in both CSF and tumor tissue. These identical B-cell clone may contribute to the pathogenesis of OMS-NB. Our results could facilitate the establishment of pathogenesis-based treatment strategies for OMS-NB.

A subarachnoid pleural fistula with massive crystal-clear pleural fluid caused by a lumbar epidural teratoma.

A subarachnoid pleural fistula - a connection between the pleural cavity and the subarachnoid space - generally presents after trauma or surgery. A 1-year 11-month-old girl without a history of trauma or surgery presented with fatigue, cyanosis and dyspnoea. A chest radiograph and computed tomography (CT) demonstrated a massive pleural effusion in the right hemithorax. About 300 ml of a crystal-clear pleural effusion, which looked like pure water, was removed by insertion of a chest drain, but it continued to collect. Cisternography and CT myelography confirmed leakage of cerebral spinal fluid into the right pleural cavity around the thoracolumbar region. Magnetic resonance imaging demonstrated an 11-mm enhanced nodule in the epidural space around the right lumbar (L) 1/2 intervertebral foramen. The patient underwent surgery and epidural tumours attached to the L1 nerve root foramen were completely resected and a fistula of the dura adjacent to the tumour was sutured. Histopathological examination demonstrated a mature teratoma containing a pancreatic component. On retrospective analysis of stored pleural fluid, a raised level of pancreatic enzymes was detected. It is presumed that digestive enzymes secreted by the pancreatic component of the teratoma lysed the dura, resulting in formation of the fistula. When a crystal-clear pleural effusion is present, even in the absence of trauma or surgery, a subarachnoid pleural fistula should be considered. As far as we know, this is the first report of a subarachnoid pleural fistula caused by a paravertebral teratoma.Abbreviations: CSF: cerebrospinal fluid; CT: computed tomography; 111In-DTPA: indium-111 diethylene triamine penta-acetic acid; MRI: magnetic resonance imaging; NIPPV: non-invasive positive pressure ventilation.

Phase I/II clinical trial of high-dose [131I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

PURPOSE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. CONCLUSION: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. TRIAL REGISTRATION NUMBER: jRCTs041180030. NAME OF REGISTRY: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 12/01/2018.

Utility of 18F-FDG-PET for detecting acute lymphoblastic leukemia: a case series of pediatric acute lymphoblastic leukemia without hematological symptoms.

Acute leukemia is typically diagnosed from presenting features related to hematological symptoms, but certain patients present with prominent musculoskeletal pain without signs of hematological abnormality. We reviewed the medical records of 58 children diagnosed with acute lymphoblastic leukemia (ALL) at our hospital to evaluate initial features. Forty six of these patients had hematological symptoms, anemia, or hemorrhage (Group H), while 12 patients had prominent musculoskeletal pain without hematological symptoms (Group P). Diagnosis of leukemia took significantly more time for those 12 patients (Group H, 17.1 days; Group P, 48.5 days). In three of the 12 patients in Group P, localized abnormal imaging findings and unremarkable blood test results led to initial diagnoses of chronic recurrent multifocal osteomyelitis, bone fracture, and septic osteomyelitis. However, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) revealed multiple intense bone foci or systemic bone marrow uptake, leading to the diagnosis of ALL. A review of 18F-FDG-PET results from 23 patients with ALL who underwent a PET scan (Group H, n = 15; Group P, n = 8) showed multiple bone foci or systemic bone marrow uptake in all cases. In conclusion, lack of hematological symptoms in ALL patients can delay diagnosis, and 18F-FDG-PET is useful for diagnosing leukemia in such cases.

Diagnostic Use of Post-therapy 131I-Meta-Iodobenzylguanidine Scintigraphy in Consolidation Therapy for Children with High-Risk Neuroblastoma.

123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy is used for evaluating disease extent in children with neuroblastoma. 131I-mIBG therapy has been used for evaluation in children with high-risk neuroblastoma, and post-therapy 131I-mIBG scintigraphy may detect more lesions compared with diagnostic 123I-mIBG scintigraphy. However, no studies have yet revealed the detection rate of hidden mIBG-avid lesions on post-therapy 131I-mIBG whole-body scan (WBS) and SPECT images in neuroblastoma children without mIBG-avid lesions as demonstrated by diagnostic 123I-mIBG scintigraphy. We retrospectively examined the diagnostic utility of post-therapy 131I-mIBG scintigraphy in children who received 131I-mIBG as consolidation therapy. Nineteen children with complete response to primary therapy were examined. Post-therapy 131I-mIBG scintigraphy was performed four days after injection. The post-therapy 131I-mIBG scintigraphy, 4 children exhibited abnormal uptake on the WBS. Post-therapy 131I-mIBG SPECT/CT provided additional information in 2 cases. In total, 6 children exhibited abnormal uptake. The site of abnormal accumulation was on the recurrence site in one case, operation sites in five cases, and bone metastasis in one case. Post-therapy 131I-mIBG scintigraphy could detect residual disease that was not recognized using diagnostic 123I-mIBG scintigraphy in 32% of children with high-risk neuroblastoma and ganglioneuroblastoma. The diagnostic use of post-therapy 131I-mIBG scintigraphy can provide valuable information for detecting residual disease.

High-dose 131I-mIBG as consolidation therapy in pediatric patients with relapsed neuroblastoma and ganglioneuroblastoma: the Japanese experience.

OBJECTIVE: Children with relapsed neuroblastoma have a poor prognosis despite modern multimodality therapy. Novel and more effective therapeutic strategies are required for relapsed neuroblastoma. We retrospectively examined the utility of consolidation therapy with high-dose 131I-meta-iodo-benzyl-guanidine (131I-mIBG) in relapsed neuroblastoma or ganglioneuroblastoma patients with complete response (CR) to induction therapy as demonstrated by diagnostic 123I-mIBG scintigraphy. METHODS: Between December 2009 and 2014, five patients with relapsed neuroblastoma and one with relapsed ganglioneuroblastoma received high-dose 131I-mIBG therapy. Overall and progression-free survival rates at five years after 131I-mIBG therapy were analyzed by the Kaplan-Meier method. RESULTS: During follow-up, three children showed no signs of disease relapse, whereas three died. One child without a relapse died from post-transplant side effects, and two children with a relapse died owing to tumor progression. The 5-year progression-free and overall survival rates after 131I-mIBG therapy were 44% and 67%, respectively. CONCLUSIONS: Consolidation therapy with high-dose 131I-mIBG for patients with 2nd CR showed good overall and progression-free survival. While the risks of radiation exposure must be considered, high-dose 131I-mIBG therapy as consolidation therapy needs to be further investigated.

High-dose 131I-metaiodobenzylguanidine therapy in patients with high-risk neuroblastoma in Japan.

OBJECTIVE: The aim of the study was to investigate the outcomes and prognostic factors of high-dose 131I-metaiodobenzylguanidine (131I-MIBG) therapy in patients with refractory or relapsed neuroblastoma (NBL) in Japan. METHODS: We retrospectively analyzed 20 patients with refractory or relapsed high-risk NBL who underwent 131I-MIBG therapy with an administration dose ranging from 444 to 666 MBq/kg at Kanazawa University Hospital, Japan, between September 2008 and September 2013. We focused on measurements regarding their initial responses, prognostic factors, survivals, and toxicities following 131I-MIBG therapy using our hospital data and questionnaires from the hospitals that these patients were initially referred from. Furthermore, we performed Kaplan-Meier survival analysis to evaluate event-free survival (EFS) and overall survival (OS). RESULTS: In 19 patients with complete follow-up data, the median age at first 131I-MIBG treatment was 7.9 years (range 2.5-17.7 years). Following 131I-MIBG therapy, 17 of the 19 patients underwent stem-cell transplantations, and their treatment response was either complete (CR) or partial (PR) in three and two cases, respectively. The EFS and OS rates at 1 year following 131I-MIBG therapy were 42% and 58%, respectively, and those at 5 years following 131I-MIBG therapy were 16% and 42%, respectively. Using the two-sample log-rank test, the OS time following 131I-MIBG therapy was significantly longer for < 3-year time interval between the initial diagnosis and 131I-MIBG therapy (p = 0.017), Curie score < 16 just before 131I-MIBG therapy (p = 0.002), without pain (p = 0.002), without both vanillylmandelic acid (VMA) and homovanillic acid (HVA) elevation (p = 0.037) at 131I-MIBG therapy, and with CR or PR following 131I-MIBG therapy (p = 0.015). Although severe hematological toxicities were identified in all 19 patients, severe nonhematological toxicity was not recorded in any patient, except for one patient with grade 3 anorexia and nausea. CONCLUSIONS: High-dose 131I-MIBG therapy in patients with refractory or relapsed high-risk NBL can provide a favorable prognosis without severe nonhematological toxicities. Better prognosis may be anticipated in patients with the initial good response, no pain at 131I-MIBG therapy, no VMA and HVA elevation at 131I-MIBG therapy, low Curie score (< 16) just before 131I-MIBG therapy, and short time interval (< 3 years) between the initial diagnosis and 131I-MIBG therapy.

Half of 'Micrococcus spp.' cases identified by conventional methods are revealed as other life-threatening bacteria with different drug susceptibility patterns by 16S ribosomal RNA gene sequencing.

Bacterial infection during chemotherapy is a fatal complication, therefore precise identification of the pathogenic microorganism is required for treatment. We report that 2 of 4 pediatric patients with malignancy who were diagnosed with Micrococcus spp. infection by conventional methods were finally revealed to have Kytococcus schroeteri and Kocuria marina infection by 16S ribosomal RNA gene sequence analysis (16S rRNA analysis). Although K. schroeteri is morphologically similar to Micrococcus spp., its drug susceptibility profile is quite different from that of Micrococcus spp. K. schroeteri is resistant to penicillin and cephalosporin, which are effective for Micrococcus spp. In fact, penicillin-resistant lethal pneumonia caused by K. schroeteri has been reported in compromised hosts. Based on our results, Micrococcus spp. determined by conventional methods could contain other life-threatening bacteria with different drug susceptibility patterns from Micrococcus spp. To develop an effective empirical treatment for immunocompromised hosts, accumulation of pathogen data by 16S rRNA analysis is required.

Accurate detection of renal leukemic involvement in children using 3-D computed tomography modeling.

BACKGROUND: The rate of renal involvement in pediatric acute lymphoblastic leukemia (ALL) at diagnosis varies between reports because renal involvement is diagnosed on renal size larger than aged-matched standards on conventional modalities. We propose a new method for precise renal involvement detection using 3-D enhanced computed tomography (CT) reconstruction. METHODS: Twenty-five children with ALL were evaluated utilizing 3-D enhanced CT reconstruction to measure renal volume before and after induction therapy, renal mass lesions and renal axis at diagnosis. Renal involvement was defined as a marked decrease of renal volume or the presence of mass lesions. RESULTS: According to the 3D-CT criteria, nine of 25 patients (36%) had renal involvement. All of them had bilateral mass lesions except for one who had diffuse nephromegaly alone. This method detected renal involvement more accurately than ultrasonography. When using conventional criteria based on the length of the renal axis, 19 of 25 (76%) had renal involvement, including many cases of false-positive nephromegaly. Patients with renal involvement had significantly more extramedullary involvement according to the 3D-CT-based criteria. CONCLUSIONS: The use of 3D-CT reconstruction was accurate in detecting renal involvement in childhood ALL, most of which consisted of piled up mass lesions. Patients with renal involvement should be worked up for the detection of other extramedullary lesions.

Improvement of refractory acyclovir-resistant herpes simplex virus type 1 infection by continuous acyclovir administration.

Resistant herpes simplex virus type 1 (HSV-1) infection is sometimes fatal for immunocompromised patients. Here, we report 10-year-old girl receiving hematopoietic stem cell transplantation developed refractory HSV-1 infection, which was persisted to intermittent acyclovir (ACV) or foscarnet (FOS) administrations but was improved by continuous ACV administration. The isolates from the lesion were identified with low susceptibilities to ACV and FOS by plaque reduction assay due to DNA pol gene mutation. Continuous ACV administration overcomes the efficacy of intermittent administration and could be the best option to treat severe HSV-1 infectious patients.

Feasibility of High-dose Iodine-131-metaiodobenzylguanidine Therapy for High-risk Neuroblastoma Preceding Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation: a Study Protocol.

OBJECTIVES: High-risk neuroblastoma is a childhood cancer with poor prognosis despite modern multimodality therapy. Internal radiotherapy using 131I-metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it is resistant to chemotherapy. The aim of this study is to evaluate the safety and efficacy of 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapy and hematopoietic stem cell transplantation. METHODS: Patients with high-risk neuroblastoma will be enrolled in this study. A total of 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG and after safety evaluation will undergo high-dose chemotherapy and hematopoietic stem cell transplantation. Autologous and allogeneic stem cell sources will be accepted. After engraftment or 28 days after hematopoietic stem cell transplantation, the safety and response will be evaluated. CONCLUSION: This is the first prospective study of 131I-MIBG with high-dose chemotherapy and hematopoietic stem cell transplantation in Japan. The results will be the basis of a future nationwide clinical trial.

A characteristic flow cytometric pattern with broad forward scatter and narrowed side scatter helps diagnose immune thrombocytopenia (ITP).

Various disorders cause severe thrombocytopenia, which can lead to critical hemorrhage. Procedures that rapidly support the diagnosis and risk factors for serious bleeding were explored, with a focus on immune thrombocytopenia (ITP). Twenty-five patients with thrombocytopenia, including 13 with newly diagnosed ITP, 3 with chronic ITP, 6 with aplastic anemia (AA), and 3 with other thrombocytopenia (one acute myeloid leukemia, one acute lymphoblastic leukemia, and one hemophagocytic lymphohistiocytosis), were reviewed. In addition to platelet-related parameters obtained by an automated hematology analyzer, flow cytometric analysis of platelets was performed. A characteristic flow cytometric pattern with broad forward scatter and narrowed side scatter, which is specific to ITP, but not other types of thrombocytopenia, was found. CD62P-positive platelets were increased in newly diagnosed ITP cases compared to control (P < 0.0001), AA (P = 0.0032). Moreover, detection of dramatic changes in these parameters on sequential monitoring may suggest internal hemorrhage, even absent skin or visible mucosal bleeding. The bleeding score for visible mucosae had a negative correlation with platelet count and a positive correlation with immature platelet fraction (%), forward scatter, and CD62P. This characteristic flow cytometric pattern makes it possible to distinguish ITP from other thrombocytopenic disorders.

Minimal contribution of severe hypertriglyceridemia in L-asparaginase-associated pancreatitis developed in a child with acute lymphocytic leukemia.

A 10-year-old girl developed L-asparaginase (ASP)-associated pancreatitis during chemotherapy for acute lymphocytic leukemia. Her symptoms showed alleviation with continuous regional arterial infusion of protease inhibitor and systemic somatostatin analog therapy. She had intermittent and marked hypertriglyceridemia, an initial trigger for pancreatitis, probably as a side effect of ASP and steroids. However, we considered the pancreatitis to have developed mainly because of factors other than hypertriglyceridemia as lipoprotein analysis confirmed chylomicron levels to be nearly undetectable. Extremely large chylomicrons contribute directly to the onset of pancreatitis by causing blockage of small vessels. Although it is necessary to examine patients for dyslipidemia developing as a side effect of ASP, therapeutic intervention for hypertriglyceridemia is not considered to prevent the onset of ASP-associated pancreatitis.

Epstein-Barr virus-associated leukemic lymphoma after allogeneic stem cell transplantation.

Leukemic Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative diseases (PTLD) following allogeneic hematopoietic stem cell transplantation are extremely rare. We can successfully treat an EBV-associated leukemic lymphoma patient with rituximab, cidofovir, and donor lymphocyte infusion (DLI). In the present case, EBV-specific T cells that were present in the peripheral blood before rituximab administration treatment rapidly increased after DLI in association with a decrease in the EBV-DNA load.