An extremely rare case of primary alveolar rhabdomyosarcoma in the central nervous system.

Background: Alveolar rhabdomyosarcoma (ARMS) shows a predilection for the peripheral extremities and is very rarely identified as a primary in the brain. Here, we report a case of ARMS with multiple lesions exclusively within the central nervous system (CNS). Case Description: A 20-year-old man presented to our hospital with a gradually increasing headache and disturbance of consciousness. Neuroimaging showed hydrocephalus and multiple tumor lesions, including in the brainstem and cerebellum, with uniform gadolinium enhancement on T1-weighted magnetic resonance imaging, as well as spinal cord seeding. Cerebrospinal fluid (CSF) analysis showed a slightly elevated cell count (6/µL; normal, <5/µL) and highly elevated protein (153 mg/dL). In addition, atypical cells were cytologically identified in the CSF. No other laboratory findings were abnormal. Emergency ventricular drainage was performed to control cerebral pressure, followed by a biopsy to confirm the diagnosis. Histological examination revealed a fascicular arrangement of oval cells with eosinophilic cytoplasm and tumor cells with pleomorphic nuclei and prominent nucleoli. Immunohistochemical studies showed negative results for glial fibrillary acidic protein and positive results for desmin and myogenin. In addition, molecular analysis revealed that this tumor had the H3F3A p.Lys28Met mutation and no paired box (PAX)3-forkhead box O1 (FOXO1) or PAX7-FOXO1 fusion genes. ARMS was, therefore, diagnosed. Chemotherapy and radiotherapy were subsequently initiated, but tumor growth could not be controlled, and the patient died 6 months after surgery. Conclusion: This report describes an extremely rare case of ARMS arising exclusively within the CNS.

Rothia mucilaginosa Meningitis in a Child with Myelodysplastic Syndromes.

Rothia mucilaginosa is a Gram-positive coccus and an opportunistic pathogen in immunocompromised hosts. The microorganism has been implicated in serious infections, including bacteremia meningitis or endocarditis. However, there is a dearth of investigations on meningitis, especially in children. As this infection is rare and only a few cases have been recorded, evidence-based guidelines for adequate infection treatment are lacking. We herein report the case of a 12-year-old boy with myelodysplastic syndromes (MDS) presenting with a change in mental status who was diagnosed as having febrile neutropenia and bacterial meningitis caused by R. mucilaginosa at 23 days after unrelated cord blood transplant. In our case, the minimum inhibitory concentrations (MICs) of meropenem and vancomycin (VCM) were both ≤1 µg/mL, whereas the MIC of daptomycin (DAP) was 4 µg/mL. The patient was treated with intravenous antimicrobial therapy due to meropenem for 43 days because he had febrile neutropenia. During follow-up, the patient had no neurological complications. We retrospectively reviewed the antimicrobial susceptibility of all R. mucilaginosa isolates (n = 5) from blood or cerebrospinal fluid cultures at our hospital. The MIC of VCM was <0.5 µg/mL for all strains, whereas the MIC of DAP was ≥2 µg/mL for all strains. The MIC of MEPM was >1 µg/mL for one strain. We recommend choosing VCM as the primary treatment for invasive R. mucilaginosa infections until antimicrobial susceptibility results are known, especially in immunocompromised children.

A Catheter-Related Bloodstream Infection by Brevibacterium casei in a Child with Acute Myeloid Leukemia: Case Report and Literature Review.

The most common organisms isolated from pediatric catheter-related bloodstream infections (CRBSIs) are Gram-positive cocci, such as coagulase-negative staphylococci and Staphylococcus aureus. There are few formal reports of Brevibacterium casei infection and even fewer reports of CRBSI due to this Gram-positive rod. Here we report the first case of CRBSI due to B. casei in an 8-year-old girl with acute myeloid leukemia in Japan. The isolate exhibited decreased susceptibility to ß-lactam antibiotics. Antimicrobial therapy with meropenem and vancomycin, in addition to the removal of central venous catheter line, consequently led to a significant clinical improvement of the patient's symptoms. A literature review found available clinical courses in 16 cases (4 pediatric cases including our case) of B. casei infection. Our case and those in literature suggested that B. casei infection often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases. Special attention should be paid to the detection of opportunistic infections due to Brevibacterium spp. in immunocompromized children who are using a central venous catheter.

Re-irradiation using proton therapy for radiation-induced secondary cancer with Li-Fraumeni syndrome: A case report and review of literature.

Li-Fraumeni syndrome (LFS) is a genetic disease that is hypersensitive to radiotherapy. Proton therapy (PT) was strongly recommended for pediatric and radiation-sensitive tumors. However, there is little information on PT for LFS. The patient was a 7-year-old girl with LFS who was diagnosed with radiation-induced right shoulder blade osteosarcoma and left chest wall malignant fibrous histiocytoma. Both tumors were in the area that had previously been irradiated (36-45 Gy by photon radiotherapy). Sixty-six GyE in 30 fractions was planned for both tumors. We set the clinical target to the minimum gross tumor volume. To comprehensively assess any adverse events, PT was conducted under hospital administration. Cisplatin was used as simultaneous combination chemotherapy. Although administration of granulocyte-colony stimulating factor was necessary for myelosuppression by chemotherapy, PT was completed without interruption. Acute radiation toxicity was observed as Grade 1 dermatitis. The dermatitis became exacerbated 2 weeks after PT but subsequently improved with conservation treatment alone. Twenty-three months after PT, magnetic resonance imaging showed an increase in the tumor on the right shoulder. A histological examination was not conducted as the family declined, but secondary cancer was suggested rather than recurrent osteosarcoma, as the tumor developed mainly from the soft tissue. Additional surgical treatment and radiotherapy were not indicated, and the patient died of tumor progression and sepsis caused by myelosuppression 27 months after undergoing PT. Up to 23 months after PT, there were no signs of Grade 2 or more late toxicities. This represents the first reported case of PT for a patient with LF to treat radiation-induced secondary cancer.

Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review.

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.

Mesenchymal Stem Cell Therapy Overcomes Steroid Resistance in Severe Gastrointestinal Acute Graft-Versus-Host Disease.

The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×106 hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.

Early detection of the PAX3-FOXO1 fusion gene in circulating tumor-derived DNA in a case of alveolar rhabdomyosarcoma.

Cell-free DNA (cfDNA), which are small DNA fragments in blood derived from dead cells including tumor cells, could serve as useful biomarkers and provide valuable genetic information about the tumors. cfDNA is now used for the genetic analysis of several types of cancers, as a surrogate for tumor biopsy, designated as "liquid biopsy." Rhabdomyosarcoma (RMS), the most frequent soft tissue tumor in childhood, can arise in any part of the body, and radiological imaging is the only available method for estimating the tumor burden, because no useful specific biological markers are present in the blood. Because tumor volume is one of the determinants of treatment response and outcome, early detection at diagnosis as well as relapse is essential for improving the treatment outcome. A 15-year-old male patient was diagnosed with alveolar RMS of prostate origin with bone marrow invasion. The PAX3-FOXO1 fusion was identified in the tumor cells in the bone marrow. After the diagnosis, cfDNA was serially collected to detect the PAX3-FOXO1 fusion sequence as a tumor marker. cfDNA could be an appropriate source for detecting the fusion gene; assays using cfDNA have proved to be useful for the early detection of tumor progression/recurrence. Additionally, the fusion gene dosage estimated by quantitative polymerase chain reaction reflected the tumor volume during the course of the treatment. We suggest that for fusion gene-positive RMSs, and other soft tissue tumors, the fusion sequence should be used for monitoring the tumor burden in the body to determine the diagnosis and treatment options for the patients.

Prolonged adrenal insufficiency after high-dose glucocorticoid in infants with leukemia.

Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis.

Therapeutic Effect of Linezolid in Children With Health Care-Associated Meningitis or Ventriculitis.

We evaluated the efficacy of linezolid treatment in 6 children with health care-associated meningitis or ventriculitis (HCAMV) caused by gram-positive cocci. All children were diagnosed and treated at the Ehime University Hospital between January 2010 and December 2017. Of these, 5 were treated with linezolid as an empirical therapy. In these 5 patients, vancomycin was initially used but was changed to linezolid because of cerebrospinal fluid (CSF) culture positivity (n = 3) and a high minimum inhibitory concentration of vancomycin (n = 2). The most common HCAMV pathogens were methicillin-resistant coagulase-negative staphylococci (n = 3). In 3 patients, vancomycin concentration was low in CSF but reached the target concentration in serum, while linezolid concentration was high in both CSF and serum. HCAMV treatment using antimicrobial agents with poor CSF penetration may increase the likelihood of therapy failure. Linezolid is more susceptible as the first-line treatment for HCAMV compared with vancomycin.

Usefulness of positron emission tomography-CT for diagnosis of primary bone marrow lymphoma in children.

Primary bone marrow lymphoma (PBML) is hard to diagnose in children, due to the difficult identification of malignant cells in bone marrow. The first case, a 5-year-old boy, showed knee swelling with an intermittent fever. The second case, a 12-year-old girl, showed fever of unknown origin without lymphadenopathy or hepatosplenomegaly. In both cases, the diagnosis was not confirmed despite the repeated bone marrow aspirations. Finally, bone marrow aspiration and biopsy at the positive site by positron emission tomography (PET)-CT contributed to definitive diagnosis of PBML. The PET-CT is useful for the accurate diagnosis of PBML in children with non-specific symptoms.

Combined morphological, immunohistochemical and genetic analyses of medulloepithelioma in the posterior cranial fossa.

Medulloepithelioma is a rare and highly malignant primitive neuroectodermal tumor that usually occurs in childhood. The diagnosis of this entity required only morphological analysis until the World Health Organization classification of central nervous system (CNS) tumors was revised, and now genetic analysis is necessary. We report a case of medulloepithelioma in the posterior cranial fossa that was diagnosed by both morphological and genetic analyses based on this classification. A 10-month-old girl was admitted to our hospital with consciousness disturbance and vomiting. Neuroimaging revealed a partially calcified mass and cyst formation in the posterior cranial fossa. Partial resection of the tumor was performed and histological findings revealed multilayered rosettes with LIN28A staining, but genetic analysis showed no amplification of the C19MC microRNA cluster at 19q14.32. Therefore, we diagnosed the tumor as medulloepithelioma belonging to other CNS embryonal tumors. The patient was immediately treated with systemic high-dose chemotherapy. Follow-up neuroimaging 10 months later showed no signs of recurrence. Medulloepitheliomas are difficult to diagnose by routine HE staining and require combined morphological, immunohistochemical and genetic analyses to provide an accurate diagnosis.

Tsukamurella inchonensis infection in a child with Hodgkin's lymphoma.

Tsukamurella spp. infection is a rare but important cause of bacteremia in immunocompromised patients. The organism is an aerobic, Gram-positive, weakly acid-fast bacillus that is difficult to differentiate from other aerobic Actinomycetales by standard laboratory methods. Here, we report on the case of a 14-year-old patient with Hodgkin's lymphoma who, after intensive chemotherapy, developed Tsukamurella inchonensis bacteremia, which was identified on the peripherally inserted central venous catheter (PICC) using 16S rRNA sequencing analysis. The bacteremia was successfully controlled with antimicrobial therapy and subsequent removal of the PICC. This is the first report of bacteremia by Tsukamurella inchonensis in immunocompromised children. Careful observation and prompt analysis of opportunistic infection, including Tsukamurella spp., is very important in immunocompromised children.

CLTC-ALK fusion as a primary event in congenital blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC-ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patient's Guthrie card were analyzed for the presence of the CLTC-ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC-ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC-ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC-ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm.