Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Extraneural recurrence of an intracranial nongerminomatous germ cell tumor to cervical lymph nodes in a pediatric patient: Case report.

BACKGROUND: Intracranial germ cell tumors (GCTs) comprise 3%-5% of pediatric primary central nervous system (CNS) tumors in Western countries. Though they are related in embryonic origin to gonadal GCTs, which are considered highly treatable with cisplatin-based chemotherapy regimens, intracranial GCTs vary in malignant potential and sensitivity to radiation and chemotherapy, generally carrying a worse prognosis. Metastases of intracranial GCTs outside of the CNS are rare, indicate a poor prognosis, and their salvage treatment is not well established. CASE: A 15-year-old boy presented with bifocal (suprasellar and pineal) intracranial nongerminomatous germ cell tumors of mixed origin. The tumors were treated to full response with a multimodal approach of neoadjuvant chemotherapy, surgical resection, and adjuvant craniospinal proton radiation. Nine months following treatment completion, the patient presented with an enlarged cervical lymph node determined on excisional biopsy to be a recurrence of pure germinoma from the primary tumors. Salvage treatment involved high-dose chemotherapy and autologous stem cell transplantation; however, the patient denied further treatment prior to planned focal radiotherapy. Thirty months post-treatment, the patient is well with no evidence of recurrence. CONCLUSION: This case demonstrated the successful salvage treatment of an extraneural recurrence of an intracranial GCT using surgical resection and a high-dose chemotherapy and autologous stem-cell transplantation regimen, highlighting the unique factors which led to the selection of this regimen.

Relationship Between Caregiver Uncertainty, Problem-Solving, and Psychological Adjustment in Pediatric Cancer.

OBJECTIVE: The current study examined the roles of constructive and dysfunctional problem-solving strategies in the relationships between illness uncertainty and adjustment outcomes (i.e., anxious, depressive, and posttraumatic stress symptoms) in caregivers of children newly diagnosed with cancer. METHODS: Two hundred thirty-eight caregivers of children (0-19 years of age) newly diagnosed with cancer (2-14 weeks since diagnosis) completed measures of illness uncertainty, problem-solving strategies, and symptoms of anxiety, depression, and posttraumatic stress. RESULTS: A mediation model path analysis assessed constructive and dysfunctional problem-solving strategies as mediators between illness uncertainty and caregiver anxious, depressive, and posttraumatic stress symptoms. Dysfunctional problem-solving scores partially mediated the relationships between illness uncertainty and anxious, depressive, and posttraumatic stress symptoms. Constructive problem-solving scores did not mediate these relationships. CONCLUSIONS: The current findings suggest that illness uncertainty and dysfunctional problem-solving strategies, but not constructive problem-solving strategies, may play a key role in the adjustment of caregivers of children newly diagnosed with cancer. Interventions aimed at managing illness uncertainty and mitigating the impact of dysfunctional problem-solving strategies may promote psychological adjustment.

Successful treatment of tacrolimus-related pure red cell aplasia and autoimmune hemolytic anemia with rituximab in a pediatric cardiac transplant patient.

Acquired pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) are rare complications of immunosuppression in pediatric solid organ transplant patients. We report a 14-month-old female child who developed Coombs positive hemolytic anemia and reticulocytopenia while on tacrolimus after cardiac transplantation. She was successfully treated with rituximab after failing treatment with corticosteroids and intravenous immunoglobulins. Clinicians should consider PRCA differential diagnosis in a patient presenting with reticulocytopenia and hemolysis. In addition, the coexistence of PRCA with AIHA, and the response to therapy with rituximab, supports a common immune-mediated pathogenesis for both disorders.

Congenital dyserythropoietic anemia type I presenting as persistent pulmonary hypertension with pigeon chest deformity.

Congenital dyserythropoietic anemia (CDA) type-1 is a rare genetic disorder of ineffective erythropoiesis, which manifests in macrocytic anemia. We report a CDA1 patient who as a newborn presented with macrocytic anemia and persistent pulmonary hypertension of the newborn (PPHN) requiring mechanical ventilation. Post-infancy, the patient developed acral dysmorphism and pectus excavatum the latter rarely found in CDA1. Patient is a compound heterozygote for a known maternal-derived missense-mutation (c.1796A > G/p.Asn589Ser) and a novel paternal-derived deletion-mutation (c.1104_1106del/Phe365del) in CDAN1. This report highlights the importance of recognizing PPHN as a presenting symptom of CDA1 and expands the repertoire of the accompanying mutations and axial skeletal malformations.

Abnormal Chest X-ray Postmyocardial Infarction.

Pulmonary hemorrhage is a rare complication of fibrinolytic therapy. Only a few cases are reported in the literature. We present a patient who had myocardial infarction, treated with fibrinolytic therapy and developed pulmonary hemorrhage. We discuss the features that suggest and support the diagnosis.

Neuroblastoma in monozygotic twins with distinct presentation pathology and outcome: is it familial or in utero metastasis.

To date ten sets of monozygotic twins with neuroblastoma have been reported in the literature. Twin-to-twin in utero metastasis have been proposed as the mechanism of tumor development in the second twin; based on similar pathology, presence of metastatic disease, absence of a primary tumor, and/or later presentation in the second twin. Hereditary neuroblastoma has not been described in this context. We propose that primary neuroblastoma can occur in monozygotic twins without twin-twin transmission; due to the different ages of presentation, histology, ploidy, and tumor behavior.

Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell lines.

BACKGROUND: Medulloblastoma comprises approximately 20% of all primary pediatric brain tumors. Despite recent advances, the survival rate for high-risk patients and the morbidity associated with these treatments remains suboptimal. To improve outcomes and decrease morbidity, more targeted therapy is required. One possible target is the Aurora Kinase family. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in medulloblastoma cell lines. PROCEDURE: Cell proliferation was measured using an MTS assay after adding an Aurora Kinase inhibitor (C1368) at different concentrations. Cell cycle analysis was carried out by Flow Cytometry using propidium iodide (PI). RNAi experiments were performed using siRNA oligonucleotides. Luciferase experiments were carried out using the Cignal Finder 10 Pathway Reporter Arrays. RESULTS: Inhibition of Aurora Kinase A induces cell death in medulloblastoma cells and lowers the IC(50) of other chemotherapeutic agents (etoposide and cisplatin) used in medulloblastoma treatment. Cell arrest at G2/M phase was significantly increased in medulloblastoma cell lines treated with C1368 Sigma at IC(30) or transfected siRNA. Inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways including Wnt, Myc, and RB as measured by luciferase reporter assays. CONCLUSIONS: These data indicate that inhibition of Aurora Kinase A inhibits cell growth in medulloblastoma through inhibition of pro-proliferative signaling pathways Wnt, Myc, and RB. Additionally, combining Aurora Kinase A inhibition with other chemotherapeutic agents significantly lowers their IC(50), which make it a promising small molecule target for medulloblastoma therapy.

Metabolic and chemical origins of cross-reactive immunological reactions to arylamine benzenesulfonamides: T-cell responses to hydroxylamine and nitroso derivatives.

Exposure to sulfamethoxazole (SMX) is associated with T-cell-mediated hypersensitivity reactions in human patients. T-cells can be stimulated by the putative metabolite nitroso SMX, which binds irreversibly to protein. The hydroxylamine and nitroso derivatives of three arylamine benzenesulfonamides, namely, sulfamethozaxole, sulfadiazine, and sulfapyridine, were synthesized, and their T-cell stimulatory capacity in the mouse was explored. Nitroso derivatives were synthesized by a three-step procedure involving the formation of nitro and hydroxylamine sulfonamide intermediates. For immune activation, female Balb-c strain mice were administered nitroso sulfonamides four times weekly for 2 weeks. After 14 days, isolated splenocytes were incubated with the parent compounds, hydroxylamine metabolites, and nitroso derivatives to measure antigen-specific proliferation. To explore the requirement of irreversible protein binding for spleen cell activation, splenocytes were incubated with nitroso derivatives in the presence or absence of glutathione. Splenocytes from nitroso sulfonamide-sensitized mice proliferated and secreted interleukin (IL)-2, IL-4, IL-5, and granulocyte monocyte colony-stimulating factor following stimulation with nitroso derivatives but not the parent compounds. Splenocytes from sensitized mice were also stimulated to proliferate with hydroxylamine and nitroso derivatives of the structurally related sulfonamides. The addition of glutathione inhibited the nitroso-specific T-cell response. Hydroxylamine metabolites were unstable in aqueous solution: Spontaneous transformation yielded appreciable amounts of nitroso and azoxy compounds as well as the parent compounds within 0.1 h. T-cell cross-reactivity with nitroso sulfonamides provides a mechanistic explanation as to why structurally related arylamine benzenesulfonamides are contraindicated in hypersensitive patients.