[show abstract][hide abstract] ABSTRACT: Human herpesvirus-6 (HHV-6) has been associated with a diverse spectrum of central nervous system (CNS) diseases and reported glial tropism.
To determine if HHV-6 is present in a series of pediatric brain tumors.
Pediatric gliomas from 88 untreated patients represented in a tissue microarray (TMA) were screened for HHV-6 by nested polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemistry (IHC) and compared to non-glial tumors (N=22) and control brain (N=32). Results were correlated with tumor grade and overall survival.
HHV-6 U57 was detected by nested PCR in 68/120 (57%) tumors and 7/32 (22%) age-matched non-tumor brain (P=0.001). HHV-6 U31 was positive in 73/120 (61%) tumors and 11/32 (34%) controls (P=0.019). Seventy-two percent (43/60) of tumors were HHV-6 Variant A. HHV-6 U57 was confirmed by ISH in 83/150 (54%) tumors and 10/32 (31%) controls (P=0.021), revealing a non-lymphocytic origin of HHV-6. HHV-6A/B gp116/64/54 late antigen was detected by IHC in 50/124 (40%) tumors and 6/32 (18%) controls (P=0.013). Interestingly, 58% of low grade gliomas (N=67) were IHC positive compared to 19% of high grade gliomas (N=21, P=0.002) and 25% of non-gliomas (N=36, P=0.001). HHV-6A/B gp116/64/54 antigen co-localized with glial fibrillary acidic protein, confirming the astrocytic origin of antigen. Overall, there was no primary association between HHV-6A/B gp116/64/54 antigen detection and survival (P=0.861).
We provide the first reported series of HHV-6 detection in pediatric brain tumors. The predominance of HHV-6 in glial tumors warrants further investigation into potential neurooncologic disease mechanisms.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 07/2009; 46(1):37-42. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose is to determine the incidence of active and latent human herpesvirus-6 (HHV-6) infection in a large cohort of adult primary and recurrent CNS tumors. We screened a tissue microarray (TMA) containing more than 200 adult primary and recurrent CNS tumors with known clinical information for the presence of HHV-6 DNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC). One hundred six of 224 (47%) CNS tumors were positive for HHV-6 U57 Major Capsid Protein (MCP) gene by ISH compared to 0/25 non tumor control brain (P = 0.001). Fourteen of 30 (47%) tumors were HHV-6 MCP positive by nested PCR compared to 0/25 non-tumor brain controls (P = 0.001), revealing HHV-6 Variant A in 6 of 14 samples. HHV-6A/B early (p41) and late (gp116/64/54) antigens were detected by IHC in 66 of 277 (24%) (P = 0.003) and 84 of 282 (35%) (P = 0.002) tumors, respectively, suggesting active infection. HHV-6 p41 (P = 0.645) and gp116/64/54 (P = 0.198) antigen detection was independent of recurrent disease. Glial tumors were 3 times more positive by IHC compared to non glial tumors for both HHV-6 gp116/64/54 (P = 0.0002) and HHV-6 p41 (P = 0.004). Kaplan Meier survival analysis showed no effect of HHV-6 gp116/64/54 (P = 0.852) or HHV-6 p41 (P = 0.817) antigen detection on survival. HHV-6 early and late antigens are detected in adult primary and recurrent CNS tumors more frequently in glial tumors. We hypothesize that the glial-tropic features of HHV-6 may play an important modifying role in tumor biology that warrants further investigation.
Journal of Neuro-Oncology 06/2009; 95(1):49-60. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: To identify targets critical to malignant childhood astrocytoma, we compared the expression of receptor tyrosine kinase- associated genes between low-grade and high-grade pediatric astrocytomas. The highest differentially overexpressed gene in high-grade astrocytoma is insulin-like growth factor- binding protein-2 (P = .0006). Immunohistochemistry confirmed overexpression of insulin-like growth factor-binding protein-2 protein (P = .027). Insulin-like growth factor- binding protein-2 stimulation had no effect on astrocytoma cell growth and migration, and minimally inhibited insulin-like growth factor-1-mediated migration, but not insulin-like growth factor-2-mediated migration. However, insulin-like growth factor-binding protein-2 stimulation significantly upregulated the major DNA repair enzyme gene, DNA-PKcs, and induced DNA-dependent protein kinase catalytic subunit protein expression in a time-dependent and dose-dependent manner, whereas insulin-like growth factor-1 had no effect. DNA-PKcs is also highly overexpressed by high-grade astrocytomas. These findings suggest insulin-like growth factor-binding protein-2 plays a role in astrocytoma progression by promoting DNA-damage repair and therapeutic resistance.
Journal of child neurology 11/2008; 23(10):1205-13. · 1.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Children less than 5 years of age with malignant central nervous system (CNS) tumors, continue to have a high rate of morbidity and mortality following administration of conventional therapy. In an attempt to avoid the neurologic sequelae associated with craniospinal radiation, strategies such as high-dose chemotherapy (HDCT) followed by peripheral stem cell rescue have been used successfully. Metronomic chemotherapy has also been reported as a potential new treatment strategy in solid tumors, particularly in adults.
A retrospective chart analysis was performed on 10 patients less than 5 years of age with CNS tumors treated with metronomic chemotherapy shortly after HDCT as part of their clinical care.
Metronomic chemotherapy was associated with minimal toxicity and all patients maintained a good quality of life. At the time of this report, all 10 patients are alive. Two patients have relapsed, and the remaining eight, including six patients with metastatic disease, continue to have stable clinical and radiographic disease at a mean of 20 months from the time of diagnosis.
Metronomic chemotherapy in this patient population is feasible and shows encouraging preliminary results, especially in patients with metastatic disease who have not received craniospinal radiation. Further investigation of this strategy in newly diagnosed patients with CNS tumors is warranted.
Pediatric Blood & Cancer 06/2008; 50(5):970-5. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: This article describes the clinical presentation, diagnostic workup, and neurologic outcome of 3 immunocompetent pediatric patients diagnosed with human herpesvirus 6 (HHV6) rhombencephalitis. Presentation of HHV6 rhombencephalitis included new onset seizures, ataxia, encephalopathy, and opsoclonus-myoclonus. Neurologic examination revealed cranial neuropathies, cerebellar dysfunction, and extremity weakness. Magnetic resonance imaging abnormalities located in the cerebellum, basal ganglia/thalamus, and cerebral hemispheres were detected in 2 patients. Diagnosis of HHV6 encephalitis was made by real-time and nested polymerase chain reaction of serum and cerebrospinal fluid. The HHV6 variant A was detected in 2 patients by sequence analysis, and HHV6 protein was detected by immunomicroscopy in a patient who underwent biopsy secondary to progressive clinical and neuroradiographic findings. Therapy with intravenous ganciclovir did not correlate with resolution of neurologic symptoms, despite eventual non-detectable HHV6. Human herpesvirus 6 should be considered in the differential diagnosis of unexplained cases of rhombencephalitis in immunocompetent children. Features may be rapidly progressive and include profound encephalopathy, seizures, ataxia, and opsoclonus-myoclonus.
Journal of Child Neurology 12/2007; 22(11):1260-8. · 1.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: To describe the relationship between symptomatology and time to diagnosis of an institutional series of patients with CNS germ cell tumor (CNSGCT) over a 16-year period.
Thirty consecutive patients newly diagnosed with CNSGCT (mean age 10.9 years; range 6 to 17 years; 70% boys) were evaluated at our institution between 1990 and 2006.
Duration of symptoms prior to diagnosis ranged from 5 days to 3 years (mean 8.4 months). Tumor location included pineal (14), suprasellar (8), pineal/suprasellar (3), pineal/thalamic (4), and basal ganglionic/thalamic (3). Five patients had disseminated disease at the time of diagnosis. Features including headache, nausea, vomiting, and visual changes led to earlier diagnosis. Symptoms including movement disorders, enuresis, anorexia, and psychiatric complaints delayed diagnosis in 9 of 30 patients, diagnosed 7 months to 3 years (mean 22.3 months) from symptom onset. In 7 of 9 patients with delayed diagnosis, enuresis was present. Seventeen of 30 patients had signs of endocrine dysfunction at presentation that included diabetes insipidus (4), hypothyroidism (8), and growth hormone deficiency (4). Ophthalmologic findings of decreased visual acuity, visual field deficits, or ocular abnormalities were present in 13 patients. Duration of symptoms did not correlate with tumor subtype or event-free survival. In three patients with basal ganglionic/temporal lobe, thalamic, or pineal/suprasellar signal abnormalities on MRI, neuroradiographic diagnosis was difficult.
Diagnosis of CNS germ cell tumor is often delayed, and presentation may include movement disorders or mimic psychiatric disease. MRI interpretation can be challenging and may require serum/CSF markers and biopsy for diagnosis.
[show abstract][hide abstract] ABSTRACT: Intense angiogenesis proliferation, a histopathological hallmark distinguishing malignant from benign astrocytoma, is vital for tumor progression. Thus, identifying and targeting specific pathways that promote malignant astrocytoma-induced angiogenesis could have substantial therapeutic benefit. Expression profiling of 13 childhood astrocytomas to determine the expression pattern of 133 angiogenesis-related genes revealed that 44 (33%) genes were differentially expressed (17 were overexpressed, and 27 were underexpressed) between malignant high-grade astrocytomas (HGAs) and benign low-grade astrocytomas. Hierarchical clustering and principal components analysis using only the 133 angiogenesis-related genes distinguished HGA from low-grade astrocytoma in 100% of the samples analyzed, as did unsupervised analyses using the entire set of 9198 expressed genes represented on the array, indicating that the angiogenesis-related genes were reliable markers of pathological grade. A striking new finding was significant overexpression of hypoxia-inducible transcription factor (HIF)-2alpha as well as high-level expression of FK506-binding protein (FKBP) 12 by HGA. Furthermore, 9 of 21 (43%) genes overexpressed by HGA were HIF/FKBP-associated genes. This group included the epidermal growth factor receptor (EGFR), which promotes HIF synthesis, as well as insulin-like growth factor-binding protein 2 (IGFBP2), a target gene of HIF activity. Differential protein expression of HIF-2alpha was validated in an independent group of 16 astrocytomas (P = 0.02). We conclude that the EGFR/FKBP12/HIF-2alpha pathway is important in childhood HGA and represents a potential new therapeutic target.
Cancer Research 05/2003; 63(8):1865-70. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Embryonal central nervous system (CNS) tumors are the most common group of malignant brain tumors in children. The diagnosis and classification of tumors belonging to this family have been controversial; however, utilization of molecular genetics is helping to refine traditional histopathologic and clinical classification schemes. Currently, this group of tumors includes medulloblastomas, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, ependymoblastomas, and medulloepitheliomas. While the survival of older children with nonmetastatic medulloblastomas has improved considerably within the past two decades, the outcomes for infants and for those with metastatic medulloblastomas or other high-risk embryonal CNS tumors remain poor. It is anticipated that the emerging field of molecular biology will greatly aid in the future stratification and therapy for pediatric patients with malignant embryonal tumors. In this review, recent advances in the diagnosis, molecular genetics, and treatment of the most common pediatric embryonal CNS tumors are discussed.
The Oncologist 02/2003; 8(2):174-86. · 4.10 Impact Factor