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ABSTRACT: BACKGROUND: Rhabdoid tumors (RTs) are aggressive tumors of early childhood that occur most often in brain (AT/RTs) or kidney (KRTs). Regardless of location, they are characterized by loss of functional SMARCB1 protein, a component of the SWI/SNF chromatin remodeling complex. The aim of this study was to determine genes and biological process dysregulated in common to both AT/RTs and KRTs. PROCEDURE: Gene expression for AT/RTs was compared to that of other brain tumors and normal brain using microarray data from our lab. Similar analysis was performed for KRTs and other kidney tumors and normal kidney using data from GEO. Dysregulated genes common to both analyses were analyzed for functional significance. RESULTS: Unsupervised hierarchical clustering of RTs identified three major subsets: two comprised of AT/RTs, and one of KRTs. Compared to other tumors, 1,187, 663, and 539 genes were dysregulated in each subset, respectively. Only 14 dysregulated genes were common to all three subsets. Compared to normal tissue, 5,209, 4,275, and 2,841 genes were dysregulated in each subset, with an overlap of 610 dysregulated genes. Among these genes, processes associated with cell proliferation, MYC activation, and epigenetic dysregulation were common to all three RT subsets. CONCLUSIONS: The low overlap of dysregulated genes in AT/RTs and KRTs suggests that factors in addition to SMARCB1 loss play a role in determining subsequent gene expression. Drugs which target cell cycle or epigenetic genes may be useful in all RTs. Additionally, targeted therapies tailored to specific RT subset molecular profiles should be considered. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 02/2013; · 1.89 Impact Factor
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Brain Pathology 01/2013; 23(1):113-6. · 3.99 Impact Factor
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Brain Pathology 11/2012; 22(6):861-4. · 3.99 Impact Factor
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ABSTRACT: Pleomorphic xanthoastrocytomas with anaplastic features (PXA-As) are rare tumors about which little is known regarding clinicopathologic and molecular features. Several studies have identified BRAF V600E mutations in PXA-As, but the percentage with mutation may differ between adult and pediatric examples, and limited information exists about immunohistochemistry for isocitrate dehydrogenase 1 (IDH1). Ten cases of adult PXA-As seen at our institution since 2000 were assessed for BRAF V600E mutation by polymerase chain reaction testing (PCR) and IDH1 by immunohistochemistry. Patients ranged in age from 18-68 years; four PXA-As affected temporal lobe and two were cystic. Four patients underwent gross total resection and 9 of 10 patients received cranial irradiation and/or adjuvant chemotherapy. Five survived less than 5 years, although 2 of 5 patients died from non-tumor causes. Four long-term survivors are alive at 7.5, 9.8, 11.4, and 11.9 years post-diagnosis. Two of four long term survivors had BRAF V600E mutation: patients were ages 18 and 28 years. A 48-year-old male without BRAF mutation survives at 9.8 years, even with thalamic location; conversely a 68-year-old female with temporal lobe tumor and BRAF mutation survived 1.9 years after diagnosis. All tumors were IDH1 immunonegative. This case series details clinicopathologic features of a subset of rare PXA-As in adults. BRAF V600E mutation was identified in 50 % of these cases.
Journal of Neuro-Oncology 10/2012; · 3.21 Impact Factor
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ABSTRACT: Congenital glioblastoma (cGBM) is an uncommon tumor of infancy with a reported variable but often poor cure rate, even with intensive therapy. Five patients with cGBMs, arising de novo and not in familial tumor predisposition kindreds, were studied for histological and biological features, using Affymetrix microarray. Tumors were large, often associated with hemorrhage, extended into the thalamus, and often bulged into the ventricles. One patient died acutely from bleeding at the time of operation. The 4 surviving patients underwent surgery (1 gross total resection, 3 subtotal resections or biopsies) and moderate intensity chemotherapy without radiation, and remain progression-free at a median time of 36 months (range, 30-110 months). Affymetrix microarrays measured gene expression on the 3 cGBMs from which frozen tissue was available. Unsupervised hierarchical clustering of cGBMs versus 168 other central nervous system tumors demonstrated that cGBMs clustered most closely with other high-grade gliomas. Gene expression profiles of cGBMs were compared with non-congenital pediatric and adult GBMs. cGBMs demonstrated marked similarity to both pediatric and adult GBMs, with only 31 differentially expressed genes identified (false discovery rate, <0.05). Unique molecular features of cGBMs included over-expression of multiple genes involved in glucose metabolism and tissue hypoxia. cGBMs show histological and biological overlap with pediatric and adult GBMs but appear to have a more favorable outcome, with good response to moderate intensity chemotherapy with only subtotal resection or biopsy. Further study may determine whether identified gene expression differences contribute to the improved survival seen in these tumors.
Neuro-Oncology 06/2012; 14(7):931-41. · 5.72 Impact Factor
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ABSTRACT: Gangliogliomas (GGs) primary to brainstem are rare, with the overwhelming majority of GGs occurring in supratentorial, especially temporal lobe, locations. A less favorable prognosis exists for brainstem GGs, despite their usually identical WHO grade I status. Few large clinical series, and limited biological information, exists on these tumors, especially gene expression.
Seven pediatric brainstem GGs, all with classic histological features, seen at our institution since 2000 were identified. Frozen section material was available for gene expression microarray profiling from five of seven brainstem GGs and compared with that from three non-brainstem pediatric GGs.
Significant upregulation of a number of genes was identified, most of which were involved in pathways of neural signaling, embryonic development, and pattern specification in pediatric brainstem GGs compared to non-brainstem. The single largest upregulated gene was a 256-fold increase in the expression of the neuropeptide prepronociceptin (PNOC); the protein product of this gene has been implicated in neuronal growth. Overexpression was validated by Western blot and by immunohistochemistry (IHC). Strong IHC expression of PNOC was seen in neoplastic neurons of 7/7 brainstem GGs, but was significantly weaker in non-brainstem GGs, and completely negative in normal pediatric autopsy brainstem controls.
PNOC IHC was often superior to IHC for NeuN, synaptophysin, or neurofilament for highlighting neoplastic neurons. Pediatr Blood Cancer 2012; 59: 1173-1179. © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 06/2012; 59(7):1173-9. · 1.89 Impact Factor
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ABSTRACT: The co-occurrence of gliomas and multiple sclerosis (MS) in the same patient is uncommon, but a well-reported phenomenon. Most have been high grade astrocytic tumors that developed after the diagnosis of MS, leading authors to postulate that chronic gliosis in demyelinative plaques might be the underlying substrate for secondary induction of a glial neoplasm. Until recently, however, genetic tools have not been available to test the hypothesis that high grade gliomas might arise from longstanding chronic gliosis, with transformation to low grade glioma, and eventually GBM, i.e., be secondary GBMs. We searched our surgical neuropathology and MS Brain Bank databases over the past 25 years (1987-2011) and identified eight cases of co-occurring MS and glioma. After careful review to guarantee both diagnoses, cases were studied by fluorescence in situ hybridization for genetic markers appropriate to diagnosis, as well as by direct sequencing for IDH1/2 and P53. No unusual genetic features were detected in our cohort; further, the 4 GBMs we did identify did not have clinical features of secondary glioblastomas nor did any of the four manifest IDH-1 immunohistochemical expression or IDH1/2 mutations, as might be expected in secondary GBMs. Conversely, PTEN loss and EGFR expression, features often found in primary GBMs, but seldom identified in secondary GBMs, were found in 3 of 4 GBMs. We conclude that gliomas in MS patients have genetic features paralleling counterparts in non-MS patients. There is no strong genetic evidence for GBMs to be secondary GBMs.
Journal of Neuro-Oncology 05/2012; 109(2):261-72. · 3.21 Impact Factor
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ABSTRACT: Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence. Differing clinical behavior between the two GH tumor subtypes, sparsely granulated (SG) versus densely granulated (DG), has been reported, but has not been used routinely in clinical management. SG tumors are more common in younger patients (<50 years), and are usually larger tumors. SG tumors have been reported to be less responsive to somatostatin analogs (SSA) than DG tumors. The mechanisms underlying these potential differences in tumor behavior, however, are poorly defined. Subsets (up to 50 %) of DG adenomas harbor a gsp mutation that can activate cAMP that provides a theoretical intracellular target for somatostatin therapy. In contrast, some SG tumors have reduced somatostatin receptor expression and mutations in the extracellular domain of the GH receptor that may contribute to SSA resistance. While DG versus SG growth hormone adenomas are readily distinguished by immunohistochemistry, other less common GH adenoma variants still require electron microscopy (EM) for confident subclassification. Whether these less common variants possess unique clinical features is unknown. Research is needed to identify clinically relevant biomarkers of GH pituitary tumors that predict risk of recurrence and response to medical therapy.
Endocrine 03/2012; 42(1):18-28. · 1.42 Impact Factor
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Acta Neuropathologica 12/2011; 122(6):783-5. · 9.32 Impact Factor
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Diane K Birks,
Andrew M Donson,
Purvi R Patel,
Christopher Dunham,
Andrea Muscat,
Elizabeth M Algar,
David M Ashley, B K Kleinschmidt-Demasters,
Rajeev Vibhakar,
Michael H Handler,
Nicholas K Foreman
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ABSTRACT: Molecular profiling of tumors has proven to be a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas, and other cancers. However, the molecular landscape of atypical teratoid/rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to sex, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of some genes associated with choroid plexus lineage in cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean, 4.7 months) in both clusters 3 and 4, compared with clusters 1 and 2 (mean, 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were upregulated in the short survival clusters, with BMP4 showing the most significant upregulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist in AT/RTs and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic, and therapeutic value.
Neuro-Oncology 09/2011; 13(12):1296-307. · 5.72 Impact Factor
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ABSTRACT: To analyze the pathology, outcomes, and prognostic factors in patients with high-grade glioma undergoing reoperation after radiotherapy (RT).
Fifty-one patients with World Health Organization Grade 3-4 glioma underwent reoperation after prior RT. The median dose of prior RT was 60 Gy, and 84% received chemotherapy as part of their initial treatment. Estimation of the percentage of necrosis and recurrent tumor in each reoperation specimen was performed. Pathology was classified as RT necrosis if ≥80% of the specimen was necrotic and as tumor recurrence if ≥20% was tumor. Predictors of survival were analyzed using log-rank comparisons and Cox proportional hazards regression.
The median interval between the completion of RT and reoperation was 6.7 months (range, 1-59 months). Pathologic analysis showed RT necrosis in 27% and recurrence in 73% of cases. Thirteen patients required a reoperation for uncontrolled symptoms. Among them, 1 patient (8%) had pathology showing RT necrosis, and 12 (92%) had tumor recurrence. Median survival after reoperation was longer for patients with RT necrosis (21.8 months vs. 7.0 months, p=0.047). In 7 patients with Grade 4 tumors treated with temozolomide-based chemoradiation with RT necrosis, median survival from diagnosis and reoperation were 30.2 months and 21.8 months, respectively.
Patients with RT necrosis at reoperation have improved survival compared with patients with tumor recurrence. Future efforts to intensify local therapy and increase local tumor control in patients with high-grade glioma seem warranted.
International journal of radiation oncology, biology, physics 09/2011; 81(1):211-7. · 4.59 Impact Factor
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ABSTRACT: Gonadotrope and null cell pituitary tumors cause significant morbidity, often presenting with signs of hypogonadism together with visual disturbances due to mass effects. Surgery and radiation are the only therapeutic options to date. To identify dysregulated genes and pathways that may play a role in tumorigenesis and/or progression, molecular profiling was performed on 14 gonadotrope tumors, with nine normal human pituitaries obtained at autopsy serving as controls. Bioinformatic analysis identified putative downstream effectors of tumor protein 53 (p53) that were consistently repressed in gonadotrope pituitary tumors, including RPRM, P21, and PMAIP1, with concomitant inhibition of the upstream p53 regulator, PLAGL1(Zac1). Further analysis of the growth arrest and DNA damage-inducible (GADD45) family revealed no change in the p53 target, GADD45α, but identified repression of GADD45β in pituitary tumors in addition to the previously reported inhibition of GADD45γ. Overexpression of GADD45β in LβT2 mouse gonadotrope cells blocked tumor cell proliferation and increased rates of apoptosis in response to growth factor withdrawal. Stable gonadotrope cell transfectants expressing increased GADD45β showed decreased colony formation in soft agar, confirming its normal role as a tumor suppressor. Unlike previous studies of GADD45γ in pituitary tumors and α and β in other tumors, bisulfite sequencing showed no evidence of hypermethylation of the GADD45β promoter in human pituitary tumor samples to explain the repression of its expression. Thus, GADD45β is a novel pituitary tumor suppressor whose reexpression blocks proliferation, survival, and tumorigenesis. Together these studies identify new targets and mechanisms to explore in pituitary tumor initiation and progression.
Endocrinology 08/2011; 152(10):3603-13. · 4.46 Impact Factor
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ABSTRACT: Spindle cell oncocytoma (SCO) is a rare sellar-region tumor recently codified in the World Health Organization (WHO) 2007 Classification as a grade I neoplasm. Despite this grading, recurrences have been demonstrated but, to date, extensive recurrent bleeding into these tumors has not been documented. A 70-year-old woman first presented in 1996 with visual difficulties and was found to have a sellar-region mass with heterogeneous neuroimaging features, leading to preoperative diagnosis of craniopharyngioma. Transsphenoidal, gross total resection was achieved despite extensive intraoperative bleeding; pathology showed an unusual spindle cell neoplasm which could not be further classified. She received no further treatment and was lost to our follow-up until 2009, when she again presented with visual deterioration. Neuroimaging demonstrated recurrence of a large sellar-region tumor with heterogeneous signal characteristics, prompting re-resection. Review of her original and recurrent tumor allowed diagnosis of SCO; extensive intratumoral hemorrhage of varying ages and widespread hemosiderin accounted for her complex neuroimaging features. Vimentin, S100, and galectin-3 immunoreactivity was consistent with SCO. EM demonstrated abundant mitochondria, short intercellular junctions, and absence of neurosecretory granules. Thyroid disease was documented clinically. SCOs are sufficiently rare that documentation of unusual features is important. Recurrent bleeding with resultant complex neuroimaging is unique to this case, but appears to overlap with a related sellar-region tumor, pituicytoma. The presence of thyroid disease also links SCO with pituicytoma. The 13-year interval to recurrence is the longest reported to date in SCO; WHO grade I designation may be premature for this neoplasm.
Journal of Neuro-Oncology 01/2011; 101(1):145-54. · 3.21 Impact Factor
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ABSTRACT: McCune-Albright syndrome (MAS) is a postzygotic (non-germline) disorder characterized by polyostotic fibrous dysplasia, cafe-au-lait macules and hypersecretory endocrinopathies. A significant percentage of MAS patients have pituitary adenomas that are either growth hormone (GH) or mixed GH/prolactin (PRL)-producing. Surgical excision may be challenging-or even impossible-due to the associated severe fibrous dysplasia of the skull base. Treatment relies on an interdisciplinary, multi-modal approach from endocrinologists, neurosurgeons and radiation oncologists. We present two cases of women with MAS and GH-secreting pituitary adenomas, encountered in our 30-year experience with pituitary diseases. The first patient successfully underwent transsphenoidal surgical resection for a pituitary microadenoma in 1997 (at age 18) and again in 2009 for recurrent disease, with a significant reduction in IGF-1 level. Immunohistochemistry (IHC) and electron microscopy (EM), performed on both specimens, showed a mammosomatotroph adenoma with GH, PRL, alpha subunit (+) IHC, with increased fibrous bodies developing over the 13-year interval. Focal hyperplasia could be discerned. EM in 1997 showed an admixture of mammosomatotrophs, mature lactotrophs and somatotrophs, with a bimodal population identified in 2009. The second MAS patient had long-standing polyostotic fibrous dysplasia, but was only recently diagnosed with GH excess and a pituitary adenoma, at the age of 29 years. Surgical resection was not advised in this patient because of the massive obstructive skull-base fibrous dysplasia. Medical therapy was initiated with somatostatin analogues, although responses in both patients have been suboptimal to date. We review the literature on GH excess in MAS to highlight its surgical and medical challenges.
Journal of Neuro-Oncology 11/2010; 104(1):215-24. · 3.21 Impact Factor
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ABSTRACT: Outcomes for average-risk medulloblastoma are excellent with 5-year event-free survival and overall survival>80%. Treatment failures include radiation-induced glioblastomas (RIG), which are often diagnosed solely on imaging. Recent studies suggest that RIGs differ from spontaneous glioblastoma multiforme (GBM), based on microarray gene-expression profiling. Retrospective review of children with average-risk medulloblastoma treated from 1996 to 2003 included 16 patients with 5 treatment failures. One died of disease progression, 1 died as a result of radiation necrosis, and 3 children died of pathology-confirmed GBM. Of these 3 GBMs, one was studied with electron microscopy, cytogenetics, and gene-expression microarray analysis. This tumor had focal medulloblastoma and similarity by gene-expression microarray with other RIGs. With both components in the recurrent tumor, we suggest it was in the process of transitioning from medulloblastoma to RIG, that is, "catching the tumor in the act." Some radiation-induced nervous system tumors may develop as a direct result of severe oncologic changes within the original tumor cells, with the tumor evolving into a different phenotypic tumor type. We recommend biopsy for tissue confirmation and genetic expression profile to shed light on the etiology of radiation-induced neoplasms.
Journal of Pediatric Hematology/Oncology 10/2010; 32(7):e272-8. · 1.16 Impact Factor
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ABSTRACT: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme.
Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used.
A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis.
The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm.
International journal of radiation oncology, biology, physics 10/2010; 81(4):1066-74. · 4.59 Impact Factor
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ABSTRACT: Intracranial chondromas are uncommon benign lesions usually attached to dura and located over the convexity of the skull. Osteochondromas are even rarer and additionally contain a benign bony component. Both lesions are reportedly difficult to distinguish from meningiomas on pre-operative neuroimaging studies, although few detailed pathologic-neuroimaging correlation studies have appeared in the literature, particularly for intracranial osteochondromas. A 33-year-old woman with a 4-year history of headaches presented with recent onset of left-sided muscle spasms and weakness. Two days prior to admission to our hospital, neuroimaging studies had shown a large right convexity mass with unusual multifocal bright signal intensities throughout an otherwise isointense mass. The bright signals were interpreted as showing multifocal hemorrhage and the mass was felt to be a convexity meningioma. However, subsequent catheter angiography characterized the lesion as being avascular. The mass was resected en bloc. Extensive histological sectioning revealed a benign osteochondroma predominantly composed of lobules of hypocellular cartilage. Microdissection of the different components revealed that the multifocal, spicule-like bright foci interpreted as hemorrhage on neuroimaging studies were instead foci of benign bone containing metaplastic bone marrow with trilineage hematopoietic cell populations and adipose tissue. Centrally, the hilum of the lesion contained avascular loose connective tissue. No recent or remote hemorrhage was identified anywhere in the lesion. Rare convexity osteochondromas may be mistaken for high-grade meningiomas on neuroimaging studies; their avascular nature, coupled with their complex signal pattern can serve as clues to the correct pre-operative diagnosis.
Journal of Neuro-Oncology 12/2009; 98(3):421-6. · 3.21 Impact Factor
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ABSTRACT: Acute hemorrhagic leukoencephalopathy (AHLE) is a rare, acute disorder characterized by perivenular demyelination and diffuse hemorrhagic necrosis of the central nervous system. AHLE is thought to represent a hyperacute form of acute disseminated encephalomyelitis. AHLE is associated with a greater morbidity and mortality and, fortunately, is much less common than acute disseminated encephalomyelitis. Since most cases of AHLE result in patient demise, forensic pathologists should be cognizant of this entity and consider it in their differential diagnosis.Here we describe an interesting case of a previously healthy 11-year-old boy who initially complained of vague gastroenteritis-like symptoms while visiting a mountain lake. The boy's symptoms evolved to include severe headache and dizziness, necessitating a visit to a rural emergency department. He presented with focal neurologic findings, and head computed tomography (CT) scan confirmed thalamic edema. Cerebrospinal fluid analysis was suggestive of infectious etiology, and multiple empiric therapies were initiated. He was transferred to our institution, and his clinical status continued to worsen. Given the poor prognosis, the family requested withdrawal of supportive care. On day 14 of symptoms the boy succumbed to his illness. An autopsy was requested to further characterize the proximate cause of death.AHLE often presents with abrupt onset of fever, neck stiffness, seizure, and/or focal neurologic signs several days following a viral illness or vaccination. Thus, AHLE can clinically mimic a direct central nervous system infection or a toxic ingestion. AHLE has a very poor prognosis, with rapid deterioration and death usually occurring within days to one week after onset of symptoms. The cause for AHLE is unclear. An autoimmune pathophysiology is likely, with immune cross-reactivity between myelin basic protein moieties and various infectious agent antigens. Treatment for AHLE is not well-established; some authors describe in recent literature that a combination of immunosuppressant medications and/or therapeutic plasma exchange may be of benefit in treating AHLE.
The American journal of forensic medicine and pathology: official publication of the National Association of Medical Examiners 12/2009; 31(1):7-11. · 0.71 Impact Factor
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ABSTRACT: Evidence suggests that West Nile virus (WNV) neuroinvasive disease occurs more frequently in both solid organ and human stem cell transplant recipients. The effect of concomitant anti-B-cell therapy with rituximab, a CD20(+) monoclonal antibody, on WNV infection in this population, however, has not been reported. We describe a case of a patient with alpha-1-antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2-A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV-specific hyperimmune globulin (Omr-Ig-Am) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis.
Clinical Transplantation 08/2009; 24(2):223-8. · 1.67 Impact Factor
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ABSTRACT: Despite advances in therapy, outcome in many high-grade pediatric central nervous system (CNS) tumors remains poor. The focus of neuro-oncology research has thus turned towards identifying novel therapeutic targets. Poly(ADP-ribose) polymerase-1 (PARP1) is a DNA repair protein that has been studied in a variety of malignancies and may interfere with therapy-induced DNA damage, however expression in pediatric CNS tumors is unknown.
We evaluated PARP1 mRNA expression in 81 pediatric CNS tumors using microarray technology. Protein expression was examined by Western blot.
PARP1 mRNA is highly expressed in high-grade tumors (P < 0.0001). PARP1 mRNA expression was greater in high-grade glioma than pilocytic astrocytoma (P = 3.5 x 10(-5)) and in large cell medulloblastoma over classic medulloblastoma (P = 0.0053). PARP1 protein was also prominent in high-grade tumors (P = 0.022).
These findings indicate that PARP1 is expressed in high-grade pediatric CNS tumors, implicating PARP1 inhibition as a potential therapeutic target.
Pediatric Blood & Cancer 06/2009; 53(7):1227-30. · 1.89 Impact Factor
