Doug Miller | University of Missouri Columbia (original) (raw)

Papers by Doug Miller

Pediatric Blood & Cancer, 2008

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by m... more We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.

Pediatric Blood & Cancer, 2008

Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor o... more Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event-free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR). Between 1991 and 2002, 43 children with sPNET were prospectively treated on two serial studies (HS I and II). After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with five cycles of ICHT (vincristine, cisplatin, cyclophosphamide, and etoposide). Patients on HS II with disseminated disease received high-dose methotrexate during ICHT. If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR. Five-year EFS and OS were 39% (95%CI: 24%, 53%) and 49 (95%CI: 33%, 62%), respectively. Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs. Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 of 20) are alive without exposure to radiation therapy. ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients.

Cureus

Extra-abdominal desmoid tumors (DTs) are rare tumors of apparent fibroblastic origin with unpredi... more Extra-abdominal desmoid tumors (DTs) are rare tumors of apparent fibroblastic origin with unpredictable clinical behavior. Though histologically benign and slow growing, DTs can be proliferative, aggressive tumors, invading the surrounding areas. DTs located extra-abdominally are most commonly found in the extremities or proximal structures like the shoulders, chest wall, and neck. Spinal involvement is very rare. Here, we describe a case where an extraabdominal DT mimicked a schwannoma in the posterior cervical spine. A 67-year-old female patient presented with acute neck and bilateral shoulder pain. After attempting conservative treatments with no symptomatic relief, a magnetic resonance imaging of the cervical spine was obtained, showing a paraspinal mass in the posterior elements from C2 to C4. The computed tomography guided needle biopsy showed rare spindle cells, suggestive of a spindle cell neoplasm, and complete surgical resection was performed. The pathology report was consistent with fibromatosis, leading to a final diagnosis of the extra-abdominal desmoid. This case demonstrates a rare presentation of an unusual tumor that often manifests with nonspecific symptoms or no symptoms at all.

American journal of clinical pathology, 2015

Neuropediatrics, 2015

Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete... more Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete absence of a brainstem segment with the rostral and caudal brainstem portions connected only by a thin cord of tissue. The outcome is poor and the majority of children die within the first 2 months of life without achieving developmental milestones. We report on the cases of two children with BD and a prolonged spontaneous survival. Neither patient required intubation or mechanical ventilation and each survived longer than 2 months (one child died at the age of 8 months, the other is alive at the age of 4.5 years). In addition, patient 1 is the only child with BD reported so far who achieved some developmental milestones. Although the long-term neurodevelopmental outcome of BD remains unfavorable, the expansion of the phenotypic spectrum may be important in terms of counseling.

Pediatric and Developmental Pathology, 2007

Viral (lymphocytic) meningitis typically does not cause sudden death, especially in the absence o... more Viral (lymphocytic) meningitis typically does not cause sudden death, especially in the absence of severe inflammation in the brain or other organs. We report 2 toddlers with clinical evidence of a viral infection who died unexpectedly and were found at autopsy to have lymphocytic meningitis associated with severe brain edema, transtentorial herniation, neurogenic pulmonary edema and hemorrhage, and cardiomegaly. Influenza A virus, demonstrated in tracheal epithelium by immunocytochemistry, is the presumed cause of the mild meningitis in 1 case; adenovirus was cultured from swabs of the brain and anus in the 2nd case. Current concepts of neurogenic pulmonary edema and acute cardiac dysfunction associated with intracranial disease are discussed in considering the mechanism of sudden death in these toddlers. These cases emphasize the possibility that mild intracranial viral infections may be a rare cause of sudden death via lethal cardiopulmonary complications. They also underscore the importance of a comprehensive autopsy, including detailed neuropathologic examination and viral testing, in determining of the cause of unexpected death in toddlers.

Archives of Pathology & Laboratory Medicine, 2012

Journal of Radiology Case Reports, 2013

Baló's concentric sclerosis is a primary inflammatory central nervous system demyelinating diseas... more Baló's concentric sclerosis is a primary inflammatory central nervous system demyelinating disease that is considered a rare, radiographically and pathologically distinct variant of multiple sclerosis. Baló's concentric sclerosis is characterized by alternating rings of demyelinated and myelinated axons, and it is most frequently diagnosed postmortem by autopsy or, more recently, by magnetic resonance imaging without pathologic verification. This report is of a case of Baló's concentric sclerosis in which the patient presented with left-sided focal sensorimotor deficits. The patient's lesion demonstrated characteristics of Baló's concentric sclerosis by magnetic resonance imaging, but since a neoplastic process was also suspected initially, the patient underwent a surgical biopsy. This pathology sample now provides the opportunity to correlate the tissue diagnosis of demyelination with characteristic magnetic resonance imaging findings; this comparison is infrequently found in the literature.

Cancer Research

We Investigated the expression and distribution of the extracellular matrix protein tenascin(TN) ... more We Investigated the expression and distribution of the extracellular matrix protein tenascin(TN) in 59astrocytomasand 11samplesof normal brain by Western blot analysisand immunohistochemistryusing antlbod lea against human TN. The tumors included 14 juvenile piocytic astro cytomas (grade I), 13 low grade fibrillary astrocytomas (grade II), S anaplastic astrocytomas (grade ifi), and 24 glloblastomas multiforme (grade IV). Proliferation indices were calculated by computer-based Im ageanalysisafter hnmunostalning with the MIB-1 antibodyagainstthe 1(1-67 prollferadon-associated antigen. Western blot analysis for TN on fresh frozen tumor tissue from 23 of the 59 astrocytomas indicated up to 4-fold higher TN expression in glioblastomas multiforme than in nontu morons control tissues. Enhanced intercellular expression of TN was observed by immunohistochemistry in glioblastomasmultiforme. More over, TN immunostaining wasconsistentlygreater within and around the walls of hyperplastic blood vessels than nonhyperplastic vessels of both high grade tumors and juvenile piocytlc astrocytomas. Juvenile piocytic astrocytomaswith IncreasedTN expressionby Western blot analysishad vascular hyperplasia by light microscopy. Proliferation indices moder ately correlated with tumor grade. Enhanced immunohistochemical ex pression of TN was associated with higher tumor grade with higher proliferation Indkes. The strong association of TN and vascular hyper plasla, regardless oftumor grade, suggests that TN may play a crucial role in angiogenesis.

SpringerPlus, 2015

It is well established that the normal human brain contains populations of neural stem/progenitor... more It is well established that the normal human brain contains populations of neural stem/progenitor cells. Recent studies suggest that they migrate toward a variety of CNS tissue injuries. In an investigation of the potential role of neural stem cells in the pathogenesis of primary CNS lymphomas (NHL-CNS), we observed that neural stem/progenitor cells appeared to accumulate at the border of the tumors with the brain and in the advancing edge of the tumors, in a pattern similar to that seen with reactive gliosis. We identified neural stem/progenitor cells using standard immunohistochemical markers thereof, including CD133, nestin, Group II Beta-tubulin, Musashi1, and the transcription factor Sox2, in neurosurgically obtained specimens of NHL-CNS metastatic carcinoma , and metastatic melanoma . We had similar results with each of these markers but found that Sox2 antibodies provided the clearest and most robust labeling of the cells at the borders of these non-glial tumors. To exclude t...

Pediatric Neurology, 2014

The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consis... more The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consisting of these three radiographic findings first described by Labrune et al. in 1996. The inheritance pattern and genetic mutation responsible for this syndrome (if any) have not been determined. We report the occurrence of this syndrome in siblings. Two sisters presented with leukoencephalopathy, cerebral calcifications, and cysts approximately 10 years apart, one at 18 years with longstanding epilepsy and the other at 25 years with postpartum stroke-like signs. In both individuals, computed tomography revealed calcifications in the basal ganglia and subcortical white matter as well as supratentorial cysts. Magnetic resonance imaging demonstrated diffuse white matter increased T2 signal and bilateral supratentorial cysts with enhancing walls. Both patients underwent biopsy, one an open biopsy and the other a stereotactic biopsy, with sections of the resected tissue revealing gliosis with Rosenthal fibers, myelin loss, and calcifications, plus in the larger sample cystic spaces and thick-walled abnormal blood vessels with hemosiderin deposition in the adjacent tissues. In these siblings, the triad of radiological findings, histopathologic findings, and lack of extraneurological findings on physical examination suggest an occurrence of familial leukoencephalopathy, cerebral calcifications, and cysts with probable autosomal recessive inheritance.

The Neurologist, 2011

Experimental and clinical studies support a pathogenic role of microglial activation and prolifer... more Experimental and clinical studies support a pathogenic role of microglial activation and proliferation (MAP) in epileptogenesis. From a consecutive series of 319 surgically treated epilepsy cases, we retrospectively reviewed the histopathological sections of 92 cases to define the prevalence and severity of MAP after excluding the other 227 because of coexisting disorders that might contribute to MAP. Severity of MAP was compared with underlying abnormalities. We assessed the response to intravenous immunoglobulin and plasmapheresis in one patient with severe MAP who had failed multiple antiepileptic drugs and epilepsy surgery. MAP was detected with routine (hematoxylin and eosin) stain in 46 of 92 cases (50%). MAP was mild in 32 cases (69.6%), moderate in 12 (26.1%), and severe in 2 (4.3%). The prevalence and severity of MAP were independent of underlying abnormalities. Immunomodulatory therapy was followed by a greater than 90% reduction in seizure activity in the treated patient. MAP is prevalent in resected human epilepsy tissue. Failure to down-regulate MAP contributes to chronic neuronal hyperexcitability. We hypothesize that MAP initiates a cycle of inflammation-induced seizures and seizure-induced inflammation. Microglia-driven epilepsy may be a primary pathogenic process in a small number of cases, as suggested by the pathology and therapeutic response in our patient, but may contribute to epileptogenesis in many more.

Rapid Communications in Mass Spectrometry, 2007

The purpose of this study is to determine the feasibility of the direct matrix-assisted laser des... more The purpose of this study is to determine the feasibility of the direct matrix-assisted laser desorption/ionization (MALDI) identification of proteins in fixed T47D breast cancer cells and murine brain tissues. The ability to identify proteins from cells and tissue may lead to biomarkers that effectively predict the onset of defined disease states, and their dynamic behavior could be an important hint for drug target discoveries. Direct tissue application of trypsin allows protein identification in cells and tissues, while maintaining spatial integrity and intracellular organization. Using a chemical printer, matrix was co-registered on trypsinized human T47D breast cancer cells and cryo-preserved sections of murine brain tissue, followed by MALDI post-source decay (PSD) or MALDI collision-induced dissociation (CID), respectively. Mass-to-charge (m/z) data from the cells and brain tissues were processed using Mascot software interrogation of the National Center for Biotechnology Information (NCBI) database. Histone H2B was identified from cultured T47D human breast cancer cells. Tubulin beta2 was identified from mouse brain cortex following an induced stroke. These results suggest that MALDI PSD/CID, combined with bioinformatics, can be used for the direct identification of proteins from cells and tissues. Refinements in preparation techniques may improve this approach to provide a tool for quantitative proteomics and clinical analysis.

Pediatric Blood & Cancer, 2007

Neurosurgery, 2006

To determine treatment outcome after surgical resection for progressive brain metastases after ga... more To determine treatment outcome after surgical resection for progressive brain metastases after gamma knife radiosurgery (GKR) and to explore the role of dynamic contrast agent-enhanced perfusion magnetic resonance imaging (MRI) and proton spectroscopic MRI studies (MRS/P) in predicting pathological findings. Between 1997 and 2002, 32 patients underwent surgical resection for suspected progression of brain metastases from a cohort of 245 patients with brain metastases treated with GKR. Postradiosurgery MRI surveillance was performed at 6 and 12 weeks, and then every 12 weeks after GKR. In some cases, additional MRI scanning with spectroscopy or perfusion (MRS/P) was used to aid differentiation of radiation change from tumor progression. The decision to perform neurosurgical resection was based on MRI or clinical evidence of lesion progression among patients with a Karnofsky performance score of 60 or more and absent or stable systemic disease. Thirteen percent (32 out of 245) of patients and 6% (38 out of 611) of lesions required surgical resection after GKR. The median time from GKR to surgical resection was 8.6 months (range, 1.7-27.1 mo). The 6-, 12-, and 24-month actuarial survival from time of GKR was 97, 78, and 47% for the resected patients and 65, 40, and 19% for the nonresected patients (P < 0.0001). The two-year survival rate of patients requiring two resections after GKR was 100% compared with 39% for patients undergoing one resection (P = 0.02). The median survival of resected patients was 27.2 months (range, 7.0-72.5 mo) from the diagnosis of brain metastases, 19.9 months (range, 5.0-60.7 mo) from GKR, and 8.9 months (range, 0.2-53.1 mo) from surgical resection. Tumor was found in 90% of resected specimens and necrosis alone in 10%. MRS/P studies were performed in 15 resected patients. Overall, MRS/P predicted tumor in 11 lesions, confirmed pathologically in nine lesions, and necrosis alone was found in two. The MRS/P predicted necrosis alone in three, whereas pathology revealed viable tumor in two and necrosis in one lesion. Surgical intervention of progressive brain metastases after GKR in selected patients leads to a meaningful improvement in survival rates. Further studies are necessary to determine the role of MRS/P in the postradiosurgery surveillance of brain metastases.

Neurosurgery, 1996

Progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by the JC papova... more Progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by the JC papovavirus, is an opportunistic infection afflicting patients with impaired cellular immunity. Although initially described in patients with hematological malignancies, PML has become associated with several other immunocompromised states, particularly human immunodeficiency virus (HIV) infection. There are numerous central nervous system manifestations in patients with acquired immunodeficiency syndrome. A major characteristic that distinguishes PML from other more common lesions, such as toxoplasmosis or non-Hodgkin's lymphoma, is the lack of contrast enhancement. We describe a case of PML that exhibits contrast enhancement, and we conclude that the diagnosis of PML must be considered in patients with HIV who have contrast-enhancing lesions. A 40-year-old woman presented with progressive hemiparesis, blurred vision, and ataxia. Magnetic resonance imaging revealed a contrast-enhancing lesion involving the left middle cerebellar peduncle, causing mild compression of the fourth ventricle. The patient underwent a stereotactic serial biopsy with the presumptive diagnosis of moderate- to high-grade glioma. Histological examination of the biopsy specimen revealed early PML. Subsequently, a test for HIV was obtained and the results were positive. We have reported another atypical radiographic characteristic of PML associated with HIV. We conclude that PML lesions can enhance after the administration of gadolinium. Therefore, the diagnosis of PML must be entertained in patients whose test results were positive for HIV with contrast-enhancing lesions and that a stereotactic serial biopsy may be necessary to provide a definitive diagnosis.

Neurosurgery, 2003

To describe the pathological features of three very similar and unusual primary central nervous s... more To describe the pathological features of three very similar and unusual primary central nervous system tumors that are not readily recognized as conventional ependymomas but which, by ultrastructural examination, have an ependymomatous character. Three distinctive tumors were found in a review of our files for cases of ependymoma. In each case, hematoxylin and eosin-stained sections were reviewed, and immunostains for epithelial membrane antigen, cytokeratin, vimentin, and glial fibrillary acidic protein were performed on formalin-fixed, paraffin-embedded sections. Electron microscopy was performed in each case. The tumors had a diffuse myxoid background, often containing tightly clustered cells that mimicked multinucleated giant cells, but lacking perivascular pseudorosettes or central lumen rosettes. Glial fibrillary acidic protein and vimentin immunostains did not reveal perivascular processes. Epithelial membrane antigen immunostains showed a dot-like cytoplasmic immunoreactivity in some cell clusters in two of the three cases. Cytokeratin was negative in all three cases. However, ultrastructurally, the cells of each tumor had extensive surface microvilli; the giant cell-like clusters had cells with extensive close appositions, some junctions, and, in two cases, lumina with microvilli. Two of the patients were adults (both with temporal lobe tumors), and one patient was 13 years old and had a cervical spinal cord intramedullary tumor. Each tumor was sharply circumscribed from adjacent central nervous system tissue but was not encapsulated. One of the cases in an adult was mitotically highly active; this tumor recurred locally 4 years after initial gross total excision. These tumors are unusual variants of ependymoma. This pattern of ependymoma is sufficiently distinctive to be recognized in hematoxylin and eosin stains once the architecture of the epithelioid clusters is appreciated.

Pediatric Blood & Cancer, 2008

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by m... more We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.

Pediatric Blood & Cancer, 2008

Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor o... more Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event-free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR). Between 1991 and 2002, 43 children with sPNET were prospectively treated on two serial studies (HS I and II). After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with five cycles of ICHT (vincristine, cisplatin, cyclophosphamide, and etoposide). Patients on HS II with disseminated disease received high-dose methotrexate during ICHT. If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR. Five-year EFS and OS were 39% (95%CI: 24%, 53%) and 49 (95%CI: 33%, 62%), respectively. Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs. Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 of 20) are alive without exposure to radiation therapy. ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients.

Cureus

Extra-abdominal desmoid tumors (DTs) are rare tumors of apparent fibroblastic origin with unpredi... more Extra-abdominal desmoid tumors (DTs) are rare tumors of apparent fibroblastic origin with unpredictable clinical behavior. Though histologically benign and slow growing, DTs can be proliferative, aggressive tumors, invading the surrounding areas. DTs located extra-abdominally are most commonly found in the extremities or proximal structures like the shoulders, chest wall, and neck. Spinal involvement is very rare. Here, we describe a case where an extraabdominal DT mimicked a schwannoma in the posterior cervical spine. A 67-year-old female patient presented with acute neck and bilateral shoulder pain. After attempting conservative treatments with no symptomatic relief, a magnetic resonance imaging of the cervical spine was obtained, showing a paraspinal mass in the posterior elements from C2 to C4. The computed tomography guided needle biopsy showed rare spindle cells, suggestive of a spindle cell neoplasm, and complete surgical resection was performed. The pathology report was consistent with fibromatosis, leading to a final diagnosis of the extra-abdominal desmoid. This case demonstrates a rare presentation of an unusual tumor that often manifests with nonspecific symptoms or no symptoms at all.

American journal of clinical pathology, 2015

Neuropediatrics, 2015

Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete... more Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete absence of a brainstem segment with the rostral and caudal brainstem portions connected only by a thin cord of tissue. The outcome is poor and the majority of children die within the first 2 months of life without achieving developmental milestones. We report on the cases of two children with BD and a prolonged spontaneous survival. Neither patient required intubation or mechanical ventilation and each survived longer than 2 months (one child died at the age of 8 months, the other is alive at the age of 4.5 years). In addition, patient 1 is the only child with BD reported so far who achieved some developmental milestones. Although the long-term neurodevelopmental outcome of BD remains unfavorable, the expansion of the phenotypic spectrum may be important in terms of counseling.

Pediatric and Developmental Pathology, 2007

Viral (lymphocytic) meningitis typically does not cause sudden death, especially in the absence o... more Viral (lymphocytic) meningitis typically does not cause sudden death, especially in the absence of severe inflammation in the brain or other organs. We report 2 toddlers with clinical evidence of a viral infection who died unexpectedly and were found at autopsy to have lymphocytic meningitis associated with severe brain edema, transtentorial herniation, neurogenic pulmonary edema and hemorrhage, and cardiomegaly. Influenza A virus, demonstrated in tracheal epithelium by immunocytochemistry, is the presumed cause of the mild meningitis in 1 case; adenovirus was cultured from swabs of the brain and anus in the 2nd case. Current concepts of neurogenic pulmonary edema and acute cardiac dysfunction associated with intracranial disease are discussed in considering the mechanism of sudden death in these toddlers. These cases emphasize the possibility that mild intracranial viral infections may be a rare cause of sudden death via lethal cardiopulmonary complications. They also underscore the importance of a comprehensive autopsy, including detailed neuropathologic examination and viral testing, in determining of the cause of unexpected death in toddlers.

Archives of Pathology & Laboratory Medicine, 2012

Journal of Radiology Case Reports, 2013

Baló's concentric sclerosis is a primary inflammatory central nervous system demyelinating diseas... more Baló's concentric sclerosis is a primary inflammatory central nervous system demyelinating disease that is considered a rare, radiographically and pathologically distinct variant of multiple sclerosis. Baló's concentric sclerosis is characterized by alternating rings of demyelinated and myelinated axons, and it is most frequently diagnosed postmortem by autopsy or, more recently, by magnetic resonance imaging without pathologic verification. This report is of a case of Baló's concentric sclerosis in which the patient presented with left-sided focal sensorimotor deficits. The patient's lesion demonstrated characteristics of Baló's concentric sclerosis by magnetic resonance imaging, but since a neoplastic process was also suspected initially, the patient underwent a surgical biopsy. This pathology sample now provides the opportunity to correlate the tissue diagnosis of demyelination with characteristic magnetic resonance imaging findings; this comparison is infrequently found in the literature.

Cancer Research

We Investigated the expression and distribution of the extracellular matrix protein tenascin(TN) ... more We Investigated the expression and distribution of the extracellular matrix protein tenascin(TN) in 59astrocytomasand 11samplesof normal brain by Western blot analysisand immunohistochemistryusing antlbod lea against human TN. The tumors included 14 juvenile piocytic astro cytomas (grade I), 13 low grade fibrillary astrocytomas (grade II), S anaplastic astrocytomas (grade ifi), and 24 glloblastomas multiforme (grade IV). Proliferation indices were calculated by computer-based Im ageanalysisafter hnmunostalning with the MIB-1 antibodyagainstthe 1(1-67 prollferadon-associated antigen. Western blot analysis for TN on fresh frozen tumor tissue from 23 of the 59 astrocytomas indicated up to 4-fold higher TN expression in glioblastomas multiforme than in nontu morons control tissues. Enhanced intercellular expression of TN was observed by immunohistochemistry in glioblastomasmultiforme. More over, TN immunostaining wasconsistentlygreater within and around the walls of hyperplastic blood vessels than nonhyperplastic vessels of both high grade tumors and juvenile piocytlc astrocytomas. Juvenile piocytic astrocytomaswith IncreasedTN expressionby Western blot analysishad vascular hyperplasia by light microscopy. Proliferation indices moder ately correlated with tumor grade. Enhanced immunohistochemical ex pression of TN was associated with higher tumor grade with higher proliferation Indkes. The strong association of TN and vascular hyper plasla, regardless oftumor grade, suggests that TN may play a crucial role in angiogenesis.

SpringerPlus, 2015

It is well established that the normal human brain contains populations of neural stem/progenitor... more It is well established that the normal human brain contains populations of neural stem/progenitor cells. Recent studies suggest that they migrate toward a variety of CNS tissue injuries. In an investigation of the potential role of neural stem cells in the pathogenesis of primary CNS lymphomas (NHL-CNS), we observed that neural stem/progenitor cells appeared to accumulate at the border of the tumors with the brain and in the advancing edge of the tumors, in a pattern similar to that seen with reactive gliosis. We identified neural stem/progenitor cells using standard immunohistochemical markers thereof, including CD133, nestin, Group II Beta-tubulin, Musashi1, and the transcription factor Sox2, in neurosurgically obtained specimens of NHL-CNS metastatic carcinoma , and metastatic melanoma . We had similar results with each of these markers but found that Sox2 antibodies provided the clearest and most robust labeling of the cells at the borders of these non-glial tumors. To exclude t...

Pediatric Neurology, 2014

The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consis... more The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consisting of these three radiographic findings first described by Labrune et al. in 1996. The inheritance pattern and genetic mutation responsible for this syndrome (if any) have not been determined. We report the occurrence of this syndrome in siblings. Two sisters presented with leukoencephalopathy, cerebral calcifications, and cysts approximately 10 years apart, one at 18 years with longstanding epilepsy and the other at 25 years with postpartum stroke-like signs. In both individuals, computed tomography revealed calcifications in the basal ganglia and subcortical white matter as well as supratentorial cysts. Magnetic resonance imaging demonstrated diffuse white matter increased T2 signal and bilateral supratentorial cysts with enhancing walls. Both patients underwent biopsy, one an open biopsy and the other a stereotactic biopsy, with sections of the resected tissue revealing gliosis with Rosenthal fibers, myelin loss, and calcifications, plus in the larger sample cystic spaces and thick-walled abnormal blood vessels with hemosiderin deposition in the adjacent tissues. In these siblings, the triad of radiological findings, histopathologic findings, and lack of extraneurological findings on physical examination suggest an occurrence of familial leukoencephalopathy, cerebral calcifications, and cysts with probable autosomal recessive inheritance.

The Neurologist, 2011

Experimental and clinical studies support a pathogenic role of microglial activation and prolifer... more Experimental and clinical studies support a pathogenic role of microglial activation and proliferation (MAP) in epileptogenesis. From a consecutive series of 319 surgically treated epilepsy cases, we retrospectively reviewed the histopathological sections of 92 cases to define the prevalence and severity of MAP after excluding the other 227 because of coexisting disorders that might contribute to MAP. Severity of MAP was compared with underlying abnormalities. We assessed the response to intravenous immunoglobulin and plasmapheresis in one patient with severe MAP who had failed multiple antiepileptic drugs and epilepsy surgery. MAP was detected with routine (hematoxylin and eosin) stain in 46 of 92 cases (50%). MAP was mild in 32 cases (69.6%), moderate in 12 (26.1%), and severe in 2 (4.3%). The prevalence and severity of MAP were independent of underlying abnormalities. Immunomodulatory therapy was followed by a greater than 90% reduction in seizure activity in the treated patient. MAP is prevalent in resected human epilepsy tissue. Failure to down-regulate MAP contributes to chronic neuronal hyperexcitability. We hypothesize that MAP initiates a cycle of inflammation-induced seizures and seizure-induced inflammation. Microglia-driven epilepsy may be a primary pathogenic process in a small number of cases, as suggested by the pathology and therapeutic response in our patient, but may contribute to epileptogenesis in many more.

Rapid Communications in Mass Spectrometry, 2007

The purpose of this study is to determine the feasibility of the direct matrix-assisted laser des... more The purpose of this study is to determine the feasibility of the direct matrix-assisted laser desorption/ionization (MALDI) identification of proteins in fixed T47D breast cancer cells and murine brain tissues. The ability to identify proteins from cells and tissue may lead to biomarkers that effectively predict the onset of defined disease states, and their dynamic behavior could be an important hint for drug target discoveries. Direct tissue application of trypsin allows protein identification in cells and tissues, while maintaining spatial integrity and intracellular organization. Using a chemical printer, matrix was co-registered on trypsinized human T47D breast cancer cells and cryo-preserved sections of murine brain tissue, followed by MALDI post-source decay (PSD) or MALDI collision-induced dissociation (CID), respectively. Mass-to-charge (m/z) data from the cells and brain tissues were processed using Mascot software interrogation of the National Center for Biotechnology Information (NCBI) database. Histone H2B was identified from cultured T47D human breast cancer cells. Tubulin beta2 was identified from mouse brain cortex following an induced stroke. These results suggest that MALDI PSD/CID, combined with bioinformatics, can be used for the direct identification of proteins from cells and tissues. Refinements in preparation techniques may improve this approach to provide a tool for quantitative proteomics and clinical analysis.

Pediatric Blood & Cancer, 2007

Neurosurgery, 2006

To determine treatment outcome after surgical resection for progressive brain metastases after ga... more To determine treatment outcome after surgical resection for progressive brain metastases after gamma knife radiosurgery (GKR) and to explore the role of dynamic contrast agent-enhanced perfusion magnetic resonance imaging (MRI) and proton spectroscopic MRI studies (MRS/P) in predicting pathological findings. Between 1997 and 2002, 32 patients underwent surgical resection for suspected progression of brain metastases from a cohort of 245 patients with brain metastases treated with GKR. Postradiosurgery MRI surveillance was performed at 6 and 12 weeks, and then every 12 weeks after GKR. In some cases, additional MRI scanning with spectroscopy or perfusion (MRS/P) was used to aid differentiation of radiation change from tumor progression. The decision to perform neurosurgical resection was based on MRI or clinical evidence of lesion progression among patients with a Karnofsky performance score of 60 or more and absent or stable systemic disease. Thirteen percent (32 out of 245) of patients and 6% (38 out of 611) of lesions required surgical resection after GKR. The median time from GKR to surgical resection was 8.6 months (range, 1.7-27.1 mo). The 6-, 12-, and 24-month actuarial survival from time of GKR was 97, 78, and 47% for the resected patients and 65, 40, and 19% for the nonresected patients (P < 0.0001). The two-year survival rate of patients requiring two resections after GKR was 100% compared with 39% for patients undergoing one resection (P = 0.02). The median survival of resected patients was 27.2 months (range, 7.0-72.5 mo) from the diagnosis of brain metastases, 19.9 months (range, 5.0-60.7 mo) from GKR, and 8.9 months (range, 0.2-53.1 mo) from surgical resection. Tumor was found in 90% of resected specimens and necrosis alone in 10%. MRS/P studies were performed in 15 resected patients. Overall, MRS/P predicted tumor in 11 lesions, confirmed pathologically in nine lesions, and necrosis alone was found in two. The MRS/P predicted necrosis alone in three, whereas pathology revealed viable tumor in two and necrosis in one lesion. Surgical intervention of progressive brain metastases after GKR in selected patients leads to a meaningful improvement in survival rates. Further studies are necessary to determine the role of MRS/P in the postradiosurgery surveillance of brain metastases.

Neurosurgery, 1996

Progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by the JC papova... more Progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by the JC papovavirus, is an opportunistic infection afflicting patients with impaired cellular immunity. Although initially described in patients with hematological malignancies, PML has become associated with several other immunocompromised states, particularly human immunodeficiency virus (HIV) infection. There are numerous central nervous system manifestations in patients with acquired immunodeficiency syndrome. A major characteristic that distinguishes PML from other more common lesions, such as toxoplasmosis or non-Hodgkin's lymphoma, is the lack of contrast enhancement. We describe a case of PML that exhibits contrast enhancement, and we conclude that the diagnosis of PML must be considered in patients with HIV who have contrast-enhancing lesions. A 40-year-old woman presented with progressive hemiparesis, blurred vision, and ataxia. Magnetic resonance imaging revealed a contrast-enhancing lesion involving the left middle cerebellar peduncle, causing mild compression of the fourth ventricle. The patient underwent a stereotactic serial biopsy with the presumptive diagnosis of moderate- to high-grade glioma. Histological examination of the biopsy specimen revealed early PML. Subsequently, a test for HIV was obtained and the results were positive. We have reported another atypical radiographic characteristic of PML associated with HIV. We conclude that PML lesions can enhance after the administration of gadolinium. Therefore, the diagnosis of PML must be entertained in patients whose test results were positive for HIV with contrast-enhancing lesions and that a stereotactic serial biopsy may be necessary to provide a definitive diagnosis.

Neurosurgery, 2003

To describe the pathological features of three very similar and unusual primary central nervous s... more To describe the pathological features of three very similar and unusual primary central nervous system tumors that are not readily recognized as conventional ependymomas but which, by ultrastructural examination, have an ependymomatous character. Three distinctive tumors were found in a review of our files for cases of ependymoma. In each case, hematoxylin and eosin-stained sections were reviewed, and immunostains for epithelial membrane antigen, cytokeratin, vimentin, and glial fibrillary acidic protein were performed on formalin-fixed, paraffin-embedded sections. Electron microscopy was performed in each case. The tumors had a diffuse myxoid background, often containing tightly clustered cells that mimicked multinucleated giant cells, but lacking perivascular pseudorosettes or central lumen rosettes. Glial fibrillary acidic protein and vimentin immunostains did not reveal perivascular processes. Epithelial membrane antigen immunostains showed a dot-like cytoplasmic immunoreactivity in some cell clusters in two of the three cases. Cytokeratin was negative in all three cases. However, ultrastructurally, the cells of each tumor had extensive surface microvilli; the giant cell-like clusters had cells with extensive close appositions, some junctions, and, in two cases, lumina with microvilli. Two of the patients were adults (both with temporal lobe tumors), and one patient was 13 years old and had a cervical spinal cord intramedullary tumor. Each tumor was sharply circumscribed from adjacent central nervous system tissue but was not encapsulated. One of the cases in an adult was mitotically highly active; this tumor recurred locally 4 years after initial gross total excision. These tumors are unusual variants of ependymoma. This pattern of ependymoma is sufficiently distinctive to be recognized in hematoxylin and eosin stains once the architecture of the epithelioid clusters is appreciated.