Howard T Chang

• MD, PhD
• Michigan State University

Aggressive primary brain tumors (APBT) glioblastoma multiforme and grade IV astrocytoma are treated with multimodality treatments that include surgery to remove as much tumor as possible without sacrificing neurological function followed by radiation therapy and chemotherapy usually temozolomide. Survivals in adults are in the range of 8–16 months....

Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft-tissue neoplasm that arises mostly in the extremities of young people and generally carries a good prognosis. Intracranial location is unusual and frequently associated with myxoid change. EWSR1 gene fusions with members of the CREB family (CREB1, ATF1, and CREM) are well-established events...

Objectives Aggressive primary brain tumors like glioblastoma multiforme (GBM) have been refractory to newer therapeutics. OBJECTIVE: In a pilot study we evaluated the feasibility and possible efficacy of combining 6 weeks of a ketogenic diet (KD) following initial neurosurgery with radiation therapy and temozolomide chemotherapy Methods Following...

INTRODUCTION Combining an adjuvant ketogenic diet (KD) with standard therapy of radiation and chemotherapy right after tissue diagnosis is feasible and safe. We report outcomes of a pilot clinical trial study using a KD combined with radiation and chemotherapy as initial therapy for glioblastoma (GBM). METHODS Eligibility criteria included: 1. Tis...

INTRODUCTION: We initiated and now report early outcomes of a pilot clinical trial study using a ketogenic diet (KD) combined with radiation and chemotherapy as initial therapy for aggressive gliomas (glioblastoma, GBM). METHODS Eligibility criteria included: 1. Tissue diagnosis; 2. Age over 18; 3. ECOG performance status of 2 or better; and 4. No...

Survival of glioblastoma multiforme (GBM) with the current recommended treatment is poor. Reported median survivals are approximately 8–15 months. Based on recent publications from animal models, combining cancer drugs, radiation, and diet-metabolic treatments may be a new route to better survivals. To investigate this possibility, we have begun a...

Tissue culture, animal studies and case reports suggests that combining a ketogenic diet (KD) with cytotoxic treatments like radiation, chemo-therapy or both may have a synergistic effect as initial treatment of aggressive gliomas. We report early results of a pilot study using a KD combined with radiation and chemo tx as initial tx of aggressive g...

e13529 Background: Aggressive primary brain cancers like glioblastoma multiforme (GBM) are metabolically active tumors. We hypothesis that abnormalexpression of metabolic enzymes may be useful in predicting survival. Methods: 60 patients (45 with GBM, 11 with anaplastic gliomas and 4 with gliosarcoma) were evaluated using Immunohistochemistry (IHC)...

INTRODUCTION Aggressive primary brain cancers like glioblastoma multiforme (GBM) are metabolically active tumors. We hypothesis that abnormal expression of metabolic enzymes may reflect the tumors increased metabolism and be useful in predicting survival. METHODS 60 patients (45 with GBM, 11 with anaplastic gliomas and 4 with gliosarcoma) were eva...

Epithelioid Schwannoma of a Spinal Nerve Root - Volume 43 Issue 3 - Rachael A. Vaubel, Howard T. Chang, Karen Fritchie, Patrice C. Abell Aleff, Mark E. Jentoft

Based on the hypothesis that cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary or alternative therapy for treatment of malignant gliomas. We report here our experience in treating two glioma patients with an IRB-approved energy-restricted ketogenic d...

INTRODUCTION: Aggressive primary brain cancers like glioblastoma multiforme (GBM) are metabolically active tumors with a poor prognosis. We hypothesize that expression of metabolic enzymes may be reflective of the tumors increased metabolism and might be useful in predicting survival. METHODS: Immunohistochemistry (IHC) reactions using formalin fix...

NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that...

BACKGROUND: A ketogenic diet (KD) has been proposed as an alternative therapy for treatment of malignant gliomas. Unlike normal brain, malignant brain tumors may not be able to efficiently metabolize ketones. The ketogenic diet exploits this metabolic difference as a possible therapeutic approach. This report reviews the past reported experiences i...

BACKGROUND: A ketogenic diet (KD) has been proposed as an alternative therapy for treatment of malignant gliomas. Unlike normal brain, malignant brain tumors may not be able to efficiently metabolize ketones. The ketogenic diet exploits this metabolic difference as a possible therapeutic approach. This report reviews the past reported experiences i...

Diffuse intrinsic pontine gliomass (DIPGss) account for 10% of pediatric brain tumors and have a universally poor prognosis. Our laboratory has shown that targeting the NOTCH pathway in glioblastoma (GBM) with gamma secretase inhibitors (GSI), inhibits the growth and viability of tumor neurospheres. Primary DIPG as well as DIPG cell lines express h...

Transient neurological dysfunction may be associated with uncommon disorders and should prompt consideration of a broad differential diagnosis when assessing patients with episodic symptoms. The most common causes of transient neurological dysfunction include transient ischemic attack (TIA), seizure disorder, and migraine and its variants. However,...

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor which is known to have frequent alteration of mTOR signaling. Analysis of DIPG tissue obtained through the Mid-Atlantic DIPG Consortium (MADC) also shows high level activation of Notch pathway effectors HES4 and HES5. We have established JHH DIPG1, a human DIPG xen...

Recent studies in animal models, based on the hypothesis that malignant glioma cells are more dependent on glycolysis for energy generation, have shown promising results using ketogenic diet (KD) therapy as an alternative treatment strategy for malignant glioma, effectively starving glioma cells while providing ketone bodies as an energy source for...

e13047 Background: We initiated a pilot study to evaluate an energy restricted ketogenic diet (ERKD) as treatment for patients with glioblastoma multiforme (GBM) whose brain tumor had progressed with standard therapy. Methods: This reports documents our experience using an ERKD with an IRB approved, clinical trials #NCTO1535911 registered treatment...

e13048 Background: The enzymatic differences in energy metabolism between normal brain tissues and malignant gliomas formed the basis for animal model studies that showed increased survival in mice with orthotopically transplanted glioblastoma multiforme (GBM) treated with energy restricted ketogenic diet (ERKD). To test the hypothesis that human b...

This study aimed to evaluate a 12 week ERKD protocol for advanced GBM. A 55 year old white male with progressive GBM was hospitalized to establish ketosis and initiate ERKD. A therapeutic range was established for serum betahydroxybutyrate (BHB) of 3–6 mmol/L and serum glucose of 50–70 mg/dl. Feeding began when patient achieved BHB of ≥3 mmol/L. Wh...

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. Due to its critical location within the brainstem, and its characteristic MRI signature, biopsy is rarely performed. Since many patients die at home in hospice care, autopsy specimens have traditionally been rare. Because of this difficulty in obtaining tissue, th...

2056 Background: Malignant glial cells may have altered expression of mitochondrial enzymes that are key for deriving energy from ketones. The novel strategy of treating malignant gliomas with a ketogenic diet has been tested in animal models with promising results. To evaluate the applicability of these findings to human patients we tested the hyp...

Chronic ingestion of yellow star thistle (Centaurea solstitialis) or Russian knapweed (Acroptilon repens) causes nigropallidal encephalomalacia (NPE) in horses with an abrupt onset of neurologic signs characterized by dystonia of lips and tongue, inability to prehend food, depression, and locomotor deficits. The objectives of this study were to ree...

We report a case of a maturing immature intraventricular teratoma in a neonate. The computed tomography and magnetic resonance imaging and pathologic findings are described. The relevant literature is reviewed and management is discussed.

With rare exceptions, pediatric tectal gliomas have been generally reported as low-grade tumors with relatively good prognosis. The patients are usually treated conservatively to manage the signs and symptoms of obstructive hydrocephalus. We report a case of a tectal glioma in a 6-years-old girl with histological features of anaplastic mixed oligoa...

Lymphomatoid granulomatosis (LG) is a rare, Epstein-Barr virus (EBV)-associated systemic angiodestructive lymphoproliferative disorder that may progress to a diffuse large B cell lymphoma. Pulmonary involvement may mimic other more common lung pathologies including pneumonias. Therapeutic standards have not been established for LG, but rituximab, i...

Endometrial adenocarcinoma is one of the most common gynecological tumors in postmenopausal women. The distant metastasis mostly involves liver, lung and bone. Scalp metastases from endometrial adenocarcinoma are very rare. A 63-year-old female with history of irregular vaginal bleeding presented with progressive headaches and a rapidly enlarging m...

A 57-year-old woman presented with a 6-month history of progressive worsening of back pain as well as numbness from below her bra line and extending distally, involving her abdomen and bilateral lower extremities. There was no associated motor weakness or bladder or bowel incontinence. Magnetic resonance imaging showed a heterogeneous T1-hypointens...

Colloid cysts of the third ventricle are benign intracranial tumors that usually become symptomatic in adults, rather than in children. Rare hemorrhages in these cysts can cause acute obstructive hydrocephalus and sudden death. We report a novel pediatric case of hemorrhagic colloid cyst in a 9-year-old girl who presented with headaches, nausea, an...

Clinicopathological correlation of three cases of subacute cervical spinal cord contusions. To correlate the pathology of subacute cervical spinal cord injury (SCI) with imaging and clinical-functional studies, and to compare with findings from previous human SCI studies and animal models of SCI. Department of Pathology, SUNY-Upstate Medical Univer...

Alzheimer disease is characterized by extracellular plaques composed of Aβ peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the Aβ1-42 peptide. This complex inactivates neuroserpin as an inhibitor of tissue plasmino...

Alzheimer disease is characterized by extracellular plaques composed of Abeta peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the Abeta(1-42) peptide. This complex inactivates neuroserpin as an inhibitor of tissue...

A 4-year-old girl had a large midline cerebellar solid and cystic mass partially attached to the meninges. The original diagnosis was glioblastoma multiforme and she was treated by a gross-total surgical resection followed by chemotherapy and radiation therapy to the posterior fossa during the ensuing 14 months. She has received no further therapy...

We describe the brain autopsy findings from three of five siblings who suffered dementia with clinical diagnoses including Alzheimer's, Parkinson's, and Pick's disease. Five other living siblings appear unaffected. All of the autopsied brains showed severe atrophy (brain weights 613, 641, and 750 g) of the frontal and temporal lobes, and to a sligh...

Balamuthia mandrillaris meningoencephalitis is a rare but often fatal infection; only 2 survivors have been reported to date worldwide. We report the case of an apparently immunocompetent patient (72-year-old woman) who developed several episodes of seizures without prior history of respiratory or skin infections. Magnetic resonance imaging with co...

Balamuthia mandrillaris meningoencephalitis is a rare but often fatal infection; only 2 survivors have been reported to date worldwide. We report the case of an apparently immunocompetent patient (72-year-old woman) who developed several episodes of seizures without prior history of respiratory or skin infections. Magnetic resonance imaging with co...

Sinus pericranii is a rare disorder characterized by a congenital or acquired epicranial blood-filled nodule of the scalp that is in communication with an intracranial dural sinus through dilated diploic veins of the skull. We describe two patients with sinus pericranii: a 3-year-old boy with a congenital lesion and a 3-year-old girl whose lesion a...

The syndrome of frontotemporal dementia represents a diverse group of diseases presenting with behavioral and cognitive disturbances. The expression of the microtubule-associated protein tau was studied in postmortem samples of frontal cortex of 19 cases (12 Pick's disease A, B, C; 4 dementia lacking distinct histology; 3 motor neuron disease type)...

An 80-year old man presented with shortness of breath and was found to have a large right pleural effusion. Cytology of the pleural fluid showed atypical papillary clusters of epithelioid cells. Multiple white-yellow nodules studding the pleural surfaces were seen at thoracoscopy, and biopsies showed solid and papillary clusters of large epithelioi...

The aim of this study was to assess the distribution of neurons immunoreactive for parvalbumin (PV), calbindin (CaBP), glutamic acid decarboxylase (GAD), and gamma-aminobutyric acid (GABA) in the somatosensory thalamus of the raccoon and to compare these features to those of other species, especially primates. Immunohistochemistry was used to study...

Robert O. Bonow, Blase A. Carabello, Kanu Chatterjee, Antonio C. de Leon, David P. Faxon, Michael D. Freed, William H. Gaasch, Bruce Whitney Lytle, Rick A. Nishimura, Patrick T. O’Gara, Robert A. O’Rourke, Catherine M. Otto, Pravin M. Shah, Jack S. Shanewise, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Elliott M. Antman...

The ventral forebrain, including the ventral striatum, the ventral pallidum and the substantia innominata, is an important region involved in the functions of the basal ganglia and the limbic system, as well as the magnocellular corticopetal neurons of the nucleus basalis of Meynert. Although previous studies have shown that this region is richly i...

Leucine5-enkephalin- and choline acetyltransferase-containing, presumably cholinergic, neurons revealed by dual label immunocytochemistry were found in the shell and core of the rat nucleus accumbens. The perikarya, dendrites and boutons of cholinergic neurons were labeled with the diaminobenzidine precipitate, whereas those of the enkephalinergic...

The phenylethanolamine-N-methyltransferase (PNMT)-containing neurons in the rostral ventrolateral medulla (RVLM) (the C1 adrenergic group) have been implicated in the generation of the tonic sympathetic nerve activity. Using a double-labeling immunohistofluorescence technique, we found that 34.6 +/- 11.4% (mean +/- S.D.) of PNMT immunoreactive neur...

We investigated (1) the topography of projection neurons in the nucleus basalis of Meynert (NBM) with efferents to restricted regions of the primary somatosensory (SI), the second somatosensory (SII), and the primary motor (MI) cortices in the rat; (2) the percentage of these NBM projection neurons that were cholinergic; and (3) the collateralizati...

Fluoro-Ruby (tetramethylrhodamine-dextran amine conjugate) has been shown recently to be an effective anterograde tracer readily visible in brain sections with fluorescence microscopy. We show in this study that further microscopic analysis of Fluoro-Ruby-labeled elements is feasible with a conventional immunoperoxidase reaction using an antiserum...

Most theories of basal ganglia functions have been based on a model circuit in which the flow of information follows a one-way loop proceeding from the cerebral cortex to the striatum, the pallidum/nigra, the thalamus, and then returns to the cortex. However, this model neglects data from several studies that show a direct feedback projection from...

A pre-embedding double-labeling immunocytochemical method was used to examine the synaptic relationships between cholinergic neurons and the parvalbumin immunoreactive (PV+) neurons. The PV+ neurons were labeled by silver-intensified colloidal gold particles, and the cholinergic neurons by immunoperoxidase reaction products. Cholinergic and PV+ axo...

Under the posterior limb of the anterior commissure, a brain region intercalated between the ventral striatum and the ventral pallidum was previously identified as the interstitial nucleus of the posterior limb of the anterior commissure by de Olmos. This region, referred here as the caudal ventral stratum (VSc), is characterized by a dense plexus...

Double-labeling immunocytochemistry reactions were carried out in the monkey and the rat nucleus basalis of Meynert (NBM) to determine the extent of overlap between cholinergic neurons and neurons immunoreactive for calbindin-D-28k (CaBP), a Vitamin D-dependent calcium binding protein. The results indicate that most, but not all, NBM cholinergic ne...

Immunoperoxidase reaction was performed using a very sensitive antisera raised against Lucifer Yellow to demonstrate that dextran amines conjugated to Lucifer Yellow are anterogradely transported by axons.

A previous study has shown that many neurons in the monkey nucleus basalis of Meynert (NBM) are immunoreactive for calbindin-D-28k (CaBP), a Vitamin D-dependent calcium binding protein (Celio and Norman, 1985). More recently, it has been shown that many cholinergic neurons (i.e., immunoreactive for choline acetyltransferase, ChAT) in the human NBM...

Fluoro-Gold has been a very popular fluorescent tracer used recently for retrogradely labeling projection neurons. In this study we described the advantages of using antibodies to Fluoro-Gold in conventional immunohistochemical reaction protocols to further extend the usefulness of this tracer for both light and electron microscopic neuroanatomical...

Intracellular recordings were made in vivo from 9 giant aspiny neurons in the neostriatum of urethane-anesthetized rats. The cells were identified by intracellular staining with HRP or biocytin. The neurons exhibited morphological features typical of neostriatal cholinergic interneurons. Six of the cells were obtained from intact animals, while 3 w...

Adrenergic input to the rat substantia innominata (SI) was studied by immunocytochemical localization of phenylethanolamine N-methyltransferase (PNMT), the synthetic enzyme for adrenaline. Using primary antibodies derived from different species, we demonstrated in double-immunofluorescence labeling experiments that all PNMT-immunoreactive fibers in...

The substantia innominata (SI) and the caudal part of the globus pallidus (GP) in the rat are densely innervated by calcitonin gene-related peptide-immunoreactive (CGRP+) axons. Electron microscopic analysis revealed that CGRP+ boutons mainly formed asymmetrical synapses with dendrites in GP and SI.

Noradrenergic input to the rat substantia innominata (SI) was analyzed in this study by immunocytochemical localization of dopamine beta-hydroxylase (DBH), the synthetic enzyme for noradrenaline. DBH immunoreactive (DBH+) axons ramified extensively within the SI and appeared to be contiguous with the DBH+ terminal fields within the bed nucleus of s...

The relationship between cholinergic neurons and dopaminergic axons in the rat striatum was examined by a dual-labeling immunocytochemical method. Cholinergic neurons were identified by their immunoreactivity for choline acetyltransferase (ChAT), and dopaminergic axon terminals were identified by their positive immunoreactivity for tyrosine hydroxy...

The synaptic relationships between substance P-containing terminals and dopaminergic neurons (immunoreactive for tyrosine hydroxylase) in the substantia nigra were studied at both light and electron microscopic levels using a pre-embedding double-labeling immunocytochemical method. Many substance P-containing terminals were found to form synapses d...

The synaptic relationships between leucine-enkephalin containing axon terminals and cholinergic neurons in the rat globus pallidus were studied at both light and electron microscopic levels using a high resolution pre-embedding double-labeling immunocytochemical method. Results indicated that leucine-enkephalin terminals very rarely form monosynapt...

Intracellular recordings were obtained from rat nucleus accumbens (NAC) neurons in brain slice preparations. Local stimulations evoked depolarizing postsynaptic potential (DPSP). Injections of low density depolarizing currents decreased the amplitude of the DPSP and reversed a later portion of the DPSP into a hyperpolarizing potential. Superfusion...

Projection neurons of nucleus accumbens (NAC) of the rat were identified by either antidromic activation from stimulation of midbrain ventral tegmental area-substantia nigra (VTA-SN) regions, or by tracing axons of intracellularly labeled NAC neurons into the ventral pallidum. The morphology of these NAC projection neurons were determined to be med...

The labeled axons of neurons intracellularly injected with horseradish peroxidase (HRP) in the rat subthalamic nucleus (STH) were studied with electron microscopy. The main axons and the efferent daughter branches were all myelinated. The morphology of the intrinsic axon terminals within STH was obscured by the dark HRP reaction products, but the l...

The normal ultrastructure of the rat subthalamic nucleus (STH) was studied. The STH consisted of tightly packed neurons distributed within a neuropil filled with large numbers of blood vessels and thinly myelinated fibers. The somata of STH neurons (diameters, D, between 10 and 25 μm) contained abundant organelles but had only a small amount of bot...

Neuronal responses of the subthalamic nucleus (STH) to stimulation of the globus pallidus (GP) and the substantia nigra (SN) were studied by intracellular recording in the decorticated rat. (1) GP and SN stimulation evoked antidromic spikes in STH neurons with a mean latency of 1.2 ms and 1.1 ms, respectively. Based on the above latencies, the mean...

Light microscopic analysis of rat subthalamic (STH) neurons which were intracellularly labeled with horseradish peroxidase, following the acquisition of electrophysiological data, revealed the following: (1) The somata of STH neurons were polygonal or oval with occasionally a few somatic spines. Usually three or four primary dendrites arose from th...

Stimulation of thalamic intralaminar nuclei or structures along the intrathalamic trajectory of thalamostriatal axons evoked complex EPSPs and subsequent hyperpolarizations in rat neostriatal spiny neurons identified by intracellular injection of horseradish peroxidase and/or antidromic activation from substantia nigra. In intact urethane-anestheti...

Excitatory postsynaptic potentials evoked in rat neostriatal spiny projections neurons were followed by a long (100-300 ms) period of membrane hyperpolarization, followed in turn by a late depolarization. Concomitant with these changes in membrane potential were inhibition and subsequent excitation of spontaneous firing and excitatory activity evok...

The large neurons in the rat neostriatum consist of at least two morphologically distinct types in Golgi preparations: Type I large cells had smooth somata whereas type II large cells had somatic spines. In the present study, the ultrastructural morphology of the Golgi-stained large neostriatal neurons in the rat was analyzed by the gold-toning tec...

At least two types of large neurons (somatic cross-sectional areas, SA > 300 μm2) and five types of medium neurons (SA between 100 and 300 μm2) were distinguished in Golgi preparations of the adult rat neostriatum. Type I large cells had aspinous somata with long, radiating, sparsely spined dendrites which were sometimes varicose distally, whereas...

The physiological and morphological (light and electron microscopic) properties of four categories of neostriatal neurons (two types of medium spiny cells and two types of aspiny cells) were analyzed using the technique of intracellular recording and intracellular labeling with horseradish peroxidase. All of the neurons in this study had excitatory...

Responses of striatal neurons to stimulation in substantia nigra were recorded intracellularly in intact rats and after acute or chronic unilateral lesions of cerebral cortex or after combined cortical lesions and unilateral thalamic transections. Spiny striatal efferent neurons were identified by intracellular injection of horseradish peroxidase....

Intracellularly labeled rat neostriatal projection neurons were analyzed with both light and electron microscopy. The axons of medium spiny neurons were traced into the globus pallidus and were found to make synaptic contacts with pallidal dendrites. Despite the common somato-dendritic morphology of the neostriatal projection neurons, two different...

The question of origin of the excitatory and inhibitory responses that occur in neostriatal neurons following electrical stimulation of the substantia nigra is complicated by the possible spread of stimulus currents to numerous unspecifiable systems of neuronal elements. The present work begins to address this problem through the study of conductio...