Biomedical subjects
Publications and source records attributed to Herbert H Engelhard.
The arachnoid membrane and pia mater are the two membranous layers that comprise the leptomeninges. Cerebrospinal fluid is made within the ventricular system by cells of the choroid plexus and ependyma. This chapter describes in detail the normal anatomic structure and physiologic interactions of the cerebrospinal fluid and leptomeningeal space that are critical to our understanding and treatment of leptomeningeal metastases.
Animal models are a critical tool for our understanding of pathogenic mechanisms and the development of therapeutic strategies. Since the 1970's, numerous syngeneic and allogeneic rodent models of leptomeningeal cancer have been developed; in this chapter, we present representative models and discuss their clinical and translational implications.
Leptomeningeal dissemination of primary CNS tumors varies widely by histologic subtype. In certain tumors including medulloblastoma, ependymoma, germ cell tumors, and primary CNS lymphoma, seeding of the cerebrospinal fluid space is a critical factor in determining stage, prognosis and appropriate therapy. Other tumor types, such as glioma, may have radiographic evidence of leptomeningeal metastases without clear impact on prognosis or therapy.
Secondary central nervous system (CNS) blastomycosis is an unusual manifestation of blastomycosis. We report a case of recurrent intracerebral blastomycosis that presented histopathologically with giant yeast-like cells and multinucleation that mimicked Coccidioides immitis. The yeast forms of Blastomyces dermatitidis usually range in size from 8 to 20 microm in diameter. Large or giant yeast forms (20-40 microm) are rare. The four cases previously reported in the literature involving giant yeast cell forms of B. dermatitidis are reviewed here. Intracerebral blastomycosis should be suspected in patients with signs and symptoms of CNS lesions and histories of primary blastomycosis, or treatment with corticosteroids, or comprised immune systems. The diagnosis should be confirmed by culture which presents typical biphasic microbiologic features.
Neuronal injury triggers the release of ciliary neurotrophic factor (CNTF), promoting local neuronal repair but producing systemic effects of anorexia and lean body weight loss. Due to the rapid rate of systemic protein loss stimulated by CNTF, we hypothesized involvement of the hepatic ubiquitin-proteasome proteolytic (UPP) pathway in CNTF-induced proteolysis. To assess the role of central CNTF in systemic UPP regulation, we measured hepatic UPP mRNA and proteasome activity in a rat model of neuronal injury and determined alterations induced by intracerebroventricular (ICV) administration of CNTF-neutralizing antibody or additional exogenous CNTF. We also assessed proteolytic parameters and nutritional status by measuring caloric intake, body weight, and protein levels. We produced neuronal injury by implanting a lateral ventricle cannula and giving daily ICV saline bolus injections, which increased hepatic 20S proteasome mRNA and enzymatic activity while reducing caloric intake, body weight, and protein levels compared to controls. Administration of ICV anti-CNTF antibodies (but not control antibodies) prevented these effects. Addition of exogenous CNTF augmented the weight loss along with the increases in 20S proteasome mRNA and proteolytic activity induced by neuronal injury. We conclude that CNTF decreases lean body weight through a combination of appetite inhibition and UPP pathway activation.
Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems.
BACKGROUND: Intraventricular hemorrhage (IVH) continues to present a challenge to neurosurgeons, often being accompanied by significant morbidity and mortality. The purpose of this paper is to present a review of the recent literature concerning the treatment of patients with IVH, and describe our current management scheme for this disorder. METHODS: A literature search was conducted to identify key articles pertaining to the pathophysiology and treatment of IVH, focusing on the more recent articles. The bibliographies of selected papers were also screened for additional useful publications. RESULTS: Management of IVH is primarily directed at controlling intracranial pressure through an external ventricular drain (EVD), but this catheter often becomes occluded by coagulated blood. The fibrinolytic system of the cerebrospinal fluid is limited, and blood may remain in the ventricles for months after a hemorrhage. IVH has a poor prognosis, partly because of the continuing mass effect of blood clots on the ventricular walls. Therefore, investigators have administered fibrinolytic agents directly into the ventricles of patients with IVH. Clinical studies of fibrinolytic therapy for IVH have found a 30 to 35% reduction in mortality with treatment, but have not yet clearly documented an improved neurologic outcome for the survivors. CONCLUSIONS: Fibrinolytic therapy may be life saving in severe cases of IVH. While many issues need to be resolved, our current practice is to administer intraventricular tissue plasminogen activator (t-PA or alteplase) if hemorrhage involves > or =30% of the volume of one of the lateral ventricles and/or the 3(rd) or 4(th) ventricle. We currently give t-PA after ruling out or treating a possible source of further bleeding, such as an unsecured aneurysm.
BACKGROUND: Recent advances that have been made in diagnostic imaging, surgical technique, chemotherapy, molecular biology, and prediction of therapeutic response could have potential impact on the optimal diagnosis and treatment of patients with brain tumors, especially those with oligodendrogliomas. In this article, the topic of oligodendroglioma and anaplastic oligodendroglioma is reviewed, highlighting the new clinical developments. METHODS: Information for this review was obtained by performing a Medline search for recent references using the term "oligodendroglioma." The bibliographies of papers obtained also were checked for articles that could provide additional understanding of this disease and its current treatment. RESULTS: The incidence of oligodendroglioma is increasing, most likely due to its improved recognition. Seizures and/or headaches are still common presenting features, and surgery continues to be the primary treatment. Positron emission tomography (PET) and molecular analysis of the surgical specimen are emerging as important diagnostic tools. Patients having either oligodendroglioma or anaplastic oligodendroglioma are likely to respond to chemotherapy. This has had an impact upon the timing of radiation therapy. Survival times are increasing, and patients can now be divided into prognostic subgroups based on the molecular features of their tumors. While procarbazine-CCNU-vincristine (PCV) chemotherapy has been the standard, other agents, notably temozolomide, are currently being tested. CONCLUSIONS: The algorithm for diagnosing and treating patients with oligodendrogliomas has changed. Neurosurgeons need to be aware of the new developments so they can offer sound advice to their patients.
Intracerebroventricular cannulation in rat models is an efficient tool for exploring the effects of substances directly injected into the CNS, bypassing the blood-brain barrier. Techniques for surgically securing the ICV cannula require a balance between ease of application and adequate stability. The authors tested several methods of lateral ventricle cannula stabilization, especially focusing on a comparison of cyanoacrylate gel to cranioplastic cement with an anchoring bone screw.
The microarray array experimental system generates noisy data that require validation by other experimental methods for measuring gene expression. Here we present an algebraic modeling of noise that extracts expression measurements true to a high degree of confidence. This work profiles the expression of 19 200 cDNAs in 35 human gliomas; the experiments are designed to generate four replicate spots/gene with switching of probes. The validity of the extracted measurements is confirmed by: (1) cluster analysis that generates a molecular classification differentiating glioblastoma from lower-grade tumors and radiation necrosis; (2) By what other investigators have reported in gliomas using paradigms for assaying molecular expression other than gene profiling; and (3) Real-time RT-PCR. The results yield a genetic analysis of gliomas and identify classes of genetic expression that link novel genes to the biology of gliomas.
OBJECT: An intracranial ependymoma is a relatively rare but very interesting variety of glioma. In this paper, the authors compiled a review of the pathological features, imaging characteristics, and treatment strategies related to this brain tumor. METHODS: A Medline search was conducted using the term "ependymoma." The bibliographies of papers obtained were also checked for articles and chapters that could provide additional understanding of this tumor. Malignant ependymomas and ependymomas of the spinal cord (including myxopapillary ependymomas) were excluded from this review. CONCLUSIONS: The posterior fossa is the most frequent site for an intracranial ependymoma. Children are frequently affected. Most authors recommend resecting as much of the tumor as is safely possible. Microscopically, ependymal tumors show both epithelial and glial features. Glial fibrillary acidic protein immunohistochemistry, therefore, helps in identifying ependymomas. Because ependymomas often recur despite surgical intervention, radiotherapy and/or radiosurgery may also play an important role in their treatment. The use of chemotherapy in the treatment of these tumors, especially in the very young, is still being studied.
OBJECT: The strategies used to diagnose and treat oligodendroglial tumors have changed significantly over the past decade. The purpose of this paper is to review the topic of oligodendroglioma, emphasizing the new developments. METHODS: Information was obtained by conducting a Medline search in which the term oligodendroglioma was used. Recent editions of standard textbooks were also studied. Because of tools such as magnetic resonance imaging, oligodendrogliomas are being diagnosed earlier, and they are being recognized more frequently histologically than in the past. Seizures are common in these patients. Functional mapping and image-guided surgery may now allow for a safer and more complete resection, especially when tumors are located in difficult areas. Genetic analysis and positron emission tomography may provide data that supplement the standard diagnostic tools. Unlike other low-grade gliomas, patients in whom residual or recurrent oligodendroglioma (World Health Organization Grade II) is present may respond to chemotherapy. Although postoperative radiotherapy prolongs survival of the patient, increasingly this therapeutic modality is being delayed until tumor recurrence, especially if a gross-total tumor resection has been achieved. Oligodendrogliomas are the first type of brain tumor for which "molecular" characterization gives important information. The most significant finding is that allelic losses on chromosomes 1p and 19q indicate a favorable response to chemotherapy. CONCLUSIONS: Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for postoperative therapy has shifted, primarily because of the lesion's relative chemosensitivity. Molecular characterization of oligodendrogliomas may become a standard practice in the near future.
BACKGROUND: Recently, important new information has become available concerning the histologic recognition and molecular biology of oligodendrogliomas. This information, in turn, impacts the way neurosurgeons diagnose and treat patients with these tumors. The purpose of this paper is to review the pathology and basic science of oligodendroglioma, highlighting these developments. METHODS: Information for this review was obtained by a Medline search using the term "oligodendroglioma," and limiting the results to articles dealing with pathology. Chapters from standard textbooks were also used, and bibliographies were checked for additional key articles contributing to the understanding of the pathobiology of this disease. RESULTS: On histologic examination, oligodendrogliomas must be differentiated from tumors including the fibrillary astrocytoma, clear cell ependymoma, central neurocytoma, and dysembryoplastic neuroepithelial tumor (DNT). There is no specific immunocytochemical marker allowing for the recognition of human oligodendroglial tumor cells. A current simplified grading scheme separates these tumors into low grade (WHO grade II) and anaplastic (WHO grade III) oligodendrogliomas. New molecular and genetic markers may aid in grading oligodendrogliomas and identifying patients with a better prognosis or response to chemotherapy. Markers studied include Ki-67, PCNA, EGFr, VEGF, platelet-derived growth factor, p16, p18, p53, bcl-2, COX-1, and chromosomal deletions. The combination of allelic losses on chromosomes 1p and 19q has been statistically associated with a longer recurrence-free survival after chemotherapy. CONCLUSIONS: A patient with an oligodendroglioma may at times still present a diagnostic challenge for the neuropathologist. Yet making an accurate diagnosis is essential, since the clinical course and optimal therapeutic approach differs from that of other gliomas. In the near future, molecular characterization of oligodendrogliomas is expected to play an even greater clinical role.