Horst P. Schmitt

Clinical impact and functional aspects of tenascin-C expression during glioma progression.

The extracellular matrix protein tenascin‐C is expressed in processes like embryogenesis and wound healing and in neoplasia. Tenascin‐C expression in gliomas has been described previously; however, the relation to clinical data remains inconsistent. Generally, analysis of tenascin‐C function is difficult due to different alternatively spliced isoforms. Our studies focus on changes in tenascin‐C expression in human gliomas, correlating these changes with tumor progression and elucidating the functional role of the glioma cell‐specific tenascin‐C isoform pool. Eighty‐six glioma tissues of different World Health Organization (WHO) grades were analyzed immunohistochemically for tenascin‐C expression. The influence of the specific tenascin‐C isoforms produced by glioblastoma cells on proliferation and migration was examined in vitro using blocking antibodies recognizing all isoforms. In general, tenascin‐C expression increased with tumor malignancy. Perivascular staining of tenascin‐C around tumor‐supplying blood vessels was observed in all glioblastoma tissues, whereas in WHO II and III gliomas, perivascular tenascin‐C staining appeared less frequently. The appearance of perivascular tenascin‐C correlated significantly with a shorter disease‐free time. Analysis of proliferation and migration in the presence of blocking antibodies revealed an inhibition of proliferation by around 30% in all 3 glioblastoma cell cultures, as well as a decrease in migration of 30.6–46.7%. Thus we conclude that the endogenous pool of tenascin‐C isoforms in gliomas supports both tumor cell proliferation and tumor cell migration. In addition, our data on the perivascular staining of tenascin‐C in WHO II and III gliomas and its correlation with a shorter disease‐free time suggest that tenascin‐C may be a new and potent prognostic marker for an earlier tumor recurrence.

Primitive neuroectodermal tumors after prophylactic central nervous system irradiation in children : association with an activated K-ras gene

Three patients had supratentorial malignant brain tumors 7 to 9 years after prophylactic central nervous system (CNS) treatment for acute lymphocytic leukemia or malignant T‐cell lymphoma. Therapy was administered at the age of 3 to 8 years and included cranial irradiation (total dose, 1800 to 2400 cGy) and intrathecal methotrexate. The brain tumors had histologic and immunohisto chemical features of primitive neuroectodermal tumors (PNET), including neuroblastic rosettes, rhythmic arrangement of tumor cells, and immunohistochemical expression of glial, and in one patient neuronal, marker proteins. Using polymerase chain reaction‐mediated DNA amplification from paraffin‐embedded tissues and subsequent DNA sequence analysis, an activating point mutation was detected in the K‐ras protooncogene in one tumor. This mutation was a G to A transition in position 2 of codon 12, substituting aspartate (GAT) for glycine (GGT). This type of mutation has not been observed before in human brain tumors, but it is frequent in radiation‐induced murine lymphomas. These observations suggest that PNET can be induced after completion of the embryonal and fetal development of the human CNS. On‐cogene‐activating point mutations may represent a pathogenetic mechanism involved in the genesis of radiation‐induced brain tumors.

Alternative splicing of the βA4 amyloid gene of Alzheimer's disease in cortex of control and Alzheimer's disease patients

Abstract An S1 nuclease protection assay was designed to study the splicing pattern of the alternatively spliced βA4 amyloid gene (APP gene) of Alzheimers disease (AD). We determined the splicing pattern of the APP gene in fetal, adult, aged adult and AD human cortex. The results suggest that alternative splicing of the APP gene in AD is not significantly different from age-matched controls, but distinct from the developing fetal brain.

Incidence of late radiation necrosis with transient mass effect after interstitial low dose rate radiotherapy for cerebral gliomas

SummaryLate radiation necroses constitute a hazard in low dose rate interstitial irradiation for inoperable gliomas. An incidence of 40% (8/20 patients) was found after permanent implantation of Iodine-125 seeds. This finding may even underestimate the real frequency, because follow-up of unaffected patients was shorter than in patients with radiation necrosis. The necrotic reactions caused a transient mass effect, which lead to a significant deterioration of performance scores. Further manifestations of late delayed radiation damage were observed in two patients.The occurrence of radiation necrosis was correlated with total radiation dose, amount of implanted radioactivity, and with velocity of tumour shrinkage. A mechanism underlying the development of radiation necrosis is proposed: A rapid shrinkage of tumour after interstitial Iodine-125 implantation may cause a significant irradiation of surrounding brain tissue, which was initially lying outside the target volume. Since most patients affected by radiation necrosis were children or adolescents, the risk of radiation damage should be minimized. This could probably be achieved either by reduction of irradiation dose, or by using temporary implants of Iodine-125.

Metastases of malignant neoplasms to intracranial tumours: the «tumour-in-a-tumour» phenomenon

This is a report of two observations of the metastatic spread of carcinomas to meningiomas. A survey of the relevant literature is given.

The relationship between target, targetoid, and targetoid/core fibers in severe neurogenic muscular atrophy

SummaryIn the m. tibialis anterior of a 68-year-old man with rapidly developing denervation atrophy in the legs since 1/2 year prior to death from heart stroke, abundant unifocal concentric fiber changes, such as target, targetoid/core, and targetoid fibers could be observed. Besides, large vacuolized fibers with multiple changes resembling cytoplasmic bodies in the peripheral zone were present as well; they are interpreted as fibers with multicentric target or targetoid formations. The target fibers displayed a broad variation of their outer appearance suggesting a continuous transition to targetoid/core fibers (with a dense center) and targetoid fibers (with a central change to aquous sarcoplasm showing a paucity of fibrillar structures). Very few fibers with a central densification of fibrillar material with or without a thin intermediate zone were fairly akin to core fibers of central core disease; others were more alike the type of targetoid fibers, previously described in the literature, showing a dense target-like center; both were summarized under the term, inaugurated by Engel et al. (1966), “targetoid/core fibers”. Simultaneous occurence of the different kinds of concentric fiber changes suggested a strong relation between all of them in the sense of representing different developmental stages of the same pathogenetic process. Thus, the central core disease, for instance, might be a disorder with a generalization of concentric fiber changes having come to arrest in the earliest stage of development.ZusammenfassungIm M. tibialis anterior eines 68 Jahre alt gewordenen Mannes, der 1/2 Jahr vor seinem Tode am Herzinfarkt eine rasch progrediente neurogene Muskelatrophie in den Beinen entwickelte, fanden sich außerordentlich zahlreiche unifokal-konzentrische Muskelfaserveränderungen wie Target-, Targetoid/Core- und Targetoidfasern. Außerdem sah man große vacuolisierte Faserquerschnitte mit multiplen fokalen Veränderungen in der Randzone, die an die früher beschriebenen „cytoplasmic bodies“ erinnerten; im vorliegenden Zusammenhang wurden sie allerdings als Fasern mit multizentrischen Target- und Targetoidformationen interpretiert. Die Targetfasern zeigten eine weitläufige Variation in der äußeren Erscheinungsform, die in der Zusammenschau kontinuierliche Übergänge zu Targetoid/Corefasern (mit dichter Zentralzone) und Targetoidfasern (mit zentraler Auflösung und Vermehrung aquösen Sarkoplasmas mit wenigen fibrillären Strukturen) erkennen ließ. Wenige Fasern mit einer zentralen Verdichtung fibrillären Materials mit oder ohne schmaler Intermediärzone waren Corefasern des Central-Core-Disease auffallend ähnlich; andere glichen mehr dem Typ von Targetoidfasern mit strukturdichtem Zentrum, wie sie in der früheren Literatur beschrieben wurden. Beide Formen wurden wegen ihrer großen Ähnlichkeit von Engel et al. (1966) unter dem Begriff „Targetoid/Core Fibers“ zusammengefaßt. Das gleichzeitige Auftreten der verschiedenen Formen konzentrischer Faserveränderungen in einem Muskel legt die Annahme nahe, daß zwischen allen eine enge Beziehung im Sinne unterschiedlicher Manifestationsstufen des grundsätzlich gleichen pathogenetischen Prozesses besteht. So wäre unter dieser Annahme beispielsweise das Central-Core-Disease eine Erkrankung mit einer Generalisation konzentrischer Faserveränderungen, die im frühesten morphologischen Entwicklungsstadium zum Stillstand gekommen sind.

Mixed chemodectoma-ganglioneuroma of the conus medullaris region

SummaryReport of a 33-year-old man with a yearlong historory of low-back pain radiating into the left leg. Neurologic examination upon admission tto the hospital revealed a spinal compression syndrome at the lovel L5. Laminectomy at L4/5 revealed an encapsulated intradural tumor measuring 4×2.5×2.5 cm. The tumor was attached to the dorsal root L4 and extended downward to the conus region. Light and electron microscopy revealed features mostly consistent with a mixed chemodectoma and ganglioneuroma.

Distribution and immunoreactivity of cerebral micro-hamartomas in bilateral acoustic neurofibromatosis (neurofibromatosis 2)

SummaryBilateral acoustic neurofibromatosis (neurofibromatosis 2, NF2) accounts for less than 10% of all cases of neurofibromatosis and manifests itself with bilateral acoustic schwannomas, multiple schwannomas of spinal nerve roots, meningiomas, glial tumors and hamartomatous CNS lesions. We have observed dysplastic foci of immature neuroectodermal cells in the cerebral cortex and basal ganglia of six patients afflicted with neurofibromatosis 2, ranging from occasional clusters of immature, dysplastic cells to numerous, confluent lesions. These cells, although often polymorphic and multinuclear did not show mitotic acitivity or a tendency for neoplastic transformation. To determine the histogenesis of these foci, extensive immunocytochemical reactions were carried out with antibodies to a variety of glial, neuronal and nonneural cell lineages. With the exception of S-100 protein, no immunoreactivity was detectable. S-100 was consistently expressed in these foci, irrespective of their size, location, and degree of polymorphism. On the basis of cytological appearance, distribution and immunoreactivity we tentatively designate these foci as glial micro-hamartomas. Although we did not systematically analyze the CNS of patients with von Recklinghausen neurofibromatosis (neurofibromatosis 1, NF1), the present study strongly suggests that these micro-hamartomas constitute a morphological hallmark of bilateral acoustic neurofibromatosis (NF2).

Epi- and intramedullary neurilemmoma of the spinal cord with denervation atrophy in the related skeletal muscles.

SummaryThe autopsy of a 68-year-old male who died of cardiac infarction revealed an ep - and intramedullary neurilemmoma of the spinal cord as an associated finding half a year prior to death. The patient had suffered from progressive weakness and sensory disturbances of the lower limbs together with muscular wasting for 6 months. Repeated neurological examinations had led to the diagnosis of an intraspinal space occupation which, however, could not be substantiated by myelography because of its surprisingly small size. The Schwann cell proliferation originated from the adventitia of the epi- and intramedullary vessels of the conus medullaris. The main tumor mass was epi-medullary and extended into the medullary parenchyma via the penetrating vessels forming intramedullary nodules. The special findings in the present case seem to support the hypothesis that intramedullary neurilemmomas originate from the perivascular nerve endings.ZusammenfassungBei einem 68jährigen, an einem Herzinfarkt verstorbenen Manne fand sich bei der Sektion ein epi- und intramedullär entwickeltes Neurilemmom im Bereiche des Conus medullaris des Rückenmarkes. Seit 1/2 Jahr vor dem Tode hatten sich gravierende motorische und sensible Störungen in den Beinen eingestellt, die nach mehrfachen neurologischen Untersuchungen klinisch auf einen intraspinalen raumfordernden Prozeß wegen der typischen Verteilung der sensiblen Störungen zurückgeführt worden waren. Myelographisch war ein solcher Prozeß allerdings nicht zu sichern. Die Schwannzellproliferation ging von den Adventitiae der pialen Rückenmarksgefäße aus und schob sich über die radiär ins Rückenmark eindringenden Gefäße in die zentralen Medullaabschnitte vor, wo sich ebenfalls kleine Tumoren entwickelten. Die eindeutige Ableitung von den Gefäßwänden scheint die Vermutung früherer Autoren zu bestätigen, daß intramedulläre Neurilemmome sich von den perivasculären Nervengeflechten aus entwickeln.

Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation

Abstract. A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30 cases of Alzheimers disease (AD) and 35 non-demented controls. In addition to the graph evaluations, neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where, by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases. However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both with and without motor neuron disease.