Biomedical subjects

W Roggendorf

Publications and source records attributed to W Roggendorf.

At least 19 recordsLinked to original sources

PubMed2007

Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses.

Certain risk groups among tumors of the central nervous system (CNS) in children take an almost inevitably fatal course. The elucidation of molecular mechanisms offers hope for improved therapy. Aberrant methylation is common in malignant brain tumors of childhood and may have implications for stratification and therapy. Methylation of p16 (INK4A), p14 (ARF), TIMP3, CDH1, p15 (INK4B )and DAPK1 in medulloblastoma (MB) and ependymoma has been discussed controversially in the literature. DUTT1 and SOCS1 have not previously been analyzed. We examined methylation in MB, sPNET and ependymoma using methylation-specific PCR (MSP), quantitative Combined Bisulfite Restriction Analysis (COBRA) and direct and clone sequencing of bisulfite PCR products. We detected methylation of p16 (INK4A) (17/43), p14 (ARF) (11/42) and TIMP3 (9/44) in MB and others by MSP. CDH1 was not only methylated in MB (31/41), but also in normal controls. Evaluation of MSP results by quantitative COBRA and sequencing yielded methylation between the detection limits of COBRA (1%) and MSP (0.1%). Only p16 (INK4A )and TIMP3 were methylated consistently in medulloblastomas (p16 (INK4A ) 14%, TIMP3 11%) and p16 (INK4A) also in anaplastic ependymomas (1/4 tumors). Methylation ranged from 1-5%. Evaluation of methylation using MSP has thus to be supplemented by quantitative methods. Our analyses raise the issue of the functional significance of low level methylation, which may disturb the delicate growth factor equilibrium within the cell. Therapeutic and diagnostic implications urge into depth analyses of methylation as a mechanism, which might fill some of the gaps of our understanding of brain tumor origin.

Adolescent↗

PubMed2006

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

Brain↗

PubMed2006

Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood.

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

Adolescent↗

PubMed2005

[Dementia with argyrophilic grains].

Dementia with argyrophilic grains (AG) is a neuropathologically defined potentially dementing disease of advanced age which was first described by H. and E. Braak in 1987. It is often combined with histopathological signs of Alzheimer's disease but has nevertheless to be considered as a distinct entity since pure bona fide cases have been reported. Clinically it may resemble either Alzheimer's or Pick's disease; it is almost exclusively confined to patients older than 60 years and progresses slowly but relentlessly. Repeatedly prominent behavioral disorders were pointed out. Useful therapeutic regimens are not available at present but acetylcholinesterase inhibitors have proven effective in some cases and amantadines as well as dopamine agonists hold some promise from a theoretical perspective, too. The diagnosis can be ascertained only by histopathological examination. For the clinician it is important to know that this disease is to be considered as an additional and differential diagnosis of both Alzheimer's disease and the frontotemporal dementias. It must be counted among the tauopathies. This review is supplemented by a detailed case report.

Brain↗

PubMed2004

Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes.

Gene expression profiling of human substantia nigra pars compacta (SNpc) from Parkinson's disease (PD) patients, was examined employing high density microarrays. We identified alterations in the expression of 137 genes, with 68 down regulated and 69 up regulated. The down regulated genes belong to signal transduction, protein degradation (e.g. ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, ion transport, protein modification/phosphorylation and energy pathways/glycolysis functional classes. Up-regulated genes, clustered mainly in biological processes involving cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism, transcription and inflammation/stress (e.g. key iron and oxygen sensor EGLN1). One major finding in the present study is the particular decreased expression of SKP1A, a member of the SCF (E3) ligase complex specifically in the substantia nigra (SN) of sporadic parkinsonian patients, which may lead to a wide impairment in the function of an entire repertoire of proteins subjected to regulatory ubiquitination. These findings reveal novel players in the neurodegenerative scenario and provide potential targets for the development of novel drug compounds.

Aged↗

PubMed2003

Neuroleptic malignant syndrome in Kufs' disease.

A patient with adult neuronal ceroid lipofuscinosis (ANCL; Kufs' disease) is described in whom neuroleptic malignant syndrome occurred, initially presenting as catatonic syndrome. Comprehensive neuroimaging studies were conducted including FDG-PET, IBZM-SPECT, and beta-CIT-SPECT, electrophysiological examinations and an ex vivo contracture test exposing muscle biopsy specimens to neuroleptics. Collectively the results argued for an involvement of the muscle in neuroleptic malignant syndrome at least in ANCL.

Adult↗

PubMed2002

[Rhabdoid meningioma. A new malignant subtype].

Of the numerous morphological variants of meningiomas only few, and among these the rhabdoid meningioma, have prognostic importance. Rhabdoid meningiomas were described for the first time in 1998 as an unusual variant with increased proliferative activity. In 2000 they have been included in the revised WHO classification of tumours of the CNS as a subtype of meningiomas with increased risk of recurrence and more aggressive growth, corresponding to WHO grade III. We report the case of a rhabdoid meningioma in a 21-year-old woman presenting as a intracerebral tumour mimicking an oligodendroglioma. The tumour showed features of a meningioma and a rhabdoid morphology with angiomatous components and was considered to be a rhabdoid meningioma. After surgery a small residual tumour remained. The patient received postoperative radiotherapy resulting in regression of the residual tumour in control examinations after 4 and 8 months. Using the presented case we discuss the differential diagnosis and prognostic significance of recognition of a rhabdoid meningioma.

Brain Neoplasms↗

PubMed2001

Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: a double labeling study.

It is not known how many non-tumorous cells in gliomas contribute to the proliferation rate. We investigated the proliferative activity of microglia in an immunohistochemical double-labeling study of pilocytic astrocytomas and astrocytomas WHO grade II-IV using the antibodies MIB-1 (Ki67) as proliferation-marker and Ki-M1P (CD68) as microglia marker. We found the highest indices of proliferating microglia in pilocytic astrocytomas with an average rate of 32% (+/- 6.8) of all proliferating cells. In contrast, the proliferation indices of microglia were lowest in fibrillary astrocytomas with 8.6% (+/- 2.5) of all proliferating cells. In anaplastic astrocytomas and glioblastomas the percentage of proliferating microglia showed a slight increase to 8.8% (+/- 3.6) and 13.4% (+/- 8.7), respectively. We conclude that microglial cells in astrocytic brain tumors proliferate and show different proliferative activities at different grades of malignancy with the highest rates of proliferating microglia especially in pilocytic astrocytomas. Thus, the proliferation rate does not solely reflect the proliferation of tumor cells, but also of non-tumorous cells. This should be considered in particular when proliferation rates are used as a criterion for prognosis and grading of pilocytic astrocytomas.

Antigens, CD↗

PubMed2001

TP53 gene mutations, nuclear p53 accumulation, expression of Waf/p21, Bcl-2, and CD95 (APO-1/Fas) proteins are not prognostic factors in de novo glioblastoma multiforme.

Glioblastoma multiforme (WHO grade IV; GBM) is the most common primary brain tumor with a median survival of less than one year despite multimodal treatment regimens. However, a small subgroup of GBM patients has a better clinical outcome, with a small number of patients surviving several years. Apoptosis, a genetically determined program of cell suicide, may be induced as a consequence of critical DNA damage. However, due to defects in the signaling pathways, cancer cells may escape apoptosis, despite carrying irreversible DNA damage. In the present study, we have analyzed tumors of two age-matched, equally treated groups of GBM patients with different postoperative time to tumor progression (TTP), defined as 'short-term' for TTP of less than 6 months (n = 54), and 'long-term' for TTP of more than 12 months (n = 39) for alterations in apoptosis regulatory pathways: Mutations of the TP53 tumor suppressor gene and/or nuclear accumulation of its gene product p53, expression of Waf/p21, CD95 (Apo1/Fas), and Bcl-2. TP53 mutations were found in 12 out of 54 (22%) GBMs of short-term survivors and 8 out of 35 (23%) tumors of long-term survivors; the respective numbers for nuclear p53 protein accumulation were 12/53 (23%) and 10/37 (27%). Waf1/p21 expression was found in 13/53 (25%) tumors of short-term survivors and 9/35 (26%) GBMs of long-term survivors. The respective numbers for Bcl-2 expression were 25/42 (60%) and 22/36 (61%) and for CD95 (Apo1/Fas) expression 20/49 (41%) and 14/36 (39%) GBMs. The percentage of alterations in genes/proteins involved in the apoptotic pathway investigated here was virtually identical in the two groups of clinically different GBM patients. Thus, our data imply that none of these alterations investigated per se has a strong impact on the overall survival of GBM patients.

Adult↗

PubMed2000

Long-term survival of glioblastoma multiforme: importance of histopathological reevaluation.

The overall prognosis for patients with glioblastoma multiforme is extremely poor. However, a small proportion of patients enjoy prolonged survival. This study investigated retrospectively the extent to which erroneous histopathological classification may contribute to long-term survival of patients initially diagnosed with "glioblastoma multiforme." We compared two age- and gender-matched patient groups with different postoperative time to tumor progression (TTP), defined as "short-term" for TTP of less than 6 months (n = 54), and "long-term" for TTP of more than 12 months (n = 52). Histological specimens of the corresponding tumors, all primarily diagnosed as glioblastoma multiforme, were reevaluated according to the current World Health Organization (WHO) classification of central nervous system tumors, with the investigators being blinded to clinical outcome. Among the tumors from short-term TTP patients, one tumor (2%) was reclassified as anaplastic oligoastrocytoma (WHO grade III) while the remaining 53 were confirmed as glioblastoma multiforme. In contrast, 13 tumors (25%) from the long-term TTP patients were reclassified, mostly as anaplastic oligodendroglioma (WHO grade III; n = 7) or anaplastic oligoastrocytoma (WHO grade III, n = 2), respectively. In addition, three were reclassified as anaplastic astrocytoma (WHO grade III), and one was identified as anaplastic pilocytic astrocytoma (WHO grade III). Our data indicate that a sizable proportion of glioblastoma patients with long-term survival actually carry malignant gliomas with oligodendroglial features. The correct histopathological recognition of these tumors has not only prognostic but also therapeutic implications, since oligodendroglial tumors are more likely to respond favorably to chemotherapy.

Adult↗

PubMed1999

Microglial/macrophage expression of interleukin 10 in human glioblastomas.

Interleukin 10 (IL-10) expression has been found to be correlated with the extent of malignancy in gliomas. In vitro, IL-10 increases proliferation and migratory capacity in human glioma cell lines. In this study, we localized the site of IL-10 synthesis in gliomas to cells of microglial origin. Biopsy specimens from 11 patients with malignant glioma were processed on native tissues and at early cell culture passages (0-4). IL-10 mRNA was analyzed by RT-PCR and in situ hybridization. Protein was quantitatively assessed by ELISA in cell culture supernatants, and cells expressing IL-10 were determined by a combination of immunohistochemistry for CD68 (specific for microglia/macrophage lineage) and IL-10 in situ hybridization. IL-10 mRNA decreased from passage 0 to 4 in all samples and was undetectable beyond passage 5. Such downregulation of mRNA leads to a steep decrease of IL-10 protein in culture supernatants (below detection level, 0.05 ng/ml, beyond passage 1). The combination of in situ hybridization for IL-10 and CD68 immunostaining revealed that only cells of the microglia/macrophage lineage produced IL-10 mRNA. Our results identify microglia/macrophage cells as the major source of IL-10 expression in gliomas which decreases markedly during early passages of primary cultures of human gliomas due to a progressive reduction of microglia/macrophages present.

Adult↗

PubMed1999

[Are morphologic changes in skeletal muscles of patients with malignant hyperthermia diagnostically useful?].

Malignant Hyperthermia (MH) represents a functional myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, and leading to metabolic disturbances of intracellular Calcium homeostasis. Central-Core-like-structures (CCLS) were recently described as central defects in enzyme-histochemical stains and well correlated to the autosomal-dominant MH-predisposition. We studied the correlation of a MH-predisposition with specific myopathological signs. Skeletal muscles of suspected MH-individuals were histochemically stained by SDH-, NADH-, COX-, Gomori-Trichrome-, ATPase-, Acid Phosphatase-, Oil-red O- und PAS-stain und evaluated without knowing MH-diagnosis by the in-vitro-contracture test. Out of 118 patients (30% MHS ["susceptible"], 63% MHN [normal], 7% MHE ["equivocal"]) 19% revealed pathological findings corresponding to CCLS. 45% of these findings were associated with MHS/MHE. With HE-staining internal nuclei were not specific, but increased with the probability of MHS/MHE from 24% to 80%. Central Cores were correlated in 100% with MHS/MHE (4 out of 118 patients). CCLS were found with about similar frequency in skeletal muscle of MHS/MHE and MHN individuals. Internal nuclei were, however, not specifically, associated with MHS. In contrast, Central Cores correlated significantly with MHS/MHE diagnosis. In conclusion, histopathological findings in skeletal muscle seem to be a reliable marker for MH-predisposition only with Central Cores.

Adolescent↗

PubMed1999

Primary intracerebral Hodgkin's disease: report of a case with Epstein-Barr virus association and review of the literature.

A case of primary intracerebral Hodgkin's disease (HD) without dural attachment in a 54-year-old immunocompetent patient is described. The infiltrate was located superficially in the occipital lobe and corresponded to the histologic type of nodular sclerosis. A typical immunohistochemical profile (membrane and cytoplasmic staining with dotlike Golgi enhancement of CD30, moderate cytoplasmic staining of CD15 in the Golgi area, membrane staining of CD20 of <10% of blastic cells, CD45RB negative) and in addition Epstein-Barr virus (EBV) latent membrane protein was detectable in Reed-Sternberg cells. Staging revealed no other organ sites of involvement. After combined surgery, postoperative radiotherapy, and chemotherapy, there are no signs of recurrence or systemic disease on follow-up for >1 year. To the authors' best knowledge, an association of EBV with primary central nervous system HD has not been demonstrated before.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

DNA ploidy and cell-cycle analysis in intracranial meningiomas and hemangiopericytomas: a study with high-resolution DNA flow cytometry.

Although various DNA flow-cytometric studies have been performed on meningiomas, the role of DNA ploidy and the S-phase fraction (SPF) in predicting biological tumor behavior remains unresolved. Discrepant results in earlier studies might be due to different preparing, staining and measuring techniques; different quality standards; and lack of sophisticated computer software. In this study, high-resolution DNA flow cytometry using the DNA-specific dye DAPI (4', 6'-diamidino-2-phenylindol) was performed on stored frozen tissue from 128 microsurgically resected meningiomas and 7 hemangiopericytomas, including 17 recurrent meningiomas and 4 recurrent hemangiopericytomas. The computer software Multicycle 2.5 was used to determine the ploidy level and to perform cell-cycle analysis. DNA aneuploidy and SPF were significantly higher in atypical, anaplastic and recurrent meningiomas and correlated well with histopathological features such as focal necrosis, infiltration of dura mater and mitotic activity. Among 128 meningiomas, 42 had additional DNA aneuploid stem lines. No association between hypo- and hyperploidy and either histological subtype or clinical outcome was found. In 7 hemangiopericytomas, SPF was significantly higher compared to the benign meningioma group, while only 1 tumor was aneuploid. In all 42 DNA aneuploid tumors, cell-cycle analysis was performed separately for the euploid and aneuploid stem lines. The proliferation parameters (SPF, G2/M phase) were significantly higher in the DNA aneuploid stem lines. DNA ploidy and SPF are thus useful indicators of different biological behavior within identical histological subgroups in meningiomas.

Aneuploidy↗

PubMed1998

Favorable outcome of giant cell glioblastoma in a child. Report of an 11-year survival period.

Giant cell glioblastomas are defined as glioblastomas with a marked predominance of bizarre, multinucleated giant cells. They represent about 5% of all glioblastomas and can occur at any site of the central nervous system, but the temporal and frontal lobes are the sites of predilection. Overall, giant cell glioblastomas show a prolonged survival period compared with common glioblastoma multiforme, and survival periods of 7 and 9 years have been reported in adults. Here we report on a child aged 11 years at diagnosis, who has so far survived for 11 years since operation and adjunctive radio- and chemotherapy.

Adult↗

PubMed1998

Expression of matrix metalloproteinases in human glioma cell lines in the presence of IL-10.

Matrix metalloproteinases have been implicated to play a vital role in glioma invasion as they degrade extracellular matrix to facilitate the subsequent migration of tumor cells into the surrounding brain tissue. The cytokine Interleukin-10 (IL-10) was detected recently in glial tumors in vivo. Expression of specific IL-10 mRNA as well as blood serum levels of IL-10 in glioma patients increased with malignancy suggesting a functional role of IL-10 in glioma progression. Moreover, glioma cell migration in vitro was enhanced in the presence of IL-10. We therefore investigated the expression of the matrix metalloproteinases (MMPs) stromelysin-1 (MMP-3), 72-kDa collagenase (MMP-2), 92-kDa collagenase (MMP-9), matrilysin (MMP-7) and the human macrophage metalloelastase (MMP-12). In addition, a possible relation between exposure of glioma cells to IL-10 and invasiveness of these cells due to MMP expression was analyzed. Experiments with Matrigel coated Boyden chambers revealed a pronounced dose dependent effect of IL-10 on glioma invasiveness. The synthetic MMP-inhibitor Marimastat markedly reduced cell invasion in the Boyden chambers confirming the significance of MMPs in the process of invasion. Subsequently, the expression level of MMPs and the serine protease uPA was investigated in 7 glioma cell lines (U373, GaMG, U251, GHE, SNB19, U138 and D54) by RT-PCR. In all but one cell line no enhancement of MMP expression by IL-10 was detected. Matrilysin in U373 cells was the only protease found to be upregulated in the presence of IL-10 dependent on cell density. The present data suggest that IL-10 related effects on the invasive properties of the cell lines are not directly mediated by an upregulation of matrix metalloproteinase expression.

Brain Neoplasms↗

PubMed1998

[Dissections of the basilar artery].

PURPOSE: To describe clinical, radiological and pathological-anatomical findings of basilar artery dissections. METHODS: During a period of three years (1994-1996) we observed 4 patients with dissections of the basilar artery, proven by angiography. Angiograms, MRI (n = 2) and autopsy results (n = 1) of these patients were correlated with clinical symptoms and long-term follow-up. RESULTS: In three patients the dissection was confined into the basilar artery. Three patients with vertebrobasilar ischaemia showed irregularities of the vessel wall on angiography, in one of these patients autopsy revealed a haematoma within the vessel wall, located between intima and media. One patient complaining of relapsing headaches had a posttraumatic basilar artery aneurysm. CONCLUSION: Dissections of the basilar artery can be separated in two types. In case of subintimal dissection patients present with vertebrobasilar ischaemia, which in contrast to extracranial dissections usually occurs without temporal delay. A second type of patients presents with subarachnoid haemorrhage. The dissection is subadventitial and pierces through a thin adventitia into the subarachnoid space.

Adult↗

PubMed1998

Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy.

Procedures involved in the diagnosis of JC virus central nervous system infection range from detection of virus specific products in biopsy material to demonstration of viral DNA in cerebrospinal fluid by PCR. Despite the fact that PCR is the most sensitive method for the detection of virus in clinical specimens, diagnostic evaluation is increasingly difficult in view of the possible subclinical activation of persistent JCV infection in the central nervous system of high risk patients. Therefore, PML diagnosis by molecular detection of JCV DNA in biopsy material was compared with diagnosis by PCR on CSF of patients with and without PML. Evaluation of the diagnostic techniques revealed that stereotactic biopsy based PCR diagnosis at present combines speed and sensitivity with the highest specificity available. Although the non invasive technique of JCV detection in CSF by PCR is even more sensitive leading to detection of about 20 genome equivalents per 1 microl of CSF, the specificity of the method is limited by subclinical presence of JCV DNA in CSF of neurologically asymptomatic HIV infected patients. Additionally, autopsy proven PML cases remaining JCV negative in PCR on CSF become a common finding. Therefore, in cases where biopsy is not performed, diagnosis of PML can only be achieved in combination with neurological and radiological diagnosis.

Brain↗