[Therapy for spontaneous intracerebral haemorrhage]. / Therapie der spontanen intrazerebralen Blutung.

Spontaneous intracerebral haemorrhage (ICH) is a common and serious disease. It is responsible for 10-17% of all strokes, and mortality exceeds 50%. A variety of underlying causes exist for ICH, advancing age and hypertension being the most important risk factors. Other causes of ICH include vascular malformations, coagulation disorders, and use of anticoagulants and thrombolytic agents. Treatment options comprise conservative as well as surgical management. In addition, a recently published clinical trial evaluating the use of activated recombinant Factor VII allows specific haemostatic therapies to be used in ICH treatment. That and other studies have significantly added to the understanding of the disease. The European Stroke Initiative, which represents the European Stroke Council, European Neurological Society, and European Federation of Neurological Societies, will soon publish recommendations for the management of spontaneous intracerebral haemorrhages. Those recommendations form the basis of this article.

Lack of association of herpesviruses with brain tumors.

Gliomas are the most frequent primary brain tumors in humans. Many studies have been carried out on their etiology; however, the only confirmed risk factors are hereditary predisposing conditions and high dose of ionizing radiation. Recently, human cytomegalovirus (HCMV) gene products and nucleic acids were reported to be present in all of 27 glioma samples investigated in contrast to other brain tissues, and it was hypothesized that HCMV might play a role in glioma pathogenesis. To evaluate these findings, samples of 40 gliomas, 31 meningiomas, and 6 acoustic neurinomas (ACNs) were analyzed for the presence of HCMV macromolecules using polymerase chain reaction (PCR) and immunohistochemistry. Additionally, corresponding blood samples from 72 patients were analyzed for the presence of HCMV DNA to check for a possible contamination of tumor tissues with HCMV-infected blood cells. No HCMV DNA sequences were found, neither in brain tumor tissues nor in corresponding blood samples. Immunohistochemistry did not detect HCMV-specific proteins. Addressing a possible role of other herpesviruses as has been suggested in seroepidemiological studies, seroprevalence of antibodies to HCMV, herpes simplex virus (HSV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV) were determined by enzyme-linked immunosorbent assay (ELISA). Serological analyses of brain tumor patients showed no significant differences in the prevalences of antibodies to HCMV, HSV, EBV, or VZV compared to the general population. Thus, the data of the present study do not support the hypothesis of an association of herpesviruses with the development of primary brain tumors.

Diagnostic performance of spectroscopic and perfusion MRI for distinction of brain tumors.

OBJECTIVE: To assess the value of spectroscopic and perfusion MRI for glioma grading and for distinguishing glioblastomas from metastases and from CNS lymphomas. METHODS: The authors examined 79 consecutive patients with first detection of a brain neoplasm on nonenhanced CT scans and no therapy prior to evaluation. Spectroscopic MRI; arterial spin-labeling MRI for measuring cerebral blood flow (CBF); first-pass dynamic, susceptibility-weighted, contrast-enhanced MRI for measuring cerebral blood volume; and T1-weighted dynamic contrast-enhanced MRI were performed. Receiver operating characteristic analysis was performed, and optimum thresholds for tumor classification and glioma grading were determined. RESULTS: Perfusion MRI had a higher diagnostic performance than spectroscopic MRI. Because of a significantly higher tumor blood flow in glioblastomas compared with CNS lymphomas, a threshold value of 1.2 for CBF provided sensitivity of 97%, specificity of 80%, positive predictive value (PPV) of 94%, and negative predictive value (NPV) of 89%. Because CBF was significantly higher in peritumoral nonenhancing T2-hyperintense regions of glioblastomas compared with metastases, a threshold value of 0.5 for CBF provided sensitivity, specificity, PPV, and NPV of 100%, 71%, 94%, and 100%. Glioblastomas had the highest tumor blood flow values among all other glioma grades. For discrimination of glioblastomas from grade 3 gliomas, sensitivity was 97%, specificity was 50%, PPV was 84%, and NPV was 86% (CBF threshold value of 1.4), and for discrimination of glioblastomas from grade 2 gliomas, sensitivity was 94%, specificity was 78%, PPV was 94%, and NPV was 78% (CBF threshold value of 1.6). CONCLUSION: Perfusion MRI is predictive in distinguishing glioblastomas from metastases, CNS lymphomas and other gliomas vs MRI and magnetic resonance spectroscopy.

Oncolytic potential of rodent parvoviruses for cancer therapy in humans: a brief review.

Summary Rodent parvoviruses are promising candidates for oncolytic virotherapy of cancer in humans because of their oncotropism (preferential killing of transformed cells) in the absence of pathogenicity. Here, we give an overview concerning the possible application of parvovirus H-1 for cancer therapy, with specific emphasis on malignant brain tumours in humans.

MRI in acute subarachnoid haemorrhage; findings with a standardised stroke protocol.

There is doubt as to whether acute haemorrhage is visible on MRI. We carried out MRI within 6 h of symptom onset on five patients with minor (low Hunt and Hess grades 1 or 2) subarachnoid haemorrhage (SAH) diagnosed by CT to search for any specific pattern. We used our standard stroke MRI protocol, including multiecho proton density (PD)- and T2-weighted images, echoplanar (EPI) diffusion- (DWI) and perfusion- (PWI) weighted imaging, and MRA. In all cases SAH was clearly visible on PD-weighted images with a short TE. In four patients it caused a low-signal rim on the T2*-weighted source images of PWI, and DWI revealed high signal in SAH. In the fifth patient SAH was perimesencephalic; susceptibility effects from the skull base made it impossible to detect SAH on EPI DWI and T2*-weighted images. Perfusion maps were normal in all cases. MRA and conventional angiography revealed an aneurysm in only one patient. Stroke MRI within 6 h of SAH thus shows a characteristic pattern.

[Prognosis of brain tumors: epidemiology, survival time and clinical course]. / Zur Prognose von Hirntumoren: Epidemiologie, Uberlebenszeit und klinischer Verlauf.

Although the frequency of primary brain tumors is relatively small compared to other tumors such as breast or lung carcinoma, brain tumors affect a particularly young and healthy patient population and possess a high portion of cancer mortality in these age groups. Generally brain tumor diseases influence the professional capacity in younger people and cause significant socioeconomical costs. Prognosis and clinical deterioration of primary brain tumors are determined by histopathological diagnosis first, by tumor location and -volume second. The clinical malignancy of brain tumors, caused by histopathological findings, has not essentially been changed in the last years despite more effective therapies. In contrast refinement in technical standards and computer-assisted micro-surgery makes a valuable progress in the treatment of biological benign brain tumors. Most of these patients recover normal efficiency including former working capability. On the other hand therapeutical nihilism is not supposed to be a sufficient answer to primary brain tumors, because in selected cases a longer lasting stabilization of the disease is possible. In future only through better understanding of the biology of brain tumors and much more effective therapies we can hope to make significant progress in the treatment of these tumors.

MR appearance of an intracranial dural arteriovenous fistula leading to cervical myelopathy.

OBJECTIVE: To report the MRI, myelographic, and angiographic findings as well as the clinical and radiologic time course of an intracranial dural arteriovenous fistula (DAVF) leading to cervical myelopathy; and to review the pertinent literature. BACKGROUND: Cervical myelopathy from an intracranial DAVF draining into spinal medullary veins is extremely uncommon. However, knowledge about the MR features of these lesions is important because an improper diagnosis might result in delayed or incorrect treatment. METHODS: In a patient with progressive cervical myelopathy, T2- and proton density (PD)-weighted MRI, contrast-enhanced T1-weighted images, and a contrast-enhanced MR angiogram of the cervical spinal cord were acquired. Additionally, intraarterial digital subtraction angiography (DSA) of the right and left common carotid arteries was performed. RESULTS: MRI findings included swelling of the cervical spinal cord, hyperintensity of the cervical cord on T2- and PD-weighted MRI, and an enlarged vessel at the ventral surface of the cord on MR angiography. No parenchymal contrast enhancement of the spinal cord was noted on T1-weighted MRI. DSA revealed an intracranial DAVF fed by four branches of the left external carotid artery and draining into spinal medullary veins. The fistula was treated with endovascular embolization, leading to considerable clinical improvement of the patient. CONCLUSIONS: To avoid an improper diagnosis or a delayed or incorrect treatment of myelopathy resulting from an intracranial DAVF, cerebral intraarterial angiography may be indicated in cases of otherwise unexplainable cervical myelopathy.

[Computerized tomography and magnetic resonance imaging findings in central neurocytoma]. / Computertomographische und magnetresonanztomographische Befunde beim zentralen Neurozytom.

PURPOSE: Analysis of our CT and MRI findings in patients with central neurocytomas in comparison with the relevant literature. MATERIALS AND METHODS: 5 patients were examined by CT and MRI. A retrospective analysis of the histologically confirmed tumors of our patient group and date from the literature was performed under the following criteria: 1. topography, 2. extent, 3. contrast medium behavior, 4. calcifications, 5. presence of intramural cysts, and 6. vascularization. These properties were evaluated according to a 5 point scale. RESULTS: All tumors originated in the roof of a lateral ventricles with participation of the pellucid septum and extended intraventricularly (5/5), showed cystic components (5/5), and took up contrast medium (5/5). Contrast medium uptake was visible in both CT and MRI. In contrast, only three of the 5 tumors revealed calcifications (3/5) and these were better visible in CT than in MRI, no pathological vessels were detected. Because of its multi-planar representations and better soft-tissue contrast, MRI was superior to CT for the exact determination of origin and position of the tumors. The small cystic, inhomogenous appearance in T2-weighted images was considered to be an especially typical feature. CONCLUSIONS: The typical appearance of central neurocytomas in CT and MRI provides information for the differential diagnosis from other intraventricular tumors. The definitive diagnosis is provided by neuropathological evaluation.

Antioxidant-induced changes of the AP-1 transcription complex are paralleled by a selective suppression of human papillomavirus transcription.

Considering the involvement of a redox-regulatory pathway in the expression of human papillomaviruses (HPVs), HPV type 16 (HPV-16)-immortalized human keratinocytes were treated with the antioxidant pyrrolidine-dithiocarbamate (PDTC). PDTC induces elevated binding of the transcription factor AP-1 to its cognate recognition site within the viral regulatory region. Despite of increased AP-1 binding, normally indispensable for efficient HPV-16 transcription, viral gene expression was selectively suppressed at the level of initiation of transcription. Electrophoretic mobility supershift assays showed that the composition of the AP-1 complex, predominantly consisting of Jun homodimers in untreated cells, was altered. Irrespective of enhanced c-fos expression, c-jun was phosphorylated and became primarily heterodimerized with fra-1, which was also induced after PDTC incubation. Additionally, there was also an increased complex formation between c-jun and junB. Because both fra-1 and junB overexpression negatively interferes with c-jun/c-fos trans-activation of AP-1-responsive genes, our results suggest that the observed block in viral transcription is mainly the consequence of an antioxidant-induced reconstitution of the AP-1 transcription complex. Since expression of the c-jun/c-fos gene family is tightly regulated during cellular differentiation, defined reorganization of a central viral transcription factor may represent a novel mechanism controlling the transcription of pathogenic HPVs during keratinocyte differentiation and in the progression to cervical cancer.

Improved efficacy of chemotherapy by parvovirus-mediated sensitisation of human tumour cells.

Increasing resistance of tumour cells towards the cytotoxic action of chemotherapeutic drugs is a major limitation in the treatment of cancer patients. The non-pathogenic human adeno-associated viruses (AAV) have been reported to sensitise HeLa cervical cancer cells to gamma irradiation in vivo and in vitro. To test whether these parvoviruses might render other human tumour cells more sensitive towards chemotherapeutic drugs, we analysed the effects of AAV type 2 (AAV-2) infection on established cancer cell lines and freshly explanted tumour biopsies treated with chemotherapeutic agents (e.g. cisplatin). AAV-2 infection significantly increased the cytotoxic activity of chemotherapeutic drugs compared with uninfected controls. AAV-2 infection without concomitant chemotherapeutic treatment had no significant effect on viability of the cells. In nude mice, combined application of AAV-2 infection and chemotherapeutic treatment significantly increased the therapeutic activity on tumours arising from subcutaneously injected tumour cells compared with tumours treated by chemotherapeutics only. These results indicate that AAV-2 infection sensitises human cancer cells towards the cytotoxic action of chemotherapeutic drugs.

Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia.

Virus infections have been thought to be involved in the development of childhood leukaemia. In order to address this issue we determined, in a case-control study, the prevalence of antibodies to viruses infecting blood or bone-marrow cells [Epstein-Barr virsus (EBV), human herpes virus type 6 (HHV-6), parvovirus B19] as well as to the human virus known for its tumour-suppressive properties, the adeno-associated virus type 2 (AAV-2), in the sera of 121 children with leukaemia in Germany, and in 197 control individuals, hospitalized for other reasons, and matched for age and gender to the cases. In addition, we developed a questionnaire to be answered by the children's parents, in order to gain information on previous infections of the children as well as to calculate for factors which may influence serological findings. Comparative determination of the prevalence of antibodies against AAV-2, B-19 or HHV-6 revealed no significant differences in cases and controls. However, antibodies to EBV were more frequently found in children with leukaemia younger than 6 years of age (age at the time of diagnosis of leukaemia) than in controls. Apparently, infection with AAV-2 has no protective effect in childhood leukaemia, in contrast to results observed for other malignancies. Similarly, and in accordance with results on leukaemia in adults, we found no indication of a protective effect of infection with the parvovirus B-19. The data suggest that EBV, which is known to be involved in various lymphomas, may play a role in the development of childhood leukaemia in young children.

Detection of adeno-associated virus DNA in human genital tissue and in material from spontaneous abortion.

The human helper virus-dependent parvovirus, adeno-associated virus (AAV) has never been associated with disease in humans [Berns et al. (1987): Advances in Virus Research 32:243-306; Siegl et al. (1985): Intervirology 23:61-73]. However, in pregnant mice, infection with AAV induces early abortion [Botquin et al. (1993): Journal of Cancer Research and Clinical Oncology 119:24]. We investigated whether this common human virus may be found in human genital tissue or in curettage material from spontaneous abortion. Using the polymerase chain reaction (PCR) AAV type 2 DNA was amplified in histological sections of 19 of 30 biopsies of the uterine mucosa. In addition, AAV-2 DNA was detected in abortion material during the first trimester of pregnancy (12/30 cases were positive) but not in material of abortion from the second or third trimester (9 cases). Whereas in tissues from the uterus AAV DNA was found only by PCR, large amounts of viral DNA were detectable by Southern blot analysis in abortion material. In situ hybridization revealed DNA of AAV to be present in the villous moiety (trophoblast) of the placenta but not in the embryo or decidua. in the same cells, AAV proteins (including the replication-associated rep proteins) were detected by immunofluorescence analysis. These results suggest (1) that AAV infects the uterine mucosa (possibly persistently) and (2) that it can replicate in trophoblast cells. This might disturb placenta development and may play a role in early miscarriage.(ABSTRACT TRUNCATED AT 250 WORDS)