[Ischemic stroke patients following intravenous thrombolysis. Outcome in a regional stroke center]. / Intravenöse Thrombolyse des ischämischen Schlaganfalls. Ergebnisse in einem regionalen Schlaganfallzentrum.

BACKGROUND: We wanted to compare the outcome following IV thrombolysis in our patients with ischemic stroke with the outcome reported from the phase 3 registration trials and other large trials. PATIENTS AND METHODS: From January 2008 through December 2009 we treated 225 patients with ischemic stroke with IV thrombolysis. Retrospectively, we analyzed their clinical data upon admission, during their stay, and upon discharge with special reference to eligibility criteria for IV thrombolysis, symptomatic hemorrhage, and clinical outcome. RESULTS: The average age of the patients was 74 years, with 34% being older than 80 years. The median time between stroke onset and initiation of treatment was 112 min. The initial median NIHSS was 11 points (Rankin score ≥ 4 in 79% of patients). The rate of symptomatic hemorrhage was 3%. The median follow-up was 14 days. At the end of the observation period, clinical symptoms had improved in 73% of patients (Rankin score ≤ 2 in 45% of patients). The mortality rate was 12%. In 55% of patients, IV thrombolysis was off label (age > 80 years in 34% of patients). CONCLUSION: The clinical results of IV thrombolysis in our stroke center are similar to the outcome reported from the registration trials and larger clinical series although we treated off label in more than half of the patients. Even larger studies have since shown that the age limit under 80 years for patients is not reasonable. The eligibility criteria should be adapted to reality at this point.

[Miller-Fisher syndrome and the spectrum of oculomotor palsies with anti-GQ1b antibodies]. / Das Miller-Fisher-Syndrom im Spektrum GQ 1b-Antikörper-positiver Erkrankungen der Augenmuskelnerven.

The author reports his experience with his own case of Miller-Fisher syndrome (MFS) and discusses the spectrum of GQ 1b-positive oculomotor nerve diseases, including MFS, Bickerstaff's brainstem encephalitis, Guillain-Barré syndrome, ophthalmoplegia without ataxia and isolated oculomotor palsies.

Adult medulloblastoma: prognostic factors and response to therapy at diagnosis and at relapse.

Adult medulloblastoma is a rare tumor with few retrospective studies published so far. The role of adjuvant chemotherapy or chemotherapy at relapse is unclear. This study reports therapy and outcome in all adult (>or=16 years old) medulloblastoma (n=34) and supratentorial primitive neuroectodermal tumor (PNET) patients (n=2) treated in 2 neuro-oncological centers between 1976 and 2002. The median age was 24.5 years (range 16-76). After resection, 16 patients were treated with craniospinal radiotherapy alone, 20 patients also received adjuvant chemotherapy (8 vincristine, CCNU, cisplatin; 7 methotrexate alone or methotrexate/vincristine-based polychemotherapy; 5 other protocols). Median survival in the whole cohort was 126 months (2+ - 200+months). Five-year and 10-year survival rates were 79 % and 56%. Adjuvant chemotherapy was associated with a non-significant trend to prolonged survival (relative risk (RR) 1.89; p=0.068). The median progression-free survival (PFS) after primary therapy was 83 months. At relapse, 10 of 12 evaluable patients achieved a complete response upon second-line therapy. The median survival times from first (n=17) and second relapse (n=9) were 21 months (0-67+ months; 5/17 without second relapse) and 20 months (1-29 months). Cox regression analysis revealed the infiltration of the floor of the 4(th) ventricle at diagnosis as the only therapy-independent prognostic factor (RR 0.48; p=0.03). In conclusion, adjuvant chemotherapy may prolong survival in adult medulloblastoma patients. Moreover, second-line therapy may be beneficial for these patients. As in pediatric medulloblastoma patients, primary infiltration of the floor of the 4(th) ventricle indicates a poor prognosis.

Response of radiochemotherapy-associated cerebral edema to a phytotherapeutic agent, H15.

Twelve patients with brain tumors and progressive edema caused by tumor progression or radiochemotherapy-related leukoencephalopathy were treated with H15, a phytotherapeutic anti-inflammatory agent. Edema was reduced in two of seven patients with glioblastoma with tumor progression and in three of five patients with treatment-related leukoencephalopathy. All patients with leukoencephalopathy improved clinically for several months.

Prednisolone therapy of experimental allergic neuritis in Lewis rats does not induce relapsing or chronic disease.

The effects of therapeutic prednisolone treatment on experimental allergic neuritis (EAN) in Lewis rats were evaluated in a controlled clinical and electrophysiological study. Since steroid therapy has been suspected to cause relapsing or chronic disease, monitoring was extended over 200 days. Short-term steroid treatment (5 days of 15 mg/kg prednisolone, n = 8) with sudden steroid withdrawal was compared with long-term application (30 days, beginning at 7.5 mg/kg) in descending dosage (n = 8). The experiment included saline-injected controls (n = 8) and controls for stress possibly exerted by the handling of the animals. Treatment was begun at the onset of clinical signs. The clinical and electrophysiological data indicated that deterioration, recovery and mild (insignificant) relapse (after day 30 and day 108) occurred in all groups at the same time. Both steroid application schemes significantly (p less than 0.03) attenuated the severity and shortened the duration of EAN. Relapse was not aggravated after steroid treatment. The clinical course and electrophysiological findings were unaltered by the experimental procedures and by mild experimental stress.

Demyelination of sciatic nerve in acute experimental allergic neuritis of the rat. A gel electrophoresis investigation.

Acute experimental allergic neuritis (EAN) of Lewis rats was monitored by clinical and electrophysiological tests for 60 days. Sciatic nerve myelin proteins were analyzed by quantitative microgel electrophoresis and electroimmunoblotting at different clinical stages of the disease. The clinical severity of EAN and the demyelination as measured by electrophysiological tests and myelin protein concentrations in sciatic nerve did not correspond during the course of the disease. Demyelination reached its peak after partial clinical recovery and was still present on day 60. The major peripheral nervous system (PNS) myelin proteins P0, P1 and P2 decreased at different rates during the course of the disease, indicating possible differences in their proteolytic degradation. Treatment with Freund's complete adjuvant (CFA) alone resulted in alterations of membrane and myelin protein patterns challenging the widely held belief that pure CFA is inert with regard to demyelination.

Spontaneous chemiluminescence activity of peripheral blood cells during experimental allergic neuritis (EAN).

In 30 Lewis rats the time course of spontaneous monocyte and granulocyte chemiluminescence activity (CLA) during myelin-induced experimental allergic neuritis (EAN) was studied. CLA of blood and peritoneal cells, and clinical, histopathological and electrophysiological findings were compared with data from 14 animals immunized with complete Freund's adjuvant and ten normal Lewis rats. About 12 days post-immunization there was a significant (p less than 0.003) rise in monocyte, but not in granulocyte CLA in EAN animals. CLA correlated significantly (p less than 0.02) with infiltrate formation in nerve roots, preceding clinical or electrophysiological signs of disease by 1-2 days. There was no increase in peritoneal monocyte CLA, which was consistently higher than blood monocyte CLA (p less than 0.002).

Influence of gangliosides on experimental allergic neuritis.

The development of myelin-induced experimental allergic neuritis (EAN) in Lewis rats can be depressed and delayed by adding a ganglioside mixture (GM1, GD1a, GD1b, GT1b) to the immunization compound; however, gangliosides may enhance the induction of adjuvant arthritis. Antibodies against multiple gangliosides are produced in rats after immunization with gangliosides after addition of myelin, but only low titers can be detected in animals immunized with myelin and complete Freund's adjuvant alone. We conclude that this antibody production is not the result of peripheral nerve inflammation but depends rather from external applied gangliosides.

The use of protease inhibitors in experimental allergic neuritis.

In experimental allergic neuritis (EAN) break-down of myelin is attributed to macrophages, which among other factors contain and secrete proteases. In vitro studies have shown that cathepsin D, an acidic aspartyl endopeptidase, and plasmin can degrade myelin proteins. In order to elucidate a potential therapeutic effect of protease inhibitors we treated Lewis rats, immunized with bovine peripheral nervous system myelin, with epsilon-amino-caproic acid (EACA) or pepstatin. EACA or pepstatin was administered twice daily by intraperitoneal injection beginning on day 6 postimmunization or from the onset of disease (on day 12) through day 24. Compared to saline-treated controls, animals treated with either of the inhibitors showed delayed development of clinical signs and electrophysiological abnormalities. Maximal severity and the further course of disease, however, were not different in control and treated groups. Immunohistological evaluation of sciatic nerve specimens on day 24 postimmunization showed equal numbers of cells positive for ED1 (macrophages) and cathepsin D in all animal groups. There was also no difference in the spontaneous proteolytic activity of the sciatic nerve homogenates at pH 2.8, 5.0, and 7.4. Incubation of the homogenates with pepstatin, however, significantly reduced proteolytic activity at pH 2.8 and 5.0, while EACA had no effect at any pH tested. These results imply that treatment to limit the infiltration of cathepsin D-positive cells or to reduce the induction or activity of cathepsin D may provide a therapeutic avenue for treating inflammatory demyelination of the peripheral nervous system.

CD95 ligand-induced apoptosis of human medulloblastoma cells.

CD95 ligand (CD95L) is a cytotoxic cytokine that induces apoptosis in susceptible target cells. Medulloblastoma is the most common non-glial intrinsic malignancy of the brain. In this study, we have studied CD95-mediated apoptosis of human medulloblastoma cell lines. We found that DAOY, MED-1 and D-283 cells are susceptible to CD95L-induced apoptosis when RNA and protein synthesis are inhibited. Preexposure of D-283, but not DAOY or MED-1 cells, to interferon-gamma or tumor necrosis factor-alpha enhances CD95 expression and primes these cells for CD95-mediated apoptosis. Inhibitors of interleukin 1-converting enzyme (ICE)-like protease (caspase) activity block CD95L-induced cytotoxicity, suggesting that caspases mediate the death signal induced by CD95L in human medulloblastoma cells. Interestingly, medulloblastoma cells belong to an increasing number of tumor cell types that coexpress CD95 and CD95L. We conclude that CD95 may be a promising target of immunochemotherapy for human medulloblastoma.

Malignant glioma: patterns of failure following individually tailored limited volume irradiation.

Treatment outcome was analyzed for 66 patients with malignant glioma treated with individually CT-planned multifield irradiation techniques. Total doses of 60 Gy were given, with the planning target volume (PTV) including 2 cm beyond the tumour indicated by preoperative CT examination. Median survival was 14 months, and 86% of recurrences occurred in the treated volume. Our results suggest that the used PTV and radiation technique should be appropriate in radiotherapy of malignant glioma.

Elevated CSF lactoferrin in superficial siderosis of the central nervous system.

This study sought to identify abnormalities in the levels of iron transport proteins in patients with superficial siderosis of the central nervous system. We compared patients with superficial siderosis (n = 7) with patients suffering from various other neurological disorders (n = 176, total). CSF and serum levels of lactoferrin, and CSF levels of transferrin were measured by enzyme-linked immunosorbent assay. Serum transferrin was measured by nephelometry. Lactoferrin, but not transferrin, levels in the CSF were significantly elevated in superficial siderosis. Unexpectedly, CSF transferrin was decreased in multiple sclerosis patients. Enhanced CSF lactoferrin may reflect an increased iron transport requirement in the central nervous system in superficial siderosis and might be a useful measure for monitoring response to therapy.

Humoral immune response to p53 in malignant glioma.

p53 immunoreactivity and humoral immune response to p53 were examined in 14 patients with malignant glioma, including 4 patients with leptomeningeal glioma cell dissemination. Twelve patients expressed p53 protein within the tumour tissue. p53 antibodies were detected in the serum in 2 of 14 patients but never in the cerebrospinal fluid (CSF). Soluble p53 protein was detected neither in serum nor in CSF of the glioma patients. CSF levels of the immunosuppressive cytokine, transforming growth factor (TGF)-beta, were elevated in the glioma patients, including those with a humoral response to p53. These preliminary findings raise the possibility of systemic humoral immune responses to antigens, including mutant p53, expressed by glioma cells in the central nervous system.

A role for preirradiation PCV chemotherapy for oligodendroglial brain tumors.

Oligodendroglial tumors have been identified as a subgroup of glial neoplasms with a distinctly better response to chemotherapy and overall survival than purely astrocytic gliomas. Here we report our experience with adjuvant postirradiation and preirradiation chemotherapy using procarbazine, lomustine, and vincristine (PCV) in 27 patients with WHO grade II or III oligodendroglioma or oligoastrocytoma. The efficacy of chemotherapy was assessed according to the Macdonald response criteria (complete response, CR; partial response, PR; stable disease, SD; progressive disease, PD) and progression-free survival intervals by computed tomography or magnetic resonance imaging. First, we confirm that PCV salvage therapy for patients progressing after radiotherapy is highly effective (n = 11, 1 CR, 5 PR, 5 SD; median progression-free survival has not yet been reached, but is longer than 18 months). Second, 3 patients who received radiotherapy plus PCV as first-line therapy achieved CR and 2 achieved SD, and all 5 are progression-free with a median follow-up of 12 months. Third, given these encouraging results, 11 patients received postoperative preirradiation PCV chemotherapy and were given radiotherapy only upon progression. Preirradiation PCV chemotherapy was also effective (2 CR, 3 PR, 6 SD; median progression-free survival has not been yet reached, but is longer than 14 months). Patients with anaplastic oligoastrocytomas were as likely to respond to PCV chemotherapy, as were patients with anaplastic oligodendroglioma. Three patients who had previously responded to PCV were successfully treated with a second course of PCV upon recurrence. PCV chemotherapy was also effective in patients with leptomeningeal spread of oligodendrogliomas. A randomized prospective trial is required to compare the effectiveness and neurotoxicity of first-line PCV chemotherapy followed by radiotherapy to the traditional reverse sequence.

Gender-related effects of indomethacin on cerebrovascular CO2 reactivity.

Prostaglandins are believed to play an important role in the regulation of resting cerebral blood flow and in the vasodilatory response to hypercapnia. Recently, we reported an increased CO2 reactivity (CR) in premenopausal women and, in the past, evidence has accumulated that estrogens might increase basal levels of prostaglandin secretion from endothelial cells. Therefore, one may speculate that gender differences in CR are possibly mediated by higher prostaglandin levels in women. Using transcranial Doppler sonography, we assessed CR before and 90 min after a single dose of 100 mg of indomethacin in 22 healthy volunteers (11 men, 11 women). Before intake of indomethacin, women had a significantly higher CR (4.53+/-0.49 vs. 3.61+/-0.74, P<0.01). Ninety minutes after indomethacin administration, CR decreased to 1.53+/-0.93 in women and 1.60+/-0.92 in men, respectively. The change of CR was 3.00+/-1.29 in women vs. 2.01+/-1.06 in men (P=0.07). For the entire study population, the decrease of CR was linearly correlated with the initial value of CR (rs=0.74, P<0.001). This gender-related difference possibly relates to higher prostaglandin levels as mediators of an increased CR in premenopausal women, although the exact features remain to be clarified.

BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study.

Malignant gliomas are rather refractory to current therapeutic approaches including surgery, radiotherapy, chemotherapy and immunotherapy. Acquired alterations in the pathways required for apoptotic cell death are thought to be responsible to the failure of glioma to respond to therapy. Here we have examined the expression of several proteins involved in the susceptibility to apoptosis in 20 human gliomas, including the BCL-2 family proteins BCL-2, BCL-X, BAX and MCL-1, as well as p53 and RB. Most gliomas expressed several BCL-2 family proteins. There was good correlation between expression of the functional antagonists, BCL-2/BCL-X and BAX, suggesting that changes in the BCL-2+BCL-X/BAX ratio are not responsible for the differential response of glioma patients to chemotherapy. The immunochemistry data were also analysed in regard to response to therapy and clinical outcome. All patients had cytoreductive surgery and received radiotherapy and nitrosourea-based adjuvant chemotherapy. There was no prominent association of outcome with the expression patterns of p53, RB, BCL-2, BCL-X or BAX. We find, however, that expression of the MCL-1 protein is associated with early tumour recurrence and shorter survival in this group of glioma patients. This preliminary observation will have to be confirmed in a larger independent sample of glioma patients.

In vitro secretion of adenoma and anterior lobe cells in two typical cases of Cushing's disease.

Fragments of adrenocorticotropic hormone (ACTH) cell adenomas and anterior lobes of two patients with Cushing's disease were obtained by transnasal operation. Both patients showed the typical clinical course, with postoperative ACTH deficit and all other pituitary functions intact. Equivalent specimens of tissue were investigated by immunocytology and in a superfusion system. The majority of adenoma cells were ACTH-positive, whereas ACTH-secreting cells of the anterior lobes were mostly inactive and were reduced in number. In vitro, adenomatous tissue showed high ACTH secretion into the superfusion medium, which was increased significantly after vasopressin application. Corticoid feedback was impaired Anterior lobe cells exhibited a significant spontaneous ACTH secretion that was reduced by cortisol, but not stimulated by vasopressin. These results support the concept of an impaired corticoid feedback at the adenoma level in the presence of suppressed ACTH secretion of the para-adenomatous anterior lobe.

Topotecan-based combination chemotherapy for human malignant glioma.

BACKGROUND: Topotecan has been considered a promising agent for the adjuvant chemotherapy of human malignant glioma because of its novel mode of action, its activity against other solid tumors, and its good penetration across the blood-brain barrier. However, the clinical effects of topotecan monotherapy in malignant glioma have been disappointing. MATERIALS AND METHODS: We sought to identify suitable partners for topotecan combination chemotherapy of malignant glioma using two well-characterized human malignant glioma cell lines, T98G and LN-229. The effects of co-exposure to topotecan and other chemotherapy drugs were assessed in cytotoxic and clonogenic cell death assays. RESULTS: We found additive, less-than-additive, or occasional antagonistic effects, but never synergistic activity of topotecan with either CCNU, VM26 or vincristine, in acute cytotoxicity or in clonogenic cell death assays, with simultaneous or sequential drug exposure. VM26 or vincristine followed by topotecan yielded the most favourable results. Further, prolonged exposure of the glioma cells to topotecan and either CCNU, VM26, vincristine, cisplatin, doxorubicin or cytarabine resulted in additive but not synergistic growth inhibition. CONCLUSIONS: The present study fails to identify a specific partner for topotecan-based combination chemotherapy of malignant glioma among the chemotherapeutic drugs examined here. While this does not exclude a possible synergy of the drug combinations examined here in vivo, a focus on novel partners for topotecan or topotecan-based chemoimmunotherapy may be more promising.

Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53.

Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type p53 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved.

Epidemiology of primary CNS lymphoma.

In the beginning of the nineties the National Cancer Institute Surveillance, Epidemiology, and End Results Program calculated the incidence of primary central nervous system non-Hodgkin's lymphoma (PCNSL) as 1:100000. The incidence of PCNSL has been increasing since the seventies in immunocompetent patients. The main increase, however, is taking place since the mid-eighties and is due to the increase of immunodeficiency and immunosuppression. The risk is 2-6% in AIDS patients according to clinical data and will probably further increase with the length of survival in these patients. Transplant patients carry a risk of 1-5% to develop a PCNSL. The risk is 1-2% for renal, and 2-7% for cardiac, lung or liver transplant recipients. Patients with congenital immune deficiency have a risk of 4%. PCNSL may also present as a secondary malignancy.