[Show abstract][Hide abstract] ABSTRACT: Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. But these studies and subsequent non-phase III studies have also shown risks associated with local chemotherapy within the central nervous system. The introduction of concomitant radiochemotherapy with temozolomide (TMZ) has later demonstrated a survival benefit in a phase III trial and has become the current treatment standard for newly diagnosed malignant glioma patients. Lately, this has resulted in clinical protocols combining local chemotherapy with BCNU wafers and concomitant radiochemotherapy with TMZ although this may carry the risk of increased toxicity. We have compiled the treatment experience of seven neurosurgical centers using implantation of carmustine wafers at primary surgery followed by 6 weeks of radiation therapy (59-60 Gy) and 75 mg/m(2)/day TMZ in patients with newly diagnosed glioblastoma followed by TMZ monochemotherapy. We have retrospectively analyzed the postoperative clinical course, occurrence and severity of adverse events, progression-free interval, and overall survival in 44 patients with newly diagnosed glioblastoma multiforme. All patients received multimodal treatment including tumor resection, BCNU wafer implantation, and concomitant radiochemotherapy. Of 44 patients (mean age 59 ± 10.8 years) with glioblastoma who received Gliadel wafer at primary surgery, 28 patients (64%) had died, 16 patients (36%) were alive, and 15 patients showed no evidence of clinical or radiographic progression after a median follow-up of 15.6 months. At time of analysis of adverse events in this patient population, the median overall survival was 12.7 months and median progression-free survival was 7.0 months. Surgical, neurological, and medical adverse events were analyzed. Twenty-three patients (52%) experienced adverse events of any kind including complications that did not require treatment. Nineteen patients (43%) experienced grade 3 or grade 4 adverse events. Surgical complications included cerebral edema, healing abnormalities, cerebral spinal fluid leakage, meningitis, intracranial abscess, and hydrocephalus. Neurological adverse events included newly diagnosed seizures, alteration of mental status, and new neurological deficits. Medical complications were thromboembolic events (thrombosis, pulmonary embolism) and hematotoxicity. Combination of both treatment strategies, local chemotherapy with BCNU wafer and concomitant radiochemotherapy, appears attractive in aggressive multimodal treatment schedules and may utilize the sensitizing effect of TMZ and carmustine on MGMT and AGT on their respective drug resistance genes. Our data demonstrate that combination of local chemotherapy and concomitant radiochemotherapy carries a significant risk of toxicity that currently appears underestimated. Adverse events observed in this study appear similar to complication rates published in the phase III trials for BCNU wafer implantation followed by radiation therapy alone, but further add the toxicity of concomitant radiochemotherapy with systemic TMZ. Save use of a combined approach will require specific prevention strategies for multimodal treatments.
[Show abstract][Hide abstract] ABSTRACT: Multifocal tumor recurrences in glioblastoma patients are described in 4% - 14% of cases. Two recent studies, treating newly diagnosed glioblastoma patients with continuous high-dose tamoxifen (TAM), reported an increased incidence of multifocal tumor recurrences in 45.5% and 33% of study patients.
Fifty newly diagnosed patients with glioblastoma were treated with 3 cycles of carboplatin, continuous high-dose TAM and radiotherapy. Tumor progression was determined on follow-up MRI studies at 3-month intervals and categorized as either local or multifocal.
Multifocal tumor recurrence was found in 16 (33%) out of 49 study patients. Compared to tumors which remained local, multifocal tumor recurrences were characterized by a significantly longer median time to tumor progression (41 vs. 23 weeks, Breslow test: p = 0.0123). Multifocal tumor recurrences were mainly observed after an initial response to the study treatment (81%), whereas local regrowth was more often associated with initial treatment failure, i.e. progressive disease (64%).
The association of the pattern of tumor recurrence with the type of response to TAM treatment suggests that acquired resistance to TAM might be an important contributing mechanism in the development of multifocal glioblastoma disease.
Anticancer research 11/2004; 24(6):4195-203. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In order to identify response predictors for a post-operative glioblastoma therapy consisting of tamoxifen, carboplatin and radiotherapy, expression of 12 antigens was evaluated in 36 newly diagnosed tumours and 13 recurrences. Results were correlated with the clinical course of the disease. Antigen expression was assessed immunohistochemically for CD44s, TGF-beta2, TGF-alpha, progesterone receptor, estrogen receptor, EGFR, urokinase, urokinase inhibitor 1, CD87, p53 protein and Ki-67. Vessel density was determined by labelling of endothelia with von Willebrand factor. Response to chemotherapy correlated positively with cell density (p < 0.05) and negatively with CD44 over-expression (p < 0.02). Further, a positive correlation between age and CD44 expression (p < 0.05) and a negative correlation between age and p53 accumulation (p < 0.01) was found. In tumour recurrences expression of CD44 was significantly higher in local recurrences than in distant multifocal recurrences (p < 0.02), suggesting that CD44 may predominantly be associated with cell adhesion in glioblastomas.
Journal of Neuro-Oncology 01/2004; 66(1-2):139-46. DOI:10.1023/B:NEON.0000013496.58236.f0 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The treatment of giant aneurysms requires a thorough surgical and endovascular planning as this entity is accompanied by complex vascular and blood flow particularities. Even in experienced neurovascular centers the clinical outcome varies considerably. Within a series of 1386 aneurysm patients 72 (5%) giant (>25 mm) aneurysms were treated in our institution. Their age ranged between 26 and 81 years (medium age 52 years). 22 patients were suffering of a subarachnoid hemorrhage (SAH). Additionally there were 50 patients with nerve palsies or unspecific symptoms due to unruptured giant aneurysms (UGA). Treatment modalities included surgical clipping (n = 35), balloon occlusion of the ICA (n = 12), endovascular coiling (n = 7) or a combined regimen of balloon occlusion, surgical clipping and EC-IC bypass (n = 8). 10 patients could not be treated on due to their high age or minor clinical status (H&H IV and V). 6 of 15 (40%) SAH-patients were discharged without any complaints compared to 26% (12 of 47 patients) in the group of unruptured aneurysms. 1 SAH-patients (7%) versus 13 UGA (28%) patients suffered persisting nerve palsies or minor neurological disorders. 32% (n = 15) of the UGA-patients were suffering of major neurological deficits and required further professional help. 5 patients remained in a vegetative state, 3 of these had been admitted with an incidental finding of an UGA. 6 of 15 (40%) SAH-patients died, 5 of them admitted with H&H grade IV or V. However only 3 of 47 (6%) UGA patients died. 2 of these had a fatal SAH before treatment, 1 underwent EC-IC bypass surgery with insufficient hemispheric vascularization followed by gross infarction. The clinical status and age of the patient are significant factors influencing treatment associated morbidity and mortality. The individual vascular situation may lead to a complex therapeutical regimen thereby predisposes higher complication rates. We believe that surgical clipping is the first choice of treatment allowing temporarily clipping and reconstruction of the normal anatomy by shrinking or/and reconstructive clipping while reducing the mass effect. Whereas endovascular coiling alone is less favorable due to the packing of the coils a combined endovascular and surgical approach have to be considered in selected cases.
Zentralblatt für Neurochirurgie 01/2002; 63(2):45-51. · 0.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Only a minority of patients with malignant gliomas respond to continuous high-dose tamoxifen (TAM) treatment. Therefore a method to predict the efficiency of TAM-treatment would be desirable. Analogous to previous studies in breast cancer patients, we investigated whether the dynamics of TGF-beta2 plasma levels allow the prediction of response to TAM-treatment in glioblastoma patients as well.
TGF-beta2 plasma levels of glioblastoma patients treated with 200 mg TAM/day on a continuous basis and of control patients not treated with TAM were measured by using an ELISA. In addition, the effect of TAM and 4-OH-TAM on the secretion of TGF-beta2 by established glioma cell lines as well as the effect of TGF-beta2 itself on cell proliferation were investigated in vitro.
The effect of TAM on TGF-beta2 plasma levels did not correlate with the clinical response to TAM-therapy in glioblastoma patients. The in vitro experiments showed that TAM and 4-OH-TAM stimulate established glioma cell lines to increase their secretion of TGF-beta2. Externally added TGF-beta2 (nM) had no effect on cell proliferation of the same cell lines.
In contrast to breast cancer patients, the clinical response to TAM in glioblastoma patients is not reflected by changes of TGF-beta2 plasma levels. It has to be assumed that, despite an increase of TGF-beta2 production by glioblastoma cells in response to TAM in vitro, such elevated production in vivo does not reach the plasma due to either the lower tumor burden in glioblastoma disease compared to breast cancer patients or due to some local sequestration process.
Anticancer research 01/2002; 22(1A):45-51. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Only less than half of the patients with malignant gliomas respond to a continuous high dose Tamoxifen (TAM) and/or Carboplatin (CP)-treatment. Therefore, a method for predicting the efficacy of TAM-treatment would be desirable.
Paralleling a clinical study, the predictive value of in vitro-sensitivity testing of TAM and TAM's metabolite 4-OH-TAM in primary cultures of tumour explants from 15 of a total of 50 patients was examined. Additionally, the influence of TAM, 4-OH-TAM, and CP on the proliferation of established glioblastoma cell lines and of those explanted from athymic nude mice and re-established in cell culture was investigated. Human glioblastomas xenotransplanted subcutaneously into athymic nude mice and subsequently treated with TAM and/or CP were examined in a parallel in vivo-study.
TAM-chemosensitivity-testing of glioblastomas failed to predict the clinical response to TAM-treatment in our patients and did not correlate with the in vivo-TAM-response of tumours xenotransplanted into nude mice. TAM's and 4-OH-TAM's ability to inhibit growth of various glioblastoma cell lines in vitro in very similar concentrations was shown to be a consistent phenomenon which seems to be independent of the in vivo response in either patients or mice as previous hosts. However, CP's antiproliferative effect on glioblastomas in vivo was paralleled by respective in vitro results. Whereas TAM showed to mediate its in vitro antiproliferative effect by inducing apoptosis in most cell lines examined, CP-treatment lead to necrosis of cells.
Combining the results obtained from our human and mouse studies, it has to be postulated that host factors other than the sensitivity to TAM of the individual cell, determine the efficacy of TAM-treatment in vivo.
[Show abstract][Hide abstract] ABSTRACT: A historically controlled phase II study was undertaken to investigate the efficacy and toxicity of a postoperative treatment consisting of high-dose continuous tamoxifen, carboplatin and radiotherapy in patients with newly diagnosed glioblastoma. Between 1995 and 1998, 50 patients with newly diagnosed glioblastomas underwent surgery and were subsequently treated with 200 mg day(-1) tamoxifen continuously, 3 cycles of carboplatin (300 mg m(-2)), and radiotherapy. Survival data for a historical control group were calculated from respective prognostic indices and were obtained from studies with comparable patient populations treated with operation and radiotherapy only. In our study, the median time to tumor progression was 30 weeks and the median survival time (MST) 55 weeks (95% confidence interval: 46-63 weeks). The MST of the control group (48 weeks) showed to be within this interval. In addition to already known prognostic factors in malignant gliomas (age, Karnofsky performance score, extent of tumor resection), the gender (females lived longer than males, p = 0.0025) showed to influence survival. Serious side effects (thrombosis, pulmonary embolism) occurred in 6 patients. A high incidence of multifocal tumor recurrences (33%), which might be related to study-treatment, was observed. In conclusion, the combined therapy failed to demonstrate a higher efficacy than standard treatment for glioblastoma patients.
Journal of Neuro-Oncology 10/2000; 49(2):147-55. DOI:10.1023/A:1026533016912 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multifocal tumor recurrence of glioblastomas occurs in up to 14% of patients. In a parallel phase-II-study investigating post-operative treatment with tamoxifen (TAM), carboplatin and radiation therapy for glioblastomas, 16 of 49 patients (33%) showed multifocal recurrence, which developed after a mean of 46 weeks, raising the question of an association with therapy. We studied the interrelation of proliferation and migration in the presence of different protein-kinase-C(PKC) inhibitors (TAM, staurosporine, hypericin) in 2 glioma cell lines. In addition, 3 cell lines were selected for TAM resistance by repeated cycles of treatment with sub-lethal concentrations of TAM. The proliferative capacity and the invasive potential of selected sub-populations were assessed using growth-curve experiments, monolayer migration, and cell-adhesion assays. Treatment with all PKC inhibitors tested resulted in a dose-dependent decrease of proliferation, while motility was altered only at significantly higher doses. Resistance to TAM occurred in all 3 selected cell lines. The TAM-resistant sub-populations showed significantly increased proliferation, migration and adhesion as compared with the parental (non-selected) cell line. The higher incidence of multifocal disease after TAM treatment was paralleled by increased migratory potential of TAM-treated cells in vitro.
International Journal of Cancer 06/2000; 86(4):468-73. DOI:10.1002/(SICI)1097-0215(20000515)86:43.0.CO;2-R · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Suprasellar meningioma continues to be diagnosed very late after the onset of first eye symptoms. This study was aimed at demonstrating the effect of delay on the long-term visual loss.
In the course of a retrospective study all 53 consecutive patients operated on for suprasellar meningioma from 1982 to 1991 were contacted (47 women, 6 men; average age 49.5 years) 46 of the 49 surviving consented to the follow-up investigation. The extent of preoperative visual loss, tumour size, presence of optic nerve atrophy and duration of visual loss, data that provide an indirect measure of how soon the correct diagnosis was made, were analysed with regard to their effect on long-term ophthalmological results.
The mean period elapsing from onset of first visual symptoms to the definitive diagnosis of suprasellar meningioma was 22.3 months. The data showed that the long-term results were the worse the later the diagnosis was made.
The commonly very late diagnosis of suprasellar meningioma as cause of visual loss is an international problem and is presumably due to the low incidence of the tumour (1-2 cases per 1 mill. population per year). If long-term results are to be improved, primary care doctors must be made aware of the differential diagnosis of visual loss caused by pressure from a tumour.
[Show abstract][Hide abstract] ABSTRACT: Most of the previously published surgical series of suprasellar meningiomas have two disadvantages: (1) patients involved were treated within a relatively long time period, making analysis more difficult, (2) radiographic long term follow-up examinations with either CT- or MRI-scans were not performed. Both disadvantages were overcome in our retrospective clinical study, consisting of 50 consecutive patients with suprasellar meningiomas treated between 1982 and 1991. Radiological, ophthalmological, and neurological investigations were performed preoperatively, postoperatively and at long term follow-up (mean: 5.7 years). A radiologically confirmed radical tumour removal could be achieved in 84% of patients. Both, the peri-operative mortality (2%) and serious operative morbidity (6%) were low. However, 12% of patients developed late onset epilepsy. At long term follow-up, visual function was improved in 67%, unchanged in 9% and worsened in 24%. In more than 50% of patients the vision showed recovery over a longer time period than the first 10 days after operation. Radiographic control examinations revealed tumour recurrences in 2 patients (both asymptomatic) and progress of residual tumour in 5 patients (2 symptomatic, 3 asymptomatic). Since introduction of modern neurosurgery, a clear improvement in the surgical treatment of suprasellar meningiomas can be observed. However, the still long delay in diagnosing these tumours correctly prevents a further improvement of the ophthalmological results at long-term follow-up. Due to a relatively high rate of late onset epilepsy, anticonvulsive prophylaxis for 6 months seems to be justified. Regarding present preoperative diagnostic measures, ia-DSA seems only be indicated in patients with CT/MRI-scans, suspicious for tumourous narrowing or invasion of major cerebral arteries. In addition, we recommend radiographic control examinations at regular time intervals to confirm radical tumour removal and to detect the "ideal" point of time for renewed treatment.
[Show abstract][Hide abstract] ABSTRACT: Because of the common belief that there is an increase in surgical risk and morbidity involved in the surgical therapy of elderly patients with acromegaly, physicians tend to either neglect therapy altogether or choose radiation therapy combined with medical treatment. In consideration of the expected increasing number of elderly patients resulting from social structure change in the coming years, we decided to investigate the outcome in 15 patients with acromegaly (13 women and 2 men) older than 64 years (mean, 68.3 yr) at the time of surgery in the form of a retrospective study. Medical treatment using either dopamine agonists (9 patients) and/or octreotide (4 patients) were attempted in 11 patients. For various reasons, however, medical therapy could not be permanently continued in any of these patients. The mean preoperative growth hormone (GH)-plasma level without medical treatment was 47.4 +/- 64.2 (mean +/- standard deviation) micrograms/L. At the time of operation, 13 of 15 patients had additional diseases, which led to an increased anesthesiological risk. Transnasal tumor removal was performed without anesthesiological or surgical complications in all patients. The radicality of tumor removal was controlled intraoperatively by GH measurements in eight patients. There was no postoperative mortality or serious morbidity. Postoperative basal GH-plasma levels were normal (< 4.5 micrograms/L) in all patients. None of the 13 patients who participated in long-term follow-up examinations (mean, 4.2 yr) revealed signs of definite tumor recurrence. The mean GH-plasma level at follow-up was 1.6 +/- 0.9 (mean +/- standard deviation) micrograms/L. One patient died 2 years after the operation of causes unrelated to pituitary surgery.(ABSTRACT TRUNCATED AT 250 WORDS)
[Show abstract][Hide abstract] ABSTRACT: We present the clinical and histological findings of 11 cases of inflammatory anterior pituitary lesions, 8 of which were obtained during surgery and 3 of which were obtained from autopsies. Additionally, we extended the conventional classification of pituitary inflammatory disease by the new entity " secondary hypophysitis". Of the surgically obtained specimens 5 consisted of inflammatory extension into the pituitary gland out of the surrounding tissue. In all of these patients the inflammation originated from an additional tumor in the sellar region (4 craniopharyngiomas, 1 prolactinoma). These will be referred to as "secondary hypophysitis", an entity which has not yet been mentioned in the literature. Of the remaining 6 cases, 2 were granulomatous hypophysitis, 2 pituitary abscesses, 1 lymphocytic hypophysitis, and 1 showed extensive scarring of the anterior pituitary lobe due to preceeding lymphocytic hypophysitis. At histological examination the basic structure of the anterior pituitary was maintained in all cases. Relative counts of hormone-producing cells were normal. In secondary hypophysitis, the affected area was composed of fibrous tissue and granulation tissue. B and T lymphocytes were present in equal amounts. Granulomas were not found. Inflammatory infiltrates, granulation tissue and fibroses were seen in different proportions. Based on our results and three other cases reported in the literature so far, we think that the presently used classification of pituitary inflammatory diseases lacks an entity which describes a non-abscess-forming inflammation of the pituitary gland originating from an associated pathological process. Therefore, we introduced the term secondary hypophysitis to describe this fourth entity of pituitary inflammatory disease.
[Show abstract][Hide abstract] ABSTRACT: Gangliocytomas are benign, slow growing neuronal tumors and are found for the most part in children and young adults. They are most often localized in either the spinal cord or the cerebral hemispheres. Gangliocytomas in the sellar region are extremely rare and only 43 such tumors (including 4 own cases) have ever been described in the literature. Although these tumors are genuine rarities without any epidemiological importance, they do provide some interesting information on tumorigenesis of pituitary adenomas: 65% of the sellar gangliocytomas are associated with a pituitary adenoma. 74% of patients with these tumors suffered hormonal oversecretion of at least one of the pituitary hormones (mostly growth hormone). With only one exception, the hypothalamic releasing hormone corresponding to the hormonal oversecretion syndrome could be demonstrated in the gangliocytoma immunohistochemically. Ultrastructural studies could demonstrate close cell to cell contacts between adenoma and gangliocytome cells. All these data support the hypothesis that chronic overstimulation by hypothalamic releasing hormones play a role in the development of hormone secreting pituitary adenomas. However, in contrast to sellar gangliocytemas, extrahypothalamic tumors secreting excessive hypothalamic hypophysiotropic hormones have never been associated with a pituitary adenoma. They have only been associated with pituitary cell hyperplasia. Therefore, the hypothesis can be made that hypothalamic releasing hormones only promote but do not initiate tumorigenesis of pituitary adenomas.
[Show abstract][Hide abstract] ABSTRACT: Three cases of a composite sellar tumour composed of a gangliocytoma and an adenoma are presented. Two patients who showed acromegaly and hyperprolactinaemia had a gangliocytoma and a growth hormone (GH)-prolactin cell adenoma in close proximity. The gangliocytoma contained growth hormone-releasing hormone (GHRH) by immunohistochemistry. At the electron microscopical level, the gangliocytoma was characterized by numerous synaptic vesicles. The third patient, a child with Cushing's disease, presented a corticotropin-releasing hormone (CRH)-positive gangliocytoma in close contact with an adrenocorticotropic hormone (ACTH) secreting adenoma, the latter a typical densely granulated ACTH cell adenoma. Ultrastructurally, the gangliocytoma revealed synaptic vesicles and sparse secretory granules. The results suggest that gangliocytomas may promote the development of pituitary adenomas by hypersecretion of releasing hormones. Whereas 20 cases of sellar GHRH producing gangliocytomas in acromegaly are reported in the literature, the combination of a CRH-positive gangliocytoma and an ACTH cell adenoma in Cushing's disease is apparently the first case.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/1994; 425(1):93-99. DOI:10.1007/BF00193956 · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hypothesis that intracranial aneurysms are inherited is based on published accounts of aneurysms occurring in two or more members of the same family. This hypothesis has been strongly supported by rare cases of intracranial aneurysms in pairs of identical twins. Seven such pairs have been reported to date. In all pairs, both twins had intracranial aneurysms, most of them located at the same site. Only rarely did they appear at exact contralateral locations. In five pairs, both twins suffered from a subarachnoid hemorrhage (SAH). In one case, the asymptomatic twin underwent angiography and was treated before an SAH occurred. We now present the first pair of identical twins. One twin had an SAH and two intracranial aneurysms. The other was asymptomatic and showed no aneurysms with either three-dimensional magnetic resonance angiography or intra-arterial digital subtraction angiography. Based on epidemiologic data, we assume that there must be many unreported cases of identical twins with at least one twin suffering from SAH. Our case indicates that the trait of intracranial aneurysms is not inherited with complete penetrance, which might otherwise be assumed on the basis of all other accounts previously described in the literature. However, as long as the exact means of inheritance of intracranial aneurysms is not understood, we still recommend an angiographic examination of the asymptomatic identical twin in cases where the other sibling had already suffered from an aneurysmal SAH.