Maria Piribauer

P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy

SummaryThe co-administration of antiepileptic drugs (AED) and chemotherapeutic agents in patients with glioblastoma multiforme (GBM) is common. Interactions of chemotherapeutic agents and AED have not been investigated sufficiently. The purpose of this study is to evaluate the effects of enzyme inducing (EI-AED) and non-EI-AED in patients with GBM treated with standard chemotherapeutic agents on survival and haematotoxicity. One hundred and sixty eight glioblastoma patients with standard treatment including surgery, radiotherapy and chemotherapy were retrospectively analysed. Patients were separated into three groups: Group A patients without AED (n=88), Group B patients with EI-AED (n=43), and Group C patients with non-EI-AED (n=37). CCNU was the most frequently used first-line drug in all three groups (Group A: 77%; Group B: 81%; Group C: 78%). Second line treatment, mainly temozolomide, was applicated in 58 of patients and third-line treatment in 9. Carbamazepine was the most frequently administered AED in Group B (81%) and valproic acid in Group C (85%). For statistical analysis, only patients with CCNU first line treatment were calculated. A significant difference regarding survival was detected between Group B (10.8 month) and Group C (13.9 month), as well as increased haematotoxicity for Group C. These results indicate that AED influence the pharmacokinetics of chemotherapeutic drugs in patients with GBM. Valproic acid might be responsible for increasing haematotoxicity. Whether the difference regarding survival between Group B and Group C is due to a decrease of efficacy of chemotherapeutic agents by EI-AED, or due to increased efficacy of chemotherapeutic agents caused by the enzyme inhibiting properties of valproic acid, has to be evaluated in future studies.

Vascular Patterns in Glioblastoma Influence Clinical Outcome and Associate with Variable Expression of Angiogenic Proteins: Evidence for Distinct Angiogenic Subtypes

No data exist on angiogenic patterns and their prognostic impact in human glioblastoma. Such data are relevant for translation of antiangiogenic therapies into clinical applications. Using immunohistochemistry for CD34, we assessed vascular patterns in 114 primary glioblastomas. Vascular patterns comprised unevenly distributed glomeruloid/garland‐like/clustered bizarre vascular formations and evenly distributed delicate capillary‐like microvessels (“classic” vascular pattern). The combination of low content of bizarre vascular formations and prominent classic vascular pattern (n=29) was an independent factor for longer survival (p= 0.006, Cox regression), as well as postoperative high Karnofsky performance status (p=0.005). In patients with a prominent classic vascular pattern, there was no difference of MIB1 labeling index whereas microvessel density and apoptotic index (TUNEL) were significantly higher as compared to all other patients (p<0.05). In addition, diffuse expression of hypoxia‐inducible factor (HIF)‐1α and strong expression of vascular endothelial growth factor were more common (p<0.05, Chi‐square test). FISH revealed loss of chromosomes 1p and 19q only in 1/7 long‐time survivors with classic pattern. We conclude that vascular patterns in primary glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins. Our findings denote for the first time distinct angiogenic subtypes of human glioblastoma which may prove relevant for anti‐angiogenic therapy approaches.

High expression of DNA topoisomerase IIα and Ki-67 antigen is associated with prolonged survival in glioblastoma patients

Assessment of tumour cell proliferation in glioblastoma (GB) has been a topic of considerable research interest over the past decade. However, the correlation of tumour proliferation and patient outcome has yielded controversial results. In this study, we examined immunohistochemically, using paraffin-embedded tissue, the expression of the proliferation-related markers DNA topoisomerase IIalpha (TIIalpha) and Ki-67 antigen in a cohort of 114 GB patients treated consecutively with surgery and radiochemotherapy, and correlated the expression with patient outcome. The TIIalpha labelling index (LI) ranged between 5.2 and 87.2% (median: 25.6%). Survival analysis disclosed an association between high TIIalpha expression levels and prolonged survival (P=0.040, log-rank test). TIIalpha expression correlates closely with Ki-67 labelling index (R=0.927, P<0.001), which itself is predictive of patient survival (P=0.044). However, in multivariate analysis, only the Karnofsky performance status remained predictive of patient survival. We conclude that high expression of TIIalpha and Ki-67 appears to be associated with a prolonged survival in our cohort of GB patients.

Stabilization of a progressive hemangioblastoma under treatment with thalidomide.

After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel–Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) controls 1, 6 and 11 months after begin of thalidomide treatment did not show further tumor progression. She remained wheelchair-bound, but mobility of her arms continuously improved. There was no thalidomide associated side-effect in this patient until her death from pneumonia due to legionnaires disease.Antiangiogenic treatment with interferon (IFN) α-2a and IFN α-2b and with SU 5416 has been reported to be effective and well tolerated in several patients with previously progressive angioblastomas and hemangioblastomas. This case adds further evidence of the efficacy of an antiangiogenic treatment concept in a progressive hemangioblastoma.

Survival improvement in patients with glioblastoma multiforme during the last 20 years in a single tertiary-care center

ZusammenfassungStudienzielZiel der retrospektiven Analyse war es, die Überlebensdauer und einen eventuellen Fortschritt von 357 konsekutiven Patienten mit Gliob lastoma multiforme (GBM) innerhalb von 3 Gruppen aus unterschiedlichen Diagnose-Zeiträumen (Gruppe A: 1982–1984, B: 1994/1995; C: 1996–1998), die während der letzten 20 Jahre an unserem tertiärem Zentrum behandelt wurden, zu untersuchen.Patienten und MethodenPatienten der Gruppe A (n=100) wurden zwischen 1982 und 1984 diagnostiziert und dienten als historische Kontrolle. Patienten der Gruppe B (n=93) wurden 1994/1995 und Patienten der Gruppe C (n=164) zwischen 1996 und 1998 diagnostiziert.Die Überlebens-Analyse wurde durchgeführt in Bezug auf die drei Patientengruppen (A versus B versus C), in Bezug auf die applizierten Therapiemodalitäten nach neurochirurgischer Intervention (keine spezifische Therapie versus Radiotherapie versus kombinierte Radio-/Chemotherapie), in Bezug auf die unterschiedlichen first-line Chemotherapien, in Bezug auf Alter, Geschlecht und Tumorlokalisation. Die non-parametrische Kaplan-Meier Methode wurde angewandt. Ein p-Wert <0,05 wurde als statistisch signifikant angesehen.Patienten der Gruppen A und B erhielten Radio- und/oder Chemotherapie in einem unterschiedlichen Ausmaß (Radiotherapie: Gruppe A: 22%, Gruppe B: 62%; Chemotherapie: Gruppe A: 6%, Gruppe B: 33%). Die Chemotherapie wurde in beiden Gruppen nach Abschluss der Radiotherapie appliziert. In Gruppe C erhielten 96% der Patienten eine kombinierte Radio-/Chemotherapie innerhalb von 3 Wochen nach der neurochriurgischen Intervention.ErgbnisseDas mediane Überleben betrug in Gruppe A 5,2 Monate, in Gruppe B 5, 1 Monate und in Gruppe C 14,5 Monate (p<0,0001). Länger als 18 Monate lebten 9% der Patienten in Gruppe A, 10% der Patienten in Gruppe B und 25% der Patienten in Gruppe C (p<0,05).SchlussfolgerungDie Überlebenszeitverbesserung in Gruppe C ist auf die frühzeitige und kombineierte Applikation von Radio-/Chemotherapie zurückzuführen. Die Therapie wurde ambulant durchgeführt; dies wurde durch ein interdisziplinäres neuro-onkologisches Team ermöglicht. Die Nebenwirkungen waren mild und die Akzeptanz bei den Patienten hervorragend.SummaryMethodologyThe survival of 357 consecutive patients with newly diagnosed glioblastoma multiforme (GBM) in three treatment groups reflecting different time-periods of diagnosis (A: 1982–1984; B: 1994/1995; C: 1996–1998) was analysed to assess the impact and the potential improvement of changing treatment strategies in our tertiary-care center.Patients and methodsGroup A (n=100) included all consecutive patients diagnosed from 1982 to 1984 and served as the historical control. Group B (n=93) included all consecutive patients diagnosed in 1994/1995 and group C (n=164) those diagnosed from 1996 to 1998. Survival in the three treatment groups (A vs. B vs. C) was analysed according to treatment given after neurosurgical intervention (i.e. no specific therapy versus radiotherapy versus combined radio-/chemotherapy), and according to first-line chemotherapy, age (<40, 40–60, ≥60), sex, and tumor location (hemispheric versus bilateral or multifocal tumors, and tumors involving eloquent brain areas). Survival was analysed using Kaplan-Meier’s non-parametric method. A p-value <0.05 was considered statistically significant.ResultsPatients in groups A and B received radio-and/or chemotherapy to a varying extent (radiotherapy: group A: 22%, group B: 62%; chemotherapy: group A: 6%, group B: 33%). Chemotherapy was administered after termination of radiotherapy in both groups. In group C, 96% of patients received combined radio-/chemotherapy which was administered concomitantly and started within three weeks after surgery.Median survival was 5.2 months in group A, 5.1 months in group B and 14.5 months in C (p<0.0001). Nine patients in group A (9%), 9 in group B (10%) and 40 in group C (25%) survived more than 18 months (p<0.05).ConclusionsSurvival improvement in group C might be attributable to the early start of combined radio-/chemotherapy. Therapy was administered on a complete outpatient basis, enabled by a dedicated interdisciplinary neuro-oncologic team caring for group C. Toxicity was mild and patients’ acceptance excellent.

Cytogenetic and comparative genomic hybridization findings in four cases of breast cancer after neoadjuvant chemotherapy

To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer.

Frequent MGMT (06-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience

Frequent MGMT (06-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience Background. The aim of this retrospective study was to analyse the MGMT (06-methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (≥ 3 years) patients with glioblastoma multiforme (GBM). Methods. The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples. Results. MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions. Conclusions. Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one.