Michael Kosteljanetz

Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial

The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with recurrent primary GBM and progression within 6 months of ending standard treatment (radiotherapy and temozolomide). Bevacizumab and irinotecan were administered IV every 2 weeks. The first 10 patients received bevacizumab 5 mg/kg, but this was increased to 10 mg/kg after interim safety analysis. Irinotecan dose was based on whether patients were taking enzyme-inducing antiepileptic drugs or not: 340 and 125 mg/m(2), respectively. Cetuximab 400 mg/m(2) as loading dose followed by 250 mg/m(2) weekly was administered IV. Forty-three patients were enrolled in the trial, of which 32 were available for response. Radiographic responses were noted in 34%, of which 2 patients had complete responses and 9 patients had partial responses. The 6-month progression-free survival probability was 30% and median overall survival was 29 weeks (95% CI: 23-37 weeks). One patient had lacunar infarction, 1 patient had multiple pulmonary embolisms, and 3 patients had grade 3 skin toxicity, for which 1 patient needed plastic surgery. One patient was excluded due to suspicion of interstitial lung disease. Three patients had deep-vein thrombosis; all continued on study after adequate treatment. Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well tolerated except for skin toxicity, with an encouraging response rate. However, the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone.

Cellular telephones and risk for brain tumors A population-based, incident case-control study

Objective: To evaluate a possible association of glioma or meningioma with use of cellular telephones, using a nationwide population-based case-control study of incident cases of meningioma and glioma. Methods: The authors ascertained all incident cases of glioma and meningioma diagnosed in Denmark between September 1, 2000, and August 31, 2002. They enrolled 252 persons with glioma and 175 persons with meningioma aged 20 to 69. The authors also enrolled 822 randomly sampled, population-based controls matched for age and sex. Information was obtained from personal interviews, medical records containing diagnoses, and the results of radiologic examinations. For a small number of cases and controls, the authors obtained the numbers of incoming and outgoing calls. They evaluated the memory of the respondents with the Mini-Mental State Examination and obtained data on socioeconomic factors from Statistics Denmark. Results: There were no material socioeconomic differences between cases and controls or participants and non-participants. Use of cellular telephone was associated with a low risk for high-grade glioma (OR, 0.58; 95% CI, 0.37 to 0.90). The risk estimates were closer to unity for low-grade glioma (1.08; 0.58 to 2.00) and meningioma (1.00; 0.54 to 1.28). Conclusion: The results do not support an association between use of cellular telephones and risk for glioma or meningioma.

Prevalence and predictive factors of post-traumatic hypopituitarism.

Objective  To estimate the prevalence and predictive factors of hypopituitarism following traumatic brain injury (TBI).

Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours

Material and Methods. We retrospectively determined the efficacy and safety of a combination of bevacizumab and irinotecan in a consecutive series of 52 heavily pre-treated patients with recurrent high-grade brain tumours. Patients received bevacizumab (10 mg/kg) and irinotecan [340 mg/m2 for those receiving enzyme-inducing antiepileptic drugs (EIAEDs) and 125 mg/m2 for those not receiving EIAEDs] every 2 weeks. Fifty-two patients were included and 47 were evaluable for response. Results. Complete or partial response was observed in 25% of all cases (30% response in grade IV glioma and 15% in grade III glioma). Estimated median progression-free survival (PFS) for both grade IV and grade III glioma was 22 weeks. The 6-month PFS was 32% for all patients, 40% for grade IV glioma and 33% for grade III glioma. Estimated median overall survival was 30 weeks for all patients, 28 weeks for grade IV glioma and 32 weeks for grade III glioma. Four patients discontinued treatment because of unmanageable toxicity: cerebral haemorrhage, cardiac arrhythmia, intestinal perforation and diarrhoea, the latter resulting in death. Discussion. We conclude that the combination of bevacizumab and irinotecan shows acceptable safety and is a clinically relevant choice of therapy in heavily pre-treated patients with recurrent high-grade brain tumours.

Acute and long‐term pituitary insufficiency in traumatic brain injury: a prospective single‐centre study

Objective  To assess the prevalence of hypopituitarism following traumatic brain injury (TBI), describe the time‐course and assess the association with trauma‐related parameters and early post‐traumatic hormone alterations.

Incidences of gliomas and meningiomas in Denmark, 1943 to 1997

OBJECTIVEThe objective of this study was to determine the nationwide, population-based incidences of intracranial gliomas and meningiomas (of all grades) during 55 years of monitoring in Denmark. METHODSOn the basis of reports in the Danish Cancer Registry, we calculated age-standardized, period-specific incidences and age- and birth cohort-specific incidences, in 5-year age and calendar intervals, for intracranial gliomas and meningiomas. RESULTSThe incidence of gliomas increased 1.7-fold from 1943 to 1947 to 1993 to 1997, whereas the incidence for meningiomas increased 3.9-fold during the same period. CONCLUSIONBased on complete notification to the Danish Cancer Registry, the overall incidences of intracranial gliomas and meningiomas increased during a 55-year period. These increases were observed for all age groups and both sexes. These increases could be explained on the basis of improved diagnoses of these tumors. For gliomas, a maximal annual incidence of approximately 4 cases/100,000 population (World Standard Population) was observed in Denmark at the end of the study period, suggesting that the effects of improved diagnostic tools have reached their maximum with respect to this tumor type. The same was not observed for the incidence of meningiomas, suggesting that perhaps underreporting is still present.

Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue

The endogenous levels of the two cannabinoid receptor ligands 2‐arachidonoyl glycerol and anandamide, and their respective congeners, monoacyl glycerols and N‐acylethanolamines, as well as the phospholipid precursors of N‐acylethanolamines, were measured by gas chromatography‐mass spectrometry in glioblastoma (WHO grade IV) tissue and meningioma (WHO grade I) tissue and compared with human non‐tumour brain tissue. Furthermore, the metabolic turnover of N‐acylethanolamines was compared by measurements of the enzymatic activity of N‐acyltransferase, N‐acylphosphatidylethanolamine‐hydrolysing phospholipase D and fatty acid amide hydrolase in the same three types of tissue. Glioblastomas were characterized by enhanced levels of N‐acylethanolamines (eightfold, 128 ± 59 pmol/μmol lipid phosphorus) including anandamide (17‐fold, 4.6 ± 3.1pmol/μmol lipid phosphorus) and several species of N‐acylphosphatidylethanolamines (three to eightfold). This was accompanied by a more than 60% reduction in the enzyme activities of N‐acylphosphatidylethanolamine‐hydrolysing phospholipase D and fatty acid amide hydrolase. By contrast, meningiomas were characterized by a massively enhanced level of 2‐monoacyl glycerols (20‐fold, 2293 ± 361 pmol/μmol lipid phosphorus) including 2‐arachidonoyl glycerol (20‐fold, 1524 ± 361 pmol/μmol lipid phosphorus). This was accompanied by an enhanced in vitro conversion of phosphatidylcholine to monoacyl glycerol (fivefold). The enhanced level of the 2‐arachidonoyl glycerol, anandamide and other N‐acylethanolamines detected in the two types of tumour tissue may possibly act as endogenous anti‐tumour mediators by stimulation of both cannabinoid and non‐cannabinoid receptor‐mediated mechanisms.

Comprehensive Analysis of DNA Repair Gene Variants and Risk of Meningioma

BACKGROUND Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility. METHODS We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case-control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided. RESULTS The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1-interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; P(trend) = 8.95 x 10(-6); P = .009 after adjusting for multiple testing). CONCLUSIONS We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.

Hypopituitarism is uncommon after aneurysmal subarachnoid haemorrhage

Objective  Aneurysmal subarachnoid haemorrhage (SAH) has recently been reported as a common cause of chronic hypopituitarism, and introduction of routine neuroendocrine screening has been advocated. We aimed at estimating the risk of hypopituitarism after SAH using strict criteria including confirmatory testing in case of suggested insufficiency.

Anterior cervical discectomy with or without fusion with ray titanium cage: a prospective randomized clinical study.

Study Design. A prospective randomized clinical study. Objective. To compare 2 surgical methods in the treatment of cervical radiculopathy caused by hard or soft disc herniation; namely, simple discectomy versus discectomy with an additional interbody fusion with a Ray titanium cage. Summary of Background Data. Although an interbody fusion after anterior decompressive surgery for hard or soft disc herniation is widely accepted, there is no scientific evidence that convincingly demonstrates that insertion of graft material for interbody fusion is necessary after discectomy and decompression of the nervous elements have been performed. To date, no randomized studies have compared simple discectomy with discectomy followed by an interbody fusion with a titanium cage. Methods. Eighty-six patients with symptoms of nerve root compression at 1 level were randomly allocated to either discectomy followed by fusion with a Ray titanium cage (40 patients) or to discectomy alone (46 patients). Clinical and radiologic follow-up was performed 3, 12, and 24 months after surgery. Results. There was no statistically significant difference between the 2 groups concerning self-reported satisfaction or severity of pain in the neck and arm. Two years after the operation, 86.1% of the patients treated with cage stated a good outcome versus 76.7% in the discectomy group (P = 0.44). The rate of fusion was 83.3% in the cage group versus 81.0% in the discectomy group (P = 0.30). Furthermore, after 2 years, also the rates of new adjacent disc degeneration or spondylosis were the same in both groups. Conclusion. This study showed no statistically significant difference between simple discectomy and discectomy followed by interbody fusion with a titanium cage in the surgical treatment of cervical radiculopathy caused by disc herniation.