Markus Wiedmann

Body mass index and the risk of meningioma, glioma and schwannoma in a large prospective cohort study (The HUNT Study)

Background:Obesity increases the risk for a number of solid malignant tumours. However, it is not clear whether body mass index (BMI) and height are associated with the risk of primary tumours of the central nervous system (CNS).Methods:In a large population study (The Nord–Trøndelag Health Study (HUNT Study)) of 74 242 participants in Norway, weight and height were measured. During follow-up, incident CNS tumours were identified by individual linkage to the Norwegian Cancer Registry. Sex- and age-adjusted and multivariable Cox regression analyses were used to evaluate BMI and height in relation to the risk of meningioma, glioma and schwannoma.Results:A total of 138 meningiomas, 148 gliomas and 39 schwannomas occurred during 23.5 years (median, range 0–25) of follow-up. In obese women (BMI ⩾30 kg m−2), meningioma risk was 67% higher (hazard ratio (HR)=1.68, 95% confidence interval (CI): 0.97–2.92, P-trend=0.05) than in the reference group (BMI 20–24.9 kg m−2), whereas no association with obesity was observed in males. There was no association of BMI with glioma risk, but there was a negative association of overweight/obesity (BMI ⩾25 kg m−2) with the risk of schwannoma (HR=0.48, 95% CI: 0.23–0.99). However, the schwannoma analysis was based on small numbers. Height was not associated with the risk for any tumour subgroup.Conclusion:These results suggest that BMI is positively associated with meningioma risk in women, and possibly, inversely associated with schwannoma risk.

Factors associated with proximal intracranial aneurysms to brain arteriovenous malformations: A prospective cohort study

BACKGROUND The risk of hemorrhage from a brain arteriovenous malformation (bAVM) is increased when an associated proximal intracranial aneurysm (APIA) is present. Identifying factors that are associated with APIA may influence the prediction of hemorrhage in patients with bAVM. OBJECTIVE To identify patient- and bAVM-specific factors associated with APIA. METHODS We analyzed a prospective database of bAVMs for factors associated with the presence of APIA. Factors analyzed included age, sex, bAVM size, aneurysm size, circulation contributing to the bAVM, location of the aneurysm, deep venous drainage, and Spetzler-Ponce categories. Multiple logistic regression was performed to identify an association with APIA. RESULTS Of 753 cases of bAVM with complete angiographic surveillance, 67 (9%) were found to have APIA. Older age (continuous variable; odds ratio, 1.04; 95% confidence interval, 1.02-1.05) and posterior circulation supply to the bAVM (odds ratio, 2.29; 95% confidence interval, 1.32-3.99) were factors associated with increased detection of APIA. The association of posterior circulation-supplied bAVM was not due to infratentorial bAVM location because 72% of posterior circulation APIAs were supplying supratentorial bAVM. CONCLUSION APIAs appear to develop with time, as evident from the increased age for those with APIAs. Furthermore, they were more likely present in bAVMs supplied by the posterior circulation. This may be due to a difference in hemodynamic stress. ABBREVIATIONS APIA, associated proximal intracranial aneurysmbAVM, brain arteriovenous malformationDSA, digital subtraction angiographySMG, Spetzler-Martin gradeSPC, Spetzler-Ponce category.

Complication-Effectiveness Analysis for Brain Arteriovenous Malformation Surgery: A Prospective Cohort Study.

BACKGROUND Intervention for brain arteriovenous malformations (bAVMs) should aim at treatment that is safe and effective. OBJECTIVE To analyze a prospective database to derive the probability of neurological deficit and adjust this risk for effectively treated bAVMs (complication-effectiveness analysis [CEA]). METHODS First, we calculated the percentage of surgical complications leading to a modified Rankin Scale >1 at 12 months after surgery for each Spetzler-Ponce class (SPC). Second, we performed a sensitivity analysis of these results by including bAVMs not undergoing surgery, to correct for bias. Third, we established the long-term cumulative incidence of freedom from recurrence from Kaplan-Meier analysis. Finally, we combined the results to calculate the risk of surgery per effective treatment in a complication-effectiveness analysis. RESULTS Seven hundred seventy-nine patients underwent 641 microsurgical resections. Complications of surgery leading to a modified Rankin Scale >1 at 12 months occurred in 1.4% (95% confidence interval [CI]: 0.5-3.3), 20% (95% CI: 15-26), and 41% (95% CI: 30-52) of SPC A, SPC B, and SPC C, respectively. The cumulative 9-year freedom from recurrence was 97% for SPC A and 92% for other bAVMs. The 9-year CEA risk was 1.4% (credible range: 0.5%-3.4%) for SPC A, 22% to 24% (credible range: 16%-31%) for SPC B, and 45% to 63% (credible range: 33%-73%) for SPC C bAVM. CONCLUSION CEA presents the treatment outcome in the context of efficacy and provides a basis for comparing outcomes from techniques with different times to elimination of the bAVM. ABBREVIATIONS bAVM, brain arteriovenous malformationCEA, complication-effectiveness analysisCI, confidence intervalCTA, computerized tomographic angiographyDSA, digital subtraction angiographyMRA, magnetic resonance angiographymRS, modified Rankin ScaleSMG, Spetzler-Martin gradeSPC, Spetzler-Ponce class.

Complication-Effectiveness Analysis for Unruptured Intracranial Aneurysm Surgery: A Prospective Cohort Study.

BACKGROUND The aim of intervention for unruptured intracranial aneurysms (UIAs) is safe, effective treatment. OBJECTIVE To analyze a prospective database for variables influencing the risk of surgery to produce a risk model adjusting this risk for effectively treated aneurysms. METHODS First, we identified variables to create a model from multiple logistic regression for complications of surgery leading to a 12-month modified Rankin Scale score >1. Second, we established the long-term cumulative incidence of freedom from retreatment or rupture (treated aneurysm) from Kaplan-Meier analysis. Third, we combined these analyses to establish a model of risk of surgery per effective treatment. RESULTS One thousand twelve patients with 1440 UIA underwent 1080 craniotomies. We found that 10.1% (95% confidence interval [CI], 8.4-12.0) of craniotomies resulted in a complication leading to a modified Rankin Scale score >1 at 12 months. Logistic regression found age (odds ratio, 1.04; 95% CI, 1.02-1.06), size (odds ratio, 1.12; 95% CI, 1.09-1.15), and posterior circulation location (odds ratio, 2.95; 95% CI, 1.82-4.78) to be significant. Cumulative 10-year risk of retreatment or rupture was 3.0% (95% CI, 1.3-7.0). The complication-effectiveness model was derived by dividing the complication risk by the 10-year cumulative freedom from retreatment or rupture proportion. Risk per effective treatment ranged from 1% for a 5-mm anterior circulation UIA in a 20-year-old patient to 70% for a giant posterior circulation UIA in a 70-year-old patient. CONCLUSION Complication-effectiveness analyses increase the information available with regard to outcome for the management of UIAs.

Microsurgery for Spetzler-Ponce Class A and B arteriovenous malformations utilizing an outcome score adopted from Gamma Knife radiosurgery: a prospective cohort study

OBJECTIVE The purpose of this study was to adapt and apply the extended definition of favorable outcome established for Gamma Knife radiosurgery (GKRS) to surgery for brain arteriovenous malformations (bAVMs). The aim was to derive both an error around the point estimate and a model incorporating angioarchitectural features in order to facilitate comparison among different treatments. METHODS A prospective microsurgical cohort was analyzed. This cohort included patients undergoing embolization who did not proceed to microsurgery and patients denied surgery because of perceived risk of treatment. Data on bAVM residual and recurrence during long-term follow-up as well as complications of surgery and preoperative embolization were analyzed. Patients with Spetzler-Ponce Class C bAVMs were excluded because of extreme selection bias. First, patients with a favorable outcome were identified for both Class A and Class B lesions. Patients were considered to have a favorable outcome if they were free of bAVM recurrence or residual at last follow-up, with no complication of surgery or preoperative embolization, and a modified Rankin Scale score of more than 1 at 12 months after treatment. Patients who were denied surgery because of perceived risk, but would otherwise have been candidates for surgery, were included as not having a favorable outcome. Second, the authors analyzed favorable outcome from microsurgery by means of regression analysis, using as predictors characteristics previously identified to be associated with complications. Third, they created a prediction model of favorable outcome for microsurgery dependent upon angioarchitectural variables derived from the regression analysis. RESULTS From a cohort of 675 patients who were either treated or denied surgery because of perceived risk of surgery, 562 had Spetzler-Ponce Class A or B bAVMs and were included in the analysis. Logistic regression for favorable outcome found decreasing maximum diameter (continuous, OR 0.62, 95% CI 0.51-0.76), the absence of eloquent location (OR 0.23, 95% CI 0.12-0.43), and the absence of deep venous drainage (OR 0.19, 95% CI 0.10-0.36) to be significant predictors of favorable outcome. These variables are in agreement with previous analyses of microsurgery leading to complications, and the findings support the use of favorable outcome for microsurgery. The model developed for angioarchitectural features predicts a range of favorable outcome at 8 years following microsurgery for Class A bAVMs to be 88%-99%. The same model for Class B bAVMs predicts a range of favorable outcome of 62%-90%. CONCLUSIONS Favorable outcome, derived from GKRS, can be successfully used for microsurgical cohort series to assist in treatment recommendations. A favorable outcome can be achieved by microsurgery in at least 90% of cases at 8 years following microsurgery for patients with bAVMs smaller than 2.5 cm in maximum diameter and, in the absence of either deep venous drainage or eloquent location, patients with Spetzler-Ponce Class A bAVMs of all diameters. For patients with Class B bAVMs, this rate of favorable outcome can only be approached for lesions with a maximum diameter just above 6 cm or smaller and without deep venous drainage or eloquent location.

Overweight, obesity and height as risk factors for meningioma, glioma, pituitary adenoma and nerve sheath tumor: a large population-based prospective cohort study

Abstract Background: In 2016, the International Agency for Research on Cancer (IARC) has announced that avoiding body fatness (i.e. overweight and obesity) contributes to prevent meningioma occurrence, but considered the available evidence for glioma inadequate. The association of body fatness with other CNS tumor subgroups is largely unknown. Objectives: To assess whether body fatness or body height are associated with risk for meningioma, glioma, pituitary adenoma (PA) or nerve sheath tumor (NST) in a large population-based Norwegian cohort. Methods: In this prospective cohort study of 1.8 million Norwegian residents, weight and height were measured at baseline and incident intracranial tumors were subsequently identified by linkage to the Cancer Registry of Norway. Cox regression analyses were performed to estimate risk for each tumor subgroup in relation to anthropometric measures, stratified by sex and in different age groups. Results: During 54 million person-years of follow-up 3335 meningiomas, 4382 gliomas, 1071 PAs and 759 NSTs were diagnosed. Obesity (BMI ≥30 kg/m2) was not associated with risk for meningioma or glioma, but was significantly associated with risk for PA (HR 1.43; 95% CI 1.09–1.88) compared with the reference group (BMI 20–24.9 kg/m2). For intracranial NSTs, obesity was associated with reduced tumor risk (HR 0.68; 95% CI 0.46–0.99). Body height was associated with increased risk for all four tumor subgroups. Conclusions: This study does not confirm overweight or obesity as risk factors for meningioma. Additionally, overweight and obesity can be quite confidently excluded as risk factors for glioma. However, this study indicates that body fatness increases the risk for PA, while it reduces the risk for NST.

The impact of body mass index and height on the risk for glioblastoma and other glioma subgroups: a large prospective cohort study

Background Glioma comprises a heterogeneous group of mostly malignant brain tumors, whereof glioblastoma (GBM) represents the largest and most lethal subgroup. Body height and body mass index (BMI) are risk factors for other cancers, but no previous study has examined anthropometric data in relation to different glioma subgroups. Methods This prospective cohort study includes 1.8 million Norwegian women and men between ages 14 and 80 years at baseline. Body weight and height were measured, and incident cases of glioma were identified by linkage to the National Cancer Registry. Cox regression analyses were performed to evaluate risk for different glioma subgroups in relation to anthropometric measures. Results During 54 million person-years of follow-up, 4,382 gliomas were identified. Overweight and obesity were not associated with risk for any glioma subgroup. Height was positively associated with risk for GBM and all other gliomas (hazard ratio [HR] per 10 cm increase: 1.24; 95% confidence interval [CI], 1.17-1.31 and 1.18; 95% CI, 1.09-1.29) but not with the proxy for isocitrate dehydrogenase (IDH)-mutant glioma (HR, 1.09; 95% CI, 0.98-1.21). In further subgroup analyses, the effect of height on glioma risk varied significantly with positive associations for oligoastrocytoma (HR, 1.74; 95% CI, 1.20-2.53) and malignant glioma not otherwise specified (NOS) (HR, 1.42; 95% CI, 1.16-1.76, but not with diffuse astrocytoma (WHO grades II and III) or oligodendroglioma. Conclusion This epidemiologic study consolidates height as a risk factor for GBM and other gliomas. It further indicates that this association is not universal for gliomas but may differ between different glioma subgroups.

Smoking, obesity and the risk of pituitary adenoma: a large prospective cohort study (The HUNT Study)

Pituitary adenomas (PAs) account for about 13.5 % of all primary brain tumors and represent the third largest group of brain tumors after meningiomas and gliomas [1]. They are either hormone secreting or non-functioning tumors and mostly benign in nature. Due to their vicinity to the optic chiasm and their disturbance of hormonal equilibrium, PAs are associated with substantial morbidity. Knowledge about the etiology of PAs is scarce. No study to date has explored overweight and obesity as risk factors for PAs despite increasing evidence that body mass index (BMI) is associated with some primary brain tumor subgroups [2–5]. Smoking in relation to the risk of PA was assessed by two recent studies without demonstrating a clear association [6, 7]. The aim of this study was to investigate the association between BMI, smoking and the risk of incidental PA in the HUNT 1 study. The HUNT 1 study is a general health survey conducted among adults in the county of Nord-Trøndelag in Norway in 1984–1986. Participants had to fill in a first questionnaire at recruitment and attended a subsequent physical examination where they received the second questionnaire. This included questions about life-style factors and medical history and was to be returned in a pre-stamped envelope. 71,920 participants, representing 84.5 % of the adult population of Nord-Trøndelag, constituted our study population after the exclusion of cases with missing follow-up data, prevalent cancer or CNS tumor diagnosis at recruitment. Further, participants who developed CNS tumors other than PA during follow-up were excluded from the analysis (N = 484). PAs, defined by topography code C 75.1 (International Classification of Disease for Oncology, third revision, ICD-O-3) and histology codes 8140/0 and 8271/0 (ICD-O-3), were identified by individual linkage to the Cancer Registry of Norway. Participants contributed person-years from the date of the physical examination until the date of PA diagnosis, any non-CNS cancer diagnosis, emigration, death or end of follow-up at December 15th, 2011, whichever occurred first. Height (in cm) and weight (in kg) were measured at baseline and BMI was calculated as weight divided by height squared (kg/m). BMI was dichotomized at 25 kg/ m, but in supplementary analyses, we also used BMI as a continuous variable, quintiles of BMI, and BMI defined according to the World Health Organization categories. Smoking status was categorized in current, former or never smoking or accumulated number of pack-years. Physical activity (walking, skiing, swimming or other sports) was assessed as frequency of the activity per week (never, 0–1 & Markus Wiedmann Markus.KH.Wiedmann@gmail.com

Radiosurgery Alters the Endothelial Surface Proteome: Externalized Intracellular Molecules as Potential Vascular Targets in Irradiated Brain Arteriovenous Malformations

Stereotactic radiosurgery (SRS) is an established treatment for brain arteriovenous malformations (AVMs) that drives blood vessel closure through cellular proliferation, thrombosis and fibrosis, but is limited by a delay to occlusion of 2–3 years and a maximum treatable size of 3 cm. In this current study we used SRS as a priming tool to elicit novel protein expression on the endothelium of irradiated AVM vessels, and these proteins were then targeted with prothrombotic conjugates to induce rapid thrombosis and vessel closure. SRS-induced protein changes on the endothelium in an animal model of AVM were examined using in vivo biotin labeling of surface-accessible proteins and comparative proteomics. LC-MS/MS using SWATH acquisition label-free mass spectrometry identified 280 proteins in biotin-enriched fractions. The abundance of 56 proteins increased after irradiation of the rat arteriovenous fistula (20 Gy, ≥1.5-fold). A large proportion of intracellular proteins were present in this subset: 29 mitochondrial and 9 cytoskeletal. Three of these proteins were chosen for further validation based on previously published evidence for surface localization and a role in autoimmune stimulation: cardiac troponin I (TNNI3); manganese superoxide dismutase (SOD2); and the E2 subunit of the pyruvate dehydrogenase complex (PDCE2). Immunostaining of AVM vessels confirmed an increase in abundance of PDCE2 across the vessel wall, but not a measurable increase in TNNI3 or SOD2. All three proteins co-localized with the endothelium after irradiation, however, more detailed subcellular distribution could not be accurately established. In vitro, radiation-stimulated surface translocation of all three proteins was confirmed in nonpermeabilized brain endothelial cells using immunocytochemistry. Total protein abundance increased modestly after irradiation for PDCE2 and SOD2 but decreased for TNNI3, suggesting that radiation primarily affects subcellular distribution rather than protein levels. The novel identification of these proteins as surface exposed in response to radiation raises important questions about their potential role in radiation-induced inflammation, fibrosis and autoimmunity, but may also provide unique candidates for vascular targeting in brain AVMs and other vascular tissues.

Deliberate employment of postoperative hypotension for brain arteriovenous malformation surgery and the incidence of delayed postoperative hemorrhage: a prospective cohort study

OBJECTIVE The aim of this study was to examine the impact of deliberate employment of postoperative hypotension on delayed postoperative hemorrhage (DPH) for all Spetzler-Ponce Class (SPC) C brain arteriovenous malformations (bAVMs) and SPC B bAVMs ≥ 3.5 cm in diameter (SPC B 3.5+). METHODS A protocol of deliberate employment of postoperative hypotension was introduced in June 1997 for all SPC C and SPC B 3.5+ bAVMs. The aim was to achieve a maximum mean arterial blood pressure (BP) ≤ 70 mm Hg (with cerebral perfusion pressure > 50 mm Hg) for a minimum of 7 days after resection of bAVMs (BP protocol). The authors compared patients who experienced DPH (defined as brain hemorrhage into the resection bed that resulted in a new neurological deficit or that resulted in reoperation during the hospitalization for microsurgical bAVM resection) between 2 periods (prior to adopting the BP protocol and after introduction of the BP protocol) and 4 bAVM categories (SPC A, SPC B 3.5- [that is, SPC B < 3.5 cm maximum diameter], SPC B 3.5+, and SPC C). Patients excluded from treatment by the BP protocol were managed in the intensive care unit to avoid moderate hypertensive episodes. The pooled cases of all bAVM treated by surgery were analyzed to identify characteristics associated with the risk of DPH. These identified characteristics were then examined by multiple logistic regression analysis in both SPC B 3.5+ and SPC C cases. RESULTS From a cohort of 641 bAVMs treated by microsurgery, 32 patients with DPH were identified. Of those, 66% (95% CI 48-80) had a permanent new neurological deficit with a modified Rankin Scale score of 2-6. This included a mortality rate of 13% (95% CI 4.4-29). The BP protocol was used to treat 162 patients with either SPC B 3.5+ or SPC C. For SPC B 3.5+, there was no significant reduction in DPH with the introduction of the BP protocol (p = 0.77). For SPC C, there was a significant (p = 0.035) reduction of DPH from 29% (95% CI 13%-53%) to 8.2% (95% CI 3.2%-18%) associated with the introduction of the BP protocol. Multiple logistic regression analysis found that the absence of the BP protocol (p = 0.011, odds ratio 7.5, 95% CI 1.6-36) remained significant for the development of DPH in patients with SPC C bAVMs. CONCLUSIONS Treating patients with SPC C bAVMs with a protocol that lowers BP immediately after resection seems to reduce the risk of DPH. For SPC A and SPC B 3.5- bAVMs, there is unlikely to be a need to do more than avoid postoperative hypertension. For SPC B 3.5+ bAVMs, a larger number of patients would be required to test the absence of benefit of the BP protocol.