In patients undergoing bone flap reinsertion after craniotomy, aseptic bone necrosis is an underestimated problem during long-term follow-up. Especially in younger patients with an expected good neurological recovery and a fragmented bone flap, an initial allograft should be considered because of an increased risk for aseptic bone flap necrosis.

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OBJECT The complication rate for cranioplasty after decompressive craniectomy is higher than that after other neurosurgical procedures; aseptic bone resorption is the major long-term problem. Patients frequently need additional operations to remove necrotic bone and replace it with an artificial bone substitute. Initial implantation of a bone substitute may be an option for selected patients who are at risk for bone resorption, but this cohort has not yet been clearly defined. The authors’ goals were to identify risk factors for aseptic bone flap necrosis and define which patients may benefit more from an initial bone-substitute implant than from autograft after craniectomy. METHODS The authors retrospectively analyzed 631 cranioplasty procedures (503 with autograft, 128 with bone substitute) by using a stepwise multivariable logistic regression model and discrimination analysis. RESULTS There was a significantly higher risk for reoperation after placement of autograft than after placement of bone substitute; aseptic bone necrosis (n = 108) was the major problem (OR 2.48 [95% CI1.11–5.51]). Fragmentation of the flap into 2 or more fragments, younger age (OR 0.97 [95% CI 0.95–0.98]; p < 0.001), and shunt-dependent hydrocephalus (OR 1.73 [95% CI1.02–2.92]; p = 0.04) were independent risk factors for bone necrosis. According to discrimination analysis, patients younger than 30 years old and older patients with a fragmented flap had the highest risk of developing bone necrosis. CONCLUSIONS Development of bone flap necrosis is the main concern in long-term follow-up after cranioplasty with autograft. Patients younger than 30 years old and older patients with a fragmented flap may be candidates for an initial artificial bone substitute rather than autograft.

Fatty acid synthase (FASN), catalyzing the de novo synthesis of fatty acids, is known to be deregulated in several cancers. Inhibition of this enzyme reduces tumor cell proliferation. Unfortunately, adverse effects and chemical instability prevent the in vivo use of the best-known inhibitors, Cerulenin and C75. Orlistat, a drug used for obesity treatment, is also considered as a potential FASN inhibitor, but its impact on glioma cell biology has not yet been described. In this study, we analyzed FASN expression in human glioma samples and primary glioblastoma cell cultures and the effects of FASN inhibition with Orlistat, Cerulenin and C75. Immunohistochemistry followed by densitometric analysis of 20 glioma samples revealed overexpression of FASN that correlated with the WHO tumor grade. Treatment of glioblastoma cells with these inhibitors resulted in a significant, dose-dependent reduction in tumor cell viability and fatty acid synthesis. Compared to Cerulenin and C75, Orlistat was a more potent inhibitor in cell cultures and cell lines. In LN229, cell-growth was reduced by 63.9 ± 8.7 % after 48 h and 200 µM Orlistat compared to controls; in LT68, the reduction in cell growth was 76.3 ± 23.7 %. Nuclear fragmentation assay and Western blotting analysis after targeting FASN with Orlistat demonstrated autophagy and apoptosis. Organotypic slice cultures treated with Orlistat showed reduced proliferation after Ki67 staining and increased caspase-3 cleavage. Our results suggest that FASN may be a therapeutic target in malignant gliomas and identify Orlistat as a possible anti-tumor drug in this setting.