Cerebral cavernous malformations: Prevalence of cardiovascular comorbidities and allergic diseases compared to the normal population.

BACKGROUND: To determine the prevalence of cardiovascular comorbidities and allergic diseases in patients with cavernous malformations of the central nervous system compared to the normal population. METHODS: Clinical and magnetic resonance imaging data of 1352 patients with cerebral cavernous malformations (CCM) from an observational, cross-sectional, single-institutional study were analyzed and compared to an age-and-gender stratified and matched sample from a population-based, epidemiological study assessing cardiovascular risk factors in the local normal population of the same area (RECALL study). RESULTS: Of 1352 patients, 810 (60%) were female. Mean age was 40.4 ± 16 years. 221 patients (16%) suffered from familial disease. Presence of cardiovascular risk factors and intake of certain drugs in the overall cohort was mostly equal to the normal population reference sample (n = 786). The prevalence of allergic diseases was found to be significantly higher in all CCM patients compared to the normal population (30% vs. 20%, odds ratio [OR] 1.35 [1.12-1.63]) and in sporadic CCM cases compared to the normal population and familial cases (32% vs. 20% (OR 1.46 [1.19-1.78], p = 0.0001) and 22% vs. 20%, respectively). CONCLUSIONS: We present novel data on CCM using a large single-institution and population-based setup. The study elaborates disease characteristics of CCM patients in detail. For the first time, evidence for an unexplained high prevalence of allergic diseases in this patient population is described (differing between sporadic and familial cases), supporting the hypothesis that immune response is involved in the pathogenesis of CCM.

PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma.

We previously reported an angiogenic and tumor-suppressor-like function of programmed cell death 10 (PDCD10) in glioblastoma (GBM). However, the underlying mechanism remains to be elucidated. We hypothesized that loss of PDCD10 activates GBM cells and tumor progression via EphB4. To this end, PDCD10 was knocked down in U87 and T98g by lentiviral mediated shRNA transduction (shPDCD10). GBM cell phenotype in vitro and tumor growth in a mouse xenograft model were investigated in presence or absence of the treatment with a specific EphB4 kinase inhibitor NVP-BHG712 (NVP). We demonstrated that knockdown of PDCD10 in GBM cells significantly upregulated the mRNA and protein expression of EphB4 accompanied by the activation of Erk1/2. EphB4 kinase activity, reflected by phospho-EphB4, significantly increased in shPDCD10 GBM cells, and in tumors derived from shPDCD10 GBM xenografts, which was abolished by the treatment with NVP. Furthermore, NVP treatment significantly suppressed PDCD10-knockdown mediated aggressive GBM cell phenotype in vitro and extensive tumor cell proliferation, the tumor neo-angiogenesis, and a quick progression of tumor formation in vivo. In summary, loss of PDCD10 activates GBM cells and promotes tumor growth via triggering EphB4. Targeting EphB4 might be an effective strategy particularly for the personalized therapy in GBM patients with PDCD10-deficiency.

Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in glioblastoma.

PURPOSE: Glioblastoma (GBM) is one of the most aggressive and incurable primary brain tumors. Identification of novel therapeutic targets is an urgent priority. Programmed cell death 10 (PDCD10), a ubiquitously expressed apoptotic protein, has shown a dual function in different types of cancers and in chemo-resistance. Recently, we reported that PDCD10 was downregulated in human GBM. The aim of this study was to explore the function of PDCD10 in GBM cells. METHODS: PDCD10 was knocked down in three GBM cell lines (U87, T98g and LN229) by lentiviral-mediated shRNA transduction. U87 and T98g transduced cells were used for phenotype study and LN229 and T98g cells were used for apoptosis study. The role of PDCD10 in apoptosis and chemo-resistance was investigated after treatment with staurosporine and temozolomide. A GBM xenograft mouse model was used to confirm the function of PDCD10 in vivo. A protein array was performed in PDCD10-knockdown and control GBM cells. RESULTS: Knockdown of PDCD10 in GBM cells promoted cell proliferation, adhesion, migration, invasion, and inhibited apoptosis and caspase-3 activation. PDCD10-knockdown accelerated tumor growth and increased tumor mass by 2.1-fold and led to a chemo-resistance of mice treated with temozolomide. Immunostaining revealed extensive Ki67-positive cells and less activation of caspase-3 in PDCD10-knockdown tumors. The protein array demonstrated an increased release of multiple growth factors from PDCD10-knockdown GBM cells. CONCLUSIONS: Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in GBM, suggesting PDCD10 as a potential target for GBM therapy.

Aneurysmal intracerebral hematoma: Risk factors and surgical treatment decisions.

OBJECTIVES: Intracerebral hematoma (ICH) complicates the course of aneurysmal subarachnoid hemorrhage (SAH). To date, there are no unique guidelines for management of aneurysmal ICH. The aim of this study was to identify risk factors for and impact of aneurysmal ICH with special attention on treatment decisions derived from ICH volume. PATIENTS AND METHODS: All patients admitted with aneurysmal SAH between 2003 and 2016 were eligible for this study. Various demographic, clinical and radiographic characteristics of patients were correlated with the occurrence and volume of ICH in univariate and multivariate manner. The associations between ICH volume and the need for surgical procedures and functional outcome were also analyzed. RESULTS: 991 patients were included into final analysis. ICH occurred in 301 (30.4%) cases. Location in the middle cerebral artery (MCA, p < 0.001, aOR = 7.04), WFNS grade 4-5 (p < 0.001, aOR = 4.43), rebleeding before therapy (p = 0.004, aOR = 2.45), intracranial pressure over 20 mmHg upon admission (p = 0.008, aOR = 1.60) and intraventricular bleeding (p = 0.008, aOR = 1.62) were independently associated with ICH presence. In turn, WFNS grade 4-5 (p < 0.001) and MCA aneurysms (p < 0.001) were the only independent predictors of ICH volume. According to the receiver operating characteristic curves, the clinically relevant cutoff for additional surgical interventions (decompression/hematoma evacuation) was 17 mL. ICH occurrence and ICH volume ≥17 mL independently predicted poor outcome at 6 months after SAH (defined as modified Rankin Scale>3). CONCLUSION: Of over 30 tested variables, the location of the ruptured aneurysm in the MCA remains the major risk factor for occurrence and volume of ICH. Given the presence of brain swelling and other bleeding components of SAH, surgical intervention on aneurysmal ICH is indicated at lower volume values, than it is generally accepted for spontaneous ICH.