Polymorphisms of the NADPH Oxidase p22phox Gene in a Caucasian Population with Intracranial Aneurysms

Background: Vascular remodeling generated by reactive oxygen species contributes to aneurysm formation. The NADPH oxidase system is a major source of superoxide anion not only in phagocytes, but also in endothelial and vascular smooth muscle cells. Polymorphisms of p22phox, an essential component of the NADPH oxidase system, are found to be associated with atherosclerosis, while a recent study found a significant association between the 214C>T polymorphism and the occurrence of ischemic cerebrovascular disease. We conducted a case-control study to investigate the relationship of five polymorphisms of the p22phox gene and the occurrence of cerebral aneurysms. Methods: The study population consisted of 113 patients with intracranial aneurysms and 53 control subjects. The 214C>T polymorphism was investigated by restriction fragment length polymorphism analysis, while polymorphisms 381T>C, 480G>A, 521C>T, and *24A>G were analyzed by direct sequencing of exon 6 and adjacent intronic sequences. Results: The analysis of a primary study sample comprising 35 cases and 28 controls failed to show a significant association between any of the five polymorphisms and the occurrence of intracranial aneurysms using both allele frequencies and genotypes (all nominal p > 0.05). Although there was a deviation from Hardy-Weinberg equilibrium in cases at the 521C>T locus (nominal p T, 521C>T, and *24A>G); haplotype frequencies in cases and controls were not significantly different. Conclusion: Although polymorphisms of the p22phox gene located in the coding region and the 3′-untranslated region were reported to be associated with atherosclerosis and cerebrovascular disease, our data provide evidence that there is no association between these polymorphisms and the occurrence of cerebral aneurysms in Caucasians.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Patient Reported Outcome (PRO) Among High-Grade Glioma Patients Receiving TTFields Treatment: A Two Center Observational Study

Study design: A two center, observational study. Introduction: Patient reported outcome (PRO) plays an increasingly important role in the evaluation of novel therapies for tumor patients. It has been shown that tumor treating fields (TTFields) in combination with standard therapy prolong survival in high-grade glioma (hgG) patients. But critics claim that TTFields significantly impacts patients' everyday life due to side effects and average daily time on therapy (18 h) in a patient population with very limited life expectancy and high symptom burden. However, very limited data exist on PRO for TTFields treatment. Methods: This two center, observational study describes PRO of 30 hgG patients receiving TTFields in combination with chemotherapy. We introduced a device-specific questionnaire (DSQ) addressing device-specific restrictions and impact on daily live after 2 months of therapy. Additionally following questionnaires were used: EORTC (European Organization for Research and Treatment of Cancer), QLQ-30 (Quality of life of cancer patients), QLQ BN20 (Quality of life brain cancer module), QLQ FA13 (Cancer-related fatigue), and SSUK-8 (social support). Results: Surveys have been completed by 91% of enrolled patients. EORTC QLQ-30 revealed better physical, emotional, and cognitive function than social and role function of study cohort. TTFields users reported frequently on positive social support and a low level of detrimental interactions. Seventy one percent of patients felt affected in daily life due to TTFields at least 2-3 times per week up to several times per day while maintaining high therapy compliance. Most frequent device-specific restrictions were duration of therapy (74%), size (66%), and weight (70%) of the device and changing time and bonding of the transducer arrays (66%, mean duration: 43.6 min). Restrictions on exercise of hobbies/work (63%/61%), body care (71%), and sexuality/relationship (64%) were most relevant. Seventy percent would recommend TTFields to others and 67% would reuse TTFields treatment again based on their current experience. Conclusion: The study shows that although TTFields treatment frequently affects everyday life in all aspects, therapy compliance was high and 67% of patients would reconsider TTFields for themselves. We propose that findings of PRO be taken into account for medical consultation about TTFields and in future device development to deliver high-value patient-centered care

Differential Retinoic Acid Signaling in Tumors of Long- and Short-term Glioblastoma Survivors

Although the prognosis of most glioblastoma patients is poor, 3%-5% patients show long-term survival of 36 months or longer after diagnosis. To study the differences in activation of biochemical pathways, we performed mRNA and protein expression analyses of primary glioblastoma tissues from 11 long-term survivors (LTS; overall survival ≥ 36 months) and 12 short-term survivors (STS; overall survival ≤ 6 months). The mRNA expression ratio of the retinoic acid transporters fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2), which regulate the differential delivery of retinoic acid to either antioncogenic retinoic acid receptors or prooncogenic nuclear receptor peroxisome proliferator-activated receptor delta, was statistically significantly higher in the tumor tissues of STS than those of LTS (median ratio in STS tumors = 3.64, 10th-90th percentile = 1.43-4.54 vs median ratio in LTS tumors = 1.42, 10th-90th percentile = −0.98 to 2.59; P < .001). High FABP5 protein expression in STS tumors was associated with highly proliferating tumor cells and activation of 3-phosphoinositide-dependent protein kinase-1 and v-akt murine thymoma viral oncogene homolog. The data suggest that retinoic acid signaling activates different targets in glioblastomas from LTS and STS. All statistical tests were two-side

TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)–mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients. Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients’ outcome. Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 92.1% sensitivity (95% CI, 78.6–98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6–21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3–17.6) vs. 8.6 mo. (95% CI, 4.1–13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6–19.2) vs. 8.3 mo. (95% CI, 2.3–14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2–18.7) vs. 8.6 mo. (95% CI, 7.5–9.8), P = 0.062] to dichotomize the patients. Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis

Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT→TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT→TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O6-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20% in the reference group and 19% (4/21 patients) in the cilengitide group. Compared with TMZ/RT→TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.https://deepblue.lib.umich.edu/bitstream/2027.42/144529/1/12967_2018_Article_1552.pd

Extended single nucleotide polymorphism and haplotype analysis of the elastin gene in Caucasians with intracranial aneurysms provides evidence for racially/ ethnically based differences. Cerebrovasc Dis

Abstract Background: There is growing evidence that genetic variants have an impact on the pathogenesis of intracranial aneurysm (IA). Recently, the genetic locus around the elastin gene (7q11) has been identified as linked to IA in a Japanese population. Our aim was to confirm these results in Caucasian populations. Methods: We conducted a case-control study in 120 Caucasian patients with IA and 172 controls to investigate 8 single nucleotide polymorphisms (SNPs) and various haplotypes within the elastin gene, which were frequently found and associated with the phenotype in the Japanese populations. Real-time PCR and melting curve analysis were used for the detection of genotypes. Results: Allele frequencies and genotypes were equally distributed between Caucasian cases and controls. We failed to identify haplotypes that are associated with the phenotype in our population, which is in contrast to the Japanese study. However, allele frequencies in control populations differ between Caucasians and Japanese. Conclusions: We found no association between SNPs and haplotypes of the elastin gene and the occurrence of IA in our Caucasian populations. However, our data provide strong evidence for racial/ethnic differences in the association of SNP and specific haplotypes of the elastin gene with the phenotype. There might be other genetic variants of the elastin gene associated with IA in Caucasians