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Ulaş Yener, Timucin Avsar, Emel Akgün, Aşkın Şeker, Yaşar Bayri, and Türker Kılıç

Object

Angiogenesis and the platelet-derived growth factor (PDGF) pathway are active in the pathogenesis of vestibular schwannomas (VSs). The purpose of this study was to test whether imatinib mesylate (Gleevec), a PDGF receptor (PDGFR) blocker, reduces angiogenic capacity in sporadic VS and in VS associated with neurofibromatosis Type 2 (NF2) using a corneal angiogenesis assay.

Methods

From 121 VS tissue samples stored in the tumor bank at the Marmara University Institute of Neurological Sciences, 10 samples (6 from sporadic cases, 4 from NF2-associated cases) were selected at random for use in this study. Expression of PDGF-A and PDGF-B and their receptors was evaluated in sporadic and NF2-associated VS as well as in glioblastoma (GBM) and normal brain tissue by means of immunohistochemistry and Western blot analysis. Corneal angiogenesis assay was then used to evaluate the angiogenic capacity of tissue specimens from sporadic and NF2-associated VS with and without imatinib treatment as well as positive and negative controls (GBM and normal brain tissue).

Results

The angiogenic potential of the sporadic and NF2-associated VS tumor tissue differed significantly from that of the positive and negative control tissues (p <0.05). Furthermore, NF2-associated VS showed significantly lower angiogenic potential than sporadic VS (p <0.05). Imatinib treatment significantly reduced the angiogenic potential in both the sporadic VS and the NF2-associated VS groups. The level of PDGF-A and PDGFR-α as well as PDGF-B and PDGFR-β expression in sporadic VS and NF2-associated VS also differed significantly (p <0.05) from the levels in controls. Additionally the level of PDGFR-β was significantly higher in sporadic VS than in NF2-associated VS (p <0.05).

Conclusions

The findings of this study indicate that NF2-associated VS has significantly more angiogenic potential than sporadic VS and normal brain tissue. Additionally, imatinib reduces the angiogenic activity of both sporadic and NF2-associated VS. The authors conclude that imatinib may be a potential treatment for VS, especially for NF2-associated lesions that cannot be cured with resection or radiosurgery.

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Mehmet Sabri Gürbüz, Adnan Dağçınar, Yaşar Bayri, Aşkın Şeker, and Hasan Güçlü

OBJECTIVE

The authors sought to develop a set of parameters that reliably predict the clinical success of endoscopic third ventriculostomy (ETV) when assessed before and after the operation, and to establish a plan for MRI follow-up after this procedure.

METHODS

This retrospective study involved 77 patients who had undergone 78 ETV procedures for obstructive hydrocephalus between 2010 and 2015. Constructive interference in steady-state (CISS) MRI evaluations before and after ETV were reviewed, and 4 parameters were measured. Two well-known standard parameters, fronto-occipital horn ratio (FOHR) and third ventricular index (TVI), and 2 newly defined parameters, infundibulochiasmatic (IC) angle and anterior third ventricular height (TVH), were measured in this study. Associations between preoperative measurements of and postoperative changes in the 4 variables and the clinical success of ETV were analyzed.

RESULTS

Of the 78 ETV procedures, 70 (89.7%) were successful and 8 (10.3%) failed. On the preoperative MR images, the mean IC angle and anterior TVH were significantly larger in the successful procedures. On the 24-hour postoperative MR images of the successful procedures, the mean IC angle declined significantly from 114.2° to 94.6° (p < 0.05) and the mean anterior TVH declined significantly from 15 to 11.2 mm (p < 0.05). The mean percentage reduction of the IC angle was 17.1%, and that of the anterior TVH was 25.5% (both p < 0.05). On the 1-month MR images of the successful procedures, the mean IC angle declined significantly from 94.6° to 84.2° (p < 0.05) and the mean anterior TVH declined significantly from 11.2 to 9.3 mm (p < 0.05). The mean percentage reductions in IC angle (11%) and anterior TVH (16.9%) remained significant at this time point but were smaller than those observed at 24 hours. The 6-month and 1-year postoperative MR images of the successful group showed no significant changes in mean IC angle or mean anterior TVH. Regarding the unsuccessful procedures, there were no significant changes observed in IC angle or anterior TVH at any of the time points studied. Reduction of IC angle and reduction of anterior TVH on 24-hour postoperative MR images were significantly associated with successful ETV. However, no clinically significant association was found between FOHR, TVI, and ETV success.

CONCLUSIONS

Assessing the IC angle and anterior TVH on preoperative and 24-hour postoperative MR images is useful for predicting the clinical success of ETV. These 2 measurements could also be valuable as radiological follow-up parameters.

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Jason K. Karimy, Daniel Duran, Jamie K. Hu, Charuta Gavankar, Jonathan R. Gaillard, Yasar Bayri, Hunter Rice, Michael L. DiLuna, Volodymyr Gerzanich, J. Marc Simard, and Kristopher T. Kahle

Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.

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Kaya Bilguvar, Mohamad Bydon, Fatih Bayrakli, A. Gulhan Ercan-Sencicek, Yasar Bayri, Christopher Mason, Michael L. DiLuna, Margretta Seashore, Richard Bronen, Richard P. Lifton, Matthew State, and Murat Gunel

Object

Greig cephalopolysyndactyly syndrome (GCPS) is one of a spectrum of overlapping clinical syndromes resulting from mutations in the gene GLI3 on chromosome 7p. Cerebral cavernous malformation (CCM) is caused by mutations in three distinct genes, including Malcavernin (CCM2), which also maps to chromosome 7p and is located 2.8 Mbp from GLI3. The authors describe a new syndrome that combines the vascular lesions characteristic of CCM with the hallmarks of GCPS, including polydactyly, hypertelorism, and developmental delay.

Methods

The authors used high-resolution array-based comparative genome hybridization (CGH) analysis to characterize the 3 million–bp deletion on chromosome 7 that accounts for this novel clinical presentation. A 4-year-old girl presented with polydactyly, hypertelorism, and developmental delay and was also found to have multiple CCMs after suffering a seizure.

Results

Genetic analysis using array-based CGH revealed a deletion affecting multiple genes in the 7p14-13 locus, the interval that includes both CCM2 and GLI3. Quantitative real-time polymerase chain reaction (RT-PCR) on genomic DNA confirmed this genomic lesion.

Conclusions

A novel syndrome, combining features of CCM and GCPS, can be added to the group of entities that result from deleterious genetic variants involving GLI3, including GCPS, acrocallosal syndrome, Pallister–Hall syndrome, and contiguous gene syndrome. The deletion responsible for this new entity can be easily detected using either array-based chromosomal analysis or quantitative RT-PCR.

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Mark W. Youngblood, Daniel Duran, Julio D. Montejo, Chang Li, Sacit Bulent Omay, Koray Özduman, Amar H. Sheth, Amy Y. Zhao, Evgeniya Tyrtova, Danielle F. Miyagishima, Elena I. Fomchenko, Christopher S. Hong, Victoria E. Clark, Maximilien Riche, Matthieu Peyre, Julien Boetto, Sadaf Sohrabi, Sarah Koljaka, Jacob F. Baranoski, James Knight, Hongda Zhu, M. Necmettin Pamir, Timuçin Avşar, Türker Kilic, Johannes Schramm, Marco Timmer, Roland Goldbrunner, Ye Gong, Yaşar Bayri, Nduka Amankulor, Ronald L. Hamilton, Kaya Bilguvar, Irina Tikhonova, Patrick R. Tomak, Anita Huttner, Matthias Simon, Boris Krischek, Michel Kalamarides, E. Zeynep Erson-Omay, Jennifer Moliterno, and Murat Günel

OBJECTIVE

Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.

METHODS

Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher’s exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.

RESULTS

Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among “mutation unknown” samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor’s underlying driver mutation.

CONCLUSIONS

Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.