Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas.

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.

Transcranial electric motor evoked potential detection of compressional peroneal nerve injury in the lateral decubitus position.

The peroneal nerve is susceptible to injury due to compression at the fibular head for patients placed in the lithotomy, hemilithotomy or lateral decubitus positions during surgery. Upper extremity somatosensory and transcranial electric motor evoked potential monitoring has proven efficacious for identifying impending positional brachial plexopathy or upper extremity peripheral neuropathy in adult and pediatric patients undergoing spine surgery. We report on two cases to illustrate the usefulness of monitoring transcranial electric motor evoked potentials recorded from tibialis anterior muscle to identify emerging peroneal nerve compression secondary to lateral decubitus positioning.

Alagille syndrome and aneurysmal subarachnoid hemorrhage. Case report and review of the literature.

The authors report the case of a 21-year-old female with a known history of Alagille syndrome (AGS) who was found to have a basilar terminus aneurysm without evidence of rupture. Prior to intervention, the patient's hospital course became complicated by multiple medical problems associated with AGS. Subsequently, the patient had an acute neurological decline. An unenhanced CT of the head demonstrated diffuse subarachnoid hemorrhage, intraparenchymal hematoma and intraventricular hemorrhage. AGS is an autosomal dominant arteriodysplastic syndrome with multiple organ system involvement caused by a mutation in the Jagged1 gene. Intracranial hemorrhage is one of the many complications observed in this patient population. While there are multiple case reports in the literature reviewing the spectrum of cerebrovascular events and abnormalities, intracranial aneurysmal rupture has only recently been described. To our knowledge, this is the third reported case of documented aneurysmal subarachnoid hemorrhage in a patient with AGS. The authors present a brief review of the vascular abnormalities both intracranial and systemic seen in AGS. The genomic abnormalities of this syndrome are also reviewed with particular attention to the Jagged1 gene and the Notch receptor signaling pathway which may reveal elements of the pathophysiology involved in aneurysm formation and rupture in AGS patients. In light of the increased incidence of intracranial hemorrhage in AGS and the possible link to aneurysmal subarachnoid hemorrhage, establishing the incidence of intracranial aneurysms in AGS and the role of screening these patients is indicated.

Lower dose of rhBMP-2 achieves spine fusion when combined with an osteoconductive bulking agent in non-human primates.

STUDY DESIGN: A non-human primate lumbar intertransverse process arthrodesis model was used to evaluate the effectiveness of different formulations of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce consistent bone formation. OBJECTIVE: To determine if the combination of rhBMP-2/absorbable collagen sponge (ACS) wrapped around a bulking agent, consisting of a biphasic calcium phosphate/collagen composite, could achieve posterolateral spine fusion with a dose of rhBMP-2 (3.0 mg/side) that previously failed to induce posterolateral fusion in rhesus monkeys with other carriers. SUMMARY OF BACKGROUND DATA: Successful bone induction in both human and non-human primates has required higher concentrations of BMP than were required in lower order models. The Food and Drug Administration approved concentration of rhBMP-2 for interbody fusion (1.5 mg/mL) when delivered on the ACS alone without a bulking agent (doses 3-9 mg/side) has failed to induce clinically relevant amounts of bone formation in a posterolateral spine fusion model in rhesus monkeys. Previously, a higher concentration of 2.0 mg/mL of rhBMP-2 delivered on stacked sheets of a biphasic calcium phosphate ceramic/collagen compression resistant matrix (CRM) was required to achieve fusion in the rhesus monkey and was the basis for this study (doses of 6-12 mg/side). METHODS: Nine skeletally mature, rhesus macaque monkeys underwent single level posterolateral arthrodesis at L4-L5. Two different rhBMP-2 doses were evaluated in 3 delivery configurations. The first 3 monkeys received 10 mg/side (2.5 mL at 4.0 mg/mL) of rhBMP-2 loadeddirectly onto a CRM carrier (15% hydroxyapatite/85%beta-tricalcium phosphate ceramic/collagen matrix), resulting in a final concentration of 2.0 mg/mL. The second 3 monkeys received 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 loaded directly on the CRM carrier, resulting in a 0.6 mg/mL final concentration. Three additional monkeys also received the 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 delivered on an ACS, which was then wrapped around the dry CRM matrix used as a bulking agent, yielding a 1.5 mg/mL final concentration of rhBMP-2 on the sponge wrapped around the bulking agent. The monkeys were euthanized at 24 weeks after surgery. Manual palpation, plain radiographs, computerized tomography, and nondecalcified histology were used to evaluate fusion in a blinded fashion. RESULTS: The 3 monkeys with 10 mg rhBMP-2 placed directly on the CRM carrier (2.0 mg/mL final concentration) achieved solid fusion. The 3 monkeys that underwent fusion with 3 mg of rhBMP-2 placed directly on the CRM carrier (0.6 mg/mL final concentration) failed to achieve fusion. In contrast, the 3 monkeys that underwent fusion with the same 3 mg dose of rhBMP-2 dispensed only on an ACS that was wrapped around the CRM achieved solid bilateral fusion. CONCLUSIONS: This study shows the importance of carrier optimization and final implant protein concentration for the successful delivery of rhBMP-2. By combining the properties of the ACS with the CRM, the required dosage of rhBMP-2 was diminished by more than 3-fold in the non-human primate model. This finding suggests that the currently available concentration of rhBMP-2 (1.5 mg/mL) could be successful for achieving posterolateral spine fusion when combined with an osteoconductive bulking agent that can support the induced new bone formation.

Evolution of the management of tentorial dural arteriovenous malformations.

OBJECTIVE: Tentorial dural arteriovenous malformations (DAVMs) are uncommon lesions associated with an aggressive natural history. Controversy exists regarding their optimal treatment. We present a single-institution series of tentorial DAVMs treated during a 12-year period, address the current controversies, and present the rationale for our current therapeutic strategy. METHODS: Twenty-two patients with tentorial DAVMs were treated between 1988 and 2000. Treatment consisted of transarterial or transvenous embolization, surgical resection, disconnection of venous drainage, or a combination of these therapies. The clinical presentations, radiological features, treatment strategies, and results were studied. RESULTS: Eighteen patients (82%) presented with intracranial hemorrhage or progressive neurological deficits. Retrograde leptomeningeal venous drainage was documented in 22 cases (100%), classifying the lesions as Borden Type III. Angiographic follow-up monitoring was performed for 0 to 120 months and clinical follow-up monitoring for 1 to 120 months. Posttreatment angiography demonstrated obliteration in 22 cases (100%). Two patients experienced neurological decline after endovascular treatment and died. All of the 20 surviving patients exhibited clinical improvement; there were no episodes of rehemorrhage or new neurological deficits. Outcomes were excellent in 17 cases (77%), good in 2 cases (9%), and fair in 1 case (5%), and there were 2 deaths (9%). CONCLUSION: Tentorial DAVMs are aggressive lesions that require prompt total angiographic obliteration. Disconnection of the venous drainage from the fistula may be accomplished with transarterial embolization to the venous side, transvenous embolization, or surgical disconnection of the fistula. We think that extensive nidal resections carry more risk and are unnecessary. We do not think there is a role for stereotactic radiosurgery in the treatment of these lesions.