Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage tracing and modeling studies demonstrated that HPS AT2 cells were primed to persist in a Krt8+ reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are novel mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.

CXCL12 defines lung endothelial heterogeneity and promotes distal vascular growth.

There is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury. However, the molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to significant pediatric lung diseases, indicating a need to uncover fetal programs promoting vascular growth. To address this, we used a transgenic mouse reporter for expression of Cxcl12, an arterial endothelial hallmark gene, and performed single-cell RNA sequencing on isolated Cxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation with gene ontology and histological analysis allowed us to segregate the developing artery endothelium into functionally and spatially distinct subpopulations. Expression of Cxcl12 is highest in the distal arterial endothelial subpopulation, a compartment enriched in genes for vascular development. Accordingly, disruption of CXCL12 signaling led to, not only abnormal branching, but also distal vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.

Insights into the Pathogenesis of Pulmonary Fibrosis from Genetic Diseases.

Pulmonary fibrosis is a disease process associated with significant morbidity and mortality, with limited therapeutic options owing to an incomplete understanding of the underlying pathophysiology. Mechanisms driving the fibrotic cascade have been elucidated through studies of rare and common variants in surfactant-related and telomere-related genes in familial and sporadic forms of pulmonary fibrosis, as well as in multisystem Mendelian genetic disorders that present with pulmonary fibrosis. In this translational review, we outline insights into the pathophysiology of pulmonary fibrosis derived from genetic forms of the disease, with a focus on model systems, shared cellular and molecular mechanisms, and potential targets for therapy.

Male Gender Associated with Post-Treatment Seizure Risk of Pediatric Arteriovenous Malformation Patients.

BACKGROUND: Seizure risk has not been fully characterized in pediatric patients with arteriovenous malformations (AVMs). OBJECTIVE: To describe the progression and risk factors of post-treatment seizure in children with AVMs. METHODS: We retrospectively reviewed pediatric patients diagnosed with intracranial AVMs at our institution between 1990 and 2013. Clinical and angiographic variables were included in univariate and multivariate Cox proportional hazard models to explore risk factors associated with time-related seizure outcomes. The outcome event is defined as first seizure occurrence after initial treatment. Kaplan-Meier survival curve is depicted for each significant variable, and survival differences were confirmed by Log-rank test. RESULTS: We included 90 pediatric patients with complete data in our study cohort. Average age is 13.3 ± 3.8 years with 43.3% male patients. Thirty-seven patients had a hemorrhagic presentation, and 39 patients presented with seizure. Post-treatment seizure occurred in 33 patients (36.7%) over an average follow-up period of 8.1 ± 10.6 years; average time to onset is 5.3 ± 8.2 years, with partial seizures as the most common presentation. Multivariate Cox proportional hazard regression revealed seizure presentation ( P = .005), male gender ( P = .026), and nonconservative treatment modality to be significantly associated with earlier onset of post-treatment seizure after adjusting for AVM location and deep venous drainage. Overall annualized seizure risk is 7.4% for patients with pretreatment seizure, and 1.4% for those without. CONCLUSION: Risk of seizure persists after treatment in pediatric AVM patients. Seizure presentation, male gender, and nonconservative management are associated with increased risk of post-treatment seizure. Early identification of these risk factors provides important information for determining seizure management strategies.

Less is more: does the addition of barrel staves improve results in endoscopic strip craniectomy for sagittal craniosynostosis?

OBJECTIVE Endoscopic strip craniectomy (ESC) with postoperative helmet orthosis is a well-established treatment option for sagittal craniosynostosis. There are many technical variations to the surgery ranging from simple strip craniectomy to methods that employ multiple cranial osteotomies. The purpose of this study was to determine whether the addition of lateral barrel-stave osteotomies during ESC improved morphological outcomes. METHODS An IRB-approved retrospective review was conducted on a consecutive series of cases involving ESC for sagittal craniosynostosis at 2 different institutions from March 2008 to August 2014. The patients in Group A underwent ESC and those in Group B had ESC with lateral barrel-stave osteotomies. Demographic and perioperative data were recorded; postoperative morphological outcomes were analyzed using 3D laser scan data acquired from a single orthotic manufacturer who managed patients from both institutions. RESULTS A total of 73 patients were included (34 in Group A and 39 in Group B). Compared with Group B patients, Group A patients had a shorter mean anesthetic time (161.7 vs 195 minutes; p < 0.01) and operative time (71.6 vs 111 minutes; p < 0.01). The mean hospital stay was similar for the 2 groups (1.2 days for Group A vs 1.4 days for Group B; p = 0.1). Adequate postoperative data on morphological outcomes were reported by the orthotic manufacturer for 65 patients (29 in Group A and 36 in Group B). The 2 groups had similar improvement in the cephalic index (CI): Group A, mean change 10.5% (mean preoperative CI 72.6, final 80.4) at a mean follow-up of 13.2 months; Group B, mean change 12.2% (mean preoperative CI 71.0, final 79.6) at a mean follow-up of 19.4 months. The difference was not statistically significant (p = 0.15). CONCLUSIONS Both ESC alone and ESC with barrel staving produced excellent outcomes. However, the addition of barrel staves did not improve the results and, therefore, may not be warranted in the endoscopic treatment of sagittal craniosynostosis.

Differences in Functional Outcome Across Subtypes with Spetzler-Martin Grade II Arteriovenous Malformations.

BACKGROUND: The Spetzler-Martin grading system for brain arteriovenous malformations (AVMs) is based on size (S), eloquence (E), and deep venous drainage (V). However, variation exists due to subgroup heterogeneity. While previous studies have demonstrated variations in outcomes within grade III AVMs, no studies have focused on grade II AVM subtypes. OBJECTIVE: We aim to delineate how functional outcomes differ among patients with subtypes of grade II AVMs. METHODS: We retrospectively reviewed patients with AVMs evaluated at our institution from 1990 to 2013. Grade II AVMs were divided into 3 subtypes: group 1 (S2V0E0), group 2 (S1V0E1), and group 3 (S1V1E0). Baseline characteristics were compared, and functional status was assessed using the modified Rankin Scale (mRS) at pretreatment and last follow-up. Differences in mRS between the 2 time points were compared. RESULTS: A total of 208 grade II patients (34.0%) were retrieved from 611 graded patients. After accounting for missing data, our cohort consisted of 137 patients. Mean age of all patients was 37.2 years, with 74 females (54.0%). No significant difference was observed across subgroups for pretreatment mRS ( P = .096), treatment modalities ( P = .943), follow-up durations ( P = .125), and mRS at last follow-up ( P = .716). In a subgroup analysis between group 1 and group 3, more patients with worsened mRS were observed in group 3 ( P = .039). This distinction was further confirmed in surgically treated patients ( P = .049), but not in patients treated with radiosurgery ( P = .863). CONCLUSION: Subtypes of grade II AVMs portend different posttreatment gains in functional outcome. Group 1 (S2V0E0) patients had the best functional outcome gain from treatment, while group 3 (S1V1E0) patients fared less well, particularly with surgical treatment.

Use of Rapid Response Teams in Psychiatry: Variables that Impact Safety.

OBJECTIVE: The addition of rapid response teams (RRTs) has emerged as a treatment option for medically deteriorating psychiatric inpatients. The goal of this study was to identify risk factors for use of RRTs at the time of initial psychiatric evaluation and develop measures to predict use of this emergent medical intervention. We have not located any studies that have previously addressed this issue. METHODS: We studied the use of RRTs and code teams (CTs) on inpatient general and specialty psychiatric services in a large urban academic psychiatric hospital. RRT or CT calls were made for 60 patients on these units between January, 2010 and December, 2012. Our retrospective chart review study compared the cases of these 60 patients with 120 matched controls. Using χ and the Fisher exact tests, we identified variables that differed significantly between the case and control groups. Next, we used a forward stepwise regression model to create prediction tools to risk stratify patients at the time of initial assessment. RESULTS: Bivariate analyses identified 14 independent statistically significant patient variables. We created 2 risk prediction tools: (1) an "exhaustive" tool (which used 12 of the total 38 factors we considered) based on a stepwise regression model that yielded an area under the receiver operating curve (AUC) of 0.91, and (2) a simplified tool referred to by the acronym "SCHEME" with 6 factors and an AUC of 0.76. CONCLUSIONS: We propose the acronym SCHEME to refer to a tool that can be used to quickly and easily assess medical risk in prospective psychiatric inpatients at the time of admission, which can help reduce the use of RRTs and CTs.

Spinal column chordoma: prognostic significance of clinical variables and T (brachyury) gene SNP rs2305089 for local recurrence and overall survival.

Background: Chordomas are rare, locally aggressive bony tumors associated with poor outcomes. Recently, the single nucleotide polymorphism (SNP) rs2305089 in the T (brachyury) gene was strongly associated with sporadic chordoma development, but its clinical utility is undetermined. Methods: In 333 patients with spinal chordomas, we identified prognostic factors for local recurrence-free survival (LRFS) and overall survival and assessed the prognostic significance of the rs2305089 SNP. Results: The median LRFS was 5.2 years from the time of surgery (95% CI: 3.8-6.0); greater tumor volume (≥100cm3) (hazard ratio [HR] = 1.99, 95% CI: 1.26-3.15, P = .003) and Enneking inappropriate resections (HR = 2.35, 95% CI: 1.37-4.03, P = .002) were independent predictors of LRFS. The median overall survival was 7.0 years (95% CI: 5.8-8.4), and was associated with older age at surgery (HR = 1.11 per 5-year increase, 95% CI: 1.02-1.21, P = .012) and previous surgical resection (HR = 1.73, 95% CI: 1.03-2.89, P = .038). One hundred two of 109 patients (93.6%) with available pathologic specimens harbored the A variant at rs2305089; these patients had significantly improved survival compared with those lacking the variant (P = .001), but there was no association between SNP status and LRFS (P = .876). Conclusions: The ability to achieve a wide en bloc resection at the time of the primary surgery is a critical preoperative consideration, as subtotal resections likely complicate later management. This is the first time the rs2305089 SNP has been implicated in the prognosis of individuals with chordoma, suggesting that screening all patients may be instructive for risk stratification.

Risk of hemorrhage in patients over age 60 with arteriovenous malformations (AVMs).

Treatment selection for patients 60years of age and older with intracranial arteriovenous malformations (AVMs), requires careful consideration of the natural history and post-treatment hemorrhagic risk. We aimed to directly compare the natural history of AVMs with post-treatment hemorrhagic risk in this population. We retrospectively reviewed our AVM database of 683 patients. Patients ⩾60years at diagnosis were included. Treatment modality was divided into four groups: surgery±embolization (SE), radiosurgery±embolization (RE), embolization only (Emb), and observation (Obs). The natural history of the AVM was defined as the annual risk of hemorrhage under observation. Risk of hemorrhage after treatment was also calculated. Sixty-one patients with complete data were included. Average age was 68.4±7.5years, with 55.7% (n=34) being male. Twenty-seven (44.3%) patients presented with intracerebral hemorrhage (ICH). At last follow-up, modified Rankin Scale was higher in patients with subsequent hemorrhages (p=0.023). Overall, obliteration was 65.5%, with 100.0% in the SE group and 43.8% in the RE group (p<0.001). During an average follow-up period of 2.8±3.2years, six patients (9.8%) experienced hemorrhage, with two (12.5%) in the RE group, three (9.4%) in the Obs group and one (9.1%) in the SE group, corresponding to a natural history of 3.5% annual hemorrhage rate and a post-treatment hemorrhagic risk of 3.6%. This post-treatment hemorrhage risk was 2.4% in the SE group and 4.9% in the RE group. Presenting with ICH (p=0.042) and race (p=0.014) were associated with a higher risk of follow-up hemorrhage. Definitive treatment for AVM patients ⩾60years should be cautiously considered. Despite higher post-treatment obliteration rates, the subsequent hemorrhagic risk may exceed that of its natural history. For AVMs with a high risk for hemorrhage, surgery reduces hemorrhagic risk and achieves the highest rate of obliteration.

Percutaneous Procedures for the Treatment of Trigeminal Neuralgia.

Three major percutaneous procedures are currently used to treat trigeminal neuralgia (TN). Percutaneous balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation interrupt afferent pain fibers by injury to the trigeminal nerve root or ganglion. Each is capable of offering immediate and durable pain relief. Each is associated with relatively low, but variable rates of complications. Patient heterogeneity, technical variation, and nonstandard outcomes plague the existing outcomes literature and limit comparisons of treatments. Rendering treatment selection a function of individual physician preference and practice patterns. Randomized, prospective trials are needed; in the meantime, percutaneous rhizotomy remains an excellent treatment for selected patients.

The metopic index: an anthropometric index for the quantitative assessment of trigonocephaly from metopic synostosis.

OBJECTIVE Because the metopic suture normally fuses during infancy, there are varying degrees of severity in head shape abnormalities associated with premature fusion. A method for the objective and reproducible assessment of metopic synostosis is needed to guide management, as current methods are limited by their reliance on aesthetic markers. The object of this study was to describe the metopic index (MI), a simple anthropometric cranial measurement. The measurements can be obtained from CT scans and, more importantly, from palpable cranial landmarks, and the index provides a rapid tool for evaluating patients in both pre- and postoperative settings. METHODS High-resolution head CT scans obtained in 69 patients (age range 0-24 months) diagnosed with metopic craniosynostosis were retrospectively reviewed. Preoperative 3D reconstructions were available in 15 cases, and these were compared with 3D reconstructions of 324 CT scans obtained in a control group of 316 infants (age range 0-24 months) who did not have any condition that might affect head size or shape and also in a subset of this group, comprising 112 patients precisely matched to the craniosynostosis patients with respect to age and sex. Postoperative scans were available and reviewed in 9 of the craniosynostosis patients at a mean time of 7.1 months after surgical repair. 3D reconstructions of these scans were matched with controls based upon age and sex. RESULTS The mean preoperative MI for patients with trigonocephaly was 0.48 (SD 0.05), significantly lower than the mean values of 0.57 (SD 0.04) calculated on the basis of all 324 scans obtained in controls (p < 0.001) and 0.58 (SD 0.04) for the subset of 112 age- and sex-matched controls (p < 0.001). For 7 patients with both pre- and postoperative CT scans available for evaluation, the mean postoperative MI was 0.55 (SD 0.03), significantly greater than their preoperative MIs (mean 0.48 [SD 0.04], p = 0.001) and comparable to the mean MI of the controls (p = 0.30). In 4 patients, clinically obtained postoperative MIs by caliper measurement were comparable to measurements derived from CT (p = 0.141). CONCLUSIONS The MI is a useful measurement of the severity of trigonocephaly in patients with metopic synostosis. This simple quantitative assessment can potentially be used in the clinical setting to guide preoperative evaluation, surgical repair, and postoperative degree of correction.

Long-term Outcomes of Patients With Giant Intracranial Arteriovenous Malformations.

BACKGROUND: Giant intracranial arteriovenous malformations (AVMs) are rare cerebrovascular lesions that pose management challenges. OBJECTIVE: To further clarify outcomes in patients with giant cerebral AVMs managed with conservative or interventional therapies. METHODS: We performed a retrospective review of all patients diagnosed with AVMs evaluated at our institution from 1990 to 2013. Patients with a single intracranial AVM >6 cm were included. Patients were divided into 2 groups: conservative management or intervention (microsurgery, radiosurgery, or embolization). Functional outcome was assessed with the modified Rankin Scale (mRS) and compared between the 2 groups. RESULTS: A total of 55 patients with giant AVMs were included, and 35 patients (63.6%) had clinical follow-up with a mean of 11.8 years. Spetzler-Martin grades were as follows: grade III, n = 2 (3.6%); grade IV, n = 15 (27.3%); and grade V, n = 38 (69.1%). Twenty-four patients (43.6%) were conservatively managed. The patients in the conservatively managed group had larger AVMs (P < .05) with more frequent involvement of the temporal lobe (P = .02). Five patients (26.3%) in the conservatively managed group and 5 (31.3%) in the intervention group experienced hemorrhage during follow-up, translating to an annualized risk of 2.7% and 4.1%, respectively. No significant difference in risk of first subsequent hemorrhage was observed (P = .78). Despite comparable mRS scores at presentation, we observed a trend toward better outcomes (mRS < 2) in patients undergoing conservative management (P = .06) compared with the intervention group at last follow-up. CONCLUSION: This study suggests that interventions for giant AVMs should be considered cautiously because hemorrhagic risk is similar regardless of management strategy and functional outcome is likely to be same or better in the conservatively managed population. ABBREVIATIONS: AVM, arteriovenous malformationmRS, modified Rankin Scale.

Lower Risk of Intracranial Arteriovenous Malformation Hemorrhage in Patients With Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Patients diagnosed with hereditary hemorrhagic telangiectasia (HHT) are at risk of developing intracranial arteriovenous malformations (AVM). However, the clinical manifestations and natural history of HHT-related AVMs remain unclear due to the rarity of these lesions. OBJECTIVE: To clarify the clinical characteristics and hemorrhagic risk in HHT-related AVMs. METHODS: We performed a retrospective review of all patients diagnosed with both HHT and intracranial AVMs who were evaluated at our institution from 1990 to 2013. Patients with missing data or lost to follow-up were excluded. Baseline characteristics and subsequent hemorrhagic risk were evaluated. RESULTS: In an AVM database of 531 patients with 542 AVMs, a total of 12 HHT patients (2.3%) with 23 AVMs were found. Mean age at diagnosis was 36.5 years, with 41.7% male. Compared to patients with sporadic AVMs, patients with HHT were less likely to present with ruptured AVM (P = .04), headaches (P = .02), and seizures (P = .02), and presented with better modified Rankin scores (P < .01). HHT-related AVMs were smaller in size (P < .01), of lower Spetzler-Martin grade (P = .01), and had less temporal lobe involvement (P = .02) compared to sporadic AVMs. Six HHT patients (50.0%) were found with multiple intracranial AVMs. One hemorrhage was found during an observation period of 149.6 patient-years and 297.5 lesion-years, translating to 1.3% per patient per year or 0.7% per AVM per year. CONCLUSION: HHT-related AVMs are smaller in size with lower Spetzler-Martin grade and less temporal lobe involvement than sporadic AVMs. Patients with HHT frequently present with multiple intracranial AVMs. Conservative management is generally recommended due to lesion multiplicity and relatively low hemorrhagic risk.

Delayed Hemorrhage After Treatment of Brain Arteriovenous Malformations (AVMs).

OBJECTIVE: The risk of delayed hemorrhage occurring greater than 2 years after treatment in brain arteriovenous malformations (AVMs) rarely is reported. In this study, we compare the risk of delayed hemorrhage across different treatment modalities. METHODS: We performed a retrospective chart review of treated patients with a single intracranial AVM seen at our institution from 1990 to 2013. Delayed hemorrhage was defined as hemorrhage occurring at least 2 years after last treatment. Survival analysis was used to assess risk of delayed hemorrhage by treatment modalities. RESULTS: Our study included 420 patients. Spetzler-Martin grades were as follows: I (12.6%), II (36.2%), III (32.6%), IV (15.0%), and V (3.6%). Average follow-up time is 5.1 years. Twenty-two patients (5.2%) were found to have 28 delayed hemorrhages. Average interval between last treatment and delayed hemorrhage was 7.6 years, with the longest being 24.2 years. Proportions of delayed hemorrhages by treatment modalities were as follows: surgery ± embolization (group I, 9.1%), radiosurgery ± embolization (group II, 63.6%), embolization only (group III, 22.7%), and surgery + radiosurgery ± embolization (group IV, 4.5%). Annualized hemorrhage risk after 2 years for each treatment group was as follows: group I (0.4%), group II (1.2%), group III (3.7%), and group IV (1.7%). Survival analysis demonstrated lowest risk of delayed hemorrhage for group 1 (P < 0.01). CONCLUSIONS: This study is the first to compare the risk of delayed hemorrhage across different treatment modalities. Surgical resection is associated with the lowest risk for delayed hemorrhage compared with other treatment modalities. Patients with partially embolized AVMs should seek timely definitive treatment to decrease the risk of delayed hemorrhage.

Shunt revision requirements after posthemorrhagic hydrocephalus of prematurity: insight into the time course of shunt dependency.

PURPOSE: Intraventricular hemorrhage (IVH) is a common affliction of preterm infants and often results in posthemorrhagic hydrocephalus (PHH). These patients typically eventually require permanent CSF diversion and are presumed to be indefinitely shunt-dependent. To date, however, there has been no study of long-term shunt revision requirements in patients with PHH. METHODS: We analyzed retrospectively collected data for 89 preterm patients diagnosed with grades III and IV IVH and PHH at our institution from 1998 to 2011. RESULTS: Sixty-nine out of 89 patients (77.5%) underwent ventriculoperitoneal (VP) shunt placement, and 33 (47.8%) required at least one shunt revision and 18 (26.1%) required multiple revisions. The mean ± standard deviation follow-up time for shunted patients was 5.0 ± 3.3 years. The majority of early failures were due to proximal catheter malfunction, while later failures were mostly due to distal catheter problems. There was a significant difference in the number of patients requiring revisions in the first 3 years following initial VP shunt insertion compared after 3 years, with 28 revisions versus 10 (p < 0.004). In 8 out of 10 patients who underwent shunt revisions after 3 years, evidence of obstructive hydrocephalus was found on imaging either in the form of an isolated fourth ventricular cyst or aqueductal stenosis. CONCLUSIONS: Our results suggest that in a distinct subset of patients with PHH, obstructive hydrocephalus may develop, resulting in long-term dependence on CSF diversion. Further study on the factors associated with long-term shunt dependence and revision requirements within the PHH group is warranted.

Natural history and treatment of craniocervical junction dural arteriovenous fistulas.

Dural arteriovenous fistulas (DAVFs) located at the craniocervical junction are rare vascular malformations with distinctive features, and their natural history and the optimal treatment strategy remains unclear. We retrospectively reviewed eight patients with craniocervical junction DAVF who were evaluated at our institution between 2009 and 2012. We also conducted a MEDLINE search for all reports of craniocervical junction DAVF between 1970 and 2013, and reviewed 119 patients from 56 studies. From a total of 127 patients, 46 (37.1%) presented with myelopathy, 53 (43.1%) with subarachnoid hemorrhage (SAH), and four (3.3%) with brainstem dysfunction. SAH was typically mild, most often Hunt and Hess Grade I or II (83.3%), and associated with ascending venous drainage via the intracranial veins (p<0.001). Higher rates of obliteration were observed after microsurgery compared to embolization. Overall, younger age (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.01-1.12; p=0.011), hemorrhagic presentation (OR 0.17; 95% CI 0.06-0.50; p=0.001), and microsurgery (OR 0.23; 95% CI 0.08-0.6; p=0.004) were independently predictive of good outcome at the last follow-up. Microsurgery was the only independent predictor of overall improvement at the last follow-up (OR 4.35; 95% CI 1.44-13.2; p=0.009). Prompt diagnosis and microsurgical management, offering a greater chance of immediate obliteration, may optimize the outcomes for patients with craniocervical junction DAVF. Endovascular treatment is often not feasible due to lesion angioarchitecture, and is associated with a higher risk of lesion recanalization or recurrence. However, long term studies with newer embolic agents such as Onyx (ev3 Endovascular, Plymouth, MN, USA) are yet to be performed.

Racial Associations with Hemorrhagic Presentation in Cerebral Arteriovenous Malformations.

BACKGROUND: Studies focusing on hemorrhagic presentation of brain arteriovenous malformations (AVMs) have largely limited their analysis to angiographic features. We report the importance of race/ethnicity as a clinical factor associated with hemorrhagic AVM presentation in addition to previously reported angiographic features. METHODS: Data were prospectively and retrospectively collected on patients (N = 194) during the period 1993-2010 who presented with a single intracranial AVM, and baseline characteristics were compared for hemorrhagic presentation versus nonhemorrhagic presentation. Features that were statistically significant in univariate analysis or clinically significant were included in a multivariate analysis. RESULTS: The median age at presentation was 32 years; 37.2% of patients were male. Spetzler-Martin grades were I in 17.5%, II in 37.1%, III in 28.9%, IV in 14.9%, and V in 1.5%. Baseline characteristics that differed significantly between patients presenting with hemorrhage compared with patients without hemorrhage were the following: race (P < 0.01), AVM size (P < 0.01), <3 feeding arteries (P = 0.01), absence of middle cerebral artery supply to AVM (P < 0.01), and AVM location (P < 0.01). Multivariate analysis revealed nonwhite race (odds ratio [OR] = 3.09 [95% confidence interval (CI) = 1.52, 6.44], P < 0.01); smaller AVM size (OR = 0.65 [95% CI = 0.19, 0.86], P < 0.01); and nonfrontal lobar (OR = 2.61 [95% CI = 1.2, 5.59], P = 0.02), basal ganglia (OR = 6.20 [95% CI = 1.52, 26.26], P = 0.01), or brainstem locations (OR = 4.41 [95% CI = 1.38, 14.92], P = 0.01) as factors associated with hemorrhagic presentation of brain AVMs. CONCLUSIONS: To our knowledge, this is the first study demonstrating that race/ethnicity is significantly associated with hemorrhagic presentation of AVMs. We also confirmed previous observations that AVM size and location are associated with hemorrhagic presentation.

Serial Imaging Surveillance for Patients With a History of Intracranial Aneurysm: Risk of De Novo Aneurysm Formation.

BACKGROUND: Although rare, de novo intracranial aneurysms (DNIAs) may develop in patients with a history of intracranial aneurysms (IAs). OBJECTIVE: To evaluate the benefit of routine radiographic screening for DNIAs. METHODS: Data for 2153 patients with IAs were retrospectively analyzed. A total of 185 patients underwent screening for DNIAs at frequent intervals. RESULTS: Overall, DNIAs were detected in 26 patients (1.2%). Of the 185 patients with surveillance, DNIAs developed in 9 (4.9%). The risk of DNIA detection was 1.14% per person-year of follow-up (95% confidence interval: 0.6%-2.2%). Patients with imaging follow-up had a significantly higher rate of DNIA detection compared with patients without regular imaging surveillance (4.9% vs 0.86%; P < .001), but surveillance was associated with smaller lesions (with surveillance: 3.8 ± 1.8 mm, without: 7.0 ± 4.4 mm, mean ± standard deviation; P = .026). A unimodal distribution of time to detection was found in those with surveillance, with a peak between 0 and 2 years. There was a trend toward an association of cigarette smoking and DNIA detection within 10 years (P = .06); 6 of the 26 patients (23.1%) with DNIAs had a history of cigarette smoking, with all 6 patients continuing to smoke up to the detection of the DNIAs, which were detected in 2.5 ± 1.8 years. CONCLUSION: The low 1.14% per-person year risk of DNIA detection and small DNIA size at detection cannot justify routine screening for DNIAs in all patients with a personal history of IAs. If imaging follow-up is considered for selected patients, early screening will likely yield the most benefit in patients who continue to smoke cigarettes.

Genetics and immunotherapy: using the genetic landscape of gliomas to inform management strategies.

Recent work in genetics has identified essential driver mutations in gliomas and has profoundly changed our understanding of tumorigenesis. New insights into the molecular basis of glioma has informed the development of therapies demonstrating considerable potential, including immunotherapeutic approaches such as peptide and dendritic cell vaccines against EGFRvIII. However, the selective targeting of one component of a dysregulated pathway may be inadequate for a durable clinical response, given the intratumoral heterogeneity of glioblastoma (GBM) and hypermutated profiles displayed by tumor recurrences. Immune checkpoint blockade with anti-cytotoxic T lymphocyte antigen-4 (CTLA) and anti-programmed cell death 1 (PD-1) have demonstrated encouraging results in clinical trials with other solid tumors, and recent data suggest that this type of therapy may be particularly useful for tumors with high mutational burdens. Although the survival for patients with GBM has remains grim, the use of immunotherapy may finally change patient outcomes.