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Simple Summary Microglia infiltrate most gliomas and have been demonstrated to promote tumor growth, invasion, and treatment resistance. To develop improved treatment methods, that take into consideration the supporting role of microglia in tumor progression, the functional and mechanistic pathways of glioma–microglia interactions need to be identified and experimentally dissected. Our recent studies and literature reports revealed the overexpression of Pyk2 and FAK in glioblastomas. Pyk2 and FAK signaling pathways have been shown to regulate migration and proliferation in glioma cells, including microglia-promoted glioma cell migration. However, the specific factors released by microglia that modulate Pyk2 and FAK to promote glioma invasiveness and proliferation are poorly understood. The aim of this study was to identify key microglia-derived signaling molecules that induce the activation of Pyk2- and FAK-dependent glioma cell proliferation and invasiveness. Abstract Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.

Background and Purpose— Understanding the hemorrhage risks associated with brain arteriovenous malformations (AVMs) before and after stereotactic radiosurgery (SRS) is important. The aims of this multicenter, retrospective cohort study are to evaluate and compare the rates of pre- and post-SRS AVM hemorrhage and identify risk factors. Methods— We pooled AVM SRS data from 8 institutions participating in the International Radiosurgery Research Foundation. Predictors of post-SRS hemorrhage were determined using a multivariate logistic regression model. Pre- and post-SRS hemorrhage rates were compared using Fisher exact test. Ruptured and unruptured AVMs were matched in a 1:1 ratio using propensity scores, and their outcomes were compared. Results— The study cohort comprised 2320 AVM patients who underwent SRS. Deep AVM location (odds ratio, 1.86; 95% CI, 1.19–2.92; P =0.007), the presence of an AVM-associated arterial aneurysm (odds ratio, 2.44; 95% CI, 1.63–3.66; P P =0.005) were independent predictors of post-SRS hemorrhage. The post-SRS hemorrhage rate was lower for obliterated versus patent AVMs (6.0 versus 22.3 hemorrhages/1000 person-years; P P =0.001). The outcomes of the matched ruptured versus unruptured AVM cohorts were similar. Conclusions— SRS appears to reduce the risk of AVM hemorrhage, although this effect is predominantly driven by obliteration. Deep-seated AVMs are more likely to rupture during the latency period after SRS. AVM-associated aneurysms should be considered for selective occlusion before SRS of the nidus to ameliorate the post-SRS hemorrhage rate of these lesions.

Glioblastoma (GBM) is the most aggressive and highly invasive primary brain tumor in adults. Evidence suggests that microglia create a microenvironment favoring glioma invasion and proliferation. Indeed, previous reports indicate the involvement of focal adhesion kinase (FAK) signaling cascades in glioma cell proliferation. Besides, studies from our laboratory support a critical role of Pyk2, a relative of FAK, in glioma invasion by tumor-infiltrating microglia. However, the microglial-released factors modulating Pyk2 and FAK signaling pathways are unknown. In this study, 20 human GBM specimens were evaluated to identify the cytokine expression patterns in purified microglia and FAK and Pyk2 phosphorylation in glioma cell fraction by RT-PCR and western blot. A Pierson correlation test demonstrated a high correlation (0.8-1.0) of gene expression for PDGFα, PDGFβ, SDF-1α, IL-6, IL-8, and EGF in percoll-purified microglia, and pPyk2(Y579/580) and pFAK(Y925) levels in glioma cell fraction. The role of cytokines in cell invasion and proliferation by Pyk2/FAK activation was further investigated in primary cell lines from three patients. Thirty percent up-regulation of pPyk2 and pFAK was detected in glioma cells treated (2 hrs.) with microglia conditioned media (MCM) compared to control cells. siPyk2 or siFAK knockdown identified IL-6 (100 μM) and EGF (1 μM) as key factors of Pyk2- and FAK-dependent activation in all glioma cell lines. Similar results with siPyk2 or siFAK were observed for matrix degradation, invadopodia formation, cell viability, and mitosis. Indeed, Tocilizumab (IL-6R blocker, 100 ng/mL) and Gefitinib (EGFR blocker, 1 μM) reversed the effect of MCM on glioma cell proliferation and invasion in all cell lines evaluated. These findings support a pivotal role of Pyk2 and FAK in enhancing proliferation and invasion of glioma tumors through IL-6 and EGF-dependent pathways. The latter could be of clinical relevance for new therapeutic developments in GBM patients.

Background Although necrotizing pneumonia (NN) is one of the most feared complications of community-acquired pneumonia, data in pediatric patients are scarce. The objective of this article is to describe children admitted to pediatric intensive care unit (PICU) because of NN. Methods Retrospective-prospective observational study in children admitted with NN to PICU (from January 1, 2010, to December 31, 2018). The data collected included information on disease epidemiology, PICU management, respiratory assistance and disease evolution. Results Fifty-one children were included, 42 of 51 had received 7-valent or 13-valent pneumococcal vaccine. Median age was 3.2 years (1.9-4.2), 15 of 51 had signs of sepsis at admission. Forty-nine patients presented pleural effusion with drainage in 46. The most common respiratory support modality was high-flow oxygen nasal cannula (17/51). Computed tomography was the gold standard for diagnosis. Etiologic diagnosis was obtained in 34 of 51, and pneumococcus was isolated in 29 of 34. In all of these cases, initial detection was made by capsular antigen in pleural fluid. Children with pneumococcal NN had fewer days of evolution prior to PICU admission (P = 0.041). Cefotaxime with clindamycin was used in 49 of 51. Surgery was necessary in 3 of 51 patients. After PICU discharge, only 5 of 51 were readmitted. There were deaths. Conclusions In our study, the NN was mainly observed in children around 3 years old. The main causal agent was pneumococcus. The evolution towards NN appeared to be faster than in case of other etiologies. Surgery management was unusual. All children required prolonged admissions but had a full clinical recovery.

OBJECTIVEDue to the complexity of Spetzler-Martin (SM) Grade IV–V arteriovenous malformations (AVMs), the management of these lesions remains controversial. The aims of this multicenter, retrospective cohort study were to evaluate the outcomes after single-session stereotactic radiosurgery (SRS) for SM Grade IV–V AVMs and determine predictive factors.METHODSThe authors retrospectively pooled data from 233 patients (mean age 33 years) with SM Grade IV (94.4%) or V AVMs (5.6%) treated with single-session SRS at 8 participating centers in the International Gamma Knife Research Foundation. Pre-SRS embolization was performed in 71 AVMs (30.5%). The mean nidus volume, SRS margin dose, and follow-up duration were 9.7 cm3, 17.3 Gy, and 84.5 months, respectively. Statistical analyses were performed to identify factors associated with post-SRS outcomes.RESULTSAt a mean follow-up interval of 84.5 months, favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RIC) and was achieved in 26.2% of patients. The actuarial obliteration rates at 3, 7, 10, and 12 years were 15%, 34%, 37%, and 42%, respectively. The annual post-SRS hemorrhage rate was 3.0%. Symptomatic and permanent RIC occurred in 10.7% and 4% of the patients, respectively. Only larger AVM diameter (p = 0.04) was found to be an independent predictor of unfavorable outcome in the multivariate logistic regression analysis. The rate of favorable outcome was significantly lower for unruptured SM Grade IV–V AVMs compared with ruptured ones (p = 0.042). Prior embolization was a negative independent predictor of AVM obliteration (p = 0.024) and radiologically evident RIC (p = 0.05) in the respective multivariate analyses.CONCLUSIONSIn this multi-institutional study, single-session SRS had limited efficacy in the management of SM Grade IV–V AVMs. Favorable outcome was only achieved in a minority of unruptured SM Grade IV–V AVMs, which supports less frequent utilization of SRS for the management of these lesions. A volume-staged SRS approach for large AVMs represents an alternative approach for high-grade AVMs, but it requires further investigation.

OBJECTIVEThe goal of stereotactic radiosurgery (SRS) for arteriovenous malformation (AVM) is complete nidus obliteration, thereby eliminating the risk of future hemorrhage. This outcome can be observed within the first 18 months, although documentation of AVM obliteration can extend to as much as 5 years after SRS is performed. A shorter time to obliteration may impact the frequency and effect of post-SRS complications and latency hemorrhage. The authors' goal in the present study was to determine predictors of early obliteration (18 months or less) following SRS for cerebral AVM.METHODSEight centers participating in the International Gamma Knife Research Foundation (IGKRF) obtained institutional review board approval to supply de-identified patient data. From a cohort of 2231 patients, a total of 1398 patients had confirmed AVM obliteration. Patients were sorted into early responders (198 patients), defined as those with confirmed nidus obliteration at or prior to 18 months after SRS, and late responders (1200 patients), defined as those with confirmed nidus obliteration more than 18 months after SRS. The median clinical follow-up time was 63.7 months (range 7–324.7 months).RESULTSOutcome parameters including latency interval hemorrhage, mortality, and favorable outcome were not significantly different between the 2 groups. Radiologically demonstrated radiation-induced changes were noted more often in the late responder group (376 patients [31.3%] vs 39 patients [19.7%] for early responders, p = 0.005). Multivariate independent predictors of early obliteration included a margin dose > 24 Gy (p = 0.031), prior surgery (p = 0.002), no prior radiotherapy (p = 0.025), smaller AVM nidus (p = 0.002), deep venous drainage (p = 0.039), and nidus location (p < 0.0001). Basal ganglia, cerebellum, and frontal lobe nidus locations favored early obliteration (p = 0.009). The Virginia Radiosurgery AVM Scale (VRAS) score was significantly different between the 2 responder groups (p = 0.039). The VRAS score was also shown to be predictive of early obliteration on univariate analysis (p = 0.009). For early obliteration, such prognostic ability was not shown for other SRS- and AVM-related grading systems.CONCLUSIONSEarly obliteration (≤ 18 months post-SRS) was more common in patients whose AVMs were smaller, located in the frontal lobe, basal ganglia, or cerebellum, had deep venous drainage, and had received a margin dose > 24 Gy.

OBJECTIVECerebellar arteriovenous malformations (AVMs) represent the majority of infratentorial AVMs and frequently have a hemorrhagic presentation. In this multicenter study, the authors review outcomes of cerebellar AVMs after stereotactic radiosurgery (SRS).METHODSEight medical centers contributed data from 162 patients with cerebellar AVMs managed with SRS. Of these patients, 65% presented with hemorrhage. The median maximal nidus diameter was 2 cm. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent radiation-induced complications (RICs). Patients were followed clinically and radiographically, with a median follow-up of 60 months (range 7–325 months).RESULTSThe overall actuarial rates of obliteration at 3, 5, 7, and 10 years were 38.3%, 74.2%, 81.4%, and 86.1%, respectively, after single-session SRS. Obliteration and a favorable outcome were more likely to be achieved in patients treated with a margin dose greater than 18 Gy (p < 0.001 for both), demonstrating significantly better rates (83.3% and 79%, respectively). The rate of latency preobliteration hemorrhage was 0.85%/year. Symptomatic post-SRS RICs developed in 4.5% of patients (n = 7). Predictors of a favorable outcome were a smaller nidus (p = 0.0001), no pre-SRS embolization (p = 0.003), no prior hemorrhage (p = 0.0001), a higher margin dose (p = 0.0001), and a higher maximal dose (p = 0.009). The Spetzler-Martin grade was not found to be predictive of outcome. The Virginia Radiosurgery AVM Scale score (p = 0.0001) and the Radiosurgery-Based AVM Scale score (p = 0.0001) were predictive of a favorable outcome.CONCLUSIONSSRS results in successful obliteration and a favorable outcome in the majority of patients with cerebellar AVMs. Most patients will require a nidus dose of higher than 18 Gy to achieve these goals. Radiosurgical and not microsurgical scales were predictive of clinical outcome after SRS.

Background The role of intervention in the management of unruptured brain arteriovenous malformations (AVM) is controversial. Objective To analyze in a multicenter, retrospective cohort study, the outcomes following radiosurgery for unruptured AVMs and determine predictive factors. Methods We evaluated and pooled AVM radiosurgery data from 8 institutions participating in the International Gamma Knife Research Foundation. Patients with unruptured AVMs and ≥12 mo of follow-up were included in the study cohort. Favorable outcome was defined as AVM obliteration, no postradiosurgical hemorrhage, and no permanently symptomatic radiation-induced changes. Results The unruptured AVM cohort comprised 938 patients with a median age of 35 yr. The median nidus volume was 2.4 cm 3 , 71% of AVMs were located in eloquent brain areas, and the Spetzler-Martin grade was III or higher in 57%. The median radiosurgical margin dose was 21 Gy and follow-up was 71 mo. AVM obliteration was achieved in 65%. The annual postradiosurgery hemorrhage rate was 1.4%. Symptomatic and permanent radiation-induced changes occurred in 9% and 3%, respectively. Favorable outcome was achieved in 61%. In the multivariate logistic regression analysis, smaller AVM maximum diameter ( P = .001), the absence of AVM-associated arterial aneurysms ( P = .001), and higher margin dose ( P = .002) were found to be independent predictors of a favorable outcome. A margin dose ≥ 20 Gy yielded a significantly higher rate of favorable outcome (70% vs 36%; P Conclusion Radiosurgery affords an acceptable risk to benefit profile for patients harboring unruptured AVMs. These findings justify further prospective studies comparing radiosurgical intervention to conservative management for unruptured AVMs.

OBJECTIVE Because of the angioarchitectural diversity of Spetzler-Martin (SM) Grade III arteriovenous malformations (AVMs), the management of these lesions is incompletely defined. The aims of this multicenter, retrospective cohort study were to evaluate the outcomes after stereotactic radiosurgery (SRS) for SM Grade III AVMs and to determine the factors predicting these outcomes. METHODS The authors analyzed and pooled data from patients with SM Grade III AVMs treated with SRS at 8 institutions participating in the International Gamma Knife Research Foundation. Patients with these AVMs and a minimum follow-up length of 12 months were included in the study cohort. An optimal outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs). Data were analyzed by univariate and multivariate regression analyses. RESULTS The SM Grade III AVM cohort comprised 891 patients with a mean age of 34 years at the time of SRS. The mean nidus volume, radiosurgical margin dose, and follow-up length were 4.5 cm3, 20 Gy, and 89 months, respectively. The actuarial obliteration rates at 5 and 10 years were 63% and 78%, respectively. The annual postradiosurgery hemorrhage rate was 1.2%. Symptomatic and permanent RICs were observed in 11% and 4% of the patients, respectively. Optimal outcome was achieved in 56% of the patients and was significantly more frequent in cases of unruptured AVMs (OR 2.3, p < 0.001). The lack of a previous hemorrhage (p = 0.037), absence of previous AVM embolization (p = 0.002), smaller nidus volume (p = 0.014), absence of AVM-associated arterial aneurysms (p = 0.023), and higher margin dose (p < 0.001) were statistically significant independent predictors of optimal outcome in a multivariate analysis. CONCLUSIONS Stereotactic radiosurgery provided better outcomes for patients with small, unruptured SM Grade III AVMs than for large or ruptured SM Grade III nidi. A prospective trial or registry that facilitates a comparison of SRS with conservative AVM management might further clarify the authors' observations for these often high-risk AVMs.

OBJECTIVE In this multicenter study, the authors reviewed the results following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs), determined predictors of outcome, and assessed predictive value of commonly used grading scales based upon this large cohort with long-term follow-up. METHODS Data from a cohort of 2236 patients undergoing GKRS for cerebral AVMs were compiled from the International Gamma Knife Research Foundation. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent symptomatic radiation-induced complications. Patient and AVM characteristics were assessed to determine predictors of outcome, and commonly used grading scales were assessed. RESULTS The mean maximum AVM diameter was 2.3 cm, with a mean volume of 4.3 cm3. A mean margin dose of 20.5 Gy was delivered. Mean follow-up was 7 years (range 1–20 years). Overall obliteration was 64.7%. Post-GRKS hemorrhage occurred in 165 patients (annual risk 1.1%). Radiation-induced imaging changes occurred in 29.2%; 9.7% were symptomatic, and 2.7% had permanent deficits. Favorable outcome was achieved in 60.3% of patients. Patients with prior nidal embolization (OR 2.1, p < 0.001), prior AVM hemorrhage (OR 1.3, p = 0.007), eloquent location (OR 1.3, p = 0.029), higher volume (OR 1.01, p < 0.001), lower margin dose (OR 0.9, p < 0.001), and more isocenters (OR 1.1, p = 0.011) were more likely to have unfavorable outcomes in multivariate analysis. The Spetzler-Martin grade and radiosurgery-based AVM score predicted outcome, but the Virginia Radiosurgery AVM Scale provided the best assessment. CONCLUSIONS GKRS for cerebral AVMs achieves obliteration and avoids permanent complications in the majority of patients. Patient, AVM, and treatment parameters can be used to predict long-term outcomes following radiosurgery.

In this study, we identified the proton-coupled folate transporter (PCFT) as a route for targeted delivery of drugs to some gliomas. Using the techniques of confocal imaging, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and small interfering (siRNA) knockdown against the PCFT, we demonstrated that Gl261 and A172 glioma cells, but not U87 and primary cultured astrocytes, express the PCFT, which provides selective internalization of folic acid (FA)-conjugated cytochrome c-containing nanoparticles (FA-Cyt c NPs), followed by cell death. The FA-Cyt c NPs (100 &micro, g/mL), had no cytotoxic effects in astrocytes but caused death in glioma cells, according to their level of expression of PCFT. Whole-cell patch clamp recording revealed FA-induced membrane currents in FA-Cyt c NPs-sensitive gliomas, that were reduced by siRNA PCFT knockdown in a similar manner as by application of FA-Cyt c NPs, indicating that the PCFT is a route for internalization of FA-conjugated NPs in these glioma cells. Analysis of human glioblastoma specimens revealed that at least 25% of glioblastomas express elevated level of either PCFT or folate receptor (FOLR1). We conclude that the PCFT provides a mechanism for targeted delivery of drugs to some gliomas as a starting point for the development of efficient methods for treating gliomas with high expression of PCFT and/or FOLR1.

Background and Purpose— The benefit of intervention for patients with unruptured cerebral arteriovenous malformations (AVMs) was challenged by results demonstrating superior clinical outcomes with conservative management from A Randomized Trial of Unruptured Brain AVMs (ARUBA). The aim of this multicenter, retrospective cohort study is to analyze the outcomes of stereotactic radiosurgery for ARUBA-eligible patients. Methods— We combined AVM radiosurgery outcome data from 7 institutions participating in the International Gamma Knife Research Foundation. Patients with ≥12 months of follow-up were screened for ARUBA eligibility criteria. Favorable outcome was defined as AVM obliteration, no postradiosurgery hemorrhage, and no permanently symptomatic radiation–induced changes. Adverse neurological outcome was defined as any new or worsening neurological symptoms or death. Results— The ARUBA-eligible cohort comprised 509 patients (mean age, 40 years). The Spetzler–Martin grade was I to II in 46% and III to IV in 54%. The mean radiosurgical margin dose was 22 Gy and follow-up was 86 months. AVM obliteration was achieved in 75%. The postradiosurgery hemorrhage rate during the latency period was 0.9% per year. Symptomatic and permanent radiation–induced changes occurred in 11% and 3%, respectively. The rates of favorable outcome, adverse neurological outcome, permanent neurological morbidity, and mortality were 70%, 13%, 5%, and 4%, respectively. Conclusions— Radiosurgery may provide durable clinical benefit in some ARUBA-eligible patients. On the basis of the natural history of untreated, unruptured AVMs in the medical arm of ARUBA, we estimate that a follow-up duration of 15 to 20 years is necessary to realize a potential benefit of radiosurgical intervention for conservative management in unruptured patients with AVM.

OBJECTIVEThe role of and technique for stereotactic radiosurgery (SRS) in the management of arteriovenous malformations (AVMs) have evolved over the past four decades. The aim of this multicenter, retrospective cohort study was to compare the SRS outcomes of AVMs treated during different time periods.METHODSThe authors selected patients with AVMs who underwent single-session SRS at 8 different centers from 1988 to 2014 with follow-up ≥ 6 months. The SRS eras were categorized as early (1988–2000) or modern (2001–2014). Statistical analyses were performed to compare the baseline characteristics and outcomes of the early versus modern SRS eras. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs).RESULTSThe study cohort comprised 2248 patients with AVMs, including 1584 in the early and 664 in the modern SRS eras. AVMs in the early SRS era were significantly smaller (p < 0.001 for maximum diameter and volume), and they were treated with a significantly higher radiosurgical margin dose (p < 0.001). The obliteration rate was significantly higher in the early SRS era (65% vs 51%, p < 0.001), and earlier SRS treatment period was an independent predictor of obliteration in the multivariate analysis (p < 0.001). The rates of post-SRS hemorrhage and radiological, symptomatic, and permanent RICs were not significantly different between the two groups. Favorable outcome was achieved in a significantly higher proportion of patients in the early SRS era (61% vs 45%, p < 0.001), but the earlier SRS era was not statistically significant in the multivariate analysis (p = 0.470) with favorable outcome.CONCLUSIONSDespite considerable advances in SRS technology, refinement of AVM selection, and contemporary multimodality AVM treatment, the study failed to observe substantial improvements in SRS favorable outcomes or obliteration for patients with AVMs over time. Differences in baseline AVM characteristics and SRS treatment parameters may partially account for the significantly lower obliteration rates in the modern SRS era. However, improvements in patient selection and dose planning are necessary to optimize the utility of SRS in the contemporary management of AVMs.

Objective ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) found better short-term outcomes after conservative management compared with intervention for unruptured arteriovenous malformations (AVMs). However, because Spetzler-Martin (SM) grade I–II AVMs have the lowest treatment morbidity, sufficient follow-up of these lesions may show a long-term benefit from intervention. The aim of this multicenter, retrospective cohort study is to assess the outcomes after stereotactic radiosurgery (SRS) for ARUBA-eligible SM grade I–II AVMs. Methods We pooled SRS data for patients with AVM from 7 institutions and selected ARUBA-eligible SM grade I–II AVMs with ≥12 months follow-up for analysis. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. Results The ARUBA-eligible SM grade I–II AVM cohort comprised 232 patients (mean age, 42 years). The mean nidus volume, SRS margin dose, and follow-up duration were 2.1 cm 3 , 22.5 Gy, and 90.5 months, respectively. The actuarial obliteration rates at 5 and 10 years were 72% and 87%, respectively; annual post-SRS hemorrhage rate was 1.0%; symptomatic and permanent radiation-induced changes occurred in 8% and 1%, respectively; and favorable outcome was achieved in 76%. Favorable outcome was significantly more likely in patients treated with a margin dose >20 Gy (83%) versus ≤20 Gy (62%; P Conclusions For ARUBA-eligible SM grade I–II AVMs, long-term SRS outcomes compare favorably with the natural history. SRS should be considered for adult patients harboring unruptured, previously untreated low-grade AVMs with a minimum life expectancy of a decade.

OBJECTIVE Brain arteriovenous malformations (AVMs) are the most common cause of spontaneous intracranial hemorrhage in pediatric patients (age < 18 years). Since the cumulative lifetime risk of AVM hemorrhage is considerable in children, an improved understanding of the risk factors influencing hemorrhagic presentation may aid in the management of pediatric AVMs. The aims of this first of a 2-part multicenter, retrospective cohort study are to evaluate the incidence and determine the predictors of hemorrhagic presentation in pediatric AVM patients. METHODS The authors analyzed pooled AVM radiosurgery data from 7 institutions participating in the International Gamma Knife Research Foundation (IGKRF). Patients younger than 18 years at the time of radiosurgery and who had at least 12 months of follow-up were included in the study cohort. Patient and AVM characteristics were compared between unruptured and ruptured pediatric AVMs. RESULTS A total of 357 pediatric patients were eligible for analysis, including 112 patients in the unruptured and 245 patients in the ruptured AVM cohorts (69% incidence of hemorrhagic presentation). The annual hemorrhage rate prior to radiosurgery was 6.3%. Hemorrhagic presentation was significantly more common in deep locations (basal ganglia, thalamus, and brainstem) than in cortical locations (frontal, temporal, parietal, and occipital lobes) (76% vs 62%, p = 0.006). Among the factors found to be significantly associated with hemorrhagic presentation in the multivariate logistic regression analysis, deep venous drainage (OR 3.2, p < 0.001) was the strongest independent predictor, followed by female sex (OR 1.7, p = 0.042) and smaller AVM volume (OR 1.1, p < 0.001). CONCLUSIONS Unruptured and ruptured pediatric AVMs have significantly different patient and nidal features. Pediatric AVM patients who possess 1 or more of these high-risk features may be candidates for relatively more aggressive management strategies.

OBJECTIVE Pediatric patients (age < 18 years) harboring brain arteriovenous malformations (AVMs) are burdened with a considerably higher cumulative lifetime risk of hemorrhage than adults. Additionally, the pediatric population was excluded from recent prospective comparisons of intervention versus conservative management for unruptured AVMs. The aims of this multicenter, retrospective cohort study are to analyze the outcomes after stereotactic radiosurgery for unruptured and ruptured pediatric AVMs. METHODS We analyzed and pooled AVM radiosurgery data from 7 participating in the International Gamma Knife Research Foundation. Patients younger than 18 years of age who had at least 12 months of follow-up were included in the study cohort. Favorable outcome was defined as AVM obliteration, no post-radiosurgical hemorrhage, and no permanently symptomatic radiation-induced changes (RIC). The post-radiosurgery outcomes of unruptured versus ruptured pediatric AVMs were compared, and statistical analyses were performed to identify predictive factors. RESULTS The overall pediatric AVM cohort comprised 357 patients with a mean age of 12.6 years (range 2.8–17.9 years). AVMs were previously treated with embolization, resection, and fractionated external beam radiation therapy in 22%, 6%, and 13% of patients, respectively. The mean nidus volume was 3.5 cm3, 77% of AVMs were located in eloquent brain areas, and the Spetzler-Martin grade was III or higher in 59%. The mean radiosurgical margin dose was 21 Gy (range 5–35 Gy), and the mean follow-up was 92 months (range 12–266 months). AVM obliteration was achieved in 63%. During a cumulative latency period of 2748 years, the annual post-radiosurgery hemorrhage rate was 1.4%. Symptomatic and permanent radiation-induced changes occurred in 8% and 3%, respectively. Favorable outcome was achieved in 59%. In the multivariate logistic regression analysis, the absence of prior AVM embolization (p = 0.001) and higher margin dose (p < 0.001) were found to be independent predictors of a favorable outcome. The rates of favorable outcome for patients treated with a margin dose ≥ 22 Gy vs < 22 Gy were 78% (110/141 patients) and 47% (101/216 patients), respectively. A margin dose ≥ 22 Gy yielded a significantly higher probability of a favorable outcome (p < 0.001). The unruptured and ruptured pediatric AVM cohorts included 112 and 245 patients, respectively. Ruptured AVMs had significantly higher rates of obliteration (68% vs 53%, p = 0.005) and favorable outcome (63% vs 51%, p = 0.033), with a trend toward a higher incidence of post-radiosurgery hemorrhage (10% vs 4%, p = 0.07). The annual post-radiosurgery hemorrhage rates were 0.8% for unruptured and 1.6% for ruptured AVMs. CONCLUSIONS Radiosurgery is a reasonable treatment option for pediatric AVMs. Obliteration and favorable outcomes are achieved in the majority of patients. The annual rate of latency period hemorrhage after radiosurgery for both ruptured and unruptured pediatric AVM patients conveys a significant risk until the nidus is obliterated.

Halimeda is a prominent part of the calcifying algae in the coral-reef lagoon ecosystems in the Caribbean. Experiments were performed on the Cayo Enrique Reef off Puerto Rico and in the laboratories of the University of Maryland to study factors influencing the calcification processes. Halimeda opuntia has a higher percentage of calcium carbonate than does Halimeda discoidea and a faster rate of incorporation. Halimeda opuntia and Halimeda discoidea show a stimulation of incorporation by light as well as a diurnal rhythm under identical conditions of illumination. Both phenomena parallel the rhythm of chloroplast migration within the plant. Calcification is also stimulated by the addition of carbon dioxide. Such evidence clearly indicated a light-linked mechanism which could involve photo-synthesis. However other metabolic processes, such as respiration, are also implicated. Aeration alone accelerates calcium incorporation. Nitrogen sources inhibit the incorporation of calcium during the day, indicating that cellular ammonia production is probably not responsible for precipitation. The differential wash-out rates of calcium absorbed during the day compared to those at night support the concept of a 2-step mechanism for calcification.