Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

Object: Microarteriovenous malformations (micro-AVMs) are a rare subgroup of brain AVMs characterized by a nidus smaller than 1 cm. The authors' purpose in this study was to assess the clinical presentation, radiological features, therapeutic management, and outcome of these lesions. Methods: All angiography studies performed at the authors' institution since 2000 for the diagnosis of AVM were retrospectively reviewed. Clinicoradiological findings, therapeutic management, and outcome were evaluated. Results: Twenty-eight patients had presented with AVMs having a nidus diameter smaller than 1 cm or no clearly identifiable nidus but an early draining vein. All patients, except 2, presented with intracranial hemorrhage, and 12 patients had a focal deficit. Supratentorial hematomas were large (mean volume 25 ml), and in 8 patients hematomas were evacuated urgently. In 6 patients cerebral digital subtraction angiography studies were normal. Magnetic resonance imaging and dynamic MR angiography revealed an AVM in 4 of these 6 patients. Treatment of the AVM consisted of surgery in 16 cases, radiosurgery in 6, and endovascular embolization in 2, and there were no posttreatment deficits. Four patients received no treatment because of their poor condition. The AVM was occluded at the follow-up in all patients treated with surgery or embolization and in 4 of the 6 patients treated with radiosurgery. The Glasgow Outcome Scale (GOS) score was good (GOS 4–5) in 23 patients (82%) and poor (GOS 3–2) in 5 (18%). Conclusions: Patients with micro-AVMs generally present with large intracranial hemorrhages and neurological deficits. If the initial angiography is negative, then delayed or superselective angiography is recommended. Magnetic resonance imaging may reveal the existence of these lesions. Surgery is the treatment of choice for superficial micro-AVMs, and radiosurgery or embolization can be considered for deep lesions.

In the past, several possible explanations for idiopathic subarachnoid hemorrhage (ISAH) have been proposed; however, neuroimaging studies have never provided conclusive data about the structural cause of the bleeding. The aim of this study is to determine whether there are anatomic differences in the deep cerebral venous drainage in patients with ISAH compared with those with aneurysmal subarachnoid hemorrhage (ASAH) and those without intracranial hemorrhage. We reviewed the venous phase of carotid digital angiograms of 100 consecutive patients who had a final diagnosis of ISAH. We also analyzed the angiograms of a control group of 112 patients with ASAH and the angiograms of a nonhemorrhagic group of 25 patients having incidental aneurysms. The anatomic variants of the basal vein of Rosenthal (BVR) on both sides were classified into the following types: Type A (normal continuous), in which the BVR is continuous with the deep middle cerebral veins and drains mainly into the vein of Galen; Type B (normal discontinuous), in which there is discontinuous venous drainage, anterior to the uncal vein and posterior to the vein of Galen; and Type C (primitive), which drains mainly to veins other than the vein of Galen. We calculated the proportions to analyze the differences in the type of venous drainage between patients with ISAH, patients with ASAH, and patients without hemorrhage. χ² statistics were used to search for differences. Types A and C venous drainage were present in 23.8 and 32.3%, respectively, of patients with ISAH compared with 58.7 and 15.4%, respectively, in the ASAH group and 57.5 and 5%, respectively, in the nonhemorrhagic group (P < 0.001). A primitive variant was present in at least 1 hemisphere in 38 patients with ISAH (41.8% of the cases) compared with 24 patients with ASAH (21.4%) and 2 patients (8%) in the nonhemorrhagic group (P < 0.001). In patients with ISAH, deep cerebral venous drainage more commonly drains directly into dural sinuses instead of via the vein of Galen compared with patients with ASAH and patients without intracranial hemorrhage. The way in which this venous configuration might influence bleeding remains unknown.

Cranioplasties are performed to protect the brain and correct cosmetic defects, but there is growing evidence that this procedure may result in neurological improvement. We prospectively studied cranioplasties performed at our hospital over a 5-year period. The National Institute of Health Stroke Scale and Barthel index were recorded prior to and within 72 h after the cranioplasty. A perfusion computed tomography (PCT) and transcranial Doppler sonography (TCDS) were performed prior to and 72 h after the surgery. For the PCT, regions irrigated by the anterior cerebral artery, the middle cerebral artery (MCA), the posterior cerebral artery, and the basal ganglia were selected, as well as the mean values for the hemisphere. The sonography was performed in the sitting and the supine position for the MCA and internal carotid. The velocities, pulsatility index, resistance index, and Lindegaard ratio (LR) were obtained, as well as a variation value for the LR (ΔLR = LR sitting – LR supine). Fifty-four patients were included in the study. Of these, 23 (42.6%) patients presented with objective improvement. The mean cerebral blood flow of the defective side (m-CBF-d) increased from 101.86 to 117.17 mL/100 g/min ( p = 0.064), and the m-CBF of the healthy side (m-CBF-h) increased from 128.14 to 145.73 mL/100 g/min ( p = 0.028). With regard to the TCDS, the ΔLR was greater on the defective side prior the surgery in those patients who showed improvement (1.295 vs. −0.714; p = 0.002). Cranioplasty resulted in clinical improvement in 40% of the patients, with an increase in the post-surgical CBF. The larger variations in the LR when the patient is moved from the sitting to the supine position might predict the clinical improvement.