Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Surgical or Endovascular Management of Middle Cerebral Artery Aneurysms: A Randomized Comparison.

OBJECTIVE: There are few randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from patients with MCA aneurysms enrolled in the CURES (Collaborative UnRuptured Endovascular vs. Surgery) and ISAT-2 (International Subarachnoid Aneurysm Trial II) randomized trials. METHODS: Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-mm to 25-mm unruptured intracranial aneurysms (UIAs), and ISAT-2 includes patients with ruptured aneurysms (RA) for whom uncertainty remains after ISAT. The primary outcome measure of CURES is treatment failure: 1) failure to treat the aneurysm, 2) intracranial hemorrhage during follow-up, or 3) residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (modified Rankin Scale score >2) at 1 year. One-year angiographic outcomes are systematically recorded. RESULTS: There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 patients with UIA have been treated and 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to treatment failure in 3/42 (7%; 95% confidence interval [CI], 0.02-0.19) for clipping and 13/48 (27%; 95% CI, 0.17-0.41) for coiling (P = 0.025). All 71 patients with RA have been treated. In ISAT-2, patients with ruptured MCA aneurysms managed surgically had died or were dependent (modified Rankin Scale score >2) in 7/38 (18%; 95% CI, 0.09-0.33) cases, and 8/33 (24%; 95% CI, 0.13-0.41) for endovascular. One-year imaging results were available in 80 patients with UIA and 62 with RA. Complete aneurysm occlusion was found in 30/40 (75%; 95% CI, 0.60-0.86) patients with UIA allocated clipping, and 14/40 (35%; 95% CI, 0.22-0.50) patients with UIA allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%; 95% CI, 0.54-0.83) patients with RA allocated clipping, and 15/28 (54%; 95% CI, 0.36-0.70) patients with RA allocated coiling. CONCLUSIONS: Randomized data from 2 trials show that better efficacy may be obtained with surgical management of patients with MCA aneurysms.

Diagnostic Reliability of Leptomeningeal Disease Using Magnetic Resonance Imaging.

Brain metastases are seen in 20%-50% of patients with metastatic solid tumors. On the other hand, leptomeningeal disease (LMD) occurs more rarely. The gold standard for the diagnosis of LMD is serial cerebrospinal fluid (CSF) analyses, although in daily practice, the diagnosis of LMD is often made by neuroimaging. Leptomeningeal metastases (LM) have been a relative contra-indication to radiosurgery. It can be noted that focal LMD can be difficult to distinguish from a superficially located/cortical-based brain metastasis which is not a contra-indication for radiosurgery. Hence, justifying the need of a reliable diagnosis method. The goal of this study was to determine the inter-observer reliability of contrast-enhanced magnetic resonance imaging (gdMRI) in the differentiation of focal cortical-based metastases from leptomeningeal spread. This is a retrospective review of a prospectively collected database of patients with brain metastases. A total of 42 cases with superficial lesions were selected for review. Additionally, eight control cases demonstrating deep and/or white-matter based lesions were included in the study. Three neuroradiologists and three radiation oncologists were asked to review each study and score the presence of LM. Inter-observer agreement was calculated using group-derived agreement coefficients (Gwet's AC1 and Gwet's AC2). Pair-wise inter-observer agreement coefficients never reached substantial values for trichotomized outcomes (LMD, non-LMD or indeterminate) but did reach a substantial value in a minority of cases for dichotomised outcomes (LMD or non-LMD). The control subgroup analysis revealed substantial agreement between most pairs for both trichotomized and dichotomised outcomes. We observed low inter-observer agreement amongst specialists for the diagnosis of focal LMD by gdMRI. Neuroimaging should not be relied upon to make treatment decisions, notably to deny patients radiosurgery.

Subdural Metastasis of Prostate Cancer.

Dural metastasis from prostate cancer is rare and may mimic a subdural hematoma (SDH). Preoperatively diagnosis may be difficult and only reveal its presence during surgery. We present such a case and review the literature to identify common characteristics. A 65-year-old man presented with headache, confusion, and progressive right upper limb weakness. Past history included a prostate adenocarcinoma with bone metastasis 3 years earlier. Head computed tomography (CT) scan without contrast revealed a multinodular bilateral hyperdense extra-axial lesion interpreted as acute SDH. At surgery planned for SDH drainage no blood was found; instead there was an en plaque subdural yellowish tumor. Histopathologic examination was consistent with metastatic adenocarcinoma of the prostate. We found 11 cases reported as dural metastasis of prostate cancer mimicking SDH. Surgery was performed on nine cases with no suspicion of dural metastasis. On preoperative nonenhanced CT scan images, three types of image patterns can be described: a nodule in SDH, multinodular metastasis surrounded by SDH, and large en plaque subdural tumor. The latter group consists of those cases where no blood but rather an en plaque subdural tumor was found at surgery. Even though rare, dural metastasis should be considered among the differential diagnoses in a patient known for prostate cancer.

Value of 3.0 T MR imaging in refractory partial epilepsy and negative 1.5 T MRI.

BACKGROUND: High-field 3.0 T MR scanners provide an improved signal-to-noise ratio which can be translated in higher image resolution, possibly allowing critical detection of subtle epileptogenic lesions missed on standard-field 1.0-1.5 T MRIs. In this study, the authors explore the potential value of re-imaging at 3.0 T patients with refractory partial epilepsy and negative 1.5 T MRI. METHODS: We retrospectively identified all patients with refractory partial epilepsy candidate for surgery who had undergone a 3.0 T MR study after a negative 1.5 T MR study. High-field 3.0 T MRIs were reviewed qualitatively by neuroradiologists experienced in interpreting epilepsy studies with access to clinical information. Relevance and impact on clinical management were assessed by an epileptologist. RESULTS: Between November 2006 and August 2009, 36 patients with refractory partial epilepsy candidate for surgery underwent 3.0 T MR study after a 1.5 T MR study failed to disclose a relevant epileptogenic lesion. A potential lesion was found only in two patients (5.6%, 95% CI: 1.5-18.1%). Both were found to have hippocampal atrophy congruent with other presurgical localization techniques which resulted in omission of an invasive EEG study and direct passage to surgery. CONCLUSIONS: The frequency of detection of a new lesion by re-imaging at 3.0 T patients with refractory partial epilepsy candidate for surgery was found to be low, but seems to offer the potential of a significant clinical impact for selected patients. This finding needs to be validated in a prospective controlled study.

Arterial Onyx embolisation of intracranial DAVFs with cortical venous drainage.

PURPOSE: To present our experience with the endovascular management of intracranial dural arteriovenous fistulas with direct cortical venous drainage by trans-arterial embolisation using Onyx. MATERIALS & METHODS: Between January 2004 and April 2008, 12 consecutive high grade intracranial dural arteriovenous fistulas (Cognard type III (eight patients) or IV (three patients)) were treated by trans-arterial embolisation with Onyx. The majority of cases were treated by Onyx embolisation alone. One case had additional embolisation with n-butyl-2-cyanoacrylate at the same session. Imaging follow-up was obtained in all but one patient (mean 3.6 months). RESULTS: Nine patients had a technical success at the end of the embolisation procedure with complete angiographic exclusion of the fistula. Two patients had a small residual fistula at the end of embolisation, one of which had residual mild cortical venous drainage. Both were stable at follow-up angiography. One patient had a residual fistula supplied by the ophthalmic artery, which was thought to be unsafe to embolise and was sent for surgery, which was curative. In one patient the microcatheter ruptured, with a fragment of the distal microcatheter left in the occipital artery. No clinical complications were observed in this series at clinical follow-up (mean 3.3 months). Two patients were noted to have significant radiation dose. CONCLUSION: Endovascular management of intracranial dural arteriovenous fistulas with direct venous cortical drainage by trans-arterial Onyx embolisation is a safe and effective treatment according to our experience. Fluoroscopy times and radiation dose may be a concern.

A comparison of cervical spine motion during orotracheal intubation with the trachlight(r) or the flexible fiberoptic bronchoscope.

BACKGROUND: Tracheal intubation of an unstable cervical spine (c-spine) patient with the flexible fiberoptic bronchoscope (FOB) is thought to minimize c-spine movement but may be technically difficult in certain patients. Intubation using a luminous stylet, such as the Trachlight(R) (TL), also produces minimal motion of the c-spine and may be an interesting alternative technique for patients with an unstable c-spine. In this study, we compared the cervical motion caused by the TL and the FOB during intubation. METHODS: Twenty patients with a normal c-spine undergoing general anesthesia, including neuromuscular blockade, for a neuroradiologic intervention were included in a prospective, randomized, controlled, nonblinded, crossover trial. Each patient was tracheally intubated sequentially with the TL and the FOB in a randomized order. Manual in-line stabilization was applied by an assistant during intubation. The motions produced by intubation from the occiput (C0) to C5 were recorded in the sagittal plane using continuous cinefluoroscopy. For movement analysis, the recordings were divided into four stages: "baseline" before intubation began; "introduction" of the intubation device; "intubation" (passage of the tube through the vocal cords); and "removal" of the device. For each intubating device, the average maximal segmental motion observed in every patient at any stage or cervical segment was calculated and compared using Student's t-test. The time required to intubate with each device was also compared. RESULTS: There was no significant difference in the mean maximum segmental motion produced during intubation with the TL versus the FOB (12 degrees +/- 6 degrees vs 11 degrees +/- 5 degrees ; P = 0.5). Segmental movements occurred predominantly at the C0-1 and C1-2 levels, and maximal movements were observed during the introduction stage in 18/20 patients for both devices. Intubation took less time with the TL (34 +/- 17 vs 60 +/- 15 s, P < 0.001). CONCLUSION: In patients under general anesthesia with neuromuscular blockade and manual in-line stabilization, we found no difference in the segmental c-spine motion produced during endotracheal intubation using the FOB and the TL.

Cervical spine motion during tracheal intubation with manual in-line stabilization: direct laryngoscopy versus GlideScope videolaryngoscopy.

BACKGROUND: The optimal tracheal intubation technique for patients with potential cervical (C) spine injury remains controversial. Using continuous cinefluoroscopy, we conducted a prospective study comparing C-spine movement during intubation using direct laryngoscopy (DL) or GlideScope videolaryngoscopy (GVL), with uninterrupted manual in-line stabilization of the head by an assistant. METHODS: Twenty patients without C-spine pathology were studied. After induction of general anesthesia with neuromuscular blockade, both DL and GVL were performed on every patient in random order. Cinefluoroscopic images of C-spine movement during GVL and DL were acquired and divided into four stages: a baseline image before airway manipulation, glottic visualization, insertion of the endotracheal tube into the glottis, and tracheal intubation. Peak segmental motion from the occiput to C5 was measured offline for each patient and each stage, averages were calculated, and movements induced by each instrument were compared using a two-way ANOVA. Also studied were the proportion of patients with occiput-C1 rotation exceeding 10, 15, or 20 degrees, and the quality of glottic visualization. RESULTS: No significant difference was found between DL and GVL regarding average segmental spine movement at any level (P values between 0.22 and 0.70). During both techniques, motion was mainly an extension concentrated in the rostral C-spine and occurred predominantly during glottic visualization. The proportion of patients with occiput-C1 extension of more than 10, 15, or 20 degrees was not significantly different. Glottic visualization was significantly better with GVL compared with DL. CONCLUSION: During intubation under general anesthesia with neuromuscular blockade and manual in-line stabilization, the use of GVL produced better glottic visualization, but did not significantly decrease movement of the nonpathologic C-spine when compared with DL.

Selective treatment of an anterior spinal artery aneurysm with endosaccular coil therapy. Case report.

The authors report the case of a 12-year-old boy with spinal cord arteriovenous malformation (AVM) and an associated anterior spinal artery (ASA) aneurysm treated with selective coil placement in the context of subarachnoid hemorrhage (SAH). The patient presented with headache. Head computed tomography scanning revealed no abnormal findings. The cerebrospinal fluid was sampled and analyzed and a diagnosis of SAH was established. Investigation, including magnetic resonance imaging of the cord as well as cerebral and spinal angiography, revealed a conus medullaris AVM and a saccular aneurysm located on the ASA at the T-11 level. The aneurysm was thought to be responsible for the bleeding. Superselective ASA angiography showed that the aneurysm was at the bifurcation between a large coronal artery supplying the AVM and the ASA. The relation of the aneurysm's neck to the main spinal axis and the aneurysm's morphological features indicated that the lesion was suited for endosaccular coil therapy. The aneurysm was selectively occluded, using electrodetachable bare platinum coils. Follow-up angiography immediately after surgery and at 6 months thereafter demonstrated complete occlusion of the aneurysm and a perfectly patent anterior spinal axis. On clinical follow-up examination, the patient remained neurologically intact. When the morphological features of a spinal aneurysm and its relation with the anterior spinal axis are favorable, selective endosaccular coil placement can successfully be achieved.

In situ beta-irradiation of a brain arteriovenous malformation model.

BACKGROUND AND PURPOSE: The treatment of large brain arteriovenous malformations (BAVMs) is challenging, and embolization alone is seldom curative. The study goal is to enhance the efficacy of arteriovenous malformation embolization by adding a beta-emitting isotope to the embolic agent. METHODS: The pig rete mirabile was used as a BAVM model. The body distribution of radioactivity was evaluated after selective rete injection of N-butyl,2-cyanoacrylate mixed with (131)I-lipiodol in 8 animals using immediate whole body gamma-scintigraphy. Activities within the whole rete mirabile and selected tissue samples were quantified with a gamma counter immediately after sacrifice. Two pigs were submitted to serial gamma-scintigraphies for 6 weeks to detect delayed isotope leaching. Long-term effects of in situ irradiation were evaluated using a mixture of 188Re/N-butyl,2-cyanoacrylate in 8 pigs. In 1 animal, autoradiography was performed to evaluate local rete mirabile distribution of the radioactivity. Seven pigs were injected with 188Re/glue in 1 rete mirabile and with glue only on the opposite side, and the degree of vascular occlusion of both sides was compared on histology at 2 (n=2) or 6 months (n=5). RESULTS: There was negligible activity outside the target. Radiation caused occlusion of vessels unreached by the glue itself but in the vicinity of the radioactive source in 5 of 7 rete mirabile. CONCLUSIONS: Selective deposition of a beta-emitter inside a BAVM model may be achieved by current embolization techniques. The adjunct use of an isotope may increase the efficacy of embolization.

Surgical construction of an in vivo carotid siphon model to test neurovascular devices.

OBJECTIVE: We developed an animal model to evaluate vascular trauma induced by endovascular devices that are proposed for the treatment of cerebrovascular diseases. METHODS: The model was constructed in six domestic swine by elongating the common carotid artery using interpositional grafts. Balloon catheters (n = 3), stents (n = 2), and a snare were tested 9 to 13 days after surgery. Device performance was evaluated by angiography, macroscopic photography, and histopathological examination. RESULTS: Animals tolerated the surgical procedure well, and artificial siphons were thought to provide realistic conditions for device testing. Balloon catheters induced minimal trauma, whereas coronary stents caused severe spasm or thrombosis and extensive macroscopic changes. CONCLUSION: Construction of an in vivo siphon model is feasible and potentially useful for testing neurovascular devices.

Endovascular treatment of intracranial aneurysms with radioactive coils: initial clinical experience.

BACKGROUND AND PURPOSE: Endovascular treatment of intracranial aneurysms is safe and effective but is associated with angiographic recurrences. Beta radiation prevents recanalization after coil embolization in experimental models. We wanted to assess the feasibility of using radioactive coil embolization to improve long-term results of endovascular treatment. METHODS: Platinum coils were ion-implanted with 0.13 to 0.26 microCi/cm of 32P. Forty-one patients aged 34 to 84 years with 44 aneurysms with a high propensity for recurrences were included. Radioactive coils were introduced into aneurysms to reach a target volumetric activity of 0.018 microCi/mm3. Nonradioactive coils were also used to ensure the same safety and the same angiographic results as the standard procedure. Angiographic results, procedure-related complications, and neurological events during follow-up were recorded. Angiographic follow-up data are available in 36 lesions 6 months after treatment. RESULTS: Forty of 44 aneurysms (91%) could be treated with radioactive coils. Target activities could be reached in 88% of lesions that could actually be coiled (35/40). Total activities ranged from 1.72 to 80.9 microCi, for a mean of 20.13+/-20.80 microCi. Procedure-related complications occurred in 7% of patients. Initial angiographic results were satisfactory (complete occlusions or residual necks) in 75% of lesions. Angiographic recurrences occurred in 11 (31%) of patients followed, within the expected range for standard coils. There was no complication from beta radiation during a mean follow-up period of 10 months. CONCLUSIONS: Radioactive coil embolization is feasible; target volumetric activities can be reached in most aneurysms considered for endovascular treatment.

High-concentration ethylene-vinyl alcohol copolymer and endovascular treatment of experimental aneurysms: feasibility of embolization without protection devices at the neck.

BACKGROUND AND PURPOSE: Coiling of intracranial aneurysms is both safe and effective but may be followed by recurrences. The purpose of this study was to assess the feasibility of endovascular treatment of aneurysms with high-concentration ethylene-vinyl alcohol copolymer (HCEVOH), without the use of protection devices at the neck. METHODS: Wide-necked bifurcation aneurysms with a high propensity for recurrences were constructed in 22 dogs. HCEVOH embolization was performed with a dedicated high-pressure microcatheter in 12 animals. Angiographic results at 3 and 12 weeks and pathologic results at 12 weeks were compared with those of a separate group of 10 animals treated with platinum coils. We used a qualitative scoring system to grade angiographic results, neointima formation, and recanalization at the neck. RESULTS: Intraaneurysmal HCEVOH injections could be performed without carotid emboli and without a protection device in 11 of 12 animals. Fragments detached upon traction of the microcatheters at the end of the procedure on two occasions. Immediate and late angiographic results were not significantly different between the two groups (P =.807), with a tendency for angiographic recurrences at 3 months (angiographic scores were significantly worse in both groups at 12 weeks as compared with T0 [P <.02]). A complete occlusion, including the neck, even at the cost of protrusion of material at the level of the branches, is necessary to decrease risks of recurrences. Neointima formation at the surface of the embolic agent was complete at the neck of aneurysms treated with HCEVOH. The neointimal score was significantly improved with HCEVOH as compared with coil embolization (P =.03). CONCLUSION: HCEVOH embolization of aneurysms without neck protection is feasible. It does not, however, eliminate recurrences in an experimental wide-necked aneurysm model.

Long-term angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils.

BACKGROUND AND PURPOSE: Our aim in this study was to assess the incidence and determining factors of angiographic recurrences after endovascular treatment of aneurysms. METHODS: A retrospective analysis of all patients with selective endosaccular coil occlusion of intracranial aneurysms prospectively collected from 1992 to 2002 was performed. There were 501 aneurysms in 466 patients (mean+/-SD age, 54.20+/-12.54 years; 74% female). Aneurysms were acutely ruptured (54.1%) or unruptured (45.9%). Mean+/-SD aneurysm size was 9.67+/-5.91 mm with a 4.31+/-1.97-mm neck. The most frequent sites were basilar bifurcation (27.7%) and carotid ophthalmic (18.0%) aneurysms. Recurrences were subjectively divided into minor and major (ideally necessitating re-treatment). The most significant predictors of angiographic recurrence were determined by logistic regression. These results were confirmed by chi2, t tests, or ANOVAs followed, when appropriate, by Tukey's contrasts. RESULTS: Short-term (< or =1 year) follow-up angiograms were available in 353 aneurysms (70.5%) and long-term (>1 year) follow-up angiograms, in 277 (55%), for a total of 383 (76.5%) followed up. Recurrences were found in 33.6% of treated aneurysms that were followed up and that appeared at a mean+/-SD time of 12.31+/-11.33 months after treatment. Major recurrences presented in 20.7% and appeared at a mean of 16.49+/-15.93 months. Three patients (0.8%) bled during a mean clinical follow-up period of 31.32+/-24.96 months. Variables determined to be significant predictors (P<0.05) of a recurrence included aneurysm size > or =10 mm, treatment during the acute phase of rupture, incomplete initial occlusions, and duration of follow-up. CONCLUSIONS: Long-term monitoring of patients treated by endosaccular coiling is mandatory.

Feasibility of radioactive embolization of intracranial aneurysms using 32P-implanted coils.

BACKGROUND AND PURPOSE: Beta radiation can prevent recanalization after embolization. Our goal was to assess the feasibility of endovascular treatment of intracranial aneurysms using coils of a predetermined activity of 32P per centimeter. METHODS: We studied the total length of coils deployed into 357 intracranial aneurysms. Aneurysmal volumes were estimated using 3 mathematical models. We simulated that coils were implanted with 0.26 microCi/cm of 32P, calculated resulting volumetric activities, and compared them with "effective" levels derived from experimental data and "safe" levels prescribed for the clinical use of 32P in cystic craniopharyngiomas. RESULTS: Effective activities would have been reached in 92% to 98% of lesions had the coils been radioactive at the time of treatment. CONCLUSIONS: Radioactive coil embolization of aneurysms is feasible in most patients.

Endovascular treatment of experimental wide neck aneurysms: comparison of results using coils or cyanoacrylate with the assistance of an aneurysm neck bridge device.

BACKGROUND AND PURPOSE: Endovascular treatment of wide neck aneurysms often results in incomplete occlusion or aneurysm recurrence. The two goals of the present study were to compare results of coil embolization with or without the assistance of an aneurysm neck bridge device (ANBD) and to explore the use of this instrument to control cyanoacrylate embolization. METHODS: Wide necked bifurcation aneurysms were constructed in 28 dogs. Coil embolization of the aneurysms was performed 2 to 4 weeks later, with (n = 11) or without (n = 10) ANBD assistance. In seven other animals, embolization was performed with cyanoacrylate, injected under the protection of ANBDs. Angiographic results were compared immediately after and at 3 and 12 weeks. Neointima formation at the neck was also compared between groups at 12 weeks. RESULTS: Initial angiographic results and recurrences at 12 weeks were not significantly different in aneurysms coiled with or without ANBDs. Neointimal scores were also similar. The use of one ANBD at the neck was not sufficient to safely deliver cyanoacrylate into aneurysms. Cyanoacrylate embolization led to improved angiographic results (P =.05) and to better neointimal sealing of the neck of the aneurysms at 12 weeks (P =.004). CONCLUSION: ANBDs did not prevent recanalization and recurrences after coil embolization of wide neck aneurysms in this animal study. ANBD-assisted cyanoacrylate embolization was unsafe but could decrease recurrences at 12 weeks.