Intrathrombus polymer coating deposition: a pilot study of 91 patients undergoing endovascular therapy for acute large vessel stroke. Part I: Histologic frequency.

BACKGROUND: Polymer coating embolism due to vascular medical device use is an increasingly recognized iatrogenic complication. This phenomenon has been linked with various adverse effects including neuroinflammation, acute ischemic stroke, cerebral hemorrhage, and death. Notably, procedure- and device-specific risks of this complication are poorly investigated. In this study, we evaluate the detectable frequency of intra-arterial polymer coating delamination among patients who underwent endovascular thrombectomy for treatment of acute ischemic stroke due to large vessel occlusion. METHODS: Ninety-two cerebral thrombectomy specimens were retrospectively analyzed for the presence of polymer coating particulates. Histologic findings were correlated with demographic and procedural details and patient outcomes. RESULTS: Evidence of polymer coating deposition was found in 30 of 92 extracted thrombi (33%). No correlation between intrathrombus polymer deposition and use of a specific thrombectomy device such as a stent retriever, aspiration catheter, or guide catheter was found. However, heterogeneous patterns of device use suggest a number of culprit devices. A trend toward longer procedure times and multiple thrombectomy passes was noted in positive cases. Intrathrombus polymer deposition was not associated with adverse clinical outcomes as measured by the 90-day modified Rankin Scale (mRS); however, small sample size and follow-up intervals limit interpretation. Ninety-day outcomes based on mRS may not fully capture the clinical effects of acute and/or delayed intracerebral polymer complications. CONCLUSION: In light of documented adverse neurologic effects, the frequency of intrathrombus polymer particulates indicates the need for consensus testing methods and large-scale long-term prospective clinical device trials, with inclusion of relevant endpoints to better assess biomaterial and device risks to patients.

Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome.

BACKGROUND: Promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. To determine the prognostic significance of MGMT protein expression as assessed by immunohistochemistry (IHC) and its relationship with methylation, we analyzed MGMT expression and promoter methylation with survival in a retrospective patient cohort. METHODS: We identified 418 patients with newly diagnosed GBM at University of California Los Angeles Kaiser Permanente Los Angeles, nearly all of whom received chemoradiation, and determined MGMT expression by IHC, and MGMT promoter methylation by methylation-specific PCR (MSP) and bisulfite sequencing (BiSEQ) of 24 neighboring CpG sites. RESULTS: With use of the median percentage of cells staining by IHC as the threshold, patients with <30% staining had progression-free survival (PFS) of 10.9 months and overall survival (OS) of 20.5 months, compared with PFS of 7.8 months (P < .0001) and OS of 16.7 months (P < .0001) among patients with ≥30% staining. Inter- and intrareader correlation of IHC staining was high. Promoter methylation status by MSP was correlated with IHC staining. However, low IHC staining was frequently observed in the absence of promoter methylation. Increased methylation density determined by BiSEQ correlated with both decreased IHC staining and increased survival, providing a practical semiquantitative alternative to MSP. On the basis of multivariate analysis validated by bootstrap analysis, patients with tandem promoter methylation and low expression demonstrated improved OS and PFS, compared with the other combinations. CONCLUSIONS: Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.

Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin.

PURPOSE: Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1(R132MUT)) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1(R132MUT) differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1(R132) mutation status. PATIENTS AND METHODS: In all, 618 treatment-naive primary GBMs and 235 lower-grade diffuse gliomas were sequenced for IDH1(R132) and analyzed for demographic, radiographic, anatomic, histologic, genomic, epigenetic, and transcriptional characteristics. RESULTS: Investigation revealed a constellation of features that distinguishes IDH1(R132MUT) GBMs from other GBMs (including frontal location and lesser extent of contrast enhancement and necrosis), relates them to lower-grade IDH1(R132MUT) gliomas, and supports the concept that IDH1(R132MUT) gliomas arise from a neural precursor population that is spatially and temporally restricted in the brain. The observed patterns of DNA sequence, methylation, and copy number alterations support a model of ordered molecular evolution of IDH1(R132MUT) GBM in which the appearance of mutant IDH1 protein is an initial event, followed by production of p53 mutant protein, and finally by copy number alterations of PTEN and EGFR. CONCLUSION: Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.

Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.

PURPOSE: This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. PATIENTS AND METHODS: Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. RESULTS: The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. CONCLUSION: Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

Rosette-forming glioneuronal tumor: a pineal region case with IDH1 and IDH2 mutation analyses and literature review of 43 cases.

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a mixed glio-neuronal neoplasm recently codified by the World Health Organization WHO Classification of Central Nervous System (CNS) Tumors (2007). To date, 43 cases have been described in the literature; most occurring in the fourth ventricle region. We report the fourth case involving the pineal region in a 16-year-old female with signs of increased intracranial pressure (ICP). A stereotactic biopsy of the mass was followed by a debulking procedure. Both specimens revealed classic RGNT histology. The patient had stable scans 7 months post-resection. The clinical, radiological and histopathologic features of the previously described 43 cases are reviewed along with our illustrative case. Mean age of patients was 30 ± 12.8 years with 1.9:1 female to male ratio. The most common presenting signs related to increased ICP and posterior fossa involvement, including: headache (62.8%), ataxia (39.5%) and vomiting and vertigo (both 16.3%). This tumor usually presents with cystic changes (54.5%) with focal enhancement (60.9%) and hydrocephalus (43.2%). Microcalcifications and satellite lesions were common radiographic observations. All reported cases had the classic biphasic pattern. Rosenthal fibers and eosinophilic granular bodies are each present in approximately two thirds of cases. Ki-67 labeling index is consistently low (mean (%): 1.8 ± 0.75 SD). The isocitrate dehydrogenase 1 or 2 mutation found in low grade diffuse gliomas is not identified in this RGNT case. Reported outcome is nearly uniformly excellent after complete or subtotal resection. A solitary report of recurrence after 10 years and the limited experience with this entity suggest that long term follow up is advisable.

"Fantastic thinking" in pathologically proven Pick disease.

BACKGROUND: Reports of false beliefs may be a unique feature of behavioral variant frontotemporal dementia (bvFTD) but the nature of these experiences is unclear. OBJECTIVE: To report a case of pathologically verified Pick disease in a patient presenting with prominent and recurrent fantasies. METHODS: We describe the clinical, neuroradiologic, and neuropathologic findings of a 53-year-old woman presenting with fantasies and meeting Clinical Consensus Criteria for bvFTD. RESULTS: Early in her course, she reported interactions with different actors, having torrid affairs with them, and other related fantasies. When confronted with her false beliefs, she admitted that these relationships were imaginary. Autopsy revealed Pick disease with tau-immunoreactive Pick bodies in the frontal and temporal cortices, and in the hippocampi. CONCLUSIONS: Fantastic thinking, or vividly experienced imagination, may be a manifestation of bvFTD that is distinct from delusions and confabulations and could be the source of previously reported delusions and confabulations in bvFTD.

Hydrophilic polymer emboli: an under-recognized iatrogenic cause of ischemia and infarct.

With the increased use of percutaneous intravascular diagnostic and therapeutic devices, there is potential for embolization of materials introduced into the vasculature. We report nine cases of foreign body emboli in patients who underwent vascular procedures using hydrophilic-coated medical devices. The procedures performed included cardiac catheterization (four cases), diagnostic cerebral angiography (two cases), therapeutic cerebral angiography with coil embolization of intracerebral aneurysm (one case), lower extremity angiography (one case), and/or orthotopic cadaveric organ transplantation (three cases). Other procedures in these patients included hemodialysis and peripheral arterial or central venous catheterization. Clinical sequelae ranged from undetectable (no symptoms) to pulmonary infarction, stroke, ongoing gangrene, and/or death occurring within days to weeks of suspected embolization of foreign material. Microscopic findings in biopsy or autopsy tissue revealed aggregates of amorphous or lamellated, non-refractile, non-polarizable, predominantly basophilic foreign substances occluding intrapulmonary, intracerebral, or peripheral arteries. This is the largest series documenting embolization of polymer gel materials. Polymer gel is now widely used on several devices for interventional procedures worldwide, and we suspect that complications associated with iatrogenic embolization of this substance are under-recognized.

Primary angiitis of the CNS (PACNS) with predominant cranial neuropathy and spinal cord involvement.

We describe a 70-year old man with a history of repeated epidural injections for chronic low back pain, presenting with headache, cranial nerve palsies and progressive myelopathy. Meningeal enhancement was initially seen in the posterior epidural space of the T(10)-T(12) spine on MRI. Extensive laboratory investigation showed normal or negative results except for persistent pleocytosis, elevated protein and absence of demonstrable microorganisms on CSF studies. Despite conventional and empirical treatments, the patient developed progressive neurological deterioration leading to death. Autopsy showed Primary angiitis of the CNS (PACNS) with predominant cranial neuropathy, spinal cord involvement and extensive myelomalacia.

Intravascular polymer material after coil embolization of a giant cerebral aneurysm.

We report the case of an 87-year-old female who died after coil embolization of an intracerebral giant aneurysm. Guglielmi detachable (Boston Scientific Neurovascular, Fremont, CA) and Matrix2 coils (Boston Scientific Neurovascular, Fremont, CA) were used during the procedure to occlude the surgically untreatable left supraclinoid carotid artery aneurysm. Postprocedure imaging studies showed scattered areas of acute infarct involving multiple bilateral vascular territories. Autopsy confirmed widespread infarction due to embolized foreign material, morphologically consistent with hydrophilic polymer originating from the coated Matrix coil and Terumo glidewire (Terumo Medical, Somerset, NJ). Polymer gel is now widely used on several medical devices for interventional procedures worldwide, and we suspect that risks associated with iatrogenic embolization of this substance are underrecognized.