Case report: Fractional brain tumor burden magnetic resonance mapping to assess response to pulsed low-dose-rate radiotherapy in newly-diagnosed glioblastoma.

Background: Pulsed low-dose-rate radiotherapy (pLDR) is a commonly used reirradiation technique for recurrent glioma, but its upfront use with temozolomide (TMZ) following primary resection of glioblastoma is currently under investigation. Because standard magnetic resonance imaging (MRI) has limitations in differentiating treatment effect from tumor progression in such applications, perfusion-weighted MRI (PWI) can be used to create fractional tumor burden (FTB) maps to spatially distinguish active tumor from treatment-related effect. Methods: We performed PWI prior to re-resection in four patients with glioblastoma who had undergone upfront pLDR concurrent with TMZ who had radiographic suspicion for tumor progression at a median of 3 months (0-5 months or 0-143 days) post-pLDR. The pathologic diagnosis was compared to retrospectively-generated FTB maps. Results: The median patient age was 55.5 years (50-60 years). All were male with IDH-wild type (n=4) and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylated (n=1) molecular markers. Pathologic diagnosis revealed treatment effect (n=2), a mixture of viable tumor and treatment effect (n=1), or viable tumor (n=1). In 3 of 4 cases, FTB maps were indicative of lesion volumes being comprised predominantly of treatment effect with enhancing tumor volumes comprised of a median of 6.8% vascular tumor (6.4-16.4%). Conclusion: This case series provides insight into the radiographic response to upfront pLDR and TMZ and the role for FTB mapping to distinguish tumor progression from treatment effect prior to redo-surgery and within 20 weeks post-radiation.

Intracranial Capillary Hemangiomas: A Peripartum Presentation and Review of the Literature.

BACKGROUND: Intracranial capillary hemangiomas (ICHs) are rare vascular tumors composed of a bed of many narrow thin-walled vessels. Within the confines of the skull, these tumors can lead to serious neurologic deficits including cranial nerve dysfunction, mood/personality disturbances, and signs of intracranial mass effect. METHODS: We report the case of a 23-year-old, 5-week postpartum woman with a history of progressive painful ophthalmalgia of the right eye presenting with rapid onset of ptosis, diplopia, and right-sided facial pain and hypesthesia. Imaging demonstrated a small extraaxial mass within the right cavernous sinus. She underwent 2 operations via an endoscopic endonasal approach for biopsy followed by complete resection. Histology showed a highly mitotic capillary hemangioma, which was negative for both estrogen and progesterone receptors. RESULTS: We review cases of ICH reported in the literature and provide an updated summary of the presentation, diagnosis, and treatment of ICH. We then present a brief analysis of the reported cases with respect to age and sex. CONCLUSIONS: We conclude that, in experienced hands, the endoscopic endonasal approach can be used to access the cavernous sinus for complete resection of ICHs of the cavernous sinus. We also suggest that further attention be paid to such cases in pregnant and peripartum women as these tumors may progress more quickly in this subpopulation.

Radiomic Features of Multiparametric MRI Present Stable Associations With Analogous Histological Features in Patients With Brain Cancer.

Magnetic resonance (MR)-derived radiomic features have shown substantial predictive utility in modeling different prognostic factors of glioblastoma and other brain cancers. However, the biological relationship underpinning these predictive models has been largely unstudied, and the generalizability of these models had been called into question. Here, we examine the localized relationship between MR-derived radiomic features and histology-derived "histomic" features using a data set of 16 patients with brain cancer. Tile-based radiomic features were collected on T1, post-contrast T1, FLAIR, and diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC) images acquired before patient death, with analogous histomic features collected for autopsy samples coregistered to the magnetic resonance imaging. Features were collected for each original image, as well as a 3D wavelet decomposition of each image, resulting in 837 features per MR and histology image. Correlative analyses were used to assess the degree of association between radiomic-histomic pairs for each magnetic resonance imaging. The influence of several confounds was also assessed using linear mixed-effect models for the normalized radiomic-histomic distance, testing for main effects of different acquisition field strengths. Results as a whole were largely heterogeneous, but several features showed substantial associations with their histomic analogs, particularly those derived from the FLAIR and postcontrast T1W images. These features with the strongest association typically presented as stable across field strengths as well. These data suggest that a subset of radiomic features can consistently capture texture information on underlying tissue histology.

Intravascular Papillary Endothelial Hyperplasia of the Pineal Region: A Case Report and Review of the Literature.

BACKGROUND: Intravascular papillary endothelial hyperplasia (IPEH) is a benign vascular lesion that is uncommon in the central nervous system. To our knowledge, there has been only one previous report of occurrence in the pineal region. We present a second case and a review of the literature. CASE DESCRIPTION: A 28-year-old woman presented with 1 month of headaches and visual auras. Brain magnetic resonance imaging scan demonstrated a 2.6- × 1.8- × 1.3-cm nonenhancing T1-hypointense, T2-/fluid-attenuated inversion recovery-hyperintense pineal region mass with cerebral aqueduct obstruction and hydrocephalus. She underwent placement of a right extraventricular drain followed by complete surgical resection. Histologic analysis was consistent with IPEH. CONCLUSIONS: Although rare, IPEH is an entity that should be considered in the differential diagnosis for intracranial masses with radiographic features characteristic of vascular lesions. Tissue sampling is imperative for distinction from more malignant entities. Complete resection is curative and is the standard of care when feasible. Given the risk of local progression and neurologic compromise with subtotal resection of central nervous system lesions, further study regarding adjuvant treatment options is warranted.

Longitudinal molecular trajectories of diffuse glioma in adults.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Cerebral Trypanosomiasis in an Immunocompromised Patient: Case Report and Review of the Literature.

BACKGROUND: We document a case of central nervous system infection with Trypanosoma cruzi. CASE DESCRIPTION: An 88-year-old woman presented with altered mental status, right-sided weakness, and slurred speech. Her medical history was significant for methotrexate intake for rheumatoid arthritis, and she tested negative for human immunodeficiency virus. Magnetic resonance imaging of the brain showed bilateral thick and peripherally enhancing white matter lesions in the frontoparietal region with extensive surrounding vasogenic edema. A lumbar puncture revealed increased protein and lymphocytic pleocytosis, and needle biopsy highlighted brain necrosis, chronic inflammation, and numerous intracellular organisms suggestive of T. cruzi amastigotes. Despite treatment with benznidazole, the patient expired soon after presentation. CONCLUSION: Chagas disease should be included in the differential diagnosis of an immunocompromised patient presenting with a central nervous system mass, meningoencephalitis, or focal neurologic signs.

Spatial discrimination of glioblastoma and treatment effect with histologically-validated perfusion and diffusion magnetic resonance imaging metrics.

The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency.

Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies. Proteomic analysis of more than 600 glioblastoma-specific proteins revealed, for the first time, that expression of acid ceramidase (ASAH1) is associated with poor glioblastoma survival. CD133+ GSCs express significantly higher ASAH1 compared to CD133- GSCs and serum-cultured glioblastoma cell lines, such as U87MG. These findings implicate ASAH1 as a plausible independent prognostic marker, providing a target for a therapy tailored toward GSCs. We further demonstrate that ASAH1 inhibition increases cellular ceramide level and induces apoptosis. Strikingly, U87MG cells, and three different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50's ranging from 11-104 µM. In comparison, the standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 µM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials.

Magnetic Resonance Imaging-Based Radiomic Profiles Predict Patient Prognosis in Newly Diagnosed Glioblastoma Before Therapy.

Magnetic resonance imaging (MRI) is used to diagnose and monitor brain tumors. Extracting additional information from medical imaging and relating it to a clinical variable of interest is broadly defined as radiomics. Here, multiparametric MRI radiomic profiles (RPs) of de novo glioblastoma (GBM) brain tumors is related with patient prognosis. Clinical imaging from 81 patients with GBM before surgery was analyzed. Four MRI contrasts were aligned, masked by margins defined by gadolinium contrast enhancement and T2/fluid attenuated inversion recovery hyperintensity, and contoured based on image intensity. These segmentations were combined for visualization and quantification by assigning a 4-digit numerical code to each voxel to indicate the segmented RP. Each RP volume was then compared with overall survival. A combined classifier was then generated on the basis of significant RPs and optimized volume thresholds. Five RPs were predictive of overall survival before therapy. Combining the RP classifiers into a single prognostic score predicted patient survival better than each alone (P < .005). Voxels coded with 1 RP associated with poor prognosis were pathologically confirmed to contain hypercellular tumor. This study applies radiomic profiling to de novo patients with GBM to determine imaging signatures associated with poor prognosis at tumor diagnosis. This tool may be useful for planning surgical resection or radiation treatment margins.

Spinal osteoblastic meningioma with hematopoiesis: radiologic-pathologic correlation and review of the literature.

Spinal meningiomas associated with bone formation and hematopoiesis are rare tumors with only 3 prior case reports in the literature. We describe a case report of a woman who presented with back pain and an isolated event of urinary incontinence. A calcified spinal canal mass at T8 was identified on computed tomographic and magnetic resonance imaging. A gross total resection of the tumor was performed and pathologic examination showed a meningioma, World Health Organization grade 1, containing bone and bone marrow elements. A review of previously reported cases and a discussion of possible mechanisms of bone and hematopoiesis development in meningioma are presented.

Extradural chondroma presenting as lumbar mass with compressive neuropathy.

The identification of a soft tissue chondroma within the spine represents a rarity and is typically not included within the differential diagnosis for patients with sensory complaints of the leg. The authors describe 46-year-old female presenting with 3-week history of decreased sensation and paresthesias of the left leg. Magnetic resonance imaging of the lumbar spine demonstrated an L3 extradural soft tissue mass. She underwent an uncomplicated excision through an L3 laminectomy and exhibited complete resolution of symptoms. Pathologic examination revealed benign cartilaginous tissue; however, the authors recommend long-term follow-up for such lesions as the potential for malignant transformation is unknown.

Precise ex vivo histological validation of heightened cellularity and diffusion-restricted necrosis in regions of dark apparent diffusion coefficient in 7 cases of high-grade glioma.

BACKGROUND: Recent conflicting reports have found both brain tumor hypercellularity and necrosis in regions of restricted diffusion on MRI-derived apparent diffusion coefficient (ADC) images. This study precisely compares ADC and cell density voxel by voxel using postmortem human whole brain samples. METHODS: Patients with meningioma were evaluated to determine a normative ADC distribution within benign fluid attenuated inversion recovery (FLAIR) T2/hyperintensity surrounding tumor. This distribution was used to calculate a minimum ADC threshold to define regions of ADC-FLAIR mismatch (AFMM), where restricted diffusion presented in conjunction with T2/FLAIR hyperintensity. Contrast-enhancing voxels were excluded from this analysis. AFMM maps were generated using imaging acquired prior to death in 7 patients with high-grade glioma who eventually donated their brains upon death. Histological samples were taken from numerous regions of abnormal FLAIR and AFMM. Each sample was computationally processed to determine cell density. Custom software was then used to downsample coregistered microscopic histology to the more coarse MRI resolution. A voxel-by-voxel evaluation comparing ADC and cellularity was then performed. RESULTS: An ADC threshold of 0.929 × 10(-3) mm(2)/s was calculated from meningioma-induced edema and was used to define AFMM. Regions of AFMM showed significantly greater cell density in 6 of 7 high-grade glioma cases compared with regions of hyperintense FLAIR alone (P < .0001). Two patients had small regions of diffusion-restricted necrosis that had significantly lower ADC than nearby hypercellularity. CONCLUSIONS: Regions of AFMM contain hypercellularity except for regions with extremely restricted diffusion, where necrosis is present.

Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics.

Cancer is a complex disease; glioblastoma (GBM) is no exception. Short survival, poor prognosis, and very limited treatment options make it imperative to unravel the disease pathophysiology. The critically important identification of proteins that mediate various cellular events during disease is made possible with advancements in mass spectrometry (MS)-based proteomics. The objective of our study is to identify and characterize proteins that are differentially expressed in GBM to better understand their interactions and functions that lead to the disease condition. Further identification of upstream regulators will provide new potential therapeutic targets. We analyzed GBM tumors by SDS-PAGE fractionation with internal DNA markers followed by liquid chromatography-tandem mass spectrometry (MS). Brain tissue specimens obtained for clinical purposes during epilepsy surgeries were used as controls, and the quantification of MS data was performed by label-free spectral counting. The differentially expressed proteins were further characterized by Ingenuity Pathway Analysis (IPA) to identify protein interactions, functions, and upstream regulators. Our study identified several important proteins that are involved in GBM progression. The IPA revealed glioma activation with z score 2.236 during unbiased core analysis. Upstream regulators STAT3 and SP1 were activated and CTNNα was inhibited. We verified overexpression of several proteins by immunoblot to complement the MS data. This work represents an important step towards the identification of GBM biomarkers, which could open avenues to identify therapeutic targets for better treatment of GBM patients. The workflow developed represents a powerful and efficient method to identify biomarkers in GBM.

Moyamoya syndrome in an adult with essential thrombocythemia.

Moyamoya syndrome is a rare cerebrovascular disorder characterized by progressive occlusion of the supraclinoid internal carotid artery and proximal portions of the anterior and middle cerebral arteries resulting in an extensive network of collateralized blood vessels and producing a characteristic angiographic appearance. Although the pathophysiology is unclear, hematologic disorders have been associated with development of the moyamoya syndrome. A case report is presented. A 29 year-old female with a history of essential thrombocythemia developed progressive ischemic strokes. Angiography revealed characteristic moyamoya changes and pathologic examination showed intimal hyperplasia with scant collagen fibers and myxoid change. This is the first reported case of moyamoya syndrome in an adult patient with essential thrombocythemia demonstrating histological findings that suggest a shared pathophysiology with moyamoya syndrome in sickle cell anemia.

Temporal lobe pleomorphic xanthoastrocytoma and chronic epilepsy: long-term surgical outcomes.

OBJECTIVE: To review clinical features and surgical outcome in patients with temporal lobe pleomorphic xanthoastrocytomas (PXAs) and intractable epilepsy. METHODS: The Rush Surgical Epilepsy Database was queried to identify patients with chronic intractable epilepsy who underwent resection of a temporal lobe PXA at Rush University Medical Center. Medical records were reviewed for demographic, procedure and follow-up data. RESULTS: Four patients were identified with a temporal lobe PXA and intractable epilepsy. Average age of seizure onset was 16.5 years and delay to surgery was 90 months. Complex partial seizures were the most common presenting symptom, shown in all 4 patients, and 3 of 4 patients presented with simple partial seizures as well. Seizures occurred with an average frequency of 4 per month (range 1-12 per month). Detailed operative and post-operative follow up data was available for all 4 patients. Gross total resection of the tumor was achieved in all 4 cases. Three of 4 cases had complete resection of the amygdala, and 3 cases had resections of the hippocampus (one partial and two complete). On histopathology, all tumors were found to be low-grade, without mitoses or necrosis. Average follow-up was 120 months (range 29-296 months) with all 4 patients achieving Engel's class I outcome. At last follow up, there was no radiographic or clinical evidence of tumor recurrence. There were no permanent complications. CONCLUSIONS: Temporal lobe pleomorphic xanthoastrocytomas causing chronic intractable epilepsy occur in younger patients, and demonstrate excellent long-term results in seizure improvement and tumor control with surgery. We support the choice between simple lesionectomy and a tailored resection with amygdalohippocampectomy guided by preoperative findings, intraoperative electrocorticography, and the severity and chronicity of the patient's epilepsy.

Histopathologic description of Wingspan stent in acute ischemic stroke.

OBJECTIVE AND IMPORTANCE: We report the histopathologic examination of Wingspan stent in acute ischemic stroke. CLINICAL PRESENTATION: A 75-year-old female presented with acute left-hemiplegia due to right carotid terminus occlusion. Mechanical embolectomy was unsuccessful. INTERVENTION: A Wingspan stent was placed from the distal intracranial carotid artery to the proximal middle cerebral artery stem and established partial antegrade flow. The patient died of malignant infarction on post-stroke day 7. At autopsy, embolized calcified atherosclerotic plaque fragments were noted within a non-occlusive thrombus over which the Wingspan stent was deployed. There was no evidence of intimal or media dissection or perforator ostium occlusion. CONCLUSION: Our case provides a rare pathological description of intracranial stent placement in the setting of acute ischemic stroke.

Chronic epilepsy associated with temporal tumors: long-term surgical outcome.

OBJECT: The authors undertook a study to review the clinical features and outcome in patients who underwent surgery for intractable chronic epilepsy caused by temporal lobe tumors. METHODS: The Rush Surgical Epilepsy Database was queried to identify patients with chronic intractable epilepsy who underwent resection of temporal lobe tumors between 1981 and 2005 at Rush University Medical Center. Medical records were reviewed for age of the patient at seizure onset, delay to referral for surgery, seizure frequency and characteristics, preoperative MR imaging results, extent of resection, pathological diagnosis, complications, duration of follow-up period, and seizure improvement. RESULTS: Thirty-eight patients were identified, all with low-grade tumors. Gangliogliomas were the most common (36.8%), followed in descending order by dysembryoplastic neuroepithelial tumors (26.3%) and low-grade diffuse astrocytoma (10.5%). The mean duration between seizure onset and surgery was 15.4 years. Complex partial seizures were the most common presenting symptom. Detailed operative data were available for 28 patients; of these, 89.3% underwent complete resection of the amygdala, and 82.1% underwent partial or complete resection of hippocampus, in addition to lesionectomy. The mean follow-up duration was 7.7 years (range 1.0-23.1 years), with 78.9% of patients having seizure status that improved to Engel Class I, 15.8% to Engel Class II, and 5.3% to Engel Class III. Permanent complications were noted in 2.6% of patients. CONCLUSIONS: The authors' examination of the long-term follow-up data in patients with temporal lobe tumors causing chronic intractable epilepsy demonstrated excellent results in seizure improvement after surgery.

Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases.

Central nervous system neoplasms with combined features of malignant glioma and primitive neuroectodermal tumor (MG-PNET) are rare, poorly characterized, and pose diagnostic as well as treatment dilemmas. We studied 53 MG-PNETs in patients from 12 to 80 years of age (median = 54 years). The PNET-like component consisted of sharply demarcated hypercellular nodules with evidence of neuronal differentiation. Anaplasia, as seen in medulloblastomas, was noted in 70%. Within the primitive element, N-myc or c-myc gene amplifications were seen in 43%. In contrast, glioma-associated alterations involved both components, 10q loss (50%) being most common. Therapy included radiation (78%), temozolomide (63%) and platinum-based chemotherapy (31%). Cerebrospinal fluid (CSF) dissemination developed in eight patients, with response to PNET-like therapy occurring in at least three. At last follow-up, 27 patients died, their median survival being 9.1 months. We conclude that the primitive component of the MG-PNET: (i) arises within a pre-existing MG, most often a secondary glioblastoma; (ii) may represent a metaplastic process or expansion of a tumor stem/progenitor cell clone; (iii) often shows histologic anaplasia and N-myc (or c-myc) amplification; (iv) has the capacity to seed the CSF; and (v) may respond to platinum-based chemotherapy regimens.