Erythropoietin-producing hepatocellular receptor B6 is highly expressed in non-functioning pituitary neuroendocrine tumors and its expression correlates with tumor size.

BACKGROUND: Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The Erythropoietin-producing hepatocellular receptor tyrosine kinase member EphB6 is a pseudokinase which has not attracted an equivalent amount of interest as its enzymatically-active counterparts. The aim of this study was to assess the expression of EphB6 in pituitary tumors. METHODS AND RESULTS: Human normal pituitaries and pituitary tumors were examined for EphB6 mRNA expression using real-time PCR and for EphB6 protein by immunohistochemistry and Western blotting. EphB6 was highly expressed in non-functioning pituitary neuroendocrine tumors (NF-PitNETs) versus the normal pituitary and GH-secreting PitNETs. EphB6 mRNA expression was correlated with tumor size. CONCLUSIONS: Our results suggest EphB6 aberrant expression in NF-PitNETs. Future studies are warranted to determine the role and significance of EphB6 in NF-PitNETs tumorigenesis.

Magnetic resonance imaging analysis predicts nanoparticle concentration delivered to the brain parenchyma.

Ultrasound in combination with the introduction of microbubbles into the vasculature effectively opens the blood brain barrier (BBB) to allow the passage of therapeutic agents. Increased permeability of the BBB is typically demonstrated with small-molecule agents (e.g., 1-nm gadolinium salts). Permeability to small-molecule agents, however, cannot reliably predict the transfer of remarkably larger molecules (e.g., monoclonal antibodies) required by numerous therapies. To overcome this issue, we developed a magnetic resonance imaging analysis based on the ΔR2* physical parameter that can be measured intraoperatively for efficient real-time treatment management. We demonstrate successful correlations between ΔR2* values and parenchymal concentrations of 3 differently sized (18 nm-44 nm) populations of liposomes in a rat model. Reaching an appropriate ΔR2* value during treatment can reflect the effective delivery of large therapeutic agents. This prediction power enables the achievement of desirable parenchymal drug concentrations, which is paramount to obtaining effective therapeutic outcomes.

Comparison of matched formalin-fixed paraffin embedded and fresh frozen meningioma tissue reveals bias in proteomic profiles.

Tissue biopsies are most commonly archived in a paraffin block following tissue fixation with formaldehyde (FFPE) or as fresh frozen tissue (FFT). While both methods preserve biological samples, little is known about how they affect the quantifiable proteome. We performed a 'bottom-up' proteomic analysis (N = 20) of short and long-term archived FFPE surgical samples of human meningiomas and compared them to matched FFT specimens. FFT facilitated a similar number of proteins assigned by MetaMorpheus compared with matched FFPE specimens (5378 vs. 5338 proteins, respectively (p = 0.053), regardless of archival time. However, marked differences in the proteome composition were apparent between FFPE and FFT specimens. Twenty-three percent of FFPE-derived peptides and 8% of FFT-derived peptides contained at least one chemical modification. Methylation and formylation were most prominent in FFPE-derived peptides (36% and 17% of modified FFPE peptides, respectively) while, most of phosphorylation and iron modifications appeared in FFT-derived peptides (p < 0.001). A mean 14% (± 2.9) of peptides identified in FFPE contained at least one modified Lysine residue. Importantly, larger proteins were significantly overrepresented in FFT specimens, while FFPE specimens were enriched with smaller proteins.

Comparison of Frame-Based Versus Frameless Image-Guided Intracranial Stereotactic Brain Biopsy: A Retrospective Analysis of Safety and Efficacy.

BACKGROUND: A definitive diagnosis of brain lesions not amenable to surgery is mainly made by stereotactic needle biopsy. The diagnostic yield and safety of the frameless versus frame-based image-guided stereotactic techniques is unclear. Our objective was to evaluate the safety and accuracy of frameless versus frame-based stereotactic brain biopsy techniques. METHODS: A total of 278 patients (153 men; mean age: 65.5 years) with intra-axial brain lesions underwent frame-based (n = 148) or frameless image-guided stereotactic brain biopsy (n = 130) using a minimally invasive twist drill technique during 2010-2016 at Sheba Medical Center. Demographic, imaging, and clinical data were retrospectively analyzed. RESULTS: The diagnostic yield (>90%) did not differ significantly between groups. Overall morbidity (6.8% vs. 8.5%), incidence of permanent neurologic deficits (2.1% vs. 1.6%), mortality rate (0.7% vs. 0.8%), and postoperative computed tomography-detected asymptomatic (14.2% vs. 16.1%) and symptomatic (2.0% vs. 1.6%) bleeding also did not differ significantly between the frame-based and frameless cohorts, respectively. The diagnostic yield and complication rates related to the biopsy technique were not significantly associated with sex, age, entry angle to the skull and skull thickness, lesion location or depth, or radiologic characteristics. Diagnostic yield was significantly associated with the mean lesion volume. Smaller lesions were less diagnostic than larger lesions in both techniques (P = 0.043 frame-based and P = 0.048 frameless). CONCLUSIONS: The frameless biopsy technique is as efficient as the frame-based brain biopsy technique with a low complication rate. Lesion volume was the only predictive factor of diagnostic yield. The minimally invasive twist drill technique is safe and efficient.

A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma.

BACKGROUND: Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation's efficacy. We sought to assess the tolerability and feasibility of this approach. METHODS: A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. RESULTS: A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. CONCLUSIONS: The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.

Utility of the Polestar N30 low-field MRI system for resecting non-enhancing intra-axial brain lesions.

BACKGROUND: To determine the utility of an intraoperative magnetic resonance imaging (iMRI) system, the Polestar N30, for enhancing the resection control of non-enhancing intra-axial brain lesions. MATERIALS AND METHODS: Seventy-three patients (60 males [83.3%], mean age 37 years) with intra-axial brain lesions underwent resection at Sheba Medical Centre using the Polestar between February 2012 and the end of August 2018. Demographic and imaging data were retrospectively analysed. Thirty-five patients had a non-enhancing lesion (48%). RESULTS: Complete resection was planned for 60/73 cases after preoperative imaging. Complete resection was achieved in 59/60 (98.3%) cases. After iMRI, additional resection was performed in 24/73 (32.8%) cases, and complete resection was performed in 17/60 (28.8%) cases in which a complete resection was intended. In 6/13 (46%) patients for whom incomplete resection was intended, further resection was performed. The extent of resection was extended mainly for non-enhancing lesions: 16/35 (46%) as opposed to only 8/38 (21%) for enhancing lesions. Further resection was not significantly associated with sex, age, intended resection, recurrence, or affected side. Univariate analysis revealed non-eloquent area, intended complete resection, and enhancing lesions to be predictive factors for complete resection, and non-enhancing lesions and scan time to be predictive factors for an extended resection. Non-enhancement was the only independent factor for extended resection. CONCLUSIONS: The Polestar N30 is useful for evaluating residual non-enhancing intra-axial brain lesions and achieving maximal resection.

CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy.

Harnessing CRISPR-Cas9 technology for cancer therapeutics has been hampered by low editing efficiency in tumors and potential toxicity of existing delivery systems. Here, we describe a safe and efficient lipid nanoparticle (LNP) for the delivery of Cas9 mRNA and sgRNAs that use a novel amino-ionizable lipid. A single intracerebral injection of CRISPR-LNPs against PLK1 (sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for antibody-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%. The ability to disrupt gene expression in vivo in tumors opens new avenues for cancer treatment and research and potential applications for targeted gene editing of noncancerous tissues.

The human tumor microbiome is composed of tumor type-specific intracellular bacteria.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.

Brain Metastases from Ovarian Carcinoma: An Evaluation of Prognostic Factors and Treatment.

AIMS AND OBJECTIVES: To review a series of patients with brain metastases from ovarian cancer at a single institution. To describe treatment modalities, their outcomes and to determine prognostic factors. PATIENTS AND METHODS: Between January 1995 and December 2014, 25 patients with ovarian cancer brain metastases were treated at The Sheba Medical Center. The medical records were retrospectively reviewed to collect demographic, clinical, and imaging data as well as the information on the treatment modalities used and their outcomes. RESULTS: Mean patient age at the time of brain metastasis diagnosis was 62.7 years. The median interval between the diagnosis of primary cancer and brain metastasis was 42.3 months. Neurologic deficits, headache, and seizure were the most common symptoms. The brain was the only site of metastasis in 20% of the patients. Active ovarian cancer at the time of diagnosis of brain metastasis was observed in half of the patients with systemic disease. Multiple brain metastases were observed in 25% of the patients. We treated 11 patients with surgery plus radiation therapy protocols in various orders: surgery followed by complementary whole-brain radiation therapy (WBRT), surgery followed by stereotactic radiosurgery (SRS), and surgery followed by WBRT and then by adjuvant SRS. Five patients underwent surgery alone and nine patients were treated with radiation alone (WBRT, SRS, or both). Univariate analysis for predictors of survival demonstrated that age above 62.7 years at the time of central nervous system involvement was a significant risk factor and leptomeningeal disease was a poor prognostic factor in reference to supra-tentorial lesions. Multivariate analysis for predictors of survival, however, showed that multiple brain lesions (>4) were a poor prognostic factor, and multivariate analysis of the time to progression revealed that combined treatments of surgery and radiation resulted in longer median periods of progression-free survival than each modality alone. CONCLUSION: We conclude that the only significant predictors of survival or progression-free survival in our cohort were the number of brain metastases and the treatment modality.

Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma.

BACKGROUND: Klotho, a single-pass transmembrane protein associated with premature aging, acts as a tumor suppressor gene by inhibiting insulin/insulin-like growth factor-1 and fibroblast growth factor pathways. Downregulated Klotho expression is reported in melanoma, mesothelioma, bladder, breast, gastric, cervix, lung, and kidney cancers and is associated with a poor prognosis. Klotho expression and Klotho promoter hypermethylation are predictive factors for patient prognosis. METHODS: To investigate the potential role of Klotho in glioblastoma-multiforme (GBM), 22 GBM samples were collected from the Sheba Tumor Bank and examined. RESULTS: We found that increased Klotho messenger ribonucleic acid (RNA) expression predicted longer survival (P = 0.03) of GBM patients. Methylation analysis was performed on bisulfite-treated deoxyribonucleic acid from the GBM patient samples using ionization time-of-flight mass spectrometry according to the Sequenom EpiTYPER protocols. Klotho promoter hypermethylation was detected in 65% of the GBM samples and correlated significantly with improved survival (P < 0.04). We found 3 major Klotho promotor hypermethylation sites located 585-579 bp, 540-533 bp, and 537-534 bp upstream of the transcription start site. Methylated deoxyribonucleic acid immunoprecipitation studies confirmed these results. Notably, the messenger RNA expression in these GBM samples revealed an unexpected linear correlation with methylation of these 3 hypermethylation sites identified in the Klotho promotor. Thus Klotho expression and methylation could predict prognosis in patients with GBM. CONCLUSIONS: Epigenetic regulation in GBM appears to be complicated. Specific CpG islands affect genes or micro RNAs that interact to control Klotho expression. The diverse effects of these islands may be due to unique factors of GBM.

Antibody array strategy for human growth factor secretome profiling of GH-secreting adenomas.

PURPOSES: To test if the antibody array strategy could be utilized to simultaneously detect the secretion of multiple growth factors by human pituitary GH-adenomas and to measure octreotide-induced alterations. METHODS: Specimens of human pituitary adenomas were cultured and incubated with or without octreotide for 24 h. Conditional media were analyzed by human growth factor antibody array and VEGF concentrations were measured by ELISA. Media were also analyzed for GH concentrations. p21 expression levels were examined by Western blot of the specimens lysates. RESULTS: The antibody arrays successfully identified growth factors secreted by GH-adenomas in vitro. Octreotide treatment induced both elevations and reductions in growth factors secretion. GH response to octreotide was measured, and in this small-sized study resistant and sensitive GH-adenomas presented with no unique secretome pattern of each of the groups. Octreotide-induced VEGF alterations analyzed by the antibody array and by ELISA were not fully matched. CONCLUSIONS: This study suggests that the broad proteomic strategy of antibody arrays may be utilized to study the growth factors secretion pattern of GH-adenomas and its regulation by somatostatin analogs or other compounds.

Radiation-induced vascular malformations in the brain, mimicking tumor in MRI-based treatment response assessment maps (TRAMs).

•Of 310 brain tumors patients recruited, histology of 99 lesions was available.•Of those, 5 were histologically confirmed as radiation-induced malformations.•TRAMs cannot differentiate active tumor from vascular malformation.

Anterior cervical approach for the treatment of axial or high thoracic levels.

PURPOSE: Application of the anterior sub-axial cervical approach to the axial spine or the high thoracic spine has been previously described. Evaluation methods to determine the feasibility of these approaches were also described but alternative method was utilized in the current study. We describe our experience expanding the boundaries of anterior cervical approach utilizing a novel algorithm for approach selection. MATERIALS AND METHODS: A retrospective analysis of patients' files and imaging data of all anterior cervical approach to treat pathologies above C2-3 disc space or below C7-D1 disc space. The decision to proceed with standard approach was based on CT or MRI scans and the pre-operative cervical range of motion. Post-operative course and surgical complications will be discussed. RESULTS: During a two year period 13 patients had undergone anterior cervical approach to the axial spine (3 patients) or the thoracic spine (10 patients). Ten patients were treated for tumour resection, one for trauma, one for myelopathy and the last for infective osteomyelitis with epidural abscess. Three patients were previously operated in another hospital via the posterior approach with remaining compressive mass necessitating anterior decompression. Complications were recorded in 30% of the patients. CONCLUSIONS: Approach to the axial or the high thoracic spine is more challenging and harbors approach-related complication. Pre-operative evaluation of patients imaging allows harnessing the standard approach for treatment of extreme levels with relative safety and efficiency. Spine surgeons' awareness to this technique may increase surgical efficacy while reducing the complication rates.

Spinal intradural extramedullary tumors: the value of intraoperative neurophysiologic monitoring on surgical outcome.

Nerve sheath tumors and meningiomas account for most intradural extramedullary (IDEM) tumors. These tumors are benign and amenable to complete surgical resection. In recent years, these surgeries are performed with intraoperative neurophysiologic monitoring (IONM) in order to minimize neurological injury, but the evidence for the statistical efficacy of this utility is lacking. This paper evaluates IONM benefits in IDEM tumor resection. Data of patients treated surgically for spinal intradural tumors from 1998 to 2003 was previously collected and analyzed. We retrospectively evaluated patients' charts operated in the years 2011 to 2013. Patients' medical files were reviewed including radiological examinations and electrophysiological reports. The data was collected and evaluated. Forty-one cases of meningioma or nerve sheath tumor resection surgery were performed in the study period. The surgical results were compared to 70 cases of historical controls. Demographic data was similar in these two groups. Sensitivity, specificity, and positive and negative predicted values of IONM were 75, 100, 100, and 97%, respectively. New neurological deficit rate was evident in 10 and 14% for the study and control groups, respectively (not significant). While IONM predicts neurological deficits with high accuracy level, this study does not suggest that there is a significant global benefit of IONM in these cases. As reported by others, in this series, the rate of new neurological deficits in non-monitored cases is similar to the monitored cases series; hence, IONM role in preventing new neurological deficits has yet to be proven.

Predicting and reducing cranioplasty infections by clinical, radiographic and operative parameters - A historical cohort study.

Cranioplasty is a relatively straightforward and common procedure, yet it carries a substantial rate of infection that causes major morbidity and mortality. The authors' objective was to assess the effect of various variables on the risk of developing post-cranioplasty infections, and to enable the prediction and reduction of its incidence, contributing to an improved patient-selection. The medical records, microbiologic cultures, imaging studies and operative reports of patients who have undergone cranioplasty between the years 2008-2014 at Sheba Medical Center, a tertiary care teaching hospital in Tel-Hashomer, Israel, were reviewed and evaluated for potential predictive factors of infection. Cox regression was applied for uni- as well as multi-variate analyses, and a Kaplan-Meier curve and Log-Rank test were used to describe the association between neurological deficit prior to operation and occurrence of infection. Eighty-eight patients who had undergone cranioplasties using autologous as well as various artificial materials were included in the study. The overall rate of infection was 13.6%; median time to infection was 30.5 days (interquartile range: 17.35-43.5). Pre-operative degree of neurological disability was the strongest predictor for infection in both uni- and multi-variate analyses (Hazard ratio [HR]=18.9, 95% confidence interval [CI]: 1.9-187 p=0.014). Patients admitted due to trauma (HR=7.04 CI: 0.9-54.6, p=0.062) and autologous graft material (HR=2.88, 95% CI: 0.92-9.09, p=0.07) were associated with a trend toward a higher risk for infection. In conclusion, careful patient selection is a key concept in avoiding harmful post-cranioplasty infections. Modified Rankin Score yields a well-established tool that predicts the risk of infection.

Harnessing nanomedicine for therapeutic intervention in glioblastoma.

INTRODUCTION: Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients. Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies. Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM.

Combination of mTOR Inhibitors Augments Potency while Activating PI3K Signaling in Pituitary Tumors.

BACKGROUND: Despite the success in treating some cancers, the efficacy of the mTOR inhibitors rapalogs as anti-cancer therapeutics has been limited. AIMS: We undertook to examine the effects of Torin1, a second-generation selective ATP-competitive mTOR inhibitor, in non-functioning pituitary tumor cells. During characterization of the molecular mechanisms that mediate Torin1 actions, there seemed to be a rationale for combining it with rapalogs. METHODS: Proliferation assays, flow cytometry and Western blotting were applied to assess the effects of Torin1, RAD001 and their combination on an MtT/E pituitary cell line and human-derived non-functioning pituitary tumor cells. RESULTS: Combined long treatments of Torin1 and RAD001 induced a pronounced reduction in cell growth and viability of both MtT/E pituitary cells and human-derived non-functioning pituitary tumor cells, superior to each drug alone. This was remarkable in the 10 nM combination and was reflected in a triggered decrease of cyclin D3 and p21/CIP expression. Interestingly, Akt-Thr308 and SIN1-Thr86 phosphorylations were robustly elevated in the combined treatment, accompanied by a reduction in PTEN expression. Phosphorylation of p70S6K was abolished in all individual and combined treatments. Akt-Ser473 phosphorylation, induced by RAD001, was reduced by the combined treatment to the same extent as when treated by Torin1 alone. CONCLUSIONS: Our results suggest that the differential signaling mechanisms induced by these compounds eventually converge to lead to an efficient blockade of the PI3K/Akt/mTOR pathway in pituitary tumor cells and may facilitate a reduction in treatment dosage.

Localized RNAi therapeutics of chemoresistant grade IV glioma using hyaluronan-grafted lipid-based nanoparticles.

Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP's surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM.

Delayed contrast extravasation MRI: a new paradigm in neuro-oncology.

BACKGROUND: Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients. METHODS: One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist. RESULTS: Histological validation confirmed that regions of contrast agent clearance in the TRAMs >1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P < .0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated. CONCLUSIONS: The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.

Human cytomegalovirus viral load in tumor and peripheral blood samples of patients with malignant gliomas.

Malignant gliomas are the most common primary brain tumors in adults. The disease has no known etiology, progresses rapidly, and is fatal despite current therapies. Human cytomegalovirus (HCMV) is a beta herpes virus that is trophic for glial cells and infects 50% to 90% of the adult human population. HCMV-mediated disease in immunosuppressed patients has highlighted the possible role of this virus in the development of other diseases, particularly inflammatory diseases such as vascular diseases, autoimmune diseases, and certain malignancies. Sensitive detection of viral DNA, mRNA, and antigens in tumor tissues, as well as seroepidemiologic evidence, suggest a link between HCMV and several human malignancies. HCMV gene products are proposed to dysregulate multiple cellular pathways involved in oncogenesis, such as cell cycle regulation, apoptosis, migration, and angiogenesis. These theories, currently being researched, suggest that HCMV acts as an oncomodulator in malignancies. We investigated the association between HCMV infection and reactivation, and malignant gliomas. An open, matched case-control, parallel group pilot study was performed in a tertiary referral center. The HCMV viral load in peripheral blood and tumor samples of 19 patients newly diagnosed with glioblastoma multiforme was compared with a matched control cohort comprising 19 patients newly diagnosed with non-malignant brain tumors. There was no significant correlation between peripheral blood and tumor tissue HCMV viral load in patients with glioblastoma multiforme compared to the control cohort. The findings of the present study did not support an oncomodulatory role for HCMV in malignant gliomas.