Sasan Karimi

A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma.Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor.Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33).R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas.After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab.Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%.Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

No proven effective medical therapy for surgery and radiation-refractory meningiomas exists. Sunitinib malate (SU011248) is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor, abundant in meningiomas.This was a prospective, multicenter, investigator-initiated single-arm phase II trial. The primary cohort enrolled patients with surgery and radiation-refractory recurrent World Health Organization (WHO) grades II-III meningioma. An exploratory cohort enrolled patients with WHO grade I meningioma, hemangiopericytoma, or hemangioblastoma. Sunitinib was administered at 50 mg/d for days 1-28 of every 42-day cycle. The primary endpoint was the rate of 6-month progression-free survival (PFS6), with secondary endpoints of radiographic response rate, safety, PFS, and overall survival. Exploratory objectives include analysis of tumoral molecular markers and MR perfusion imaging.Thirty-six patients with high-grade meningioma (30 atypical and 6 anaplastic) were enrolled. Patients were heavily pretreated (median number of 5 recurrences, range 2-10). PFS6 rate was 42%, meeting the primary endpoint. Median PFS was 5.2 months (95% CI: 2.8-8.3 mo), and median overall survival was 24.6 months (95% CI: 16.5-38.4 mo). Thirteen patients enrolled in the exploratory cohort. Overall toxicity included 1 grade 5 intratumoral hemorrhage, 2 grade 3 and 1 grade 4 CNS/intratumoral hemorrhages, 1 grade 3 and 1 grade 4 thrombotic microangiopathy, and 1 grade 3 gastrointestinal perforation. Expression of VEGFR2 predicted PFS of a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2-positive patients (P = .005).Sunitinib is active in recurrent atypical/malignant meningioma patients. A randomized trial should be performed.

Biomarkers can facilitate diagnosis, monitor treatment response, and assess prognosis in some patients with cancer. YKL-40 and matrix metalloproteinase-9 (MMP-9) are two proteins highly differentially expressed by malignant gliomas. We obtained prospective longitudinal serum samples from patients with gliomas to determine whether YKL-40 or MMP-9 could be used as serum markers.Serum samples were obtained concurrently with magnetic resonance imaging scans. YKL-40 and MMP-9 were determined by ELISA and the values correlated with the patient's radiographic status and survival.High-grade glioma patients who underwent a surgical resection of their tumor had transient increase of both YKL-40 and MMP-9 serum levels in the postoperative period. Glioblastoma multiforme (GBM) patients with no radiographic evidence of disease (n = 10 patients, 50 samples) had a significantly lower level of YKL-40 and MMP-9 than patients with active tumor (n = 66 patients, 209 samples; P = 0.0003 and 0.0002, respectively). Anaplastic glioma patients with no radiographic evidence of disease (n = 32 patients, 107 samples) also had a significantly lower level of YKL-40 compared with those patients with active tumor (n = 48 patients, 199 samples; P = 0.04). There was a significant inverse association between YKL-40 and survival in GBM, hazard ratio (hazard ratio, 1.4; P = 0.02), and anaplastic astrocytoma patients (hazard ratio, 2.2; P = 0.05).YKL-40 and MMP-9 can be monitored in patients' serum and help confirm the absence of active disease in GBM and YKL-40 in anaplastic glioma patients. YKL-40 can be used as predictor of survival in patients with high-grade glioma. Longitudinal studies with a larger patient population are needed to confirm these findings.

Purpose Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM. Patients and Methods Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m 2 days 1 to 7 and 15 to 21) or metronomic (50 mg/m 2 continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O 6 -methylguanine–DNA methyltransferase (MGMT) promoter methylation status. Results Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm). Conclusion Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery.Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables.At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. K(trans) is volume transfer constant. In a stepwise Cox regression, skewness of K(trans) (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001).Our study shows that skewness of K(trans) was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter K(trans) as a predictor of outcome in these patients.

The purpose of this study was to review the craniofacial and intracranial clinical and radiologic manifestations of patients diagnosed with Langerhans cell histiocytosis (LCH). This report will compare the frequency of the various manifestations found in our series with those reported in the medical literature.In LCH, involvement of the calvaria, skull base, maxillofacial bones, and hypothalamic-pituitary axis is fairly common. The precise location of these lesions contributes to the variety of clinical manifestations of LCH, which includes scalp and/or facial swelling, seizures, hearing loss, recurrent otitis media, gingival bleeding, proptosis, diabetes insipidus, and cranial nerve palsies.

High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role.In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment.Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors.The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood-brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clin Cancer Res; 22(19); 4786-96. ©2016 AACR.

Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1-mutated glioblastoma.

Cancers of the oral cavity and pharynx are the most common head and neck cancers in the United States, and squamous cell carcinoma is the most frequent histologic type. The clinical behavior and outcome of tumors in the oral cavity is distinct from those of the oropharynx. As a general rule, surgical resection is the primary treatment for oral cavity squamous cell carcinoma, whereas oropharyngeal squamous cell carcinomas are treated with radiation with or without chemotherapy. A clear understanding of the anatomy and knowledge of clinical behavior and spread patterns of oral cavity and oropharyngeal squamous cell carcinoma are essential for radiologists to make a meaningful contribution to the treatment of these patients.

The objective of this study was to evaluate whether longitudinal levels of serum YKL-40 correlate with disease status or survival in adults with gliomas. Patients with histologically confirmed gliomas were eligible for this longitudinal study. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. YKL-40 levels determined by ELISA were correlated with radiographic disease status and survival. We performed a multivariate survival analysis including well-known prognostic factors such as age, performance status, and extent of surgical resection. Three hundred and forty-three patients with gliomas (41 low-grade, 105 anaplastic, and 197 glioblastoma) were accrued. Two-year survival from registration was 29% for glioblastomas, 62% for anaplastic gliomas, and 83% for low-grade gliomas. A total of 1740 serum samples were collected, and 95.6% of samples had matching MRI scans. Serum YKL-40 level was significantly lower in patients with no radiographic disease compared with patients with radiographic disease in both the anaplastic glioma (P= .0008) and the glioblastoma (P= .0006) cohorts. Serum levels of YKL-40 in patients with low-grade gliomas were not associated with radiographic disease status. Increases in YKL-40 were independently associated with worse survival in anaplastic gliomas (hazard ratio [HR] = 1.4, P= .01) and glioblastomas (HR = 1.4, P< .0001). Longitudinal increases in serum YKL-40 are associated with increased risk of death in patients with glioblastomas and anaplastic gliomas. YKL-40 is also a putative indicator of disease status in these patients.

Most response criteria for patients with glioblastoma rely on increases in the contrast enhancing abnormality to determine tumor progression. Our aim was to determine retrospectively in patients with glioblastoma whether diffusion restriction can predict the development of new enhancing mass lesions.We reviewed the brain MR imaging scans (including DWI and ADC maps) of 208 patients with glioblastoma. Patients with restricted diffusion in or adjacent to the tumor were identified, with further analysis only performed on those patients with low-ADC lesions without enhancement. These patients were followed to determine if new concordant enhancement developed at the site of the low-ADC lesion. A Wilcoxon signed rank test, competing risk analysis, and Kaplan-Meier curves were used to compare the mean drop in ADC values, assess enhancement-free survival, and determine overall survival, respectively.In 67 of the 208 patients (32.2%), visibly detectable restricted diffusion was seen during treatment. The study cohort was formed by the 27 patients with low-ADC lesions and no corresponding enhancement. Twenty-three (85.2%) patients developed gadolinium-enhancing tumor at the site of restricted diffusion a median of 3.0 months later (95% CI, 2.6-4.1 months). The mean decrease in ADC was 22.9% from baseline (P < .001). The 3-month enhancement-free survival probability was 0.481 (95% CI, 0.288-0.675). The 12-month overall survival probability was 0.521 (95% CI, 0.345-0.788). Restricted diffusion predicted enhancement regardless of antiangiogenic therapy with bevacizumab.In a subset of patients with glioblastoma, development of a new focus of restricted diffusion during treatment may precede the development of new enhancing tumor.

Abstract Blood oxygenation‐level dependent (BOLD) MRI has gained particular attention in functional brain imaging studies, where it can be used to localize areas of brain activation with high temporal resolution. To a higher degree than in the brain, skeletal muscles show extensive but transient alterations of blood flow between resting and activation state. Thus, there has been interest in the application of the BOLD effect in studying the physiology of skeletal muscles (healthy and diseased) and its possible application to clinical practice. This review outlines the potential of skeletal muscle BOLD MRI as a diagnostic tool for the evaluation of physiological and pathological alterations in the peripheral limb perfusion, such as in peripheral arterial occlusive disease. Moreover, current knowledge is summarized regarding the complex mechanisms eliciting BOLD effect in skeletal muscle. We describe technical fundaments of the procedure that should be taken into account when performing skeletal muscle BOLD MRI, including the most often applied paradigms to provoke BOLD signal changes and key parameters of the resulting time courses. Possible confounding effects in muscle BOLD imaging studies, like age, muscle fiber type, training state, and drug effects are also reviewed in detail. J. Magn. Reson. Imaging 2012;35:1253–1265. © 2012 Wiley Periodicals, Inc.

Posterior reversible encephalopathy syndrome (PRES) is a disorder of cerebrovascular autoregulation that can result in brain edema, hemorrhage, and infarction. We sought to investigate whether certain imaging characteristics in PRES are associated with clinically significant patient outcomes. We retrospectively reviewed all cases of PRES occurring between 2008 and 2014 at two major academic medical centers. Demographic, clinical, and radiographic data were collected. We analyzed imaging studies for vasogenic edema, hemorrhage, and diffusion restriction. We performed univariate analysis and stepwise logistic regression to assess the association between our radiologic findings of interest and clinical outcomes as defined by hospital discharge disposition and modified Rankin scale (mRS) at time of discharge. We identified 99 cases of PRES in 96 patients. The median age was 55 years (IQR 30–65) and 74% were women. In 99 cases, 60% of patients had active cancer, 19% had history of bone marrow or organ transplantation, 14% had autoimmune disease, and 8% were peripartum. Imaging at clinical presentation showed extensive vasogenic edema in 39%, hemorrhage in 36%, hemorrhage with mass effect in 7%, and restricted diffusion in 16%. In our final logistic regression models, the presence of extensive vasogenic edema, hemorrhage with mass effect, or diffusion restriction was associated with worse clinical outcome as defined by both discharge disposition (OR = 4.3; 95% CI: 1.4–36.3; p = 0.047) and mRS (OR = 3.6; 95% CI: 1.2–10.7; p = 0.019). Extensive vasogenic edema, hemorrhage, and restricted diffusion on initial imaging in PRES are associated with worse clinical outcomes.

Accurate glioma grading is crucial for treatment planning and predicting prognosis. We performed a quantitative volumetric analysis to assess the diagnostic accuracy of histogram analysis of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) T1-weighted perfusion imaging in the preoperative evaluation of gliomas.Sixty-three consecutive patients with pathologically confirmed gliomas who underwent baseline DWI and DCE-MRI were enrolled. The patients were classified by histopathology according to tumor grade: 20 low-grade gliomas (grade II) and 43 high-grade gliomas (grades III and IV). Volumes-of-interest were calculated and transferred to DCE perfusion and apparent diffusion coefficient (ADC) maps. Histogram analysis was performed to determine mean and maximum values for Vp and Ktrans , and mean and minimum values for ADC. Comparisons between high-grade and low-grade gliomas, and between grades II, III, and IV, were performed. A Mann-Whitney U test at a significance level of corrected P ≤ .01 was used to assess differences.All perfusion parameters could differentiate between high-grade and low-grade gliomas (P < .001) and between grades II and IV, grades II and III, and grades III and IV. Significant differences in minimum ADC were also found (P < .01). Mean ADC only differed significantly between high and low grades and grades II and IV (P < .01). There were no differences between grades II and III (P = .1) and grades III and IV (P = .71).When derived from whole-tumor histogram analysis, DCE-MRI perfusion parameters performed better than ADC in noninvasively discriminating low- from high-grade gliomas.

Concurrent bevacizumab with hypofractionated stereotactic radiation therapy (HSRT) is safe and effective for the treatment of recurrent high-grade gliomas (HGG). The objective of this study was to characterize the patterns of failure after this treatment regimen.Twenty-four patients with recurrent enhancing HGG were previously treated on an institutional review board-approved protocol of concurrent bevacizumab and reirradiation. Patients received 30 Gy in 5 fractions to the recurrent tumor with HSRT. Brain magnetic resonance imaging (MRI) was performed every 2 cycles, and bevacizumab was continued until clinical or radiographic tumor progression according to the criteria of Macdonald et al. MRI at the time of progression was fused to the HSRT treatment plan, and the location of recurrence was classified on the basis of volume within the 95% isodose line. Outcomes based on patient characteristics, tumor grade, recurrence pattern, and best response to treatment were analyzed by the Kaplan-Meier method.Twenty-two patients experienced either clinical or radiographic progression. Recurrent tumor was enhancing in 15 (71.4%) and nonenhancing in 6 (28.6%) patients. Eleven patients (52.4%) had recurrence within the radiation field, 5 patients (23.8%) had marginal recurrence, and 5 patients had recurrence outside the radiation field. Pattern of enhancement and location of failure did not correlate with overall survival or progression-free survival. Radiographic response was the only variable to significantly correlate with progression-free survival.Despite the promising initial response seen with the addition of HSRT to bevacizumab as salvage treatment for recurrent HGG, approximately half of patients ultimately still experience failure within the radiation field. The rate of local failure with the addition of HSRT seems to be lower than that seen with bevacizumab alone in the salvage setting. Our data underscore the radioresistance of HGG and the need for better salvage treatments.

<h3>BACKGROUND AND PURPOSE:</h3> Vertebral hemangiomas are benign vascular lesions that are almost always incidentally found in the spine. Their classic typical hyperintense appearance on T1- and T2-weighted MR images is diagnostic. Unfortunately, not all hemangiomas have the typical appearance, and they can mimic metastases on routine MR imaging. These are generally referred to as atypical hemangiomas and can result in misdiagnosis and ultimately additional imaging, biopsy, and unnecessary costs. Our objective was to assess the utility of dynamic contrast-enhanced MR imaging perfusion in distinguishing vertebral atypical hemangiomas and malignant vertebral metastases. We hypothesized that permeability and vascular density will be increased in metastases compared with atypical hemangiomas. <h3>MATERIALS AND METHODS:</h3> Consecutive patients from 2011 to 2015 with confirmed diagnoses of atypical hemangiomas and spinal metastases from breast and lung carcinomas with available dynamic contrast-enhanced MR imaging were analyzed. Time-intensity curves were qualitatively compared among the groups. Perfusion parameters, plasma volume, and permeability constant were quantified using an extended Tofts 2-compartment pharmacokinetic model. Statistical significance was tested using the Mann-Whitney <i>U</i> test. <h3>RESULTS:</h3> Qualitative inspection of dynamic contrast-enhanced MR imaging time-intensity curves demonstrated differences in signal intensity and morphology between metastases and atypical hemangiomas. Quantitative analysis of plasma volume and permeability constant perfusion parameters showed significantly higher values in metastatic lesions compared with atypical hemangiomas (<i>P</i> &lt; .001). <h3>CONCLUSIONS:</h3> Our data demonstrate that plasma volume and permeability constant perfusion parameters and qualitative inspection of contrast-enhancement curves can be used to differentiate atypical hemangiomas from vertebral metastatic lesions. This work highlights the benefits of adding perfusion maps to conventional sequences to improve diagnostic accuracy.

Primary brain tumor patients are at increased risk for stroke from disease and treatment-specific mechanisms.We conducted a retrospective review of patients with primary brain tumors diagnosed with MRI-confirmed ischemic stroke between 1996 and 2006. Data were collected including risk factors, diagnostic workup, and treatment for stroke. Modified Rankin Scale (MRS) scores at stroke diagnosis were determined, and stroke etiology was assigned using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria for nonpostoperative strokes.Sixty-eight cases of confirmed ischemic stroke in 66 patients (56% men) were analyzed. The median age at time of stroke was 60 years. The distribution of stroke risk factors was comparable to the general stroke population. The most common brain tumors were gliomas, 60%; meningiomas, 25%; and primary CNS lymphoma, 6%. Stroke was the initial clinical diagnosis in only 43% of cases. The distribution of stroke etiology was operative complication, 49%; cardioembolic, 12%; small vessel lacune, 12%; large vessel, 6%; other, 15%; and undetermined, 7%. Seventeen patients (25%) had strokes related to delayed effects of radiation. The median latency from radiation to stroke diagnosis was 3.2 years. Therapy for secondary prevention of stroke was added in one-half of patients. Median survival from the time of stroke was 1.7 years and was correlated with MRS scores.Treatment complications from surgery and radiotherapy account for the majority of ischemic strokes in patients with primary brain tumors. Stroke is often a missed diagnosis that can contribute additional neurologic disability in an already susceptible patient population.

Brain tumors affecting language-relevant areas may influence language lateralization. The purpose of this study was to systematically investigate language lateralization in brain tumor patients using clinical language fMRI, comparing the results with a group of healthy volunteers.Fifty-seven strictly right-handed patients with left-hemispheric-space intracranial masses (mainly neoplastic) affecting either the Broca area (n = 19) or Wernicke area (n = 38) were prospectively enrolled in this study. Fourteen healthy volunteers served as a control group. Standardized clinical language fMRI, using visually triggered sentence- and word-generation paradigms, was performed on a 1.5T MR scanner. Semiautomated analyses of all functional data were conducted on an individual basis using BrainVoyager. A regional lateralization index was calculated for Broca and Wernicke areas separately versus their corresponding right-hemisphere homologs.In masses affecting the Broca area, a significant decrease in the lateralization index was found when performing word generation (P = .0017), whereas when applying sentence generation, the decrease did not reach statistical significance (P = .851). Masses affecting the Wernicke area induced a significant decrease of the lateralization index when performing sentence generation (P = .0007), whereas when applying word generation, the decrease was not statistically significant (P = .310).Clinical language fMRI was feasible for patients with brain tumors and provided relevant presurgical information by localizing essential language areas and determining language dominance. A significant effect of the brain masses on language lateralization was observed, with a shift toward the contralesional, nondominant hemisphere. This may reflect compensatory mechanisms of the brain to maintain communicative abilities.

In Brief Study Design. This was a retrospective study focusing on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess treatment response in patients with spinal metastases. Objective. To demonstrate DCE-MRI changes before and after radiation treatment and correlating with other imaging and clinical findings. Summary of Background Data. Currently, conventional imaging is limited in evaluating early treatment success or failure, which impacts patient care. Methods. Consecutive patients with known spinal metastases underwent DCE-MRI before and after radiotherapy. Perfusion data on 19 lesions were analyzed. Radiotherapy was classified as success (n = 17) or failure (n = 2) on the basis of evidence of tumor contraction (n = 4), negative positron emission tomography (n = 2), or stability for more than 11 months (n = 11). Perfusion parameters blood plasma volume (Vp), time-dependent leakage (Ktrans), area under the curve, and peak enhancement were derived from the signal intensity-time curves and changes in parameter values from pre- to post-treatment were calculated. Curve morphologies were also qualitatively assessed in 13 pre- and 13 post-treatment scans. Results. Vp was the strongest predictor of treatment response (false-positive rate = 9.38 × 10−9 and false-negative rate = 0.055). All successfully treated lesions showed decreases in Vp, and the 2 treatment failures showed drastic increases in Vp. Changes in area under the curve and peak enhancement demonstrated similar relationships to the observed treatment response, whereas changes in Ktrans showed no significant relationship. Signal intensity curve morphologies also demonstrated specificity for active disease (11 of 13) and treated disease (8 of 13). Conclusion. Changes in perfusion, particularly Vp, reflect tumor responses to radiotherapy in spinal bone metastases. These changes were able to predict positive outcomes earlier than 6 months after treatment in 16 of 17 tumors. The ability of DCE-MRI to detect early treatment response has the potential to improve patient care and outcome. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) was performed before and after radiotherapy to spine metastases. Perfusion parameters indicate a correlation between reduced tumor perfusion and a positive treatment response, and between increased perfusion and treatment failure. DCE MRI may differentiate between treatment success and failure earlier than routine MRI, reflecting that significant endothelial damage occurs in tumors after treatment.

<h3>Objective:</h3> The goal of this study was to assess whether the <i>APOE</i> ε4 allele and other <i>APOE</i> single nucleotide polymorphisms (SNPs) influence neuropsychological and neuroimaging outcomes in patients with brain tumors. <h3>Methods:</h3> Two hundred eleven patients with brain tumors participated in the study. All patients completed standardized neuropsychological tests and provided a blood sample for <i>APOE</i> genotyping. Ratings of white matter abnormalities were performed on MRI scans. Patients were classified into 2 groups based on the presence (n = 50) or absence (n = 161) of at least one <i>APOE</i> ε4 allele. Additional <i>APOE</i> SNPs were genotyped in a subset of 150 patients. <h3>Results:</h3> Patients with at least one <i>APOE</i> ε4 allele had significantly lower scores in verbal learning and delayed recall, and marginally significant lower scores in executive function, in comparison to noncarriers of an ε4 allele. Patients with at least one ε4 allele and history of cigarette smoking had significantly higher scores in working memory and verbal learning than ε4 carriers who never smoked. Nine additional <i>APOE</i> SNPs were significantly associated with attention and executive and memory abilities. There were no significant differences between ε4 carriers and noncarriers on the extent of white matter abnormalities on MRI. <h3>Conclusions:</h3> The findings suggest that patients with brain tumors who are carriers of the <i>APOE</i> ε4 allele may have increased vulnerability to developing memory and executive dysfunction, and that additional SNPs in the <i>APOE</i> gene may be associated with cognitive outcome.

Cognitive dysfunction is common among patients with brain tumors and can be associated with the disease and treatment with radiotherapy and chemotherapy. However, little is known about genetic risk factors that may moderate the vulnerability for developing cognitive dysfunction. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in the catechol-O-methyl transferase (COMT), brain-derived neurotrophic factor (BDNF), and dystrobrevin-binding protein 1 (DTNBP1) genes with cognitive functions and neuroimaging outcomes in patients with brain tumors. One hundred and fifty patients with brain tumors completed neuropsychological tests of attention, executive functions, and memory and were genotyped for polymorphisms in the COMT, BDNF, and DTNBP1 genes. Ratings of white matter (WM) abnormalities on magnetic resonance imaging scans were performed. Multivariate regression shrinkage analyses, adjusted for age, education, treatment type, time since treatment completion, and tumor location, indicated a significant association between the COMT SNP rs4680 (Val158Met) and memory with lower scores in delayed recall (P < .01) among homozygotes (valine/valine). Additional COMT, BDNF and DTNBP1 SNPs were significantly associated with attention, executive functions, and memory scores. This is the first study to suggest that known and newly described polymorphisms in genes associated with executive and memory functions in healthy individuals and other clinical populations may modulate cognitive outcome in patients with brain tumors.

To compare glioblastoma and brain metastases using T1-weighted dynamic contrast-enhanced (DCE)-MRI perfusion technique.26 patients with glioblastoma and 32 patients with metastatic brain lesions with no treatment who underwent DCE-MRI were, retrospectively, analyzed. DCE perfusion parameters K(trans) and Vp were calculated for the whole tumor. Signal intensity time curves were quantified by calculating the area under the curve (AUC) and the logarithmic slope of the washout phase to explore the heterogeneous tumor characteristics.Glioblastoma did not differ from all brain metastases in K(trans) (P = .34) or Vp (P = .47). Glioblastoma and melanoma metastases differed from hypovascular metastases in AUC and log slope of the washout phase of the signal intensity time curve (P < .05); however, glioblastoma and melanoma metastases did not differ from each other (AUC: P = .78, Log slope: P = .77). Glioblastoma and melanoma metastases differed from hypovascular metastases in the ratio of Voxelneg /Voxelpos (P< .03); however, they did not differ from each other. Glioblastoma and melanoma metastases differed from each other in Voxelneg_threshold at higher negative log slope threshold.DCE-MRI showed that it has a potential to differentiate glioblastomas, melanoma metastases and hypovascular brain tumors. Logarithmic slope of the washout phase and AUC of the signal intensity time curve were shown to be the best discriminator between hypervascular and hypovascular neoplasms.

Posterior reversible encephalopathy syndrome (PRES) is a variable cerebrovascular syndrome associated with hypertension and autoregulatory failure. Steroids have been reported to both precipitate and treat PRES. We sought to determine the prevalence of steroid therapy at the time of PRES and to assess the relationship between steroid therapy and extent of vasogenic edema.We performed a retrospective review of radiology reports between 2008 and 2014 from two academic medical centers to identify cases of PRES. Clinical and radiographic data were collected. Descriptive statistics were used to determine the prevalence of corticosteroid therapy at the time of PRES onset and the latency from steroid initiation to PRES onset. The association between steroid therapy and extent of vasogenic edema was assessed in multiple regression models.We identified 99 cases of PRES in 96 patients. The median age was 55years (IQR 30-65) and 74% were women. Steroid therapy at time of PRES onset was identified in 44 of 99 cases. Excluding patients on chronic therapy, the median duration of steroid exposure before PRES onset was 6 (IQR, 3-10) days. Steroid therapy was not associated with extent of vasogenic edema in unadjusted or linear and logistic regression models adjusted for age, sex, and maximum systolic blood pressure on day of onset.Corticosteroid therapy, often of brief duration, frequently preceded the onset of PRES and was not associated with severity of vasogenic edema.

Routine anatomical imaging with CT and MRI does not reliably indicate the true extent or the most malignant areas of gliomas and cannot identify the functionally critical parts of the brain. The aim of the study was to see if the use of MR spectroscopic imaging (MRSI) along with functional MRI (fMRI) can better define both the target and the critical structures to be avoided to improve radiation delivery in gliomas. 12 patients with gliomas underwent multivoxel MRS and functional imaging using GE processing software. The choline to creatine ratio (Cho:Cr), which represents the degree of abnormality for each individual voxel on MRSI, was derived, converted into a grayscale grading system, fused to the MRI images and then transferred to the planning CT images. An intensity-modulated radiation therapy (IMRT) plan was developed using the dose constraints based on both the anatomical and the functionally critical regions. Cho:Cr consistently identified the gross tumour volume (GTV) within the microscopic disease (clinical target volume, CTV) and allowed dose painting using IMRT. No correlation between MRSI based Cho:Cr > or =2 and MR defined CTV nor their location was noted. However, MRSI defined Cho:Cr > or =3 was smaller by 40% compared with post-contrast T1 weighted MRI defined GTV volumes. fMRI helped in optimizing the orientation of the beams. In conclusion, both MRSI and fMRI provide additional information to conventional imaging that may guide dose painting in treatment planning of gliomas. A Phase I IMRT dose intensification trial in gliomas using this information is planned.

Imaging of Metastatic CNS NeuroblastomaNicholas D'Ambrosio1, John K. Lyo, Robert J. Young, Sophia S. Haque and Sasan KarimiAudio Available | Share

The role of DCE-MR imaging in the study of bone marrow perfusion is only partially developed, though potential applications for routine use in the clinical setting are beginning to be described. We hypothesize that DCE-MR imaging can be used to discriminate between hypervascular and hypovascular metastases based on measured perfusion variables.We conducted a retrospective study of 26 patients using conventional MR imaging and DCE-MR imaging. Patients were assigned to a hypervascular or hypovascular group based on tumor pathology. ROIs were drawn around normal-appearing bone marrow (internal controls) and enhancing tumor areas. Average wash-in enhancement slope, average peak enhancement signal percentage change, and average peak enhancement signal percentage change in areas of highest wash-in enhancement slope were calculated. Indices were compared among control, hypervascular, and hypovascular groups. Conventional imaging was assessed by calculating pre- to postgadolinium signal percentage changes in hypervascular and hypovascular lesions.Hypervascular and hypovascular tumors differed significantly with regard to wash-in enhancement slope (P < .01; hypervascular 95% CI, 22.5-26.5 AU/s; hypovascular 95% CI, 14.1-20.9 AU/s) and peak enhancement signal percentage change in areas of highest wash-in enhancement slope (P < .01; hypervascular 95% CI, 174.1-323.3%; hypovascular 95% CI, 39.5-150.5%). Peak enhancement signal percentage change over all voxels was not significant (P = .62). Areas of normal-appearing marrow showed no appreciable contrast enhancement. Conventional contrast-enhanced MR imaging was unable to differentiate between hypervascular and hypovascular tumors (P = .58).Our data demonstrate that, unlike conventional MR imaging sequences, DCE-MR imaging may be a more accurate technique in discriminating hypervascular from hypovascular spinal metastases.

Primary central nervous system lymphoma (PCNSL) belongs to the group of extranodal non-Hodgkin's lymphoma, and the management of the disease is radically different from other central nervous system neoplasms. Owing to its varied appearance on imaging, diagnosis of PCNSL can be challenging. The purpose of this pictorial review is to depict the brain findings of PCNSL during initial diagnosis in immunocompetent individuals. Multimodal imaging integrating advanced sequences can facilitate differentiation of PCNSL from other CNS neoplasms.

Dynamic contrast-enhanced magnetic resonance imaging offers noninvasive characterization of the vascular microenvironment and hemodynamics. Stereotactic radiosurgery, or stereotactic body radiation therapy, engages a vascular component of the tumor response which may be detectable using dynamic contrast-enhanced magnetic resonance imaging. The purpose of this study is to examine whether dynamic contrast-enhanced magnetic resonance imaging can be used to predict local tumor recurrence in patients with spinal bone metastases who undergo high-dose radiotherapy with stereotactic radiosurgery.We conducted a study of 30 patients with spinal metastases who underwent dynamic contrast-enhanced magnetic resonance imaging before and after radiotherapy. Twenty patients received single-fraction stereotactic radiosurgery (24 Gy), while 10 received hypofractionated stereotactic radiosurgery (3-5 fractions, 27-30 Gy total). Kaplan-Meier analysis was used to estimate the actuarial local recurrence rates. Two perfusion parameters (Ktrans: permeability and Vp: plasma volume) were measured for each metastasis. Percentage change in parameter values from pre- to posttreatment was calculated and compared.At 20-month median follow-up, 5 of the 30 patients had pathological evidence of local recurrence. One- and 3-year actuarial local recurrence rates were 24% and 44% for the hypofractionated stereotactic radiosurgery cohort versus 5% and 16% for the single-fraction stereotactic radiosurgery cohort (P = .20). The average change in Vp and Ktrans for patients without local recurrence versus those with local recurrence was -76% and -66% versus +28% and -14% (P < .01 for both). With a cutoff point of -20%, Vp had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 98%, 91%, and 100%, respectively, for the detection of local recurrence following high-dose radiotherapy. Using this definition, dynamic contrast-enhanced magnetic resonance imaging identified local recurrence up to 18 months (mean [standard deviation], 6.6 [6.8] months) earlier than standard magnetic resonance imaging.We demonstrated that changes in perfusion parameters, particularly Vp, after high-dose radiotherapy to spinal bone metastases were predictive of local tumor recurrence. These changes predicted local recurrence on average >6 months earlier than standard imaging did.

Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy.

Rationale and Objectives The aim of this study was to assess the intrasubject and intersubject reproducibility of functional magnetic resonance imaging (fMRI) language paradigms on language localization and lateralization. Materials and Methods Fourteen healthy volunteers were enrolled prospectively and underwent language fMRI using visually triggered covert and overt sentence generation (SG) and word generation (WG) paradigms. Semiautomated analysis of all functional data was performed using Brain Voyager on an individual basis. Regions of interest for Broca's area, Wernicke's area, and their contralateral homologues were drawn. The Euclidean coordinates of the center of gravidity (x, y, and z) of the respective blood oxygenation level–dependent (BOLD) activation cluster, and the correlation of the measured hemodynamic response to the applied reference function (r), relative BOLD signal change as BOLD signal characteristics were measured in each region of interest. Regional lateralization indexes were calculated for Broca's area, Wernicke's area, and their contralateral homologues separately. Wilcoxon's signed-rank test was applied for statistical comparisons (P values < .05 were considered significant). Ten of the 14 volunteers had three repeated measurements to test intrasession reproducibility and intersession reproducibility. Results Overall activation rates for the four paradigms were 89% for covert SG, 82% for overt SG, 89% for covert WG, and 100% for overt WG. When comparing covert and overt paradigms, language localization was significantly different in 17% (Euclidean coordinates) and 19% (BOLD signal characteristics), respectively. Language lateralization was significantly different in 75%. Intrasubject and intersubject reproducibility was excellent, with 3.3% significant differences among all five parameters for language localization and 0% significant differences for language lateralization using covert paradigms. Conclusions Covert language paradigms (SG and WG) provided highly robust and reproducible localization and lateralization of essential language centers for scans performed on the same and different days. Their overt counterparts achieved confirmatory localization but lower lateralization capabilities. Reference data for presurgical application are provided. The aim of this study was to assess the intrasubject and intersubject reproducibility of functional magnetic resonance imaging (fMRI) language paradigms on language localization and lateralization. Fourteen healthy volunteers were enrolled prospectively and underwent language fMRI using visually triggered covert and overt sentence generation (SG) and word generation (WG) paradigms. Semiautomated analysis of all functional data was performed using Brain Voyager on an individual basis. Regions of interest for Broca's area, Wernicke's area, and their contralateral homologues were drawn. The Euclidean coordinates of the center of gravidity (x, y, and z) of the respective blood oxygenation level–dependent (BOLD) activation cluster, and the correlation of the measured hemodynamic response to the applied reference function (r), relative BOLD signal change as BOLD signal characteristics were measured in each region of interest. Regional lateralization indexes were calculated for Broca's area, Wernicke's area, and their contralateral homologues separately. Wilcoxon's signed-rank test was applied for statistical comparisons (P values < .05 were considered significant). Ten of the 14 volunteers had three repeated measurements to test intrasession reproducibility and intersession reproducibility. Overall activation rates for the four paradigms were 89% for covert SG, 82% for overt SG, 89% for covert WG, and 100% for overt WG. When comparing covert and overt paradigms, language localization was significantly different in 17% (Euclidean coordinates) and 19% (BOLD signal characteristics), respectively. Language lateralization was significantly different in 75%. Intrasubject and intersubject reproducibility was excellent, with 3.3% significant differences among all five parameters for language localization and 0% significant differences for language lateralization using covert paradigms. Covert language paradigms (SG and WG) provided highly robust and reproducible localization and lateralization of essential language centers for scans performed on the same and different days. Their overt counterparts achieved confirmatory localization but lower lateralization capabilities. Reference data for presurgical application are provided.

There has been increasing experience in the utilization of intraoperative magnetic resonance imaging (iMRI) for intracranial surgery. Despite this trend, only a few U.S centers have examined the use of this technology for transsphenoidal resection of tumors of the sella. We present the largest series in North America examining the role of iMRI for pituitary adenoma resection. We retrospectively reviewed our institutional experience of 59-patients who underwent transsphenoidal procedures for sellar and suprasellar tumors with iMRI guidance. Of these, 52 patients had a histological diagnosis of pituitary adenoma. The technical results of this subgroup were examined. A 1.5-T iMRI was integrated with the BrainLAB (Feldkirchen, Germany) neuronavigation system. The majority (94%) of tumors in our series were macroadenomas. Seventeen percent of tumors were confined to the sella, 49% had suprasellar extensions without involvement of the cavernous sinus, 34% had frank cavernous sinus invasion. All patients underwent at least one iMRI, and 19% required one or more additional sets of intraoperative imaging. In 58% of patients, iMRI led to the surgeon attempting more resection. A gross total resection was obtained in 67% of the patients with planned total resections. There was one case of permanent postoperative diabetes insipidus and no other instances of new hormone replacement. In summary, iMRI was most useful for tumors of the sella with and without suprasellar extension where the information from the iMRI extended the complete resection rate from 40 to 72% and 55 to 88%, respectively. As one would expect, it did not substantially increase the rate of resection of tumors with cavernous sinus invasion. Overall, iMRI was particularly useful in guiding resection safely, aiding in clinical decision making, and allowing identification and preservation of the pituitary stalk and normal pituitary gland. Limitations of the iMRI include a need for additional personnel and training as well as additional operative time, which diminishes over time as personnel learn to optimize workflow efficiency. Additional costs are mitigated in part by using the iMRI as an immediate postoperative scan. Other data emerging from our experience suggest that preservation of normal gland and thus avoidance of hypopituitarism may be improved by iMRI use, but longer follow-up periods are required to test this conclusion. iMRI can detect unsuspected complications sooner than routine postoperative imaging, potentially leading to improved outcomes. However, larger studies are needed.

A total of 40 patients with spinal metastases from renal cell carcinomas (RCCs) or prostate carcinomas (PCs) were studied using DCE-MRI (dynamic contrast-enhanced magnetic resonance imaging).To evaluate spinal metastases from RCC and PC to assess the sensitivity and specificity of perfusion parameters obtained by quantitative and semiquantitative methods, which would allow for noninvasive discrimination between hypovascular and hypervascular lesions.Conventional MRI can be inconclusive in assessing diagnostically complex spinal lesions in patients with cancer in whom fibrosis, infarction, edema related to compression fractures, and infection may simulate malignant neoplasm. Conventional MRI is also of limited value in assessing tumor vascularity and identifying hypervascular tumors. DCE-MRI offers an advantage over conventional MRI in that it provides anatomical, physiological, and hemodynamic information about neoplastic lesions.DCE perfusion parameters: vascular permeability, plasma volume (V(p)), wash-in slope, and peak-enhancement parameter were measured to assess their potential as discriminators of tumor vascularity. A Mann-Whitney U test (at P ≤ 0.01), was performed to quantify and compare significance of perfusion parameters between the 2 groups.Of the 4 perfusion parameters studied, V(p) was observed to have the largest difference in mean (μ) between PC (μ = 3.29/s) and RCC metastases (μ = 5.92/s). This was followed by the peak-enhancement, vascular permeability, and wash-in parameters. A Mann-Whitney U test showed a significant difference between V(p) values for PC and RCC lesions (P ≤ 0.001). Similarly, peak-enhancement parameter showed a significant difference between the 2 histologies (P ≤ 0.001), as did vascular permeability (P ≤ 0.01). The receiver operating characteristic curve showed that V(p) recorded the highest area under the curve (0.867).V(p) was shown to be the best discriminator between spinal metastases from PC and RCC with the mean V(p) of RCC metastasis being 1.8 times that of the PC lesions, thus discriminating between hyper- and hypovascular metastases, which has important clinical implications.

Blood-oxygenation-level-dependent (BOLD) contrast in magnetic resonance (MR) imaging of skeletal muscle mainly depends on changes of oxygen saturation in the microcirculation. In recent years, an increasing number of studies have evaluated the clinical relevance of skeletal muscle BOLD MR imaging in vascular diseases, such as peripheral arterial occlusive disease, diabetes mellitus, and chronic compartment syndrome. BOLD imaging combines the advantages of MR imaging, i.e., high spatial resolution, no exposure to ionizing radiation, with functional information of local microvascular perfusion. Due to intrinsic contrast provoked via changes in hemoglobin oxygen saturation, it is a safe and easy applicable procedure on standard whole-body MR devices. Therefore, BOLD MR imaging of skeletal muscle is a potential new diagnostic tool in the clinical evaluation of vascular, inflammatory, and muscular pathologies. Our review focuses on the current evidence concerning the use of BOLD MR imaging of skeletal muscle under pathological conditions and highlights ways for future clinical and scientific applications.

ABSTRACT BACKGROUND AND PURPOSE To evaluate whether breath‐holding (BH) blood oxygenation level‐dependent (BOLD) fMRI can quantify differences in vascular reactivity (VR), as there is a need for improved contrast mechanisms in gliomas. METHODS 16 patients (gliomas, grade II = 5, III = 2, IV = 9) were evaluated using the BH paradigm: 4‐second single deep breath followed by 16 seconds of BH and 40 seconds of regular breathing for five cycles. VR was defined as the difference in BOLD signal between the minimal signal seen at the end of the deep breath and maximal signal seen at the end of BH (peak‐to‐trough). VR was measured for every voxel and compared for gray versus white matter and tumor versus normal contralateral brain. VR maps were compared to the areas of enhancement and FLAIR/T2 abnormality. RESULTS VR was significantly lower in normal white matter than gray matter ( P &lt; .05) and in tumors compared to the normal, contralateral brain ( P &lt; 0.002). The area of abnormal VR (1103 ± 659 mm 2 ) was significantly greater ( P = .019) than the enhancement (543 ± 530 mm 2 ), but significantly smaller ( P = .0011) than the FLAIR abnormality (2363 ± 1232 mm 2 ). However, the variability in the areas of gadolinium contrast enhancement versus VR abnormality indicates that the contrast mechanism elicited by BH (caused by abnormal arteriolar smooth muscles) appears to be fundamentally different from the contrast mechanism of gadolinium enhancement (caused by the presence of “leaky” gap junctions). CONCLUSIONS BH maps based on peak‐to‐trough can be used to characterize VR in brain tumors. VR maps in brain tumor patients appear to be caused by a different mechanism than gadolinium enhancement.

Recent advances in image guidance and stereotactic body radiotherapy (SBRT) have resulted in unprecedented local control for spinal metastases of all histologies. However, little is known about early imaging biomarkers of local control.This study aimed to identify early magnetic resonance imaging (MRI) biomarkers to predict local control after SBRT for patients with sarcoma spine metastases.This study used a retrospective case series at a large tertiary cancer center.From 2011 to 2014, 9 consecutive patients with 12 metastatic sarcoma lesions to the spine were treated with SBRT and underwent evaluation with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) both pre- and post-SBRT.Changes in perfusion metrics, including the wash-in rate constant (Ktrans), plasma volume (Vp), composite multiparametric magnetic resonance imaging (mpMRI) score, bi-dimensional tumor size, and a graded response assessment were performed and correlated to local control.All measurements were independent and blinded by two neuroradiologists. R2 statistics were performed to document correlation, and two-tailed t tests were used to compare groups. p<.05 was deemed statistically significant.The median time from SBRT until posttreatment MRI was 57 days. Local failure developed in one lesion (8.3%) 10 months after SBRT. The Vp mean, Ktrans mean, Vp max, and Ktrans max were significantly decreased post-SBRT as compared with pre-SBRT (58.7%, 63.2%, 59.0%, and 55.2%; all p-values <.05). Bi-dimensional tumor measurements demonstrated an average increase in size across the cohort, and 50%, 25%, and 25% of the treated lesions demonstrated features of "worsening," "no change," or "improvement," respectively, by both radiologists' graded impressions. There was good inter-reader reliability for both size and subjective disease response scores (R2=0.84). The mpMRI score had 100% accuracy in predicting local control at time of last follow-up. There was no apparent correlation with size changes compared with the mpMRI score change post-SBRT (R2=0.026).We report the first analysis on the utility of DCE-MRI for metastatic sarcoma spine metastases treated with SBRT. We demonstrate that early assessment at 2 months post-SBRT using size and subjective neuroradiology impressions is insufficient to judge ultimate disease progression, and that a combination of perfusion parameters provides excellent correlation to local control.

Glioblastomas treated with bevacizumab may develop low-signal apparent diffusion coefficient (low-ADC) lesions, which may reflect increased tumor cellularity or atypical necrosis. The purpose of this study was to examine the relationship between low-ADC lesions and overall survival (OS). We hypothesized that growing low-ADC lesions would be associated with shorter OS.We retrospectively identified 52 patients treated with bevacizumab for the first (n = 42, 81%) or later recurrence of primary glioblastoma, who had low-ADC lesions and 2 post-bevacizumab scans ≤90 days apart. Low-ADC lesion volumes were measured, and normalized 5th percentile histogram low-ADC values were recorded. Using OS as the primary endpoint, semiparametric Cox models were fitted to ascertain univariate and multivariate hazard ratios (HRs) with significance at P = .05.Median OS was 9.1 months (95% CI = 7.2-14.3). At the second post-bevacizumab scan, the volume of the low-ADC lesion (median: 12.94 cm(3)) was inversely associated with OS, with larger volumes predicting shorter OS (HR = 1.014 [95% CI = 1.003-1.025], P = .009). The percent change in low-ADC volume (median: 6.8%) trended toward increased risk of death with growing volumes (P = .08). Normalized 5th percentile low-ADC value and its percent change were not associated with OS (P > .51). Also correlated with shorter OS were the pre-bevacizumab nonenhancing volume (P = .025), the first post-bevacizumab enhancing volume (P = .040), and the second post-bevacizumab enhancing volume (P = .004).The volume of low-ADC lesions at the second post-bevacizumab scan predicted shorter OS. This suggests that low-ADC lesions may be considered important imaging markers and included in treatment decision algorithms.

Abstract Objective: To evaluate YKL‐40 and MMP‐9 proteins as tumor biomarkers in serum samples from patients with primary central nervous system lymphoma (PCNSL). Methods: In this prospective longitudinal study, serum samples from consecutive patients with histologically confirmed PCNSL were collected concurrently with magnetic resonance imaging (MRI) scans at multiple time points and were analyzed for levels of YKL‐40 and MMP‐9 by enzyme‐linked immunosorbent assay. Marker levels were correlated to disease status and survival. Results: Forty‐five patients with PCNSL were accrued. Median follow‐up for survivors was 25 months, and 21 (47%) died during the study. A total of 230 serum samples were collected, and 93% had corresponding MRI scans. PCNSL patients without evidence of radiographic disease (29 patients, 131 samples) had significantly lower levels of serum YKL‐40 and MMP‐9 than patients with active tumor (n = 34 patients, 84 samples; p = 0.03 and 0.01, respectively). There was a significant inverse correlation between survival and doubling of the YKL‐40 level (hazard ratio, 1.7; p = 0.01). Interpretation: In patients with PCNSL, serum levels of YKL‐40 and MMP‐9 are associated with radiographic disease status. Longitudinal increase in serum levels of YKL‐40, but not MMP‐9, predicts survival in patients with PCNSL. ANN NEUROL 2011

OBJECTIVE High-dose image-guided radiation therapy (HD IGRT) has been instrumental in mitigating some limitations of conventional RT. The recent emergence of dynamic contrast-enhanced (DCE) MRI to investigate tumor physiology can be used to verify the response of human tumors to HD IGRT. The purpose of this study was to evaluate the near-immediate effects of HD IGRT on spine metastases through the use of DCE MRI perfusion studies. METHODS Six patients with spine metastases from prostate, thyroid, and renal cell carcinoma who underwent HD IGRT were studied using DCE MRI prior to and 1 hour after HD IGRT. The DCE perfusion parameters plasma volume (Vp) and vascular permeability (Ktrans) were measured to assess the near-immediate and long-term tumor response. A Mann-Whitney U-test was performed to compare significant changes (at p ≤ 0.05) in perfusion parameters before and after RT. RESULTS The authors observed a precipitous drop in Vp within 1 hour of HD IGRT, with a mean decrease of 65.2%. A significant difference was found between Vp values for before and 1 hour after RT (p ≤ 0.05). No significant change was seen in Vp (p = 0.31) and Ktrans (p = 0.1) from 1 hour after RT to the first follow-up. CONCLUSIONS The data suggest that there is an immediate effect of HD IGRT on the vascularity of spine metastases, as demonstrated by a precipitous decrease in Vp. The DCE MRI studies can detect such changes within 1 hour after RT, and findings are concordant with existing animal models.

Patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer's disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population.One hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood-brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs.Multivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities.This novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.

The contemporary embrace of endoscopic technology in the approach to the anterior skull base has altered the perioperative landscape for patients requiring pituitary surgery. Utility of a multi-disciplinary unit in management decisions facilitates the delivery of optimal care. Evolution of technology and surgical expertise in pituitary surgery mandates ongoing review of all components of the care central to these patients. The many areas of potential variability in the pre, intra and post-operative timeline of pituitary surgery are readily identifiable. Core undertakings and contemporary controversies in the peri-operative management of patients undergoing endoscopic transsphenoidal pituitary surgery are assessed against the available literature with a view to providing guidance for the best evidence-based practice.

Background Dynamic contrast agent-enhanced (DCE) perfusion MRI may help differentiate between nonneoplastic and malignant lesions in the spine. Purpose To investigate the correlation between fractional plasma volume (Vp), a parameter derived from DCE perfusion MRI, and histopathologic diagnosis for spinal lesions. Materials and Methods In this retrospective study, patients who underwent DCE perfusion MRI and lesion biopsy between May 2015 and May 2018 were included. Inclusion criteria were short time interval (<30 days) between DCE perfusion MRI and biopsy, DCE perfusion MRI performed before biopsy, and DCE perfusion MRI performed at the same spine level as biopsy. Exclusion criteria were prior radiation treatment on vertebrae of interest, poor DCE perfusion MRI quality, nondiagnostic biopsy, and extensive spinal metastasis or prior kyphoplasty. One hundred thirty-four lesions were separated into a nonneoplastic group (n = 51) and a malignant group (n = 83) on the basis of histopathologic analysis. Two investigators manually defined regions of interest in the vertebrae. DCE perfusion MRI parameter Vp was calculated by using the Tofts pharmacokinetic two-compartment model. Vp was quantified, normalized to adjacent normal vertebrae, and compared between the two groups. A Mann-Whitney U test and receiver operating characteristic analysis was performed to verify the difference in Vp between the nonneoplastic and malignant groups. Reproducibility was assessed by calculating the Cohen κ coefficient. Results One hundred patients (mean age, 65 years ± 11 [standard deviation]; 52 men) were evaluated. Vp was lower in nonneoplastic lesions versus malignant lesions (1.6 ± 1.3 vs 4.2 ± 3.0, respectively; P < .001). The sensitivity of Vp was 93% (77 of 83; 95% confidence interval [CI]: 85%, 97%), specificity was 78% (40 of 51; 95% CI: 65%, 89%), and area under the receiver operating characteristic curve was 0.88 (95% CI: 0.82, 0.95). Cohen κ coefficient suggested substantial agreement in both intra- (κ = 0.72) and interreader (κ = 0.70) reproducibility. Conclusion This study indicated that dynamic contrast agent-enhanced perfusion MRI parameter, fractional plasma volume, was able to differentiate between nonneoplastic spinal lesions and malignant lesions. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Haller in this issue.

To differentiate pathologic from benign vertebral fractures, which can be challenging. We hypothesized that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can aid in the noninvasive distinction between pathologic and benign fractures.Consecutive patients with vertebral fractures who underwent DCE-MRI, biopsy, and kyphoplasty were reviewed. Forty-seven fractures were separated into pathologic and benign fractures. Benign fractures were in turn separated into acute and chronic fractures for further comparison. Regions of interest (ROIs) were placed over fractured vertebral bodies. Perfusion parameters: plasma volume (Vp ), K(trans) , wash-in slope, peak enhancement, and area under the curve (AUC) were measured and compared between the three different groups of fractures. A Mann-Whitney U-test was conducted to assess the difference between the groups.Pathologic fractures had significantly higher (P < 0.01) perfusion parameters (Vp , K(trans) , wash-in slope, peak enhancement, and AUC) compared with benign fractures. We also found significant differences (P < 0.001) in all parameters between chronic and acute fractures. Vp and K(trans) were able to differentiate between pathologic and acute fractures (P < 0.01). No significant differences were found with peak enhancement (P = 0.21) and AUC (P = 0.4) between pathologic and acute fractures.Our data demonstrate that T1 -weighted DCE-MRI has potential to differentiate between pathologic vs. benign, acute vs. chronic, and most important, benign acute vs. pathologic vertebral fractures.

The diagnosis of leptomeningeal metastasis (LM) has increased in frequency, as new therapies have lengthened the survival of patients with cancer. Early diagnosis and intervention help improve quality of life and prevent further neurological deterioration in LM. The detection of LM is often established by magnetic resonance imaging examinations, cerebrospinal fluid analysis, or both. We present a series of cases where LM was identified on fluid-attenuated inversion recovery or T2-weighted image but was nonenhancing on the traditionally more sensitive postcontrast T1-weighted sequences. Nonenhancing LM is unusual and not yet fully understood but should be considered in the appropriate clinical context and may become more common with increased utilization of antiangiogenic therapies.

The reprogramming of cellular metabolism is a hallmark of cancer diagnosis and prognosis. Proton magnetic resonance spectroscopic imaging (MRSI) is a non-invasive diagnostic technique for investigating brain metabolism to establish cancer diagnosis and IDH gene mutation diagnosis as well as facilitate pre-operative planning and treatment response monitoring. By allowing tissue metabolism to be quantified, MRSI provides added value to conventional MRI. MRSI can generate metabolite maps from a single volume or multiple volume elements within the whole brain. Metabolites such as NAA, Cho and Cr, as well as their ratios Cho:NAA ratio and Cho:Cr ratio, have been used to provide tumor diagnosis and aid in radiation therapy planning as well as treatment assessment. In addition to these common metabolites, 2-hydroxygluterate (2HG) has also been quantified using MRSI following the recent discovery of IDH mutations in gliomas. This has opened up targeted drug development to inhibit the mutant IDH pathway. This review provides guidance on MRSI in brain gliomas, including its acquisition, analysis methods, and evolving clinical applications.

OBJECTIVE The utility and safety of intraoperative MRI (iMRI) for resection of pituitary adenomas is not clearly established in the context of advances in endoscopic approaches. The goal in this study was to evaluate the safety and efficacy of iMRI for pituitary adenoma resection, with endoscopic transsphenoidal (ETS) versus microscopic transsphenoidal (MTS) approaches. METHODS Radiographic and clinical outcomes of all pituitary adenomas resected using iMRI between 2008 and 2017 at a single institution were retrospectively evaluated. RESULTS Of 212 tumors treated, 131 (62%) underwent further resection based on iMRI findings, resulting in a significant increase in gross-total resection on postoperative MRI compared with iMRI (p = 0.0001) in both ETS and MTS groups. iMRI increased rates of gross-total resection for cavernous sinus invasion Knosp grades 1 and 2, but not in Knosp ≥ 3 across treatment groups (p &lt; 0.0001). The extent of resection on postoperative MRI was significantly correlated with increased progression-free survival (p &lt; 0.0001). Initial hormone remission off medical therapy was achieved in 64%, with a significantly higher rate of remission in tumors resected via the ETS approach (81%) compared with the MTS approach (55%) (p = 0.02). The rate of persistent new hormone deficit was low at 8%, including a 2.8% rate of permanent diabetes insipidus, and 45% of patients had improvement in preoperative hormone deficit following surgery. Serious postoperative complications including CSF leaks requiring reoperation were rare at 1%, with no postoperative infections. CONCLUSIONS These results suggest that iMRI is a safe and effective method of increasing the extent of resection for pituitary adenomas while preserving hormone function. When paired with the endoscope, iMRI may offer the ability to tailor more aggressive removal of tumors while optimizing pituitary function, resulting in high rates of secretory hormone remission. Secretory tumors and adenomas with Knosp grade &lt; 3 cavernous sinus invasion may benefit most from the use of iMRI.

The objective of this study was to evaluate if longitudinal measurements of serum matrix metalloproteinase-9 (MMP-9) correlated with disease status or survival in adults with gliomas. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. MMP-9 levels were determined by ELISA and correlated with radiographic disease status and survival. Forty-one patients with low-grade gliomas, 105 with anaplastic gliomas, and 197 with glioblastoma enrolled in this study from August 2002 to September 2008. A total of 1,684 serum samples (97.1% of all MMP-9 samples) had a matching MRI scan. No statistically significant association was observed between levels of serum MMP-9 and radiographic disease status in low-grade gliomas (P = 0.98), anaplastic gliomas (P = 0.39) or glioblastomas (P = 0.33). Among patients with glioblastoma, longitudinal increases in MMP-9 had a weak association with shorter survival (HR = 1.1 per each doubling in MMP-9 levels, 95% CI, 1.0–1.3, P = 0.04) but they were not independently associated with survival when adjusted for age, extent of resection, and performance status. Changes in serum MMP-9 were not associated with survival in the anaplastic glioma cohort. Serum MMP-9 showed no utility in determining glioma disease status and was not a clinically relevant prognostic marker of survival.

This was a retrospective study comparing dynamic contrast-enhanced magnetic resonance (DCE-MR) perfusion with digital subtraction angiography (DSA) in determining the vascularity of spinal tumors.To report on the efficacy of DCE-MR perfusion as a potential noninvasive surrogate for measuring vascularity and thus determine the need for preoperative embolization.Although primary spinal tumors are rare, spine metastases are relatively common and symptomatic in approximately 14% of patients. Symptomatic patients require palliation with radiotherapy and/or surgery, with possible preoperative endovascular embolization of the tumor.A retrospective review revealed 10 patients with 11 diseased vertebral bodies who had received spine DCE-MR perfusion studies and subsequently underwent spinal DSA. Processed MR data were used to calculate a blood flow ratio comparing blood flow with a diseased and an adjacent normal vertebral body. Spinal tumor vascularity was graded on the basis of angiographic tumor blush from 0 (decreased enhancement compared with a normal vertebral body) to 4 (marked tumor blush with early arteriovenous shunting).Eight vertebral bodies demonstrated increased vascularity on DSA with blood flow ratios of greater than 1.8, 2 vertebral bodies demonstrated normal enhancement on DSA with cerebral blood flow (CBF) ratio of 0.55 to 1.14, and 1 vertebral body level had decreased enhancement on DSA, with a CBF ratio of 0.43. There was a strong correlation between CBF ratio and DSA score, with Spearman ρ = 0.87 (P = 0.00012).These data show a statistically significant correlation between CBF ratio and DSA and suggest that DCE-MR perfusion can serve as a surrogate to DSA for determining tumor vascularity in patients with extramedullary spinal metastases.

<h3>BACKGROUND AND PURPOSE:</h3> Chordomas notoriously demonstrate a paucity of changes following radiation therapy on conventional MR imaging. We hypothesized that dynamic contrast-enhanced MR perfusion imaging parameters of chordomas would change significantly following radiation therapy. <h3>MATERIALS AND METHODS:</h3> Eleven patients with pathology-proved chordoma who completed dynamic contrast-enhanced MR perfusion imaging pre- and postradiation therapy were enrolled. Quantitative tumor measurements were obtained by 2 attending neuroradiologists. ROIs were used to calculate vascular permeability and plasma volume and generate dynamic contrast-enhancement curves. Quantitative analysis was performed to determine mean and maximum plasma volume and vascular permeability values, while semiquantitative analysis on averaged concentration curves was used to determine the area under the curve. A Mann-Whitney <i>U</i> test at a significance level of <i>P</i> &lt; .05 was used to assess differences of the above parameters between pre- and postradiation therapy. <h3>RESULTS:</h3> Plasma volume mean (pretreatment mean = 0.82; posttreatment mean = 0.42), plasma volume maximum (pretreatment mean = 3.56; posttreatment mean = 2.27), and vascular permeability mean (pretreatment mean = 0.046; posttreatment mean = 0.028) in the ROIs significantly decreased after radiation therapy (<i>P</i> &lt; .05); this change thereby demonstrated the potential for assessing tumor response. Area under the curve values also demonstrated significant differences (<i>P</i> &lt; .05). <h3>CONCLUSIONS:</h3> Plasma volume and vascular permeability decreased after radiation therapy, suggesting that these dynamic contrast-enhanced MR perfusion parameters may be useful for monitoring chordoma growth and response to radiation therapy. Additionally, the characteristic dynamic MR signal intensity–time curve of chordoma may provide a radiographic means of distinguishing chordoma from other spinal lesions.

Objectives To compare different methods of measuring tumor growth after resection of vestibular schwannoma and to identify predictors of growth. Study Design Retrospective case review. Setting Tertiary referral center, inpatient surgery with ambulatory follow-up. Patients All patients who underwent vestibular schwannoma resection by the senior author from September 1991 to April 2012 and had two or more postoperative MRI scans. Interventions Vestibular schwannoma resection. Measurement of tumor size and enhancement pattern on postoperative magnetic resonance imaging scans. Main Outcome Measures Tumor size as measured in one (linear), two (planar), and three (volumetric) dimensions using standard radiology workstation tools versus time elapsed since surgical resection. Results Eighty-eight patients were included with mean follow-up of 3.9 years. Linear measurement of tumor size was found to have modest correlation with planar and volumetric measurements. Excellent correlation was found between the planar and volumetric methods. Nodular enhancement increased risk for tumor growth (OR 6.25, p = 0.03 on planar analysis). If there was growth, tumors with nodular enhancement typically showed increase in size beginning 2 years postoperatively, whereas those with linear or no enhancement were typically stable in size through 5 years. Younger age and larger preoperative tumor size were also risk factors for growth (OR 0.9/p = 0.01 and OR 1.09/p = 0.02). Conclusion Simple planar measurement is an efficient method that correlates well with the more time-consuming volumetric method. The major risk factor for tumor growth is nodular enhancement on a baseline scan, a finding that warrants annual MRI beginning 2 years postoperatively. Younger age and larger preoperative size minimally increased risk of growth.

Background Artificial intelligence (AI) applications for cancer imaging conceptually begin with automated tumor detection, which can provide the foundation for downstream AI tasks. However, supervised training requires many image annotations, and performing dedicated post hoc image labeling is burdensome and costly. Purpose To investigate whether clinically generated image annotations can be data mined from the picture archiving and communication system (PACS), automatically curated, and used for semisupervised training of a brain MRI tumor detection model. Materials and Methods In this retrospective study, the cancer center PACS was mined for brain MRI scans acquired between January 2012 and December 2017 and included all annotated axial T1 postcontrast images. Line annotations were converted to boxes, excluding boxes shorter than 1 cm or longer than 7 cm. The resulting boxes were used for supervised training of object detection models using RetinaNet and Mask region-based convolutional neural network (R-CNN) architectures. The best-performing model trained from the mined data set was used to detect unannotated tumors on training images themselves (self-labeling), automatically correcting many of the missing labels. After self-labeling, new models were trained using this expanded data set. Models were scored for precision, recall, and F1 using a held-out test data set comprising 754 manually labeled images from 100 patients (403 intra-axial and 56 extra-axial enhancing tumors). Model F1 scores were compared using bootstrap resampling. Results The PACS query extracted 31 150 line annotations, yielding 11 880 boxes that met inclusion criteria. This mined data set was used to train models, yielding F1 scores of 0.886 for RetinaNet and 0.908 for Mask R-CNN. Self-labeling added 18 562 training boxes, improving model F1 scores to 0.935 (P < .001) and 0.954 (P < .001), respectively. Conclusion The application of semisupervised learning to mined image annotations significantly improved tumor detection performance, achieving an excellent F1 score of 0.954. This development pipeline can be extended for other imaging modalities, repurposing unused data silos to potentially enable automated tumor detection across radiologic modalities. © RSNA, 2022 Online supplemental material is available for this article.

Recent therapeutic advances have led to increased survival times for patients with metastatic disease. Key to survival is early diagnosis and subsequent treatment as well as early detection of treatment failure allowing for therapy modifications. Conventional MR imaging techniques of the spine can be at times suboptimal for identifying viable tumor, as structural changes and imaging characteristics may not differ pretreatment and posttreatment. Advanced imaging techniques such as DCE-MRI can allow earlier and more accurate noninvasive assessment of viable disease by characterizing physiologic changes and tumor microvasculature.

magnetic resonance spectroscopic imaging (MRSI) can improve the accuracy of target delineation for gliomas, but it lacks the anatomic resolution needed for image fusion. This paper presents a simple protocol for fusing simulation computer tomography (CT) and MRSI images for glioma intensity‐modulated radiotherapy (IMRT), including a retrospective study of 12 patients. Each patient first underwent whole‐brain axial fluid‐attenuated‐inversion‐recovery (FLAIR) MRI (3 mm slice thickness, no spacing), followed by three‐dimensional (3D) MRSI measurements (TE/TR: ) of a user‐specified volume encompassing the extent of the tumor. The nominal voxel size of MRSI ranged from to . A system was developed to grade the tumor using the choline‐to‐creatine (Cho/Cr) ratios from each MRSI voxel. The merged MRSI images were then generated by replacing the Cho/Cr value of each MRSI voxel with intensities according to the Cho/Cr grades, and resampling the poorer‐resolution Cho/Cr map into the higher‐resolution FLAIR image space. The FUNCTOOL processing software was also used to create the screen‐dumped MRSI images in which these data were overlaid with each FLAIR MRI image. The screen‐dumped MRSI images were manually translated and fused with the FLAIR MRI images. Since the merged MRSI images were intrinsically fused with the FLAIR MRI images, they were also registered with the screen‐dumped MRSI images. The position of the MRSI volume on the merged MRSI images was compared with that of the screen‐dumped MRSI images and was shifted until agreement was within a predetermined tolerance. Three clinical target volumes (CTVs) were then contoured on the FLAIR MRI images corresponding to the Cho/Cr grades. Finally, the FLAIR MRI images were fused with the simulation CT images using a mutual‐information algorithm, yielding an IMRT plan that simultaneously delivers three different dose levels to the three CTVs. The image‐fusion protocol was tested on 12 (six high‐grade and six low‐grade) glioma patients. The average agreement of the MRSI volume position on the screen‐dumped MRSI images and the merged MRSI images was 0.29 mm with a standard deviation of 0.07 mm. Of all the voxels with Cho/Cr grade one or above, the distribution of Cho/Cr grade was found to correlate with the glioma grade from pathologic finding and is consistent with literature results indicating Cho/Cr elevation as a marker for malignancy. In conclusion, an image‐fusion protocol was developed that successfully incorporates MRSI information into the IMRT treatment plan for glioma.

Osteochondromas are the most common benign bone tumor, most commonly found in the ends of long bones; however, they rarely involve facial bones, particularly the mandible. Osteochondromas involving the coronoid process have rarely been reported in the literature but pose a diagnostic dilemma. When large enough, osteochondromas of the mandibular coronoid process can form a joint with the zygomatic arch (Jacob's disease). This pseudoarticulation results in restricted jaw motion, which can clinically be mistaken for temporomandibular joint dysfunction. We report a case of a 39-year-old man with chronic restricted jaw motion undiagnosed for several years.

Abstract Magnetic resonance spectroscopic imaging (MRSI) is currently used clinically in conjunction with anatomical MRI to assess the presence and extent of brain tumors and to evaluate treatment response. Unfortunately, the clinical utility of MRSI is limited by significant variability of in vivo spectra. Spectral profiles show increased variability because of partial coverage of large voxel volumes, infiltration of normal brain tissue by tumors, innate tumor heterogeneity, and measurement noise. We address these problems directly by quantifying the abundance (i.e. volume fraction) within a voxel for each tissue type instead of the conventional estimation of metabolite concentrations from spectral resonance peaks. This ‘spectrum separation’ method uses the non‐negative matrix factorization algorithm, which simultaneously decomposes the observed spectra of multiple voxels into abundance distributions and constituent spectra. The accuracy of the estimated abundances is validated on phantom data. The presented results on 20 clinical cases of brain tumor show reduced cross‐subject variability. This is reflected in improved discrimination between high‐grade and low‐grade gliomas, which demonstrates the physiological relevance of the extracted spectra. These results show that the proposed spectral analysis method can improve the effectiveness of MRSI as a diagnostic tool. Copyright © 2008 John Wiley &amp; Sons, Ltd.

Characterize hypertrophic olivary degeneration (HOD) that develops from posterior fossa masses and their treatments.Retrospectively reviewed MR images and clinical data of 10 patients with posterior fossa masses and HOD.Eight patients had cerebellar lesions, and two patients had pontine lesions. Lesions consisted of tumors, demyelination, and nonspecific necrosis. MRI showed T2 hyperintense signal in the inferior olive a median 86 days after the diagnosis of a posterior fossa lesion. HOD presented prior to surgery (n=2), after surgery (n=3), after surgery/radiation therapy (n=4), or without treatment (n=1).HOD may develop from posterior fossa masses and surgical and/or radiation therapy.

To compare compressed diffusion spectrum imaging (CS-DSI) with diffusion tensor imaging (DTI) in patients with intracranial masses. We hypothesized that CS-DSI would provide superior visualization of the motor and language tracts. We retrospectively analyzed 25 consecutive patients with intracranial masses who underwent DTI and CS-DSI for preoperative planning. Directionally-encoded anisotropy maps, and streamline hand corticospinal motor tracts and arcuate fasciculus language tracts were graded according to a 3-point scale. Tract counts, anisotropy, and lengths were also calculated. Comparisons were made using exact marginal homogeneity, McNemar's and Wilcoxon signed-rank tests. Readers preferred the CS-DSI over DTI anisotropy maps in 92% of the cases, and the CS-DSI over DTI tracts in 84%. The motor tracts were graded as excellent in 80% of cases for CS-DSI versus 52% for DTI; 58% of the motor tracts graded as acceptable in DTI were graded as excellent in CS-DSI (p = 0.02). The language tracts were graded as excellent in 68% for CS-DSI versus none for DTI; 78% of the language tracts graded as acceptable by DTI were graded as excellent by CS-DSI (p < 0.001). CS-DSI demonstrated smaller normalized mean differences than DTI for motor tract counts, anisotropy and language tract counts (p ≤ 0.01). CS-DSI was preferred over DTI for the evaluation of motor and language white matter tracts in patients with intracranial masses. Results suggest that CS-DSI may be more useful than DTI for preoperative planning purposes.

Calcifying pseudoneoplasms of the neuraxis are extremely rare calcified lesions that can occur anywhere in the central nervous system. These non-neoplastic lesions have been reported to arise both in the brain and spine with similar frequency and can be found intra-axially as well as extra-axially. The associated symptoms are generally due to mass effect rather than local invasion as calcifying pseudoneoplasms of the neuraxis are usually considered to be benign non-infiltrative lesions. We report a unique case of a 67-year-old male patient who developed lower extremity weakness and gait instability with imaging and histological features of calcifying pseudoneoplasm of the neuraxis occurring in the spine with adhesive features and intradural extension. Calcifying pseudoneoplasms are benign, slow-growing masses that can present with a wide variety of symptoms depending on the size and location of the tumor. The differential diagnosis for these entities can be narrowed taking into consideration relevant imaging features as well as important clinical information.

2025 Background: Increased contrast enhancement on brain imaging following chemoradiotherapy is often interpreted as progression of disease (PD). However, there is growing evidence that radiographic and even clinical worsening may result from effects of therapy, i.e. PsPr, rather than from true PD. Methods: 80 patients (pts) with GBM were treated in an IRB-approved phase 2 clinical trial with concurrent RT and TMZ followed by adjuvant TMZ. MRI was performed post-RT. PsPr was defined as increased contrast enhancement on the initial post-RT MRI scan that improved without changing chemotherapy, or as histologically documented necrosis. True PD was defined as continued progression on subsequent scans, or histologically documented viable tumor. MR perfusion imaging with relative cerebral blood volume (rCBV) and FDG PET imaging were collected in subsets of patients. Results: There were 33 pts with increased enhancement on the initial post-RT MRI; 8 (24%) had PsPr, 17 (52%) had true PD, and 8 (24%) discontinued TMZ (PsPr vs. true PD unknown). Of the 8 pts with PsPr, 2 had MR perfusion scans; both demonstrated increased rather than decreased rCBV. Two others had FDG PET scans; both showed hyper- rather than hypometabolism. Of the 17 patients with true PD, 5 had MR perfusion scans: 4 had increased rCBV and 1 had decreased rCBV; none had PET scans. The single patient with histologically documented PsPr had at the time of surgery, after 2 cycles of adjuvant TMZ, both increased rCBV and hypermetabolic PET scan; perfusion imaging was not performed with his first post-RT MRI. 6 of the 8 pts with PsPr were clinically worse at their post-RT visit; 7 of the 17 with true PD were clinically worse. Conclusions: At least 24% of our pts with increased contrast enhancement post-RT had PsPr; the incidence could be as high as 48% if all 8 pts who discontinued TMZ for a worsening scan actually had PsPr. MR perfusion, FDG PET, and clinical status were not predictive of PsPr versus true PD. It may be reasonable to consider findings on the post-RT MRI as a new baseline, rather than an assessment of response to chemo-RT, because of the high (24–48%) risk of PsPr. This approach would also minimize the likelihood of overestimating the benefits of second-line treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Schering-Plough

Granular cell tumor is a rare, benign breast neoplasm that may mimic malignancy both clinically and radiologically. We present 2 cases in which granular cell tumor was initially diagnosed by sonographically guided percutaneous biopsies. Sonographic guidance confirmed needle placement during multiple passes and thereby decreased the likelihood of sampling error. A diagnosis of granular cell tumor prior to definitive resection enables optimal therapeutic planning and allows radical surgery to be avoided.

<b>SUMMARY:</b> We present the first description of CT of a meningioma of the mandible in the literature. Extracranial meningiomas are exceedingly rare. There have been 3 cases of meningioma of the mandible described in the literature, but none characterized with cross-sectional imaging. We describe the clinical and CT features used to establish the diagnosis as well as how to differentiate this lesion from other pathology of the mandible.

The hallmark radiological finding in metastatic brain disease is multiple enhancing lesions. We report a case of metastatic lung cancer to the brain with a lack of contrast enhancement. We believe that this unusual finding is due to inadvertent “treatment” of the metastases with the antiangiogenic agent bevacizumab (Avastin).

ABSTRACT INTRODUCTION Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system (CNS) that classically occurs in children and adolescents. It characteristically presents with acute inflammation, resulting in demyelination, often following an infectious disease. ADEM has been described in adult patients, but the incidence in the adult and especially elderly population is low. CASES We describe five older adults (age 57 to 85) who presented with acute neurological symptoms. Three patients presented with an infectious illness preceding the event, 4 patients were encephalopathic, and oligoclonal bands (OCBs) were negative in all tested cases. The clinical scenario and imaging studies suggested alternative diagnoses, such as metastasis, primary CNS tumor, or stroke. Two patients had contrast enhancing lesions, two other patients had lesions with restricted diffusion on diffusion‐weighted imaging. Neuropathologic diagnostic from biopsy or autopsy was eventually conclusive, showing perivascular zones of myelin loss with relative axonal sparing in all five cases. CONCLUSION Each of these patients was found to have pathological findings of acute demyelination on tissue diagnosis, suggesting ADEM or ADEM‐like disease. The initial presentation and imaging was pointing toward other diagnoses. Broad differential diagnosis is important, especially for older patients, and pathological proof might be warranted for a conclusive diagnosis.

OBJECTIVE Percutaneous vertebral augmentation procedures such as vertebroplasty and kyphoplasty are often performed in cancer patients to relieve mechanical axial-load pain due to pathological collapse deformities. The collapsed vertebrae in these patients can be associated with varying degrees of spinal canal compromise that can be worsened by kyphoplasty. In this study the authors evaluated changes to the spinal canal, in particular the cross-sectional area of the thecal sac, following balloon kyphoplasty (BKP) prior to stereotactic radiosurgery (SRS). METHODS The authors retrospectively reviewed the records of all patients with symptomatic vertebral compression fractures caused by metastatic disease who underwent kyphoplasty prior to single-fraction SRS. The pre-BKP cross-sectional image, usually MRI, was compared to the post-BKP CT myelogram required for radiation treatment planning. The cross-sectional area of the thecal sac was calculated pre- and postkyphoplasty, and intraprocedural CT imaging was reviewed for epidural displacement of bone fragments, tumor, or polymethylmethacrylate (PMMA) extravasation. The postkyphoplasty imaging was also evaluated for evidence of fracture progression or fracture reduction. RESULTS Among 30 consecutive patients, 41 vertebral levels were treated with kyphoplasty, and 24% (10/41) of the augmented levels showed a decreased cross-sectional area of the thecal sac. All 10 of these vertebral levels had preexisting epidural disease and destruction of the posterior vertebral body cortex. No bone fragments were displaced posteriorly. Minor epidural PMMA extravasation occurred in 20% (8/41) of the augmented levels but was present in only 1 of the 10 vertebral segments that showed a decreased cross-sectional area of the thecal sac postkyphoplasty. CONCLUSIONS In patients with preexisting epidural disease and destruction of the posterior vertebral body cortex who are undergoing BKP for pathological fractures, there is an increased risk of further mass effect upon the thecal sac and the potential to alter the SRS treatment planning.

The development of new surrogate markers of atherosclerosis is a crucial goal in the clinical setting, as they may allow physicians to recognize unstable lesions early and identify individuals with vulnerable or unstable lesions who bear an increased risk of future cardio--and cerebrovascular complications. These surrogate markers should be capable of being measured noninvasively using safe and reliable methods. Recently, Nambi et al. demonstrated how the combined measurement of carotid intima media thickness (CIMT) and occurrence of carotid plaques improves the risk prediction of cardiovascular outcomes. These results confirm the value of carotid ultrasound (US) when combined with traditional Framingham risk factors in assessing a patient's risk for atherosclerotic disease. Contrast-enhanced ultrasound (CEUS) is a new imaging approach that is evolving and may become a standard clinical tool for further atherosclerotic risk stratification in the future. The contrast agents used in US imaging are safe, commercially available, and approved for use in echocardiography by the FDA. Thus, CEUS is technically feasible with existing approved commercial equipment and can be performed at the bedside or in an outpatient setting. However, US contrast agents are not yet approved by the FDA for visualization and assessment of the carotid artery and its associated pathologies. The cost effectiveness of CEUS has been shown in the context of gastrointestinal imaging, and CEUS of carotid atherosclerotic lesions is emerging as an approach to complement unenhanced US imaging. By providing the direct visualization of adventitial vasa vasorum (VV) and intraplaque neovascularization, CEUS is capable of depicting two new surrogate markers of atherosclerosis - namely, adventitial VV and intraplaque neovascularization.

2036 Background: Preclinical data suggest BEV may sensitize tumor endothelia to RT and disrupt vascular niches harboring cancer stem cells. Due to radioprotective effects, BEV also allows for more aggressive RT schedules. In our previous phase II trial of BEV and HFSRT in recurrent GBM, the 6-m progression-free survival (PFS) was 65%, and 1y overall survival (OS) was 54%. Encouraged by these results, we initiated a phase II study in newly diagnosed GBM utilizing HFSRT, BEV and TMZ. Methods: Pts with newly diagnosed GBM and tumor volume under 60cc were eligible. Treatment consisted of HFSRT (6 treatments over 2 weeks: 6x6 Gy to contrast-enhancing tumor and 6×4 Gy to FLAIR hypersignal, with dose painting), concomitant with BEV (10 mg/kg days 1 and 15) and TMZ (75 mg/m2 daily), followed by adjuvant BEV (10 mg/kg every 2 weeks) and TMZ (150-200 mg/m2 in 5/28 days). Correlative studies include neuropsychological evaluation, perfusion MRI, analysis of circulating angiogenic factors, bone marrow-derived hematopoietic/endothelial progenitor cells, tumor MGMT promoter methylation and expression of hypoxia/angiogenesis-related factors. Primary endpoint is 1-year OS (single-stage binomial design, n = 40 planned). Results: To date, 30 pts have been enrolled, and 25 have started treatment (11 women; median age: 55 y; median KPS: 90). MGMT promoter was methylated in 5 pts, unmethylated in 14, not available in 6. Grades 3 and 4 toxicities were lymphopenia (3 pts), platelets (3), hemoglobin (1), neutrophils (2), bilirubin (1), ALT (2), pulmonary embolism (1) and thrombotic microangiopathy/renal failure (1). With a median followup of 30 weeks, the 6m- PFS was 87% (95% CI 64-97%); median PFS was 37 weeks; no patient has experienced pseudo progression or radionecrosis. Among evaluable pts (n = 13), a complete response has been observed in 2 pts and partial response in 8; disease was stable in 3 pts. Conclusions: This treatment is safe, more convenient for patients and is associated with a significant decrease in the rate of pseudo progression, despite the hypofractionated RT schedule. PFS has been superior to standard treatment, but longer followup is needed for evaluation of OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech, Novartis, Pfizer, Schering-Plough

The primary hand motor region is classically believed to be in the “hand knob” area in the precentral gyrus (PCG). However, hand motor task-based activation is often localized outside this area. The purpose of this study is to investigate the structural and functional connectivity driven by different seed locations corresponding to the little, index, and thumb in the PCG using probabilistic diffusion tractography (PDT) and resting-state functional magnetic resonance imaging (rfMRI). Twelve healthy subjects had three regions of interest (ROIs) placed in the left PCG: lateral to the hand knob (thumb area), within the hand knob (index finger area), and medial to the hand knob (little finger area). Connectivity maps were generated using PDT and rfMRI. Individual and group level analyses were performed. Results show that the greatest hand motor connectivity between both hemispheres was obtained using the ROI positioned just lateral to the hand knob in the PCG (the thumb area). The number of connected voxels in the PCG between the two hemispheres was greatest in the lateral-most ROI (the thumb area): 279 compared with 13 for the medial-most ROI and 9 for the central hand knob ROI. Similarly, the highest white matter connectivity between the two hemispheres resulted from the ROI placed in the lateral portion of PCG (p < 0.003). The maximal functional and structural connectivity of the hand motor area between hemispheres occurs in the thumb area, located laterally at the “hand knob.” Thus, this location appears maximal for rfMRI and PDT seeding of the motor area.

Purpose: The purpose of this study was to investigate how incorporation of magnetic resonance spectroscopy imaging (MRSI) into radiotherapy planning would increase the target volume for patients with recurrent glioma. Methods: After prior standard radiotherapy, 25 patients with recurrent glioma were treated with bevacizumab and concurrent hypofractionated stereotactic radiotherapy (HFSRT), delivering 30 Gy in five fractions. MRSI were acquired for 12 patients. Areas with markedly higher choline levels relative to the levels of total creatine and N-acetylaspartate were identified and referred to as MRSI voxels with elevated metabolite ratios (EMR). Gross tumor volume (GTV) consisted of contrast-enhancing tumor on T1-weighted magnetic resonance images (MRI) and computed tomography. Clinical target volume (CTV) was GTV + 5 mm margin and MRSI voxels with EMR. Overall survival (OS) and 6-month progression free survival (PFS) for these patients were reported in a prior publication [Gutinet al., Int. J. Radiat. Oncol., Biol., Phys. 75(1), 156–163 (2009)], and the outcome was correlated with the GTV and the volume of MRSI voxels with EMR in this study. Results: Seven of the 12 patients had MRSI voxels with EMR. If none of the MRSI voxels with EMR were included, the CTV would range from 9.2 to 73.0 cm3 with a median of 31.0 cm3, whereas if all voxels were included, the CTV would range from 27.4 to 74.4 cm3 with a median of 35.0 cm3. For three of the seven patients, including the voxels with EMR, would have increased the CTV by 14%–23%. For one patient, where the MRSI voxels with EMR did not overlap the GTV, including these voxels would increase the CTV by 198%. No correlation could be found between the OS and PFS and the GTV or the volume of MRSI voxels with EMR. Conclusions: Seven of 12 patients with recurrent glioma had MRSI voxels with EMR. For four of these seven patients, including the MRSI voxels with EMR, significantly increased the CTV. This study does not have statistical power to conclude on the importance of including areas with MRSI-suspect disease into the radiation target volume.

The corpus callosum (CC) has an important role in regulating interhemispheric transfer and is thought to be instrumental in contralateral brain reorganization in patients with brain tumors, as suggested by a previous study reporting callosal differences between language dominance groups through diffusion tensor imaging (DTI) characteristics. The purpose of this study was to explore the structural differences in the CC between high-grade gliomas (HGGs) and metastatic tumors (METs) using the DTI characteristics of fractional anisotropy (FA), mean diffusivity (MD), and axial diffusivity (AD).HGG (n = 30) and MET (n = 20) subjects with Magnetic Resonance Imaging (MRI) scans including DTI were retrospectively studied. The tumor and CC were segmented using the 3-dimensional T1-weighted scans to determine their volumes. The region of interest (ROI; mean volume of the ROI = 3,090 ± 464 mm3 ) of the body of the CC was overlaid onto the DTI parametric maps to obtain the averaged FA, MD, and AD values.There were significant differences in the distributions of FA and MD values between the two patient groups (mean FA for HGG/MET = .691/.646, P < .05; mean MD for HGG/MET = .894×10-3 mm 2/ second /.992×10-3 mm2 /second, P < .01), while there was no correlation between the DTI parameters and the anatomical volumes.These results suggest that there is more contralateral brain reorganization in HGG patients than MET patients and that neither the tumor nor callosal volume impact the degree of contralateral brain reorganization.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.

We evaluated a recent report that suggested that a "3-layer" appearance of the endometrium on sonography is diagnostic of ectopic pregnancy in symptomatic pregnant patients.We reviewed the log of pelvic sonograms performed to rule out ectopic pregnancy in women presenting with first-trimester bleeding and/or pain during a 29-month period. Medical records and sonograms of patients without sonographic evidence of intrauterine pregnancy were reviewed to determine final diagnoses and whether the 3-layer pattern was present.One hundred twenty patients with available follow-up had no sonographic evidence of intrauterine pregnancy. Fifty-nine (49%) had ectopic pregnancy. An endometrial 3-layer pattern was noted sonographically in 15 patients (13%), of whom 6 (40%) had ectopic pregnancy. As a diagnostic sign of ectopic pregnancy, the endometrial 3-layer pattern had a sensitivity of 10.2%, specificity of 85.2%, positive predictive value of 40%, negative predictive value of 50.5%, and accuracy of 49.2%.The endometrial 3-layer pattern is neither sensitive nor specific for the diagnosis of ectopic pregnancy.

Ac ti va tion rate uni for mity is the first prop erty which is con sid ered in the de sign of a prompt g-ray in vivo neu tron ac ti va tion anal y sis fa cil ity.Pre lim i nary stud ies on the ac ti va tion rate distri bu tion in the body can be done by use of Monte Carlo codes, such as the MCNP.In this paper, dif fer ent bi lat eral con fig u ra tions of an IVNAA sys tem are con sid ered in or der to improve the ac ti va tion rate uni for mity in a wa ter phan tom mea sur ing 32 cm ´ 100 cm ´ 16 cm.In the best case, uni for mity pa ram e ters are U = 1.003 and R = 1.67, with the mean ac ti va tion rate of 1.85×10 -6 cm -3 .In more ac cu rate cal cu la tions, the wa ter phan tom is re placed by a body model.The model in ques tion is a 5 year-old ORNL phan tom filled with just soft tis sue.For uni for mity stud ies, the in ter nal or gans are not sim u lated.Fi nally, uni for mity pa ram e ters in this case are U = 1.005 and R = 12.2.

Two pediatric patients with diffuse pontine tumors underwent MR spectroscopic imaging pre- and postradiation. Choline/creatine (Cho/Cr) and Cho/N-acetylaspartate (NAA) ratios were elevated before treatment, with no MR imaging contrast enhancement. These ratios were further elevated at 2 posttreatment follow-up studies, despite signs of excellent clinical improvement at initial follow-up. This study suggests that MR spectroscopic imaging is more specific in assessing the aggressiveness of diffuse pontine tumors than conventional MR imaging and can serve as a valuable tool in early prognostication.

2028 Background: Bevacizumab is a humanized monoclonal antibody directed at vascular endothelial growth factor A (VEGF-A). Preclinical studies suggest that inhibition of VEGF-A improves glioma response to radiotherapy. The concurrent use of bevacizumab and cranial radiotherapy has not been investigated. The objective of this study is to determine the safety of this combination. Methods: Patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytomas (AA) less than 3.5 cm received bevacizumab (10 mg/kg IV) every 2 weeks. MRI after cycle 1 (28 days) was done to reassess response and for RT planning. Patients then received stereotactic intensity modulated radiation therapy (IMRT): 30Gy in 5 fractions over 15 days. Bevacizumab treatment, given every 2 weeks, was administered during radiotherapy and continued until tumor progression. Brain MRI to assess response was performed after odd cycles. MR T1 and T2* perfusion were performed at baseline and after cycle 1. Results: 12 patients (10 GBM, 2 AA) with median age 53 (range, 30–61) and median KPS 90 (range, 80–100) received a median of 5.5 cycles of bevacizumab. In 1 patient, stereotactic IMRT could not be delivered safely to tumor. Grade III events occurred in 10 patients including hypertension, headache, seizures, neutropenia, hyponatremia and hypophosphatemia. There were no grade IV or V events, no dose limiting toxicities and no intracranial hemorrhage. 7/12 patients had objective responses (3 CR and 4 PR). In 5, SD was the best reported response. At last follow up, ten patients remain on study; 2 have come off for PD. Estimated 6 month PFS is 76%. MR perfusion imaging demonstrated a decrease in mean perfusion values after 1 cycle of bevacizumab. Conclusions: Bevacizumab in combination with RT is safe and well tolerated. Imaging responses and duration of disease control suggest that this regimen is active in this subset of recurrent glioma patients. Further investigations to determine efficacy and possible synergy of bevacizumab with radiotherapy are warranted. [Table: see text]

Interpretation of MRI abnormalities in patients with malignant gliomas (MG) treated with bevacizumab is challenging. Recent reports describe quantitative analyses of diffusion-weighted imaging abnormalities not available in standard clinical settings, to differentiate tumor recurrence from treatment necrosis. We retrospectively reviewed bevacizumab treated MG patients who underwent surgery or autopsy to correlate radiographic recurrence patterns with pathologic findings. 32 patients with MG (26 glioblastoma, three anaplastic astrocytoma and three anaplastic oligodendroglioma) were identified. Recurrence patterns: local enhancing (n = 23), distant enhancing (n = 1), nonenhancing (n = 7) and leptomeningeal (n = 1). Histology: tumor (n = 25), mixed tumor/necrosis (n = 5) and all necrosis (n = 2). On diffusion-weighted imaging, 5/32 had restricted diffusion (three mixed and two necrosis). Irrespective of radiographic recurrence pattern, tumor was found in 94% of cases. Restricted diffusion correlated with necrosis.

We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (&gt;1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.

2048 Background: In GBM, VEGF inhibition decreases vascular permeability and MRI contrast enhancement (CE), which may or may not reflect meaningful anti-tumor activity. We sought to evaluate the relationships between different imaging modalities and anti-tumor activity in a prospective phase II trial of BEV, TMZ and HFSRT in GBM. Methods: Newly diagnosed GBM pts (N=40) received HFSRT with concomitant/ adjuvant BEV and TMZ. All pts underwent dynamic susceptibility contrast MR perfusion (DSC) at baseline, after HFSRT and every 2m. An FDG-PET scan was done at cycle 6. McDonald and RANO response criteria were applied. Results: DSC showed early/progressive decreases in relative cerebral blood volume (rCBV): baseline mean rCBV: 2.77; 6 weeks: 1.65 (p=0.014); 2m: 1.07 (p<0.001); 4m: 0.98 (p<0.001). Conversely, the extent of FLAIR hypersignal progressively increased (mean diameter product: 953, 1165, 1145, 1384 at 6 wks, 2m, 4m and 6m). Response rates per McDonald vs RANO were: complete response (27 vs 10%), partial (63 vs 63%), stable disease (3% vs 20%), progression (7 vs 7%). Because progressive FLAIR occurred within the RT port, time to radiographic progression per McDonald and RANO were identical: median 13m. Residual hypermetabolism seen at the 6m PET (N=6/31) predicted poor survival (p<0.001). Three pts with progressive FLAIR but not CE underwent re-resection; two had true PD and one had mainly radionecrosis. Conclusions: As treatment failure was mostly local, RANO criteria did not shorten time to progression compared to McDonald. DSC depicted early changes in rCBV linked to VEGF modulation, validating DSC as a reliable tool to evaluate anti-VEGF properties of new drugs in vivo. However, VEGF modulation was not predictive of durable anti-tumor activity. A positive PET at 6m predicted poor survival, indicating treatment failure even if other imaging modalities suggested otherwise. However, tumor progression may still be present despite negative PET and DSC, particularly in the setting of increasing non-enhancing FLAIR within the RT port. New imaging tools and improved response criteria are needed to guide management of these pts.

Section I. Diagnostic Evaluation Section II. Differential Diagnosis in Adult Otology and Neurotology Section III. Differential Diagnosis in Pediatric Otology and Neurotology Section IV. Differential Diagnosis in Adult Rhinology and Sinus Disease Section V. Differential Diagnosis in Pediatric Rhinology and Sinus Disease Section VI. Differential Diagnosis in the Oral Cavity (Adult and Pediatric) Section VII. Differential Diagnosis in the Larynx, Pharynx, Trachea, and Esophagus (Adult and Pediatric) Section VIII. Differential Diagnosis of the Adult Skin, Face, and Neck including the Thyroid and Parathyroid Section IX. Differential Diagnosis of Pediatric Skin, Face, and Neck Disorders Section X. Differential Diagnosis in Cosmetic and Plastic Surgery, Trauma, and Reconstruction Section XI. Using New and Forthcoming Technologies for Differential Diagnosis.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; &lt;i&gt;P&lt;/i&gt; = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (&lt;i&gt;P&lt;/i&gt; = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. &lt;i&gt;Clin Cancer Res; 20(19); 5023–31. ©2014 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;Supplementary Data 1 ELIGIBILITY CRITERIA. Supplementary Data 2 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY PLANNING. Supplementary Data 3 MRI ACQUISITION PARAMETERS AND PROCESSING. Supplementary Data 4 Nanostring-based Tissue Correlates Methods. Supplementary Data 5 Number of patients experiencing Grades 3-5 treatment-related toxicities. Supplementary Data 6 Univariate analysis of DSC MR perfusion and diffusion MRI. Supplementary Data 7 NEUROPSYCHOLOGICAL TEST Z-SCORES, QUALITY OF LIFE, DEPRESSION AND FATIGUE SCORES OVER TIME.&lt;/p&gt;

&lt;p&gt;Supp. Fig.1. CONSORT Flow Diagram Supp. Fig.2. MRI Perfusion Parameters Supp. Fig. 3. Immunohistochemistry Supp. Fig. 4. Gene Expression Profile Supp. Table 1. Adverse Events Supp. Table 2. Pharmacokinetic Data Supp. Table 3. Molar Drug Levels Supplemental Methods&lt;/p&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; &lt;i&gt;P&lt;/i&gt; = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (&lt;i&gt;P&lt;/i&gt; = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. &lt;i&gt;Clin Cancer Res; 20(19); 5023–31. ©2014 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood–brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133&lt;sup&gt;+&lt;/sup&gt; CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood–brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. &lt;i&gt;Clin Cancer Res; 22(19); 4786–96. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood–brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133&lt;sup&gt;+&lt;/sup&gt; CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood–brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. &lt;i&gt;Clin Cancer Res; 22(19); 4786–96. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;Supplementary Data 1 ELIGIBILITY CRITERIA. Supplementary Data 2 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY PLANNING. Supplementary Data 3 MRI ACQUISITION PARAMETERS AND PROCESSING. Supplementary Data 4 Nanostring-based Tissue Correlates Methods. Supplementary Data 5 Number of patients experiencing Grades 3-5 treatment-related toxicities. Supplementary Data 6 Univariate analysis of DSC MR perfusion and diffusion MRI. Supplementary Data 7 NEUROPSYCHOLOGICAL TEST Z-SCORES, QUALITY OF LIFE, DEPRESSION AND FATIGUE SCORES OVER TIME.&lt;/p&gt;

&lt;p&gt;Supp. Fig.1. CONSORT Flow Diagram Supp. Fig.2. MRI Perfusion Parameters Supp. Fig. 3. Immunohistochemistry Supp. Fig. 4. Gene Expression Profile Supp. Table 1. Adverse Events Supp. Table 2. Pharmacokinetic Data Supp. Table 3. Molar Drug Levels Supplemental Methods&lt;/p&gt;

Dynamic contrast-enhanced MRI (DCE) is an emerging modality in the study of vertebral body malignancies. DCE-MRI analysis relies on a pharmacokinetic model, which assumes that contrast uptake is simultaneous in the feeding of arteries and tissues of interest. While true in the highly vascularized brain, the perfusion of the spine is delayed. This delay of contrast reaching vertebral body lesions can affect DCE-MRI analyses, leading to misdiagnosis for the presence of active malignancy in the bone marrow. To overcome the limitation of delayed contrast arrival to vertebral body lesions, we shifted the arterial input function (AIF) curve over a series of phases and recalculated the plasma volume values (Vp) for each phase shift. We hypothesized that shifting the AIF tracer curve would better reflect actual contrast perfusion, thereby improving the accuracy of Vp maps in metastases. We evaluated 18 biopsy-proven vertebral body metastases in which standard DCE-MRI analysis failed to demonstrate the expected increase in Vp. We manually delayed the AIF curve for multiple phases, defined as the scan-specific phase temporal resolution, and analyzed DCE-MRI parameters with the new AIF curves. All patients were found to require at least one phase-shift delay in the calculated AIF to better visualize metastatic spinal lesions and improve quantitation of Vp. Average normalized Vp values were 1.78 ± 1.88 for zero phase shifts (P0), 4.72 ± 4.31 for one phase shift (P1), and 5.59 ± 4.41 for two phase shifts (P2). Mann–Whitney U tests obtained p-values = 0.003 between P0 and P1, and 0.0004 between P0 and P2. This study demonstrates that image processing analysis for DCE-MRI in patients with spinal metastases requires a careful review of signal intensity curve, as well as a possible adjustment of the phase of aortic AIF to increase the accuracy of Vp.

The demands of a round-the-clock service and globalized society have led to an increase in long working hours. This trend has been accompanied by a corresponding rise in sleep disorders. Additionally, sedative-tranquilizers have been reported as the third most commonly misused drug class in the U.S. Given the prevalence of long working hours among the U.S. working population, it is expected that there will be a continued increase in the use of sleep aid medications among this population, along with an associated increase in substance abuse to aid sleep.

Significant advancements in cancer treatment have led to improved survival rates for patients, particularly in the context of spinal metastases. However, early detection and monitoring of treatment response remain crucial for optimizing patient outcomes. Although conventional imaging methods such as bone scan, PET, MR imaging, and computed tomography are commonly used for diagnosing and monitoring treatment, they present challenges in differential diagnoses and treatment response monitoring. This review article provides a comprehensive overview of the principles, applications, and practical uses of dynamic contrast-enhanced MR imaging and diffusion-weighted imaging in the assessment and monitoring of marrow-replacing disorders of the spine.

<h3>BACKGROUND AND PURPOSE:</h3> Current imaging techniques have difficulty differentiating treatment success and failure in spinal metastases undergoing radiation therapy. This study investigated the correlation between changes in dynamic contrast-enhanced MR imaging perfusion parameters and clinical outcomes following radiation therapy for spinal metastases. We hypothesized that perfusion parameters will outperform traditional size measurements in discriminating treatment success and failure. <h3>MATERIALS AND METHODS:</h3> This retrospective study included 49 patients (mean age, 63 [SD, 13] years; 29 men) with metastatic lesions treated with radiation therapy who underwent dynamic contrast-enhanced MR imaging. The median time between radiation therapy and follow-up dynamic contrast-enhanced MR imaging was 62 days. We divided patients into 2 groups: clinical success (<i>n</i> = 38) and failure (<i>n</i> = 11). Failure was defined as PET recurrence (<i>n</i> = 5), biopsy-proved (<i>n</i> = 1) recurrence, or an increase in tumor size (<i>n</i> = 7), while their absence defined clinical success. A Mann-Whitney <i>U</i> test was performed to assess differences between groups. <h3>RESULTS:</h3> The reduction in plasma volume was greater in the success group than in the failure group (−57.3% versus +88.2%, respectively; <i>P </i>&lt; .001). When we assessed the success of treatment, the sensitivity of plasma volume was 91% (10 of 11; 95% CI, 82%–97%) and the specificity was 87% (33 of 38; 95% CI, 73%–94%). The sensitivity of size measurements was 82% (9 of 11; 95% CI, 67%–90%) and the specificity was 47% (18 of 38; 95% CI, 37%–67%). <h3>CONCLUSIONS:</h3> The specificity of plasma volume was higher than that of conventional size measurements, suggesting that dynamic contrast-enhanced MR imaging is a powerful tool to discriminate between treatment success and failure.

Purpose/Objective(s)Concurrent bevacizumab with hypofractionated stereotactic radiotherapy (HFSRT) has been shown to be safe and effective for the treatment of recurrent high-grade gliomas (HGG). The objective of this study was to characterize the patterns of failure following this treatment regimen.Materials/MethodsTwenty-four patients with recurrent enhancing HGG were treated on an IRB-approved protocol of concurrent bevacizumab and reirradiation. Patients had received prior radiotherapy to a median dose of 59.4 Gy. At the time of recurrence, patients received bevacizumab (10 mg/kg i.v.) every 2 weeks of a 28-day cycle. After the first cycle of bevacizumab, patients received 30 Gy in 5 fractions with HFSRT over 2 weeks to the recurrent tumor. The median planning target volume was 35 cm3 (range, 3–62). Brain MRI was performed every two cycles after cycle 2. Bevacizumab was continued until tumor progression.ResultsPatients had a median age of 56 years (range, 30–80), median KPS 80% (range, 70–100) and received a median of 7 cycles (range, 1.5–37) of bevacizumab. Six patients were alive at the time of analysis. The median progression-free survival (PFS) was 6.9 months (range, 0.6–34.3) and median overall survival (OS) was 12.2 months (range, 3.9–34.4). At last follow-up, 21 patients were removed from the study for radiographic progression, 1 patient expired before tumor recurrence, and 2 remain on the study with stable disease. Radiographic progression occurred within the radiation field in 12 (57%), outside of the radiation field in 4 (19%) and at both sites in 5 patients (24%). One patient developed leptomeningeal disease. Recurrent tumor was enhancing in 13 (65%) and non-enhancing in 7 patients (35%). Enhancement did not vary by recurrence site or correlate with PFS or OS. Out-of-field recurrence marginally correlated with worse PFS (p = 0.08).ConclusionsFailure is more likely to occur outside of the radiation field after reirradiation and bevacizumab than after primary radiation for HGG, yet the rate of recurrence within the radiation field remains high. The majority of recurrent HGG continue to enhance after bevacizumab and reirradiation with HRSRT. However, similar to patterns of failure for patients treated with bevacizumab alone or in combination with other chemotherapeutic agents, the non-enhancing tumor volume appears more extensive than after initial treatment with radiation and Temodar. While HFSRT with bevacizumab is a promising treatment approach for recurrent HGG, the recurrence pattern demonstrates the radioresistance of HGG. Therefore, higher dose radiation with concurrent bevacizumab for recurrent HGG should be investigated for improved tumor control. Purpose/Objective(s)Concurrent bevacizumab with hypofractionated stereotactic radiotherapy (HFSRT) has been shown to be safe and effective for the treatment of recurrent high-grade gliomas (HGG). The objective of this study was to characterize the patterns of failure following this treatment regimen. Concurrent bevacizumab with hypofractionated stereotactic radiotherapy (HFSRT) has been shown to be safe and effective for the treatment of recurrent high-grade gliomas (HGG). The objective of this study was to characterize the patterns of failure following this treatment regimen. Materials/MethodsTwenty-four patients with recurrent enhancing HGG were treated on an IRB-approved protocol of concurrent bevacizumab and reirradiation. Patients had received prior radiotherapy to a median dose of 59.4 Gy. At the time of recurrence, patients received bevacizumab (10 mg/kg i.v.) every 2 weeks of a 28-day cycle. After the first cycle of bevacizumab, patients received 30 Gy in 5 fractions with HFSRT over 2 weeks to the recurrent tumor. The median planning target volume was 35 cm3 (range, 3–62). Brain MRI was performed every two cycles after cycle 2. Bevacizumab was continued until tumor progression. Twenty-four patients with recurrent enhancing HGG were treated on an IRB-approved protocol of concurrent bevacizumab and reirradiation. Patients had received prior radiotherapy to a median dose of 59.4 Gy. At the time of recurrence, patients received bevacizumab (10 mg/kg i.v.) every 2 weeks of a 28-day cycle. After the first cycle of bevacizumab, patients received 30 Gy in 5 fractions with HFSRT over 2 weeks to the recurrent tumor. The median planning target volume was 35 cm3 (range, 3–62). Brain MRI was performed every two cycles after cycle 2. Bevacizumab was continued until tumor progression. ResultsPatients had a median age of 56 years (range, 30–80), median KPS 80% (range, 70–100) and received a median of 7 cycles (range, 1.5–37) of bevacizumab. Six patients were alive at the time of analysis. The median progression-free survival (PFS) was 6.9 months (range, 0.6–34.3) and median overall survival (OS) was 12.2 months (range, 3.9–34.4). At last follow-up, 21 patients were removed from the study for radiographic progression, 1 patient expired before tumor recurrence, and 2 remain on the study with stable disease. Radiographic progression occurred within the radiation field in 12 (57%), outside of the radiation field in 4 (19%) and at both sites in 5 patients (24%). One patient developed leptomeningeal disease. Recurrent tumor was enhancing in 13 (65%) and non-enhancing in 7 patients (35%). Enhancement did not vary by recurrence site or correlate with PFS or OS. Out-of-field recurrence marginally correlated with worse PFS (p = 0.08). Patients had a median age of 56 years (range, 30–80), median KPS 80% (range, 70–100) and received a median of 7 cycles (range, 1.5–37) of bevacizumab. Six patients were alive at the time of analysis. The median progression-free survival (PFS) was 6.9 months (range, 0.6–34.3) and median overall survival (OS) was 12.2 months (range, 3.9–34.4). At last follow-up, 21 patients were removed from the study for radiographic progression, 1 patient expired before tumor recurrence, and 2 remain on the study with stable disease. Radiographic progression occurred within the radiation field in 12 (57%), outside of the radiation field in 4 (19%) and at both sites in 5 patients (24%). One patient developed leptomeningeal disease. Recurrent tumor was enhancing in 13 (65%) and non-enhancing in 7 patients (35%). Enhancement did not vary by recurrence site or correlate with PFS or OS. Out-of-field recurrence marginally correlated with worse PFS (p = 0.08). ConclusionsFailure is more likely to occur outside of the radiation field after reirradiation and bevacizumab than after primary radiation for HGG, yet the rate of recurrence within the radiation field remains high. The majority of recurrent HGG continue to enhance after bevacizumab and reirradiation with HRSRT. However, similar to patterns of failure for patients treated with bevacizumab alone or in combination with other chemotherapeutic agents, the non-enhancing tumor volume appears more extensive than after initial treatment with radiation and Temodar. While HFSRT with bevacizumab is a promising treatment approach for recurrent HGG, the recurrence pattern demonstrates the radioresistance of HGG. Therefore, higher dose radiation with concurrent bevacizumab for recurrent HGG should be investigated for improved tumor control. Failure is more likely to occur outside of the radiation field after reirradiation and bevacizumab than after primary radiation for HGG, yet the rate of recurrence within the radiation field remains high. The majority of recurrent HGG continue to enhance after bevacizumab and reirradiation with HRSRT. However, similar to patterns of failure for patients treated with bevacizumab alone or in combination with other chemotherapeutic agents, the non-enhancing tumor volume appears more extensive than after initial treatment with radiation and Temodar. While HFSRT with bevacizumab is a promising treatment approach for recurrent HGG, the recurrence pattern demonstrates the radioresistance of HGG. Therefore, higher dose radiation with concurrent bevacizumab for recurrent HGG should be investigated for improved tumor control.