An Update on the Approach to the Imaging of Brain Tumors.

PURPOSE OF REVIEW: Neuroimaging plays a critical role in diagnosis of brain tumors and in assessment of response to therapy. However, challenges remain, including accurately and reproducibly assessing response to therapy, defining endpoints for neuro-oncology trials, providing prognostic information, and differentiating progressive disease from post-therapeutic changes particularly in the setting of antiangiogenic and other novel therapies. RECENT FINDINGS: Recent advances in the imaging of brain tumors include application of advanced MRI imaging techniques to assess tumor response to therapy and analysis of imaging features correlating to molecular markers, grade, and prognosis. This review aims to summarize recent advances in imaging as applied to current diagnostic and therapeutic neuro-oncologic challenges.

Yield of urinary tract cancer diagnosis with repeat CT urography in patients with hematuria.

OBJECTIVE. The purpose of this study was to evaluate the yield of repeat CT urography (CTU) in detecting urinary tract malignancies in patients with hematuria. MATERIALS AND METHODS. A review of 5525 patients who underwent CTU between 2000 and 2011 revealed 751 (13.6%) patients who underwent repeat CTU. We excluded 127 patients with more than 3 years between examinations, 409 with nonhematuria indications, and 13 with less than 1 year of follow-up from a negative repeat examination. An additional 54 patients with malignancy diagnosed on the initial evaluation were excluded, leaving 148 patients in the study cohort (77 men and 71 women; mean age, 57 years). Patients were categorized on the basis of the presence or absence of findings suspicious for malignancy on initial CTU reports. Repeat CTU reports were correlated with cystoscopy, pathology, and clinical follow-up to determine the incidence of malignancy. Examinations negative for malignancy were confirmed with at least 1 year of clinical follow-up. CTU examinations of patients diagnosed with malignancy on repeat examination were reviewed by two radiologists in consensus. RESULTS. Initial CTU showed no findings suspicious for malignancy in 103 (70%) of 148 patients; of these, none had malignancy identified on repeat CTU. Among 45 (30%) patients with suspicious initial CTU findings, four malignancies were identified on repeat CTU (8.9%). Three were incidental to the initial suspicious finding; in retrospect, two were present on the initial CTU examination. CONCLUSION. In patients with hematuria, repeat CTU within 3 years is unlikely to show a urinary tract malignancy. These results support currently published guidelines.

Outcomes of pregnancies with a low-lying placenta diagnosed on second-trimester sonography.

OBJECTIVES: The purpose of this study was to determine how often a low-lying placenta, defined as a placenta ending within 2 cm of the internal cervical os but not covering it, diagnosed sonographically in the second trimester resolves before delivery. METHODS: After Institutional Review Board approval was obtained, 1416 pregnancies with a sonographically diagnosed low-lying placenta between 16 and 24 weeks' gestation were identified from our ultrasound database over a 5-year period. We reviewed medical records to determine the gestational age at which the low-lying placenta was first diagnosed, the gestational age at which the placenta was no longer sonographically low lying or covering the cervix, and, of those whose placentas that never cleared the internal cervical os sonographically, how many went on to cesarean delivery as a result of placental location. RESULTS: In total, 1220 of 1240 low-lying placentas (98.4%) that had sonographic follow up resolved to no previa before delivery; 89.9% of placentas cleared the cervix by 32 weeks, and 95.9% cleared by 36 weeks. Twenty patients (1.6%) had persistent sonographic placenta previa or a low-lying placenta at or near term, including 5 complete previas, 7 marginal previas, 5 low-lying placentas, and 3 vasa previas; all had cesarean deliveries. CONCLUSIONS: A low-lying placenta sonographically diagnosed in the second trimester typically resolves by the mid third trimester. Only rarely (1.6% of the time) does it persist to term or near term. Follow-up sonography is warranted to diagnose persistent placenta previa or vasa previa, a complication of a low-lying placenta.

Preterm birth results in alterations in neural connectivity at age 16 years.

Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p=0.003), verbal (p=0.043), and performance IQ tests (p=0.001), as well as CTOPP phonological awareness (p=0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p=0.01; right: p=0.004), bilateral external capsules (left: p<0.001; right: p<0.001), the splenium of the corpus callosum (p=0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p<0.001; right: p=0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r=0.314, p=0.038; right: r=0.336, p=0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r=0.424, p=0.004; right: r=0.301, p=0.047). These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

Infections of Deep Neck Spaces.

Identifying infections of the deep neck spaces and understanding how they spread can be a diagnostic challenge that is complicated by complex anatomy and far-reaching clinical implications. Deep neck infections have the potential to quickly spread throughout the neck and chest, leading to widespread disease that can be rapidly fatal and resistant to treatment. This article provides a foundation for evaluating deep neck infections through a review of essential anatomy and a discussion of important diseases that interact with these spaces.

Interleukin-17 in transverse myelitis and multiple sclerosis.

CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.

Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy.

BACKGROUND: Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting T(H)2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials. OBJECTIVE: To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes. DESIGN: Before-and-after trial. SETTING: A university MS specialty center. PATIENTS: Ten patients with relapsing-remitting MS. INTERVENTIONS: Treatment with glatiramer for 12 months and serial phlebotomy. MAIN OUTCOME MEASURES: Cytokine production, CKR expression, and cell migration. RESULTS: The glatiramer-reactive T cells were T(H)2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the T(H)1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells. CONCLUSIONS: Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery.

Kinetics of CCR7 expression differ between primary activation and effector memory states of T(H)1 and T(H)2 cells.

We explored the kinetics of CCR7 expression on T(H)1 and T(H)2 polarized cells as well as on antigen-specific T cell lines at various stages of differentiation. A striking pattern of early (days 7-14) inducible CCR7 expression was seen preferentially on primary T(H)1 cell lines, as compared to T(H)2 cells, and was dependent on the strength and duration of the T cell receptor signal. Upon repeated restimulation (days 21-28) and differentiation, a switch occurred in which T(H)2 cells had high CCR7 expression, whereas T(H)1 cells lost CCR7 expression. Chronic (8 weeks and later) effector memory cell lines were 95% CCR7 negative. These data demonstrate an ordered pattern of CCR7 expression that suggest more rapid priming of T(H)1 cells in the lymph node, and delayed priming with prolonged CCR7 expression during T(H)2 responses, and may have implications for tracking T(H)1 effector T cells ex vivo in autoimmune diseases.

Reduced radiation exposure for face transplant surgical planning computed tomography angiography.

OBJECTIVE: To test the hypothesis that wide area detector face transplant surgical planning CT angiograms with simulated lower radiation dose and iterative reconstruction (AIDR3D) are comparable in image quality to those with standard tube current and filtered back projection (FBP) reconstruction. MATERIALS AND METHODS: The sinograms from 320-detector row CT angiography of four clinical candidates for face transplantation were processed utilizing standard FBP, FBP with simulated 75, 62, and 50% tube current, and AIDR3D with corresponding dose reduction. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured at muscle, fat, artery, and vein. Image quality for each reconstruction strategy was assessed by two independent readers using a 4-point scale. RESULTS: Compared to FBP, the median SNR and CNR for AIDR3D images were higher at all sites for all 4 different tube currents. The AIDR3D with simulated 50% tube current achieved comparable SNR and CNR to FBP with standard dose (median muscle SNR: 5.77 vs. 6.23; fat SNR: 6.40 vs. 5.75; artery SNR: 43.8 vs. 45.0; vein SNR: 54.9 vs. 55.7; artery CNR: 38.1 vs. 38.6; vein CNR: 49.0 vs. 48.7; all p-values >0.19). The interobserver agreement in the image quality score was good (weighted κ = 0.7). The overall score and the scores for smaller arteries were significantly lower when FBP with 50% dose reduction was used. The AIDR3D reconstruction images with 4 different simulated doses achieved a mean score ranging from 3.68 to 3.82 that were comparable to the scores from images reconstructed using FBP with original dose (3.68-3.77). CONCLUSIONS: Simulated radiation dose reduction applied to clinical CT angiography for face transplant planning suggests that AIDR3D allows for a 50% reduction in radiation dose, as compared to FBP, while preserving image quality.

Upper extremity composite tissue allotransplantation imaging.

OBJECTIVE: Upper extremity (UE) transplantation is the most commonly performed composite tissue allotransplantation worldwide. However, there is a lack of imaging standards for pre- and posttransplant evaluation. This study highlights the protocols and findings of UE allotransplantation toward standardization and implementation for clinical trials. METHODS: Multimodality imaging protocols for a unilateral hand transplant candidate and a bilateral mid-forearm level UE transplant recipient include radiography, computed tomography (CT), magnetic resonance (MR) imaging, catheter angiography, and vascular ultrasonography. Pre- and posttransplant findings, including dynamic CT and MR performed for assessment of motor activity of transplanted hands, are assessed, and image quality of vessels and bones on CT and MR evaluated. RESULTS: Preoperative imaging demonstrates extensive skeletal deformity and variation in vascular anatomy and vessel patency. Posttransplant images confirm bony union in anatomical alignment and patency of vascular anastomoses. Mild differences in rate of vascular enhancement and extent of vascular networks are noted between the 2 transplanted limbs. Dynamic CT and MR demonstrate a 15° to 30° range of motion at metacarpophalangeal joints and 90° to 110° at proximal interphalangeal joints of both transplanted hands at 8 months posttransplant. Image quality was slightly better for CT than for MR in the first subject, while MR was slightly better in the second subject. CONCLUSION: Advanced vascular and musculoskeletal imaging play an important role in surgical planning and can provide novel posttransplantation data to monitor the success of the procedure. Implementation of more standardized protocols should enable a more comprehensive assessment to evaluate the efficacy in clinical trials.

Expression of CCR7 and CD45RA in CD4+ and CD8+ subsets in cerebrospinal fluid of 134 patients with inflammatory and non-inflammatory neurological diseases.

We investigated CD45RA and CCR7 expression in CD4+ and CD8+ subsets of cerebrospinal fluid (CSF) lymphocytes, both immediately ex vivo and after stimulation, from 134 patients with a variety of inflammatory and non-inflammatory neurological diseases. Most inflammatory diseases had a higher CD4+:CD8+ ratio and higher percentage of effector memory T cells (T(EM)) than non-inflammatory controls, excluding active infection. Moreover, we found that patients with highly elevated cell counts in the CSF tended to have a lower percentage of central memory T cells (T(CM)) than patients with low or absent pleocytosis, with a concomitant increase in T(EM). We also found that samples with elevated IgG index or presence of oligoclonal bands had a significantly higher CD4+:CD8+ ratio than normal samples, consistent with increased CD4+ help for intrathecal IgG synthesis by B cells.

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis.

We have analyzed the localization of dendritic cells (DCs) in non-lesional gray matter (NLGM) in comparison to non-lesional white matter (NLWM) and acute or chronic active multiple sclerosis (MS) lesions. Immunohistochemistry was performed on cryostat sections for DCs markers (CD209, CD205, CD83) and other markers for inflammatory cells (CD68, CD8, CD4, CD3, CCR7, CCR5). We found cells expressing CD209 and containing myelin basic protein in both perivascular and parenchymal areas of NLGM. Our findings showing the expression of CD209(+) cells in NLGM parenchymal areas are surprising relative to the previous literature which reported the presence of CD209(+) DCs only in MS plaque perivascular areas. Although less numerous than CD209(+) cells, NLGM cells expressing mature DCs marker CD205 were consistently detected in perivascular cuffs of most lesions. In double labeling experiments, some but not all of the CD209(+) cells also expressed CD68 and CCR5. We also found CD209(+) cells in close contact with CD3(+) lymphocytes suggesting that DCs might contribute to the local activation of pathogenic T cells in the NLGM. Since injury to the NLGM is one of the key factors associated with disability accumulation, targeting DCs may represent a possible new therapeutic approach in MS to prevent disease progression.

Potassium channels Kv1.3 and Kv1.5 are expressed on blood-derived dendritic cells in the central nervous system.

OBJECTIVE: Potassium (K(+)) channels on immune cells have gained attention recently as promising targets of therapy for immune-mediated neurological diseases such as multiple sclerosis (MS). We examined K(+) channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course. METHODS: We identified K(+) channels on blood-derived DCs by whole-cell patch-clamp analysis, confirmed by immunofluorescent staining. We also stained K(+) channels in brain sections from MS patients and control subjects. To test functionality, we blocked K(v)1.3 and K(v)1.5 in stimulated DCs with pharmacological blockers or with an inducible dominant-negative K(v)1.x adenovirus construct and analyzed changes in costimulatory molecule upregulation. RESULTS: Electrophysiological analysis of DCs showed an inward-rectifying K(+) current early after stimulation, replaced by a mix of voltage-gated K(v)1.3- and K(v)1.5-like channels at later stages of maturation. K(v)1.3 and K(v)1.5 were also highly expressed on DCs infiltrating MS brain tissue. Of note, we found that CD83, CD80, CD86, CD40, and interleukin-12 upregulation were significantly impaired on K(v)1.3 and K(v)1.5 blockade. INTERPRETATION: These data support a functional role of K(v)1.5 and K(v)1.3 on activated human DCs and further define the mechanisms by which K(+) channel blockade may act to suppress immune-mediated neurological diseases.

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.