Meningiomas occurring during long-term survival after treatment for childhood cancer

Childhood cancer is rare but improvements in treatment over the past five decades have resulted in a cohort of more than 30,000 long-term survivors of childhood cancer in the UK with more added annually. These long-term survivors are at risk of late effects of cancer treatment which replace original tumour recurrence as the leading cause of premature death. Second neoplasms are a particular risk and in the central nervous system meningiomas occur increasingly with increased radiation dose to central nervous system tissue and length of time after exposure, resulting in a 500-fold increase above that expected in the normal population by 40 years of follow up. This multidisciplinary author group and others met to discuss the issue. Our pooled information, and consensus that screening should only follow symptoms, was published online by the Royal College of Radiologists in 2013. We outline here the current knowledge and management of these neoplasms secondary to childhood cancer treatment

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome

There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV‐6) and Epstein–Barr virus (EBV) have been proposed as infectious triggers. Thirty CFS patients with elevated IgG antibody titers against HHV‐6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double‐blind, placebo‐controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI‐20) and Fatigue Severity Scale (FSS) scores, self‐reported cognitive function, and physician‐determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels. VGCV patients experienced a greater improvement by MFI‐20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI‐20 mental fatigue subscore ( P  = 0.039), FSS score ( P  = 0.006), and cognitive function ( P  = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders ( P  = 0.029). In the VGCV arm, monocyte counts decreased ( P  < 0.001), neutrophil counts increased ( P  = 0.037) and cytokines were more likely to evolve towards a Th1‐profile ( P  < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted. J. Med. Virol. 85:2101–2109, 2013 . © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100139/1/jmv23713.pd

Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Cyclophosphamide-Induced Cystitis Increases Bladder CXCR4 Expression and CXCR4-Macrophage Migration Inhibitory Factor Association

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in cystitis and a non-cognate ligand of the chemokine receptor CXCR4 in vitro. We studied whether CXCR4-MIF associations occur in rat bladder and the effect of experimental cystitis. METHODS AND FINDINGS: Twenty male rats received saline or cyclophosphamide (40 mg/kg; i.p.; every 3(rd) day) to induce persistent cystitis. After eight days, urine was collected and bladders excised under anesthesia. Bladder CXCR4 and CXCR4-MIF co-localization were examined with immunhistochemistry. ELISA determined MIF and stromal derived factor-1 (SDF-1; cognate ligand for CXCR4) levels. Bladder CXCR4 expression (real-time RTC-PCR) and protein levels (Western blotting) were examined. Co-immunoprecipitations studied MIF-CXCR4 associations.Urothelial basal and intermediate (but not superficial) cells in saline-treated rats contained CXCR4, co-localized with MIF. Cyclophosphamide treatment caused: 1) significant redistribution of CXCR4 immunostaining to all urothelial layers (especially apical surface of superficial cells) and increased bladder CXCR4 expression; 2) increased urine MIF with decreased bladder MIF; 3) increased bladder SDF-1; 4) increased CXCR4-MIF associations. CONCLUSIONS: These data demonstrate CXCR4-MIF associations occur in vivo in rat bladder and increase in experimental cystitis. Thus, CXCR4 represents an alternative pathway for MIF-mediated signal transduction during bladder inflammation. In the bladder, MIF may compete with SDF-1 (cognate ligand) to activate signal transduction mediated by CXCR4

Tonsillar ectopia in idiopathic scoliosis: does it play a role in the pathogenesis and prognosis or is it only an incidental finding?

ABSTRACT: BACKGROUND: There is an ongoing controversy about the significance of tonsillar ectopia among patients with idiopathic scoliosis (IS). AIM: To find out if tonsillar ectopia occurs more frequently among patients with IS and if it plays any etiological or prognostic role in IS. STUDY DESIGN: Retrospective study. METHODS: Retrospective analysis of 155 consecutive spine MRIs (79 patients with IS and 76 controls; aged 7-25 years; 55% were female) with regard to the position of the cerebellar tonsils in relation to foramen magnum and the sagittal diameter of foramen magnum. All images were evaluated independently by two neuroradiologists. Interobserver and intraobserver reliability analysis was performed by calculation of kappa-value, intraclass correlation coefficient, and systematic and random errors. The occurrence of tonsillar ectopia among patients with IS and controls was estimated and the association of tonsillar ectopia with different predictors has been tested. Statistical significance was set to P </= 0.05. RESULTS: The interobserver and intraobserver agreement with regard to the occurrence of tonsillar ectopia was almost perfect (kappa 0.84 and 0.89, respectively). Tonsillar ectopia was found in 37% of patients with IS compared with 13% among controls (p < 0.001 and odds ratio of 3.8, 95% CI 1.7-8.5). The occurrence of tonsillar ectopia was not associated with the severity of scoliotic deformity (p = 0.85), or rapid progression of scoliosis (p = 0.76). Neurological deficit occurs twice as frequently in patients with tonsillar ectopia as in those with no tonsillar ectopia. Two of five patients with tonsillar ectopia showed improvement of their neurological deficit after the surgical correction of scoliosis. CONCLUSION: As tonsillar ectopia is significantly more frequent among patients with IS and may exhibit some prognostic utility in patients with neurological deficit, we forward the hypothesis that tonsillar ectopia may play a role in the development of the deformity in some patients with IS. However, occurrence of tonsillar ectopia among 13% of controls precludes stating a definitive role of tonsillar ectopia in the pathogenesis of IS. Some patients with IS, tonsillar ectopia and neurological deficit showed neurological improvement following the surgical correction of scoliosis

Methods for selecting the best evidence to inform a NICE technology appraisal on selective internal radiation therapies for hepatocellular carcinoma

Background: Systematic reviews of medical devices are particularly challenging as the quality of evidence tends to be more limited than evidence on pharmaceutical products. This article describes the methods used to identify, select and critically appraise the best available evidence on selective internal radiation therapy devices for treating hepatocellular carcinoma, to inform a technology appraisal for the National Institute for Health and Care Excellence. Methods: A comprehensive search of ten medical databases and six grey literature sources was undertaken to identify studies of three devices (TheraSphere®, SIR-Spheres® and QuiremSpheres®) for treating hepatocellular carcinoma. The large evidence base was scoped before deciding what level of evidence to include for data extraction and critical appraisal. The methodological quality of the included studies was assessed using criteria relevant to each study design. Results: Electronic searches identified 4755 records; over 1000 met eligibility criteria after screening titles and abstracts. A hierarchical process was used to scope these records, prioritising comparative studies over non-comparative studies, where available. 194 full papers were ordered; 64 met the eligibility criteria. For each intervention, studies were prioritised by study design and applicability to current UK practice, resulting in 20 studies subjected to critical appraisal and data extraction. Only two trials had a low overall risk of bias. In view of the poor quality of the research evidence, our technology appraisal focused on the two higher quality trials, including a thorough critique of their reliability and generalisability to current UK practice. The 18 poorer quality studies were briefly summarised; many were very small and results were often contradictory. No definitive conclusions could be drawn from the poorer quality research evidence available. Conclusions: A systematic, pragmatic process was used to select and critically appraise the vast quantity of research evidence available in order to present the most reliable evidence on which to develop recommendations

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

The utility of superficial abdominal reflex in the initial diagnosis of scoliosis: a retrospective review of clinical characteristics of scoliosis with syringomyelia

<p>Abstract</p> <p>Background</p> <p>With increasing use of magnetic resonance imaging (MRI), underlying syringomyelia is increasingly found in patients with presumed idiopathic scoliosis. To determine the indications for MRI in the differential diagnosis of scoliosis, several clinical characteristics of syringomyelia have been reported. Neurological signs, particularly abnormal superficial abdominal reflex (SAR), are important in establishing the initial diagnosis of scoliosis. However, the prevalence of abnormal SAR in patients with scoliosis and the sensitivity of this sign in predicting syringomyelia are not well known. We aimed to determine the diagnostic utility of SAR and other characteristics of syringomyelia in patients with scoliosis.</p> <p>Methods</p> <p>We reviewed the medical records of 93 patients with scoliosis, 90 of whom underwent corrective surgery. All patients underwent MRI to determine the presence of syringomyelia. Mean age at surgery was 12.5 years. Abnormal SAR was defined as unilateral or bilateral absence or hyporeflexia of SAR. We calculated indices of diagnostic utility of abnormal SAR for non-idiopathic scoliosis and for syringomyelia. Abnormal SAR, left thoracic curve pattern, gender, and curve flexibility were compared between scoliosis with syringomyelia and idiopathic scoliosis. Logistic regression analysis was performed with the existence of syringomyelia as the dependent variable and curve flexibility as the independent variable.</p> <p>Results</p> <p>Abnormal SAR was observed in 20 patients (prevalence 22%). All 6 patients with myopathic scoliosis displayed bilateral absence of SAR. The sensitivity of abnormal SAR for non-idiopathic scoliosis was 38%, with 96% specificity, 90% PPV (positive predictive value), and 60% NPV (negative predictive value). Syringomyelia was identified in 9 of the 93 patients (9.7%); 8 of these had abnormal SAR. The sensitivity of abnormal SAR for syringomyelia in presumed idiopathic scoliosis was 89%, with 95% specificity, 80% PPV, and 98% NPV. Gender, abnormal neurological findings, and curve flexibility differed significantly between patients with syringomyelia and those with idiopathic scoliosis (P < 0.05). In the logistic regression model, the area under the receiver operating characteristic (ROC) curve was 0.79 and the cut-off value of curve flexibility for syringomyelia was 50% (P = 0.08).</p> <p>Conclusion</p> <p>Abnormal SAR was a useful indicator not only for syringomyelia, but also for myogenic scoliosis.</p