A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

INTRODUCTION: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4ß7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. OBJECTIVE: The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. METHODS: A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. RESULTS: Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. CONCLUSION: We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.

Magnetic resonance perfusion for differentiating low-grade from high-grade gliomas at first presentation.

BACKGROUND: Gliomas are the most common primary brain tumour. They are graded using the WHO classification system, with Grade II-IV astrocytomas, oligodendrogliomas and oligoastrocytomas. Low-grade gliomas (LGGs) are WHO Grade II infiltrative brain tumours that typically appear solid and non-enhancing on magnetic resonance imaging (MRI) scans. People with LGG often have little or no neurologic deficit, so may opt for a watch-and-wait-approach over surgical resection, radiotherapy or both, as surgery can result in early neurologic disability. Occasionally, high-grade gliomas (HGGs, WHO Grade III and IV) may have the same MRI appearance as LGGs. Taking a watch-and-wait approach could be detrimental for the patient if the tumour progresses quickly. Advanced imaging techniques are increasingly used in clinical practice to predict the grade of the tumour and to aid clinical decision of when to intervene surgically. One such advanced imaging technique is magnetic resonance (MR) perfusion, which detects abnormal haemodynamic changes related to increased angiogenesis and vascular permeability, or "leakiness" that occur with aggressive tumour histology. These are reflected by changes in cerebral blood volume (CBV) expressed as rCBV (ratio of tumoural CBV to normal appearing white matter CBV) and permeability, measured by Ktrans. OBJECTIVES: To determine the diagnostic test accuracy of MR perfusion for identifying patients with primary solid and non-enhancing LGGs (WHO Grade II) at first presentation in children and adults. In performing the quantitative analysis for this review, patients with LGGs were considered disease positive while patients with HGGs were considered disease negative.To determine what clinical features and methodological features affect the accuracy of MR perfusion. SEARCH METHODS: Our search strategy used two concepts: (1) glioma and the various histologies of interest, and (2) MR perfusion. We used structured search strategies appropriate for each database searched, which included: MEDLINE (Ovid SP), Embase (Ovid SP), and Web of Science Core Collection (Science Citation Index Expanded and Conference Proceedings Citation Index). The most recent search for this review was run on 9 November 2016.We also identified 'grey literature' from online records of conference proceedings from the American College of Radiology, European Society of Radiology, American Society of Neuroradiology and European Society of Neuroradiology in the last 20 years. SELECTION CRITERIA: The titles and abstracts from the search results were screened to obtain full-text articles for inclusion or exclusion. We contacted authors to clarify or obtain missing/unpublished data.We included cross-sectional studies that performed dynamic susceptibility (DSC) or dynamic contrast-enhanced (DCE) MR perfusion or both of untreated LGGs and HGGs, and where rCBV and/or Ktrans values were reported. We selected participants with solid and non-enhancing gliomas who underwent MR perfusion within two months prior to histological confirmation. We excluded studies on participants who received radiation or chemotherapy before MR perfusion, or those without histologic confirmation. DATA COLLECTION AND ANALYSIS: Two review authors extracted information on study characteristics and data, and assessed the methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We present a summary of the study characteristics and QUADAS-2 results, and rate studies as good quality when they have low risk of bias in the domains of reference standard of tissue diagnosis and flow and timing between MR perfusion and tissue diagnosis.In the quantitative analysis, LGGs were considered disease positive, while HGGs were disease negative. The sensitivity refers to the proportion of LGGs detected by MR perfusion, and specificity as the proportion of detected HGGs. We constructed two-by-two tables with true positives and false negatives as the number of correctly and incorrectly diagnosed LGG, respectively, while true negatives and false positives are the number of correctly and incorrectly diagnosed HGG, respectively.Meta-analysis was performed on studies with two-by-two tables, with further sensitivity analysis using good quality studies. Limited data precluded regression analysis to explore heterogeneity but subgroup analysis was performed on tumour histology groups. MAIN RESULTS: Seven studies with small sample sizes (4 to 48) met our inclusion criteria. These were mostly conducted in university hospitals and mostly recruited adult patients. All studies performed DSC MR perfusion and described heterogeneous acquisition and post-processing methods. Only one study performed DCE MR perfusion, precluding quantitative analysis.Using patient-level data allowed selection of individual participants relevant to the review, with generally low risks of bias for the participant selection, reference standard and flow and timing domains. Most studies did not use a pre-specified threshold, which was considered a significant source of bias, however this did not affect quantitative analysis as we adopted a common rCBV threshold of 1.75 for the review. Concerns regarding applicability were low.From published and unpublished data, 115 participants were selected and included in the meta-analysis. Average rCBV (range) of 83 LGGs and 32 HGGs were 1.29 (0.01 to 5.10) and 1.89 (0.30 to 6.51), respectively. Using the widely accepted rCBV threshold of <1.75 to differentiate LGG from HGG, the summary sensitivity/specificity estimates were 0.83 (95% CI 0.66 to 0.93)/0.48 (95% CI 0.09 to 0.90). Sensitivity analysis using five good quality studies yielded sensitivity/specificity of 0.80 (95% CI 0.61 to 0.91)/0.67 (95% CI 0.07 to 0.98). Subgroup analysis for tumour histology showed sensitivity/specificity of 0.92 (95% CI 0.55 to 0.99)/0.42 (95% CI 0.02 to 0.95) in astrocytomas (6 studies, 55 participants) and 0.77 (95% CI 0.46 to 0.93)/0.53 (95% CI 0.14 to 0.88) in oligodendrogliomas+oligoastrocytomas (6 studies, 56 participants). Data were too sparse to investigate any differences across subgroups. AUTHORS' CONCLUSIONS: The limited available evidence precludes reliable estimation of the performance of DSC MR perfusion-derived rCBV for the identification of grade in untreated solid and non-enhancing LGG from that of HGG. Pooled data yielded a wide range of estimates for both sensitivity (range 66% to 93% for detection of LGGs) and specificity (range 9% to 90% for detection of HGGs). Other clinical and methodological features affecting accuracy of the technique could not be determined from the limited data. A larger sample size of both LGG and HGG, preferably using a standardised scanning approach and with an updated reference standard incorporating molecular profiles, is required for a definite conclusion.

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.

Indocyanine green-loaded nanoparticles for image-guided tumor surgery.

Detecting positive tumor margins and local malignant masses during surgery is critical for long-term patient survival. The use of image-guided surgery for tumor removal, particularly with near-infrared fluorescent imaging, is a potential method to facilitate removing all neoplastic tissue at the surgical site. In this study we demonstrate a series of hyaluronic acid (HLA)-derived nanoparticles that entrap the near-infrared dye indocyanine green, termed NanoICG, for improved delivery of the dye to tumors. Self-assembly of the nanoparticles was driven by conjugation of one of three hydrophobic moieties: aminopropyl-1-pyrenebutanamide (PBA), aminopropyl-5ß-cholanamide (5ßCA), or octadecylamine (ODA). Nanoparticle self-assembly, dye loading, and optical properties were characterized. NanoICG exhibited quenched fluorescence that could be activated by disassembly in a mixed solvent. NanoICG was found to be nontoxic at physiologically relevant concentrations and exposure was not found to inhibit cell growth. Using an MDA-MB-231 tumor xenograft model in mice, strong fluorescence enhancement in tumors was observed with NanoICG using a fluorescence image-guided surgery system and a whole-animal imaging system. Tumor contrast with NanoICG was significantly higher than with ICG alone.

An integrated widefield imaging and spectroscopy system for contrast-enhanced, image-guided resection of tumors.

UNLABELLED: Tumor recurrence following surgery is a common and unresolved medical problem of great importance since surgery is the most widely used treatment for solid-mass tumors worldwide. A contributing factor to tumor recurrence is the presence of residual tumor remaining at or near the surgical site following surgery. GOAL: The primary objective of this study was to develop and evaluate an image-guided surgery system based on a near-infrared, handheld excitation source and spectrograph in combination with a widefield video imaging system. METHODS: This system was designed to detect the fluorescence of near-infrared contrast agents and, in particular, indocyanine green (ICG). The imaging system was evaluated for its optical performance and ability to detect the presence of ICG in tumors in an ectopic murine tumor model as well as in spontaneous tumors arising in canines. RESULTS: In both settings, an intravenous ICG infusion provided tumor contrast. In both the murine models and surgical specimens from canines, ICG preferentially accumulated in tumor tissue compared to surrounding normal tissue. The resulting contrast was sufficient to distinguish neoplasia from normal tissue; in the canine surgical specimens, the contrast was sufficient to permit identification of neoplasia on the marginal surface of the specimen. CONCLUSION: These results demonstrate a unique concept in image-guided surgery by combining local excitation and spectroscopy with widefield imaging. SIGNIFICANCE: The ability to readily detect ICG in canines with spontaneous tumors in a clinical setting exemplifies the potential for further clinical translation; the promising results of detecting neoplasia on the marginal specimen surface underscore the clinical utility.

Principles of T2 *-weighted dynamic susceptibility contrast MRI technique in brain tumor imaging.

Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is used to track the first pass of an exogenous, paramagnetic, nondiffusible contrast agent through brain tissue, and has emerged as a powerful tool in the characterization of brain tumor hemodynamics. DSC-MRI parameters can be helpful in many aspects, including tumor grading, prediction of treatment response, likelihood of malignant transformation, discrimination between tumor recurrence and radiation necrosis, and differentiation between true early progression and pseudoprogression. This review aims to provide a conceptual overview of the underlying principles of DSC-MRI of the brain for clinical neuroradiologists, scientists, or students wishing to improve their understanding of the technical aspects, pitfalls, and controversies of DSC perfusion MRI of the brain. Future consensus on image acquisition parameters and postprocessing of DSC-MRI will most likely allow this technique to be evaluated and used in high-quality multicenter studies and ultimately help guide clinical care.

Use of apparent diffusion coefficient values for diagnosis of pediatric posterior fossa tumors.

We prospectively compared the ability of neuroradiologists to diagnose medulloblastoma with novice raters using only apparent diffusion coefficient (ADC) values measured on ADC maps. One hundred and three pediatric patients with pre-operative magnetic resonance imaging scans showing a posterior fossa tumor with histological verification were retrospectively identified from a ten-year period at a tertiary care medical center. A single observer measured the lowest ADC values in all tumors to determine the mean minimum ADC (ADCmin) value that provided greatest accuracy in distinguishing medulloblastomas from other tumors, which was determined to be 0.66×10(-3) mm(2)/s. Imaging studies, including ADC maps, from 90 patients were provided to two neuroradiologists, who provided a diagnosis, which was later dichotomized as medulloblastoma or other. Two medical students measured ADCmin within tumors and those with ADCmin < 0.66×10(-3) mm(2)/s were recorded as medulloblastoma; any other value was recorded as other. Diagnostic accuracy was measured. ADCmin values allowed a correct identification of lesions as either medulloblastoma or other in 91% of cases. After diagnoses by the two neuroradiologists were categorized as either medulloblastoma or other, their diagnoses were correct in 90% and 84% of cases, respectively. In 19 cases, at least one neuroradiologist was incorrect; the addition of ADC values to clinical interpretation would have allowed a correct diagnosis in 63% of such cases. Diagnostic accuracy based on ADC values by medical students was comparable to that of subspecialty-trained neuroradiologists. Our findings suggest that the addition of ADC values to standard film interpretation may improve the diagnostic rate for these tumors.

Evaluation of apparent diffusion coefficient thresholds for diagnosis of medulloblastoma using diffusion-weighted imaging.

We assess a diffusion-weighted imaging (DWI) analysis technique as a potential basis for computer-aided diagnosis (CAD) of pediatric posterior fossa tumors. A retrospective medical record search identified 103 children (mean age: 87 months) with posterior fossa tumors having a total of 126 preoperative MR scans with DWI. The minimum ADC (ADCmin) and normalized ADC (nADC) values [ratio of ADCmin values in tumor compared to normal tissue] were measured by a single observer blinded to diagnosis. Receiver operating characteristic (ROC) curves were generated to determine the optimal threshold for which the nADC and ADCmin values would predict tumor histology. Inter-rater reliability for predicting tumor type was evaluated using values measured by two additional observers. At histology, ten tumor types were identified, with astrocytoma (n=50), medulloblastoma (n=33), and ependymoma (n=9) accounting for 89%. Mean ADCmin (0.54 × 10(-3) mm(2)/s) and nADC (0.70) were lowest for medulloblastoma. Mean ADCmin (1.28 × 10(-3) mm(2)/s) and nADC (1.64) were highest for astrocytoma. For the ROC analysis, the area under the curve when discriminating medulloblastoma from other tumors using nADC was 0.939 and 0.965 when using ADCmin. The optimal ADCmin threshold was 0.66 × 10(-3) mm(2)/s, which yielded an 86% positive predictive value, 97% negative predictive value, and 93% accuracy. Inter-observer variability was very low, with near perfect agreement among all observers in predicting medulloblastoma. Our data indicate that both ADCmin and nADC could serve as the basis for a CAD program to distinguish medulloblastoma from other posterior fossa tumors with a high degree of accuracy.

Perfusion MRI: the five most frequently asked clinical questions.

OBJECTIVE: This article addresses questions that radiologists frequently ask when planning, performing, processing, and interpreting MRI perfusion studies in CNS imaging. CONCLUSION: Perfusion MRI is a promising tool in assessing stroke, brain tumors, and neurodegenerative diseases. Most of the impediments that have limited the use of per-fusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.

Tumor cells upregulate normoxic HIF-1α in response to doxorubicin.

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact.

Increasing rate of detection of wrong-patient radiographs: use of photographs obtained at time of radiography.

OBJECTIVE: The objective of our study was to evaluate whether facial and chest photographs obtained simultaneously with radiographs increase radiologists' detection rate of labeling errors. MATERIALS AND METHODS: We obtained simultaneous portable radiographs and photographs of 34 patients. We generated 88 pairs of chest radiographs (one recent radiograph, one prior radiograph) and compiled a set of 20 pairs for reader review. Two, three, or four mismatched pairs (i.e., pairs containing radiographs of different patients) were introduced into each list. Ten radiologist readers blinded to the presence of mismatches interpreted the 20 radiograph pairs. Readers then reviewed a second set of 20 pairs containing mismatches but photographs of the patients obtained at the time of imaging were attached to the radiographs. Readers were not instructed regarding the purpose of the photographs. The mismatch detection rate and time for interpretation was recorded for both sessions. The two-tailed Fisher exact test was used to evaluate differences in mismatch detection rates between sessions, with a p value of less than 0.05 being considered significant. RESULTS: The error detection rates without (3/24 = 12.5%) and with (16/25 = 64%) photographs significantly differed (p = 0.0003). The average interpretation times without and with photographs were 35.73 and 26.51 minutes, respectively (two-tailed Student t test, p = 0.1165). CONCLUSION: The use of photographs increased the detection of errors without a concomitant increase in film interpretation time, which may translate into improvements in patient safety without an increase in interpretation time.

Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.

Perfusion MRI: the five most frequently asked technical questions.

OBJECTIVE: This and its companion article address the 10 most frequently asked questions that radiologists face when planning, performing, processing, and interpreting different MR perfusion studies in CNS imaging. CONCLUSION: Perfusion MRI is a promising tool in assessing stroke, brain tumors, and patients with neurodegenerative diseases. Most of the impediments that have limited the use of perfusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.

Assessment of intra-observer variability in measurement of high-grade brain tumors.

A 25% increase in bidimensional products (BPs) of tumor diameter has been used as a criterion for brain tumor progression. We studied intra-observer variability in measurements of BPs. Ten patients with contrast-enhancing glioblastoma multiforme underwent baseline and follow-up MR imaging. Seven observers measured BPs in various planes. Differences in BPs between scans were expressed as a percentage of baseline. This calculation was performed for both readings of the baseline and follow-up scans. Differences between change from baseline to follow-up on each reading (termed D values) were calculated for each reader (total of 196 D values). Median D value in each plane was calculated for each reader. Range of D values was 12.36-33.64% in axial plane (average 10.63%), 12.18-38.62% in coronal plane (average 26.84%) and 15.12-35.48% in sagittal plane (average 26.11%). Across all planes, 88 (45%) D values were >25%. When all imaging planes for any single observation were combined, in 76% of cases, at least one D value of >25% was seen. Based on the high degree of intra-observer variability, tumor measurements producing an increase in BP of >25% can routinely be obtained solely by chance.

Hand-held spectroscopic device for in vivo and intraoperative tumor detection: contrast enhancement, detection sensitivity, and tissue penetration.

Surgery is one of the most effective and widely used procedures in treating human cancers, but a major problem is that the surgeon often fails to remove the entire tumor, leaving behind tumor-positive margins, metastatic lymph nodes, and/or satellite tumor nodules. Here we report the use of a hand-held spectroscopic pen device (termed SpectroPen) and near-infrared contrast agents for intraoperative detection of malignant tumors, based on wavelength-resolved measurements of fluorescence and surface-enhanced Raman scattering (SERS) signals. The SpectroPen utilizes a near-infrared diode laser (emitting at 785 nm) coupled to a compact head unit for light excitation and collection. This pen-shaped device effectively removes silica Raman peaks from the fiber optics and attenuates the reflected excitation light, allowing sensitive analysis of both fluorescence and Raman signals. Its overall performance has been evaluated by using a fluorescent contrast agent (indocyanine green, or ICG) as well as a surface-enhanced Raman scattering (SERS) contrast agent (pegylated colloidal gold). Under in vitro conditions, the detection limits are approximately 2-5 × 10(-11) M for the indocyanine dye and 0.5-1 × 10(-13) M for the SERS contrast agent. Ex vivo tissue penetration data show attenuated but resolvable fluorescence and Raman signals when the contrast agents are buried 5-10 mm deep in fresh animal tissues. In vivo studies using mice bearing bioluminescent 4T1 breast tumors further demonstrate that the tumor borders can be precisely detected preoperatively and intraoperatively, and that the contrast signals are strongly correlated with tumor bioluminescence. After surgery, the SpectroPen device permits further evaluation of both positive and negative tumor margins around the surgical cavity, raising new possibilities for real-time tumor detection and image-guided surgery.

Applications of nanotechnology to imaging and therapy of brain tumors.

In the past decade, numerous advances in the understanding of brain tumor physiology, tumor imaging, and tumor therapy have been attained. In some cases, these advances have resulted from refinements of pre-existing technologies (eg, improvements of contrast-enhanced magnetic resonance imaging). In other instances, advances have resulted from development of novel technologies. The development of nanomedicine (ie, applications of nanotechnology to the field of medicine) is an example of the latter. In this review, the authors explain the principles that underlay nanoparticle design and function as well as the means by which nanoparticles can be used for imaging and therapy of brain tumors.

Imaging findings of structural causes of epilepsy in children: a guide for the radiologist in the emergency room.

Evaluation of the child with epilepsy is a relatively common indication for imaging in the emergency room setting. This room outlines some of the more important imaging features of causes of epilepsy in children.

Bidimensional measurements in brain tumors: assessment of interobserver variability.

OBJECTIVE: Bidimensional tumor measurements indicating a greater than 25% increase in tumor size are generally accepted as indicating tumor progression. We hypothesized that use of digital images and a homogeneous reader population would have lower interobserver variability than in previous studies. SUBJECTS AND METHODS: Eight board-certified radiologists measured tumor diameters in three planes in two consecutive MRI examinations of 22 patients with contrast-enhancing high-grade brain tumors. Products of tumor measurements were calculated, and determinations were made about tumor progression (> 25% increase in area). A variance components model was run on diameter products and the ratios of consecutive maximal diameter products. The variance components included patient examination effect, reader effect, and residual effect. RESULTS: Complete agreement was found among readers in 10 cases (45%), all indicating stable disease. In the other 12 cases, at least one reader considered progressive disease present. The variance components model showed variance due to readers was small, indicating only modest bias among readers. The residual variance component was large (0.038), indicating that repeated measurements on the same image likely are variable even for the same reader. This variability in measurement implies that repeated measurements by the typical reader have an inherent 14% false-positive rate in the diagnosis of progression of tumors that are stable. CONCLUSION: Our hypothesis was disproved. We found substantial interreader disagreement and indications that the very nature of the measurement method produces a high rate of false-positive readings of stable tumors. These findings should be considered in interpretation of images with this widely accepted criterion for brain tumor progression.

Newborn screening for Krabbe disease: the New York State model.

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.

Molecular imaging and quantitative measurement of epidermal growth factor receptor expression in live cancer cells using immunolabeled gold nanoparticles.

OBJECTIVE: The goal of this study was to assess whether immunolabeled nanoparticle biomarkers are comparable to fluorescent marker imaging in measuring epidermal growth factor receptor (EGFR) expression. MATERIALS AND METHODS: EGFR expression was quantified using both imaging methods in four cell lines: A431 human epidermoid carcinoma cells, which are known to have high EGFR expression; two cell lines with lower EGFR expression (270-GBM human glioblastoma xenograft cells and H2224 human glioblastoma xenograft cells); and MDA-MB-453 breast carcinoma cells, which do not express EGFR. To enhance contrast of the nanoparticle biomarkers, a darkfield microspectroscopy system was used that includes a custom epi-illumination light train. RESULTS: Nanoparticle-bound cells were clearly distinguished from control cells not bound to nanoparticles in that they showed a significant increase in detected intensity under darkfield illumination due to nanoparticle scattering. The average nanoparticle-scattering intensity for A431 cells was 41.5 counts per cell compared with 24.7 for 270-GBM cells, 8.77 for H2224 cells, and 0.44 for MDA-MB-453 cells. The average fluorescence intensity for A431 cells was 35.3 counts per cell compared with 28.7 for 270-GBM cells, 5.91 for H2224 cells, and 2.07 for MDA-MB-453 cells. A plot of fluorescence intensity versus nanoparticle-scattering intensity for all four cell lines showed that the data agree with a linear relationship given by the following equation: NP = 1.0691 x FL - 0.3873, where NP is the nanoparticle-scattering intensity and FL is the fluorescence intensity. The covariance of the data with the trend line was R(2) = 0.9409. The average peak wavelength of nanoparticle scattering was 570.93 nm for A431 cells, 565.26 nm for 270-GBM cells, and 562.70 nm for H2224 cells (with no clear peaks observed for MDA-MB-453 cells). This spectral trend shows that nanoparticle scattering may reveal additional information about their nanoenvironment via refractive index sensitivity. CONCLUSION: Immunolabeled nanoparticles can quantify receptor expression with performance comparable to fluorescence markers and show promise to better characterize receptor expression via their refractive index sensitivity.