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Background: Posterior reversible encephalopathy syndrome (PRES) can cause short-term cerebrovascular complications, such as brain infarction and hemorrhage. We hypothesized that PRES is also associated with an increased long-term risk of stroke. Methods: We performed a retrospective cohort study in the United States using statewide all-payer claims data from 2016 to 2018 on all admissions to nonfederal hospitals in 11 states. Adults with PRES were compared with adults with renal colic (negative control) and transient ischemic attack (TIA; positive control). Any stroke and the secondary outcomes of ischemic and hemorrhagic stroke were ascertained using International Classification of Diseases, Tenth Revision, Clinical Modification codes . We excluded prevalent stroke. We used time-to-event statistics to calculate incidence rates and Cox proportional hazards analyses to evaluate the association between PRES and stroke, adjusting for demographics and stroke risk factors. In a sensitivity analysis, outcomes within 2 weeks of index admission were excluded. Results: We identified 1606 patients with PRES, 1192 with renal colic, and 38 216 with TIA. Patients with PRES had a mean age of 56±17 years; 72% were women. Over a median follow-up of 0.9 years, the stroke incidence per 100 person-years was 6.1 (95% CI, 5.0–7.4) after PRES, 1.0 (95% CI, 0.62–1.8) after renal colic, and 9.7 (95% CI, 9.4–10.0) after TIA. After statistical adjustment for patient characteristics and risk factors, patients with PRES had an elevated risk of stroke compared with renal colic (hazard ratio [HR], 2.3 [95% CI, 1.7–3.0]), but lower risk than patients with TIA (HR, 0.67 [95% CI, 0.54–0.82]). In secondary analyses, compared with TIA, PRES was associated with hemorrhagic stroke (HR, 2.0 [95% CI, 1.4–2.9]). PRES was associated with ischemic stroke when compared with renal colic (HR, 1.9 [95% CI, 1.4–2.7]) but not when compared with TIA (HR, 0.49 [95% CI, 0.38–0.63]). Results were similar with 2-week washout. Conclusions: Patients with PRES had an elevated risk of incident stroke.

Cerebrovascular complications among critically ill patients with COVID-19 have yet to be fully characterized. In this retrospective case series from a single academic tertiary care referral center in New York City, we present 12 patients with ischemic or hemorrhagic strokes that were found on imaging after a period of prolonged sedation in the setting of COVID-19 pneumonia. This series demonstrates a pattern of cerebrovascular events clinically masked by deep sedation required for management of COVID-19 related acute respiratory distress syndrome (ARDS). Of the 12 patients included, 10 had ischemic stroke, 4 of which had hemorrhagic conversion, and 2 had primary intracerebral hemorrhage. Ten patients were on therapeutic anticoagulation prior to discovery of their stroke, and the remainder received intermediate dose anticoagulation (in a range between prophylactic and therapeutic levels). Additional studies are needed to further characterize the counterbalancing risks of ischemic and hemorrhagic stroke, as well as the optimal management of this patient population.

Introduction: Posterior reversible encephalopathy syndrome (PRES) can cause brain infarction and hemorrhage in the acute phase. We hypothesized that PRES is also associated with an increased long-term risk of stroke. Methods: We performed a retrospective cohort study using statewide all-payer claims data from 2016-2018 for all admissions to nonfederal hospitals in 11 states. Adult patients with PRES were compared to patients with TIA (positive control) and renal colic (negative control), as done in prior studies. The primary outcome was any stroke, and secondary outcomes were ischemic and hemorrhagic stroke. Diagnoses were ascertained using ICD-10-CM codes. We excluded patients with stroke before and during index admissions for PRES and controls. We used Cox proportional hazards analyses to evaluate associations between PRES and stroke, adjusting for demographics, stroke risk factors, and factors associated with PRES (cancer, kidney disease, rheumatological disease). In a sensitivity analysis, stroke events within 4 weeks of index admissions were excluded. Results: We identified 3,086 patients with PRES, 85,189 with TIA, and 3,094 with renal colic. Patients with PRES (55±17 years) and renal colic (54±18 years) were younger than those with TIA (72±14 years). Median follow-up was 1.1 years and similar between groups. Stroke incidence was 3.2 per 100 person-years after PRES, 3.8 per 100 person-years after TIA, and 0.4 per 100 person-years after renal colic (Figure). After adjustment, patients with PRES had a similar stroke risk as patients with TIA (HR, 0.9; 95% CI, 0.8-1.2), and a higher stroke risk than patients with renal colic (HR, 2.6; 95% CI, 2.0-3.5). Compared to TIA, PRES had a higher risk of hemorrhagic stroke (HR, 2.9; 95% CI, 2.2-3.9) and a lower risk of ischemic stroke (HR, 0.7; 95% CI, 0.6-0.9). Results were similar with a 4-week washout period. Conclusions: PRES is associated with an increased risk of future stroke, specifically hemorrhagic stroke.

CSF-venous fistula is an important treatable cause of spontaneous intracranial hypotension that is often difficult to detect using traditional imaging techniques. Herein, we describe the technical aspects and diagnostic performance of MR myelography when used for identifying CSF-venous fistulas. We report 3 cases in which the CSF-venous fistula was occult on CT myelography but readily detected using MR myelography.

While the diagnosis of traumatic brain injury (TBI) is a clinical decision, neuroimaging remains vital for guiding management on the basis of identification of intracranial pathologic conditions. CT is the mainstay of imaging of acute TBI for both initial triage and follow-up, as it is fast and accurate in detecting both primary and secondary injuries that require neurosurgical intervention. MRI is more sensitive for the detection of certain intracranial injuries (eg, axonal injuries) and blood products 24-48 hours after injury, but it has limitations (eg, speed, accessibility, sensitivity to motion, and cost). The evidence primarily supports the use of MRI when CT findings are normal and there are persistent unexplained neurologic findings or at subacute and chronic periods. Radiologists should understand the role and optimal imaging modality to use, in addition to patterns of primary brain injury and their influence on the risk of developing secondary brain injuries related to herniation. ©RSNA, 2019 See discussion on this article by Mathur and Nicolaou.

As the coronavirus disease 2019 (COVID-19) pandemic strains the healthcare system, radiology residents across the United States have become a vital part of the redeployed workforce. Through a series of four cases of COVID-19 patients encountered on the wards, we highlight the insight and unique set of skills redeployed radiology residents possess that are essential to patient care during this crisis. By increasing visibility through active participation on the clinical team, we demonstrate the fundamental role radiology has in the greater field of medicine., Highlights • Radiology residents are an asset to the redeployed workforce and have meaningful contribution to patient care. • Dynamic imaging rounds became critical in clinical decision-making and expediting appropriate management. • Redeployment increases the visibility of radiology and highlights the essential role of the radiologist.

Objective Benefits of a diverse physician workforce are numerous and the impact of a lack of diversity has been highlighted with the COVID-19 pandemic. Despite the commitment of professional societies such as the American College of Radiology to diversity in Radiology, the field and its residency training programs remain the least diverse. With COVID-19 related suspension of in-person medical student rotations, our Department of Radiology redesigned and implemented a virtual radiology internship for underrepresented minority (URM) medical students. Methods A four-week virtual radiology internship was designed to provide clinical exposure to radiology and to allow students to gain an understanding of what a career in radiology entails. Course design included videoconference patient care sessions, didactic lectures, online modules, mentoring, and extra-clinical curriculum. Feedback from students was collected using online surveys assessing pre- and postcourse attitudes and understanding of a career in radiology and the students’ perceived aptitude for such a career, as well as course component evaluation. Results Three participants were enrolled in the inaugural clerkship. All noted exceptional educational course content and ample opportunities to build connections with faculty and residents—with mentoring seen as the highlight of the course. All indicated a significant shift in perception of the field and in declaring interest in pursuing a career in radiology. Conclusion Virtual radiology internship for URM students is a feasible paradigm to address potential impediments to diversification of the specialty by both engaging interested URM medical students in a career in radiology and arming them with the tools for a successful application to radiology residency.

The focus of diagnostic radiology training is on creating competent professionals, whereas confidence and its calibration receive less attention. Appropriate confidence is critical for patient care both during and after training. Overconfidence can adversely affect patient care and underconfidence can create excessive costs. We reviewed the psychology and medical literature pertaining to confidence and competence to collect insights and best practices from the psychology and medical literature on confidence and apply them to radiology training. People are rarely accurate in assessments of their own competence. Among physicians, the correlation between perceived abilities and external assessments of those abilities is weak. Overconfidence is more prevalent than underconfidence, particularly at lower levels of competence. On the individual level, confidence can be calibrated to a more appropriate level through efforts to increase competence, including sub-specialization, and by gaining a better understanding of metacognitive processes. With feedback, high-fidelity simulation has the potential to improve both competence and metacognition. On the system level, systems that facilitate access to follow-up imaging, pathology, and clinical outcomes can help close the gap between perceived and actual performance. Appropriate matching of trainee confidence and competence should be a goal of radiology residency and fellowship training to help mitigate the adverse effects of both overconfidence and underconfidence during training and independent practice.

Accurate and timely diagnosis of amyotrophic lateral sclerosis (ALS) is a diagnostic challenge given the lack of specific diagnostic and imaging biomarkers as well as the significant clinic overlap with mimic syndromes. We hypothesize that MR quantitative susceptibility mapping (QSM) can help differentiate ALS from mimic diagnoses.In a blinded retrospective study of MRIs with QSM from 2015 to 2018, we compared motor cortex susceptibility along the hand and face homunculi in ALS patients and patients with similar clinical presentations. Inclusion required a confirmed ALS or a mimic diagnosis. Comparative groups included age-matched patients with MRIs performed for non-motor neuron symptoms that were reported as normal or demonstrated leukoaraiosis. Quantitative susceptibility values were compared with ANOVA and Tukey-Kramer (post-hoc). ROC analysis and Youden's index were used to identify optimal cutoff values.Fifty ALS, 35 mimic, and 70 non-motor neuron symptom patients (35 normal, 35 leukoaraiosis) were included. Hand and face homunculus mean susceptibility values were significantly higher in the ALS group compared to the mimic (p=0.001, p=0.004), leukoaraiosis (p0.001, p=0.003), and normal (p0.001, p0.001) groups. ROC curve analysis comparing ALS to mimics resulted in an area under the curve of 0.71 and 0.67 for the hand and face homunculus measurements, respectively. In differentiating ALS from mimics, Youden's index showed 100% specificity and 36% sensitivity for hand homunculus measurements.QSM has diagnostic potential in the assessment of suspected ALS patients, demonstrating very high specificity in differentiating ALS from mimic diagnoses.

Given that artificial intelligence and machine learning is now a reality of modern existence, rapidly being applied to medicine, and especially radiology, we submit a new educational perspective. By codifying technology education during the diagnostic radiology internship, we believe it is not only possible but necessary, to reframe the identity of diagnostic radiology. This paper describes the restructuring of the radiology clinical internship, limiting clinical rotations to high-yield essentials, thereby allowing for the introduction of data and technology science, and comprehensive medical physics training. By linking modality-immersion based training with the physics of each technology, we postulate a more thorough understanding and, ultimately, the mastery of current and future technological innovations. Concurrently we advocate for the study of artificial intelligence and machine learning in order to understand how radiologists can apply this technology to help patients on the precision and population health levels. This training would allow interns to spend the majority of their time under the umbrella of a radiology department, in lieu of multiple rotations on an assortment of clinical services. An in-depth technology and physics exam at the end of the internship would be a natural transition to the start of the R1 year, allowing for the application of this newly attained knowledge throughout their residency. Diagnostic radiologists have led medicine into the digital era, and now we should lead the medical community into this transformational era as the "Data-Driven Physician" of the 21

Posterior reversible encephalopathy syndrome (PRES) is characterized by the acute onset of neurologic symptoms (headache, altered mental status, visual changes, seizures) with accompanying vasogenic edema on brain imaging. Risk factors for PRES include infection, uremia, malignancy, autoimmune disorders, the peripartum state and hypertension. PRES is classically described as being posterior (i.e. parieto-occipital) but radiologic variants are increasingly recognized. This pictorial review demonstrates the heterogeneity of the different radiologic presentations of PRES in reference to lesion distribution, hemorrhage, diffusion restriction, contrast enhancement, and other associated findings.

Diffusion tensor imaging (DTI) and quantitative susceptibility mapping (QSM) have been proposed as methods to aid in the diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), both diseases affecting upper motor neurons. We test the performance of DTI and QSM alone and in combination to distinguish patients with diseases affecting upper motor neurons (ALS/PLS) from patients with other motor symptom-predominant neurologic disorders.3.0 Tesla MRI with DTI and QSM in patients referred to a subspecialty neurology clinic for evaluation of motor symptom-predominant neurologic disorders were retrospectively reviewed. Corticospinal tract fractional anisotropy and maximum motor cortex susceptibility were measured. Subjects were categorized by diagnosis and imaging metrics were compared between groups using Student's t-tests. Receiver operating characteristic curves were generated for imaging metrics alone and in combination.MRI scans for 43 patients with ALS or PLS and 15 patients with motor symptom predominant, non-upper motor neuron disease (mimics) were reviewed. Fractional anisotropy was lower (0.57 vs. 0.60, p 0.01) and maximum motor cortex magnetic susceptibility higher (64.4 vs. 52.7, p = 0.01) in patients with ALS/PLS compared to mimics. There was no significant difference in area under the curve for these metrics alone (0.73, 0.63; p 0.05) or in combination (0.75; p 0.05).We found significant differences in DTI and QSM metrics in patients with diseases affecting upper motor neurons (ALS/PLS) compared to mimics, but no significant difference in the performance of these metrics in diagnosing ALS/PLS compared to mimics.

Percutaneous image-guided rupture of lumbar facet synovial cysts can improve clinical outcomes and obviate the need for open surgery. This series describes eleven patients who had successful CT-guided lumbar facet synovial cyst ruptures, 82% of which experienced excellent pain relief at a minimum of one-year follow-up. Of the five patients who failed prior fluoroscopic-guided synovial cyst rupture, 80% had a successful CT-guided rupture and one-year sustained pain relief. These findings reinforce minimally invasive CT-guided treatment as an excellent option to improve patient symptoms and potentially avoid open surgery.

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.

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.

To assess quantitative susceptibility mapping (QSM) in the depiction of the subthalamic nucleus (STN) by using 3-T magnetic resonance (MR) imaging.This study was HIPAA compliant and institutional review board approved. Ten healthy subjects (five men, five women; mean age, 24 years ± 3 [standard deviation]; age range, 21-33 years) and eight patients with Parkinson disease (five men, three women; mean age, 57 years ± 14; age range, 25-69 years) who were referred by neurologists for preoperative navigation MR imaging prior to deep brain stimulator placement were included in this study. T2-weighted (T2w), T2*-weighted (T2*w), R2* mapping (R2*), phase, susceptibility-weighted (SW), and QSM images were reconstructed for STN depiction. Qualitative visualization scores of STN and internal globus pallidus (GPi) were recorded by two neuroradiologists on all images. Contrast-to-noise ratios (CNRs) of the STN and GPi were also measured. Measurement differences were assessed by using the Wilcoxon rank sum test and the signed rank test.Qualitative scores were significantly higher on QSM images than on T2w, T2*w, R2*, phase, or SW images (P.05) for STN and GPi visualization. Median CNR was 6.4 and 10.7 times higher on QSM images than on T2w images for differentiation of STN from the zona incerta and substantia nigra, respectively, and was 22.7 and 9.1 times higher on QSM images than on T2w images for differentiation of GPi from the internal capsule and external globus pallidus, respectively. CNR differences between QSM images and all other images were significant (P.01).QSM at 3-T MR imaging performs significantly better than current standard-of-care sequences in the depiction of the STN.

BACKGROUND AND PURPOSE: Increased oxygen extraction fraction on PET has been considered a risk factor for stroke in patients with carotid stenosis or occlusion, though the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between increased oxygen extraction fraction and ipsilateral stroke risk. MATERIALS AND METHODS: A comprehensive literature search was performed. We included studies with baseline PET oxygen extraction fraction testing, ipsilateral stroke as the primary outcome, and at least 1 year of follow-up. A meta-analysis was performed by use of a random-effects model. RESULTS: After screening 2158 studies, 7 studies with 430 total patients with mean 30-month follow-up met inclusion criteria. We found that 6 of 7 studies were amenable to meta-analysis. Although 4 of the 6 studies independently did not reach statistical significance, meta-analysis revealed a significant positive relationship between abnormal oxygen extraction fraction and future ipsilateral stroke, with a pooled OR of 6.04 (95% CI, 2.58–14.12). There was no statistically significant difference in OR in the subgroup analyses according to testing method or disease site. CONCLUSIONS: Abnormal oxygen extraction fraction remains a powerful predictor of stroke in carotid stenosis or occlusion and is a valuable reference standard to compare and validate MR imaging–based measures of brain oxygen metabolism. However, there is a need for further evaluation of oxygen extraction fraction testing in patients with high-grade but asymptomatic carotid disease.

An epidural blood patch (EBP) has become standard of care for management of postdural puncture headache, and in recent years, attempts have been made to expand its applicability. Its utility in the management of postsurgical pseudomeningocele remains poorly defined, and few reports describe its use in children. In this case, we report the successful management of lumbar pseudomeningocele via EBP in a 3-year-old after tethered cord release, thereby obviating the need for surgical repair and its potential morbidity.

The aim of this study was to determine the predictive value of the preoperative three-dimensional reconstructed volume (3D volumetry) for outcomes of laparoscopic splenectomy. The impact of splenomegaly on the feasibility of laparoscopic splenectomy is still debated. We hypothesized that splenic volumetry may accurately estimate splenic volume preoperatively and be used by surgeons to select patients for laparoscopic splenectomy.We performed a retrospective review of 88 patients seen at a tertiary referral center undergoing laparoscopic or open splenectomy between 2001 and 2010. Patients included in the study underwent elective splenectomy without associated procedures and had preoperative imaging available at our institution. We evaluated clinical, demographic characteristics and perioperative imaging as predictors of outcome. Study endpoints included conversion to open splenectomy, operating time, estimated blood loss (EBL), length of stay (LOS), postoperative complications, and mortality.In all, 53 procedures were started laparoscopically. Among them, 7 (13.2 %) were converted to open splenectomy and 7 (13.2 %) to hand-assisted laparoscopic splenectomy. The conversion group was matched with 35 patients who underwent open splenectomy to determine differences in outcomes between these groups. There were no conversions in spleens measuring1100 cc, whereas spleens of 1100 to 2700 cc had a conversion rate of 41 %. Spleen volume2700 cc was associated with an 87.5 % conversion rate. Spleen 3D volumetry2700 cc was the only independent predictor of surgical conversion on multivariate analysis (odds ratio 38.0, confidence interval 4.02-358.75, p = 0.001). Patients who underwent open splenectomy had shorter operating times (160.3 vs. 253.0 min, p = 0.001) than those converted from laparoscopic to open splenectomy.A 3D reconstructed splenic volume of2700 cc is a predictor of conversion from laparoscopic to open splenectomy. For spleens measuring2700 cc, laparoscopic splenectomy may be performed by experienced surgeons with low to moderate rates of conversion. For spleens with a 3D reconstructed volume2700 cc, laparoscopic splenectomy is associated with high rates of conversion to open surgery.

Purpose: Protection of bone marrowagainst radiotoxicity during radioimmunotherapy and in some cases external beamradiationtherapy suchashemi-body irradiationwould permitadministrationof significantlyhigher dosesto tumors, resulting in increased efficacy and safety of treatment. Melanin, a naturally occurring pigment, possesses radioprotective properties. We hypothesized that melanin, which is insoluble, could be delivered to the bone marrow by intravenously administrated melanin-covered nanoparticles (MNs) because of the human body’s ‘‘selfsieving’’ ability, protecting it against ionizing radiation. Methods and Materials: The synthesis of MNs was performed via enzymatic polymerization of 3,4-dihydroxyphenylalanine and/or 5-S-cysteinyl-3,4-dihydroxyphenylalanine on the surface of 20-nm plain silica nanoparticles. The biodistribution of radiolabeled MNs in mice was done at 3 and 24 h. Healthy CD-1 mice (Charles River Laboratories International, Inc., Wilmington, MA) or melanoma tumor‐bearing nude mice were given MNs intravenously, 50 mg/kg of body weight, 3 h before either whole-body exposure to 125 cGy or treatment with 1 mCi of 188 Re-labeled 6D2 melanin-binding antibody. Results: Polymerization of melanin precursors on the surface of silica nanoparticles resulted in formation of a 15nm-thick melanin layer as confirmed by light scattering, transmission electron microscopy, and immunofluorescence. The biodistribution after intravenous administration showed than MN uptake in bone marrow was 0.3% and 0.2% of injected dose per gram at 3 and 24 h, respectively, whereas pre-injection with pluronic acid increased the uptake to 6% and 3% of injected dose per gram, respectively. Systemic MN administration reduced hematologic toxicity in mice treated with external radiation or radioimmunotherapy, whereas no tumor protection by MNs was observed. Conclusions: MNs or similar structures provide a novel approach to protection of bone marrow from ionizing radiation based on prevention of free radical formation by melanin. 2010 Elsevier Inc. Melanin, Nanoparticles, Bone marrow, Radiation protection, Radioimmunotherapy.

Many microorganisms such as bacteria and fungi possess so-called capsules made of polysaccharides which protect these microorganisms from environmental insults and host immune defenses. The polysaccharide capsule of Cryptococcus neoformans, a human pathogenic yeast, is capable of self-assembly, composed mostly of glucuronoxylomannan (GXM), a polysaccharide with a molecular weight of approximately 2,000,000, and has several layers with different densities. The objective of this study was to model pore-hindered diffusion and binding of the GXM-specific antibody within the C. neoformans capsule. Using the finite-element method (FEM), we created a model which represents the in vivo binding of a GXM-specific antibody to a C. neoformans cell taking into account the intravenous infusion time of antibody, antibody diffusion through capsular pores, and Michaelis-Menten kinetics of antibody binding to capsular GXM. The model predicted rapid diffusion of antibody to all regions of the capsule where the pore size was greater than the Stokes diameter of the antibody. Binding occurred primarily at intermediate regions of the capsule. The GXM concentration in each capsular region was the principal determinant of the steady-state antibody-GXM complex concentration, while the forward binding rate constant influenced the rate of complex formation in each region. The concentration profiles predicted by the model closely matched experimental immunofluorescence data. Inclusion of different antibody isotypes (IgG, IgA, and IgM) into the modeling algorithm resulted in similar complex formation in the outer capsular regions, but different depths of binding at the inner regions. These results have implications for the development of new antibody-based therapies.

Introduction Melanins are high-molecular-weight pigments that are ubiquitous in nature and can also be synthesized in the laboratory from a variety of precursors. Melanins possess numerous interesting physicochemical characteristics, including electromagnetic radiation absorption properties and ability to chelate metals. We have recently reported that melanin has remarkable ionizing-radiation-shielding properties, possibly because it can interact with photons via Compton scattering. We hypothesized that, if administered internally, melanin could play a beneficial role by scavenging various radionuclides, in addition to radiation shielding. Methods Three melanins were synthesized from dopamine, 3,4-dihydroxyphenylalanine (l-Dopa) and a combination of l-cysteine and l-Dopa. For control, synthetic melanin made from tyrosine polymerization (Sigma) was used. Melanins were characterized by elemental analysis. The chemosorption of 111 In, 225 Ac and 213 Bi by melanins was studied at 37°C for up to 48 h. Results The C-to-N molar ratios for dopamine, l-Dopa and tyrosine melanins were very close at 7.92, 8.39 and 8.48, respectively, while in mixed l-cysteine/l-Dopa melanin, that ratio was much lower at 3.63. This mixed melanin also contained 22.33% sulfur, thus confirming incorporation of S-containing motifs into its structure. Dopamine, l-Dopa and tyrosine melanins were very similar in their abilities to decrease the activity of 111 In, 225 Ac and 213 Bi and their radioactive daughters in supernatants by >10-fold in comparison with the starting levels, while mixed l-cysteine/l-Dopa melanin was able to chemosorb only 111 In. Conclusions We have demonstrated that synthetic melanins made of diverse precursors can chemosorb 111 In, 213 Bi and 225 Ac, with dopamine, l-Dopa and tyrosine melanins being the most efficient towards all three of these radionuclides. Such properties of synthetic melanins can contribute to the development of the novel melanin-based radioprotective materials.

Often complementary to clinical assessment, imaging of the brachial and lumbosacral plexus can be used to characterize plexus involvement by primary neoplasm, metastases, or conditions related to treatment. The imaging modality of choice, magnetic resonance (MR) without and with contrast, typically includes T1-weighted and fat-suppressed T2-weighted images. MR can delineate primary plexus neoplasms, including benign and malignant peripheral nerve sheath tumors, and accurately characterizes the extent of plexus involvement due to infiltrative malignancy. In cases in which there is clinical uncertainty between recurrent tumor and radiation injury, MR has been shown to be highly sensitive and specific. Positron emission tomography/computed tomography has also been shown to be useful in excluding recurrent tumor. MR imaging techniques that have been more recently investigated in plexus imaging, including diffusion-weighted imaging, isotropic three-dimensional imaging, diffusion tensor imaging, and fiber tractography, show potential to further complement clinical evaluation.

Melanized microorganisms are often found in environments with very high background radiation levels such as in nuclear reactor cooling pools and the destroyed reactor in Chernobyl. These findings and the laboratory observations of the resistance of melanized fungi to ionizing radiation suggest a role for this pigment in radioprotection. We hypothesized that the radioprotective properties of melanin in microorganisms result from a combination of physical shielding and quenching of cytotoxic free radicals. We have investigated the radioprotective properties of melanin by subjecting the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum in their melanized and non-melanized forms to sublethal and lethal doses of radiation of up to 8 kGy. The contribution of chemical composition, free radical presence, spatial arrangement, and Compton scattering to the radioprotective properties of melanin was investigated by high-performance liquid chromatography, electron spin resonance, transmission electron microscopy, and autoradiographic techniques. Melanin protected fungi against ionizing radiation and its radioprotective properties were a function of its chemical composition, free radical quenching, and spherical spatial arrangement.

Brown tumors rarely develop in the spine, and neurological compromise is exceedingly uncommon. There is a growing body of literature describing brown tumors that involve the spine, but few emphasize the radiographic findings. In the present case, we illustrate the development and progression of biopsy-proven brown tumors leading to neurological compromise through radiographs, computed tomography, magnetic resonance, and nuclear imaging acquired over a 4-year span.

Melanoma is a cancer with a rising incidence, and metastatic disease is almost always lethal. We investigated the feasibility of targeting melanin, an intracellular melanocyte pigment, to deliver cytotoxic radiation to human melanoma cellsin vivoby using a melanin-binding mAb (6D2). Nude mice bearing MNT1 pigmented human melanoma tumors were treated with mAb 6D2 labeled with 1.5 mCi (1 Ci = 37 GBq) of the β-emitter 188-Rhenium (188Re) and manifested inhibition of tumor growth and prolonged survival. mAb 6D2 bound tumor melanin and demonstrated no crossreactivity with normal melanized tissues in black mice. The mechanism of melanin targeting involved Ab binding to extracellular melanin released during tumor cell turnover or to dying cells with permeable membranes. In this approach, the cytotoxic radiation emanating from labeled Ab bound to melanin is presumably delivered by “crossfire” effect to the adjacent viable tumor cells. Our results establish the feasibility of targeting melanin released from dead melanoma cells in tumors with radiolabeled Abs to achieve a therapeutic effect. In contrast to conventional tumor antigens, melanin is insoluble, resistant to degradation, and can be expected to accumulate in targeted tissues, suggesting that the efficacy of therapy could increase with each subsequent treatment cycle.

Background and Purpose— MRI characterization of carotid plaque has been studied recently as a potential tool to predict stroke caused by carotid atherosclerosis. We performed a systematic review and meta-analysis to summarize the association of MRI-determined intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap with subsequent ischemic events. Methods— We performed a comprehensive literature search evaluating the association of carotid plaque composition on MRI with ischemic outcomes. We included cohort studies examining intraplaque hemorrhage, lipid-rich necrotic core, or thinning/rupture of the fibrous cap with mean follow-up of ≥1 month and an outcome measure of ipsilateral stroke or transient ischemic attack. A meta-analysis using a random-effects model with assessment of study heterogeneity and publication bias was performed. Results— Of the 3436 articles screened, 9 studies with a total of 779 subjects met eligibility for systematic review. The hazard ratios for intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap as predictors of subsequent stroke/transient ischemic attack were 4.59 (95% confidence interval, 2.91–7.24), 3.00 (95% confidence interval, 1.51–5.95), and 5.93 (95% confidence interval, 2.65–13.20), respectively. No statistically significant heterogeneity or publication bias was present in the 3 main meta-analyses performed. Conclusions— The presence of intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap on MRI of carotid plaque is associated with increased risk of future stroke or transient ischemic attack in patients with carotid atherosclerotic disease. Dedicated MRI of plaque composition offers stroke risk information beyond measurement of luminal stenosis in carotid atherosclerotic disease.

Molecular and genetic testing is becoming increasingly relevant in GBM. We sought to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion imaging could predict EGFR-defined subtypes of GBM. We retrospectively identified 106 consecutive glioblastoma (GBM) patients with known EGFR gene amplification, and a subset of 65 patients who also had known EGFRvIII gene mutation status. All patients underwent T2* DSC MRI perfusion. DSC perfusion maps and T2* signal intensity time curves were evaluated, and the following measures of tumor perfusion were recorded: (1) maximum relative cerebral blood volume (rCBV), (2) relative peak height (rPH), and (3) percent signal recovery (PSR). The imaging metrics were correlated to EGFR gene amplification and EGFRvIII mutation status using univariate analyses. EGFR amplification was present in 44 (41.5 %) subjects and absent in 62 (58.5 %). Among the 65 subjects who had undergone EGFRvIII mutation transcript analysis, 18 subjects (27.7 %) tested positive for the EGFRvIII mutation, whereas 47 (72.3 %) did not. Higher median rCBV (3.31 versus 2.62, p = 0.01) and lower PSR (0.70 versus 0.78, p = 0.03) were associated with high levels of EGFR amplification. Higher median rPH (3.68 versus 2.76, p = 0.03) was associated with EGFRvIII mutation. DSC MRI perfusion may have a role in identifying patients with EGFR gene amplification and EGFRvIII gene mutation status, potential targets for individualized treatment protocols. Our results raise the need for further investigation for imaging biomarkers of genetically unique GBM subtypes.

Although a certain degree of arteriovenous shunting may be expected in glioblastoma, to our knowledge, the coexistence of a glioblastoma and arteriovenous fistula has not been previously reported. In this case report, we present such a lesion and discuss its diagnosis with a multimodal imaging approach. Additionally, we discuss treatment considerations for such a lesion.

BACKGROUND AND PURPOSE: Epidermal growth factor receptor amplification is a common molecular event in glioblastomas. The purpose of this study was to examine the potential usefulness of morphologic and diffusion MR imaging signs in the prediction of epidermal growth factor receptor gene amplification status in patients with glioblastoma. MATERIALS AND METHODS: We analyzed pretreatment MR imaging scans from 147 consecutive patients with newly diagnosed glioblastoma and correlated MR imaging features with tumor epidermal growth factor receptor amplification status. The following morphologic tumor MR imaging features were qualitatively assessed: 1) border sharpness, 2) cystic/necrotic change, 3) hemorrhage, 4) T2-isointense signal, 5) restricted water diffusion, 6) nodular enhancement, 7) subependymal enhancement, and 8) multifocal discontinuous enhancement. A total of 142 patients had DWI available for quantitative analysis. ADC maps were calculated, and the ADC mean , ADC min , ADC max , ADC ROI , and ADC ratio were measured. RESULTS: Epidermal growth factor receptor amplification was present in 60 patients (40.8%) and absent in 87 patients (59.2%). Restricted water diffusion correlated with epidermal growth factor receptor amplification ( P = .04), whereas the other 7 morphologic MR imaging signs did not ( P > .12). Quantitative DWI analysis found that all ADC measurements correlated with epidermal growth factor receptor amplification, with the highest correlations found with ADC ROI ( P = .0003) and ADC mean ( P = .0007). CONCLUSIONS: Our results suggest a role for diffusion MR imaging in the determination of epidermal growth factor receptor amplification status in glioblastoma. Additional work is necessary to confirm these results and isolate new imaging biomarkers capable of noninvasively characterizing the molecular status of these tumors.

There is a need for radioprotectors that protect normal tissues from ionizing radiation in patients receiving high doses of radiation and during nuclear emergencies. We investigated the possibility of creating an efficient oral radioprotector based on the natural pigment melanin that would act as an internal shield and protect the tissues via Compton scattering followed by free radical scavenging. CD-1 mice were fed melanin-containing black edible mushrooms Auricularia auricila-judae before 9 Gy total body irradiation. The location of the mushrooms in the body before irradiation was determined by in vivo fluorescent imaging. Black mushrooms protected 80% of mice from the lethal dose, while control mice or those given melanin-devoid mushrooms died from gastrointestinal syndrome. The crypts of mice given black mushrooms showed less apoptosis and more cell division than those in control mice, and their white blood cell and platelet counts were restored at 45 days to preradiation levels. The role of melanin in radioprotection was proven by the fact that mice given white mushrooms supplemented with melanin survived at the same rate as mice given black mushrooms. The ability of melanin-containing mushrooms to provide remarkable protection against radiation suggests that they could be developed into oral radioprotectors.

Background: Melanin, a high-molecular weight pigment that is ubiquitous in nature, protects melanized microorganisms against high doses of ionizing radiation. However, the physics of melanin interaction with ionizing radiation is unknown. Methodology/Principal Findings: We rationally designed melanins from either 5-S-cysteinyl-DOPA, L-cysteine/L-DOPA, or LDOPA with diverse structures as shown by elemental analysis and HPLC. Sulfur-containing melanins had higher predicted attenuation coefficients than non-sulfur-containing melanins. All synthetic melanins displayed strong electron paramagnetic resonance (2.14?10 18 , 7.09?10 18 , and 9.05?10 17 spins/g, respectively), with sulfur-containing melanins demonstrating more complex spectra and higher numbers of stable free radicals. There was no change in the quality or quantity of the stable free radicals after high-dose (30,000 cGy), high-energy ( 137 Cs, 661.6 keV) irradiation, indicating a high degree of radical stability as well as a robust resistance to the ionizing effects of gamma irradiation. The rationally designed melanins protected mammalian cells against ionizing radiation of different energies. Conclusions/Significance: We propose that due to melanin’s numerous aromatic oligomers containing multiple p-electron system, a generated Compton recoil electron gradually loses energy while passing through the pigment, until its energy is sufficiently low that it can be trapped by stable free radicals present in the pigment. Controlled dissipation of high-energy recoil electrons by melanin prevents secondary ionizations and the generation of damaging free radical species.

Melanized microorganisms are often found in environments with very high background radiation levels such as in nuclear reactor cooling pools and the destroyed reactor in Chernobyl. These findings and the laboratory observations of the resistance of melanized fungi to ionizing radiation suggest a role for this pigment in radioprotection. We hypothesized that the radioprotective properties of melanin in microorganisms result from a combination of physical shielding and quenching of cytotoxic free radicals. We have investigated the radioprotective properties of melanin by subjecting the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum in their melanized and non-melanized forms to sublethal and lethal doses of radiation of up to 8 kGy. The contribution of chemical composition, free radical presence, spatial arrangement, and Compton scattering to the radioprotective properties of melanin was investigated by high-performance liquid chromatography, electron spin resonance, transmission electron microscopy, and autoradiographic techniques. Melanin protected fungi against ionizing radiation and its radioprotective properties were a function of its chemical composition, free radical quenching, and spherical spatial arrangement.

Metastatic melanoma is almost always deadly and new methods of treatment are urgently needed. Recently, we established the feasibility of radioimmunotherapy (RIT) for experimental melanoma in mice using a 188-rhenium (188Re)-labeled monoclonal antibody (mAb) 6D2 (IgM) to melanin. Our objective was to determine the effects of varying tumor melanin concentration and of different diffusivities and lymphatic clearance rates of the normal tissue, on the absorbed dose to the tumor in simulated therapy, in preparation for a clinical trial of RIT for melanoma. Using finite element analysis (FEA), we created a pharmacokinetic model that describes melanin-targeting RIT of a melanoma micrometastasis (1.3-mm radius) imbedded in normal tissue (14.3-mm radius). Our method incorporates antibody plasma kinetics, transcapillary transport, interstitial diffusion, and lymphatic clearance. Michaelis-Menten kinetics was used to model mAb binding to tumor melanin for melanin concentrations of 76, 7.6, 0.76, 0.076, and 0.0076 micromol/l. An absorbed dose was calculated, after accounting for direct and crossfire irradiation, on the basis of a 7.4-GBq intravenous dose of 188Re-6D2. The results showed that penetration of mAb into the tumor was inversely proportional to tumor melanin concentration. Decreased diffusivity and increased lymphatic clearance of the surrounding normal tissue decreased the dose to the tumor. The formation of mAb-melanin complex was remarkably similar within a 1000-fold range of melanin concentration, resulting in total doses of 2840, 2820, 2710, and 1990 cGy being delivered to tumors with melanin concentrations of 76, 7.6, 0.76, and 0.076 micromol/l, respectively. In conclusion, RIT of metastatic melanoma can be effective over a wide range of tumor melanin concentrations. The results can be useful in the design of a clinical trial of melanin-targeting RIT in patients with metastatic melanoma.

The incidence of melanoma is rising, and therapeutic options for metastatic melanoma are limited. We report the results of experimental melanoma therapy with 188-Rhenium-labeled melanin-binding decapeptide ((188)RE-HYNIC-4B4) and a comprehensive safety evaluation of this treatment. (188)RE-HYNIC- 4B4 bound only to nonviable eumelanotic MNT1 and pheomelanotic SK-28-MEL human melanoma cells in vitro, as determined by immunofluorescence, which is consistent with the inaccessibility of intracellular melanin in live cells, and suggests specificity for tumors with a significant amount of extracellular melanin. Administration of 1 mCi (188)RE-HYNIC-4B4 to MNT1 tumor-bearing mice significantly slowed tumor growth, with the therapeutic effect being a result of specific binding to tumor melanin, as irrelevant (188)RE-labeled decapeptide did not produce therapeutic gain. Repeated doses of (188)RE-HYNIC-4B4 had a more profound effect on tumor growth than a single dose. Treatment of tumors with 0.3-0.4 cm diameter was more effective than of larger ones (0.5-0.7 cm). There was no difference in uptake of (188)REHYNIC- 4B4 in melanized tissues of black C57BL6 mice and no histologically apparent damage to these tissues in comparison with white BALB/C mice. Treatment of C57BL6 mice with (188)RE-HYNIC-4B4 did not change their behavior, as established by SHIRPA protocol, and did not cause damage to neurons and glial cells. These results indicate that radiolabeled melanin-binding peptides are efficient and safe in treatment of melanoma and could be potentially useful against this tumor.