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Please see the Editorial Comment by Jonathan L. Mezrich discussing this article. Background: In community settings, radiologists commonly function as multispecialty radiologists, interpreting exami...

RATIONALE AND OBJECTIVES: Glioblastoma image evaluation utilizes MRI contrast-enhanced, T1-weighted and non-contrast T2-weighted FLAIR acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression. MATERIALS AND METHODS: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRM(rFLAIR+)), decreased (PRM(rFLAIR−)), or unchanged (PRM(rFLAIR0)) rFLAIR intensity. We determined response by rFLAIR between pre-treatment and 10 weeks post-treatment. Risk of disease progression in a subset of subjects (N=26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRM(rFLAIR) between weeks 10 and 20 and continuously until the PRM(rFLAIR+) exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection. RESULTS: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand 68Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated levels of prostate-specific antigen (PSA) after initial therapy. Methods:68Ga-PSMA-11 hybrid PET was performed on 2,005 patients at the time of biochemically recurrent prostate cancer after radical prostatectomy (RP) (50.8%), definitive radiation therapy (RT) (19.7%), or RP with postoperative RT (PORT) (29.6%). The presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis, creating a disease burden estimate from the presence or absence of local (prostate/prostate bed), nodal (N1: pelvis), and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of 68Ga-PSMA-11 PET/CT confirmed by histopathology. Results: After RP, the scan detection rate increased significantly with rising PSA level (44.8% at PSA 10 ng/mL; P

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)2. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

Background and purpose Astroblastoma is a rare type of glial tumor, histologically classified into two types with different prognoses: high and low grade. We aimed to investigate the CT and MRI findings of astroblastomas by collecting studies with analyzable neuroimaging data and extracting the imaging features useful for tumor grading. Methods We searched for reports of pathologically proven astroblastomas with analyzable neuroimaging data using PubMed, Scopus, and Embase. Sixty-five studies with 71 patients with astroblastomas met the criteria for a systematic review. We added eight patients from our hospital, resulting in a final study cohort of 79 patients. The proportion of high-grade tumors was compared in groups based on the morphology (typical and atypical) using Fisher's exact test. Results High- and low-grade tumors were 35/71 (49.3%) and 36/71 (50.7%), respectively. There was a significant difference in the proportion of high-grade tumors based on the tumor morphology (typical morphology: high-grade = 33/58 [56.9%] vs. atypical morphology, 2/13 [15.4%], p = .012). The reviews of neuroimaging findings were performed using the images included in each article. The articles had missing data due to the heterogeneity of the collected studies. Conclusions Detailed neuroimaging features were clarified, including tumor location, margin status, morphology, CT attenuation, MRI signal intensity, and contrast enhancement pattern. The classification of tumor morphology may help predict the tumor's histological grade, contributing to clinical care and future oncologic research.

Assessment tools for early cystic fibrosis (CF) lung disease are limited. Detecting early pulmonary disease is crucial to increasing life expectancy by starting interventions to slow the progression of the pulmonary disease with the many treatment options available. To compare the utility of lung T1-mapping MRI with ultrashort echo time (UTE) MRI in children with cystic fibrosis in detecting early stage lung disease and monitoring pulmonary exacerbations. We performed a prospective study in 16 children between September 2017 and January 2018. In Phase 1, we compared five CF patients with normal spirometry (mean 11.2 years) to five age- and gender-matched healthy volunteers. In Phase 2, we longitudinally evaluated six CF patients (median 11 years) in acute pulmonary exacerbation. All children had non-contrast lung T1-mapping and UTE MRI and spirometry testing. We compared the mean normalized T1 value and percentage lung volume without T1 value in CF patients and healthy subjects in Phase 1 and during treatment in Phase 2. We also performed cystic fibrosis MRI scoring. We evaluated differences in continuous variables using standard statistical tests. In Phase 1, mean normalized T1 values of the lung were significantly lower in CF patients in comparison to healthy controls (P=0.02) except in the right lower lobe (P=0.29). The percentage lung volume without T1 value was also significantly higher in CF patients (P=0.006). UTE MRI showed no significant differences between CF patients and healthy volunteers (P=0.11). In Phase 2, excluding one outlier case who developed systemic disease in the course of treatment, the whole-lung T1 value increased (P=0.001) and perfusion scoring improved (P=0.02) following therapy. We observed no other significant changes in the MRI scoring. Lung T1-mapping MRI can detect early regional pulmonary CF disease in children and might be helpful in the assessment of acute pulmonary exacerbations.

BACKGROUND: Deficits in social cognition are pervasive in schizophrenia (SZ) and strong predictors of poor functional outcomes. Understanding of the mechanisms underlying critical social cognitive dysfunctions in SZ will advance our understanding of the disorder and help design targeted treatment. In this presentation, we examine a basic building block of social cognition—eye gaze perception—in SZ and bipolar psychosis (BP). Given the frequent documentations of visual perceptual anomaly in SZ, we specifically evaluate the role of visual disturbances in altered gaze processing in psychosis. We used psychophysics to isolate distinctive cognitive processes involved in gaze perception (Study 1) and applied dynamic causal modeling (DCM) to fMRI data to illuminate aberrant brain dynamics responsible for altered gaze processing (Study 2). METHODS: In Study 1, 157 participants (47 SZ; 55 BP; and 55 healthy controls, HC) viewed faces with varying gaze directions and made two-forced choice eye contact judgments (“yes” or “no”). In each individual, eye contact endorsement was examined as a logistic function of gaze direction. The slope and absolute threshold of this perception curve were used to index, respectively, visual perceptual sensitivity and self-referential bias. Individual measures and group differences were estimated using hierarchical Bayesian modeling. Markov Chain Monte Carlo (MCMC) implemented in WinBUGS was used to sample from the joint posterior distribution to estimate posterior probabilities of the parameters. In Study 2, 27 SZ participants and 22 HC completed a gaze perception task during BOLD fMRI. They viewed faces with varying gaze directions and made two-forced choice judgments of eye contact or gender (control task). Time series from the V2 visual cortex (V2), posterior superior temporal sulcus (pSTS), inferior parietal lobule (IPL), and posterior medial prefrontal cortex (pMPFC) were extracted and subject to DCM analysis. Initial model family comparison showed that models with gaze modulations on both bottom-up connections from V2 and top-down connections from pMFC had the highest evidence compared with models with gaze modulations on either bottom-up or top-down connections. Models from this model family were then subject to post-hoc Bayesian model selection to select the best model for each individual. Parameter estimates of the winning model were taken to group-level analyses using t-tests. RESULTS: In Study 1, both clinical groups showed high posterior probabilities of reduced perceptual sensitivity (SZ: 99.96%; BP: 98.7%) and increased self-referential bias (SZ: 98.7%; BP: 93.71%) when compared with HC during gaze perception. Although BP generally positioned in between SZ and HC, it was not statistically distinguishable from SZ. In Study 2, DCM revealed that, as expected, attending to gaze (vs. gender) strengthened bottom-up connections from V2 to IPL (t= 3.50, p = .001) and to pSTS (t= 2.53, p = .015) across participants. Compared with HC, SZ showed weakened sensory input to V2 (t = -2.12, p = .042) and reduced feedforward connectivity from V2 to IPL (t = -2.09, p = .045). When processing gaze (vs. gender), HC relaxed pMFC suppression of V2, perhaps to allow more data-driven processes; conversely, SZ increased pMFC inhibition of V2 (t = -3.22, p = .002), presumably to compensate for impaired bottom-up processes by relying more on higher-level cognition to determine the self-referential nature of gaze. CONCLUSIONS: These findings suggest that gaze perception in psychosis, regardless of diagnostic category, is characterized by altered cognitive processes at both the perceptual and interpretation levels. However, effective connectivity analyses suggest that abnormal gaze processing may originate from dysfunctions of the visual cortex, and that aberrant top-down processes may be a compensatory mechanism. We are currently working on replicating these fMRI findings and will be launching an experimental study using transcranial magnetic stimulation to confirm the causal role of visual cortical dysfunction in altered gaze processing in psychosis.

Purpose: Hyperglycemia affects FDG uptake in the brain, potentially emulating Alzheimer’s disease in normal individuals. This study investigates global and regional cerebral FDG uptake as a function of plasma glucose in a cohort of patients. Methods: 120 consecutive male patients with FDG PET/CT for initial oncologic staging (July–Dec 2015) were reviewed. Patients with dementia, cerebrovascular accident, structural brain lesion, prior oncology treatment or high metabolic tumor burden (recently shown affecting brain FDG uptake) were excluded. 53 (24 nondiabetic) eligible patients (age 65.7 ± 2.8 mean ± SE) were analyzed with parametric computer software, MIMneuro™. Regional Z-scores were evaluated as a function of plasma glucose and age using multi variable linear mixed effects models with false discovery analysis adjusting for multiple comparisons. If the regression slope was significantly (p

Background Standardized definitions and methods of surveillance for local recurrence of nonmelanoma skin cancer are critical in determining cure rates attributed to treatment modalities. Objective We sought to offer a standard definition of local recurrence after surgical treatment of nonmelanoma skin cancer and to propose an acceptable surveillance period and tracking methods. Methods A literature search was performed for background definitions of local recurrence and tracking methods. The American College of Mohs Surgery (ACMS) Registry and Outcomes Committee then conducted a modified Delphi process to arrive at consensus definitions. Results We define local recurrence as a tumor with comparable histology, with contiguity to the surgical scar after treatment, and that arises within the area of the previously treated tumor. Limitations This project reports the results of a modified Delphi method process involving members of the ACMS. The model described may not be useful for nonexcision type treatments such as topical chemotherapy, electrodessication and curettage, or radiation treatment. Conclusions Previous definitions of recurrence and surveillance methods after surgical treatment of nonmelanoma skin cancer are variable and nonstandard. We describe consensus standards for defining and tracking recurrence that should allow for consistent scientific evaluation and development of performance data in skin cancer outcomes registries.

We assessed the value of fusion 18F-fluoromethylcholine (18F-choline) Positron Emission To-mography / Magnetic Resonance Imaging (PET/MRI) for image-guided (targeted) prostate biop-sies to detect significant prostate cancer (Gleason ≥ 3+4) compared to standard (systematic 12-core) biopsies. Methods: Within an ongoing prospective clinical trial, hybrid 18F-choline Positron Emission Tomography / Computed Tomography (PET/CT) and multi-parametric 3T MRI (mpMRI) of the pelvis were performed in 36 subjects with rising prostate specific antigen (PSA) for known (n = 15) or suspected (n = 21) prostate cancer prior to a prostate biopsy procedure. PET and T2-weighted (T2w) Magnetic Resonance (MR) volumes of the prostate were spatially registered using commercially available software. Biopsy targets were selected based on visual appearance on MRI and graded as low, intermediate or high risk for significant disease. Volumes of interest (VOI) were defined for MR-identified lesions. 18F-choline uptake measures were obtained from the MR-target and a mirrored background VOI. The biopsy procedure was performed after registration of real-time transrectal ultrasound (TRUS) with T2w MR and included image-guided cores plus standard cores. Histological results were determined from standard and targeted biopsy cores, as well as prostatectomy specimens (n = 10). Results: Fifteen subjects were ultimately identified with Gleason ≥ 3+4 prostate cancer, of which targeted biopsy identified significantly more (n = 12) than standard biopsies (n = 5; P = 0.002). A total of 52 lesions were identified by mpMRI (19 low; 18 intermediate; 15 high risk), and mpMRI-assigned risk was a strong predictor of final pathology (area under the curve (AUC) = 0.81; P < 0.001). Using the mean 18F-choline target-to-background ratio (TBR), the addition of 18F-choline to mpMRI significantly improved the prediction of Gleason ≥ 3+4 cancers over mpMRI alone (AUC = 0.92; p

Objective Atrial fibrillation (AF) is frequently detected after ischemic stroke for the first time, and brain regions involved in autonomic control have been suspected to trigger AF. We examined whether specific brain regions are associated with newly detected AF after ischemic stroke. Methods Patients with acute cerebral infarctions on diffusion-weighted magnetic resonance imaging were included in this lesion mapping study. Lesions were mapped and modeled voxelwise using Bayesian Spatial Generalised Linear Mixed Modeling to determine differences in infarct locations between stroke patients with new AF, without AF and with AF already known before the stroke. Results 582 patients were included (median age 68 years; 63.2% male). AF was present in 109/582 patients [(18.7%); new AF: 39/109 (35.8%), known AF: 70/109 (64.2%)]. AF patients had larger infarct volumes than patients without AF (mean: 29.7 ± 45.8 ml vs. 15.2 ± 35.1 ml; p Conclusions In the search for brain areas potentially triggering cardiac arrhythmias infarct size should be accounted for. After controlling for infarct size, there is currently no evidence that ischemic stroke lesions of specific brain areas are associated with new AF compared to patients without AF. This challenges the neurogenic hypothesis of AF according to which a relevant proportion of new AF is triggered by ischemic brain lesions of particular locations.

The purpose of this article is to evaluate the safety of T-fastener removal immediately after percutaneous gastrostomy tube placement by assessing difference in complication rates between early and delayed gastropexy removal.A retrospective review was performed of the electronic medical records of all patients who underwent percutaneous gastrostomy at our institution from January 2015 to June 2017. A total of 722 patients successfully underwent gastrostomy tube insertion during this period. Two hundred twenty-two patients were excluded from analysis on the basis of our exclusion criteria. Twelve patients were lost to follow-up. The remaining patients were divided into two groups: group 1 included 350 patients who had their T-fasteners released immediately after gastrostomy, and group 2 included 138 patients whose T-fasteners were left in place for 2 weeks. Electronic medical records were reviewed for postprocedure complications for up to 1 month. Complications were classified according to Society of Interventional Radiology classification. Statistical analysis was performed using a logistic regression model with calculation of odds ratios, power, p values, and 95% CIs.Seven (2.0%) major and 24 (6.8%) minor complications occurred in group 1. Two (1.4%) major and 11 (7.9%) minor complications occurred in group 2. There was no statistically significant difference in complication rates between immediate and delayed gastropexy removal.In our study, immediate removal of T-fasteners was not associated with a higher complication rate.

Objective Abnormal engagement of the posterior medial frontal cortex (pMFC) occurs during performance monitoring in obsessive-compulsive disorder (OCD), including in pediatric patients. Yet, the development of pMFC function in OCD-affected youth remains poorly understood. Method A total of 69 patients with pediatric OCD and 72 healthy controls (HC), 8 to 19 years of age, were scanned during the Multisource Interference Task (MSIT). The effects of group, age, performance, and interactions on pMFC response to errors and interference were tested in the region of interest [ROI]) and whole-brain analyses. Secondary analyses considered bilateral anterior insula/frontal operculum (aI/fO), given the contribution of these regions with pMFC to a cingulo-opercular network (CON) for task control (e.g., error and interference processing). Results Error-related pMFC activity was greater for OCD patients than for HC, increased with age in OCD patients, but decreased with age in HC. Greater pMFC activation associated with better performance in HC but not OCD patients. In the patients, greater pMFC activation to errors was associated with lower OCD severity. Altered error-related activation and performance associations were also observed in the right aI/fO in OCD patients, whereas the left aI/fO response to interference was associated with lower OCD severity. Conclusion Atypical increase in error-related pMFC activation with age in pediatric OCD suggests altered development of pMFC function during the early course of illness. Greater pMFC activation with better performance in HC, and with age and lower symptom severity in OCD patients, suggests an adaptive function of heightened pMFC response to errors that could be further enhanced (e.g., via cognitive training) to improve outcomes in OCD from the early course of illness.

Purpose To assess the impact of clinical history on the maximum Prostate Imaging Recording and Data System (PI-RADS) version 2 (v2) score assigned to multiparametric magnetic resonance (MR) imaging of the prostate. Materials and Methods This retrospective cohort study included 120 consecutively selected multiparametric prostate MR imaging studies performed between November 1, 2016, and December 31, 2016. Sham clinical data in four domains (digital rectal examination, prostate-specific antigen level, plan for biopsy, prior prostate cancer history) were randomly assigned to each case by using a balanced orthogonal design. Six fellowship-trained abdominal radiologists independently reviewed the sham data, actual patient age, and each examination while they were blinded to interreader scoring, true clinical data, and histologic findings. Readers were told the constant sham histories were true, believed the study to be primarily investigating interrater agreement, and were asked to assign a maximum PI-RADS v2 score to each case. Linear regression was performed to assess the association between clinical variables and maximum PI-RADS v2 score designation. Intraclass correlation coefficients (ICCs) were obtained to compare interreader scoring. Results Clinical information had no significant effect on maximum PI-RADS v2 scoring for any of the six readers (P = .09-.99, 42 reader-variable pairs). Distributions of maximum PI-RADS v2 scores in the research context were similar to the distribution of the scores assigned clinically and had fair-to-excellent pairwise interrater agreement (ICC range: 0.53-0.76). Overall interrater agreement was good (ICC: 0.64; 95% confidence interval: 0.57, 0.71). Conclusion Clinical history does not appear to be a substantial bias in maximum PI-RADS v2 score assignment. This is potentially important for clinical nomograms that plan to incorporate PI-RADS v2 score and clinical data into their algorithms (ie, PI-RADS v2 scoring is not confounded by clinical data).

Parametric response mapping (PRM) of paired CT lung images has been shown to improve the phenotyping of COPD by allowing for the visualization and quantification of non-emphysematous air trapping component, referred to as functional small airways disease (fSAD). Although promising, large variability in the standard method for analyzing PRMfSAD has been observed. We postulate that representing the 3D PRMfSAD data as a single scalar quantity (relative volume of PRMfSAD) oversimplifies the original 3D data, limiting its potential to detect the subtle progression of COPD as well as varying subtypes. In this study, we propose a new approach to analyze PRM. Based on topological techniques, we generate 3D maps of local topological features from 3D PRMfSAD classification maps. We found that the surface area of fSAD (SfSAD) was the most robust and significant independent indicator of clinically meaningful measures of COPD. We also confirmed by micro-CT of human lung specimens that structural differences are associated with unique SfSAD patterns, and demonstrated longitudinal feature alterations occurred with worsening pulmonary function independent of an increase in disease extent. These findings suggest that our technique captures additional COPD characteristics, which may provide important opportunities for improved diagnosis of COPD patients.

The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 800 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term “off-label” does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.

E26 transformation-specific (ETS) transcription factors are known to be involved in gene aberrations in various malignancies including prostate cancer; however, their role in melanoma oncogenesis has yet to be fully explored. We have completed a comprehensive fluorescence in situ hybridization (FISH)-based screen for all 27 members of the ETS transcription factor family on two melanoma tissue microarrays, representing 223 melanomas, 10 nevi, and 5 normal skin tissues. None of the melanoma cases demonstrated ETS fusions; however, 6 of 114 (5.3%) melanomas were amplified for ETV1 using a break-apart FISH probe. For the six positive cases, locus-controlled FISH probes revealed that two of six cases were amplified for the ETV1 region, whereas four cases showed copy gains of the entire chromosome 7. The remaining 26 ETS family members showed no chromosomal aberrations by FISH. Quantitative polymerase chain reaction showed an average 3.4-fold (P value = .00218) increased expression of ETV1 in melanomas, including the FISH ETV1-amplified cases, when compared to other malignancies (prostate, breast, and bladder carcinomas). These data suggest that a subset of melanomas overexpresses ETV1 and amplification of ETV1 may be one mechanism for achieving high gene expression.

To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning.Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model.There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT.This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.

Vascular-targeted therapies have shown promise as adjuvant cancer treatment. As these agents undergo clinical evaluation, sensitive imaging biomarkers are needed to assess drug target interaction and treatment response. In this study, dynamic contrast enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI) were evaluated for detecting response of intracerebral 9L gliosarcomas to the antivascular agent VEGF-Trap, a fusion protein designed to bind all forms of Vascular Endothelial Growth Factor-A (VEGF-A) and Placental Growth Factor (PGF). Rats with 9L tumors were treated twice weekly for two weeks with vehicle or VEGF-Trap. DCE- and DW-MRI were performed one day prior to treatment initiation and one day following each administered dose. Kinetic parameters (K trans , volume transfer constant; kep ,e fflux rate constant from extravascular/extracellular space to plasma; and vp, blood plasma volume fraction) and the apparent diffusion coefficient (ADC) over the tumor volumes were compared between groups. A significant decrease in kinetic parameters was observed 24 hours following the first dose of VEGF-Trap in treated versus control animals (p

Purpose: Currently, radiologic response of brain tumors is assessed according to the Macdonald criteria 10 weeks from the start of therapy. There exists a critical need to identify nonresponding patients early in the course of their therapy for consideration of alternative treatment strategies. Our study assessed the effectiveness of the parametric response map (PRM) imaging biomarker to provide for an earlier measure of patient survival prediction. Experimental Design: Forty-five high-grade glioma patients received concurrent chemoradiation. Quantitative MRI including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired pretreatment and 3 weeks midtreatment on a prospective institutional-approved study. PRM, a voxel-by-voxel image analysis method, was evaluated as an early prognostic biomarker of overall survival. Clinical and conventional MR parameters were also evaluated. Results: Multivariate analysis showed that PRMADC+ in combination with PRMrCBV− obtained at week 3 had a stronger correlation to 1-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, nonresponders [median survival (MS) of 5.5 months, 95% CI: 4.4–6.6 months], partial responders (MS of 16 months, 95% CI: 8.6–23.4 months), and responders (MS has not yet been reached). Conclusions: Inclusion of PRMADC+ and PRMrCBV− into a single imaging biomarker metric provided early identification of patients resistant to standard chemoradiation. In comparison to the current standard of assessment of response at 10 weeks (Macdonald criteria), the composite PRM biomarker potentially provides a useful opportunity for clinicians to identify patients who may benefit from alternative treatment strategies. Clin Cancer Res; 17(14); 4751–60. ©2011 AACR.

Background & Aims Dysplasia is a premalignant condition in Barrett's esophagus that is difficult to detect on endoscopy because of its flat architecture and patchy distribution. Peptides are promising for use as novel molecular probes that identify cell surface targets unique to disease and can be fluorescence-labeled for detection. We aim to select and validate an affinity peptide that binds to esophageal dysplasia for future clinical studies. Methods Peptide selection was performed using phage display by removing nonspecific binders using Q-hTERT (intestinal metaplasia) cells and achieving specific binding against OE33 (esophageal adenocarcinoma) cells. Selective binding was confirmed on bound phage counts, enzyme-linked immunosorbent assay (ELISA), flow cytometry, competitive inhibition, and fluorescence microscopy. On stereomicroscopy, specific peptide binding to dysplasia on endoscopically resected specimens was assessed by rigorous registration of fluorescence intensity to histology in 1-mm intervals. Results The peptide sequence SNFYMPL was selected and showed preferential binding to target cells. Reduced binding was observed on competition with unlabeled peptide in a dose-dependent manner, an affinity of K d = 164 nmol/L was measured, and peptide binding to the surface of OE33 cells was validated on fluorescence microscopy. On esophageal specimens (n = 12), the fluorescence intensity (mean ± SEM) in 1-mm intervals classified histologically as squamous (n = 145), intestinal metaplasia (n = 83), dysplasia (n = 61), and gastric mucosa (n = 69) was 46.5±1.6, 62.3±5.8, 100.0±9.0, and 42.4 ± 3.0 arb units, respectively. Conclusions The peptide sequence SNFYMPL binds specifically to dysplasia in Barrett's esophagus and can be fluorescence labeled to target premalignant mucosa on imaging.

Purpose To assess whether a new method of quantifying therapy-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high-grade glioma. Patients and Methods Patients with high-grade glioma received concurrent chemoradiotherapy. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired before chemoradiotherapy and at week 3 during treatment on a prospective institutional review board–approved study. Pseudoprogression was defined as imaging changes 1 to 3 months after chemoradiotherapy that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional magnetic resonance (MR) parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Results Median radiation dose was 72 Gy (range, 60 to 78 Gy). Of 27 patients, stable disease/partial response was noted in 13 patients and apparent progression was noted in 14 patients. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in six patients. Based on PRM analysis, a significantly reduced blood volume (PRMrCBV) at week 3 was noted in patients with progressive disease as compared with those with pseudoprogression (P < .01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and Radiation Therapy Oncology Group recursive partitioning analysis classification did not distinguish progression from pseudoprogression. Conclusion PRMrCBV at week 3 during chemoradiotherapy is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in patients with high-grade glioma.

Purpose: Functional imaging biomarkers of cancer treatment response offer the potential for early determination of outcome through the assessment of biochemical, physiologic, and microenvironmental readouts. Cell death may result in an immunologic response, thus complicating the interpretation of biomarker readouts. This study evaluated the temporal effect of treatment-associated inflammatory activity on diffusion magnetic resonance imaging and 2-[18F]-fluoro-2-deoxy-d-glucose-positron emission tomography imaging (FDG-PET) biomarkers to delineate the effects of the inflammatory response on imaging readouts. Experimental Design: Rats with intracerebral 9L gliosarcomas were separated into four groups consisting of control, an immunosuppressive agent dexamethasone (Dex), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and BCNU+Dex. Animals were imaged using diffusion-weighted magnetic resonance imaging and FDG-PET at 0, 3, and 7 days posttreatment. Results: In the BCNU- and BCNU+Dex-treated animal groups, diffusion values increased progressively over the 7-day study period to ∼23% over baseline. The FDG percentage change of standard uptake value decreased at day 3 (−30.9%) but increased over baseline levels at day 7 (+20.1%). FDG-PET of BCNU+Dex-treated animals were found to have percentage of standard uptake value reductions of −31.4% and −24.7% at days 3 and 7, respectively, following treatment. Activated macrophages were observed on day 7 in the BCNU treatment group with much fewer found in the BCNU+Dex group. Conclusions: Results revealed that treatment-associated inflammatory response following tumor therapy resulted in the accentuation of tumor diffusion response along with a corresponding increase in tumor FDG uptake due to the presence of glucose-consuming activated macrophages. The dynamics and magnitude of potential inflammatory response should be considered when interpreting imaging biomarker results. Clin Cancer Res; 16(5); 1542–52

BACKGROUND AND PURPOSE: Does the K-means algorithm do a better job of differentiating benign and malignant neck pathologies compared to only mean ADC? The objective of our study was to analyze the differences between ADC partitions to evaluate whether the K-means technique can be of additional benefit to whole-lesion mean ADC alone in distinguishing benign and malignant neck pathologies. MATERIAL AND METHODS: MR imaging studies of 10 benign and 10 malignant proved neck pathologies were postprocessed on a PC by using in-house software developed in Matlab. Two neuroradiologists manually contoured the lesions, with the ADC values within each lesion clustered into 2 (low, ADC-ADCL; high, ADC-ADCH) and 3 partitions (ADCL; intermediate, ADC-ADCI; ADCH) by using the K-means clustering algorithm. An unpaired 2-tailed Student t test was performed for all metrics to determine statistical differences in the means of the benign and malignant pathologies. RESULTS: A statistically significant difference between the mean ADCL clusters in benign and malignant pathologies was seen in the 3-cluster models of both readers (P = .03 and .022, respectively) and the 2-cluster model of reader 2 (P = .04), with the other metrics (ADCH, ADCI; whole-lesion mean ADC) not revealing any significant differences. ROC curves demonstrated the quantitative differences in mean ADCH and ADCL in both the 2- and 3-cluster models to be predictive of malignancy (2 clusters: P = .008, area under curve = 0.850; 3 clusters: P = .01, area under curve = 0.825). CONCLUSIONS: The K-means clustering algorithm that generates partitions of large datasets may provide a better characterization of neck pathologies and may be of additional benefit in distinguishing benign and malignant neck pathologies compared with whole-lesion mean ADC alone.

The presence of two intermingled malignant components within the same cutaneous tumor is rare. Herein, we report a case of an exceedingly rare squamo-melanocytic tumor, favored to be a melanoma variant. Although the biologic behavior and prognostic significance of this tumor remain to be established, this unique case reaffirms the potential morphologic diversity of melanoma. We review the literature reporting similar neoplasms and discuss the potential histogenesis of this squamo-melanocytic tumor.

To retrospectively assess the diagnostic performance of magnetic resonance cholangiopancreatography (MRCP) performed by using a high-spatial-resolution isotropic three-dimensional (3D) fast-recovery fast spin-echo (FSE) sequence with parallel imaging for the evaluation of possible biliary disease.This HIPAA-compliant study was approved by the institutional review board; informed consent was waived. Ninety-five patients (58 female, 37 male; mean age, 51 years; range, 15-91 years) underwent MRCP by using the respiratory-triggered isotropic 3D fast-recovery FSE sequence and endoscopic or percutaneous direct visualization between March 2003 and June 2007. Two independent readers evaluated the MRCP images for strictures, dilatation, and intraductal filling defects. Sensitivity, specificity, and interobserver agreement (kappa statistics) were determined.The respective sensitivity and specificity for strictures, dilatation, and intraductal filling defects (all choledocholithiasis) were 86% (40 of 47) and 94% (45 of 48), 98% (57 of 58) and 100% (37 of 37), and 68% (19 of 28) and 97% (65 of 67) for reader 1 and 88% (41 of 47) and 94% (45 of 48), 96% (56 of 58) and 100% (37 of 37), and 75% (21 of 28) and 99% (66 of 67) for reader 2. The sensitivity for stones larger than 3 mm was 94% (15 of 16) for reader 1 and 100% (16 of 16) for reader 2, whereas the sensitivity for stones 3 mm or smaller was 33% (four of 12) for reader 1 and 42% (five of 12) for reader 2. Agreement between readers was good to excellent, with kappa values of 0.76, 0.85, and 0.98 for strictures, dilatation, and choledocholithiasis, respectively.MRCP by using the respiratory-triggered isotropic 3D fast-recovery FSE sequence with parallel imaging demonstrates excellent diagnostic capabilities for possible biliary disease, although it is limited for stones 3 mm or smaller in size.

To assess the diagnostic performance of various Doppler ultrasonographic (US) vascularity measures in conjunction with grayscale (GS) criteria in differentiating benign from malignant breast masses, by using histologic findings as the reference standard.Institutional Review Board and HIPAA standards were followed. Seventy-eight women (average age, 49 years; range, 26-70 years) scheduled for breast biopsy were included. Thirty-eight patient scans were partially analyzed and published previously, and 40 additional scans were used as a test set to evaluate previously determined classification indexes. In each patient, a series of color Doppler images was acquired and reconstructed into a volume encompassing a suspicious mass, identified by a radiologist-defined ellipsoid, in which six Doppler vascularity measures were calculated. Radiologist GS ratings and patient age were also recorded. Multivariable discrimination indexes derived from the learning set were applied blindly to the test set. Overall performance was also confirmed by using a fourfold cross-validation scheme on the entire population.By using all cases (46 benign, 32 malignant), the area under the receiver operating characteristic curve (A(z)) values confirmed results of previous analyses: Speed-weighted pixel density (SWPD) performed the best as a diagnostic index, although statistical significance (P = .01) was demonstrated only with respect to the normalized power-weighted pixel density. In both learning and test sets, the three-variable index (SWPD-age-GS) displayed significantly better diagnostic performance (A(z) = 0.97) than did any single index or the one two-variable index (age-GS) that could be obtained without the data from the Doppler scan. Results of the cross validation confirmed the trends in the two data sets.Quantitative Doppler US vascularity measurements considerably contribute to malignant breast tissue identification beyond subjective GS evaluation alone. The SWPD-age-GS index has high performance (A(z) = 0.97), regardless of incidental performance variations in its single variable components.

The hypoxia-inducible factor-1 alpha (HIF-1 alpha) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected F-18-labeled azomycin arabinoside (F-8-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide (I-125-3-iodo-DTyr(4)-cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or I-125-Gluco-RGD) (assessing angiogenesis via binding to alpha v beta 3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-to-muscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1 alpha protein distribution was compared with F-18-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO2) for 4 In until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of F-18-FAZA and I-125-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant F-18-FAZA and I-125-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the F-18-FAZA and I-125-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean F-18-FAZA tumor-to-muscle ratio, no significant changes were observed for I-125 -Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence alpha v beta 3 integrin receptor expression. The HIF-1 alpha-positive (HIFpos tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIFpos tumor section surface was much smaller than the tumor section surface of increased F-18-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the F-18-FAZA and I-125-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxia-activated cytotoxins and antiangiogenic drugs) for hypoxic tumors.

Introduction: Many surgeons use the ‘‘10% rule’’ to define whether a lymph node is a sentinel node (SLN) when staging malignant melanoma. However, this increases the number of SLN removed and the time and cost of the procedure. We examined the impact of raising this threshold on the accuracy of the procedure. Methods: We reviewed the records of 561 patients with melanoma (624 basins) who underwent SLN with technetium Tc99 labeled sulfur colloid using a definition of a SLN as 10% of that of the node with the highest counts per minute (CPM). Results: Of the 624 basins, 154 (25%) were positive for metastases. An average of 1.9 nodes per basin were removed (range 1–6). Metastases were found in the hottest node in 137 cases (89% of positive basins, 97% of basins overall). Increasing the threshold above 10% decreased the number of nodes excised and the costs involved, but incrementally raised the number of false negative cases above baseline (a 4% increase for a ‘‘20% rule,’’ 5% for a ‘‘30% rule,’’ 6% for a ‘‘40% rule,’’ and 7% for a ‘‘50% rule’’). Taking only the hottest node would raise the false negative rate by 11%. Conclusions: Although using thresholds higher than 10% for the definition of a SLN will minimize the extent of surgery and decrease the costs associated with the procedure, it will compromise the accuracy of the procedure and is not recommended. J. Surg. Oncol. 2007;95:623–628. 2007 Wiley-Liss, Inc.

Purpose To assess the effect of diuretic administration on the image quality of excretory magnetic resonance urography (MRU) obtained following intravenous hydration, and to determine whether intravenous hydration alone is sufficient to produce diagnostic quality studies of nondilated upper tracts. Materials and Methods A total of 22 patients with nondilated upper tracts were evaluated with contrast-enhanced MRU. All patients received 250 mL of saline intravenously immediately prior to the examination. A total of 11 patients received 10–20 mg furosemide in addition to saline. Imaging was performed with a three-dimensional (3D) and two-dimensional (2D) breathhold spoiled gradient-echo sequences. Excretory MRU images were acquired five minutes after the administration of 0.1 mmol/kg gadolinium and were independently reviewed by two radiologists, who were blinded to the MRU technique. Readers evaluated the calyces, renal pelvis, and ureters qualitatively for degree of opacification, distention, and artifacts on a four-point scale. Statistical analysis was performed using a permutation test. Results There was no significant disagreement between the two readers (P = 0.14). Furosemide resulted in significant improvement in calyceal and renal pelvis distention (P < 0.005), and significant artifact reduction in all upper tract segments (P < 0.001) compared to the effect of saline alone. Conclusion Intravenous furosemide significantly improves the image quality of excretory MRU studies obtained following intravenous hydration. Intravenous saline alone is insufficient to produce diagnostic quality studies of the non-dilated upper tracts. J. Magn. Reson. Imaging 2007. © 2007 Wiley-Liss, Inc.

Quantitative magnetic resonance imaging (MRI)-based biomarkers, which capture physiological and functional tumor processes, were evaluated as imaging surrogates of early tumor response following chemoradiotherapy in glioma patients. A multiparametric extension of a voxel-based analysis, referred as the parametric response map (PRM), was applied to quantitative MRI maps to test the predictive potential of this metric for detecting response. Fifty-six subjects with newly diagnosed high-grade gliomas treated with radiation and concurrent temozolomide were enrolled in a single-site prospective institutional review board-approved MRI study. Apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired before therapy and 3 weeks after therapy was initiated. Multiparametric PRM (mPRM) was applied to both physiological MRI maps and evaluated as an imaging biomarker of patient survival. For comparison, single-biomarker PRMs were also evaluated in this study. The simultaneous analysis of ADC and rCBV by the mPRM approach was found to improve the predictive potential for patient survival over single PRM measures. With an array of quantitative imaging parameters being evaluated as biomarkers of therapeutic response, mPRM shows promise as a new methodology for consolidating physiologically distinct imaging parameters into a single interpretable and quantitative metric.

Differentiating tumor from normal brain is a major barrier to achieving optimal outcome in brain tumor surgery. New imaging techniques for visualizing tumor margins during surgery are needed to improve surgical results. We recently demonstrated the ability of stimulated Raman scattering (SRS) microscopy, a nondestructive, label-free optical method, to reveal glioma infiltration in animal models. We show that SRS reveals human brain tumor infiltration in fresh, unprocessed surgical specimens from 22 neurosurgical patients. SRS detects tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy (κ = 0.86). The unique chemical contrast specific to SRS microscopy enables tumor detection by revealing quantifiable alterations in tissue cellularity, axonal density, and protein/lipid ratio in tumor-infiltrated tissues. To ensure that SRS microscopic data can be easily used in brain tumor surgery, without the need for expert interpretation, we created a classifier based on cellularity, axonal density, and protein/lipid ratio in SRS images capable of detecting tumor infiltration with 97.5% sensitivity and 98.5% specificity. Quantitative SRS microscopy detects the spread of tumor cells, even in brain tissue surrounding a tumor that appears grossly normal. By accurately revealing tumor infiltration, quantitative SRS microscopy holds potential for improving the accuracy of brain tumor surgery.

Secondary lymphedema is a frequent complication after lymphadenectomy in melanoma patients, although few studies in melanoma adequately characterize risk factors for lymphedema, and of these, sample size is limited. This study aims to identify risk factors associated with the lymphedema after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in a more robust cohort of melanoma patients.We identified 269 ALND or ILND melanoma patients treated between 2008 and 2014. Demographic, clinical, and postoperative data were collected by review of the electronic medical record. Univariate and multivariate analysis were used to determine independent predictors of lymphedema.Fifty-six (20.8%) of the patients developed lymphedema after lymph node dissection with a median staging group of 3. ILND (odds ratio [OR] = 4.506, P.001, 95% confidence interval [CI]: 2.289 to 8.869) and peripheral vascular disease (PVD; OR = 3.849, P = .020, 95% CI: 1.237 to 11.975) were significant predictors of lymphedema in multivariate analysis. Obese body mass index approached significance (OR = 1.802, P = .069, 95% CI: .955 to 3.399).PVD and ILND were the 2 factors associated with the highest risk of lymphedema in melanoma surgery with PVD increasing risk 2-fold in ILND patients and 3-fold in ALND patients. These findings may improve surgeon-patient communication of care goals and surgical risk assessment.

PurposeTo evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information.Materials and methodsA total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3-7 days (Hull University), 8-11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (ResultsMean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|ΔADC|ConclusionThis study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements.

Drug-induced vascular injury (DIVI), defined as arterial medial degeneration/necrosis usually associated with perivascular inflammation, is frequently observed in the mesenteric arteries of rats but the relevance to humans remains a hurdle for drug development. Here, we describe the evaluation of commercially available optical imaging biomarkers using a rat DIVI model. Male Sprague Dawley rats were administered 10 mg/kg/day of a proprietary soluble guanylate cyclase activator (sGCa). Optical agents, AngioSense for the detection of vessel permeability, MMPSense for the detection of activated matrix metalloproteinases (MMPs), and IntegriSense for the detection of α v β 3 integrin, were injected via tail vein 24 hours before fluorescence (FL) ex vivo imaging. Imaging found a statistically significant difference in FL from all optical agents between treated and vehicle groups (p < .05). Mesenteric arteries were further analyzed by histopathology, flow cytometry, and immunohistochemistry. Histopathology confirmed perivascular inflammation and/or arterial medial degeneration in the sGCa-treated animals. Flow cytometry of digested arteries revealed myeloid cells as a main source of MMPSense signal. Immunohistochemical analysis further identified elevated MMP-9 expression within arterial walls and surrounding tissue of treated animals. Together, these data demonstrate that MMPSense and AngioSense are sensitive optical imaging biomarkers for the quantification of DIVI in rat mesenteric arteries.

RATIONALE AND OBJECTIVES: Integral to the mission of the National Institutes of Health-sponsored Lung Imaging Database Consortium is the accurate definition of the spatial location of pulmonary nodules. Because the majority of small lung nodules are not resected, a reference standard from histopathology is generally unavailable. Thus assessing the source of variability in defining the spatial location of lung nodules by expert radiologists using different software tools as an alternative form of truth is necessary.MATERIALS AND METHODS: The relative differences in performance of six radiologists each applying three annotation methods to the task of defining the spatial extent of 23 different lung nodules were evaluated. The variability of radiologists' spatial definitions for a nodule was measured using both volumes and probability maps (p-map). Results were analyzed using a linear mixed-effects model that included nested random effects.RESULTS: Across the combination of all nodules, volume and p-map model parameters were found to be significant at P CONCLUSION: Radiologists represent the major source of variance as compared with drawing tools independent of drawing metric used. Although the random noise component is larger for the p-map analysis than for volume estimation, the p-map analysis appears to have more power to detect differences in radiologist-method combinations. The standard deviation of the volume measurement task appears to be proportional to nodule volume.

The purpose of this study was to assess the ability of MRI to characterize sonographically indeterminate adnexal masses and to define the sonographic features contributing to indeterminate diagnoses.Two blinded radiologists retrospectively reviewed the MRI examinations of 87 patients with 95 sonographically indeterminate adnexal masses. Reviewers determined the origin of a mass, its tissue content (cystic, solid, complex cystic, or cystic and solid), tissue characteristics (fat, blood, fibrous, or leiomyomatous), and benignity versus malignancy. Sonograms were reviewed by three reviewers to determine the origin of a mass, its tissue content, and reasons for an indeterminate diagnosis. Sensitivity and specificity of MRI were calculated, and agreement of sonography and MRI with the final diagnosis was determined using kappa statistics. The final diagnosis was determined by histopathology, surgical findings, or imaging or clinical follow-up.The sensitivity of MRI for identifying malignancy (n = 5) was 100% and its specificity for benignity (n = 90) was 94%. Excellent agreement was seen between MRI and the final diagnosis for determining the origin (kappa = 0.93), tissue content (kappa = 0.98), and tissue characteristics (kappa = 0.91) of a mass. Sonography had poor agreement with the final diagnosis for the origin (kappa = 0.19) and tissue content (kappa = 0.33) of a mass. The main reasons for indeterminate sonographic diagnoses were the inability to determine origin because of location and large mass size and the appearances of purely solid or complex cystic masses.Sonographically indeterminate adnexal masses of uncertain origin and solid or complex cystic content benefit from further evaluation with MRI, which is highly accurate for identifying the origin of a mass and characterizing its tissue content, obviating surgery.

Physical signs of corpus callosum (CC) dysfunction in some ALS patients have been reported in the form of mirror movements, which reflect a disruption in communication between motor hemispheres while an individual performs motor tasks (1). These studies suggest that sub-clinical levels of this damage may occur as an early manifestation of the disease, warranting further in vivo study of the CC in these patients. This proposition, as well as knowledge of its involvement in landmark histologic studies (2,3), has prompted the study of the CC with diffusion tensor imaging. While diffusion tensor imaging (DTI) results show that there are consistent abnormal microstructural changes manifesting in the CC in ALS (4–6), few studies have examined macro-structural differences of this region. One identified reduced gross size of the CC compared to controls (7), while another found evidence for increased white matter density (8). Given these discrepant results, the aim of this study was to examine size differences in geometrically-defined sub-regions of the CC in the native space of brain magnetic resonance images of patients with ALS compared to healthy controls. A difference in CC size observed in either direction would add another dimension to the current understanding of the micro-structural changes observed in studies cited above. For instance, a confirmed increase in CC area in ALS patients might indicate an underlying proliferative process such as reactive astrocytosis in response to neuronal death, whereas a smaller CC area in patients could instead imply isolated atrophy of neurons. A confirmation of CC macro-structural change could warrant additional study of the CC of individuals at various stages of the disease in order to illuminate the role of this structure in the natural history of motor neuron degeneration.

BACKGROUND AND OBJECTIVES: The American Recovery and Reinvestment Act of 2009 accelerated the implementation of electronic health records (EHRs) in pediatric offices. We sought to determine the prevalence and functionalities of EHRs, as well as pediatricians’ perceptions of EHRs. METHODS: An 8-page self-administered questionnaire was sent randomly to 1621 nonretired US members of the American Academy of Pediatrics from July to December 2012. Responses were compared with a similar survey in 2009. RESULTS: The percent of pediatricians, who are using EHRs, increased significantly from 58% in the 2009 survey to 79% in 2012. Only 31% used an EHR considered to have basic functionality, and only 14% used a fully functional EHR. Providers with equal or greater than 20% public insurance patients (threshold for meaningful use eligibility) were more likely to have an EHR. Solo/2-physician practices were least likely to have adopted an EHR. Younger physicians were more likely to consider an EHR important to quality care and perceived the presence of an EHR as more important in recruiting. CONCLUSIONS: The number of office-based pediatricians who are using an EHR has steadily risen to almost 80%. EHR cost and reduction in productivity remain serious concerns. Despite the widespread adoption of EHRs by pediatricians, only few use a basic or fully functional EHR and even fewer have added pediatric functionality. There is a role for the EHR certification process to advance functionalities used by pediatricians and to increase efficiency, data exchange capability, and general EHR functionality.

Mechanical properties of tumors differ substantially from normal cells and tissues. Changes in stiffness or elasticity regulate pro-metastatic behaviors of cancer cells, but effects have been documented predominantly in isolated cells or in vitro cell culture systems. To directly link relative stiffness of tumors to cancer progression, we combined a mouse model of metastatic breast cancer with ex vivo measurements of bulk moduli of freshly excised, intact tumors. We found a high, inverse correlation between bulk modulus of resected tumors and subsequent local recurrence and metastasis. More compliant tumors were associated with more frequent, larger local recurrences and more extensive metastases than mice with relatively stiff tumors. We found that collagen content of resected tumors correlated with bulk modulus values. These data establish that relative differences in tumor stiffness correspond with tumor progression and metastasis, supporting further testing and development of tumor compliance as a prognostic biomarker in breast cancer.

Rationale and Objectives The longitudinal relationship between regional air trapping and emphysema remains unexplored. We have sought to demonstrate the utility of parametric response mapping (PRM), a computed tomography (CT)–based biomarker, for monitoring regional disease progression in chronic obstructive pulmonary disease (COPD) patients, linking expiratory- and inspiratory-based CT metrics over time. Materials and Methods Inspiratory and expiratory lung CT scans were acquired from 89 COPD subjects with varying Global Initiative for Chronic Obstructive Lung Disease (GOLD) status at 30 days (n = 13) or 1 year (n = 76) from baseline as part of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) clinical trial. PRMs of CT data were used to quantify the relative volumes of normal parenchyma (PRMNormal), emphysema (PRMEmph), and functional small airways disease (PRMfSAD). PRM measurement variability was assessed using the 30-day interval data. Changes in PRM metrics over a 1-year period were correlated to pulmonary function (forced expiratory volume at 1 second [FEV1]). A theoretical model that simulates PRM changes from COPD was compared to experimental findings. Results PRM metrics varied by ∼6.5% of total lung volume for PRMNormal and PRMfSAD and 1% for PRMEmph when testing 30-day repeatability. Over a 1-year interval, only PRMEmph in severe COPD subjects produced significant change (19%–21%). However, 11 of 76 subjects showed changes in PRMfSAD greater than variations observed from analysis of 30-day data. Mathematical model simulations agreed with experimental PRM results, suggesting fSAD is a transitional phase from normal parenchyma to emphysema. Conclusions PRM of lung CT scans in COPD patients provides an opportunity to more precisely characterize underlying disease phenotypes, with the potential to monitor disease status and therapy response.

The management of bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation presents many challenges, both diagnostically and therapeutically. We developed a computed tomography (CT) voxel-wise methodology termed parametric response mapping (PRM) that quantifies normal parenchyma, functional small airway disease (PRMfSAD,) emphysema, and parenchymal disease as relative lung volumes. We now investigate the use of PRM as an imaging biomarker in the diagnosis of BOS. PRM was applied to CT data from 4 patient cohorts: acute infection (n = 11), BOS at onset (n = 34), BOS plus infection (n = 9), and age-matched, nontransplant control subjects (n = 23). Pulmonary function tests and bronchoalveolar lavage were used for group classification. Mean values for PRMfSAD were significantly greater in patients with BOS (38% +/- 2%) when compared with those with infection alone (17% +/- 4%, P 28% highly indicative of BOS occurrence. PRM may provide a major advance in our ability to identify the small airway obstruction that characterizes BOS, even in the presence of concurrent infection. (C) 2014 American Society for Blood and Marrow Transplantation.

Opioids are often prescribed to children for pain relief related to procedures, acute injuries, and chronic conditions. Round-the-clock dosing of opioids can produce opioid dependence within 5 days. According to a 2001 Consensus Paper from the American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine, dependence is defined as “a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.” Although the experience of many children undergoing iatrogenically induced withdrawal may be mild or goes unreported, there is currently no guidance for recognition or management of withdrawal for this population. Guidance on this subject is available only for adults and primarily for adults with substance use disorders. The guideline will summarize existing literature and provide readers with information currently not available in any single source specific for this vulnerable pediatric population.

FLECHTNER-MORS, MARION, HERWIG H. DITSCHUNEIT, TIMOTHY D. JOHNSON, MARK A. SUCHARD, AND GUIDO ADLER. Metabolic and weight loss effects of long-term dietary intervention in obese patients: Four-year results. Obes Res. 2000;8:399 ‐ 402. Objective: To investigate the contribution of meal and snack replacements for long-term weight maintenance and risk factor reduction in obese patients. Research Methods and Procedures: Prospective, randomized, two-arm, parallel intervention for 12 weeks followed by a prospective single-arm 4-year trial in a University Hospital clinic. One hundred patients, .18 years old and with a body mass index . 25 and # 40 kg/m 2 , were prescribed a 1200 to 1500 kcal/d control diet (Group A) or an isoenergetic diet, including two meal and snack replacements (vitamin- and mineral-fortified shakes, soups, and bars) and one meal high in fruits and vegetables (Group B). Following a 3 months of weight loss, all patients were prescribed the same energy-restricted diet (1200 to 1500 kcal) with one meal and one snack replacement for an additional 4 years. Results: All 100 patients were evaluated at 12 weeks. Mean percentage weight loss was 1.5 6 0.4% and 7.8 6 0.5% (mean 6 SEM) for Groups A and B, respectively. At 12 weeks systolic blood pressure, plasma triacylglycerol, glucose, and insulin concentrations were significantly reduced in Group B, whereas no changes occurred in Group A. After 4 years, 75% of the patients were evaluated. Total mean weight loss was 3.2 6 0.8% for Group A and 8.4 6 0.8% (mean 6 SEM) for Group B. Both groups showed significant improvement in blood glucose and insulin (p , 0.001), but only Group B showed significant improvement in triacylglycerol and systolic blood pressure compared to baseline values (p , 0.001). Discussion: Providing a structured meal plan via vitaminand mineral-fortified liquid meal replacements is a safe and effective dietary strategy for obese patients. Long-term maintenance of weight loss with meal replacements can improve certain biomarkers of disease risk.