Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial.

BACKGROUND & AIMS: Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology. METHODS: In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence. RESULTS: All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure. CONCLUSIONS: Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.

Multiparametric magnetic resonance imaging/magnetic resonance elastography assesses progression and regression of steatosis, inflammation, and fibrosis in alcohol-associated liver disease.

BACKGROUND: Magnetic resonance imaging (MRI) and MRI-based elastography (MRE) are the most promising noninvasive techniques in assessing liver diseases. The purpose of this study was to evaluate an advanced multiparametric imaging method for staging disease and assessing treatment response in realistic preclinical alcohol-associated liver disease (ALD). METHODS: We utilized four different preclinical mouse models in our study: Model 1-mice were fed a fast-food diet and fructose water for 48 weeks to induce nonalcoholic fatty liver disease; Model 2-mice were fed chronic-binge ethanol (EtOH) for 10 days or 8 weeks to induce liver steatosis/inflammation. Two groups of mice were treated with interleukin-22 at different time points to induce disease regression; Model 3-mice were administered CCl4 for 2 to 4 weeks to establish liver fibrosis followed by 2 or 4 weeks of recovery; and Model 4-mice were administered EtOH plus CCl4 for 12 weeks. Mouse liver imaging biomarkers including proton density fat fraction (PDFF), liver stiffness (LS), loss modulus (LM), and damping ratio (DR) were assessed. Liver and serum samples were obtained for histologic and biochemical analyses. Ordinal logistic regression and generalized linear regression analyses were used to model the severity of steatosis, inflammation, and fibrosis, and to assess the regression of these conditions. RESULTS: Multiparametric models with combinations of biomarkers (LS, LM, DR, and PDFF) used noninvasively to predict the histologic severity and regression of steatosis, inflammation, and fibrosis were highly accurate (area under the curve > 0.84 for all). A three-parameter model that incorporates LS, DR, and ALT predicted histologic fibrosis progression (r = 0.84, p < 0.0001) and regression (r = 0.79, p < 0.0001) as measured by collagen content in livers. CONCLUSION: This preclinical study provides evidence that multiparametric MRI/MRE can be used noninvasively to assess disease severity and monitor treatment response in ALD.

Endoscopic, Radiologic, and Histologic Healing With Vedolizumab in Patients With Active Crohn's Disease.

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.

Pulmonary nodules with ground-glass opacity can be reliably measured with low-dose techniques regardless of iterative reconstruction: results of a phantom study.

OBJECTIVE: Pulmonary nodules of ground-glass opacity represent one imaging manifestation of a slow-growing variant of lung cancer. The objective of this phantom study was to quantify the effect of the radiation dose used for the examination (volume CT dose index [CTDI(vol)]), type of reconstruction algorithm, and choice of postreconstruction enhancement algorithms on the measurement error when assessing the volume of simulated lung nodules with CT, focusing on two radiodensity levels. MATERIALS AND METHODS: Twelve synthetic nodules of two radiodensities (-630 and -10 HU), three shapes (spherical, lobulated, and spiculated), and two sizes (nominal diameters of 5 and 10 mm) were inserted into an anthropomorphic chest phantom and scanned with techniques varying in CTDI(vol) (from subscreening dose [0.8 mGy] to diagnostic levels [6.5 mGy]), reconstruction algorithms (iterative reconstruction and filtered back projection), and different postreconstruction enhancement algorithms. Nodule volume was measured from the resulting reconstructed CT images with a matched filter estimator. RESULTS: No significant over- or underestimation of nodule volume was observed across individual variables, with low percentage error overall (-1.4%) and for individual variables (range, -3.4% to 0.4%). The magnitude of percentage error was also low (overall average percentage error < 6% and SD values < 4.5%) and for individual variables (absolute percentage error range 3.3-5.6%). No clinically significant differences were observed between different levels of CTDI(vol), use of iterative reconstruction algorithms, or use of different postreconstruction enhancement algorithms. CONCLUSION: These results indicate that, if validated for other measurement tools and scanners, lung nodule volume measurements from scans acquired and reconstructed with significantly different acquisition and reconstruction techniques can be reliably compared.

Magnetic Resonance Enterography Assessment of Transmural Healing with Vedolizumab in Moderate to Severe Crohn's Disease: Feasibility in the VERSIFY Phase 3 Clinical Trial.

Purpose: The VERSIFY phase 3 trial in patients with Crohn's disease (CD) treated with vedolizumab was the first to include a substudy that used a standardized magnetic resonance enterography (MRE) protocol to assess features of transmural inflammation (bowel edema and wall thickness) and extramural disease activity (enlarged lymph nodes). Patients and Methods: Patients received intravenous vedolizumab (300 mg) at weeks 0 (baseline), 2, and 6, and then every 8 weeks for 26 or 52 weeks. Post hoc analyses included a subpopulation with a Magnetic Resonance Index of Activity score of ≥7 in at least one bowel segment at baseline and at least one postbaseline MRE assessment. Changes in transmural inflammation, including intramural bowel edema and wall thickness, were evaluated. Patient-level and segment-level analyses were performed. Results: MRE images were evaluated in 27 patients with 83 evaluable bowel segments at baseline and week 26, and 13 patients with 38 evaluable segments at baseline, week 26, and week 52. At baseline, all patients had bowel wall edema and wall thickness of >3 mm in at least one bowel segment. The proportion of patients with edema decreased at weeks 26 (17/27 [63.0%]) and 52 (4/13 [30.8%]) and the proportion with bowel wall thickness of >3 mm decreased at weeks 26 (25/27 [92.6%]) and 52 (10/13 [76.9%]). Conclusion: In patients with CD treated with vedolizumab for 26 and 52 weeks, the number of patients, and bowel segments, with MRE-detected transmural inflammation was reduced. These results highlight the impact of vedolizumab on components of transmural inflammation in CD and demonstrate that using MRE in CD multicenter clinical trials is feasible. Trial Registration: ClinicalTrials.gov NCT02425111, April 23, 2015, http://www.clinicaltrials.gov NCT02425111; EU Clinical Trials Register EudraCT 2014-003509-13, https://www.clinicaltrialsregister.eu.

Quantification of Celiac Disease Severity Using Video Capsule Endoscopy: A Comparison of Human Experts and Machine Learning Algorithms.

BACKGROUND: Video capsule endoscopy (VCE) is an attractive method for diagnosing and objectively monitoring disease activity in celiac disease (CeD). Its use, facilitated by artificial intelligence- based tools, may allow computer-assisted interpretation of VCE studies, transforming a subjective test into a quantitative and reproducible measurement tool. OBJECTIVE: To evaluate and compare objective CeD severity assessment as determined with VCE by expert human readers and a machine learning algorithm (MLA). METHODS: Patients ≥ 18 years with histologically proven CeD underwent VCE. Examination frames were scored by three readers from one center and the MLA, using a 4-point ordinal scale for assessing the severity of CeD enteropathy. After scoring, curves representing CeD severity across the entire small intestine (SI) and individual tertiles (proximal, mid, and distal) were fitted for each reader and the MLA. All comparisons used Krippendorff's alpha; values > 0.8 represent excellent to 'almost perfect' inter-reader agreement. RESULTS: VCEs from 63 patients were scored. Readers demonstrated strong inter-reader agreement on celiac villous damage (alpha=0.924), and mean value reader curves showed similarly excellent agreement with MLA curves (alpha=0.935). Average reader and MLA curves were comparable for mean and maximum values for the first SI tertile (alphas=0.932 and 0.867, respectively) and the mean value over the entire SI (alpha=0.945). CONCLUSION: A novel MLA demonstrated excellent agreement on whole SI imaging with three expert gastroenterologists. An ordinal scale permitted high inter-reader agreement, accurately and reliably replicated by the MLA. Interpreting VCEs using MLAs may allow automated diagnosis and disease burden assessment in CeD.

CT or MR Enterography to Assess Response During Vedolizumab Therapy for Small Bowel Crohn's Disease.

Background: To describe response to therapy of small bowel (SB) Crohn's disease (CD) at CT or MR enterography (CTE/MRE) in patients on vedolizumab. Methods: Patients with SB CD who underwent CTE/MRE exams greater than 12 months apart on vedolizumab therapy were included. Length (in cm) and inflammation severity (EMBARK score) of inflamed SB segments were assessed. Changes in inflammation length of 3.4 cm or greater or inflammation severity of 2 EMBARK points or greater was categorized as response or progression, as appropriate, with development of newly inflamed segments, strictures, or penetrating complications also indicating progression. Patients not meeting the criteria for response or progression were categorized as having stable disease. Results: Of 36 SB CD patients, the large majority had prior surgery (86%; 31), anti-TNF use (92%; 33), and internal penetrating (78%; 28) disease. Thirty-two patients had paired baseline and follow-up CTE/MRE exams without interval surgery, with clinical response observed in 24/32 (75%). Based on imaging response criteria, 22% (7/32; 95% CI: 9%-40%) had response, 50% (16/32; 95% CI: 32%-68%) were stable, and 28% (9/32; 95% CI: 14%-47%) had disease progression. Fifty-six percent of (18/32; 95% CI: 38%-74%) patients had clinical improvement with response or stable disease by imaging. Patients with stable disease had shorter median baseline lengths of SB inflammation (P = .012). Proportion of patients with colonic inflammation, perianal disease, or penetrating complications did not change. Conclusions: Most patients on vedolizumab for over 12 months demonstrated response or stable SB disease when using objective cross-sectional radiologic imaging criteria using CTE/MRE.

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development.

Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.

One size does not fit all: Factors associated with increased frequency of radiation overexposure alerts based on fixed-alert thresholds.

OBJECTIVES: Quantify the expected rate of CT radiation dose alerts for three body regions using accepted radiation dose benchmarks and assess key determinants of alert frequency. METHODS: This IRB-approved retrospective cohort study evaluated consecutive CT examinations performed between July and December 2013 within an academic medical system. CTDIvol x-ray tube output metrics were compared to the body-region-specific benchmark levels, Achievable Doses (AD), Diagnostic Reference Levels (DRL), and Dose Notification Values (DNV). A logistic regression model for the simulated alerts was fit as a function of the independent predictors: scanner, body region, gender, weight, and age. RESULTS: For 17,000 exams, the proportion of events triggering alerts increased with patient weight. Significant covariates were scanner, body region, patient weight and patient age (all p < 0.0001). Odds of alert generation for the AD, DRL, and DNV benchmarks increased by 7.6%, 6.6% and 2.9% per kilogram, respectively, and by 0.8%, 1.1% and -2.7% per year of age (all p < 0.0001). Compared to the most highly optimized scanner, odds of alert generation varied by a factor of 595 for AD, 1126 for DRL, and 13 for DNV. CONCLUSION: Alert frequency was significantly correlated with weight, age, body region and scanner. Controllable factors include scanner functionality and associated protocol optimization. Patient factors driving alert frequency are predominantly weight, and to a lesser degree, age. Size-agnostic fixed dose thresholds can frequently produce false positive alerts in appropriately performed exams of large patients, while missing opportunities to identify outlier scans of higher-than-expected dose in small patients.

Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis.

BACKGROUND: Gastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction. AIM: To evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5-HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids. METHODS: Single-centre, placebo-controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99m Tc-egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111 In-charcoal delivered in methacrylate-coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2 . Statistical analysis used baseline parameters as covariates (ANCOVA). RESULTS: Patients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying T1/2 , colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2 ) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG. CONCLUSION: I.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short-term treatment of gastric and intestinal motility disorders. ClinicalTrials.gov #NCT03281577.

Detection of unwarranted CT radiation exposure from patient and imaging protocol meta-data using regularized regression.

BACKGROUND: Variability in radiation exposure from CT scans can be appropriate and driven by patient features such as body habitus. Quantitative analysis may be performed to discover instances of unwarranted radiation exposure and to reduce the probability of such occurrences in future patient visits. No universal process to perform identification of outliers is widely available, and access to expertise and resources is variable. OBJECTIVE: The goal of this study is to develop an automated outlier detection procedure to identify all scans with an unanticipated high radiation exposure, given the characteristics of the patient and the type of the exam. MATERIALS AND METHODS: This Institutional Review Board-approved retrospective cohort study was conducted from June 30, 2012 - December 31, 2013 in a quaternary academic medical center. The de-identified dataset contained 28 fields for 189,959 CT exams. We applied the variable selection method Least Absolute Shrinkage and Selection Operator (LASSO) to select important variables for predicting CT radiation dose. We then employed a regression approach that is robust to outliers, to learn from data a predictive model of CT radiation doses given important variables identified by LASSO. Patient visits whose predicted radiation dose was statistically different from the radiation dose actually received were identified as outliers. RESULTS: Our methodology identified 1% of CT exams as outliers. The top-5 predictors discovered by LASSO and strongly correlated with radiation dose were Tube Current, kVp, Weight, Width of collimator, and Reference milliampere-seconds. A human expert validation of the outlier detection algorithm has yielded specificity of 0.85 [95% CI 0.78-0.92] and sensitivity of 0.91 [95% CI 0.85-0.97] (PPV = 0.84, NPV = 0.92). These values substantially outperform alternative methods we tested (F1 score 0.88 for our method against 0.51 for the alternatives). CONCLUSION: The study developed and tested a novel, automated method for processing CT scanner meta-data to identify CT exams where patients received an unwarranted amount of radiation. Radiation safety and protocol review committees may use this technique to uncover systemic issues and reduce future incidents.

Measurement Accuracy of Atherosclerotic Plaque Structure on CT Using Phantoms to Establish Ground Truth.

RATIONALE AND OBJECTIVES: The purpose of this study was to characterize analytic performance of software-aided arterial vessel structure measurements across a range of scanner settings for computed tomography angiography where ground truth is known. We characterized performance for measurands that may be efficiently measured for clinical cases without use of software, as well as those that may be done manually but which is generally not done due to the effort level required unless software is employed. MATERIALS AND METHODS: Four measurands (lumen area, stenosis, wall area, wall thickness) were evaluated using tissue-mimicking phantoms to estimate bias, heteroscedasticity, and limits of quantitation both pooled across scanner settings and individually for eight different settings. Reproducibility across scanner settings was also estimated. RESULTS: Measurements of lumen area have a near constant bias of +1.3 mm for measurements ranging from 3 mm2 to 40 mm2; stenosis bias is +7% across a 30%-70% range; wall area bias is +14% across a 50-450 mm2 range; and wall thickness bias is +1.2 mm across a 3-9 mm range. All measurements possess properties that make them suitable for measuring longitudinal change. Lumen area demonstrates the most sensitivity to scanner settings (bias from as low as +.1 mm to as high as +2.7 mm); wall thickness demonstrates negligible sensitivity. CONCLUSIONS: Variability across scanner settings for lumen measurands was generally higher than bias for a given setting. The converse was true for the wall measurands, where variability due to scanner settings was very low. Both bias and variability due to scanner settings of vessel structure were within clinically useful levels.

Quantitative assessment of nonsolid pulmonary nodule volume with computed tomography in a phantom study.

BACKGROUND: To assess the volumetric measurement of small (≤1 cm) nonsolid nodules with computed tomography (CT), focusing on the interaction of state of the art iterative reconstruction (IR) methods and dose with nodule densities, sizes, and shapes. METHODS: Twelve synthetic nodules [5 and 10 mm in diameter, densities of -800, -630 and -10 Hounsfield units (HU), spherical and spiculated shapes] were scanned within an anthropomorphic phantom. Dose [computed tomography scan dose index (CTDIvol)] ranged from standard (4.1 mGy) to below screening levels (0.3 mGy). Data was reconstructed using filtered back-projection and two state-of-the-art IR methods (adaptive and model-based). Measurements were extracted with a previously validated matched filter-based estimator. Analysis of accuracy and precision was based on evaluation of percent bias (PB) and the repeatability coefficient (RC) respectively. RESULTS: Density had the most important effect on measurement error followed by the interaction of density with nodule size. The nonsolid -630 HU nodules had high accuracy and precision at levels comparable to solid (-10 HU) nonsolid, regardless of reconstruction method and with CTDIvol as low as 0.6 mGy. PB was <5% and <11% for the 10- and 5-mm in nominal diameter -630 HU nodules respectively, and RC was <5% and <12% for the same nodules. For nonsolid -800 HU nodules, PB increased to <11% and <30% for the 10- and 5-mm nodules respectively, whereas RC increased slightly overall but varied widely across dose and reconstruction algorithms for the 5-mm nodules. Model-based IR improved measurement accuracy for the 5-mm, low-density (-800, -630 HU) nodules. For other nodules the effect of reconstruction method was small. Dose did not affect volumetric accuracy and only affected slightly the precision of 5-mm nonsolid nodules. CONCLUSIONS: Reasonable values of both accuracy and precision were achieved for volumetric measurements of all 10-mm nonsolid nodules, and for the 5-mm nodules with -630 HU or higher density, when derived from scans acquired with below screening dose levels as low as 0.6 mGy and regardless of reconstruction algorithm.

MRI Phenotyping of COL9A2/Trp2 and COL9A3/Trp3 Alleles in Lumbar Disc Disease: A Case-control Study in South-Western Iranian Population Reveals a Significant Trp3-Disease Association in Males.

STUDY DESIGN: A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging. OBJECTIVE: To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population. SUMMARY OF BACKGROUND DATA: A number of genetic predisposing factors have been identified in elevating the risk of developing DDD. Specifically, the Trp2 and Trp3 alleles of COL9A2 and COL9A3 genes have been suggested as DDD risk variants. METHODS: A total of 108 patients (mean age = 41±11.8 yrs, range = 20-66 yrs) with 57 controls (mean age = 35±10.0 yrs, range = 20-58 yrs) participated in the study. The frequency of G/A polymorphism in COL9A2 gene on location 326 on chromosome 1 and G/A/C/ or T polymorphism in 103 location of COL9A3 gene on chromosome 20 was assessed using a PCR short-primer technique. Outcome measure was defined as presence of DDD on MRI. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the likelihood of DDD given occurrence of Trp2(3). RESULTS: Each allele was present in both patients and controls. The Trp2 allele was positive in 28.5% of individuals (31.5% of patients; 22.8% of controls), OR 1.55 (0.71-3.56). The Trp3 allele, the frequency was 23.6% in all patients (26.9% patients; 17.5% controls), OR 1.72 (0.73-4.33). We observed a 5.8-fold increase in the odds of DDD in males when the Trp3 allele was present, OR 5.83 (1.09-9.98), P = 0.0273. CONCLUSION: Both Trp2 and Trp3 alleles occurred more frequently compared with other studied ethnicities. The sampled Iranian population exhibited a similar Trp2 frequency to a Southern Chinese population, and Trp3 occurrence to Finnish and Greek population. We found that male patient were much more likely to develop DDD when Trp 3 was present. LEVEL OF EVIDENCE: N/A.

Volumes Learned: It Takes More Than Size to "Size Up" Pulmonary Lesions.

RATIONALE AND OBJECTIVES: This study aimed to review the current understanding and capabilities regarding use of imaging for noninvasive lesion characterization and its relationship to lung cancer screening and treatment. MATERIALS AND METHODS: Our review of the state of the art was broken down into questions about the different lung cancer image phenotypes being characterized, the role of imaging and requirements for increasing its value with respect to increasing diagnostic confidence and quantitative assessment, and a review of the current capabilities with respect to those needs. RESULTS: The preponderance of the literature has so far been focused on the measurement of lesion size, with increasing contributions being made to determine the formal performance of scanners, measurement tools, and human operators in terms of bias and variability. Concurrently, an increasing number of investigators are reporting utility and predictive value of measures other than size, and sensitivity and specificity is being reported. Relatively little has been documented on quantitative measurement of non-size features with corresponding estimation of measurement performance and reproducibility. CONCLUSIONS: The weight of the evidence suggests characterization of pulmonary lesions built on quantitative measures adds value to the screening for, and treatment of, lung cancer. Advanced image analysis techniques may identify patterns or biomarkers not readily assessed by eye and may also facilitate management of multidimensional imaging data in such a way as to efficiently integrate it into the clinical workflow.

Combination of texture and shape features to detect pulmonary abnormalities in digital chest X-rays.

PURPOSE: To improve detection of pulmonary and pleural abnormalities caused by pneumonia or tuberculosis (TB) in digital chest X-rays (CXRs). METHODS: A method was developed and tested by combining shape and texture features to classify CXRs into two categories: TB and non-TB cases. Based on observation that radiologist interpretation is typically comparative: between left and right lung fields, the algorithm uses shape features to describe the overall geometrical characteristics of the lung fields and texture features to represent image characteristics inside them. RESULTS: Our algorithm was evaluated on two different datasets containing tuberculosis and pneumonia cases. CONCLUSIONS: Using our proposed algorithm, we were able to increase the overall performance, measured as area under the (ROC) curve (AUC) by 2.4 % over our previous work.

On the same page--physicist and radiologist perspectives on protocol management and review.

To sustain compliance with accreditation requirements of the ACR, Joint Commission, and state-specific statutes and regulatory requirements, a CT protocol review committee requires a structure for systematic analysis of protocols. Safe and reproducible practice of CT in a complex environment requires that physician supervision processes and protocols be precisely and clearly presented. This article discusses necessary components for data structure, and a description of an IT-based approach for protocol review based on experiences at 2 academic centers, 3 community hospitals, 1 cancer center, and 2 outpatient clinics.

Automatic tuberculosis screening using chest radiographs.

Tuberculosis is a major health threat in many regions of the world. Opportunistic infections in immunocompromised HIV/AIDS patients and multi-drug-resistant bacterial strains have exacerbated the problem, while diagnosing tuberculosis still remains a challenge. When left undiagnosed and thus untreated, mortality rates of patients with tuberculosis are high. Standard diagnostics still rely on methods developed in the last century. They are slow and often unreliable. In an effort to reduce the burden of the disease, this paper presents our automated approach for detecting tuberculosis in conventional posteroanterior chest radiographs. We first extract the lung region using a graph cut segmentation method. For this lung region, we compute a set of texture and shape features, which enable the X-rays to be classified as normal or abnormal using a binary classifier. We measure the performance of our system on two datasets: a set collected by the tuberculosis control program of our local county's health department in the United States, and a set collected by Shenzhen Hospital, China. The proposed computer-aided diagnostic system for TB screening, which is ready for field deployment, achieves a performance that approaches the performance of human experts. We achieve an area under the ROC curve (AUC) of 87% (78.3% accuracy) for the first set, and an AUC of 90% (84% accuracy) for the second set. For the first set, we compare our system performance with the performance of radiologists. When trying not to miss any positive cases, radiologists achieve an accuracy of about 82% on this set, and their false positive rate is about half of our system's rate.

Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease.

RATIONALE: Treatment of pulmonary nontuberculous mycobacteria, especially Mycobacterium abscessus, requires prolonged, multidrug regimens with high toxicity and suboptimal efficacy. Options for refractory disease are limited. OBJECTIVES: We reviewed the efficacy and toxicity of inhaled amikacin in patients with treatment-refractory nontuberculous mycobacterial lung disease. METHODS: Records were queried to identify patients who had inhaled amikacin added to failing regimens. Lower airway microbiology, symptoms, and computed tomography scan changes were assessed together with reported toxicity. MEASUREMENTS AND MAIN RESULTS: The majority (80%) of the 20 patients who met entry criteria were women; all had bronchiectasis, two had cystic fibrosis and one had primary ciliary dyskinesia. At initiation of inhaled amikacin, 15 were culture positive for M. abscessus and 5 for Mycobacterium avium complex and had received a median (range) of 60 (6, 190) months of mycobacterial treatment. Patients were followed for a median of 19 (1, 50) months. Eight (40%) patients had at least one negative culture and 5 (25%) had persistently negative cultures. A decrease in smear quantity was noted in 9 of 20 (45%) and in mycobacterial culture growth for 10 of 19 (53%). Symptom scores improved in nine (45%), were unchanged in seven (35%), and worsened in four (20%). Improvement on computed tomography scans was noted in 6 (30%), unchanged in 3 (15%), and worsened in 11 (55%). Seven (35%) stopped amikacin due to: ototoxicity in two (10%), hemoptysis in two (10%), and nephrotoxicity, persistent dysphonia, and vertigo in one each. CONCLUSIONS: In some patients with treatment-refractory pulmonary nontuberculous mycobacterial disease, the addition of inhaled amikacin was associated with microbiologic and/or symptomatic improvement; however, toxicity was common. Prospective evaluation of inhaled amikacin for mycobacterial disease is warranted.