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1.
Biochem J ; 481(18): 1143-1171, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39145956

ABSTRACT

Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-κB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138A alteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-κB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1 (mTORC1), which stimulated keratinocyte metabolism, but not for NF-κB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.


Subject(s)
CARD Signaling Adaptor Proteins , Cell Proliferation , Endosomes , Keratinocytes , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Humans , Animals , Keratinocytes/metabolism , Mice , CARD Signaling Adaptor Proteins/metabolism , CARD Signaling Adaptor Proteins/genetics , Endosomes/metabolism , Signal Transduction , Psoriasis/metabolism , Psoriasis/pathology , Psoriasis/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , NF-kappa B/metabolism , NF-kappa B/genetics , B-Cell CLL-Lymphoma 10 Protein/metabolism , B-Cell CLL-Lymphoma 10 Protein/genetics , Ubiquitination , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , TNF Receptor-Associated Factor 6/metabolism , TNF Receptor-Associated Factor 6/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , HEK293 Cells , Protein Transport , Guanylate Cyclase
2.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Article in English | MEDLINE | ID: mdl-34493667

ABSTRACT

The Santa Rosa fossil locality in eastern Perú produced the first Paleogene vertebrate fauna from the Amazon Basin, including the oldest known monkeys from South America. This diverse paleofauna was originally assigned an Eocene age based largely on the stage of evolution of the site's caviomorph rodents and marsupials. Here, we present detrital zircon dates that indicate that the maximum composite age of Santa Rosa is 29.6 ± 0.08 Ma (Lower Oligocene), although several zircons from Santa Rosa date to the Upper Oligocene. The first appearance datum for Caviomorpha in South America is purported to be the CTA-27 site in the Contamana region of Perú, which is hypothesized to be ∼41 Ma (Middle Eocene) in age. However, the presence of the same caviomorph species and/or genera at both CTA-27 and at Santa Rosa is now difficult to reconcile with a >11-My age difference. To further test the Middle Eocene age estimate for CTA-27, we ran multiple Bayesian tip-dating analyses of Caviomorpha, treating the ages of all Paleogene species from Perú as unknown. These analyses produced mean age estimates for Santa Rosa that closely approximate the maximum 29.6 ± 0.08 Ma composite date provided by detrital zircons, but predict that CTA-27 is much younger than currently thought (∼30 Ma). We conclude that the ∼41 Ma age proposed for CTA-27 is incorrect, and that there are currently no compelling Eocene records of either rodents or primates in the known fossil record of South America.


Subject(s)
Animal Migration/physiology , Bayes Theorem , Biological Evolution , Fossils , Haplorhini/classification , Phylogeny , Rodentia/classification , Animals , Geography , South America
3.
BMC Urol ; 18(1): 18, 2018 Mar 09.
Article in English | MEDLINE | ID: mdl-29523118

ABSTRACT

BACKGROUND: The non-invasive Cxbladder urine test system has demonstrated clinical utility in ruling out urothelial carcinoma (UC) in patients with asymptomatic microscopic hematuria (AMH), suggesting that the number of invasive diagnostic tests, including cystoscopy, used in this patient population may be reduced by Cxbladder testing prior to conducting a full urological work-up. The aim of this study was to demonstrate the enhanced clinical utility of communicating objective information on diagnostic decisions made by individual physicians on individual patients with AMH. METHODS: Three hundred ninety-six physician-patient decisions were generated from twelve participant physicians evaluating real world case notes from the same 33 patients presenting with AMH. Each physician reviewed and recommended diagnostic tests and procedures based on each patient's referral data and then re-evaluated their clinical recommendation following disclosure of the non-invasive Cxbladder urine test result. Changes assessed were the total number of requested diagnostic procedures and the number of invasive procedures, including cystoscopy, following addition of information from Cxbladder in the Triage and Triage and Detect modalities. RESULTS: Physicians made significant changes to their diagnostic behavior for patients with AMH when presented with Cxbladder test results, including a reduction in the number of total and invasive procedures including cystoscopy for individuals identified as having a low probability of UC. The intensity of investigation was targeted and increased, including use of total procedures and cystoscopy, for patients identified by Cxbladder tests as having a high probability of UC: urologists increased the level of investigation for both total procedures and invasive procedures. The outcome resulted in patients with a high risk of UC receiving appropriate guideline-recommended invasive diagnostic tests. Patients who tested negative were offered fewer and significantly less invasive procedures. This change in physician behavior results in an increased clinical and patient utility, lower risk of missed UC and invasive test-related harm incidents. CONCLUSIONS: This study demonstrated the potential for increased clinical resolution and significantly enhanced patient management, when physicians consider Cxbladder test results in their clinical evaluation. The change in physician behavior led to more appropriate diagnostic procedure selection and resource allocation to the benefit of both patients and healthcare systems.


Subject(s)
Clinical Decision-Making/methods , Hematuria/diagnostic imaging , Hematuria/urine , Physician-Patient Relations , Statistics as Topic/methods , Diagnostic Tests, Routine/methods , Hematuria/epidemiology , Humans , Prospective Studies , Risk Assessment , Urinalysis/methods
4.
Oncol Ther ; 6(1): 73-85, 2018 Jun.
Article in English | MEDLINE | ID: mdl-32700139

ABSTRACT

INTRODUCTION: International guidelines advocate regular surveillance of patients following urothelial carcinoma (UC). A validated molecular diagnostic non-invasive urine test, Cxbladder Monitor, correctly identifies patients with a UC history who have low-probability of recurrence. The present study assesses the clinical utility of Cxbladder Monitor in reducing the number and frequency of urologic procedures ordered without missing detection of recurrent UC. METHODS: Data from 828 physician-patient assessments were generated from 18 participant physicians who each evaluated the same real-world clinical case data for 30 patients undergoing surveillance for recurrent UC. Each physician ordered tests and procedures and their timing, following review of the patient's demographic data, pre-existing conditions, risk factors and clinical history before and after disclosure of Cxbladder Monitor results. Changes in the number, type and timing of procedures ordered were assessed. RESULTS: The addition of Cxbladder Monitor significantly reduced the overall number of tests ordered by 38.7%, including flexible cystoscopy by 43%, for patients whose Cxbladder Monitor result was low-probability. When the result was elevated-probability, the number of procedures ordered, including cystoscopy, was increased consistent with the increased risk of recurrent UC. Importantly, based on the tests ordered by each physician for each of the patients, all cases of recurrent UC would have been detected. CONCLUSION: The increase in clinical utility of Cxbladder Monitor for the management of patients undergoing surveillance for recurrent UC was shown to be driven by the reduction in procedures ordered for low-probability patients and for the more invasive procedures ordered for elevated-probability patients. In this study, the total number of procedures ordered, including the number of cystoscopies, was reduced especially in patients with low-probability of UC. The invasive procedures were ordered in a more targeted fashion for elevated-probability patients, without compromising the detection of recurrent UC. CLINICALTRIALS. GOV IDENTIFIER: NCT02700659. FUNDING: Pacific Edge Limited.

5.
Adv Ther ; 34(5): 1087-1096, 2017 05.
Article in English | MEDLINE | ID: mdl-28341930

ABSTRACT

INTRODUCTION: This study aimed to demonstrate the clinical utility of non-invasive multigene Cxbladder urine tests in reducing the overall number of diagnostic tests and invasive procedures used in the clinical evaluation of patients presenting with microhematuria, a key symptom of urothelial carcinoma (UC). There is a belief that using non-invasive molecular diagnostic tests in patients with hematuria may lead to patients undergoing unnecessary and costly invasive procedures that can cause adverse events and decrease patient quality of life. The objective of this study was to determine whether or not this was the case, using Cxbladder. METHODS: Data from 396 patient-by-urologist interactions generated 792 decision points from a standardized cohort of 33 patients evaluated by 12 urologists. Participant physicians recommended a selection of tests and procedures based on referral data, then reviewed and amended their recommendations in the context of diagnostic information from Cxbladder used in the Triage and Triage and Detect clinical modalities. RESULTS: All urologists changed their diagnostic behavior in at least one patient case with the addition of Cxbladder results. The total number of diagnostic procedures was reduced by 5% and 25% following disclosure of results from Cxbladder in the Triage and the Triage and Detect modalities, respectively. The total number of requested invasive procedures was reduced from 425 at referral to 379 (-11%) and 292 (-31%) following disclosure of Cxbladder information in the Triage and Triage and Detect modalities, respectively. CONCLUSIONS: Urologists made compelling changes to their clinical decision-making when they were provided with Cxbladder results for patients presenting with hematuria. Cxbladder provides an increase in clinical utility by focusing the use of invasive diagnostic procedures to appropriate patients, reducing both the total number and number of invasive procedures used in the clinical management of patients with hematuria, thereby improving the diagnostic experience and outcomes for patients. FUNDING: Pacific Edge Ltd.


Subject(s)
Biomarkers, Tumor/urine , Carcinoma/diagnosis , Carcinoma/genetics , Hematuria/diagnosis , RNA/urine , Urethral Neoplasms/diagnosis , Urethral Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Male , Middle Aged
6.
J Urol ; 197(6): 1419-1426, 2017 06.
Article in English | MEDLINE | ID: mdl-27986532

ABSTRACT

PURPOSE: Urothelial carcinoma is associated with a high rate of recurrence. Guidelines recommend rigorous, regular surveillance programs that are invasive and expensive. This study describes a noninvasive urine test with sufficient sensitivity to rule out recurrent urothelial carcinoma, thereby reducing invasive diagnostic evaluations without compromising patient care. METHODS AND MATERIALS: A total of 1,036 urine samples were prospectively collected from 763 patients undergoing routine surveillance for recurrent urothelial carcinoma of the bladder. The purpose was to develop and validate a test with combined high sensitivity and high negative predictive value. Cxbladder Monitor combines gene expression, clinical and patient data, and it is designed to rule out the presence of recurrent urothelial carcinoma. RESULTS: Cxbladder Monitor showed an internally validated sensitivity of 0.93 with a negative predictive value of 0.97 and a test negative rate of 0.34. Sensitivity was 0.95 for recurrent disease with a high risk of progression (all high grade disease and low grade, stage T1 or greater disease) compared with 0.86 for low grade Ta disease. Subgroup analyses indicated that diagnostic performance was not significantly different in different age groups, or by gender or tumor stage. Sensitivity was not affected by adjuvant bacillus Calmette-Guérin treatment within the last 6 months. False-negative findings were reported in fewer than 1.5% of all samples collected. CONCLUSIONS: The Cxbladder Monitor test offers combined high sensitivity and high negative predictive value to rule out urothelial carcinoma. This test has clinical utility as a confirmatory negative adjunct to cystoscopy, potentially justifying the postponement/avoidance of cystoscopic investigations to monitor recurrence in patients.


Subject(s)
Biomarkers, Tumor/urine , Carcinoma, Transitional Cell/urine , Neoplasm Recurrence, Local/urine , Urinary Bladder Neoplasms/urine , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/genetics , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/genetics , Population Surveillance , Predictive Value of Tests , Prospective Studies , Urinary Bladder Neoplasms/genetics
7.
Int J Surg Pathol ; 25(3): 281-286, 2017 May.
Article in English | MEDLINE | ID: mdl-27829209

ABSTRACT

Composite lymphoma (CL) describes the rare occurrence of 2 or more distinct types of lymphoma in a single anatomical location. We present the case of a 78-year-old man presenting with a 3-month history of weakness, malaise, and increasing dyspnea. A lymph node excised from the posterior triangle of the neck revealed the coexistence of 2 morphologically and phenotypically distinct lymphoid neoplasms consistent with a blastoid variant of mantle cell lymphoma (MCL) occurring in composite with classical Hodgkin lymphoma (cHL), mixed cellularity subtype. A t(11;14)(q13;q32) translocation was demonstrated by fluorescence in situ hybridization in the MCL and Hodgkin Reed-Sternberg cells of the cHL. Multiplex polymerase chain reaction detected clonal Immunoglobulin heavy chain (VFR1-J, VFR2-J, and VFR3-J), clonal immunoglobulin light chain kappa (V-J and V/JC intron-kde) and clonal immunoglobulin light chain lambda (V-J) gene rearrangements in the MCL. This report represents the first case of a blastoid variant of MCL occurring in composite with cHL.


Subject(s)
Composite Lymphoma/pathology , Hodgkin Disease/pathology , Lymphoma, Mantle-Cell/pathology , Aged , Composite Lymphoma/genetics , Hodgkin Disease/genetics , Humans , In Situ Hybridization, Fluorescence , Lymph Nodes/pathology , Lymphoma, Mantle-Cell/genetics , Male , Multiplex Polymerase Chain Reaction
8.
Biochem J ; 473(12): 1759-68, 2016 06 15.
Article in English | MEDLINE | ID: mdl-27071417

ABSTRACT

Inherited and de novo mutations in the CARD14 gene promote the development of psoriasis, an inflammatory disease of the skin. Caspase recruitment domain-containing protein 14 (CARD14) is a member of the CARMA protein family that includes the structurally related CARD11 adaptor that mediates NF-κB activation by antigen receptors. We investigated the mechanism by which CARD14 mutation in psoriasis activates NF-κB. In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes. These alterations disrupted the inhibitory effect of the CARD14 linker region (LR) on NF-κB activation by facilitating BCL10 binding. Therefore, psoriasis mutations activated CARD14 by a mechanism analogous to oncogenic CARD11 mutations in non-Hodgkin B cell lymphomas. CARD14(E138A) also stimulated MALT1 paracaspase activity and activated both ERK1/2 and p38α MAP kinases. Inhibition of MALT1 with mepazine reduced CARD14(E138A)-induced expression of specific psoriasis-associated transcripts in keratinocytes. Our results establish the mechanism whereby gain-of-function CARD14 variants, which induce psoriatic disease in affected individuals, activate pro-inflammatory signalling.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , CARD Signaling Adaptor Proteins/metabolism , Caspases/metabolism , Guanylate Cyclase/metabolism , Membrane Proteins/metabolism , NF-kappa B/metabolism , Neoplasm Proteins/metabolism , Psoriasis/metabolism , Adaptor Proteins, Signal Transducing/genetics , B-Cell CLL-Lymphoma 10 Protein , CARD Signaling Adaptor Proteins/genetics , Caspases/genetics , Cell Line , Guanylate Cyclase/genetics , Humans , Immunoprecipitation , Keratinocytes/metabolism , MAP Kinase Signaling System/genetics , MAP Kinase Signaling System/physiology , Membrane Proteins/genetics , Mitogen-Activated Protein Kinase 14/metabolism , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Mutation/genetics , Neoplasm Proteins/genetics , Protein Binding/genetics , Protein Binding/physiology , Psoriasis/genetics , RNA, Small Interfering , Signal Transduction/genetics , Signal Transduction/physiology
9.
BMC Med Res Methodol ; 15: 45, 2015 May 12.
Article in English | MEDLINE | ID: mdl-25962444

ABSTRACT

BACKGROUND: Comparing the relative utility of diagnostic tests is challenging when available datasets are small, partial or incomplete. The analytical leverage associated with a large sample size can be gained by integrating several small datasets to enable effective and accurate across-dataset comparisons. Accordingly, we propose a methodology for a holistic comparative analysis and ranking of cancer diagnostic tests through dataset integration and imputation of missing values, using urothelial carcinoma (UC) as a case study. METHODS: Five datasets comprising samples from 939 subjects, including 89 with UC, where up to four diagnostic tests (cytology, NMP22®, UroVysion® Fluorescence In-Situ Hybridization (FISH) and Cxbladder Detect) were integrated into a single dataset containing all measured records and missing values. The tests were firstly ranked using three criteria: sensitivity, specificity and a standard variable (feature) ranking method popularly known as signal-to-noise ratio (SNR) index derived from the mean values for all subjects clinically known to have UC versus healthy subjects. Secondly, step-wise unsupervised and supervised imputation (the latter accounting for the 'clinical truth' as determined by cystoscopy) was performed using personalized modelling, k-nearest-neighbour methods, multiple logistic regression and multilayer perceptron neural networks. All imputation models were cross-validated by comparing their post-imputation predictive accuracy for UC with their pre-imputation accuracy. Finally, the post-imputation tests were re-ranked using the same three criteria. RESULTS: In both measured and imputed data sets, Cxbladder Detect ranked higher for sensitivity, and urine cytology a higher specificity, when compared with other UC tests. Cxbladder Detect consistently ranked higher than FISH and all other tests when SNR analyses were performed on measured, unsupervised and supervised imputed datasets. Supervised imputation resulted in a smaller cross-validation error. Cxbladder Detect was robust to imputation showing a 2% difference in its predictive versus clinical accuracy, outperforming FISH, NMP22 and cytology. CONCLUSION: All data analysed, pre- and post-imputation showed that Cxbladder Detect had higher SNR and outperformed all other comparator tests, including FISH. The methodology developed and validated for comparative ranking of the diagnostic tests for detecting UC, may be further applied to other cancer diagnostic datasets across population groups and multiple datasets.


Subject(s)
Algorithms , Carcinoma, Transitional Cell/diagnosis , Diagnostic Tests, Routine/methods , Urinary Bladder Neoplasms/diagnosis , Carcinoma, Transitional Cell/genetics , Cytodiagnosis , Databases, Factual/statistics & numerical data , Diagnostic Tests, Routine/standards , Diagnostic Tests, Routine/statistics & numerical data , Humans , In Situ Hybridization, Fluorescence , Reproducibility of Results , Sensitivity and Specificity , Urinary Bladder Neoplasms/genetics
10.
BMC Urol ; 15: 23, 2015 Mar 27.
Article in English | MEDLINE | ID: mdl-25888331

ABSTRACT

BACKGROUND: Hematuria can be symptomatic of urothelial carcinoma (UC) and ruling out patients with benign causes during primary evaluation is challenging. Patients with hematuria undergoing urological work-ups place significant clinical and financial burdens on healthcare systems. Current clinical evaluation involves processes that individually lack the sensitivity for accurate determination of UC. Algorithms and nomograms combining genotypic and phenotypic variables have largely focused on cancer detection and failed to improve performance. This study aimed to develop and validate a model incorporating both genotypic and phenotypic variables with high sensitivity and a high negative predictive value (NPV) combined to triage out patients with hematuria who have a low probability of having UC and may not require urological work-up. METHODS: Expression of IGFBP5, HOXA13, MDK, CDK1 and CXCR2 genes in a voided urine sample (genotypic) and age, gender, frequency of macrohematuria and smoking history (phenotypic) data were collected from 587 patients with macrohematuria. Logistic regression was used to develop predictive models for UC. A combined genotypic-phenotypic model (G + P INDEX) was compared with genotypic (G INDEX) and phenotypic (P INDEX) models. Area under receiver operating characteristic curves (AUC) defined the performance of each INDEX: high sensitivity, NPV >0.97 and a high test-negative rate was considered optimal for triaging out patients. The robustness of the G + P INDEX was tested in 40 microhematuria patients without UC. RESULTS: The G + P INDEX offered a bias-corrected AUC of 0.86 compared with 0.61 and 0.83, for the P and G INDEXs respectively. When the test-negative rate was 0.4, the G + P INDEX (sensitivity = 0.95; NPV = 0.98) offered improved performance compared with the G INDEX (sensitivity = 0.86; NPV = 0.96). 80% of patients with microhematuria who did not have UC were correctly triaged out using the G + P INDEX, therefore not requiring a full urological work-up. CONCLUSION: The adoption of G + P INDEX enables a significant change in clinical utility. G + P INDEX can be used to segregate hematuria patients with a low probability of UC with a high degree of confidence in the primary evaluation. Triaging out low-probability patients early significantly reduces the need for expensive and invasive work-ups, thereby lowering diagnosis-related adverse events and costs.


Subject(s)
Biomarkers, Tumor/urine , Hematuria/diagnosis , Hematuria/epidemiology , Triage/methods , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/urine , Adult , Aged , Aged, 80 and over , Australia/epidemiology , Causality , Comorbidity , Female , Hematuria/urine , Humans , Incidence , Male , Middle Aged , Neoplasm Proteins/urine , New Zealand/epidemiology , Reproducibility of Results , Risk Assessment/methods , Sensitivity and Specificity , Triage/statistics & numerical data
11.
Clin Imaging ; 39(2): 247-50, 2015.
Article in English | MEDLINE | ID: mdl-25467424

ABSTRACT

PURPOSE: Understanding the radiographic appearance and normal rate of fluid accumulation after pneumonectomy is important in order to detect postoperative complications. METHODS: Upright posterior-anterior chest radiographs of 94 postpneumonectomy patients were assessed for the rate of pleural fluid accumulation as a percentage of hemithorax volume. RESULTS: Overall median time to 70% hemithoracic opacification was 3 days and mean time was 27 days. The median time to 100% opacification was 66 days and mean time was 96 days. CONCLUSION: The median time to 70% hemithoracic opacification postpneumonectomy is 3 days, while median time to 100% opacification was 66 days.


Subject(s)
Pleural Cavity/diagnostic imaging , Pneumonectomy/adverse effects , Postoperative Complications/diagnostic imaging , Adult , Aged , Aged, 80 and over , Female , Humans , Lung Neoplasms/surgery , Male , Middle Aged , Radiography, Thoracic , Retrospective Studies , Young Adult
12.
J Urol ; 188(3): 741-7, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22818138

ABSTRACT

PURPOSE: We investigated whether the RNA assay uRNA® and its derivative Cxbladder® have greater sensitivity for the detection of bladder cancer than cytology, NMP22™ BladderChek™ and NMP22™ ELISA, and whether they are useful in risk stratification. MATERIALS AND METHODS: A total of 485 patients presenting with gross hematuria but without a history of urothelial cancer were recruited prospectively from 11 urology clinics in Australasia. Voided urine samples were obtained before cystoscopy. The sensitivity and specificity of the RNA tests were compared to cytology and the NMP22 assays using cystoscopy as the reference. The ability of Cxbladder to distinguish between low grade, stage Ta urothelial carcinoma and more advanced urothelial carcinoma was also determined. RESULTS: uRNA detected 41 of 66 urothelial carcinoma cases (62.1% sensitivity, 95% CI 49.3-73.8) compared with NMP22 ELISA (50.0%, 95% CI 37.4-62.6), BladderChek (37.9%, 95% CI 26.2-50.7) and cytology (56.1%, 95% CI 43.8-68.3). Cxbladder, which was developed on the study data, detected 82%, including 97% of the high grade tumors and 100% of tumors stage 1 or greater. The cutoffs for uRNA and Cxbladder were prespecified to give a specificity of 85%. The specificity of cytology was 94.5% (95% CI 91.9-96.5), NMP22 ELISA 88.0%, (95% CI 84.6-91.0) and BladderChek 96.4% (95% CI 94.2-98.0). Cxbladder distinguished between low grade Ta tumors and other detected urothelial carcinoma with a sensitivity of 91% and a specificity of 90%. CONCLUSIONS: uRNA and Cxbladder showed improved sensitivity for the detection of urothelial carcinoma compared to the NMP22 assays. Stratification with Cxbladder provides a potential method to prioritize patients for the management of waiting lists.


Subject(s)
Biomarkers, Tumor/urine , Carcinoma, Transitional Cell/diagnosis , Carcinoma, Transitional Cell/urine , Hematuria/urine , RNA/urine , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/urine , Aged , Carcinoma, Transitional Cell/complications , Carcinoma, Transitional Cell/genetics , Female , Hematuria/etiology , Humans , Male , Middle Aged , Nuclear Proteins/genetics , Prospective Studies , Risk Assessment/methods , Sensitivity and Specificity , Urinary Bladder Neoplasms/complications , Urinary Bladder Neoplasms/genetics , Urine/cytology
13.
AJR Am J Roentgenol ; 197(6): W985-91, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22109344

ABSTRACT

OBJECTIVE: It is assumed that memory has a role to play in repeated radiologic observation studies. The main objective of this study was to examine this assumption and evaluate the effect that memory may have on receiver operating characteristic (ROC) methods. MATERIALS AND METHODS: A two-center observer study was performed with a total of 24 experienced radiologists. Over two viewings, chest radiographs showing the tip of a central line in either the superior vena cava or the azygos vein were presented. Half of the images were changed between the two viewings. The participants' attention was directed on the first reading to the position of the central line. At the second reading, the participants were asked to assign a confidence score on a 6-point scale about whether each image had been included in the first reading. RESULTS: For the images that were scored as "definitely included" in the first viewing, readers at our two centers recalled only an average of 2.5 and 4.9 of the 20 repeated images, which is close to a random allocation of images to each score. As the confidence levels diminished for positive identification of repeated images, the numbers of correct answers increased. For images scored as not having been previously included, the numbers of correct answers remained low suggesting that identification of nonrepeated images is poor. Images with a greater number of incidental abnormalities and with more striking abnormalities were recognized more accurately than those with fewer and less striking abnormalities. CONCLUSION: This study shows a "memory effect" when the same images are presented at a second viewing within a small interval period. This effect appears to occur mainly at low confidence levels. These results suggest that including images with obvious incidental abnormalities in reader performance studies should be avoided.


Subject(s)
Memory , Radiography, Thoracic , Clinical Competence , Diagnostic Errors , Humans , Observer Variation , ROC Curve
14.
Semin Ultrasound CT MR ; 32(5): 365-76, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21963160

ABSTRACT

Primary sarcomas of the thorax are uncommon. The purpose of this review is to describe the radiologic findings of sarcomas affecting the thorax, in particular the chest wall, pleura, and lungs. Most primary sarcomas affecting the thorax arise in the chest wall, and the most common sarcomas of the chest wall are chondrosarcoma, osteosarcoma, Ewing's sarcoma/primitive neuroectodermal tumor, malignant fibrous histiocytoma, and fibrosarcoma. Primary pleural and pulmonary sarcomas are rare. Although histologic analysis is almost always required for accurate diagnosis, imaging is important for staging of these tumors, and several of these tumors have distinctive radiologic features, allowing the radiologist to narrow the differential diagnosis.


Subject(s)
Diagnostic Imaging , Lung Neoplasms/diagnosis , Pleural Neoplasms/diagnosis , Sarcoma/diagnosis , Thoracic Neoplasms/diagnosis , Contrast Media , Diagnosis, Differential , Humans , Radiopharmaceuticals
15.
Semin Ultrasound CT MR ; 32(5): 442-55, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21963165

ABSTRACT

Soft tissue and osseous sarcomas of the extremities are uncommon malignancies that represent very important diagnostic entities because of their aggressive nature. Radiologic investigations, including plain film, computed tomography, contrast-enhanced magnetic resonance imaging; scintigraphy, ultrasound, and positron emission tomography-computed tomography, play critical roles in providing a differential, establishing the diagnosis, demonstrating prognostic characteristics, and tailoring tumor treatment. The purpose of this review is to describe the most common soft tissue and osseous sarcomas of the extremities, with emphasis on their plain film and magnetic resonance imaging characteristics with the aim of aiding the reader to accurately describe the important imaging features and generate an appropriate differential diagnosis to aid the referring clinician with prompt appropriate management and treatment.


Subject(s)
Bone Neoplasms/diagnosis , Diagnostic Imaging , Extremities , Sarcoma/diagnosis , Soft Tissue Neoplasms/diagnosis , Contrast Media , Diagnosis, Differential , Humans , Prognosis , Radiopharmaceuticals
16.
AJR Am J Roentgenol ; 196(4): 783-7, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21427325

ABSTRACT

OBJECTIVE: The purpose of this study was to determine, first, the accuracy with which radiologists reading posteroanterior chest radiographs differentiate whether a central venous line is in the superior vena cava or the azygos vein and, second, the circumstances in which radiologists may omit the lateral view to determine the position of a central venous line. MATERIALS AND METHODS: Twenty-four radiologists evaluated 60 posteroanterior chest radiographs to determine the position of a central venous line in the superior vena cava or azygos vein. Investigators evaluated the appearance of the central venous lines to refine rules for determining central venous line position on a frontal radiograph and omitting the lateral view. RESULTS: The accuracy of posteroanterior radiography for determining central venous line position was 90% at one study location and 85.5% at the other. No central venous line in the azygos vein extended more than 10.9 mm caudal to the cephalic edge of the right main bronchus. No central venous line in the superior vena cava had a down-the-barrel or curved appearance at the caudal edge. CONCLUSION: For central venous lines extending at least 15 mm caudal to the cephalic edge of the right main bronchus and having no down-the-barrel or curved caudal appearance, categorization was nearly 100% accurate. Therefore, if desired to save radiation exposure and cost, it may be feasible to omit lateral views in radiography of patients with central venous lines extending at least 15 mm caudal to the cephalic edge of the right main bronchus in whom the caudal edge does not have a down-the-barrel or curved appearance.


Subject(s)
Azygos Vein/diagnostic imaging , Catheterization, Central Venous , Radiography, Thoracic , Vena Cava, Superior/diagnostic imaging , Humans , Ireland , ROC Curve , Radiology Information Systems , United States
17.
Radiol Clin North Am ; 46(3): 475-86, v, 2008 May.
Article in English | MEDLINE | ID: mdl-18707958

ABSTRACT

Positron emission tomography (PET)-computed tomography (CT) is a useful device in identifying musculoskeletal lesions that require biopsy. It can be used to localize the primary lesion, identify a site to biopsy, and evaluate metastatic lesions that require follow-up biopsies. Not all malignant tumors have hypermetabolic activity, and there are many benign lesions and physiologic processes that do have increased F-18 fluorodeoxyglucose uptake. Knowledge of these issues is important when reviewing PET-CT and directing subsequent musculoskeletal biopsies.


Subject(s)
Biopsy, Needle/methods , Bone Neoplasms/pathology , Muscle Neoplasms/pathology , Musculoskeletal System/pathology , Positron-Emission Tomography/methods , Tomography, X-Ray Computed/methods , Adolescent , Adult , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Female , Fluorodeoxyglucose F18 , Humans , Male , Middle Aged , Muscle Neoplasms/diagnostic imaging , Necrosis , Radiopharmaceuticals
18.
Can Assoc Radiol J ; 59(2): 77-82, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18533396

ABSTRACT

OBJECTIVE: To provide an overview of the current status of percutaneous vertebroplasty (PVP) practice in Canada, including the preprocedure work up, operative technique and follow-up practice of physicians performing the procedure in this country. METHODS: Questionnaires were emailed to 31 institutions performing percutaneous vertebroplasty across Canada. RESULTS: Twenty-three (74.2%) completed surveys were returned, representing data from 1516 vertebroplasties performed by 66 radiologists and surgeons. Preoperative routine imaging and screening practice varies widely. The majority of respondents perform PVP under conscious sedation; however, an anaesthetist is present in only 22% of institutions. Biplane fluoroscopy is used in 43.5% of practices. The preference for unipedicular or bipedicular injection varies: in 7 institutions, a unipedicular approach is used in at least 80% of cases. Patients receive a follow-up by the screening physician in 65.2% of institutions. There were 4 complications requiring treatment. Venous and intradiscal extravasation rates were 20.8% and 25.3%, respectively; however, the vast majority of these were clinically insignificant. CONCLUSION: PVP complication rates reported in our Canadian survey compare favourably with those in the published literature. The number of PVPs performed annually in the institutions surveyed appears small, relative to the figures from the United States. The prevalence of osteoporosis and incidence of vertebral compression fractures in Canada is increasing as the population ages, and demand for PVP is likely to rise significantly in the coming years.


Subject(s)
Minimally Invasive Surgical Procedures/methods , Practice Patterns, Physicians'/statistics & numerical data , Vertebroplasty/methods , Canada , Fractures, Compression/surgery , Health Care Surveys/statistics & numerical data , Humans , Minimally Invasive Surgical Procedures/adverse effects , Minimally Invasive Surgical Procedures/statistics & numerical data , Postoperative Care/methods , Preoperative Care/methods , Spinal Fractures/surgery , Spine/surgery , Surveys and Questionnaires , Vertebroplasty/adverse effects , Vertebroplasty/statistics & numerical data
20.
AJR Am J Roentgenol ; 190(6): 1605-9, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18492913

ABSTRACT

OBJECTIVE: The purpose of this study was to assess the radiographic features of pulmonary fusariosis, an increasingly encountered cause of severe opportunistic mold pneumonia. CONCLUSION: Pulmonary fusariosis has radiographic manifestations that are suggestive of an angioinvasive mold. Nodules or masses were the most common findings at CT, seen in 82% of patients compared with only 45% on chest radiography. The halo sign was not seen. Chest radiographs showed nonspecific findings in 30% of patients, and findings were normal at presentation in 25%. All of the patients had underlying hematologic malignancies. Thirteen of the 20 patients studied (65%) died within 1 month of diagnosis of pulmonary fusariosis. Because early initiation of intense antifungal therapy offers the best chance for survival in pulmonary fusariosis, early CT and appropriate microbiologic investigation should be obtained in severely immunocompromised patients.


Subject(s)
Fusarium , Hematologic Neoplasms/complications , Hematologic Neoplasms/diagnostic imaging , Lung Diseases, Fungal/complications , Lung Diseases, Fungal/diagnostic imaging , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Radiographic Image Enhancement/methods , Reproducibility of Results , Sensitivity and Specificity
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