A holistic comparative analysis of diagnostic tests for urothelial carcinoma: a study of Cxbladder Detect, UroVysion® FISH, NMP22® and cytology based on imputation of multiple datasets.

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.

A segregation index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers from a urine sample to triage out patients presenting with hematuria who have a low probability of urothelial carcinoma.

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.

Radiographic evaluation of the pleural fluid accumulation rate after pneumonectomy.

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.

Imaging of thoracic sarcomas of the chest wall, pleura, and lung.

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.

Imaging of soft tissue and osseous sarcomas of the extremities.

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.

Full thickness burn caused by exposure to giant hogweed: delayed presentation, histological features and surgical management.

We report the case of a 10-year-old boy with a full thickness chemical burn on his right pretibial area due to phytophotodermatitis (PPD) following contact with giant hogweed (Heracleum mantegazzianum). Although cutaneous burns due to plants are a well-established cause of chemical burn, previous reports described partial thickness burns that healed with conservative measures. This patient presented to our unit two weeks after the initial injury with an established full thickness burn. Debridement and split thickness skin grafting was required. We presented the histological features of the debrided skin specimen and discussed potential factors leading to this unexpected full thickness injury.

Positron emission tomography-CT imaging in guiding musculoskeletal biopsy.

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.

The current status of percutaneous vertebroplasty in Canada.

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.

Imaging of pulmonary fusariosis in patients with hematologic malignancies.

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.

The effects of freezing on the tensile properties of repaired porcine flexor tendon.

PURPOSE: When conducting complex testing of tendon repairs, it is essential that the samples are adequately preserved to prevent degradation. Freezing of samples is the most convenient method of preservation; however, there is no evidence in the literature to prove that freezing tendon before or after repair is acceptable. We aimed to prove that freezing tendons does not significantly alter the results of linear load-to-failure testing of tendon repairs. METHODS: After a power study, 150 tendons were harvested from porcine forelimbs and randomized into 5 groups of 30 tendons. After division, tendons were repaired using a Pennington modified core technique with a Silfverskiöld peripheral cross-stitch. Tendons in group 1 were divided, repaired, and tested within 3 hours postmortem. Tendons in group 2 were refrigerated at 4 degrees C for 24 hours prior to repair and testing. Tendons in group 3 were frozen at -25 degrees C for 3 months prior to repair and testing. Tendons in group 4 were frozen at -25 degrees C for 6 months prior to repair and testing. Tendons in group 5 were frozen at -25 degrees C for 6 months, repaired, refrozen for 1 month, and then tested. All repairs were linear load tested to ascertain the ultimate strength and force to produce 3-mm gap in the repair. RESULTS: Analysis of variance analysis of the results did not demonstrate any significant differences between groups. CONCLUSIONS: Freezing tendons both before and after suture repair is an acceptable method of preservation when investigating the force to produce 3-mm gap and ultimate strength of tendon repairs.

Homogeneous time-resolved fluorescence assays for the detection of activity and inhibition of phosphatase enzymes employing phosphorescently labeled peptide substrates.

A rapid, homogenous, antibody-free assay for phosphatase enzymes was developed using the phosphorescent platinum (II)-coproporphyrin label (PtCP) and time-resolved fluorescent detection. An internally quenched decameric peptide substrate containing a phospho-tyrosine residue, labeled with PtCP-maleimide and dabcyl-NHS at its termini was designed. Phosphatase catalysed dephosphorylation of the substrate resulted in a minor increase in PtCP signal, while subsequent cleavage by chymotrypsin at the dephosphorylated Tyr-Leu site provided a 3.5 fold enhancement of PtCP phosphorescence. This phosphorescence phosphatase enhancement assay was optimized to a 96 well plate format with detection on a commercial TR-F plate reader, and applied to measure the activity and inhibition of alkaline phosphatase, recombinant human CD45, and tyrosine phosphatases in Jurkat cell lysates within 40 min. Parameters of these enzymatic reactions such as Km's, limits of detection (L.O.D's) and IC50 values for the non-specific inhibitor sodium orthovanadate were also determined.

Sonographically guided percutaneous muscle biopsy in diagnosis of neuromuscular disease: a useful alternative to open surgical biopsy.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of sonographically guided percutaneous muscle biopsy in the investigation of neuromuscular disorders. METHODS: Sonographically guided percutaneous needle biopsy of skeletal muscle was performed with a 14-gauge core biopsy system in 40 patients over a 24-month period. Patients were referred from the Department of Neurology under investigation for neuromuscular disorders. Sonography was used to find suitable tissue and to avoid major vascular structures. A local anesthetic was applied below skin only. A 3- to 4-mm incision was made. Three 14-gauge samples were obtained from each patient. All samples were placed on saline-dampened gauze and sent for neuropathologic analysis. As a control, we retrospectively assessed results of the 40 most recent muscle samples acquired via open surgical biopsy. RESULTS: With the use of sonography, 32 (80%) of 40 patients had a histologic diagnosis made via percutaneous needle biopsy. This included 26 (93%) of 28 patients with acute muscular disease and 6 (50%) of 12 patients with chronic disease. In the surgical group (all acute disease), 38 (95%) of 40 patients had diagnostic tissue attained. CONCLUSIONS: Sonographically guided percutaneous 14-gauge core skeletal muscle biopsy is a useful procedure, facilitating diagnosis in acute muscular disease. It provides results comparable with those of open surgical biopsy in acute muscular disease. It may also be used in chronic muscular disease but repeated or open biopsy may be needed.

Pre-medication for bronchoscopy: a randomised double blind trial comparing alfentanil with midazolam.

This study was designed to compare the effects of alfentanil and midazolam pre-medication on patient comfort during and after flexible bronchoscopy. A randomised, double-blind study was performed; 40 patients received alfentanil and 29 midazolam. Subjects completed questionnaires about discomfort and adverse effects immediately post-procedure and 24 h later. The bronchoscopist also completed a questionnaire. No difference in patient discomfort was found immediately post-procedure and no differences were found for amount of topical lignocaine used or minimum oxygen saturation. Operators reported no overall difference between the agents for ease of procedure but about 20% less cough was reported in the alfentanil group (P = 0.02). Patient discomfort scores in the 24h questionnaire were significantly lower in patients given midazolam (P = 0.01 for nasal discomfort, P = 0.003 for throat discomfort) but drowsiness was commoner in this group (P = 0.04). There was no significant difference in patients' reports of cough, nausea or vomiting or their willingness to have a repeat procedure. In conclusion, cough during bronchoscopy was slightly less marked with alfentanil than midazolam pre-medication but this made no difference to the ease of procedure or to overall patient discomfort. Patients given midazolam reported less discomfort when asked about the test 24 h later.

Evaluation of the phosphorescent palladium(II)-coproporphyrin labels in separation-free hybridization assays.

Palladium(II)-coproporphyrin label and a set of corresponding monofunctional labeling reagents with different linker arms were evaluated for labeling of oligonucleotides and subsequent use in hybridization assays. The properties of resulting oligonucleotide probes including phosphorescence spectra, quantum yields, lifetimes, and labeling yields were examined as functions of the label and oligonucleotide structures. Upon hybridization with complementary sequences bearing dabcyl, QSY-7, and rhodamine green dyes, the probes displayed strong quenching due to close proximity effects. Intensity and lifetime changes of the phosphorescence, distance, and temperature dependences were investigated in detail. The potential of the new label and probes for sensitive and separation-free hybridization assays was discussed.

Synthesis and evaluation of phosphorescent oligonucleotide probes for hybridisation assays.

Monofunctional, p-isothiocyanatophenyl-derivatives of platinum (II)-coproporphyrin-I (PtCP-NCS) were evaluated as phosphorescent labelling reagents for synthetic oligonucleotides containing a 3'- or 5'-amino modification. Synthesis and purification conditions were optimised to generate high yields and purity of PtCP-labelled oligonucleotide probes. Phosphorescent properties of the PtCP label have been shown to be largely unaffected by conjugation to oligonucleotides of various length, GC composition and label attachment site. 5'-PtCP-labelled oligonucleotides were shown to work efficiently as primers in a standard PCR. A dedicated 532 nm laser-based time-resolved fluorescence plate reader enabled highly sensitive detection of PtCP-labelled oligonucleotides and PCR products, both in solution and in agarose gels, with limits of detection in the order of 0.3 pM. A model system employing two complementary oligonucleotides labelled with PtCP and QSY 7 dye (dark quencher) showed strong (approximately 20-fold) and specific proximity quenching of PtCP label upon hybridisation in solution. The potential applications of PtCP-labelled probes in hybridisation assays were discussed.

The economic benefit for family/general medicine practices employing physician assistants.

OBJECTIVE: To measure the economic benefit of a family/general medicine physician assistant (PA) practice. STUDY DESIGN: Qualitative description of a model PA practice in a family/general medicine practice office setting, and comparison of the financial productivity of a PA practice with that of a non-PA (physician-only) practice. METHODS: The study site was a family/general medicine practice office in southwestern Pennsylvania. The description of PA practice was obtained through direct observation and semistructured interviews during site visits in 1998. Comparison of site practice characteristics with published national statistics was performed to confirm the site's usefulness as a model practice. Data used for PA productivity analyses were obtained from site visits, interviews, office billing records, office appointment logs, and national organizations. RESULTS: The PA in the model practice had a same-task substitution ratio of 0.86 compared with the supervising physician. The PA was economically beneficial for the practice, with a compensation-to-production ratio of 0.36. Compared with a practice employing a full-time physician, the annual financial differential of a practice employing a full-time PA was $52,592. Sensitivity analyses illustrated the economic benefit of a PA practice in a variety of theoretical family/general medicine practice office settings. CONCLUSIONS: Family/general medicine PAs are of significant economic benefit to practices that employ them.