Multiparametric Large Field of View Rheumatology Imaging for Axial Spondyloarthropathy Detects Enthesitis in Setting of Inactive Sacroiliac Joint Disease and Impacts Clinical Diagnosis.

AIM: To test the diagnostic efficacy of a multiparametric rheumatology lumbosacral magnetic resonance (MR) imaging protocol in detection and characterization of axial spondylarthritis (SpA) and compare it with serology and clinical findings. METHODS: A consecutive series of multiparametric rheumatology lumbosacral MR imaging examinations performed on 3T MR scanner. Three-dimensional inversion recovery turbo spin echo, precontrast and postcontrast fat-suppressed T1-weighted images, as well as diffusion-weighted images were used to detect active erosions and enthesitis using established criteria. Pearson χ2 was used for categorical variables. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were measured for magnetic resonance imaging (MRI) and serology, based on the final diagnosis from rheumatologists. An alpha error below 0.05 was considered statistically significant. RESULTS: The final study sample included 130 consecutive patients (80 women and 50 men; mean ± SD 44 ± 13 and 45 ± 14 years, respectively). Seventy-eight subjects were diagnosed with axial SpA and 52 with non-SpA arthropathy. In the non-SpA group, 27 patients were diagnosed with osteoarthritis, 6 had unremarkable imaging, whereas 19 were considered as clinically undetermined. There was positive correlation between positive MRI results and SpA diagnosis (P < 0.00001). No correlation existed between positive serology alone and SpA diagnosis (P = 0.0634). Although MRI and serology proved equally sensitive in detecting SpA, the specificity and overall accuracy of MRI were significantly higher. Inflammatory activity was detected in 45 (57.7%) cases, in the pelvic enthesis in 29 (37.2%) cases, in the lumbosacral spine in 16 (20.5%) cases, in the hip joints in 15 (19.2%) cases, and in the pubic symphysis in 5 (6.4%). Inactive sacral disease was seen in 7 of 35 enthesitis patients (20.0%), and in 2 SpA cases, there were no sacral lesions. CONCLUSIONS: The results suggest that in patients with suspected SpA, MRI should not be limited to the sacroiliac joints, but also include enthesitis sites and other joints of the axial skeleton. The multiparametric rheumatology protocol increases the efficacy of MRI in detecting enthesitis and joint inflammatory disease, thereby offering additional information to the clinician and assisting in the early diagnosis/detecting disease activity.

Consolidated BRCA1/2 Variant Interpretation by MH BRCA Correlates with Predicted PARP Inhibitor Efficacy Association by MH Guide.

BRCA1/2 variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of BRCA1/2 variants from patients with HBOC-related cancer using MH BRCA, a novel computational technology that combines the ACMG guidelines with expert-curated variant annotations. Evaluation of BRCA1/2 variants (n = 1040) taken from four HBOC studies showed strong concordance within the pathogenic (98.1%) subset. Comparison of MH BRCA's ACMG classification to ClinVar submitter content from ENIGMA, the international consortium of investigators on the clinical significance of BRCA1/2 variants, the ARUP laboratories, a clinical testing lab of the University of UTAH, and the German Cancer Consortium showed 99.98% concordance (4975 out of 4976 variants) in the pathogenic subset. In our patient cohort, refinement of patients with variants of unknown significance reduced the uncertainty of cancer-predisposing syndromes by 64.7% and identified three cases with potential family risk to HBOC due to a likely pathogenic variant BRCA1 p.V1653L (NM_007294.3:c.4957G > T; rs80357261). To assess whether classification results predict PARP inhibitor efficacy, contextualization with functional impact information on DNA repair activity were performed, using MH Guide. We found a strong correlation between treatment efficacy association and MH BRCA classifications. Importantly, low efficacy to PARP inhibition was predicted in 3.95% of pathogenic variants from four examined HBOC studies and our patient cohort, indicating the clinical relevance of the consolidated variant interpretation.

Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data.

Background and Objective: Radium-223 dichloride (Xofigo®) is a calcium mimetic agent approved for the treatment of castration-resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease. This targeted, α-particle-emitting therapy has demonstrated significant survival benefit accompanied by a favorable safety profile. Nevertheless, recent evidence suggests that its combined use with abiraterone and prednisone/prednisolone may be associated with increased risk of death and fractures. While the precise pathophysiologic mechanisms of these events are not yet clear, collecting evidence from more clinical trials and translational studies is necessary. The aim of our present study is to assess whether accessible sources of patient outcome data can help gain additional clinical insights to radium-223 dichloride's safety profile. Materials and Methods: We performed a retrospective analysis of cases extracted from the FDA Adverse Event Reporting System and characterized side effect occurrence by using reporting ratios. Results: A total of ~1500 prostate cancer patients treated with radium-223 dichloride was identified, and side effects reported with the use of radium-223 dichloride alone or in combination with other therapeutic agents were extracted. Our analysis demonstrates that radium-223 dichloride may often come with hematological-related reactions, and that, when administered together with other drugs, its safety profile may differ. Conclusions: While more prospective studies are needed to fully characterize the toxicological profile of radium-223 dichloride, the present work constitutes perhaps the first effort to examine its safety when administered alone and in combination with other agents based on computational evidence from public real-world post marketing data.

Multiparametric Assessment of Treatment Response in High-Grade Soft-Tissue Sarcomas with Anatomic and Functional MR Imaging Sequences.

PURPOSE: To determine the added value of quantitative diffusion-weighted and dynamic contrast material-enhanced imaging to conventional magnetic resonance (MR) imaging for assessment of the response of soft-tissue sarcomas to neoadjuvant therapy. MATERIALS AND METHODS: MR imaging examinations in 23 patients with soft-tissue sarcomas who had undergone neoadjuvant therapy were reviewed by two readers during three sessions: conventional imaging (T1-weighted, fluid-sensitive, static postcontrast T1-weighted), conventional with diffusion-weighted imaging, and conventional with diffusion-weighted and dynamic contrast-enhanced imaging. For each session, readers recorded imaging features and determined treatment response. Interobserver agreement was assessed and receiver operating characteristic analysis was performed to evaluate the accuracy of each session for determining response by using results of the histologic analysis as the reference standard. Good response was defined as less than or equal to 5% residual viable tumor. RESULTS: Of the 23 sarcomas, four (17.4%) showed good histologic response (three of four with >95% granulation tissue and <5% necrosis, one of four with 95% necrosis and <5% viable tumor) and 19 (82.6%) showed poor response (viable tumor range, 10%-100%). Interobserver agreement was substantial or excellent for imaging features in all sequences (k = 0.789-1.000). Receiver operating characteristic analysis showed an increase in diagnostic performance with the addition of diffusion-weighted and dynamic contrast-enhanced MR imaging for prediction of response compared with that for conventional imaging alone (areas under the curve, 0.500, 0.676, 0.821 [reader 1] and 0.506, 0.704, 0.833 [reader 2], respectively). CONCLUSION: Adding functional sequences to the conventional MR imaging protocol increases the sensitivity of MR imaging for determining treatment response in soft-tissue sarcomas.

How to learn about gene function: text-mining or ontologies?

As the amount of genome information increases rapidly, there is a correspondingly greater need for methods that provide accurate and automated annotation of gene function. For example, many high-throughput technologies--e.g., next-generation sequencing--are being used today to generate lists of genes associated with specific conditions. However, their functional interpretation remains a challenge and many tools exist trying to characterize the function of gene-lists. Such systems rely typically in enrichment analysis and aim to give a quick insight into the underlying biology by presenting it in a form of a summary-report. While the load of annotation may be alleviated by such computational approaches, the main challenge in modern annotation remains to develop a systems form of analysis in which a pipeline can effectively analyze gene-lists quickly and identify aggregated annotations through computerized resources. In this article we survey some of the many such tools and methods that have been developed to automatically interpret the biological functions underlying gene-lists. We overview current functional annotation aspects from the perspective of their epistemology (i.e., the underlying theories used to organize information about gene function into a body of verified and documented knowledge) and find that most of the currently used functional annotation methods fall broadly into one of two categories: they are based either on 'known' formally-structured ontology annotations created by 'experts' (e.g., the GO terms used to describe the function of Entrez Gene entries), or--perhaps more adventurously--on annotations inferred from literature (e.g., many text-mining methods use computer-aided reasoning to acquire knowledge represented in natural languages). Overall however, deriving detailed and accurate insight from such gene lists remains a challenging task, and improved methods are called for. In particular, future methods need to (1) provide more holistic insight into the underlying molecular systems; (2) provide better follow-up experimental testing and treatment options, and (3) better manage gene lists derived from organisms that are not well-studied. We discuss some promising approaches that may help achieve these advances, especially the use of extended dictionaries of biomedical concepts and molecular mechanisms, as well as greater use of annotation benchmarks.

Cross-sectional imaging of adult crystal and inflammatory arthropathies.

This article highlights the key aspects and current perspectives of the role of cross-sectional imaging in adult crystal and inflammatory arthropathies in adults, briefly discussing CT, and particularly focusing on MRI and US imaging as it supplements the conventional radiography. The role of conventional and advanced MR imaging techniques and imaging findings in this domain is discussed and illustrated with case examples. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article contains images and data, which were collected from patients as a part of a retrospective IRB from the institutional teaching files and informed consent was waived.

Biggest challenges in bioinformatics.

The third Heidelberg Unseminars in Bioinformatics (HUB) was held on 18th October 2012, at Heidelberg University, Germany. HUB brought together around 40 bioinformaticians from academia and industry to discuss the 'Biggest Challenges in Bioinformatics' in a 'World Café' style event.

Advanced MR imaging of peripheral nerve sheath tumors including diffusion imaging.

Peripheral nerve sheath tumors (PNSTs) are neoplasms derived from neoplastic Schwann cells or their precursors. Whereas benign PNSTs are relatively common and considered curable lesions, their malignant counterparts are rare but highly aggressive and require early diagnosis and treatment. MR imaging has been the modality of choice for noninvasive evaluation of PNSTs. This article discusses the features of PNSTs in conventional and advanced MR imaging, and it emphasizes the features that help differentiate benign and malignant variants.

High-resolution 3-T MR neurography of the lumbosacral plexus.

The lumbosacral plexus comprises a network of nerves that provide motor and sensory innervation to most structures of the pelvis and lower extremities. It is susceptible to various traumatic, inflammatory, metabolic, and neoplastic processes that may lead to lumbrosacral plexopathy, a serious and often disabling condition whose course and prognosis largely depend on the identification and cure of the causative condition. Whereas diagnosis of lumbrosacral plexopathy has traditionally relied on patients' medical history, clinical examination, and electrodiagnostic tests, magnetic resonance (MR) neurography plays an increasingly prominent role in noninvasive characterization of the type, location, and extent of lumbrosacral plexus involvement and is developing into a useful diagnostic tool that substantially affects disease management. With use of 3-T MR imagers, improved coils, and advanced imaging sequences, which provide exquisite spatial resolution and soft-tissue contrast, MR neurography provides excellent depiction of the lumbrosacral plexus and its peripheral branches and may be used to confirm a diagnosis of lumbrosacral plexopathy with high accuracy or provide superior anatomic information should surgical intervention be necessary.

Technical innovation in dynamic contrast-enhanced magnetic resonance imaging of musculoskeletal tumors: an MR angiographic sequence using a sparse k-space sampling strategy.

OBJECTIVE: We demonstrate the clinical use of an MR angiography sequence performed with sparse k-space sampling (MRA), as a method for dynamic contrast-enhanced (DCE)-MRI, and apply it to the assessment of sarcomas for treatment response. MATERIALS AND METHODS: Three subjects with sarcomas (2 with osteosarcoma, 1 with high-grade soft tissue sarcomas) underwent MRI after neoadjuvant therapy/prior to surgery, with conventional MRI (T1-weighted, fluid-sensitive, static post-contrast T1-weighted sequences) and DCE-MRI (MRA, time resolution = 7-10 s, TR/TE 2.4/0.9 ms, FOV 40 cm(2)). Images were reviewed by two observers in consensus who recorded image quality (1 = diagnostic, no significant artifacts, 2 = diagnostic, <25 % artifacts, 3 = nondiagnostic) and contrast enhancement characteristics by static MRI (presence/absence of contrast enhancement, percentage of enhancement) and DCE-MRI (presence/absence of arterial enhancement with time-intensity curves). Results were compared with histological response (defined as <5 % viable tumor [soft tissue sarcoma] or <10 % [bone sarcoma] following resection). RESULTS: Diagnostic quality for all conventional and DCE-MRI sequences was rated as 1. In 2 of the 3 sarcomas, there was good histological response (≤5 % viable tumor); in 1 there was poor response (50 % viable tumor). By static post-contrast T1-weighted sequences, there was enhancement in all sarcomas, regardless of response (up to >75 % with good response, >75 % with poor response). DCE-MRI findings were concordant with histological response (arterial enhancement with poor response, no arterial enhancement with good response). CONCLUSION: Unlike conventional DCE-MRI sequences, an MRA sequence with sparse k-space sampling is easily integrated into a routine musculoskeletal tumor MRI protocol, with high diagnostic quality. In this preliminary work, tumor enhancement characteristics by DCE-MRI were used to assess treatment response.

Meralgia paresthetica: 3-Tesla magnetic resonance neurography.

OBJECTIVE: To assess the diagnostic accuracy and observer performance of 3-Tesla magnetic resonance neurography (MRN) in the evaluation of meralgia paresthetica (MP). MATERIALS AND METHODS: Two independent readers were blinded to the clinical diagnosis and evaluated the MRN studies of the pelvis of 11 patients with MP and 28 control participants. In each study, the lateral femoral cutaneous nerves were assessed for signal alteration and/or neuroma formation, indicating lateral femoral cutaneous neuropathy, at various levels along their course. Intra- and inter-observer reliability was evaluated. RESULTS: Both readers exhibited substantial intraobserver agreement in detecting signal alterations and neuroma formation of the lateral femoral cutaneous nerve (LFCN). The readers demonstrated moderate interobserver agreement in detecting signal alteration of the LFCN and poor interobserver agreement in diagnosing neuroma formation. Sensitivity, specificity, positive predictive value, and negative predictive value of LFCN neuropathy diagnosis were ≥ 71 % and ≥ 94 % for both readers respectively. The diagnostic test accuracy was ≥ 90 % for both readers. CONCLUSION: 3-Tesla MRN provides reliable and accurate diagnostic evaluation of meralgia paresthetica.

Spectrum of Hand Arthritis: Doppler Ultrasound, Diffusion-Weighted MR Imaging, and Perfusion MR Imaging Evaluation.

Early diagnosis of arthritis is of paramount importance to slow the progression of disease and joint destruction. Because of temporal dissemination of the clinical and laboratory manifestations of the inflammatory arthritis and overlap of the findings, diagnosis can be challenging in early stages of the disease. This article highlights the utility of advanced cross-sectional imaging, including color-Doppler ultrasound, diffusion-weighted MR imaging, and perfusion MR imaging in the domain of arthropathy so that the reader can apply these principles and techniques in their practices for timely and accurate diagnosis and improved multidisciplinary communications for better management of such conditions.

Soft-tissue lesions: when can we exclude sarcoma?

OBJECTIVE: A wide spectrum of space-occupying soft-tissue lesions may be discovered on MRI studies, either as incidental findings or as palpable or symptomatic masses. Characterization of a lesion as benign or indeterminate is the most important step toward optimal treatment and avoidance of unnecessary biopsy or surgical intervention. CONCLUSION: The systemic MRI interpretation approach presented in this article enables the identification of cases in which sarcoma can be excluded.

3-T high-resolution MR neurography of sciatic neuropathy.

OBJECTIVE: The sciatic nerve may normally exhibit mild T2 hyperintensity in MR neurography (MRN) images, rendering assessment of sciatic neuropathy difficult. The purpose of this case-control study was to evaluate whether a quantitative and qualitative analysis of the sciatic nerves and regional skeletal muscles increases the accuracy of MRN in detecting sciatic neuropathy. MATERIALS AND METHODS: We retrospectively reviewed the MRN studies of the pelvis and thighs of 34 subjects (12 men and 22 women; mean [± SD] age, 50 ± 15 years), of which 17 had a final diagnosis of sciatic neuropathy according to electrodiagnostic or surgical confirmation, and 17 had no evidence of sciatic neuropathy and served as control subjects. On each side, the sciatic nerves were evaluated for signal intensity (SI), size, course, and fascicular shape, whereas the regional skeletal muscles were evaluated for edema, fatty replacement, and atrophy. In addition, the nerve-to-vessel SI ratio was registered for each side at the same time and 8 months later. RESULTS: The sciatic nerves of the abnormal sides exhibited higher nerve-to-vessel SI ratios and higher incidences of T2 hyperintensity, enlargement, and abnormal fascicular shape compared to the nerves of the normal sides. The regional muscles of the abnormal sides demonstrated a higher grade of fatty infiltration and higher frequencies of edema and atrophy. A cutoff value of nerve-to-vessel SI ratio of 0.89 exhibited high sensitivity and specificity in predicting sciatic neuropathy. Calculation of the nerve-to-vessel SI ratio demonstrated excellent inter- and intraobserver reliability. CONCLUSION: Both qualitative and quantitative criteria should be used to suggest the MRN diagnosis of sciatic neuropathy.

Current perspectives on the advantages of 3-T MR imaging of the wrist.

The use of 3-T magnetic resonance (MR) imaging systems with improved coil designs and high-resolution MR imaging sequences allows visualization of the musculoskeletal anatomy in exquisite detail and accurate characterization of abnormalities both in soft tissues and in bone. Current high-field-strength MR systems offer particular advantages for diagnostic imaging of the small joints of the extremities, especially the wrists, where multiple overlapping soft-tissue structures may be visually inseparable at lower field strengths because of limited contrast resolution. Diagnostic accuracy obtained with 3-T MR imaging of the wrist performed with an acquisition protocol that includes three-dimensional and proton density-weighted imaging sequences is nearly commensurate with that obtained with MR arthrography. Abnormalities of the ligaments, tendons, cartilage, nerves, blood vessels, and bone are clearly depicted, allowing accurate characterization of perforations, tears, and fractures, as well as various soft-tissue and intraosseous lesions (eg, ganglion cysts), vascular malformations, aneurysms, and neuropathies.

Neurological complications of foot and ankle surgery.

Postoperative neurological complications following foot and ankle surgery are common. This article reviews the structural architecture of peripheral nerves and innervation patterns around the foot and ankle; describes the pathophysiology of surgery-related nerve injury; and illustrates the postoperative neurological complications using specific case examples.

Martini: using literature keywords to compare gene sets.

Life scientists are often interested to compare two gene sets to gain insight into differences between two distinct, but related, phenotypes or conditions. Several tools have been developed for comparing gene sets, most of which find Gene Ontology (GO) terms that are significantly over-represented in one gene set. However, such tools often return GO terms that are too generic or too few to be informative. Here, we present Martini, an easy-to-use tool for comparing gene sets. Martini is based, not on GO, but on keywords extracted from Medline abstracts; Martini also supports a much wider range of species than comparable tools. To evaluate Martini we created a benchmark based on the human cell cycle, and we tested several comparable tools (CoPub, FatiGO, Marmite and ProfCom). Martini had the best benchmark performance, delivering a more detailed and accurate description of function. Martini also gave best or equal performance with three other datasets (related to Arabidopsis, melanoma and ovarian cancer), suggesting that Martini represents an advance in the automated comparison of gene sets. In agreement with previous studies, our results further suggest that literature-derived keywords are a richer source of gene-function information than GO annotations. Martini is freely available at http://martini.embl.de.

High resolution magnetic resonance imaging of the patellar retinaculum: normal anatomy, common injury patterns, and pathologies.

The medial patellar retinaculum (MPR) and the lateral patellar retinaculum (LPR) are vital structures for the stability of the patella. Failure to identify or treat injury to the patellar retinaculum is associated with recurrent patellar instability and contributes to significant morbidity. High-resolution magnetic resonance imaging (MRI) readily depicts the detailed anatomy of various components (layers) of the retinacula. In this review article, we discuss normal anatomy, important landmarks, common injury patterns, and other pathologies encountered in patellar retinacula. High field strength MRI is an excellent noninvasive tool for evaluation of patellar retinaculum anatomy and pathology. This article will help the reader become familiar with normal imaging findings and the most commonly occurring injuries/pathologies in MPR and LPR.

High-resolution 3-T MR neurography of peroneal neuropathy.

The common peroneal nerve (CPN), a major terminal branch of the sciatic nerve, can be subject to a variety of pathologies, which may affect the nerve at any level from the lumbar plexus to its distal branches. Although the diagnosis of peripheral neuropathy is traditionally based on a patient's clinical findings and electrodiagnostic tests, magnetic resonance neurography (MRN) is gaining an increasing role in the definition of the type, site, and extent of peripheral nerve disorders. Current high-field MR scanners enable high-resolution and excellent soft-tissue contrast imaging of peripheral nerves. In the lower extremities, MR neurography has been employed in the demonstration of the anatomy and pathology of the CPN, as well as in the detection of associated secondary muscle denervation changes. This article reviews the normal appearance of the CPN as well as typical pathologies and abnormal findings at 3.0-T MR neurography of the lower extremity.

Advanced MR neurography imaging of radial nerve entrapment at the spiral groove: a case report.

High-resolution magnetic resonance neurography (MRN) is being increasingly employed for the evaluation of peripheral nerves. We describe a case of spiral groove syndrome (Saturday night palsy) and illustrate the role of advanced 3 Tesla MRN imaging techniques, including three-dimensional diffusion-weighted fat-suppressed reversed fast imaging with steady-state precession and diffusion tensor imaging.