Tumour necrosis factor alpha blockade in treatment resistant pigmented villonodular synovitis

BACKGROUND: Pigmented villonodular synovitis (PVNS) is considered to be a neoplastic-like disorder of the synovium histologically characterised by villonodular hyperplasia, resulting in dense fibrosis and haemosiderin deposition. The pathogenesis of the disease is still unknown. CASE REPORT: A patient presented with severe treatment resistant PVNS of the right knee joint. Several conventional treatment regimens, including open surgical synovectomy and intra-articular injections of yttrium-90 ((90)Y) failed to control the disease. After finding marked tumour necrosis factor alpha (TNF alpha) expression in arthroscopic synovial tissue samples, treatment with an anti-TNF alpha monoclonal antibody (infliximab) at a dose of 5 mg/kg was started. Additional courses with the same dose given 2, 6, 14, and 20 weeks later, and bimonthly thereafter up to 54 weeks, controlled the signs and symptoms. Immunohistological analysis at follow up identified a marked reduction in macrophage numbers and TNF alpha expression in the synovium. DISCUSSION: This is probably the first case which describes treatment with TNF alpha blockade of PVNS in a patient who is refractory to conventional treatment. It provides the rationale for larger controlled studies to elucidate further the efficacy of TNFalpha blockade treatment in refractory PVNS

Psychometric qualities of the patient rated Wrist/Hand evaluation (PRWHE) in dutch primary care patients with wrist complaints

BACKGROUND: Knowledge on the course, disability and functionality of wrist complaints is still compendious in primary care guidelines, despite the high prevalence in primary care. Valid questionnaires can facilitate the monitoring of patients in primary care and research initiatives. In this study, we aimed to study the psychometric qualities of the Dutch version of the Patient Rated Wrist/Hand Evaluation (PRWHE-DLV) among adults with (sub)acute wrist complaints in primary care. METHODS: An observational cohort of 35 adults with (sub)acute wrist complaints in Dutch primary care was established. The content validity of the PRWHE-DLV was validated by assessing the floor and ceiling effects at baseline (T0). Reproducibility was assessed by the test-retest reliability between T0 and T1 (2–5 days after T0), using the Intra-class Correlation Coefficient. The construct validity was assessed based on the correlation between the PRWHE-DLV and the Quick-DASH, Physical Component Score (SF-12), VAS-function, Physical Functioning (SF-12), VAS-pain and Bodily Pain (SF-12) at T0. Responsiveness was defined as the ability of the PRWHE-DLV to measure change 3 weeks after T0 (internal) and the relation of these changes to clinically important outcomes (external). RESULTS: Psychometric qualities of the PRWHE-DLV demonstrated high content validity with no floor or ceiling effects, excellent reliability (Intra-class correlation coefficient = 0.90; 95% CI 0.80–0.95), high construct validity with the validated Quick-DASH and VAS score (r = 0.85 with Quick-DASH, r = 0.75 with VAS-function and r = 0.78 with VAS-pain) and high responsiveness. CONCLUSION: The PRWHE-DLV provided reliable and adequate information for primary care clinical practice

Diagnostic accuracy of history taking, physical examination and imaging for phalangeal, metacarpal and carpal fractures: a systematic review update

BACKGROUND: The standard diagnostic work-up for hand and wrist fractures consists of history taking, physical examination and imaging if needed, but the supporting evidence for this work-up is limited. The purpose of this study was to systematically examine the diagnostic accuracy of tests for hand and wrist fractures. METHODS: A systematic search for relevant studies was performed. Methodological quality was assessed and sensitivity (Se), specificity (Sp), accuracy, positive predictive value (PPV) and negative predictive value (NPV) were extracted from the eligible studies. RESULTS: Of the 35 eligible studies, two described the diagnostic accuracy of history taking for hand and wrist fractures. Physical examination with or without radiological examination for diagnosing scaphoid fractures (five studies) showed Se, Sp, accuracy, PPV and NPV ranging from 15 to 100%, 13-98%, 55-73%, 14-73% and 75-100%, respectively. Physical examination with radiological examination for diagnosing other carpal bone fractures (one study) showed a Se of 100%, with the exception of the triquetrum (75%). Physical examination for diagnosing phalangeal and metacarpal fractures (one study) showed Se, Sp, accuracy, PPV and NPV ranging from 26 to 55%, 13-89%, 45-76%, 41-77% and 63-75%, respectively. Imaging modalities of scaphoid fractures showed predominantly low values for PPV and the highest values for Sp and NPV (24 studies). Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Ultrasonography (US) and Bone Scintigraphy (BS) were comparable in diagnostic accuracy for diagnosing a scaphoid fracture, with an accuracy ranging from 85 to 100%, 79-100%, 49-100% and 86-97%, respectively. Imaging for metacarpal and finger fractures showed Se, Sp, accuracy, PPV and NPV ranging from 73 to 100%, 78-100%, 70-100%, 79-100% and 70-100%, respectively. CONCLUSIONS: Only two studies were found on the diagnostic accuracy of history taking for hand and wrist fractures in the current review. Physical examination was of moderate use for diagnosing a scaphoid fracture and of limited use for diagnosing phalangeal, metacarpal and remaining carpal fractures. MRI, CT and BS were found to be moderately accurate for the definitive diagnosis of clinically suspected carpal fractures

Expression of IL-20 in synovium and lesional skin of patients with psoriatic arthritis: differential response to alefacept treatment

Introduction: Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown.Methods: Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively.Results: IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68+ macrophages and CD55+ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept.Conclusions: Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression

The role of concomitant ligament injury in the development of post-traumatic osteoarthritis after distal radius fractures: a protocol for a systematic review

Introduction Treatment of distal radius fractures (DRFs) aims to restore anatomic position of the fracture fragments and congruity of the articular surface to optimise functional outcomes and prevent osteoarthritis in the long term. While ligament injury of the wrist is often associated with DRFs and sole ligament injuries of the wrist lead to osteoarthritis, it is plausible that concomitant ligament injury in DRFs may aggravate degenerative changes of the wrist. The relationship between concomitant ligament injury and post-traumatic osteoarthritis in patients with DRFs is unclear. This study aims to identify the types of associated ligament injury in patients with a DRF and to elucidate the association of ligament injury on the development of post-traumatic osteoarthritis. Methods and analysis This protocol is written in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P) guidelines. An electronic search in MEDLINE, Embase, Web of Science, Cochrane Central Register of Trials and Google Scholar has been created and performed by a Health Sciences librarian with expertise in systematic review searching. Original research articles in English literature, which report on concomitant ligament injury of the wrist in relation to post-traumatic osteoarthritis, patient-reported outcome measures or clinician-reported outcome measures in patients (aged ≥18 years) with DRFs will be included. Two reviewers will independently screen and appraise articles and perform data extraction. In case of any disagreements, a third reviewer will be consulted. A systematic qualitative synthesis will be performed using text and tables. Ethics and dissemination No ethical approval is required, since this is a protocol for a systematic review. The systematic review will be submitted for publication in a peer-reviewed scientific journal and for presentation at relevant conferences

Systematic assessment of the growth plates of the wrist in young gymnasts: Development and validation of the Amsterdam MRI assessment of the Physis (AMPHYS) protocol

Objectives To develop and validate a protocol for MRI assessment of the distal radial and ulnar periphyseal area in gymnasts and non-gymnasts. Methods Twenty-four gymnasts with wrist pain, 18 asymptomatic gymnasts and 24 non-gymnastic controls (33 girls) underwent MRI of the wrist on a 3T scanner. Sequences included coronal proton density-weighted images with and without fat saturation, and three-dimensional water-selective cartilage scan and T2 Dixon series. Skeletal age was determined using hand radiographs. Three experienced musculoskeletal radiologists established a checklist of possible (peri)physeal abnormalities based on literature an

Clinically SUspected ScaPhoid fracturE: treatment with supportive bandage or CasT? 'Study protocol of a multicenter randomized controlled trial' (SUSPECT study)

Introduction Some scaphoid fractures become visible on radiographs weeks after a trauma which makes normal radiographs directly after trauma unreliable. Untreated scaphoid fractures can lead to scaphoid non-union progressing to osteoarthritis. Therefore, the general treatment for patients with a clinically suspected scaphoid fracture and normal initial radiographs is immobilisation with below-elbow cast for 2 weeks. However, most of these patients are treated unnecessarily because eventually less than 10% of them are diagnosed with an occult scaphoid fracture. To reduce overtreatment and costs as a result of unnecessary cast treatment in patients with a clinically suspected scaphoid fracture and normal initial radiographs, we designed a study to compare below-elbow cast treatment with supportive bandage treatment. We hypothesise that the functional outcome after 3 months is not inferior in patients treated with supportive bandage compared to patients treated with below-elbow cast, but with lower costs in the supportive bandage group. Methods and analysis The SUSPECT study is an open-labelled multicentre randomised controlled trial with non-inferiority design. A total of 180 adult patients with a clinically suspected scaphoid fracture and normal initial radiographs are randomised between two groups: 3 days of supportive bandage or 2 weeks of below-elbow cast. We aim to evaluate the functional outcome and cost-effectiveness of both treatments. The primary outcome is the functional outcome after 3 months, assessed with the Quick Disability of the Arm, Shoulder and Hand score. Secondary outcomes include functional outcome, recovery of function, pain, patient satisfaction, quality of life and cost-effectiveness measured by medical consumption, absence from work or decreased productivity. Ethics and dissemination The Medical Ethics Committee of the Erasmus MC Medical Centre, Rotterdam, approved the study protocol (MEC-2017-504). We plan to present the results after completion of the study at (inter)national conferences and publish in general peer-reviewed journals

PYTHIA 6.4 Physics and Manual

The PYTHIA program can be used to generate high-energy-physics `events', i.e. sets of outgoing particles produced in the interactions between two incoming particles. The objective is to provide as accurate as possible a representation of event properties in a wide range of reactions, within and beyond the Standard Model, with emphasis on those where strong interactions play a role, directly or indirectly, and therefore multihadronic final states are produced. The physics is then not understood well enough to give an exact description; instead the program has to be based on a combination of analytical results and various QCD-based models. This physics input is summarized here, for areas such as hard subprocesses, initial- and final-state parton showers, underlying events and beam remnants, fragmentation and decays, and much more. Furthermore, extensive information is provided on all program elements: subroutines and functions, switches and parameters, and particle and process data. This should allow the user to tailor the generation task to the topics of interest.Comment: 576 pages, no figures, uses JHEP3.cls. The code and further information may be found on the PYTHIA web page: http://www.thep.lu.se/~torbjorn/Pythia.html Changes in version 2: Mistakenly deleted section heading for "Physics Processes" reinserted, affecting section numbering. Minor updates to take into account referee comments and new colour reconnection option

HER-2 status of circulating tumor cells in a metastatic breast cancer cohort: A comparative study on characterization techniques

Background Personalized targeted treatment in metastatic breast cancer relies on accurate assessment of molecular aberrations, e.g. overexpression of Human Epidermal growth factor Receptor 2 (HER-2). Molecular interrogation of circulating tumor cells (CTCs) can provide an attractive alternative for real-time biomarker assessment. However, implementation of CellSearch-based HER-2 analysis has been limited. Immunofluorescent (IF) image interpretation is crucial, as different HER-2 categories have been described. Major questions in CTC research are how these IF categories reflect gene expression and amplification, and if we should consider ‘medium’ HER-2 expressing CTCs for patient selection. Methods Tumor cells from spiked cell lines (n = 8) and CTCs (n = 116 samples) of 85 metastatic breast cancer patients were enriched using CellSearch. Comparative analysis of HER-2 expression by IF imaging (ACCEPT, DEPArray, and visual scoring) with qRT-PCR and HER-2/neu FISH was performed. Results Automated IF HER-2-profiling by DEPArray and ACCEPT delivered comparable results. There was a 98% agreement between 17 trained observers (visual scoring) and ACCEPT considering HER-2neg and HER-2high expressing CTCs. However, 89% of HER-2med expressing CTCs by ACCEPT were scored negative by observers. HER-2high expressing tumor cells demonstrated HER-2/neu gene amplification, whereas HER-2neg and HER-2med expressing tumor cells and CTCs by ACCEPT were copy-number neutral. All patients with HER-2-positive archival tumors had �1 HER-2high expressing CTCs, while 80% of HER-2- negative patients did not. High relative gene expression of HER-2 measured on enriched CTC lysates correlated with having �1 HER-2high expressing CTCs. Conclusion Automated images analysis has enormous potential for clinical implementation. HER-2 characterization and clinical trial design should be focused on HER-2high expressing CTCs