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Background: The identification of implant wear particles and non-implant related particles and the characterization of the inflammatory responses in the periprosthetic neo-synovial membrane, bone, and the synovial-like interface membrane (SLIM) play an important role for the evaluation of clinical outcome, correlation with radiological and implant retrieval studies, and understanding of the biological pathways contributing to implant failures in joint arthroplasty. The purpose of this study is to present a comprehensive histological particle algorithm (HPA) as a practical guide to particle identification at routine light microscopy examination., Methods: The cases used for particle analysis were selected retrospectively from the archives of two institutions and were representative of the implant wear and non-implant related particle spectrum. All particle categories were described according to their size, shape, colour and properties observed at light microscopy, under polarized light, and after histochemical stains when necessary. A unified range of particle size, defined as a measure of length only, is proposed for the wear particles with five classes for polyethylene (PE) particles and four classes for conventional and corrosion metallic particles and ceramic particles., Results: All implant wear and non-implant related particles were described and illustrated in detail by category. A particle scoring system for the periprosthetic tissue/SLIM is proposed as follows: 1) Wear particle identification at light microscopy with a two-step analysis at low (× 25, × 40, and × 100) and high magnification (× 200 and × 400); 2) Identification of the predominant wear particle type with size determination; 3) The presence of non-implant related endogenous and/or foreign particles. A guide for a comprehensive pathology report is also provided with sections for macroscopic and microscopic description, and diagnosis., Conclusions: The HPA should be considered a standard for the histological analysis of periprosthetic neo-synovial membrane, bone, and SLIM. It provides a basic, standardized tool for the identification of implant wear and non-implant related particles at routine light microscopy examination and aims at reducing intra-observer and inter-observer variability to provide a common platform for multicentric implant retrieval/radiological/histological studies and valuable data for the risk assessment of implant performance for regional and national implant registries and government agencies., Competing Interests: Approval for the use of the periprosthetic tissue was obtained by the Institutional Review Board, Hospital for Special Surgery (Protocol Number 26085) and the Ethics Commission of the Medical Board of Rheinland-Pfalz; Mainz, Germany [Case Number 837.230.15 (9998)].Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background and purpose - The most frequent cause of arthroplasty failure is aseptic loosening-often induced by particles. Abrasion material triggers inflammatory reactions with lymphocytic infiltration and the formation of synovial-like interface membranes (SLIM) in the bone-implant interface. We analyzed CD3 quantities in SLIM depending on articulating materials and possible influences of proven material allergies on CD3 quantities. Patients and methods - 222 SLIM probes were obtained from revision surgeries of loosened hip and knee arthroplasties. SLIM cases were categorized according to the SLIM-consensus classification and to the particle algorithm. The CD3 quantities were analyzed immunohistochemically, quantified, and correlated to the particle types. Results - Metal-metal pairings showed the highest CD3 quantities (mean 1,367 counted cells). CD3 quantities of metal-polyethylene (mean 243), ceramic-polyethylene (mean 182), and ceramic-ceramic pairings (mean 124) were significantly smaller. Patients with contact allergy to implant materials had high but not statistically significantly higher CD3 quantities than patients without allergies. For objective assessment of the CD3 response as result of a pronounced inflammatory reaction with high lymphocytosis (adverse reaction), a defined CD3 quantity per high power field was established, the "CD3 focus score" (447 cells/0.3 mm 2 , sensitivity 0.92; specificity 0.90; positive predictive value 0.71; negative predictive value 0.98). Interpretation - The high CD3 quantities for metal-metal pairings may be interpreted as substrate for previously described adverse reactions that cause severe peri-implant tissue destruction and SLIM formation. It remains unclear whether the low CD3 quantities with only slight differences in the various non-metal-metal pairings and documented contact allergies to implant materials have a direct pathogenetic relevance.

In the histopathological particle algorithm polyethylene (PE) particles with maximum lengths of more than 100μm - called PE supramacroparticles - are identified exclusively for knee joint and hip prostheses. However, a definitive characterisation, detection in all joint localisations and a causal clarification of the pathogenesis are lacking. In this study a total of 175 SLIM (synovial-like interface membrane) cases with PE supramacroparticles of knee joint prostheses (n=89), hip joint prostheses (n=44), ankle joint prostheses (n=36) and prostheses in three localisations of the upper extremities (n=6) were systematically investigated. The arithmetic mean of the particle length varied greatly within the prosthesis types. This had a significant positive correlation with the prosthesis lifetime and negative correlation with the date of implantation. It can be concluded that both the lifetime and the time of implantation have an influence on the particle length. The prostheses with supramacroparticulate damage moreover showed a clearly reduced survival rate compared with other data published on the prosthesis lifetime. The material wear therefore could not be attributed solely to the usual fatigue factors. Since loosening of the prostheses, decentring of the PE components or damage to the PE inlay existed in all cases, mechanical dysloading seems to be the most probable cause of PE supramacroparticle genesis. Due to the striking length and for demarcation from PE macroparticles, the term supramacroparticulate PE is proposed for a length of more than 100μm. In the extended histopathological particle algorithm supramacroparticulate PE has been included in the macroparticles category and should be taken into account and interpreted causally in histopathological diagnostics of joint prosthesis failure., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

The histopathological synovitis score evaluates in a graded approach, as is largely usual for diagnostic histopathological scores, the immunological and inflammatory changes caused by synovitis. A synovitis score of between 1 and ≤ 4 is classified as low-grade (osteoarthritis-related synovitis, post-traumatic synovitis, meniscopathy-related synovitis and synovitis in hemochromatosis). Synovitis scores of between ≥ 5 and 9 are classified as high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme's arthritis, post-infection/reactive arthritis and peripheral arthritis in Bechterew disease); sensitivity is 61.7% and sensitivity 96.1%. According to receiver operating characteristic (ROC) analysis (AUC: 0.8-0.9), diagnostic value is good. National and international acceptance of the synovitis score has grown since the first publication in 2002 and a related follow-up publication in 2006. PubMed data analysis (as of 11.01.2017) yielded the following citation values according to "cited by PubMed Central articles" for two publications relating to the synovitis score: there were 29 cited-by-PubMed articles for DOI: 10.1078/0344-0338-5710261 , and 44 cited-in-PubMed articles for the second publication, DOI: 10.1111/j.1365-2559.2006.02508 . This makes a total of 73 PubMed citations over a period of 15 years, thereby evidencing the score's international acceptance. Immunohistochemical determination of a number of CD antigens relevant to inflammation has been proposed to further specify the synovitis score for the purposes of risk stratification of high-grade synovitis (e.g., risk of progression and sensitivity to biological agents).

The histopathological synovitis score evaluates the immunological and inflammatory changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores. The score results from semiquantitative evaluation of the width of the synovial surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration into 4 semiquantitative levels (normal 0, mild 1, moderate 2, severe 3). The addition of these values results in a final score of 0-9 out of 9. On the basis of this summation the condition is divided into low-grade synovitis and high-grade synovitis: A synovitis score of 1 to≤4 is called low-grade synovitis (arthrosis-associated/OA synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with haemochromatosis). A synovitis score of≥5 to 9 is called high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection/reactive arthritis and peripheral arthritis with Bechterew's disease). By means of the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1%. The diagnostic accuracy according to ROC analysis (AUC: 0.8-0.9) is good. Since the first publication (2002) and an associated subsequent publication (2006), the synovitis score has nationally and internationally been accepted for histopathological assessment of the synovitis. In a PubMed data analysis (status: 14.02.2017), the following citation rates according to Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/j.1365-2559.2006.02508 there were 44 Cited by PubMed Central articles. Therefore a total of 73 PubMed citations are observed over a period of 15 years, which demonstrates an international acceptance of the score. This synovitis score provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method enabling a contribution to the differential diagnosis of chronic inflammatory general joint diseases. This is particularly the case by incorporation into the joint pathology algorithm. To specify the synovitis score an immunohistochemical determination of various inflammation-relevant CD antigens is proposed to enable a risk stratification of high-grade synovitis (e.g.: progression risk and sensitivity for biologicals)., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Introduction: The aim of the work was to validate the CD15 focus score for the infection pathology of periprosthetic joint infection in a large group and to clarify whether a stratification into low-virulence and high-virulence microbial pathogens is possible by means of the CD15 focus score (quantification of CD15 positive granulocytes)., Methods: The histopathology of 275 synovial tissue samples taken intraoperatively during revision operations (n=127 hip, n=141 knee, n=2 shoulder, n=5 ankle) was evaluated according to the SLIM consensus classification (SLIM=synovial-like interface membrane). Neutrophilic granulocytes (NG) were quantified by the CD15 focus score on the basis of the principle of focal maximum infiltration (focus) with evaluation of one field of vision (about 0.3mm 2 ). The quantification values were compared with the microbiological diagnoses taking into consideration the virulence groups of low-virulence and high-virulence microbial pathogens and mixed infection., Results: The patients with positive microbiological findings (n=160) had significantly (p<0.001, Mann-Whitney U test) higher CD15 focus score values than patients with negative microbiological findings (n=115), the cut-off value being 39 cells per high power field (HPF). The CD15 focus score values of low-virulence microbial pathogens (n=94) were significantly lower (p<0.001, Mann-Whitney U test) than the values of high-virulence microbial pathogens (n=55), the cut-off value being 106 cells per HPF. Based on the microbiological diagnosis the sensitivity with respect to a microbial infection is 0.91, the specificity 0.92 (PPV=0.94; NPV=0.88; accuracy: 0.92; AUC=0.95). Based on the differentiation of the CD15 focus score values between low-virulence and high-virulence microbes the sensitivity is 0.70 and the specificity 0.77 (PPV=0.63; NPV=0.81; accuracy=0.74; AUC=0.74)., Conclusion: As a result of the high sensitivity and specificity, the easy to use CD15 focus score is a diagnostically valid score for microbial periprosthetic infection. A differentiation between low-virulence and high-virulence microorganism of sufficiently high diagnostic quality is additionally possible as a result of the defined quantification of CD15 positive granulocytes (the CD15 focus score) histopathological diagnosis of microbial infections is possible, which on the one hand supports the microbiological diagnosis and on the other hand by the stratification into low-virulence and high-virulence microbial pathogens could represent an additional basis for a pathogen-specific antibiotic treatment in the event of unclear constellations of findings., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

This extended classification of joint implant related pathology is a practical histopathologic classification based on defined morphological criteria covering the complete spectrum of pathohistologic changes in periprosthetic tissues. These changes may occur as a consequence of endoprosthetic replacement of large joints and may lead to a reduction in the prosthesis survival rate. We describe the established consensus classification of the periprosthetic membrane, in which aseptic and septic prosthetic loosening can be subdivided into four histological types, as well as histopathological criteria for additional significant pathologies including endoprosthetic-associated arthrofibrosis, particle-induced immunological, inflammatory and toxic mechanisms (adverse reactions), and bone tissue pathologies. These characteristic tissue alterations and their relationships are summarized in the extended classification. Since particle heterogeneity in periprosthetic tissue is high and particle identification is a necessary part of diagnosis, the identification of different types of particles is described in the histopathological particle algorithm. The morphological qualities of prosthetic material particles and the demarcation between abrasion and non-abrasion endogenous particles are also summarized. This feasible classification which is based on low cost standard tissue processing and examination and on well-defined diagnostic criteria is a solid platform for the histological diagnosis of implant associated pathologies providing a stable and reproducible tool for the surgical pathologist. Since this classification is suitable for standardized histopathological diagnostics, it might also provide a useful data set for joint arthroplasty registers, particularly for registers based on so-called routine data., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Background: Treatment and diagnosis of osteomyelitis are still a challenging problem for surgeons, microbiologists and histopathologists. A direct microbiological detection of bacteria in tissues is still gold standard, but it is not always successful for example in chronic osteomyelitis and/or when an antibiotic treatment has already been started or in cases of low virulent bacteria. The goal of this study was to define diagnostic criteria of osteomyelitis, the inflammatory regression of osteomyelitis ("osteomyelitis score") under specific therapy by the correlation of histopathological and microbiological and clinical standard tests., Methods: In this retrospective analysis patients with medical history and clinically clear signs of bacterial infection and osteomyelitis underwent surgery between 01.01.2013 and 31.12.2012. Their formal consent was given. Tissue samples were taken during surgery according to defined criteria including surgical interventions. Histopathological diagnosis was carried out by conventional techniques based on defined criteria of bacterial infection in connective tissue, peri-implant membrane and bone. These results were carried out in tables by numbers representing the histopathological criteria of acute osteomyelitis (A1 to A3) as well as the chronic criteria (C1 and C2) in a semiquantitative way (scale 0 to 3). On the other hand a notational, graduated histopathological report was performed. Preoperative clinical diagnosis, perioperative macroscopic diagnosis, histopathological and microbiological findings were correlated., Results: Histopathological samples of 52 surgical interventions based on the preoperative diagnosis "osteomyelitis" (AOM, ECOM or COM) were included. 37 times preoperatively signs of a chronic osteomyelitis (COM), 10 times preoperatively acute osteomyelitis (AOM) was diagnosed. Another 5 patients were preoperatively diagnosed as acute exacerbated osteomyelitis (ECOM). The correlation of the histopathological infection including the inflammatory activity and microbiological detection of bacteria was 57%. The correlation between preoperative diagnosis and histopathological findings was 68%., Conclusion: The relatively small 68% correlation between clinical preoperative and histopathological diagnosis and 57% correlation between preoperative clinical diagnosis and microbiological findings indicates: Clinical findings are not sufficient for the diagnosis "osteomyelitis".Clinical findings are not sufficient for the differentiation between AOM, ECOM and COM.Histopathological analysis is the critical factor for the diagnosis ("osteomyelitis") and differential diagnosis (AOM vs. COM).Histopathological analysis represents the basis for further treatment.HOES facilitates the classification of the histopathological findings.HOES is a sufficient tool for the treating physician in order to define the further treatment.

Arthrofibrosis (af) is defined as a fibrosing disease of the synovial membrane, after joint operations, with painful restricted range of motion. The aim of this paper was to describe the histopathological substrate of af, hitherto only defined by clinical criteria. Based on a group of 222 tissue samples, the characteristic changes to af were analyzed. The control group comprised 29 cases with neosynovialis of the indifferent type. Due to cytoplasmic SM-actin positivity and the absence of specific cytoplasmic reactivity in CD 68 representation, af fibroblasts were characterized as myofibroblasts. In confocal laser-scanning microscopy, β-catenin-positive aggregates were detected in the cytoplasm. Over and above this, unequivocal colocalization of β-catenin and the tight junction protein ZO-1 became manifest, particularly on the cell membrane and, partly, in the cytoplasm. A threshold value of 20 β-catenin-positive cells/HPF was determined. This enables the histopathological diagnosis of an af to be made (sensitivity: 0.733, specificity: 0.867). Af is a fibrosing disease of the synovial membrane with variable grade of fibrotization (fibroblast cellularity). A threshold value of 20 β-catenin-positive fibroblasts per HPF was defined, which enables the histopathological diagnosis of af., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

The revised classification of the periprosthetic membrane (synovial-like interface membrane SLIM) encompasses all pathological alterations which can occur as a result of endoprosthetic replacement of major joints and lead to a reduction in durability of prostheses. This also includes the established consensus classification of SLIM by which aseptic and septic prosthetic loosening can be subdivided into four histological types and histopathological criteria for additional pathologies: endoprosthesis-associated arthrofibrosis, immunological/allergic alterations and osseous pathologies. This revision represents the foundation for the histopathological diagnostics of the total spectrum of diseases associated with joint prostheses, is a suitable basis for a standardized diagnostic procedure and etiological clarification of endoprosthesis failure and also as a data standard for endprosthesis registers, in particular for registers based on routine data (e.g. German endoprosthesis register).

After rheumatologic conservative medical therapy has been exhausted in degenerative and inflammatory joint diseases, arthroplastic operations are an important option to restore quality of life. Endoprosthesis-associated arthrofibrosis is a severe fibrosing disease of the synovial membrane after endoprosthetic operations. Neither the morphological substrate nor histopathological criteria have been described. The aim was to describe the histopathological substrate of arthrofibrosis and to define histological and immunohistochemical criteria of arthrofibrosis on the basis of tissue samples derived from revision. In histopathological analyses arthrofibrosis revealed a synovialitis with varying fibrosis, without detectable ossification and without minimal wear particle reaction (so-called synovialitis of arthrofibrotic type, SAT). A 3-stage grading was determined based on the cellular density of the fibrous tissue (fibroblast cellularity). In 191 cases with SAT, grade 1 was found in 24.1 % (n = 46), grade 2 was found in 51.8 % (n = 99) and grade 3 was found in 24.1 % (n = 46). The control group consisted of 29 cases with synovialitis of indifferent type (type IV membrane). If SAT grades 2 and 3 are summed together, i.e. the distance between the fibroblasts was less than two cell lengths, the difference of the fibroblast cellularity compared with the type IV membrane was significant (p < 0.001). Above SAT grade 2 the diagnosis of arthrofibrosis could be made with a sensitivity 0.7592 and specificity 0.8276. The SM-alpha-actin cytoplasmic positivity of fibroblasts indicates a myofibroblast phenotype and the β-catenin positivity suggests a resemblance to fibromatosis or a keloid-like process. In the quantitative evaluation of the β-catenin positive fibroblasts, there was a significant difference (p < 0.001) between type IV membrane and SAT. A threshold value of 20 beta-catenin positive cells per microscopic high power field (HPF) was determined, which represents in conjunction with the clinical information a new histopathological diagnosis component (sensitivity 0.720, specificity 0.867).

Background: Magnetic drug targeting is a new treatment principle for tumors using cytostatics coupled to ferromagnetic nanoparticles and extracorporeal magnets. Higher concentrations in tumor tissue with lower systemic concentrations and without damage of healthy organs should be achieved., Materials and Methods: n = 42 adult Wag/Rij rats were transfected with rhabdomyosarcoma R(1)H in their right gastrocnemius muscle. In the biodistribution trial (n = 36) concentrations of mitoxantrone-iron oxide with and without an extracorporeal 0.6 tesla magnet and regular mitoxantrone were measured in plasma and tumor tissue for one- and two-dose administration. In the plasma iron trial (n = 6) iron concentrations were measured in plasma before, during, and up to 30 min after drug administration. Seven days after the trial liver, spleen and tumor samples were obtained and histologically assessed., Results: Mitoxantrone iron-oxide concentration in plasma was significantly (P < 0.05) lower when a magnet was placed over the tumor area and as low as uncoupled mitoxantrone. Mitoxantrone concentration in tumor tissue was always significantly higher with magnetic drug targeting when compared with uncoupled mitoxantrone. Two doses resulted in drug accumulation in tumor tissue. Plasma iron concentrations rose when the drug was first administered. Plasma levels fell below the starting level with a magnet applied. A rebound phenomenon with rising iron concentrations was observed after the magnet was removed. Tumors showed fresh necrosis and liver and spleen had detectable iron depositions but no necrosis 7 d after treatment. No allergies or toxic reactions were observed., Conclusions: We showed that magnetic drug targeting achieves higher concentrations of cytostatics in tumor tissue compared with blood. During magnetic drug targeting, iron particles are quickly sliced and kept in the tumor area. Organs of the reticuloendothelial system are not affected by cytostatic damage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Magnetic drug targeting (MDT) is a new treatment principle for tumors. Passive MDT (pMDT) uses cytostatics coupled to ferromagnetic nanoparticles, whereas in active MDT (aMDT), extracorporeal magnets are additionally placed over the tumor area., Purpose: Mitoxantrone-magnetite-dextran composite particles were used to assess the distribution and effect of MDT., Methods: We conducted two trials with n = 60 rats transfected with R(1)H rhabdomyosarcoma cells. In the biodistribution trial (n = 36) mitoxantrone concentrations in tumor tissue versus plasma were measured after one or two dose administration for aMDT, pMDT, and uncoupled mitoxantrone. The dose/effect trial (n = 24) assessed change in tumor volume at day 1 and 7 days after administration of 4, 6, or 8 doses of mitoxantrone using aMDT., Results: Mitoxantrone-magnetite-dextran concentration in blood was significantly (p < 0.05) lower when using aMDT and as low as uncoupled mitoxantrone. Concentrations in tumor tissue were always significantly higher using MDT when compared to uncoupled mitoxantrone. Two doses resulted in drug accumulation inside the tumor. Tumor growth was significantly decreased with four doses using aMDT versus no treatment. Tumor size on day 8 versus day 1 was significantly (p < 0.05) reduced after administration of six doses of mitoxantrone-magnetite-dextran. No allergies/toxic reactions were observed., Conclusions: The MDT achieves higher levels of cytostatics in tumor tissue without increased systemic concentrations and succeeds in reducing tumor volume.

Aim: To assess the overall impact of the most common contemporary prostate cancer therapies (radical prostatectomy, percutaneous irradiation, brachytherapy, hormonal therapy) with regard to physical and psychological well-being, as well as to general patient satisfaction., Patients and Methods: In October 2006, a questionnaire focused on patients' opinions and satisfaction regarding their previous prostate cancer therapies was published in a patient cancer journal (Krebsmagazin). Results were collected until March, 2007 and analyzed using Wilcoxon and Student's t-tests., Results: Answers were obtained from 634 patients (radical prostatectomy: 61%; percutaneous irradiation: 17%; brachytherapy: 2%; hormonal therapy: 15%; other/combined: 5%). Concerning late side effects and convenience of treatment, 96% of all patients who had undergone percutaneous irradiation were very satisfied with their choice and would choose the same therapy again (brachytherapy: 93%; hormonal therapy: 84%; radical prostatectomy: 79%). Erectile dysfunction with inability to perform sexual intercourse was reported by 32% of all patients who underwent percutaneous irradiation (brachytherapy: 21%; hormonal therapy: 63%; radical prostatectomy: 52%). No sexual problems at all were reported by 22% of patients who underwent percutaneous irradiation (brachytherapy: 21%; hormonal therapy: 13%; radical prostatectomy: 4%). With regard to psychological and physical deficits (fear; depression; urinary, bowel, erectile dysfunction; hormonal disorders), percutaneous irradiation was superior to the other treatment options (no deficits: percutaneous irradiation; 49%; brachytherapy: 36%; hormonal therapy: 17%; radical prostatectomy: 15%)., Conclusion: Radiotherapy showed superior results regarding patient convenience and satisfaction in comparison to hormonal therapy and surgery in the treatment of patients with prostate cancer.

Bacterial infection of the bone is a severe disease with complications, potentially including long-term physical disability. The diagnosis and therapy of osteomyelitis include several elements: histopathology, microbiology, radiologic imagining, as well as antibiotic and surgical therapy. Histopathologists differentiate between acute osteomyelitis (infiltration of cancellous bone with neutrophil granulocytes); specific osteomyelitis (epithelioid-like granulomatous inflammation, tuberculosis, mycotic infections); primary/secondary chronic osteomyelitis (lymphocytic infiltration); and special forms of chronic osteomyelitis (varying histomorphology, Brodie abscess, SAPHO syndrome). Another important task in the histopathological diagnosis of inflammatory bone diseases is to differentiate osteomyelitis from malignant entities (sarcoma, lymphoma). Therefore, biopsy samples should be of sufficient size for safe diagnosis. Clinical information and imaging as well as interdisciplinary teamwork between radiologists, microbiologists, orthopedic surgeons and pathologists is mandatory to verify these diagnoses.

We report on seed migration to the vertebral venous plexus after low dose rate prostate brachytherapy with (125)I. A 74-year-old man with T1c N0 M0 adenocarcinoma of the prostate with a Gleason score of 6 (3+3) and prostate-specific antigen level of 14.94 ng/ml underwent interstitial prostate brachytherapy. Six weeks after treatment at the follow-up to determine aftercare a migrated seed was detected in the vertebral venous plexus and a second one in the right lung. No tissue damage around the migrated seeds was documented and the patient exhibited no clinical symptoms.

Although histopathology of meniscal degeneration plays an important role, no criteria to assess severity of the degeneration are available to date. Our aim was to create a histopathological scoring system for meniscal degeneration with good interobserver variability, taking matrix degradation and cellularity in meniscal tissue into consideration. Degeneration is classified as follows: grade 1 (low), grade 2 (intermediate), grade 3 (high). The pattern of NITEGE deposits (G1 fragment of aggrecan) was assessed immunohistochemically (n=38) and compared with the grades of degeneration. In 48% of the patients with grade 2 or 3 degeneration extracellular NITEGE deposits (specificity 100%) were found, whereas grade 1 patients showed no deposits. Extracellular NITEGE deposits correlated positively with the grade of degeneration. In all, 30 cases (10 per grade) were assessed by three pathologists (A, B, C). Grading conformity was 70% for grade 1, 66% for grade 2 and 100% for grade 3. Cohen's Kappa coefficient was 0.6--0.7 between pairs of observers. Combining grade 1 and 2 to low-grade degeneration, compared to a grade-3 high-grade degeneration achieved Kappa coefficients of between 0.93 and 1.0. This reproducible degeneration score for fibrous cartilage could form the basis for the standardized assessment of meniscal degeneration.

Background: Meniscal degeneration (MD) is a structural change of fibrous cartilage that is common in orthopaedic diagnostics and relevant for health insurance matters. So far, there has been neither a standardised scoring system nor an immunohistochemical marker for MD., Material and Method: In this retrospective trial, the meniscal tissue of 60 patients was assessed immunohistochemically for NITEGE (G1 fragment of the proteoglycan aggrecan) expression. NITEGE expression was correlated with defined grades of MD: little (grade 0/1), medium (grade 2), or severe (grade 3)., Results: Detection of extracellular NITEGE deposits in grade 2 or 3 MD had a positive predictive value and specificity of 100%, whereas no deposits were found in grade 0/1 MD. Sensitivity in advanced MD was 55%. Detection of extracellular NITEGE correlated positively with the grade of degeneration, as did patient age and the grade of degeneration. The patient age of those with grade 0/1 MD was significantly lower than for grade 3 (p<0.0001)., Conclusion: The thoroughly defined degeneration score (grade 1 - grade 3 MD) is suitable to assess the severity of degeneration. Extracellular NITEGE deposits can be regarded as an immunohistochemical marker for advanced (grades 2 and 3) MD.

Sjögren's syndrome is an autoimmune disease which targets the salivary and lacrimal glands in particular, causing sicca syndrome. Extraglandular manifestations are often seen. Chronic sialadenitis of the parotid gland is the most common symptom to be assessed for differential diagnosis. Common HE and Giemsa slices are histopathologically examined and graduated for lymphocyte infiltration (focus): grade 0: absent, grade 1: slight, grade 2: moderate non-focal infiltration, grade 3: 1 focus (> or =50 lymphocytes) per 4 mm2, grade 4: >1 focus. Grade 3 infiltrates correspond to a focus score of 1, which is one of four disease-classifying criteria acknowledged for diagnosis. Bioptic examination is also performed to rule out different (non-) immunologic sialadenitises, such as the necrotizing or epithelioid-like form (in sarcoidosis), and the extranodal marginal-zone lymphoma. Extraglandular manifestations of Sjögren's syndrome can also be safely diagnosed by histopathological examination. Emphases lie on vasculitides and myositides. Bioptic work-up, therefore, is not only reasonable but also an essential tool for diagnostics in Sjögren's syndrome.

The surgeon's duty to inform patients determines the indication to a therapeutic and/ or diagnostic procedure. Despite ongoing information made available by the professional associations, the complaints against surgeons providing treatment are on the increase. Only careful health education information with records kept of the course of treatment adopted will safeguard the doctor in charge from patients' claims for damages. Case law demands that the doctor put the patient in a position to understand what is happening to him or her and for him or her to be able to make a decision freely. The patient's compliance after being provided with health education information makes the corpus delicti of bodily harm void. A special form is the matter of fact of "transfer negligence", when the doctor and/ or the hospital is aware, prior to execution of the treatment, that treatment is not possible lege artis. What continues to be applicable to health education information is that the more urgent the operation, the less information is indicated, so that in emergencies such operation can be completely done without. Apart from general risks, such as wound infection and/or the danger of thrombosis, information must also be provided about special risks and the course of any follow-up treatment. Legal practice shows that simply handing over forms is not sufficient. The patient may forgo treatment. Aborting an operation for purposes of providing health information is balancing between the patient's interests in immediate execution of the indicated measure, on the one hand, and the right of self-determination on the other. Should the operation be able to be aborted without any serious consequences for the patient, then it is to be thus done.What does principally apply in civil litigation is the rule of the burden of proof.

Histopathological examination of synovial specimens can contribute to the diagnosis of chronic joint diseases. A so-called synovitis score has been introduced as a standardised grading system, based on the semi-quantitative evaluation of the three determining features of chronic synovitis: enlargement of synovial lining, density of synovial stroma and inflammatory infiltrate, giving a score between 0 and 9. The present study examines the reliability of this procedure by comparison with exact measurements using computer-assisted image analysis (CAIA). Seventy-one synovial specimens from patients with osteoarthritis (OA, n=22), psoriatic arthritis (PsA, n=7), rheumatoid arthritis (RA, n=35) and from a control group (Co, n=7) were evaluated using both the synovitis score and CAIA. The measurements were transformed to semi-quantitative values analogous to the synovitis score. The differences between the transformed CAIA scores and the pathologist's scores were 0 or +/-1 in 40 cases, whereas in 31 cases the difference was greater than 1 (correlation coefficient r=0.725). The CAIA scores differed significantly between Co and RA cases (p=0.000) as well as between OA and RA (p=0.000). We conclude that the synovitis score was validated by CAIA and can be regarded a reliable grading system that contributes to the diagnostic procedure of chronic joint inflammation.

Background: Nowadays, obesity is frequently an indication for implantation of an adjustable stomach or gastric band. Among the side effects, in addition to band erosion and port chamber complications, pouch dilation in the sense of increasing enlargement of the forestomach and resulting insufficiency of initial surgical measures consistently occurs. Implantation of a soft basket band will prevent this. The objective of this study was to investigate the practical feasibility of the soft basket band., Methods: Ten patients were investigated in an observation study over a period from November 2006 to June 2007. Seven patients were women and three patients were men, with an average age of 43.6 years (25-66 years)., Results: The average body mass index (BMI) at the time of the operation was 47.4 +/- 5.5 kg/m(2), with an average body weight of 134.5 +/- 24.6 kg. After a median follow-up period of 1 month, an average BMI of 44.9 +/- 5.8 kg/m(2) was achieved, and after 3 months, an average BMI of 41.4 +/- 4.8 kg/m(2). The excessive weight loss was 7.4 +/- 4.3 kg after 1 month and 17.9 +/- 6.4 kg after 3 months. A local wound infection occurred as a complication in one patient., Conclusion: Laparoscopy procedures enable mortality to be lowered compared to bypass operations with minimal complications and substantial reduction of weight.

The aim of the study was to identify markers for the early diagnosis of endoprosthesis loosening, for the differentiation between wear particle-induced and septic loosening and to gather new insights into the pathogenesis of endoprosthesis loosening. Gene expression profiles were generated from five periprosthetic membranes of wear particle-induced and five of infectious (septic) type using Affymetrix HG U133A oligonucleotide microarrays. The results of selected differentially expressed genes were validated by RT-PCR (n = 30). The enzyme activity and the genotype of chitinase-1 were assessed in serum samples from 313 consecutive patients hospitalized for endoprosthesis loosening (n = 54) or for other reasons, serving as control subjects (n = 259). Eight hundred twenty-four genes were differentially expressed with a fold change greater than 2 (data sets on http://www.ncbi.nlm.nih.gov/geo/ GSE 7103). Among these were chitinase 1, CD52, calpain 3, apolipoprotein, CD18, lysyl oxidase, cathepsin D, E-cadherin, VE-cadherin, nidogen, angiopoietin 1, and thrombospondin 2. Their differential expression levels were validated by RT-PCR. The chitinase activity was significantly higher in the blood from patients with wear particle-induced prosthesis loosening (p = 0.001). However, chitinase activity as a marker for early diagnosis has a specificity of 83% and a sensitivity of 52%, due to a high variability both in the disease and in the control group., (Copyright 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

This review will suggest an algorithm for standardised histopathological diagnosis of synovial biopsies and synovectomy specimens. In principal, changes of the synovial membrane can be inflammatory or non-inflammatory. To the latter group belong some benign tumors, such as tenosynovial giant cell tumor, lipoma or synovial chondromatosis. Rare non-inflammatory changes are the group of storage diseases. Inflammatory synovial diseases can be differentiated into crystal-induced arthropathy, such as gout and pseudogout, granulomatous diseases, such as tuberculosis, sarcoidosis and foreign body reactions and into the large group of non-granulomatous synovitis. This last group is by far the most common and often causes difficulties in assigning the histopathological findings to a definite diagnosis. Therefore, the synovitis score should be applied in these cases as a diagnostic means, leading to the diagnosis of low-grade synovitis (which is associated with degenerative and posttraumatic arthropathies) or high-grade synovitis (associated with rheumatic diseases), the sensitivity and specificity being 60.5% and 95.5%, respectively. In detritus synovitis the synovitis score is not applicable.

Rheumatoid nodule (RN) represents a palisading granuloma with central fibrinoid necrosis, which is not only a classical manifestation of rheumatoid arthritis (RA) and part of the American College of Rheumatology (ACR)-criteria, but also is its diagnostic hallmark. The pathogenesis of RN is still not fully understood. At present, only data on serum analyses indicating a complement-mediated pathogenesis in the development of RA are available. Equivalent examinations for RN have not yet been performed. Granuloma annulare (GA) represents another type of palisading granuloma. A special subtype of GA, subcutaneous GA (SGA), is an important differential diagnosis to RN. Therefore, our aim was to examine RN and SGA regarding the complement deposition (C4d) by immunohistochemical means. All RN and GA were stained by hematoxylin/eosin and different special stains. In addition, all specimens were stained immunohistochemically with antibodies against CD68. Five GA and five RN were analyzed immunohistochemically with antibodies against C4d and CD68, and evaluated using single- and doublestaining immunohistochemistry. All RN and GA displayed depositions of C4d within their central necroses and between the surrounding palisading macrophages. Most importantly, C4d/CD68 double staining was visible in the palisading macrophages next to the necroses, while macrophages in the periphery were negative for C4d but positive for CD68. The main difference between RN and GA was a quantitative phenomenon with less positively reacting macrophages in a more incomplete palisade in GA. The positive reactions of all central necroses to C4d and colocalization of CD68 and C4d suggest that a complement-mediated mechanism may be operative in the formation of fibrinoid necrosis. This mechanism may be involved in any form of "fibrinoid necrosis", since no different patterns of C4d/CD68 expression could be observed in GA. This may explain why RG/GA are not distinguishable morphologically.

Histopathological assessment of synovial biopsies has an established value. The value for inflammatory joint diseases without standardized rating mechanisms was, however, unknown until recently. The exemplary use of the synovitis score in four cases all including recurrent bruises of the knee joint portrays its value for diagnosis and therapy. Usage of the score includes assessing the enlargement of the lining layer, cellular density of synovial stroma and leucocyte infiltration by giving each a score of 0-3 points and adding them. Presence of high-grade synovitis (>or=4 points) in all cases displayed the reason for the joint bruises within a primarily inflammatory, rheumatoid circle. In this report we show the broad variety of uses for the synovitis score dealing with cases of Lyme arthritis, rheumatoid arthritis, seronegative monarthritis and HLA-B27-positive peripheral arthritis.

Whether an operation is indicated or not is a question that is a frequent subject of discussion between physicians and the legal front. As the state has the duty to protect its citizens, any physical surgical operation is legally seen as a personal injury. Only if the patient completely agrees to the surgery after being carefully informed about it is the element of criminal offense (personal injury) revoked. The obligation to disclose medical information on the surgery applies to information on the operation itself and on the possible consequences to the patient in his/her physical and mental social environment. In particular, the patient must be given all information about the risks that could arise during and after the surgery. The legislative aim of this is not to treat a list of questions and to mention all possible risks, but the legislator wants to oblige physicians to give patients who have reached the age of majority full information on diagnosis and therapy and to enable them to consider the pros and cons of the surgery carefully and then to agree to the operation or to refuse it. Besides the obligation to disclose medical information in emergency cases, the obligation to disclose medical information to minors also makes heavy demands on the physician. Examples of contraindications are given.

Legal consent to medical treatment requires comprehensive clarification and the patient's capability to consent. Minors under 14 years are usually not capable of consent -- the right to decide rests with the parents. With persons over 14 years the doctor must test for capability to consent. With adults incapable of consent the court-appointed guardian decides. In acute cases the doctor may act first and obtain permission afterwards. Contractual capability is decisive for a treatment contract to be effective and the doctor's claim for remuneration. Minors up to 7 years are absolutely contractually incapable. Since minors under 18 years are only limitedly contractually capable, the approval of the statutory guardian suffices. With contractually incapable adults the court-appointed guardian or in serious cases the Guardianship Court decides. The legal position is explained, using three sample cases.

With the introduction of DRGs (diagnosis related groups) in 2004, a new charging system was initiated in Germany. Changes primarily involve lump sum based charging of inpatient cases regardless of the duration or complexity of diagnostic procedures and therapy, and the equalization of costs for similar services. Calculation of DRGs also includes the costs of autopsy. This has three major consequences for autopsy practice: Quality assurance: continuous monitoring of professional quality under lump sum payment can only be permanently guaranteed and independently and reliably attained by autopsy. This is the only way to overcome the danger of abolishing essential diagnostic procedures because of economic pressure and thus risking incorrect diagnoses. Economy: additional diagnoses revealed by autopsy will, in many cases, raise calculated charges. This could have a significant financial impact. Legal certainty: autopsies increase the accuracy and objectivity of diagnoses. Thus, they protect the attending physician from incorrect charging which may be unintended but could be legally relevant, especially when the cause of death is unclear. For these reasons, autopsy should become more important in clinical routine.

Rheumatoid granuloma (RG) is histomorphologically defined as a subcutaneous palisading granuloma with central fibrinoid necrosis. Clinically, it presents as a nodule typically localized at pressure points near the joints. From the rheumatic pathological point of view, the main diagnostic challenge is the differentiation of RG from granuloma anulare, especially if clinical information on the site of removal, known diseases, duration of illness, medication and existing American College of Rheumatology (ACR) criteria are missing. Other granulomatous lesions, such as mycobacterial infections, foreign body granulomas, necrobiosis lipoidica or sarcoidosis, can be differentiated from RG by histopathological criteria or by additional examinations such as pathogen specification or PCR. An immunohistochemical marker for the differential diagnosis of granulomas is not yet available. Diagnosis is based on conventional H-E staining, alcian blue-PAS staining, polarizing analysis or PCR. In the following article, the most important granulomatous entities in the differential diagnosis of RG are introduced and the main diagnostic characteristics are discussed.

The Hamburg University Institute of Legal Medicine presents 2 cases of injuries of crossbow arrows where the patients survived. Crossbows are used nowadays as sports and hunting weapons. They are freely obtainable, and since people without practice can shoot them, there are constant injuries and fatal cases. Crossbow arrows have a high penetration force and can even pierce bone. Depending on the tip of the arrow used, they bore or cut through tissue, here damage to the tissue being restricted to the direct surroundings. Due to the elasticity of the tissue, the arrow shaft in the wound track may have the effect of an incomplete tamponade so that major hemorrhaging is prevented. In this condition, the injured person may be conscious and capacitated. From the medical viewpoint, crossbow arrows should therefore be invariably left in the wound, secured against displacement during transport, and only removed in the hospital.

Hepatitis C is the most common indication for liver transplantation. Recurrence of HCV is universal leading to graft failure in up to 40% of all patients. The differentiation between acute rejection and recurrent hepatitis C is crucial as rejection treatments are likely to aggravate HCV recurrence. Histological examination of liver biopsy remains the gold standard for diagnosis of acute rejection but has failed in the past to distinguish between acute rejection and recurrent hepatitis C. We have recently reported that C4d as a marker of the activated complement cascade is detectable in hepatic specimen in acute rejection after liver transplantation. In this study, we investigate whether C4d may serve as a specific marker for differential diagnosis in hepatitis C reinfection cases. Immunohistochemical analysis of 97 patients was performed. A total of 67.7% of patients with acute cellular rejection displayed C4d-positive staining in liver biopsy whereas 11.8% of patients with hepatitis C reinfection tested positive for C4d. In the control group, 6.9% showed C4d positivity. For the first time we were able to clearly demonstrate that humoral components, represented by C4d deposition, play a role in acute cellular rejection after LTX. Consequently C4d may be helpful to distinguish between acute rejection and reinfection after LTX for HCV.

Appendicitis is diagnosed by synoptic evaluation of typical symptoms, laboratory tests and sonography. The only therapy is a prompt operation. The main reason for appendicitis mortality is the condition not detected or not detected in time. The case of a 50 year old male who died from a non-detected perityphlitic appendicitis with abscesses in the liver is presented. Only if appendicitis can be reliably ruled out an operation is not indicated. The not performed surgical intervention is often interpreted as a treatment error by the courts. In doubt, an operation should therefore be performed.

Almost no data exist concerning the role of antibody-mediated mechanisms in human acute cellular liver allograft rejection (ACR). Therefore, the aim of this study was to determine whether ACR is associated with depositions of complement split products and increased infiltration by B-lymphocytes, plasma cells and macrophages. A total of 35 liver biopsy specimens (ACR n=22, controls n=13) were analyzed by immunohistochemical single and double staining. The average numbers of CD 20(+), CD 38(+) and CD 68(+) cells per portal tract were established while the presence of C4d and C3d deposits was evaluated semiquantitatively. Significantly greater numbers of CD 20(+) (P=0.029) and CD 38(+) (P=0.014) cells were found in the ACR specimens than in the control specimens. Additionally, 50% of patients diagnosed with ACR showed C4d deposits along portal capillaries, which was associated with a significantly increased portal infiltration by macrophages (P=0.007). Taken together these results support the involvement of humorally mediated mechanisms in some cases of ACR.

Acute cellular (CLR) and humoral liver allograft rejection (HLR) are the most important immunological obstacles to successful liver transplantation. In HLR, serum antibodies play the central pathogenetic role. In CLR, CD3+ T lymphocytes drive the destructive immune response. Although CLR and HLR show different clinical symptoms and can be kept apart in most cases, they share histomorphological similarities. In CLR, hepatic B lymphocytes and plasma cells as well as B-cell-activating cytokines have recently been described, indicating that, in addition to T cells, antibody-mediated mechanisms might be involved. To analyze the impact of hepatic B cells in CLR and HLR, the immunoglobulin (Ig) variable (V)-region gene repertoire was determined from tissue of one case of CLR and one case of HLR. Complement deposits and lymphocytic infiltrate were determined using immunohistochemistry. T cells, B lymphocytes and plasma cells could be detected in both cases, whereas C3c and C4d deposits could only be demonstrated in the HLR case. The molecular analysis of 63 V-region genes showed that B cells in both allografts expressed selected V-gene repertoires. All sequences differed from the putative germline sequences by multiple somatic mutations. This suggests a clonal expansion of selected effector B cells in the portal tracts of liver allografts. Locally accumulated B cells and their antibodies might be involved in IgG-mediated complement activation in CLR and HLR.

The German health care system has been based on the Hospital Financing Act, which the German government introduced in 1972. According to that, the federal states plan hospitals and make investments. The health insurance funds finance the operating costs. But now the Hospital Financing Act is obsolete, because both the health insurance funds and the federal states are in financial trouble and try to avoid the costs, which are nevertheless rising. In order to freeze costs, the legislators have introduced a new remuneration system, called DRGs (Diagnosis Related Groups), which will be mandatory from 2007 onwards. In this system, the treatment provided will be coded and remunerated on the basis of the primary diagnosis. Periods of hospitalisation and different remuneration systems will no longer be relevant. Transparency and quality will thus be promoted, and the upshot will be more competition among the hospitals. Hospitals that cannot meet quality standards will lose patients and will ultimately have to close. Other participants in the health care system, such as, for example, nursing staff, physicians, pharmacies, rehabilitaion centres and patients, will also be concerned in many ways. The consequences of the DRGs for the health care system, its future development and possible alternatives are discussed in this article.

Background: Although antibody mechanisms play a pathogenetic role in liver allograft rejection, no data exist on B lymphocytes, plasma cells, complement, and chemokines in rejected liver tissue., Methods: Liver biopsy specimens from 25 patients with acute allograft rejection (AR) (rejection activity index, RAI score: 1-9) were analyzed by immunohistochemistry (IH) and reverse transcriptase-polymerase chain reaction (RT-PCR) and compared with biopsy specimens taken prior to implantation (PI). The number of CD20 and CD138 cells was evaluated, and the presence and abundance of the chemokines macrophage inflammatory protein (MIP)-3alpha, CXCL9, CXCL10, CXCL11, CXCL12, and their receptors CCR-6, CXCR3, and CXCR4 were examined. Complement depositions were visualized by C4d IH., Results: The numbers of B lymphocytes (P=0.002) and plasma cells (P=0.022) were significantly higher in AR biopsy specimens compared with PI biopsy specimens. MIP-3alpha and CCR-6 cells were detected in the portal fields of all AR biopsy specimens. IH double staining revealed a colocalization of MIP-3alpha/CD20 cells; C4d deposits could be demonstrated along the portal capillaries. All examined chemokines and receptors could be detected in normal liver tissue and in AR biopsy specimens by RT-PCR and semiquantitative RT-PCR, demonstrating an overexpression of CXCL10 and -11., Conclusions: The significant increase of B lymphocytes and plasma cells during acute rejection, together with the lack of a significant increase of proliferating cells, indicates that the migration of B lymphocytes and plasma cells-promoted by the expression of B-cell activating chemokines/receptors-plays a key role in acute liver rejection. The C4d deposits along the portal capillaries indicate a humorally mediated alloresponse caused by the accumulated B and plasma cells.