[Vasculopathy in Sjögren's syndrome]. / Vaskulopathien bei Sjögren-Syndrom.

Sjögren's syndrome is a systemic autoimmune disease with a predominant involvement of exocrine glands leading to sicca symptoms. Extraglandular involvement occurs in about 40% of patients with skin, musculoskeletal, neurological and organ manifestations. Systemic vasculitic manifestations of Sjögren's syndrome can be assumed in approximately 5%-10% of patients. Leukocytoclastic or cryoglobulinemic vasculitis represent classic vasculitic manifestations of Sjögren's syndrome. In the pathogenesis of vasculitis, B-cell-driven autoimmune processes play a major role by producing autoantibodies against the Ro/SS-A and La/SS-B antigens and cryoglobulins. In patients with Sjögren's syndrome, manifestation of vasculitis, non-Hodgkin's lymphoma and glomerulonephritis, as well as positive cryoglobulins and decreased levels of complement factors, are considered negative prognostic markers. Various immunosuppressive strategies, usually in co-medication with glucocorticoids, are used for the treatment of vasculitis in Sjögren's syndrome. For refractory and severe manifestations, a B-cell-targeted therapy with Rituximab should be also considered.

Co-expression and prognostic value of gross cystic disease fluid protein 15 and mammaglobin in primary breast cancer.

Gross cystic disease fluid protein (GCDFP-15) and mammaglobin are both widely used and accepted markers for epithelia of breast origin. We aimed to evaluate their relation of expression on parallel whole tissue sections in primary breast cancer by immunohistochemistry and also to correlate it with clinico-pathological parameters including patient survival. Primary breast carcinomas from 165 patients with a mean clinical follow-up of 73 months were immunostained using commercially available antibodies against GCDFP-15 and mammaglobin. An immunoreactive score (IRS) was calculated based on the cytoplasmic staining intensity and the number of cells stained. Cytoplasmic expression of GCDFP-15 and mammaglobin was observed in 73.3% and 72.1% of invasive breast carcinomas respectively. 91.8% of breast cancer cases expressed at least one of both markers. Both markers strongly correlated with each other and were significantly associated with lower tumour grading. Additionally, GCDFP-15 negativity was significantly associated with shortened disease-free survival times in univariate and multivariate analyses. We demonstrated the strong correlation of GCDFP-15 and mammaglobin with each other and showed that only very few primary breast cancers are completely negative for both markers. The significantly longer disease free survival times for patients with GCDFP-15 positive tumours clearly warrants further study.

Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists.

HER2 is an important tumour marker in breast cancer. However, there is controversy regarding which method reliably measures HER2 status. This study evaluates the concordance between HER2 gene amplification in invasive breast cancer determined by fluorescence in situ hybridisation (FISH) and a new silver enhanced in situ hybridisation (SISH) technique. Ninety-nine cases were analysed by direct-labelled manual FISH (PathVysion(R), Abbott/Vysis) and bright field automated SISH (INFORM(R), Ventana). For comparison, all specimens were stained by immunohistochemistry (Dako-HercepTesttrade mark and Ventana-PATHWAY(R)4B5). Evaluation was performed by five pathologists following the algorithms of the manufacturers and the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. Concordance was calculated and the value of kappa statistics estimated. Overall concordance between FISH and SISH was 96.0% (kappa = 0.754, 95%CI). Discrepancies were mostly seen in tumours with intra-tumoural heterogeneity of HER2 amplification. In conclusion, HER2 gene copy status can be reliably determined by SISH. The 96% concordance with FISH fulfils the ASCO/CAP requirement of greater than 95% concordance for amplified vs non-amplified cases. There was a low inter-observer variability in the interpretation of SISH, suggesting that SISH is equally reliable in determining HER2 amplification as FISH. Because SISH combines bright field microscopy with molecular analysis and full automation, it appears to be particularly suited for routine application in surgical pathology.

Expression of AGR2 in non small cell lung cancer.

We aimed to evaluate immunohistochemically the expression of the human Anterior Gradient-2 (AGR2), a gene which has recently been proposed as an oncogene for lung carcinoma development, in non small cell lung cancer and to correlate the findings to clinico-pathological data including patient survival. 95 cases of NSCLC were immunostained using a polyclonal AGR2 antibody and statistical analyses were applied to test for prognostic and diagnostic associations. AGR2 was expressed in 66.3% of cases, preferentially adenocarcinomas. There were no relevant associations with clinico-pathological parameters. A prognostic value of AGR2 could not be demonstrated neither in multivariate nor in univariate analyses. Interestingly, this is the first study to demonstrate AGR2 expression in squamous cell carcinomas. Although a prognostic value of AGR2 seems unlikely further studies are warranted to investigate the biological role of AGR2 in NSCLC and its differential expression according to histology.

[Necessity of increasing autopsy frequency following the introduction of DRGs]. / Notwendigkeit der Obduktionssteigerung durch Einführung der DRGs.

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.

[Labial salivary gland biopsy in Sjögren's syndrome]. / Beurteilung von Lippendrüsenbiopsaten beim Sjögren-Syndrom.

In the majority of cases, autoimmune sialadenitis is a feature of Sjögren's syndrome. This systemic autoimmune disease is, therefore, clinically characterised by sicca symptoms such as xerostomia and keratoconjunctivitis sicca. Since autoimmune sialadenitis affects major as well as minor salivary glands, histopathological examination is almost always carried out using labial salivary gland biopsies. A positive histopathological result is determined as a focal lymphocytic sialadenitis with at least one aggregate of 50 or more lymphocytes and histiocytes per 4 mm2 of salivary gland tissue. As one out of four objective findings, focus scoring belongs to the classification criteria for Sjögren's syndrome according to the American-European consensus group.

Escherichia coli strain Nissle 1917 ameliorates experimental colitis via toll-like receptor 2- and toll-like receptor 4-dependent pathways.

Toll-like receptors (TLRs) are key components of the innate immune system that trigger antimicrobial host defense responses. The aim of the present study was to analyze the effects of probiotic Escherichia coli Nissle strain 1917 in experimental colitis induced in TLR-2 and TLR-4 knockout mice. Colitis was induced in wild-type (wt), TLR-2 knockout, and TLR-4 knockout mice via administration of 5% dextran sodium sulfate (DSS). Mice were treated with either 0.9% NaCl or 10(7) E. coli Nissle 1917 twice daily, followed by the determination of disease activity, mucosal damage, and cytokine secretion. wt and TLR-2 knockout mice exposed to DSS developed acute colitis, whereas TLR-4 knockout mice developed significantly less inflammation. In wt mice, but not TLR-2 or TLR-4 knockout mice, E. coli Nissle 1917 ameliorated colitis and decreased proinflammatory cytokine secretion. In TLR-2 knockout mice a selective reduction of gamma interferon secretion was observed after E. coli Nissle 1917 treatment. In TLR-4 knockout mice, cytokine secretion was almost undetectable and not modulated by E. coli Nissle 1917, indicating that TLR-4 knockout mice do not develop colitis similar to the wt mice. Coculture of E. coli Nissle 1917 and human T cells increased TLR-2 and TLR-4 protein expression in T cells and increased NF-kappaB activity via TLR-2 and TLR-4. In conclusion, our data provide evidence that E. coli Nissle 1917 ameliorates experimental induced colitis in mice via TLR-2- and TLR-4-dependent pathways.

C4d in acute rejection after liver transplantation--a valuable tool in differential diagnosis to hepatitis C recurrence.

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.