[Grading of lung cancer]. / Grading von Lungenkarzinomen.

In comparison with other tumor entities there is no common generally accepted grading system for lung cancer with clearly defined criteria and clinical relevance. In the recent fourth edition of the World Health Organization (WHO) classification from 2015 of tumors of the lungs, pleura, thymus and heart, there is no generally applicable grading for pulmonary adenocarcinomas, squamous cell carcinomas or rarer forms of carcinoma. Since the new IASLC/ATS/ERS classification of adenocarcinomas published in 2011, 5 different subtypes with significantly different prognosis are proposed. This results in an architectural (histologic) grading, which is usually applied to resection specimens. For squamous cell carcinoma the number of different histological subtypes in the new WHO classification was reduced compared to earlier versions but without a common grading system. In recent publications nesting and budding were proposed as the main (histologic) criteria for a grading of squamous cell carcinomas. The grading of neuroendocrine tumors (NET) of the lungs in comparison with NET in other organs is presented in a separate article in this issue. Certain rare tumor types are high grade per definition: small cell, large cell and pleomorphic carcinomas, carcinosarcomas and pulmonary blastomas. In the future it is to be expected that these developments will be further refined, e. g. by adding further subtypes for adenocarcinomas and cytologic and/or nuclear criteria for adenocarcinoma and/or squamous cell carcinomas.

[Guideline (S2k, AWMF) of the Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin and the Deutsche Gesellschaft für Arbeitsmedizin und Umweltmedizin "Diagnostics and Expert Opinion in the Occupational Disease No. 4101 Silicosis (Including Coal Worker's Pneumoconiosis)"]. / S2k-Leitlinie nach AWMF-Schema der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Gesellschaft für Arbeitsmedizin und Umweltmedizin "Diagnostik und Begutachtung der Berufskrankheit Nr. 4101 Quarzstaublungenerkrankung (Silikose) der Berufskrankheitenverordnung".

During the last 1.5 years an update of the guideline on silicosis was made by an interdisciplinary working group. New medical and scientific knowledge and the experience in expert opinion practice were taken into account.By preparing the initial guideline in 2010 standardization of diagnostics and adaption of the "Moers convention" which was not based on medical knowledge was in the focus, whereas the current update deals with fine emendation and extension, especially of the compensation rate (adaption with the Reichenhall recommendation).The diagnosis of silicosis (including mixed dust pneumoconiosis) is based on a detailed occupational history, and predominantly on the typical radiological findings. However, at initial diagnosis the standardized LD-HRCT takes an important role because of its high sensitivity and specificity. Exceptional cases are those with characteristic findings in chest X-ray follow-up. Correspondingly, it is mentioned in the guideline: "The standardized appraisal of the Low-Dose-Volume HRCT requires application of the CT classification (ICOERD, International Classification of Occupational and Environmental Respiratory diseases). In order to diagnose silicosis in CT scan opacities with sharp borders in both central upper lung fields and their circumferencies have to be documented. By comparing with ILO standard radiographs at least profusion category 1 in the right and left upper lung fields has to be reached (total profusion category 2)."The pathologic minimal requirement for the diagnosis of silicosis which has undergone controversial discussion has now also been defined. Corresponding to Hnizdo et al. 2000 it is now mentioned: "Finding of less than 5 silicotic granuloma per lung lobe by palpation is regarded as insignificant." This is a convention and not a threshold based on detailed medical scientific and statistical studies; it is based on extended experience in the South African gold mines.This guideline also deals with silicotic hilar (and sometimes mediastinial) lymph nodes; according to the guideline working group they do not closely correlate with the degree of pulmonary involvement. Extended conglomerating and enduring lymph-node processes may lead to dislocation of the hili with impairment of large bronchi and vessels. Shell-like calcifications dominating in the periphery of lymph nodes produce so-called egg-shell hili.The paragraph on exercise testing is now extended: if neither ergometry nor spiroergometry can be performed a 6 minute walking test by measuring oxygen saturation should be done.Furthermore, in individual expert opinion examinations right heart catheterization (the patient is not obliged to give informed consent) may be recommended, if echo cardiography gives evidence for pulmonary hypertension or if it is difficult to differentiate between right and left heart failure. The presence of pulmonary hypertension which is of prognostic relevance has to be considered when grading reduction in earning capacity.For interpretation of spirometry values the new GLI reference values has to be applied. Grading of impairment is due to the recommendation of the DGP.According to current medical scientific knowledge it is unclear, whether certain disorders of the rheumatic group such is scleroderma or Caplan syndrome which are sometimes associated with silicosis (or coal workers' pneumoconiosis) belong in toto to the occupational disease number 4101 (silicosis). Within this context, additional studies are needed to clarify the role of occupational quartz exposure and other risk factors.The guideline working group hopes that this update will help to optimize diagnostics and expert opinion of silicotic patients.

Application in Europe of a urine-based rapid diagnostic test for confirmation of Schistosoma mansoni infection in migrants from endemic areas.

In February 2015, a male patient from Eritrea with persistent abdominal pain and rectal bleeding was diagnosed with Schistosoma mansoni infection upon examination of a rectal biopsy. In May 2015, repeated stool microscopy identified S. mansoni infection in another Eritrean patient with abdominal pain and considerable eosinophilia (34%). Use of point-of-care circulating cathodic antigen (POC-CCA) tests on urine confirmed S. mansoni infection in both patients. Wider application of non-invasive POC-CCA urine tests will improve schistosomiasis diagnosis and clinical management in migrants.

Real-time quantitative RT-PCR after laser-assisted cell picking.

The present study describes a technique for quantitation of mRNA in a few isotypic cells obtained from an intact organ structure by combining laser-assisted cell picking and real-time PCR. The microscopically controlled lasering of selected cells in stained tissue sections was applied to lung alveolar macrophages, which are unique in that they can alternatively be gathered as a pure cell population from intact lungs by bronchoalveolar lavage as a reference technique. TNF-alpha was chosen as the transcriptionally inducible target gene to be quantified in alveolar macrophages of control rat lung, as well as low- and high-challenge lungs stimulated by endotoxin and IFN-gamma nebulization. Online fluorescence detection for quantitation of the number of amplified copies was based on 5' nuclease activity of Taq polymerase cleaving a sequence-specific dual-labeled fluorogenic hybridization probe. A pseudogene-free sequence of PBGD served as an internal calibrator for comparative quantitation of target. A quick procedure and minimized loss of template were achieved by avoiding RNA extraction, DNase digestion and nested-PCR. Using this approach, we demonstrated dose-dependent manifold upregulation of the ratio of TNF-alpha mRNA copies per one copy of PBGD mRNA in alveolar macrophages of the challenged lungs. The quantitative data obtained from laser-picked alveolar macrophages were well matched with those of lavaged alveolar macrophages carried out in parallel. We suggest that this new combination of laser-assisted cell picking and real-time PCR has great promise for quantifying mRNA expression in a few single cells or oligocellular clusters in intact organs, allowing assessment of transcriptional regulation in defined cell populations.

Severe respiratory distress syndrome unresponsive to intensive care treatment--diagnostic and therapeutic considerations.

Respiratory Distress Syndrome (RDS) is a common complication in preterm neonates. If RDS is not responding to conventional treatment modalities (surfactant therapy, ventilatory support, etc.), an underlying pathology (pulmonary lymphangiectasia, capillary alveolar dysplasia, alpha-1 antitrypsin deficiency, etc.) other then prematurity should be taken into consideration.Here, we report on a preterm neonate with the unusual simultaneous occurrence of pulmonary and systemic lymphangiectasia and homozygous alpha-1 antitrypsin deficiency who developed severe RDS that was refractory to conventional treatment. The diagnostic and therapeutic approach in this patient is presented.

Immunhistochemical analysis for expression of calpain 1, calpain 2 and calpastatin in ovarian cancer.

Calpains, also called calcium activated neutral proteases (CANP), are expressed ubiquitously. They are intracellular, non-lysosomal cytoplasmic cysteine endopeptidases. Calcium is required for their activation. Their endogenous specific inhibitor is calpastatin, which is expressed ubiquitously and coexists within cells besides calpain. When calcium is present, calpastatin and calpain attach to each other inhibiting the protease. The calpain system plays an important role in many processes including apoptosis, necrosis, ischemia formation and exocytosis. So far, many reports exist on studies about the influence of calpains in different tumors (skin, breast, renal cell and prostate cancers). The role of calpains in pathogenesis or further tumor progression has always been proved in related studies, but their exact function could not be demonstrated. So far, no studies on calpains being involved in the pathogenesis of ovarian cancer have been published. In our study we focused on the expression of the enzymes calpain 1, calpain 2 and their inhibitor calpastatin in normal and malign ovarian tissue. Therefore, we performed immunohistochemical stainings of paraffin slices and evaluated staining intensity (SI), percentage of positive cells (PP) and immunoreactive score (IRS). We evaluated the correlation between enzyme expression in malign and benign ovarian tissues. In malignant ovarian tissue, we found decreased expression, staining intensity and immunoreactive score of calpastatin. With higher grading of the ovarian carcinoma, staining intensity and immunoreactive score of calpain 1 decreased. Staining intensity of calpain 2 in ovarian carcinoma decreased with increasing lymph node status. We clearly demonstrated differences between enzyme expressions in malign and benign tissue. This study could not find any specific function of calpains. Only few studies in the literature have been found that deal with calpain evaluation of ovarian cancer. Additional studies including more patients are required to elucidate the functional role and impact of calpain in tumors in detail.

c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis.

Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.

Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease.

PURPOSE: Transient elastography (FibroScan, [TE]) and serum fibrosis markers such as the FibroTest (FT) are established methods for the noninvasive staging of liver fibrosis. A study using real-time elastography (HI-RTE), which is integrated in a conventional ultrasound system, was recently published with comparable results to transient elastography. The aim of the present study was to validate real-time elastography using the formulas calculated in previous studies and to compare the results to transient elastography and FibroTest for the noninvasive assessment of liver fibrosis. MATERIALS AND METHODS: One hundred and thirty-four patients with chronic liver disease and either histological assessment of liver fibrosis (n = 112) or proven liver cirrhosis (n = 22) were included in the study. All patients received TE, HI-RTE, and biochemical evaluation on the same day as presentation. The calculation of the elasticity score of real-time elastography was performed in accordance with the two previously published studies. RESULTS: The Spearman correlation coefficient between transient elastography, real-time elastography and FibroTest with the histological Chevallier score was statistically significant with 0.78, 0.34, and 0.67, respectively (p < 0.01). The diagnostic accuracy expressed as areas under ROC curves was 0.84, 0.69 and 0.85 for the diagnosis of significant fibrosis (F > or = 2), and 0.97, 0.65, and 0.83 for the diagnosis of cirrhosis, respectively. CONCLUSION: Real-time elastography in its present form cannot replace transient elastography for noninvasive assessment of liver fibrosis.

Quantitative 3D micro-CT imaging of the human feto-placental vasculature in intrauterine growth restriction.

OBJECTIVE: Placental vascular development matches fetal growth and development. Quantification of the feto-placental vasculature in placentas from pregnancies is complicated by intrauterine growth restriction (IUGR) revealed confounding results. Therefore, the feto-placental vascular volume in IUGR placentas was assessed by 3D micro-computed tomography (micro-CT). METHODS AND RESULTS: Placental probes from IUGR (n=24) and healthy control placentas (n=40) were perfused in situ with Microfil or BaSO(4) and randomly chosen samples were scanned by micro-CT. Using 3D images, we quantitated the feto-placental vascular volume fraction (VVF). A subanalysis was performed at three different levels, reaching from the chorionic plate artery (level A), to intermediate arteries (level B) and capillary system (level C). Results were complemented by histology. The significance of differences in vascular volume measurements was tested with analysis of variance [ANOVA]. RESULTS: Microfil perfused placentas showed a total vascular volume fraction of 20.5+/-0.9% in healthy controls. In contrast, the VVF decreased to 7.9+/-0.9% (p<0.001) in IUGR placentas. Significant differences were found between Microfil and BaSO(4) perfused placentas in the vascular volume fraction using micro-CT and histology. Micro-CT demonstrated localized concentric luminal encroachments in the intermediate arteries in placentas complicated by IUGR. CONCLUSION: Micro-CT imaging is feasible for quantitative analysis of the feto-placental vascular tree in healthy controls and pregnancies complicated by IUGR.

Management of vulvar melanoma and review of the literature.

BACKGROUND: Vulvar melanoma represents a rare group of malignancies and is the second most common vulvar malignancy. Treatment options range from local excision of the tumor and sentinel lymph node dissection to radical resection involving en bloc vulvectomy and inguinofemoral lymphanedectomy. Vulvar melanomas have an overall poor prognosis, and there is lack of consensus in the published literature regarding treatment options. OBJECTIVE: To discuss the management of vulvar melanomas through review of the actual literature. METHODS: Identification of studies through computerized searches (January 2006) was conducted using MEDLINE (1966 to present), the Cochrane Central Register of Controlled Trials, the National Research Register and the Medical Research Council's Clinical Trials Register. The medical subject headings and text words used were: vulvar melanoma, malignant, management, case report, and therapy. The literature review was done over the past 36 years. RESULT: Results of these primary retrospective series have shown no improvement in the overall recovery or disease survival rates. CONCLUSION: Patients with malignant melanoma are often diagnosed at 70 years of age with multiple comorbidities. Less radical surgery presents a more realistic option for many patients without decreasing their survival rates. Surgery is still the gold standard of treatment and offers the best available treatment for controlling and potential curing of malignant melanomas. However, the whole concept of therapy should be tailored to meet the specific needs of individual patients.