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1.  Histological Analysis of γδ T Lymphocytes Infiltrating Human Triple-Negative Breast Carcinomas 
Breast cancer is the leading cause of cancer death in women and the second most common cancer worldwide after lung cancer. The remarkable heterogeneity of breast cancers influences numerous diagnostic, therapeutic, and prognostic factors. Triple-negative breast carcinomas (TNBCs) lack expression of HER2 and the estrogen and progesterone receptors and often contain lymphocytic infiltrates. Most of TNBCs are invasive ductal carcinomas (IDCs) with poor prognosis, whereas prognostically more favorable subtypes such as medullary breast carcinomas (MBCs) are somewhat less frequent. Infiltrating T-cells have been associated with an improved clinical outcome in TNBCs. The prognostic role of γδ T-cells within CD3+ tumor-infiltrating T lymphocytes remains unclear. We analyzed 26 TNBCs, 14 IDCs, and 12 MBCs, using immunohistochemistry for the quantity and patterns of γδ T-cell infiltrates within the tumor microenvironment. In both types of TNBCs, we found higher numbers of γδ T-cells in comparison with normal breast tissues and fibroadenomas. The numbers of infiltrating γδ T-cells were higher in MBCs than in IDCs. γδ T-cells in MBCs were frequently located in direct contact with tumor cells, within the tumor and at its invasive border. In contrast, most γδ T-cells in IDCs were found in clusters within the tumor stroma. These findings could be associated with the fact that the patient’s prognosis in MBCs is better than that in IDCs. Further studies to characterize these γδ T-cells at the molecular and functional level are in progress.
PMCID: PMC4261817  PMID: 25540645
γδ T-cells; breast cancer; triple-negative breast cancer; histology; paraffin material
3.  Local effects of high-powered neodymium-doped yttrium aluminium garnet laser systems on the pulmonary parenchyma: an experimental study on the isolated perfused pig lung lobe 
Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser systems (with a power output up to 100 W, wavelength 1318 nm) have been introduced into clinical practice for resecting lung metastases. However, the extent of the local effect on the lung parenchyma and the role of the application time are unknown. All experiments were performed on normothermal, whole-blood-perfused paracardiac pig lung lobes (n = 6). Lobes were not ventilated during the laser application. The laser itself was clamped into a hydraulic feed system that moves horizontally at two different constant rates (10 and 20 mm/s). A 30-mm focus distance from the pulmonary parenchyma was maintained at all times. At each feed rate, the laser was applied thrice along a horizontal path using laser power outputs of 40, 60 and 100 W. After lasering, we recruited the lungs via a ventilation tube using pressures of up to 40 cm H2O and tested lung tightness. Both a gross inspection and a histological examination revealed larger coagulation zones for higher power outputs and lower laser feed rates. Exposure to higher outputs for shorter application times reduced the laser effect. When lungs were manually recruited, all lungs were airtight up to a pressure of 40 mmHg. Reducing the exposure time reduces local tissue coagulation even when the laser power output is increased.
PMCID: PMC3397735  PMID: 22535543
Nd:YAG laser; Laser power output; Application time; Lung parenchyma
4.  Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation 
Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality.
Case presentation
We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1.
To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.
PMCID: PMC3662564  PMID: 23683442
AFOP; Influenza A/H1N1; Acute lung failure; Lung transplantation; Viral infection
5.  Simultaneous Multi-Antibody Staining in Non-Small Cell Lung Cancer Strengthens Diagnostic Accuracy Especially in Small Tissue Samples 
PLoS ONE  2013;8(2):e56333.
Histological subclassification of non-small cell lung cancer (NSCLC) has growing therapeutic impact. In advanced cancer stages tissue specimens are usually bioptically collected. These small samples are of extraordinary value since molecular analyses are gaining importance for targeted therapies. We therefore studied the feasibility, diagnostic accuracy, economic and prognostic effects of a tissue sparing simultaneous multi-antibody assay for subclassification of NSCLC. Of 265 NSCLC patients tissue multi arrays (TMA) were constructed to simulate biopsy samples. TMAs were stained by a simultaneous bi-color multi-antibody assay consisting of TTF1, Vimentin, p63 and neuroendocrine markers (CD56, chromogranin A, synaptophysin). Classification was based mainly on the current proposal of the IASLC with a hierarchical decision tree for subclassification into adenocarcinoma (LAC), squamous cell carcinoma (SCC), large cell neuroendocrine carcinoma (LCNEC) and NSCLC not otherwise specified. Investigation of tumor heterogeneity showed an explicit lower variation for immunohistochemical analyses compared to conventional classification. Furthermore, survival analysis of our combined immunohistochemical classification revealed distinct separation of each entity's survival curve. This was statistically significant for therapeutically important subgroups (p = 0.045). As morphological and molecular cancer testing is emerging, our multi-antibody assay in combination with standardized classification delivers accurate and reliable separation of histomorphological diagnoses. Additionally, it permits clinically relevant subtyping of NSCLC including LCNEC. Our multi-antibody assay may therefore be of special value, especially in diagnosing small biopsies. It futher delivers substantial prognostic information with therapeutic consequences. Integration of immunohistochemical subtyping including investigation of neuroendocrine differentiation into standard histopathological classification of NSCLC must, therefore, be considered.
PMCID: PMC3572034  PMID: 23418554
6.  The history of pathology informatics: A global perspective 
Pathology informatics has evolved to varying levels around the world. The history of pathology informatics in different countries is a tale with many dimensions. At first glance, it is the familiar story of individuals solving problems that arise in their clinical practice to enhance efficiency, better manage (e.g., digitize) laboratory information, as well as exploit emerging information technologies. Under the surface, however, lie powerful resource, regulatory, and societal forces that helped shape our discipline into what it is today. In this monograph, for the first time in the history of our discipline, we collectively perform a global review of the field of pathology informatics. In doing so, we illustrate how general far-reaching trends such as the advent of computers, the Internet and digital imaging have affected pathology informatics in the world at large. Major drivers in the field included the need for pathologists to comply with national standards for health information technology and telepathology applications to meet the scarcity of pathology services and trained people in certain countries. Following trials by a multitude of investigators, not all of them successful, it is apparent that innovation alone did not assure the success of many informatics tools and solutions. Common, ongoing barriers to the widespread adoption of informatics devices include poor information technology infrastructure in undeveloped areas, the cost of technology, and regulatory issues. This review offers a deeper understanding of how pathology informatics historically developed and provides insights into what the promising future might hold.
PMCID: PMC3714902  PMID: 23869286
History; pathology informatics; clinical informatics; electronic medical record; laboratory information systems; pathology education
7.  Molecular modeling and description of a newly characterized activating mutation of the EGFR gene in non-small cell lung cancer 
Diagnostic Pathology  2012;7:146.
Lung cancer is the leading cause of death among malignant diseases in humans worldwide. In the last decade development of new targeted drugs for the treatment of non-small cell lung cancer proved to be a promising approach to prolong the otherwise very poor prognosis of patients with advanced UICC stages. Epidermal growth factor receptor (EGFR) has been in the focus of this lung cancer science and specific activating mutations are eligible for the treatment with specific tyrosine kinase inhibitors like gefitinib or erlotinib. Beside typical deletions in exon 19 and point mutations in exons 18 and 21 several insertions in exon 19 have been described and attributed activating properties as well. This is the first European and overall the 5th description in English literature of one of these specific insertions. To elucidate its structural changes leading to the activating properties we performed molecular modeling studies. These revealed conformational and electrostatic force field changes in the kinase domain of EGFR. To not miss uncommon mutations thorough and precise characterization of EGFR hotspots, i. e. at least exons 18, 19 and 21, should therefore be conducted to provide best medical care and to offer lung cancer patients appropriate cancer treatment.
Virtual slides
The vistual slides for this article can be found here:
PMCID: PMC3523061  PMID: 23088930
8.  Virtual slides in peer reviewed, open access medical publication 
Diagnostic Pathology  2011;6:124.
Application of virtual slides (VS), the digitalization of complete glass slides, is in its infancy to be implemented in routine diagnostic surgical pathology and to issues that are related to tissue-based diagnosis, such as education and scientific publication.
Electronic publication in Pathology offers new features of scientific communication in pathology that cannot be obtained by conventional paper based journals. Most of these features are based upon completely open or partly directed interaction between the reader and the system that distributes the article. One of these interactions can be applied to microscopic images allowing the reader to navigate and magnify the presented images. VS and interactive Virtual Microscopy (VM) are a tool to increase the scientific value of microscopic images.
Technology and Performance
The open access journal Diagnostic Pathology has existed for about five years. It is a peer reviewed journal that publishes all types of scientific contributions, including original scientific work, case reports and review articles. In addition to digitized still images the authors of appropriate articles are requested to submit the underlying glass slides to an institution (, and for digitalization and documentation. The images are stored in a separate image data bank which is adequately linked to the article. The normal review process is not involved. Both processes (peer review and VS acquisition) are performed contemporaneously in order to minimize a potential publication delay. VS are not provided with a DOI index (digital object identifier). The first articles that include VS were published in March 2011.
Results and Perspectives
Several logistic constraints had to be overcome until the first articles including VS could be published. Step by step an automated acquisition and distribution system had to be implemented to the corresponding article. The acceptance of VS by the reader is high as well as by the authors. Of specific value are the increased confidence to and reputation of authors as well as the presented information to the reader. Additional associated functions such as access to author-owned related image collections, reader-controlled automated image measurements and image transformations are in preparation.
Virtual Slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3275477  PMID: 22182763
Virtual slide; virtual microcopy; open access publication; image interpretation; image content information
9.  History and structures of telecommunication in pathology, focusing on open access platforms 
Diagnostic Pathology  2011;6:110.
Telecommunication has matured to a broadly applied tool in diagnostic pathology.
Technology and Systems
Contemporary with the development of fast electronic communication lines (Integrated digital network services (ISDN), broad band connections, and fibre optics, as well as the digital imaging technology (digital camera), telecommunication in tissue - based diagnosis (telepathology) has matured. Open access (internet) and server - based communication have induced the development of specific medical information platforms, such as iPATH, UICC-TPCC (telepathology consultation centre of the Union International against Cancer), or the Armed Forces Institute of Pathology (AFIP) teleconsultation system. They have been closed, and are subject to be replaced by specific open access forums (Medical Electronic Expert Communication System (MECES) with embedded virtual slide (VS) technology). MECES uses php language, data base driven mySqL architecture, X/L-AMPP infrastructure, and browser friendly W3C conform standards.
The server - based medical communication systems (AFIP, iPATH, UICC-TPCC) have been reported to be a useful and easy to handle tool for expert consultation. Correct sampling and evaluation of transmitted still images by experts reported revealed no or only minor differences to the original images and good practice of the involved experts. β tests with the new generation medical expert consultation systems (MECES) revealed superior results in terms of performance, still image viewing, and system handling, especially as this is closely related to the use of so - called social forums (facebook, youtube, etc.).
Benefits and Expectations
In addition to the acknowledged advantages of the former established systems (assistance of pathologists working in developing countries, diagnosis confirmation, international information exchange, etc.), the new generation offers additional benefits such as acoustic information transfer, assistance in image screening, VS technology, and teaching in diagnostic sampling, judgement, and verification.
PMCID: PMC3231812  PMID: 22059444
Telepathology; telemedicine; virtual slide; open access forum; MECES
10.  To be at the right place at the right time 
Diagnostic Pathology  2011;6:68.
To analyze the hypothesis of events or neighborhood interactions that is based upon recognizable structures of systems which possess a surface in a four dimensional space - time constellation {x, y, z, t}. To include the theory of hierarchic order of structures and aspects of thermodynamically open systems, especially entropy, structural entropy and entropy flow.
Any structure is a space - time constellation that occupies a unique space in its environment. The environment can be a system too, and is assumed to be (nearly) constant. Structures can interact in their environment and create a new structure at a higher order level. Interacting structures that create a surface are called a system. Starting from the bottom, such a system is characterized by its inner structures, its surface function, and its neighborhood. Interaction with a neighboring system is called an event. An event can alter a system, create new systems or induce the decay of a system, dependent upon the surrounding lower level system (background).
The hypothesis results in a uniform theory about matter, life, diseases, or behavior. Concrete applications permit the estimation of duration of life in man, for example the effect of solid cancer in man, or appearance of protozoans in sexual or asexual reduplication. In addition, it can successfully describe the development of the universe (small exceed of matter above antimatter at the big bang), or the increase of structures (and systems) with increasing time (development of intelligent systems). The three dimensional space possesses the lowest number of mandatory dimensions to implement such a system.
PMCID: PMC3154858  PMID: 21781323
Neighborhood interaction; order of structures; event; surface; entropy
11.  Rhino-Orbitocerebral Zygomycosis Caused by Conidiobolus incongruus in an Immunocompromised Patient in Germany▿  
Journal of Clinical Microbiology  2010;48(11):4322-4325.
Mucorales (subphylum Mucoromycotina) are well-known agents of invasive mucormycosis, whereas Entomophthorales (subphylum Entomophthoromycotina) are rarely encountered in human diseases in temperate zones. Here we report a fatal case of invasive rhino-orbitocerebral entomophthoramycosis caused by Conidiobolus incongruus in a 78-year-old woman with myelodysplastic syndrome.
PMCID: PMC3020825  PMID: 20861341
12.  Interactive and automated application of virtual microscopy 
Diagnostic Pathology  2011;6(Suppl 1):S10.
Virtual microscopy can be applied in an interactive and an automated manner. Interactive application is performed in close association to conventional microscopy. It includes image standardization suitable to the performance of an individual pathologist such as image colorization, white color balance, or individual adjusted brightness. The steering commands have to include selection of wanted magnification, easy navigation, notification, and simple measurements (distances, areas). The display of the histological image should be adjusted to the physical limits of the human eye, which are determined by a view angle of approximately 35 seconds. A more sophisticated performance should include acoustic commands that replace the corresponding visual commands. Automated virtual microscopy includes so-called microscopy assistants which can be defined similar to the developed assistants in computer based editing systems (Microsoft Word, etc.). These include an automated image standardization and correction algorithms that excludes images of poor quality (for example uni-colored or out-of-focus images), an automated selection of the most appropriate field of view, an automated selection of the best magnification, and finally proposals of the most probable diagnosis. A quality control of the final diagnosis, and feedback to the laboratory determine the proposed system. The already developed tools of such a system are described in detail, as well as the results of first trials. In order to enhance the speed of such a system, and to allow further user-independent development a distributed implementation probably based upon Grid technology seems to be appropriate. The advantages of such a system as well as the present pathology environment and its expectations will be discussed in detail.
PMCID: PMC3073203  PMID: 21489181
13.  E-education in pathology including certification of e-institutions 
Diagnostic Pathology  2011;6(Suppl 1):S11.
E–education or electronically transferred continuous education in pathology is one major application of virtual microscopy. The basic conditions and properties of acoustic and visual information transfer, of teaching and learning processes, as well as of knowledge and competence, influence its implementation to a high degree. Educational programs and structures can be judged by access to the basic conditions, by description of the teaching resources, methods, and its program, as well as by identification of competences, and development of an appropriate evaluation system. Classic teaching and learning methods present a constant, usually non-reversible information flow. They are subject to personal circumstances of both teacher and student. The methods of information presentation need to be distinguished between static and dynamic, between acoustic and visual ones. Electronic tools in education include local manually assisted tools (language assistants, computer-assisted design, etc.), local passive tools (slides, movies, sounds, music), open access tools (internet), and specific tools such as Webinars. From the medical point of view information content can be divided into constant (gross and microscopic anatomy) and variable (disease related) items. Most open access available medical courses teach constant information such as anatomy or physiology. Mandatory teaching resources are image archives with user–controlled navigation and labelling, student–oriented user manuals, discussion forums, and expert consultation. A classic undergraduate electronic educational system is WebMic which presents with histology lectures. An example designed for postgraduate teaching is the digital lung pathology system. It includes a description of diagnostic and therapeutic features of 60 rare and common lung diseases, partly in multimedia presentation. Combining multimedia features with the organization structures of a virtual pathology institution will result in a virtual pathology education institution (VPEI), which can develop to a partly automated distant learning faculty in medicine.
PMCID: PMC3073204  PMID: 21489182
14.  Grid computing in image analysis 
Diagnostic Pathology  2011;6(Suppl 1):S12.
Diagnostic surgical pathology or tissue–based diagnosis still remains the most reliable and specific diagnostic medical procedure. The development of whole slide scanners permits the creation of virtual slides and to work on so-called virtual microscopes. In addition to interactive work on virtual slides approaches have been reported that introduce automated virtual microscopy, which is composed of several tools focusing on quite different tasks. These include evaluation of image quality and image standardization, analysis of potential useful thresholds for object detection and identification (segmentation), dynamic segmentation procedures, adjustable magnification to optimize feature extraction, and texture analysis including image transformation and evaluation of elementary primitives.
Grid technology seems to possess all features to efficiently target and control the specific tasks of image information and detection in order to obtain a detailed and accurate diagnosis.
Grid technology is based upon so-called nodes that are linked together and share certain communication rules in using open standards. Their number and functionality can vary according to the needs of a specific user at a given point in time. When implementing automated virtual microscopy with Grid technology, all of the five different Grid functions have to be taken into account, namely 1) computation services, 2) data services, 3) application services, 4) information services, and 5) knowledge services.
Although all mandatory tools of automated virtual microscopy can be implemented in a closed or standardized open system, Grid technology offers a new dimension to acquire, detect, classify, and distribute medical image information, and to assure quality in tissue–based diagnosis.
PMCID: PMC3073205  PMID: 21516880
15.  How to measure diagnosis-associated information in virtual slides 
Diagnostic Pathology  2011;6(Suppl 1):S9.
The distribution of diagnosis-associated information in histological slides is often spatial dependent. A reliable selection of the slide areas containing the most significant information to deriving the associated diagnosis is a major task in virtual microscopy. Three different algorithms can be used to select the appropriate fields of view: 1) Object dependent segmentation combined with graph theory; 2) time series associated texture analysis; and 3) geometrical statistics based upon geometrical primitives. These methods can be applied by sliding technique (i.e., field of view selection with fixed frames), and by cluster analysis. The implementation of these methods requires a standardization of images in terms of vignette correction and gray value distribution as well as determination of appropriate magnification (method 1 only). A principle component analysis of the color space can significantly reduce the necessary computation time. Method 3 is based upon gray value dependent segmentation followed by graph theory application using the construction of (associated) minimum spanning tree and Voronoi’s neighbourhood condition. The three methods have been applied on large sets of histological images comprising different organs (colon, lung, pleura, stomach, thyroid) and different magnifications, The trials resulted in a reproducible and correct selection of fields of view in all three methods. The different algorithms can be combined to a basic technique of field of view selection, and a general theory of “image information” can be derived. The advantages and constraints of the applied methods will be discussed.
PMCID: PMC3073227  PMID: 21489204
16.  Lactate-Dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1 
Diagnostic Pathology  2010;5:22.
As one of the five Lactate dehydrogenase (LDH) isoenzymes, LDH5 has the highest efficiency to catalyze pyruvate transformation to lactate. LDH5 overexpression in cancer cells induces an upregulated glycolytic metabolism and reduced dependence on the presence of oxygen. Here we analyzed LDH5 protein expression in a well characterized large cohort of primary lung cancers in correlation to clinico-pathological data and its possible impact on patient survival.
Primary lung cancers (n = 269) and non neoplastic lung tissue (n = 35) were tested for LDH5 expression by immunohistochemistry using a polyclonal LDH5 antibody (ab53010). The results of LDH5 expression were correlated to clinico-pathological data as well as to patient's survival. In addition, the results of the previously tested Transketolase like 1 protein (TKTL1) expression were correlated to LDH5 expression.
89.5% (n = 238) of NSCLC revealed LDH5 expression whereas LDH5 expression was not detected in non neoplastic lung tissues (n = 34) (p < 0.0001). LDH5 overexpression was associated with histological type (adenocarcinoma = 57%, squamous cell carcinoma = 45%, large cell carcinoma = 46%, p = 0.006). No significant correlation could be detected with regard to TNM-stage, grading or survival. A two sided correlation between the expression of TKTL1 and LDH5 could be shown (p = 0.002) within the overall cohort as well as for each grading and pN group. A significant correlation between LDH5 and TKTL1 within each histologic tumortype could not be revealed.
LDH5 is overexpressed in NSCLC and could hence serve as an additional marker for malignancy. Furthermore, LDH5 correlates positively with the prognostic marker TKTL1. Our results confirm a close link between the two metabolic enzymes and indicate an alteration in the glucose metabolism in the process of malignant transformation.
PMCID: PMC2861018  PMID: 20385008
17.  Gene expression profiles of lung adenocarcinoma linked to histopathological grading and survival but not to EGF-R status: a microarray study 
BMC Cancer  2010;10:77.
Several different gene expression signatures have been proposed to predict response to therapy and clinical outcome in lung adenocarcinoma. Herein, we investigate if elements of published gene sets can be reproduced in a small dataset, and how gene expression profiles based on limited sample size relate to clinical parameters including histopathological grade and EGFR protein expression.
Affymetrix Human Genome U133A platform was used to obtain gene expression profiles of 28 pathologically and clinically annotated adenocarcinomas of the lung. EGFR status was determined by fluorescent in situ hybridization and immunohistochemistry.
Using unsupervised clustering algorithms, the predominant gene expression signatures correlated with the histopathological grade but not with EGFR protein expression as detected by immunohistochemistry. In a supervised analysis, the signature of high grade tumors but not of EGFR overexpressing cases showed significant enrichment of gene sets reflecting MAPK activation and other potential signaling cascades downstream of EGFR. Out of four different previously published gene sets that had been linked to prognosis, three showed enrichment in the gene expression signature associated with favorable prognosis.
In this dataset, histopathological tumor grades but not EGFR status were associated with dominant gene expression signatures and gene set enrichment reflecting oncogenic pathway activation, suggesting that high immunohistochemistry EGFR scores may not necessarily be linked to downstream effects that cause major changes in gene expression patterns. Published gene sets showed association with patient survival; however, the small sample size of this study limited the options for a comprehensive validation of previously reported prognostic gene expression signatures.
PMCID: PMC2843676  PMID: 20196851
18.  Five-Year Long-Term Followup of a Primary Lymph node Gastrinoma: Is a Pancreaticoduodenectomy Justified? 
Case Reports in Medicine  2009;2009:762791.
Background. Gastrinoma-positive lymph nodes and failed localization of the primary tumor during surgical exploration are described. Specialists suppose that these lymph nodes are metastases rather than a primary gastrinoma. Methods. Case report with a five-year long-term followup. A 60-year-old patient with an confirmed gastrinoma was treated in our department. All preoperative evaluations including somatostatin-receptor-scintigraphy and F-Dopa PET failed to localize the gastrinoma. Explorative laparotomy revealed a gastrinoma in two peripancreatic lymph nodes. Despite extensive intraoperative exploration, no primary gastrinoma could be detected in typical localization. Results. Over a period of 5 years, the patient's gastrin level stayed in the normal range and the patient seems to be completely cured. Conclusion. A prophylactic partial pancreatoduodenectomy is not indicated to avoid recurrence, since complete biochemical cure by local resection of the lymph node gastrinoma is possible.
PMCID: PMC2734937  PMID: 19724657
19.  The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis 
Treatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far.
84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival.
Fifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis.
Intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.
PMCID: PMC2717064  PMID: 19604398
20.  Severe Organizing Pneumonia after Two Cycles of Docetaxel as Fourth-Line Chemotherapy for Advanced Non-Small Cell Carcinoma of the Lung 
Case Reports in Oncology  2009;2(1):12-19.
Organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia, BOOP) is an inflammatory process of the bronchioles that can lead to the destruction of small airways and surrounding lung tissue. Although the majority of cases are idiopathic, certain chemicals and drugs can induce OP. Here, we report a 54-year-old male patient with advanced non-small cell lung cancer (NSCLC) who developed therapy-associated OP. He had undergone several other chemotherapies before being switched to docetaxel as monotherapy (75 mg/m2). Treatment was initially well tolerated, but after the second cycle the patient developed increasing shortness of breath. Computed tomography (CT) for staging after the second cycle showed bilateral predominantly interstitial infiltration highly suggestive of acute lung fibrosis. Bronchoscopy revealed signs of chronic bronchitis and watery discharge from both lungs. Bronchoalveolar lavage and transbronchial needle biopsy was performed. Based on histopathologic examination, diagnosis of OP was made. After cessation of docetaxel and initial high dose steroids, the infiltration ameliorated rapidly. This is the second case in the literature that associates docetaxel with rapid onset of bronchiolitis obliterans. Therefore, patients with lung cancer receiving docetaxel who develop respiratory symptoms should be suspected to develop OP.
PMCID: PMC2918823  PMID: 20740139
Docetaxel; Taxane; Bronchiolitis obliterans organizing pneumonia, BOOP; Organizing pneumonia, OP
21.  Theory of sampling and its application in tissue based diagnosis 
A general theory of sampling and its application in tissue based diagnosis is presented. Sampling is defined as extraction of information from certain limited spaces and its transformation into a statement or measure that is valid for the entire (reference) space. The procedure should be reproducible in time and space, i.e. give the same results when applied under similar circumstances. Sampling includes two different aspects, the procedure of sample selection and the efficiency of its performance. The practical performance of sample selection focuses on search for localization of specific compartments within the basic space, and search for presence of specific compartments.
When a sampling procedure is applied in diagnostic processes two different procedures can be distinguished: I) the evaluation of a diagnostic significance of a certain object, which is the probability that the object can be grouped into a certain diagnosis, and II) the probability to detect these basic units. Sampling can be performed without or with external knowledge, such as size of searched objects, neighbourhood conditions, spatial distribution of objects, etc. If the sample size is much larger than the object size, the application of a translation invariant transformation results in Kriege's formula, which is widely used in search for ores. Usually, sampling is performed in a series of area (space) selections of identical size. The size can be defined in relation to the reference space or according to interspatial relationship. The first method is called random sampling, the second stratified sampling.
Random sampling does not require knowledge about the reference space, and is used to estimate the number and size of objects. Estimated features include area (volume) fraction, numerical, boundary and surface densities. Stratified sampling requires the knowledge of objects (and their features) and evaluates spatial features in relation to the detected objects (for example grey value distribution around an object). It serves also for the definition of parameters of the probability function in so – called active segmentation.
The method is useful in standardization of images derived from immunohistochemically stained slides, and implemented in the EAMUS™ system . It can also be applied for the search of "objects possessing an amplification function", i.e. a rare event with "steering function". A formula to calculate the efficiency and potential error rate of the described sampling procedures is given.
PMCID: PMC2649041  PMID: 19220904
22.  Posttraumatic Reactive Fibrous Bone Neoformation of the Anterior Skull Base Mimicking Osteosarcoma 
Skull Base  2008;18(5):345-351.
Objectives: Malignant bone tumors and fibro-osseous bone lesions of the skull base are uncommon, although fibrous dysplasia in this anatomic location is not a rare condition. In general, fibro-osseous lesions of the skull are often difficult to classify on either clinical presentation, radiological findings, or histological presentation alone. The objective of this article is to present a probably important differential in the management of bony neoformations of the skull and to highlight the diagnostic difficulties when dealing with osseous and fibro-osseous conditions affecting the craniofacial bones. Design: We present here a novel case of posttraumatic reactive fibrous bone neoformation of the anterior skull base mimicking osteosarcoma in a 16-year-old boy. Results: Diagnostic steps, clinical, histological, and radiological presentation, as well as surgical treatment are described in detail. The international medical literature concerning reactive fibrous bone neoformations is reviewed, and the problem of adjusting the correct differential diagnosis when dealing with fibro-osseous bone lesions of the skull base is discussed. Conclusions: The highlights of this case are an uncommon location of a rare pathological entity, which might constitute an important differential of fibro-osseous conditions affecting the craniofacial bones.
PMCID: PMC2637060  PMID: 19240834
Skull base; bone neoplasm; fibrous dysplasia of bone; bone diseases; osteosarcoma
23.  How to measure image quality in tissue-based diagnosis (diagnostic surgical pathology) 
Diagnostic Pathology  2008;3(Suppl 1):S11.
Automated image analysis, measurements of virtual slides, and open access electronic measurement user systems require standardized image quality assessment in tissue-based diagnosis.
To describe the theoretical background and the practical experiences in automated image quality estimation of colour images acquired from histological slides.
Theory, material and measurements
Digital images acquired from histological slides should present with textures and objects that permit automated image information analysis. The quality of digitized images can be estimated by spatial independent and local filter operations that investigate in homogenous brightness, low peak to noise ratio (full range of available grey values), maximum gradients, equalized grey value distribution, and existence of grey value thresholds. Transformation of the red-green-blue (RGB) space into the hue-saturation-intensity (HSI) space permits the detection of colour and intensity maxima/minima. The feature distance of the original image to its standardized counterpart is an appropriate measure to quantify the actual image quality. These measures have been applied to a series of H&E stained, fluorescent (DAPI, Texas Red, FITC), and immunohistochemically stained (PAP, DAB) slides. More than 5,000 slides have been measured and partly analyzed in a time series.
Analysis of H&E stained slides revealed low shading corrections (10%) and moderate grey value standardization (10 – 20%) in the majority of cases. Immunohistochemically stained slides displayed greater shading and grey value correction. Fluorescent stained slides are often revealed to high brightness. Images requiring only low standardization corrections possess at least 5 different statistically significant thresholds, which are useful for object segmentation. Fluorescent images of good quality only posses one singular intensity maximum in contrast to good images obtained from H&E stained slides that present with 2 – 3 intensity maxima.
Evaluation of image quality and creation of formally standardized images should be performed prior to automatic analysis of digital images acquired from histological slides. Spatial dependent and local filter operations as well as analysis of the RGB and HSI spaces are appropriate methods to reproduce evaluated formal image quality.
PMCID: PMC2500119  PMID: 18673499
24.  Image standards in Tissue-Based Diagnosis (Diagnostic Surgical Pathology) 
Diagnostic Pathology  2008;3:17.
Progress in automated image analysis, virtual microscopy, hospital information systems, and interdisciplinary data exchange require image standards to be applied in tissue-based diagnosis.
To describe the theoretical background, practical experiences and comparable solutions in other medical fields to promote image standards applicable for diagnostic pathology.
Theory and experiences
Images used in tissue-based diagnosis present with pathology – specific characteristics. It seems appropriate to discuss their characteristics and potential standardization in relation to the levels of hierarchy in which they appear. All levels can be divided into legal, medical, and technological properties. Standards applied to the first level include regulations or aims to be fulfilled. In legal properties, they have to regulate features of privacy, image documentation, transmission, and presentation; in medical properties, features of disease – image combination, human – diagnostics, automated information extraction, archive retrieval and access; and in technological properties features of image acquisition, display, formats, transfer speed, safety, and system dynamics. The next lower second level has to implement the prescriptions of the upper one, i.e. describe how they are implemented. Legal aspects should demand secure encryption for privacy of all patient related data, image archives that include all images used for diagnostics for a period of 10 years at minimum, accurate annotations of dates and viewing, and precise hardware and software information. Medical aspects should demand standardized patients' files such as DICOM 3 or HL 7 including history and previous examinations, information of image display hardware and software, of image resolution and fields of view, of relation between sizes of biological objects and image sizes, and of access to archives and retrieval. Technological aspects should deal with image acquisition systems (resolution, colour temperature, focus, brightness, and quality evaluation procedures), display resolution data, implemented image formats, storage, cycle frequency, backup procedures, operation system, and external system accessibility. The lowest third level describes the permitted limits and threshold in detail. At present, an applicable standard including all mentioned features does not exist to our knowledge; some aspects can be taken from radiological standards (PACS, DICOM 3); others require specific solutions or are not covered yet.
The progress in virtual microscopy and application of artificial intelligence (AI) in tissue-based diagnosis demands fast preparation and implementation of an internationally acceptable standard. The described hierarchic order as well as analytic investigation in all potentially necessary aspects and details offers an appropriate tool to specifically determine standardized requirements.
PMCID: PMC2362107  PMID: 18423031
25.  Neuroendocrine differentiation and neuroendocrine morphology as two different patterns in large-cell bronchial carcinomas: outcome after complete resection 
In 1999, large-cell neuroendocrine carcinoma of the lung was introduced by the World Health Organization (WHO) as a new tumor entity in the group of non-small cell, epithelial tumors, a differentiated classification of neuroendocrine tumors of the lung not existing until this time. Scientific knowledge on prognosis and therapy of these tumors, especially between those with neuroendocrine morphology only and those showing additional expression of neuroendocrine markers, is fragmentary. In this analysis, we studied the clinical behavior and the prognosis of these two rare tumor entities.
Patients and Methods
The analysis comprises 12 patients of a total of 2053, who underwent thoracotomy for non small-cell lung carcinoma between 1997 and 2005 in the Department of Thoracic Surgery at the University Hospital of Freiburg. Clinical data, pathological examinations as well as complete follow-up were reviewed from large-cell carcinoma with neuroendocrine morphology only (n=4) and from large-cell carcinoma expressing neuroendocrine markers (n=8).
The median survival of patients with neuroendocrine morphology was 30 months (11–96 months). In the patient group showing the expression of neuroendocrine markers, the median survival time was 20 months (2–26 months). Tumor recurrences occurred in the group with neuroendocrine morphology, without exception, in the form of distant metastases and in the group with neuroendocrine markers as intrapulmonary metastases.
Large-cell neuroendocrine carcinomas of the lung show aggressive behavior with a poor prognosis. Expression of neuroendocrine markers markedly reduce tumor-free interval as well as survival and might influence the site of metastases.
PMCID: PMC1570460  PMID: 16953887

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