Frequency of primary cutaneous lymphoma variants in Austria: retrospective data from a dermatology referral centre between 2006 and 2013.

BACKGROUND: Primary cutaneous lymphomas (PCL) are a heterogenous group of rare lymphoid neoplasms with incomplete information on global and regional prevalence. The recently introduced lymphoma classifications define distinctive clinicopathological disease entities that should allow for more accurate epidemiological assessment. OBJECTIVE: The aim of this study was to evaluate the prevalence and clinical spectrum of PCL diagnosed and treated at the Department of Dermatology and Venereology in St. Pölten, Lower Austria, a dermatology referral centre providing secondary and tertiary care for a population of about 600 000. METHODS: In this retrospective study pathology reports, electronically archived between 2006 and 2013, were screened for the terms lymphoma, mycosis fungoides (MF) and lymphomatoid papulosis (LyP). Patients were diagnosed according to the current WHO-EORTC classification for cutaneous lymphomas and results were compared with data from European, US and Asian centres. RESULTS: Among 86 patients with PCL (age 58.3 ± 17.35 years, mean ± SD; women 38%, n = 33; men 62%, n = 53) 83% (n = 71) were classified as cutaneous T-cell lymphomas (CTCL) and 17% (n = 15) as cutaneous B-cell lymphomas (CBCL). Nine patients with CTCL showed associated haematological disorders and malignomas. Among 47 MF patients following variants were observed: pilotropic MF (n = 2), follicular mucinosis (n = 1), unilesional MF (n = 1), large-cell transformation (n = 3), erythrodermic MF (n = 1), poikilodermatous MF (n = 2) and posttransplant lymphoproliferative disorder (CD8(+) MF with gamma/delta phenotype after renal transplantation) (n = 1). One patient had MF concurrent with lymphomatoid papulosis. The group of CBCL comprised six cases (40%) of PCMZL and PCFCL each, 20% (n = 3) were classified as PCLBCL, LT. CONCLUSION: This study for the first time provides data on the distribution of PCL clinicopathologic variants and stages according to the latest classification and staging systems in an Austrian referral centre.

Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients.

BACKGROUND: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. METHODS: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis). RESULTS: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. CONCLUSION: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer.

BACKGROUND: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. PATIENTS AND METHODS: We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis. RESULTS: After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. CONCLUSION: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro.

Toxin A but not toxin B, appears to mediate intestinal damage in animal models of Clostridium difficile enteritis. The purpose of this study was to investigate the electrophysiologic and morphologic effects of purified C. difficile toxins A and B on human colonic mucosa in Ussing chambers. Luminal exposure of tissues to 16-65 nM of toxin A and 0.2-29 nM of toxin B for 5 h caused dose-dependent epithelial damage. Potential difference, short-circuit current and resistance decreased by 76, 58, and 46%, respectively, with 32 nM of toxin A and by 76, 55, and 47%, respectively, with 3 nM of toxin B, when compared with baseline (P < 0.05). 3 nM of toxin A did not cause electrophysiologic changes. Permeability to [3H]mannitol increased 16-fold after exposure to 32 nM of toxin A and to 3 nM of toxin B when compared with controls (P < 0.05). Light and scanning electron microscopy after exposure to either toxin revealed patchy damage and exfoliation of superficial epithelial cells, while crypt epithelium remained intact. Fluorescent microscopy of phalloidin-stained sections showed that both toxins caused disruption and condensation of cellular F-actin. Our results demonstrate that the human colon is approximately 10 times more sensitive to the damaging effects of toxin B than toxin A, suggesting that toxin B may be more important than toxin A in the pathogenesis of C. difficile colitis in man.

Testing for induction of DNA synthesis in human hepatocyte primary cultures by rat liver tumor promoters.

Parenchymal liver cells were isolated from human liver pieces of surgical waste as well as from rat livers. DNA synthetic activity was measured after different times in primary culture by [3H]thymidine incorporation and autoradiography. Labeling of control cultures of human hepatocytes at densities between 8,000 and 15,000 cells/cm2 was very low (0.4 to 1.3%). Human recombinant epidermal growth factor increased labeling 2- to 4-fold (P less than 0.01). Treatment with known inducers of liver growth in rats, namely, cyproterone acetate, alpha-hexachlorocyclohexane, nafenopin, phenobarbital, and rifampicin did not increase the number of labeled human liver cells. In some of the experiments, a 24-h exposure to the chemicals of rat or human hepatocytes was followed by a 24-h treatment with epidermal growth factor (EGF). In rat hepatocytes, incorporation rates were significantly increased. Cyproterone acetate and EGF acted in an additive manner, alpha-hexachlorocyclohexane and EGF were clearly overadditive, and phenobarbital had little effect. In human hepatocytes, little alteration in labeling indices was found; in some cases labeling was, rather, found to be lower than in cultures treated with EGF alone. These results show that human hepatocytes cultured in vitro are sensitive to stimulation of DNA synthesis by EGF; they differ from rat hepatocytes in their response to some drugs which show liver growth-promoting activity in rodents.

Osteopontin expression in ductal adenocarcinomas and undifferentiated carcinomas of the pancreas.

Osteopontin (OPN) is a non-collagenous extracellular matrix protein with pleiotropic functions, including mediation of cell adhesion and migration. Recently, high OPN serum levels were found in pancreatic ductal adenocarcinomas (PDACs) in which OPN mRNA was identified in macrophages. We investigated OPN expression at the protein level in 15 PDACs and 10 undifferentiated pancreatic carcinomas (UCs), 4 of them with osteoclast-like giant cells (OCGCs), to find out whether the degree of OPN expression is related to tumor infiltration by macrophages and the adhesive capacity of tumor cells. With regard to its potential adhesive function, we compared OPN expression in PDACs and UCs with that of E-cadherin and beta-catenin, two well-known adhesive molecules. OPN positivity was observed in two-thirds of PDACs (10/15) and in 7 UCs (7/10), including all 4 UCs with OCGCs. Apart from tumor cells, OPN was expressed in macrophages and OCGCs. When we assessed the relationship between the number of OPN-positive macrophages and tumor cells, we did not find any statistically significant correlation. There was also no correlation, either positive or negative, between OPN expression and E-cadherin and beta-catenin expression. The results demonstrated that, in PDACs and UCs, OPN is expressed in both tumor-associated macrophages and tumor cells. The biological significance of this dual expression pattern is not yet known. It is, however, unlikely that OPN has an adhesive function, since its expression pattern differs distinctly from that of E-cadherin or beta-catenin.

Pancreatic diseases past and present: a historical examination of exhibition specimens from the Collectio Rokitansky in Vienna.

The Viennese collection of pathological specimens (Collectio Rokitansky) comprises a large number of objects from all fields of pathological anatomy and is one of the largest historical collections in the entire world. We reviewed the original diagnoses in a series of pancreatic specimens using modern histopathological techniques. It was found that the histological structure of eleven pancreatic specimens was surprisingly well preserved. In three cases of extrapancreatic pseudocysts, we identified chronic pancreatitis as the underlying disease. Two specimens contained tumours that proved to be ductal adenocarcinomas. A third, rather large tumour was identified as a solid-pseudopapillary carcinoma and a fourth one as a neuroendocrine carcinoma. The remaining cases were classified as fibrotic atrophy, congenital cysts, microcystic serous cystadenoma, and necrotic sequestration of the pancreas. The application of immunohistochemical methods failed. In conclusion, the surprisingly well-preserved exhibits from the Collectio Rokitansky, which have been on display for more than 100 years, are accessible to modern histopathological investigation without the use of immunohistochemical techniques. Such examinations allow us to assess the occurrence of diseases and tumours in the sociocultural environment of the 19th century.

Apoptosis in human colorectal tumours: ultrastructure and quantitative studies on tissue localization and association with bak expression.

Apoptotic cell death in human tumours has been demonstrated by electron and light microscopy. In adenomas, fragmented and apoptotic nuclei and signs of phagocytosis have been observed close to the basement membrane. In carcinomas the characteristic structures were apoptotic bodies with small fragments of chromatin. DNA fragmentation was shown by in situ end-labelling. Quantitative assessment of apoptosis and proliferation revealed a high apoptotic index (AI) in all types of adenoma (tubular: 1.77+/-0.35%, tubulovillous: 2.38+/-0.41%; villous: 3.3+/-0.39%) as well as loss of compartmentalization of proliferating and dying cells. In carcinomas a shift towards proliferation was evident, as shown by lower AIs than in adenomas (0.9+/-0.68% and 1.1+/-0.12% for moderately and poorly differentiated tumours), higher Ki67 indices (38.32+/-2.23% and 57+/-3.89%, respectively) and higher mitosis (0.9+/-0.56% and 1.21+/-0.17%, respectively). However, apoptosis was observed in all tumours and is available as a target for therapeutic intervention. Expression of the apoptosis related proteins bcl-2 and bak also reflected loss of compartmentalization. While bcl-2 did not show a consistent relationship to AI in tumour specimens, bak was positively correlated with apoptosis in 4 of 8 adenomas and 4 of 7 carcinomas, suggesting a role for this protein in the induction of apoptosis in a subset of tumours.

Prognostic relevance of intracytoplasmic cytokeratin pattern, hormone expression profile, and cell proliferation in pituitary adenomas of akromegalic patients.

Seventy-six pituitary adenomas of akromegalic patients were investigated to find out the prognostic relevance of the intracytoplasmic distribution of cytokeratins (CK), immunohistochemically defined hormone production profile, proliferative activity and clinical presentation. CK distribution, growth fraction (MIB1 index) and hormone production profile were analyzed by means of immunohistochemistry. Apoptotic activity was investigated by the TUNEL method. Two different CK distribution patterns were seen: a dot-like pattern in 29 cases (type 1 adenomas), and a perinuclear fibrillary pattern in 47 cases (type 2 adenomas). Type 2 adenomas showed more prominent coexpression of prolactin (p < 0.0001), luteotrophic hormone (p < 0.002), follicle-stimulating hormone (p < 0.005), thyroid-stimulating hormone (p < 0.0001), and alpha-subunit (p < 0.005), as compared to type 1 adenomas. The mean MIB1 index was significantly higher in type 1 vs. type 2 tumors (4.23%, range: 1.93% - 9.83% vs. 2.07%, range: 0.67% - 4.87%, p < 0.0001). Apoptotic activity was too low in both examined groups to be used for balancing of tumor cell turnover. Clinical analysis of patients with type 1 adenomas revealed female predominance, younger age, larger tumor size, and more frequently aggressive growth with higher incidence of suprasellar extension (p < 0.0001) and cavernous sinus infiltration (p < 0.0001), as well as larger proportions of re-operations and incomplete resections (34.5% vs. 8.51%). Additionally, the interval until re-operation was shorter in type 1 adenomas (mean: 16 months, range: 9 - 21 months vs. mean: 57 months, range: 18- 158 months). We conclude that classification of adenomas of akromegalic patients based on intracytoplasmic CK distribution, combined with examination of proliferative activity, and immunohistochemically defined hormone production profile, provides important prognostic information for the management of akromegalic patients.

Chaodynamic loss of complexity and self-similarity in cancer.

'Omnis cellula a cellula': each cell descends from another cell--and most complex organ structures are built up of multiple cells at least. Even the underlying mechanisms of physiological as well as pathological processes reflect complexity in a pronounced manner. Loss of complexity, however, has been detected in aging and apparently also in the case of a number of diseases. This paper describes the loss of complexity in both carcinogenesis and the related growth pattern of cancer. After disruption of the cell's stability as a result of mutations, a decrease in the ability of the cell to induce a self-organized response is associated with the loss of control parameters at the cellular and molecular level. Complexity, understood as a principle of order, is altered in certain malignant tumors, as is indicated by a loss of the golden mean and by the disappearance of self-similarity. The lack of self-similarity could, therefore, be an ideal practical marker of malignancy in medical image analysis.

The potential role of apoptosis (programmed cell death) in a chaotic determined carcinogenesis.

The proposed hypothesis may interpret apoptosis as a dynamic parameter by means of chaos theory. Regular tissue renewal is determined by the quantity of mitosis and cell death (mainly apoptosis). These two components are describable as so-called 'limit cycle attractor' representing a reference cycle of the tissue system. If tissue kinetics remain within these limits, the system stays in a homeostatic equilibrium. Disruptive factors such as genetic alterations may have the ability to destabilize this homeostasis and induce the quasiperiodic development which represents one way in which a system becomes chaotic. The inhibition of apoptosis prevents the elimination of mutation-affected cells which leads to an uncoordinated proliferation of a mutated cell clone. Thus, this clone represents an independent oscillator which effects a new attractor: it is called 'torus' attractor. Additional perturbations induce the chaotic 'strange attractor': the system is bound to shift into chaos, morphologically detectable as cancer.

Fractal tumours: their real and virtual images.

Autonomous and uncoordinated proliferation of epithelia leads to various well-known growth patterns such as expansive (cauliflower-like), radiating infiltrative, polycyclic, and roundish-ovoid figures. All attempts to describe such natural growth patterns graphically by Euclidean geometry have failed and remain no more than works of art. However, fractal geometry is a new tool for the characterization of irregularly-shaped and complex figures. Moreover, behind a fractal structure there is a basic power-law which provides the opportunity to simulate these forms artificially. A prerequisite for achieving this goal of simulating tumour growth by computer is to establish whether typical tumour growth patterns are fractal. Hence, an investigation was undertaken of 20 tumours (malignant, metastases or benign) exhibiting the above-mentioned typical patterns. If tumour outlines are fractal they have to possess a fractal non-integer dimension which significantly exceeds the integer Euclidean dimension. The fractal dimension of tumour outlines was determined using the box-counting method. Almost all tumours presented a fractal dimension and virtual tumour images were created by utilizing available fractal software. In conclusion, the determination of the fractal dimension of solid neoplasms may be an additional morphometric parameter for growth assessment and it probably provides further opportunity to simulate cancer growth and infiltration by computer animation.

[Nonlinear dynamics, chaos theory and wavelet analysis of the heart]. / Nichtlineare Dynamik, Chaostheorie und Waveletanalyse des Herzens.

Over the past years, techniques of nonlinear dynamics have gained increasing attention in cardiology. This kind of partly interdisciplinary research is supposed to provide a better understanding of cardiac disease, especially in the field of tachyarrhythmia. This article intends to introduce the principles of diagnostic procedures in terms of nonlinear dynamics, chaos theory and stochastic processes related to cardiology. An introduction to a new technique of wavelet analysis is given, and possible applications in the quantitative classification of high-risk patients for sudden cardiac death are discussed.

[Actinic brachial plexus lesion]. / Aktinische Plexus brachialis-Läsion.

Radiation-induced brachial plexus lesions are progressive and irreversible complications. Until now, there is no way to successful prevention and treatment of this problem. In our series, relief of pain could be achieved by neurolysis in some cases, but there was no recovery of sensory and motor function. In order to improve the vascularity and nerve tissue regeneration, we performed muscle or gliding tissue flaps after neurolysis in our department. Since 1975, 25 patients who developed radiation-induced plexopathy were treated in our department. We followed 18 patients to evaluate the benefits of our surgical intervention. None of the patients had improvement of their sensory or motor impairment. Relief of severe pain was achieved in 83% either by neurolysis only with or without muscle or gliding tissue flap. In some cases, paresis worsened postoperatively. We also observed a return of severe pain after the operation.

[Fractal analysis of a breast carcinoma--presentation of a modern morphometric method]. / Fraktale Analyse eines Mammakarzinoms--Vorstellung einer modernen morphometrischen Methode.

Fractal analysis techniques are common tools in physics and image processing. In the past few years they have gained increasing attention in medical sciences, e.g., cardiology, pathology and radiology, respectively. This article intends to describe this new technique by applying fractal analysis to the instant of a breast carcinoma. One of the advantages of fractal analysis is the ability to describe an irregular and complex object by a measureable value, called the fractal dimension. The fractal dimension can be determined by using the box-counting method. We applied this technique to the mammography as well as to the histologic section of a breast carcinoma. The application of fractal analysis provides a specific measureable value of the growth pattern of a tumor. Thus, the fractal dimension serves in addition to the common used metric diameter.

Protein kinase C tissue localization in human colonic tumors suggests a role for adenoma growth control.

BACKGROUND & AIMS: Protein kinase C (PKC) has been implicated as a mediator of growth control during colorectal carcinogenesis, but the mechanisms involved are still a matter of dispute. The aim of this study was to analyze PKC patterns and tissue distribution to gain further insight in PKC function during tumor development in the gut. METHODS: PKC isoenzymes alpha, beta 1, beta 2, delta, and eta and the proliferation antigen Ki67 were analyzed in formalin-fixed normal, premalignant, and malignant specimens using immunohistochemistry. RESULTS: In normal colonic mucosa, protein levels of all PKC isoenzymes followed an increasing gradient from the bottom to the top of the crypt, staining mainly terminally differentiated, resting cells. Atypical crypts observed in the normal mucosa adjacent to tumors expressed higher levels of Ca(2+)-dependent isoenzymes than the surrounding tissue. In tumors, the number and abundance of PKC isoenzymes was inversely related to proliferation in 7 adenomas and 9 carcinomas. Areas containing PKC-beta 1 as the only isoenzyme had the highest proliferation rates (50%-82% Ki67-positive cells). CONCLUSIONS: The data suggest a function of PKCs, especially PKC-beta 1, in colorectal carcinogenesis and tumor growth control.