Heart infarct as the major cause of death of hematological patients as identified by autopsy.

BACKGROUND: Despite progress in diagnostic procedures, clinical diagnosis is not always confirmed by an autopsy. An autopsy is a valuable tool in evaluating diagnostic accuracy. OBJECTIVES: The aim of the study was to compare clinical diagnoses of immediate causes of death with autopsy findings in patients with hematological malignancies or aplastic anemia. MATERIAL AND METHODS: In this study, the results of 154 autopsies (1993-2004) of patients with hematological diseases were reviewed and compared with clinical data. The most probable causes of death in the case of particular hematological diseases as well as the discordances between clinical and autopsy diagnoses and their relation to the clinical characteristic were identified in the studied cohort, which primarily included patients whose death at that particular time was not explained by the clinical course, and in 50% of cases was sudden. RESULTS: Although various combined infections have been found to be responsible for the largest number of deaths (26.6%), the most common single cause was myocardial infarction (29 patients, 18.8%). The discordance between clinical and post-mortem diagnoses of immediate causes of death was found in 55 patients (35.7%; 95% CI 28.2-42.8%), with 50.9% of cases considered class I discrepancies according to Goldman's criteria. The myocardial infarction was found to be clinically undiagnosed in 69% of cases. In 41% of cases, it was a class I discrepant diagnosis. CONCLUSIONS: This data suggests that hematological patients require special attention and probably preventive measures concerning coronary heart disease, particularly during the initiation of antineoplastic therapy.

Expression of E-cadherin, ß-catenin, and epithelial membrane antigen does not predict survival in patients with high-risk non-muscle-invasive bladder cancer.

THE AIM OF THE STUDY: The aim of the study was to validate the value of E-cadherin and ß-catenin expression and to test an alternative prognostic marker, epithelial membrane antigen (EMA). MATERIAL AND METHODS: Forty-nine consecutive patients with primary stage T1 non-muscle-invasive bladder cancer (NMIBC) were enrolled in this study. Tissue specimens were stained with the following mouse anti-human antibodies: anti-E-cadherin, anti-ß-catenin, and anti-EMA. Reaction intensity within cancer cells was assessed according to the immunoreactive score (IRS). Finally, the association between the expression of selected proteins and patient survival was assessed. RESULTS: The mean follow-up was 34.8 months. Recurrence-free survival, progression-free survival, and overall survival (OS) were 47.5%, 72.5%, and 72.5%, respectively. Differences in the IRS for ß-catenin and EMA were found clinically, but were not statistically significant in prediction of the risk of disease progression (p > 0.05). No difference in protein expression was observed regarding the risk of recurrence, OS, or cancer-specific mortality (p > 0.05). Stratification of patients based on the IRS into three groups (poor, moderate, and intensive reaction) failed to identify a prognostic marker among the tested proteins (p > 0.05). CONCLUSIONS: Expression of E-cadherin, ß-catenin, and EMA cannot reliably predict survival in patients with high-risk NMIBC. Further searches are needed to identify tissue markers of progression and recurrence in NMIBC.

Immunohistochemical differentiation between muscularis mucosae and muscularis propria for improving the staging of bladder cancer in patients undergoing transurethral resection of bladder tumours.

Microscopic differentiation between muscularis mucosae (MM) and muscularis propria (MP) of the bladder in the material obtained during transurethral resection (TUR) remains difficult. The study was aimed at determination of the usefulness of immunohistochemical staining in this context. Forty-seven TUR specimens were stained with 5 mouse anti-human antibodies: anti-desmin, anti-filamin, anti-type IV collagen, anti-smoothelin, and anti-vimentin. Slides were assessed under light microscopy and the intensity of the immune reaction within MM and MP was evaluated on a four-level visual scale as follows: negative (0) and weakly (1), moderately (2), or strongly (3) positive. MM was identified in 27 patients (57.4%). The modal values of reaction intensity in MM and MP was 0 and 2 for desmin (p > 0.05), 2 and 2 for filamin (p = 0.01), 2 and 2 for type IV collagen (p > 0.05), 1 and 2 for smoothelin (p = 0.03), and 2 and 0 for vimentin (p = 0.02), respectively. Identical intensity within MM and MP was observed in 7.1%, 28.6%, 20%, 30.1%, 5.6%, respectively. Immunohistochemistry can help differentiate between MM and MP in TUR specimens. As of yet, no single marker can reliably differentiate between MM and MP; however, a combination of anti-filamin, anti-smoothelin, and anti-vimentin antibodies may be reasonable for diagnostic purposes.

Morphofunctional Renal Alterations in Progeny of Mice Fed Rhodiola kirilowii Extracts or Epigallocatechin During Pregnancy and Lactation.

Treating infections in pregnant patients is potentially dangerous even when herbal medicines are used. Many herbal medicines, among them extracts from plants of Rhodiola genus, have antimicrobial, anti-inflammatory, and immunostimulatory properties owing to their polyphenol content; they may, however, affect fetal development due to their antiangiogenic properties. The aim of this study was to explain whether daily feeding pregnant and lactating mice with 20 mg/kg Rhodiola kirilowii aqueous (RKW) or 50% hydro-alcoholic (RKW-A) extracts, or 0.2 mg/kg epigallocatechin (EGC, antiangiogenic compound of Rhodiola extracts), may lead to abnormalities in morphology and function of the kidneys of adult progeny. Such abnormalities were not observed in the kidneys of 6-week-old offspring, neither in RKW nor in the control group. However, the progeny of RKW-A- or EGC-fed mothers presented morphometric abnormalities in the kidney structure, with a significantly higher number of glomeruli/mm2 and a lower diameter of glomeruli (RKW-A group) or a significantly higher glomeruli diameter (EGC), than in the control and RKW groups. Abnormalities in serum vascular endothelial growth factor, tumor necrosis factor (TNF)-alpha, urea, creatinine, and cystatin C levels were also found. We recommend caution in long-term use of RKW-A extract and EGC-rich foods during pregnancy and lactation.

WITHDRAWN: Study coexistence albumin, fibrinogen and complement on surface blood vessels and placental.

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Antigenic profile of muscularis mucosae and muscularis propria of the urinary bladder.

BACKGROUND: Differentiation between the muscularis mucosae (MM) and muscularis propria (MP) of the bladder remains challenging. OBJECTIVE: To identify MM- and MP-specific antigens that could be of potential value for staging of urothelial carcinoma in a pilot study. METHOD: The expression of 12 protein antigens in 11 human bladder specimens was examined. There were 5 post radical cystectomy specimens and 6 normal bladder autopsy specimens. Antibodies against actin, caldesmon, type IV collagen, cytokeratin, desmin, elastin, fibronectin, filamin, laminin, miotilin, smoothelin, and vimentin were used. Slides were stained with immunohistochemical reagents and assessed using light microscopy. The intensity of the immune reaction within MM and MP was evaluated in a four-level scale as negative and weakly, moderately or strongly positive. RESULTS: The presence of MM was noticed in 63.6% of specimens. The expression of desmin, filamin, and smoothelin was stronger within MP compared to MM in all cases. Stronger reaction with anti-type IV collagen antibodies was noticed within MP in 80% of the cases. In the whole study group, the expression of vimentin was stronger within MM than MP. CONCLUSIONS: MM and MP cells are of different antigenic characteristics. This can be used in the microscopic diagnostics of selected cases. The results need to be validated in a series of specimens from transurethral resection.

The study of the protein complement in myocardial infarction.

BACKGROUND: Activation of the complement system during myocardial ischemia and reperfusion results in its injury by multiple processes. The aim of this study was to evaluate contribution of innate, humoral mechanisms of nonspecific immune response in the myocardium subjected to infarction. Complement components and inhibitors were analyzed. MATERIALS AND METHODS: Myocardial specimens from the archives of Chair and Department of Pathology, Medical University of Warsaw from 2010 to 2013, were used in the study. The examined proteins were evaluated using immunohistochemistry and immunofluorescence techniques. Tissues from 36 men and 14 women, mean age 65.02 ± 14.65, were used in the study. The control group comprised healthy myocardial tissue collected from 10 subjects. RESULTS: Statistical analysis of IHC reaction for proteins and inhibitors of the complement system and membrane attack complex demonstrated markedly higher immunoreactivity level in the myocardium with ischemic necrosis versus healthy myocardial tissue. A correlation analysis demonstrated statistically significant positive correlation between the examined proteins and inhibitors of the complement system and protectin and membrane attack complex. A significant correlation was not found between immunoreactivity of the examined proteins and clinical and morphological parameters of the analyzed cases. CONCLUSIONS: Studies have shown that of the complement proteins presence on the surface of the myocardium subjected to ischemic destruction exacerbate.

Possible role of complement factors and their inhibitors in the myocardial infarction: an immunohistochemical study.

Ongoing development of our civilization is accompanied by a marked increase of incidence of cardiovascular diseases and cardiovascular mortality. Ischemic heart disease with its extreme form - myocardial infarction - is one of the main problems of modern medicine. Despite much research devoted to this disease entity, its pathomechanism remains incompletely understood. Basing on research reports, more and more emphasis is put on immune reactions in the myocardium. Available literature lacks detailed studies examining the role of complement system and its inhibitors in the development and pathogenesis of myocardial infarction. Cells of ischemic myocardium were proven to become foreign antigens for the immune system of the patient's body. This results in complement activation of formation of so called membrane attacking complex that injures myocardial cells. By binding to its surface, it extends the myocardial destruction caused by the infarction itself. Results of immunochemistry studies presented in this paper have demonstrated the existence colocalization of complement components (C4d, C9) and membrane inhibitors (CD55, CD59) as well as soluble inhibitors (factor H) of the complement in the examined muscle tissue that underwent ischemic necrosis. Positive immunohistochemical reaction was found in the myocardial cells, intercellular matrix and blood vessels.

Spontaneous regression of renal cell carcinoma.

Renal cell carcinoma (RCC) comprises 3-4% of all malignant tumours among adults in Poland. Spontaneous regression of RCC is a rare but well-known phenomenon. Its frequency is estimated to be approximately 1% and a large part of the percentage is accounted for by the regression of pulmonary metastases in the course of clear type of RCC treatment. We searched PubMed, Embase and SciVerse Scopus databases, identifying 59 case reports of spontaneous regression of RCC. Those medical histories come from reports from around the world and date back up to 40 years. This review includes their analysis as well as description of possible explanations of this phenomenon postulated by different authors, including both misdiagnosis and immunological reactions. This study indicates that reliable diagnostics and reporting of all the cases of spontaneous regression play a key role, as this is the only method which enables a better perspective in understanding this issue.

Loss of the orphan nuclear receptor SHP is more pronounced in fibrolamellar carcinoma than in typical hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a major problem in oncology. The molecular mechanisms which underlie its pathogenesis are poorly understood. Recently the Small Heterodimer Partner (SHP), an orphan nuclear receptor, was suggested to be involved as a tumor suppressor in hepatocellular carcinoma development. To date, there are no such studies regarding fibrolamellar carcinoma, a less common variant of HCC, which usually affects young people and displays distinct morphological features. The aim of our project was to evaluate the SHP levels in typical and fibrolamellar hepatocellular carcinoma with respect to the levels of one of the cell cycle regulators, cyclin D1. We assessed the immunoreactivity levels of SHP and cyclin D1 in 48 typical hepatocellular carcinomas, 9 tumors representing the fibrolamellar variant, 29 non malignant liver tissues and 7 macroregenerative nodules. We detected significantly lower SHP immunoreactivity in hepatocellular carcinoma when compared to non malignant liver tissue. Moreover, we found that SHP immunoreactivity is reduced in fibrolamellar carcinoma when compared to typical hepatocellular carcinoma. We also found that SHP is more commonly lost in HCC which arises in the liver with steatosis. The comparison between the cyclin D1 and SHP expression revealed the negative correlation between these proteins in the high grade HCC. Our results indicate that the impact of loss of SHP protein may be even more pronounced in fibrolamellar carcinoma than in a typical form of HCC. Further investigation of mechanisms through which the loss of SHP function may influence HCC formation may provide important information in order to design more effective HCC therapy.

Urothelial bladder carcinoma in young patients is characterized by a relatively good prognosis.

INTRODUCTION AND AIM: Urothelial bladder carcinoma (UBC) is a very rare condition in patients aged below 50 years. The aim of the study was to answer the question whether the characteristics of cancer in this group of patients differ from general UBC features. MATERIAL AND METHODS: Altogether 2160 patients treated with primary transurethral resection due to a bladder tumor were included in the study. The mean age of the cohort was 69.1 years (range 11-100). Patients were divided into three subgroups depending on age: age <41 years (group 1), age 41-50 years (group 2), age >50 years (group 3). Sex ratio, tumor grade, and stage of disease were recorded. RESULTS: Women constituted 18.5%, 19.2%, and 25.8% of the patients in groups 1, 2, and 3, respectively (P < 0.05). WHO grade 3 tumors were diagnosed in 0%, 8.5%, and 17.2%, respectively (P < 0.05). Non-invasive papillary carcinoma was found in 100.0%, 76.7%, and 62.7%, respectively (P < 0.05). The incidence of muscle-invasive bladder cancer was 0%, 11.0%, and 15.6%, respectively (P < 0.05). CONCLUSIONS: Pathological characteristics of UBC are dependent on the patients' age. Being a very rare condition, UBC in young patients is characterized by a relatively good prognosis.

Current concepts on pathogenesis and biology of metastatic osteosarcoma tumors.

Osteosarcoma (OS) remains the most common malignancy among orthopaedic neoplasms. Despite advanced surgical techniques and attempts to use second-line chemotherapy, 5 year overall survival in OS patients is still reported to be as low as 60-70%. Progression to metastatic disease is the main cause of treatment failures. Broadening current knowledge on the pathogenesis and biology of metastatic OS tumors is a key element in improving treatment results, i.e. identifying potential therapeutic targets. Recent studies have brought new concepts into this field. This paper outlines the most important issues which may influence treatment methods in the near future. In a few sections, we discuss (1) a model of OS dissemination with special regard to proteins mediating the lysis of the extracellular matrix; (2) the mechanisms protecting circulating OS cells from programmed death; (3) the relationship between angiogenesis, its pathogenesis, and OS metastatic potential; (4) the role of cytokines in OS progression and site-specific metastasis formation; (5) an example of treatment resistance mechanism - the P glycoprotein efflux pump; and, finally, we theorize on (6) whether cancer stem cells may play a role in OS progression.

[Relationship between heart development and pathogenesis of congenital heart defects in current literature]. / Wspólzaleznosci miedzy wadami wrodzonymi serca a jego rozwojem w swietle wspólczesnych badan naukowych.

This work presents current ideas on embryonic heart development and is an attempt to elucidate pathogenesis of congenital heart defects. The heart develops from 2 areas, the so-called "heart fields", which differ in the expression of various genes and in sensitivity to certain substances (for example retinoid acid). Heart fields are the source of cardiomyocytes and endocardial endothelial cells for the developing heart tube. Neural crest cells attaining the heart take part in the formation of tunica media of great vessels and the aorto-pulmonary septum. An interaction between the cells of the secondary heart field and neural crest cells migrating to the heart plays a significant role in heart development. This interaction is accomplished by various mediators released into the cell environment (e.g. activation of Notch, which induces secretion of growth factors such as Fgf8). Disturbances in signaling between these cellular populations lead to malformations of the cardiac outflow tract. The sinus venosus is the source of endothelial cells of the coronary vasculature, whereas the proepicardium provides cells for the epicardium, smooth muscle cells and fibroblasts.

Role of C3d and C4d complement fragments in the diagnostics of acute allograft rejection after transplantations.

Transplantation is a widely recognized method of treatment at the terminal stages of many renal, cardiac, hepatic and pulmonary diseases. Despite considerable advances in that field, graft rejection is still an important clinical problem. The reaction of the graft recipient to an organ presenting foreign antigens is dependent on complex immune mechanisms, involving both acquired and congenital immune responses. In most general terms, cellular and humoral immunity can be distinguished. The kidneys and the heart are the organs whose acute humoral rejection has been thoroughly investigated and defined, and the role of C4d and C3d fragments of the complement system has been confirmed by numerous studies. The studies concerning C4d and C3d expression in patients with acute humoral lung and liver rejection conducted to date have given contradictory results. Some of them confirm, while others fail to confirm, the correlation between their increased expression and AHR. From the practical point of view, C4d and C3d could be used in liver transplantology for differential diagnostics of acute graft rejection and recurrence of HCV infection. A few preliminary studies suggest the usefulness of these markers in the diagnostics of AMR and differentiation between both liver pathologies. There are only single reports concerning the role of C4d complement fragment in the diagnostics of acute rejection with a humoral component in case of small intestine grafts, as well as complex ones such as the hands and face, and their results suggests that these complement fragments are not important markers of acute rejection of these organs.

Morphological features and differential diagnosis of hepatitis C recurrence after liver transplantation - literature review and results of single transplantation center.

Orthotopic liver transplantation (OLT) is an established method of treatment for advanced and irreversible liver diseases. Type C (HCV) viral hepatitis is the most common indication for OLT in Western Europe, USA, and also in Poland. Recurrence of primary disease, that led to OLT, constitutes the crucial problem in medical care of transplanted patients. HCV recurrence is nearly universal, but the course of reinfection is unpredictable. There are many risk factors predisposing to more severe liver disease, related to characteristics of donor, recipient and virus. It was noted, that the course of HCV reinfection was more aggressive in patients transplanted in recent years. Generally, chronic HCV infection develops more aggressively in the liver allograft compared to the native liver and leads more rapidly to liver cirrhosis and graft failure. There are no certain laboratory tests or imaging techniques reflecting the status of infected liver. Morphological examination of liver biopsies is still essential to assess actual organ status, the activity and progression of the inflammatory process and the presence of other posttransplant complications. Results concerning the course of HCV reinfection are equivocal and differ in various populations. Many unresolved issues still remain. In the presented study pathomorphological features of HCV reinfection, differential diagnosis, and the basic results of authors' investigations concerning the relationship between many clinical and histopathological data and aggressiveness of HCV reinfection are described.

The possible role of factor H in colon cancer resistance to complement attack.

A soluble complement inhibitor factor H (FH) and its splice variant factor H-like protein (FHL) have been recently discovered to play a major role in malignant cell escape from complement-mediated cytotoxicity in lung-, ovarian- and glia-derived neoplasms. The role of FH in colon cancer has not yet been examined. Here, we studied immunocytochemically FH/FHL expression in tumor samples derived from 40 patients, with both primary colon adenocarcinoma and metastatic foci in the liver. FH/FHL immunoreactivity was present in stroma of both primary and metastatic tumors, in virtually all patients. The cellular immunoreactivity was observed infrequently. Importantly, when analyzed quantitatively, FH/FHL immunoreactivity was significantly increased in liver metastases when compared with the primary sites. In addition, we have analyzed FH and FHL expression in 5 colon cancer cell lines: SW480, SW620, HCT116, HT-29 and Lovo. FH mRNA and FH secretion were observed in SW620 and HT-29 cells, whereas FHL was produced only by HT-29 cell-line. By confocal and electron microscopy, FH immunoreactivity was associated with the plasma membrane and intracellular vesicular structures. Finally, we have analyzed the role of FH in the susceptibility of SW620 colon cancer cells to complement-mediated damage. When FH function was blocked, using specific antibody, the cells became more susceptible to lysis. Taken together, our results suggest an important role of FH/FHL in colon cancer cells defense against complement-mediated cytotoxicity, and in metastatic process.

[Current opinion in pathogenesis of pheochromocytoma]. / Wspólczesne poglady na patogeneze guza chromochlonnego.

Pheochromocytoma is a neuroendocrine tumor with significant clinical relevance. Is one of the causes of secondary hypertension. Most of the tumors are benign, but sometimes malignant cases are seen and there prognosis is unfavorable. So far, none of the factors which could initiate development of pheochromocytoma are known, besides genetic ones. In this review, most common familial syndromes connected with pheochromocytoma are characterized.

[The effect of retinoic acid on primary cultures of human pheochromocytoma cells]. / Wplyw kwasu retinowego na komórki pheochromocytoma.

INTRODUCTION: Retinoic acid is a regulator of gene expression which, by binding to its nuclear receptor, determines the degree of differentiation in multiple cancer cell types. On the basis of this capability it was introduced, e.g. in the therapy of neuroblastoma. In cells derived from neural crest, such as neuroblastoma cells, retinoic acid initiates differentiation into neurons. This substance acts in a similar way on a rat pheochromocytoma cell line PC12. The aim of our work was to examine the influence of retinoic acid on the phenotype of human pheochromocytoma cells in primary culture. MATERIAL AND METHODS: Observations were made on two primary cultures isolated from human pheochromocytoma. Cells were grown in RPMI1640 medium supplemented with 10% foetal bovine serum. Subsequently, the cultures were treated with 100 mMol retinoic acid for three-days. An evaluation of the phenotype change was performed by estimating the expression levels of F-actin, MAP-2 protein, and chromogranin, with the use of a confocal microscopy. RESULTS: The introduction of retinoic acid into the culture caused an increase in the F-actin level and its redistribution in the form of stress fibers. Simultaneously, the cells changed their shape, generating more processes. No change was detected in the expression level of neuroendocrine markers: MAP-2 and chromogranin. CONCLUSIONS: Retinoic acid appears to have an influence on some phenotype parameters of human pheochromocytoma cells. Further work is needed to determine the molecular mechanisms of this process, and to evaluate thoroughly the benefits of introducing retinoic acid into therapy of pheochromocytoma tumors.

Morphometric and functional abnormalities of kidneys in the progeny of mice fed chocolate during pregnancy and lactation.

Even most commonly consumed beverages like tea, coffee, chocolate and cocoa contain methylxanthines, biogenic amines and polyphenols, among them catechins, that exhibit significant biological activity and might profoundly affect the organism homeostasis. We have previously shown that 400 mg of bitter chocolate or 6 mg of theobromine added to the daily diet of pregnant and afterwards lactating mice affected embryonic angiogenesis and caused bone mineralization disturbances as well as limb shortening in 4-weeks old offspring. The aim of the present study was the morphometric and functional evaluation of kidneys in the 4-weeks old progeny mice fed according to the protocol mentioned above. Progeny from the mice fed chocolate presented considerable morphometric abnormalities in the kidney structure, with the lower number of glomeruli per mm2 and their increased diameter. Moreover, higher serum creatinine concentration was observed in that group of offspring. No morphometric or functional irregularities were found in the progeny of mice fed theobromine. Abnormalities demonstrated in the offspring of mice fed chocolate are not related to its theobromine content. Consequently, identification of active compound(s) responsible for the observed effects is of vital importance.