Search

Data analysis of the incidence, mortality and basic data regarding therapy of esophageal cancer in the Czech Republic and determining possible ways to improve the current situation.Analysis was performed using data obtained from the Czech National Cancer Registry and from the Registry of Thoracic Procedures from the Section of Thoracic Surgery of the Czech Surgical Society. Analysis of specialized literature provided generally accepted risk factors for the development of esophageal cancer.Esophageal cancer represents 0.7% of all solid malignant tumours in the Czech Republic (1.1% in males and 0.2% in females). During 1977 to 2008, the incidence increased from 2 to 5.4 cases per 100.000 inhabitants and mortality from 1.9 to 4.1 cases per 100.000 inhabitants. In absolute numbers, the incidence was 561 cases (5.4 per 100.000 inhabitants) in 2008. Absolute mortality rate was 452 deaths (4.3 per 100.000 inhabitants) and absolute prevalence (number of patients living with cancer or with its medical history) was 791 subjects(7.6 per 100.000 inhabitants). When compared to international data, the incidence in the Czech Republic is the 84th highest in the world and 17th highest in Europe (mortality rates are at the 85th place in the world and the 18th place in Europe). In the Czech Republic, the highest incidence is in the Moravian-Silesian and Zlin regions (6.1 per 100.000), the lowest in the Plzen (4.2) and Vysocina (4.1) regions. The average age at the time of diagnosis is 62 years in males and 68 years in females, the maximum incidence is between 55 and 69 years in males and between 58 and 79 years in females. Upon diagnosis, advanced stages of the disease predominate. In 2008, 28% of the detected esophageal cancer cases were stage I and II disorders, 60 % were stage III and IV disorders, and in 12% of the cases the stage was not determined. In the treated patient group, the five-year survival rate was 15.5% in total, based on an analysis of data from 2004 - 2007. The five-year survival was 30% in stage I and II diosease cases, 12% in stage III disorders and 2% in stage IV cases. When comparing the analysis of data from 2004 to 2007 with the analysis of data from 2000 to 2003, there is a 10% improvement in stages I and II and a 4% improvement in stage III disorders. According to the Thoracic Surgery Registry of Thoracic Procedures data covering the period 2007 to 2010, thoracic procedures are performed at 19 to 22 surgical departments, esophageal resections are performed at 13 to 14 surgical departments, but only in 8 to 9 of these departments is the frequency of such procedures more than 10 operations per year. At the authors' department, 53 esophageal resections have been performed in the past five years with a 3.8% postoperative mortality rate and a 23 % total postoperative morbidity rate. Forty-nine percent of the cases were adenocarcinomas.Based on its incidence in our population, esophageal cancer can be considered an unfrequent tumour. This analysis shows regions of the Czech Republic with higher incidence and the most at-risk age group in males. Significant risk factors for squamous cell cancer such as smoking and alcohol consumption have already been previously identified; in adenocarcinoma it is primarily Barrett's esophagus. Other risk groups include patients with achalasia and with strictures after corrosion injury to the esophagus. Acceptable treatment results may only be achieved in patients with less severe stages of the disease and it would therefore be appropriate to actively search for such patients in at-risk regions and among the risk groups as part of the preventive programs. To date, universally accepted guidelines for monitoring of such patients have not been defined. Surgical treatment is a highly specialized domain of thoracic surgeons focused on esophageal surgery and patients should be concentrated in specialized centres.

Introduction Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with dramatic blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, the role of Perp in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp function in the mammary gland. Methods Immunofluorescence and Western blot analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined by using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared with those in untransformed cells with Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14-Cre/+;p53fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed, and tumor-free survival was assessed using Kaplan-Meier analysis. Results We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared with untransformed cells. Importantly, Perp deficiency also promotes the development of mouse mammary cancer. Conclusions Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy.

The article is an overview of major trends in the development of diagnostic and clinical registries which constitute a significant component of the informational background of personalized medicine. The rapid development of diagnostic methods has allowed data analysis to enter into the decisions about diagnosis and treatment of many diseases. However, practical application of the analyses still has serious limits related to the availability of complex, quality data. The basic trends of research in this field are the increasing standardization of content and structure of clinical databases and their association with clinical patient's records on an individual basis and ensuring the development of modern analytical tools.

Everolimus is an oral mTOR kinase inhibitor approved for the treatment of patients with metastatic renal cell carcinoma (mRCC) progressing during or after treatment with vascular endothelial growth factor (VEGF)-targeted agents. Using the national RENIS clinical registry, we have retrospectively analysed outcomes of patients treated for mRCC with everolimus. A total of 78 patients were evaluable. Median progression-free survival from the start of everolimus therapy was 7 months (95% confidence interval 2-12 months). Partial response or stable disease was achieved in 69% of patients. Treatment toxicity was predictable and serious adverse events occurred in only 6% of patients the most common being respiratory toxicity. Everolimus therapy provides significant clinical benefit for heavily pretreated mRCC patients after failure of VEGF-targeted therapy.

Implementation and introducing of first trimester screening using nuchal translucency (NT), nasal bone (NB), maternal serum pregnancy associated plasma protein-A and free beta-human chorionic gonadotropin (PAPP-A and fbeta-hCG) as a new method of screening for Down's Syndrome in a One-Stop-Clinic for Assessment of Risk for chromosomal abnormalities in the Czech Republic. To prove its effectiveness and make it part of our daily practice. Modify and/or withdraw the existing current practice.Prospective study of 5010 singleton pregnancies who attended our clinic for prenatal screening for chromosomal and congenital abnormalities between 11-13+6 weeks gestation from January 2005 to December 2007. Pregnancies were followed up to ascertain live birth of Down syndrome babies.The uptake was 100% for screening and around 95% for invasive testing in the screen positive group. All expected trisomies 21 were detected along with many other aneuploidies for false positive rate of 4.4%. The study demonstrated the feasibility and efficacy of introducing OSCAR for chromosomal abnormalities in a University Hospital setting. The introduction of an examination of nasal bone reduced our false positive results and increased our sensitivity. Women who participated in our screening strategy were no longer advised to undergo the triple test.

The exponential growth in medical knowledge is closely followed by expanding range of therapeutic options as well as increasing expenses associated with the use of new diagnostic techniques and treatments. This development requires organizational steps that would ensure that the expenditure is associated with the maximum benefit. The following text discusses foundation and development of a network of cancer care centres in the Czech Republic.

The aim of this work was to point out the role and the significance of surgery in the management of oncology patients in the Czech Republic (CR).Involvement of surgery in the management of patients with solid tumors is documented based on statistical data collected from the National Oncologic Registry.In the Czech Republic, the number of patients operated for newly diagnosed malignant tumors is constantly increasing, e.g. over 44,000 patients in 2005. Considering tumor locations, various surgical specialists are involved in the surgical management of solid tumors. Overall, during the studied period, surgeons were involved in 32,760 surgical procedures, i.e. 73.6 % of all newly diagnosed malignant solid tumors. Oncosurgical procedures are, to a certain extent, performed in all surgical clinics in the Czech Republic (currently, there are 157 surgical clinics in the Czech Republic). The rates of procedures for individual diagnoses do not correspond with the "high volume hospital" principle.Based on the analysis of the current situation in the management of solid tumors in the Czech Republic, the authors recommend rational concentration of oncosurgical procedures to fewer surgical clinics, adequate financing of sophisticated oncosurgical procedures in these clinics and classification of oncosurgery as a recognized official medical specialty.

The nation-wide register of patients with the exsudative age-related macular degeneration surveys the appearance and the success rate of the treatment of this disease in the Czech Republic. During the 12 months follow-up period of 38 patients treated with Macugen in monotherapy, receiving at least 7 injections of Macugen during one year period, we found the loss of less than 15 letters of the ETDRS chart in 62.2 % of treated eyes. During the 12 months follow-up period of 205 patients treated with Lucentis in monotherapy, receiving at least 3 injections of Lucentis, we found the loss of less than 15 letters of the EDTRS chart in 82.0 % of treated eyes. During the 12 months follow-up period of patients treated with Visudyne in monotherapy we found the loss of 15 letters of the EDRTS chart in 77.1% of treated eyes.

The Czech Ophthalmologic Society (member of the Czech Medical Society of Jan Evangelista Purkyne) in collaboration with the Institute of Biostatistics and Analysis of the Masaryk University in Brno established a nation-wide information system for the follow-up of the epidemiology and treatment of the exsudative age-related macular degeneration (ARMD). The project named AMADEUS is a multi-centric, non-invasive, observation prospective study with the aim to improve the patients' treatment and to unify the criteria for the follow-up of the ARMD in the real clinical practice in the Czech Republic. The basic instrument of the whole project is a clinical register collecting parametric data from 9 specialized centers. Especially the project monitors the photodynamic therapy with Verteporfyrine (Visudyne) and treatment by anti-VEGF agents, or Pegaptanib (Macugen) and Ranibizumab (Lucentis). The project's protocol is trying to collect representative data about ARMD diagnosis and treatment; during regularly controls, the efficacy and safety of the treatment are followed-up.The data collecting does not influence the treatment strategy or the availability of chosen treatment for the patient. Since October 2008 until the end of the year 2009, the registry collected complex information about more than 1402 newly treated ARMD patients; out of them, in 582 cases the one-year follow-up period was regularly terminated. The available data shows well-considered indication of drugs indications by the doctors; the treated patients fulfill the indications criteria set by the scientific society. According to the data from the registry, in some treating centers the application schedule is not followed-up in some drugs (especially Pegaptanib); there is the possibility to improve the treatment. All the clinical centers participating in the AMADEUS registry will continue in the data collecting, which after a longer period of time will facilitate further treatment optimization and eliminating of the established imperfections. Further information about the project may be found at the web site: www.amadeus.registry.cz.

All three cancer screening programmes recommended by the Council of the EU are available to defined target age groups in the Czech Republic. Organized programmes for screening of breast, colorectal and cervical cancer have been initiated in the last decade.A system for information support, as an essential component of organized screening programmes, has been implemented in all screening programmes. It comprises the Czech National Cancer Registry to monitor the cancer burden and population impact of the programmes, the National Reference Centre as a provider of nationwide insurance claims data, and the specialised databases of all three programmes, which collect information on screening, diagnostics and final diagnoses.Early diagnostics of malignant neoplasms and progress in therapy have helped to stabilize mortality, even in diagnoses with increasing incidence. The coverage of the Czech screening programmes has constantly been rising; however, it is still insufficient: 51.2%, 17.9% and 48.4% of the target population was covered at the end of 2008 in breast, colorectal and cervical screening programmes, respectively. In 2008, a total of 468,419 women underwent screening mammography and 2,128 tumours were detected (4.5 per 1,000 screened). According to the screening colonoscopy registry, more than 13,000 men and women underwent preventive colonoscopy in 2009, 4,085 patients were diagnosed with adenoma and 619 with colorectal cancer, mostly in the early stages. The information system for cervical screening was implemented in 2009 and has been running in pilot mode; the first results are expected at the end of 2010.The system for information support within organised cancer screening programmes enables monitoring of the performance of screening and diagnostic centres and thus helps to maintain continuous quality improvements, which are a necessary presumption for replicating the promising results of clinical trials. To achieve a substantial impact on population incidence and mortality, a large increase in test coverage in target populations will be necessary. The programmes should be transformed to a population-based form, which involves inviting all people in the target population to be screened.

The Czech Republic is ranked among those countries with the highest cancer burden in Europe and worldwide. The purpose of this study is to summarize long-term trends in the cancer burden and to provide up-to-date estimates of incidence and mortality rates from 2007.The Czech National Cancer Registry (CNCR) was instituted in 1977 and contains information over a 30-year period of standardized registration covering 100% of cancer diagnoses and the entire Czech population. The analysis of CNCR is supported by demographic data of the Czech Republic and by the Death Records Database as civil registration systems. The epidemiology of malignant tumours in the Czech population is available online at www.svod.cz.All neoplasms, including non-melanoma skin cancer, reached a crude incidence rate of almost 736 cases per 100,000 men and 648 cases per 100,000 women in 2007. The annual mortality rate exceeded 263 deaths per 100,000 population; each year, more than 27,000 persons die of cancer. The overall incidence of malignancies has increased during the last decade with growth index + 26.4% (1997-2007) while the mortality rate has stabilized over this time span (growth index in 1977-2007: -2.5%). Consequently, the prevalence has significantly increased in the registration period and in 2007 it exceeded 400,000 cases. In addition to the demographic ageing of the Czech population, the cancer burden is increased by the growing incidence of multiple primary tumours (recently more than 11% of the total incidence). The most frequent diagnoses include colorectal cancer, lung cancer, breast cancer and prostate cancer. Although some neoplasms are increasingly diagnosed at an early stage (e.g. proportion of stage I + II in female breast cancer: 71.9%, skin melanoma: 81.3%), in general early diagnostics is insufficient in the Czech Republic. This is the case even for highly prevalent colorectal carcinoma (only 43.2% of incident cases recently diagnosed at stage I or II).The Czech Republic is well equipped with high-quality and functional facilities for collecting and analysing population-based data on malignant tumours. The data survey has enabled the priorities of cancer management in the Czech Republic to be defined. This will undoubtedly lead to a sustained reduction in late diagnosed cases and a reduction in the remarkable regional differences in diagnostic efficiency.

Czech Republic is the first in the incidence of colorectal carcinoma (CRC) in all over the world. There is 60% development of liver metastases in the patients with colorectal carcinoma (LMCRC). Liver resection as the most effective therapeutic choice potentially curative is available only in 20% of the patients with CRC. Surgery with adjuvant chemotherapy leads to 5yr. survival in 50% of patients with LMCRC.To evaluate how many patients with LMCRC are indicated for liver surgery and how many patients are predicted for surgery every year in Czech Republic.A questionnaire was sent to 140 surgical department of Czech Republic in 2001, 142 in 2009 respectively with questions regarding to surgical treatment of LMCRC. The data were compared to similar survey evaluation on The Netherlands and Austria and data from Czech national oncology registry.217 liver resection (57 major including) resp. 466 (140 major including) were done in Czech Republic in 2000, resp. 2008 (114.7% growth). Number of liver resections providing in 2000 resp. 2008 compared to predictive number of liver surgery was 24.1%. resp. 49.4% (approx. 100% growth). Number of liver resections for primary as well for secondary malignancy in Czech national oncology registry was involved together.High incidence of CRC leads to high incidence of LMCRC in Czech Republic. About 1.000 patients with LMCRC can be expected in Czech Republic in the 60% development of LMCRC and 20% resectability every year. Only 50% of patients with LMCRC have the chance for adequate therapy nowadays. For the evaluation of quality of surgical department other studies are needed.

The registry of patients treated with Thromboreductin (anagrelide) in the Czech Republic contains data concerning patients that have been treated using this drug since 2004. As of June 2009, the total number of patients was 549. The current analysis focused mainly on evaluation of anagrelide dosage needed to achieve a complete response in high-risk patients: reduction in platelet count to below 400 x 10(9)/l, which was also considered as reaching the therapeutic goal. The outcomes of the registry confirm that although anagrelide (Thromboreductin) is a very effective platelet-reducing agent, the administration of which is related to a low incidence of adverse effects and complications, the therapeutic goal is not achieved in all cases and or despite a quick treatment response, the therapeutic goal is achieved more slowly.

Cholesterol levels were measured at public places (mostly department stores) from 2005 to 2008. Sampling was conducted at random, from volunteers, without any prior dietary restrictions. In total, 14,539 persons were assessed. We did not find any significant differences between sexes in cholesterol levels (overall median was 5 mmol/l; 4.9 mmol/l in men and 5.1 mmol/l in women). Smaller proportion of women than men had cholesterol levels lower than 5.0 mmol/l (53.0% of men and 45.2% of women). Cholesterol levels raise with age in both sexes, stagnate at a certain point and subsequently decline; we identified a significant difference in this between men and women--the levels start to stagnate at the age of 50 in men and beyond the age of 65-70 years in women. The levels fall with increasing age in both sexes after the age 65 years. Cholesterol levels rise with age in both sexes before the age of 50 years; this trend is the same in both sexes (i.e. there is no significant difference between sexes, p = 0.687). Nevertheless, cholesterol levels are statistically significantly higher in women than in men in the over 55 years age group (the difference in the cholesterol level values median is up to 0.8-0.9 mmol/l). This difference is retained to advanced age of75 years.

Bone incidents today represent, in terms of frequency and the overall effect on the quality of life of patients with breast cancer, a serious health problem. In a number of clinical studies bisphosphonates have been shown to have a positive impact on reducing the risk of bone events and therefore to be effective in the prevention of bone events. The primary objective of this project was to identify the incidence of bone events in patients with metastatic breast cancer treated in the Czech and Slovak Republics.Retrospective, multi-centre, non-interventional, epidemiological and explorative studies to identify the incidence of bone events in the defined group of patients and a description of the practice of prevention and treatment of skeletal events in the years 2000-2005. Enrolled were patients with advanced metastatic breast cancer diagnosed in 2000.Analysis of overall survival and survival to disease progression, analysis of patterns of treatment of bone events and the practice of the use of bisphosphonates in the prevention of bone events in metastatic skeleton affection in the normal conditions of clinical practice, analysis of patient compliance in the treatment with bisphosphonates, analysis of the time interval between the occurrence of bone metastases and the occurrence of bone events and, last but not least, survival analysis of patients in relation to bone events.This work has shown that the practice of treatment with bisphosphonates since 2000 and assessed the survival of patients with metastatic breast cancer.

The retrospective part of the IKARUS Project (Incidence of Skeletal Related Events in Breast Cancer) was focused on monitoring the incidence of skeletal related events in patients with metastatic breast cancer treated in the Czech and Slovak Republics.The aim was to describe the experience with data collection management in the conditions of the Czech and Slovak Republics.Retrospective collection of data in multi-centre, non-interventional, epidemiological and explorative studies. Female patients diagnosed since 2000 were involved in the project in order to respect the five-year period of monitoring and to describe the treatment of the period.During the initiation phase of the retrospective study each of the 18 Complex Cancer Centres in the Czech Republic (see www.linkos.cz) and 18 chosen oncology centres in the Slovak Republic were addressed. In the end, data were collected from 13 oncology centres in the Czech Republic and 12 oncology centres in the Slovak Republic. The initial plan to enrol 650 patients was not completed; data on 254 patients from the Czech Republic and 125 patients from the Slovak Republic were finally analysed.The effectiveness of retrospective data collection in the conditions of Czech and Slovak oncology corresponded with the possibilities of access to data of formerly diagnosed and treated patients. In searching for retrospective data the present hospital information systems could not be used in most oncology centres.Therefore, the cost of retrospective data collection was estimated and was shown to be relatively high.The binding methodical conclusion is that unless a systemic change is made in the functionality of hospital information systems and standardised electronic documentation is introduced, the retrospective collection of clinical data in our conditions will be associated with high costs and a relatively low recovery factor.

The analysis of therapeutic load and evaluation of quality of care require data collected on a long-term basis. The Czech Society for Oncology develops a comprehensive information system that combines data from population-based and clinical registries and that covers all key aspects of health care assessment: monitoring of population risks and associated therapeutic burden, predictions of number of patients to be treated, evaluation of results of diagnostics and of cancer care outcomes. Accessible data proves high cancer burden in the Czech population, colorectal carcinoma being a typical example. Czech population reveals one of the highest incidence of colorectal cancer in the world. Regardless of steadily increasing incidence of colorectal carcinoma, Czech cancer care has managed to stabilize mortality of this disease and also probability of 5-yr relative survival was significantly improved in last 15 years. Developed data base allows to assess burden and results of all therapeutic modalities, including surgery. This work is aimed to present Czech data platform that can be employed in any relevant health care assessment. To keep its position in current financially limited health care system, modern surgery must effectively use all accessible data sources.

The CORD trials tested ramipril and losartan in patients with hypertension.CORD IA involving switching from an angiotensin-converting enzyme inhibitor (ACEI) to the angiotensin II receptor blocker (ARB) losartan. 4,016 patients with blood pressure (BP)160/100 mm Hg who had been treated with an ACEI for3 months were enrolled. The mean age was 62.6 +/- 11.6 years and 53.1% were women. The patients discontinued ACEI and switched to losartan 50 mg once daily. BP, heart rate, biochemistry, blood counts and ECGs were measured at day 1 and months 1, 3, 6 and 12. If the BP wasor = 140/90 mm Hg after 1 month or more, the dose of losartan was increased to 100 mg. After 1 month the BP decreased from 147.4 +/- 14.8/87.7 +/- 9.3 mm Hg to 139.7 +/- 11.8/83.0 +/- 9.3 mm Hg (p0.001) and after 1 year to 133.7 +/- 11.3/79.1 +/- 7.06 mm Hg (p0.001). The rate of adverse events did not significantly increase and no changes in plasma sodium, potassium, urea or creatinine were observed. CORD IB compared ramipril and losartan. 3,813 patients with BPor = 140/90 mm Hg who were not being treated with an ACEI or ARB were enrolled. The mean age was 60.5 +/- 12.2 years and 50.5% were women. The patients were randomised to ramipril 5 mg (n = 1,926) or losartan 50 mg (n = 1,887). The dose was doubled if BP after 1 month wasor = 140/90 mm Hg. If the BP after 3 months still wasor = 140/90 mm Hg, another antihypertensive drug was added, typically athiazide diuretic.After 1 yearthe BP decreased in the ramipril group from 155.9 +/- 13.1/93.0 +/- 8.9 mm Hg to 134.1 +/- 11.2/81.5 +/- 6.8 mm Hg (p0.001) and in the losartan group from 156.5 +/- 13.1/93.4 +/- 8.8 to 134.55 +/- 11.3/80.16 +/- 6.6 mm Hg (p0.001). No significant differences were found between the groups. A slight increase in plasma potassium (0.2 mmol in both groups) and urea (0.3 mmol in both groups) was observed, but no change in plasma creatinine. There was a small, insignificant decrease in plasma uric acid (in the ramipril group from 325.5 to 320.7 micromol/l and in the losartan group from 321.6 to 318.3 micromol/l) and a slight decrease in plasma glucose and triglycerides (0.2 mmol/l in both measures in both groups). No severe adverse events were observed, but dry cough was 8 times more frequently reported in the ramipril group.CORD IA confirmed that switching from an ACEI to losartan is safe and effective. Titrating the dose upwards or adding diuretics leads to good BP control in the majority of patients (2/3). CORD IB showed no differences between ramipril and losartan in lowering BP and both drugs showed a trend to improve metabolic parameters such as glycaemia, triglyceridaemia and uric acid equally. Dry cough was more frequent after ACEI.

Pemphigus vulgaris (PV) is an autoimmune bullous disease in which autoantibodies against proteins of the desmosomal adhesion complex perturb desmosomal function, leading to intercellular adhesion defects in the oral mucosa and skin. Previous studies have demonstrated a central role for downregulation of the desmosomal cadherin desmoglein 3 (DSG3) in the pathogenesis of PV. However, the effects of non-cadherin desmosomal proteins in modulating the cellular manifestations of PV remain poorly understood. Here, we characterize the expression and functional importance of Perp, a newly discovered tetraspan desmosomal protein, in PV. Our data demonstrate that PV autoantibodies disrupt Perp expression at the membrane and trigger its internalization along with DSG3 into the endosomal pathway, where it is ultimately targeted to the lysosome for degradation. We further show that Perp deficiency exacerbates the pathogenic effects of PV autoantibodies on keratinocytes by enhancing both the depletion of desmosomal DSG3 and intercellular adhesion defects. Together, our findings highlight the importance of non-cadherin desmosomal proteins in modulating PV phenotypes and provide new insight into Perp's role in the desmosome.

The directive of the Ministry of Health, called "The obligatory report on malignant tumors", specify the conditions of collecting and processing data about the patients with tumors. This material is presented in the Bulletin of the Ministry of Health 2000, part 10-12, Act No. 576/2004 of the Statute Book, and amended by the Amendment No. 662/2007 of the Statute Book. National Cancer Registry of the Slovak Republic, National Health Information Centre, would like to answer many requests for an easy and comprehensible access to the national data on cancer epidemiology. The working group created a new analytic web-page, called "National portal on cancer epidemiology". All data are valid, adapted for publications and quotation and the access to the web-page is free for the wide professional public (Ref. 5).

The registry of patients treated with Thromboreductine (anagrelid) in the contributing centres in the Czech Republic has been updated with data on the patients receiving this medication since 2004. The original purpose of the registry was to record responses to Thromboreductine therapy and adverse drug reactions in patients with essential thrombocytopenia. However, data on additional Ph negative myeloproliferations, as well as data on cytoreductive therapies other than exclusively that using Thromboreductine has also been recorded in the course of its compilation, including data on combined regimes. At present, the database contains data on 421 patients, and valid conclusions can be drawn if the level of data filling is enhanced. Evaluation has been currently focused on the analysis of the risk of development of clinical symptoms of thrombosis and on the standards of treatment from the viewpoint of the achieved treatment response. Analyses of data from the registry corroborate the special importance of the proof of JAK2 mutation, and of the test for factor V Leiden mutation, and of protein of S for the assessment of the risk of thromboembolic complications. The output of the analysis confirms that anagrelid is a very efficient thromboreductive agent the administration of which is associated with a low incidence of non-serious adverse effects (10.9%). However, in spite of a fast response to therapy, the therapeutic goal consisting in the reduction of the platelet count below 400 (or below 600) x 10(9)/l, i.e. the complete (or partial) treatment response, is relatively slow to achieve. This is likely to be due to lack of radical corrections in the dosage of the drug for different reasons.

Growing incidence of testicular cancer around the world stimulates research attempting to explain the trends. This study quantified the contribution of different types of potential risk factors for testicular germ-cell cancer (TGCC) with differentiation between seminoma and non-seminoma. A standardized questionnaire containing demographic data, pre- and perinatal factors, social, lifestyle and occupational parameters was prepared. The data file consists of n = 356 TGCCs (seminoma: n = 195; non-seminoma: n = 161) and n = 317 controls, frequency matched on age to cases. The following factors were significantly associated with the risk of TGCCs in univariate analyses (ORs): atrophic testis (5.3), smoking over 12 pack-yr (4.9), cryptorchidism (2.9), testicular trauma (2.0), birth weight under 3,000 g (1.6), low degree of education (3.0) in correlation with manual occupation (2.3) and finally, overall familial cancer history (1.5) and familial history of breast (1.8) and prostate cancer (3.9). On the other hand, maternal age over 20 yr (OR0.4) and moderate recreational sport activity (OR = 0.5) significantly reduced the risk of TGCCs. A significant risk was associated with cryptorchidism (OR = 2.9; 95% CI = 1.5 - 5.9) where orchidopexy was delayed after 5 yr of age (OR = 5.2; 95% CI = 1.5-18.1). Delayed orchidopexy was associated namely with the risk of seminomas (OR = 7.5; 95% CI = 2.1-26.7). Only some of the variables were retained in multivariate model for TGCCs as well as for histological subtypes (multivariate adjusted OR for all TGCCs): atrophic testis (5.9), family history of prostate cancer (4.8), cryptorchidism (3.8) and interaction term 'low degree of educationmanual occupation' (3.0). Familial history of breast cancer elevated risk of TGCCs and of seminomas (OR: 2.01 - 2.18). Birth weight under 3,000 g was retained in a multivariate model for TGCCs with a borderline significance (OR = 1.67). We could not rule out any type of risk factors, as each one was significantly represented in the final multivariate models. Familial cancer history remained to be an influential risk factor, altogether with some lifestyle and occupational parameters. This suggests that both environmental exposures and genetic inheritance can play role in the moderation of the risk of TGCC.

Improved survival has been observed in poor-risk diffuse large B-cell lymphoma (DLBCL) patients treated with high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in first complete remission. Retrospective studies have suggested that HDT with ASCT can improve survival also in partial responders but some doubts about the advantage of intensive therapy in such patients still remain. We evaluated retrospectively the results of HDT and ASCT in 55 patients with confirmed DLBCL treated between May 1999 and July 2006. Thirty-six patients (65%) showed partial remission (PR) and 19 patients (35%) reached complete remission (CR) after induction treatment with (44%) or without (56%) concomitant rituximab (R) immunotherapy. After HDT and ASCT, 69% of patients fulfilled the criteria of CR, 22% had unconfirmed CR (CRu), 7% remained in PR and 1 patient (2%) relapsed. Twenty patients in PR after the induction treatment reached CR after ASCT, 12 other PR patients achieved CRu. The 5-year event-free survival (EFS) of the 55 transplanted patients was 76% (95% confidence interval /CI/, 63% to 89%) and the 5-year overall survival (OS) was 85% (95% CI, 73% to 97%). The EFS and OS rates differed significantly only between patients younger than 40 years and older groups (p=0.022 and p=0.046, respectively). On univariate analysis of prognostic factors, EFS and OS were not affected by any of the following: age, sex, stage, subtype of DLBCL, initial lactate dehydrogenase, beta-2-microglobulin and serum thymidine kinase levels, International Prognostic Index (IPI) and age-adjusted IPI scores, induction treatment with or without rituximab and type of primary therapeutic response (CR vs PR). These results show that first-line HDT and ASCT for adults up to the age of 65 years with poor-risk DLBCL is a feasible and effective treatment option even in the era of R-chemotherapy in CR as well as for patients in PR.

To evaluate the clinical status and radiographic progression in patients with rheumatoid arthritis (RA) being followed by the Czech National Registry of biological treatments.Patients who failed at least two disease-modifying antirheumatic drugs and had high disease activity (DAS285.1) were treated with infliximab. Radiographic progression was measured with a modified version of the Sharp score (TSS) after 54 weeks of treatment.Ninety-nine patients with an average disease duration of 13.7 years were enrolled. The DAS28 dropped from 6.66 to 4.07 (p0.001). Before treatment the mean TSS was 90.1 and the mean estimated yearly disease progression was 8.56. After 54 weeks of infliximab, radiographic progression was 4.15 times slower than the estimated rate before treatment and 63 patients did not show any radiographic progression at all. In the remaining 36 patients, the progression rate slowed to 3.8 +/- 0.9 from the estimated TSS of 10.9 +/- 6.9 before the initiation of treatment (p = 0.011).Data derived from the Czech National Registry, which reflect general clinical practice, show a significant retardation of radiographic progression in patients treated with anti-TNF and the magnitude of the improvement seen is similar to results from clinical trials.

Since 2005, registers of patients treated with Thromboreductin (anagrelid) kept by some centres in the Czech Republic have been supplied with data concerning patients whose treatment with this preparation started in 2004. The purpose of the register is to record responses to therapy by Thromboreductin and adverse events in patients with essential thrombocytemia and other myeloproliferations, and to subsequently analyse the data. Another objective is to detect predisposition to clinical symptomatology and disease complications. Apart from thrombocyte count, additional risk factors are monitored. The database currently contains data for 336 patients. Initial analyses of data from the register point to the fact that anagrelid is a highly effective thromboreductive agent the administration of which is associated with relatively low incidence of adverse events (11.8 %) of mild and usually transitory nature. The therapeutic objective is attained at a relatively slow rate (according to overall stratification under 400 or under 600 x 10(9)/l thrombocytes), which is probably due to insufficient dose adjustment.

Breast conserving surgery followed by adjuvant radiotherapy and eventually by systemic treatment represent the current trend in therapy of the early-stage breast carcinoma. Local control and the final cosmetic effect are important factors in breast conserving therapeutic approaches. We evaluated 215 patients who underwent breast conserving surgery (BCS) followed by adjuvant radiotherapy (RT) in our institute between October 1996 and February 2004. External beam radiotherapy (EBRT) was performed using a Cobalt- 60 or linear accelerator (LINAC), the boost was administered via high dose rate interstitial brachytherapy (HDR BRT) employing the Gammamed afterloading system. Patient survival was evaluated using the Kaplan-Meier method (disease-free survival DFS, overall survival OS). Late radiotherapy effects were evaluated using the LENT scales. The cosmetic effect (CE) was rated on a 4-grade scale by the patient and a committee; the Breast Retraction Assessment (BRA) was used to objectively assess the extent of the breast deformation and areolar deviation. The median follow-up in our group of patients was 70 months (from 20 to 136 months). Local control of the disease after 5 years was achieved in 98.5% of the patients, DFS was 88.7%, the distant disease-free survival (DDFS) was 89.9% and the overall 5-year survival was 91,8%. Medium vs. heavy fibrosis were recorded in 31.2% vs. 4.2% of the patients, medium vs. heavy teleangiectasia in 11.2% vs. 14.0% of the patients, and medium vs. heavy pigmentations in 6.5% vs. 3.3% of the patients, respectively. In all other cases none or minimal late radiotherapy effects occurred. The total CE was significantly influenced by the extent of the surgery (smaller deformations following tumorectomy65 cm3), by the type and orientation of the surgical incision (better results with discontinuous scars then with radial continuous scars), by the depth of the applied HDR BRT needles, by the rate of intermediate and severe postradiation late effects, plus by the value of the objective BRA parameters. Our data show that the HDR interstitial brachytherapy boost offers both excellent local control and favorable cosmetic effect to the patient, as long as the indications are followed closely. This therapeutic approach is suitable for treatment of tumors localized deeper than 2.8 cm under the surface and in patients with voluminous breasts.

To assess the prognostic relevance of activating mutations of FLT3 gene on outcome of allogeneic transplantations in AML patients, we performed an analysis of all patients with FLT3 mutations registered in the Czech Acute Leukemia Clinical Register (ALERT) from 2003 till the end of 2005. Within the mentioned period 170 patients with AML of median age 56 years (23-77) were investigated for FLT3 mutation, within them 36 cases (21%) with FLT3 mutations (32 FLT3 ITD and 4 FLT3 D835) were found. Out of FLT3 ITD positive patients 13 had allogeneic transplantation, 20 patients with mutations of FLT3 were treated with chemotherapy without transplantation. Results of the treatment of these patients were compared with the results of the group of patients without FLT3 mutation, which was according to other characteristics identical with the group of patients with FLT3 mutations (n=134). Median overall survival (OS) was significantly shorter for patients with FLT3 ITD (34.8 weeks) than for those without FLT3 mutations (67.7 weeks; P=0.028). Median OS of patients with FLT3 ITD who had allogeneic transplantation was 42.5 weeks; median OS of patients with FLT3 ITD treated only with chemotherapy was 29.6 weeks (P=0.362). After allogeneic transplantation, median OS of FLT3 mutations negative patients was similar to FLT3 ITD positive patients (46.7 versus 42.5 weeks; P=0.443). Our results suggest that at present there is no strong evidence that FLT3 status alone should influence the decision to proceed to allogeneic transplantation in AML patients. Decision to proceed to alogeneic transplantation should not be based on the FLT3 status only, but it should also consider other prognostic factors.

Medulloblastoma, a primitive neuroectodermal tumor growing in cerebellum, is one of the most sensitive to radiation therapy childhood brain tumors. The radiotherapy is an essential method of treatment for these tumours, but the surgery is the primary treatment of choice in medulloblastoma. I this study between January 1997 and March 2005 were post-operative irradiated a total number of 33 pediatric patients aged under 15 years (median age 8.7 years) with medulloblastoma. All tumors were histologically proved and were localizated infratentorially in the posterior fossa. All of the patients were irradiated with a dose of 24-36 Gy to the whole craniospinal axis and boost with conformal therapy restricted to the tumor bed to the total dose of 50-54 Gy (30-36 Gy "high risk", 24-30 Gy "standard risk" group). Chemotherapy received 26 patients (78%). Patients with craniospinal irradiation were placed in supine position and fixed by a vacuum-form body immobilizer and head mask. Irradiation was performed using standard fractionation (5 fractions per week) with a single dose of 1.5-1.8 Gy for craniospinal axis by photon beam (6 MV) of the linear accelerator. The median overall survival for the whole group was 55.3 months. The median of disease-free survival was 20.6 months, 8 patients (24%) died. In our study the statistical difference in survival rate between standard and high-risk patients with medulloblastoma was not shown. No relationship was found between survival and age, sex or tumor size. Endocrine deficits occurred in 45% (8 patients of the group were hypothyroid, 6 patients needed growth hormone replacement therapy, 1 patient had early puberty). This results (results of overall and disease-free survival) and side-effects of technique of craniospinal axis irradiation in supine position are comparable with results of technique in prone position. Further evaluation of the effectiveness of our therapy is not feasible due to the small number of patients.

Summary The desmosomal cadherins, which include desmogleins and desmocollins, are Ca2+-dependent adhesion molecules that cooperate to make up the adhesive core of intercellular junctions known as desmosomes. The roles of desmosomal cadherins in epidermal integrity and as targets in human cutaneous disease have been well established. However, the molecular basis of these disorders is still poorly understood, due in part to a lack of fundamental knowledge about the organization of the adhesive interface and molecular machinery that dictates the proper presentation of desmogleins and desmocollins on the cell surface. Further, the diversity of the desmosomal cadherin family, and their individualized expression patterns within complex tissues, suggests that these adhesion molecules may have differentiation-specific functions that transcend their roles in intercellular adhesion. Here we will review the most recent data from our own group and others that are beginning to unveil the diverse properties and functions of this complex family of adhesion molecules.

In the group of 270 patients with multiple myeloma (MM) treated during 1991-2004 by conventional chemotherapy, the prognostic value and practical utility of IPI (International Prognostic Index) was assessed and compared with five other actual staging systems. Prognostic significance was assessed using the curves of overall survival (OS) according to Kaplan-Meier and log rank test (p0.05). Good practical utility and prognostic significance of Durie-Salmon (D-S) system was confirmed (p0.001). Good overall prognostic significance was observed in simple staging systems based on the measurement of beta2-microglobulin and albumin serum levels according to Bataille (p0.001), SWOG (South West Oncology Group, p0.001) and IPI (p0.001). Regardless of a short 5-year duration of the study, the scoring system according to San Miguel enclosing apart from other parameters also propidium iodide proliferation index (PC-PI) of myeloma plasmocytes seems to be promising with very different characteristics of curves of overall survival (p0.001). Very good prognostic value and easy practical utility were examined in Olomouc staging system (OSS) based on the measurement of beta2-microglobulin and thymidinekinase serum levels (p0.001). With regard to detection of patients of stage 1, i. e. "low risk", not requiring an immediate initiation of conventional chemotherapy ("wait and see" approach), the most suitable was the system according to D-S, SWOG and IPI (median OS 77, 76 and 77 months). To select a cohort of "high risk" patients, i.e. stage 3, with very unfavourable disease prognosis, the most advantageous was the system OSS and San Miguel (median OS was 5 and 6 months) and/or SWOG system selecting patients of stage 4, i.e. "worst prognosis", with median OS 8 months. It was found that IPI did not meet expectations for effective identification of "high risk" patients (median OS of stage 3 was 20 months) nor for the distinction of different prognosis of patients during initial 25 months of MM course at stage 2 vs. 3. The study indicates that under conditions of common clinical practice and conventional chemotherapy, the staging system according to D-S is still useful, while practical application of SWOG and IPI as simpler alternative to the assessment of clinical stage should be verified by further comparative studies. In harmony with the progress in cytogenetics and molecular biology as well as a prospective requirement of individual target therapy, a future suitable stratification system should be based on parameters of internal biological properties of myeloma tissue and microenvironment of bone marrow, allowing in addition a continuous evaluation of the disease course and the effect of therapy.

Anagrelide hydrochloride is an effective drug used in patients with ET and other myeloproliferative disorders with thrombocythemia to selectively decrease the number of thrombocytes. Indications for use of anagrelide were described in detail in Czech medical literature. Since 2005 data concerning treatment with anagrelide in some medical clinics have been collected in patient register showing course of treatment from 2004, when the medicament obtained marketing authorization from State Institute for Drug Control to be used in the treatment of thrombocythemia in myeloproliferative disorders. Aim of patient register is to monitor medical effect of anagrelide therapy and incidence of adverse effects in patients with ET and other myeloproliferative disorders and subsequent analysis of collected data. At the moment patient register contains data from 154 patients.

The aim of this study was a contemporaneous measurement of plasma cells proliferative and apoptotic activity in patients examined at the time of multiple myeloma (MM) diagnosis before initiation of chemotherapy, focussed on the following aspects: determination of prognostic significance of plasma cell propidium iodide (PC-PI) and annexin-V FITC (PC-AI) indices; optimal cut off of PC-PI and PC-AI with regard to overall survival; calculation of summary kinetic index of plasma cells (PC-PI/AI ratio) for evaluation of its prognostic importance; determination of an index (out of PC-PI, PC-AI and PC-PI/AI) showing the closest relation to prognosis of multiple myeloma. The analyzed 122 patients fulfilling SWOG multiple myeloma criteria were treated by conventional chemotherapy. Plasma cell proliferative activity was measured by means of PC-PI examined by flow cytometry using a DNA/CD138 double staining technique. For detection of plasma cells entering apoptosis (PC-AI), flow-cytometry method with annexin-V FITC and MoAb CD138 was used. The PC-PI median in 122 patients was 2.6(0.4-4.8)%. The sequence prognostic analysis showed that the optimal PC-PI cut off was 2.9% and displayed a significant relationship with overall survival (OS) (p=0.031). The group of 94 patients had PC-AI median of 5.0(1.4-24.5)%. The best statistical significance of the rate of apoptosis related to overall survival was found at cut off value of 4.4% (p=0.022). The median of overall kinetic index of plasma cells (PC-PI/AI) examined in 94 MM patients was 0.5(0.05-2.60) and the overall kinetic index was found to display a very good relationship to OS at the cut off value of 0.71 (p=0.032). All the three indices expressing various aspects of kinetics of plasma cells allow the stratification of patients into two prognostically different groups with statistically significantly different medians of overall survival: good risk - OS still undeterminable at the time of analysis; bad risk - M: OS was for PC-PI 17 months, for PC-AI 23 months and for PC-PI/AI 16 months. The ratio of both indices, i.e. PC- PI/AI, however did not bring any further contribution to overall survival/prognosis evaluation, when compared with single PC-PI and PC-AI. Results of present study indicates that the evaluation of both proliferation and apoptotic activities of plasma cells is important for prognosis thus extending possibilities of initial stratification of MMpatients into groups with different prognostic risk.

The primary endpoint of this study was to evaluate the efficacy (objective response rate; ORR) of combined chemotherapy with raltitrexed plus oxaliplatin as second-line treatment in patients with metastatic colorectal cancer (CRC). Secondary endpoints were overall survival (OS), time to progression (TTP) and toxicity (NCI-CTC criteria). The target population were patients with metastatic colorectal adenocarcinoma who progressed after first-line chemotherapy. Treatment consisted of raltitrexed 3 mg/m2 as a 15-minute intravenous (IV) infusion followed 45 minutes later by oxaliplatin 130 mg/m(2) IV as a 2-h infusion on Day 1, repeated every 3 weeks until further disease progression (PD), unacceptable toxicity or the decision of the patient. A total of 51 patients, all with WHO performance status 0-2 received a median of 6 treatment cycles (range 1-11). After 3 cycles, 8 of the 47 evaluable patients (17%) had experienced an ORR, 28 patients (59.6%) had experienced stable disease (SD) and 11 patients (23.4%) had PD. After 6 cycles, 1 of the 29 evaluable patients (3.5%) had an ORR, 13 patients (44.8%) had SD and 15 patients (51.7%) had PD. After a median follow-up of 48.9 weeks, median TTP was 18 weeks and median overall survival was 54.4 weeks. Treatment was well tolerated; grade 3 toxicities occurred in only 5/51 patients (9.8%). The most common toxicities were paraesthesia (62.7%), diarrhoea (23.5%), nausea (41.2%), vomiting (33.3%), hepatotoxicity (25.5%), and hematological toxicity (41.2%). In conclusion, the combination of oxaliplatin plus raltitrexed appears to be effective and well tolerated as second-line therapy in patients with disseminated CRC.

STAT 1, a member of signal transducer and transcription activator family has been implicated as key downstream mediator of interferon (IFN) signaling. Its functional activation requires phosphorylation at Tyr 701 and Ser 727 residues. Various STAT abnormalities have been found in cancer cells but their relation to oncogenesis, tumor behavior and disease outcome remains mostly unknown. We have examined the inducibility of STAT 1 phosphorylation by IFN alpha/gamma in primary cultures established from melanoma lymph node metastases at first progression and correlated our results with disease outcome and overall survival. Forty-four patients at clinical stage I-III at initial diagnosis entered the study. STAT 1 inducibility of phosphorylation by IFNs was assessed in melanoma cell lysates by means of standard immunoprecipitation and Western blotting using polyclonal and monoclonal antibodies. Lack of STAT 1 phosphorylation at Ser 727 after either IFN was recorded in 75% of patients, however, no correlations with disease evolution could be proved. In contrast, STAT 1 phosphorylation response at Tyr 701 after IFNalpha occurred in 13 (29.5%) and after IFNgamma in 32 (73%) patients. Inducibility of STAT 1 activation at Tyr 701 but not at Ser 727 driven by IFNgamma but not by IFNalpha significantly and unfavorably [corrected] influenced disease- free interval and overall survival. In conclusion, these results show that the absence of IFNgamma inducibility of STAT 1 phosphorylation at Tyr 701 positively correlates with disease outcome in malignant melanoma patients and may represent new independent prognostic marker.

Genetically modified (GM) rice (LibertyLink, event LLRICE62) that is tolerant to glufosinate ammonium (Liberty) herbicide was compared with a near-isogenic (NI) conventional medium-grain brown rice (cultivar, Bengal) and a commercially milled long-grain brown rice in diets for growing-finishing pigs. The GM and NI rice were grown in 2000. The GM rice was from fields treated (GM+) or not treated (GM-) with glufosinate herbicide. The GM- and NI rice were grown using herbicide regimens typical of southern United States rice production practices. The four rice grains were similar in composition. Growing-finishing pigs (n = 96) were fed fortified rice-soybean meal diets containing the four different rice grains from 25 to 106 kg BW. Diets contained 0.99% lysine initially (growing phase), with lysine decreased to 0.80% (early finishing phase) and 0.65% (late finishing phase), when pigs reached 51 and 77 kg, respectively. The percentage of rice in the four diets was constant during each of the three phases (72.8, 80.0, and 85.8% for the growing, early-finishing, and late-finishing phases, respectively). There were six pen replicates (three pens of barrows and three pens of gilts) and four pigs per pen for each dietary treatment. All pigs were slaughtered at the termination of the study to collect carcass data. At the end of the 98-d experiment, BW gain, feed intake (as-fed basis), and feed:gain ratio did not differ (P0.05) for pigs fed the GM+ vs. conventional rice diets, but growth performance traits of pigs fed the GM+ rice diets were superior (P0.05) to those of pigs fed the GM- rice diet (ADG = 0.86, 0.79, 0.81, and 0.85 kg/d; ADFI = 2.41, 2.49, 2.37, and 2.45 kg/d; feed:gain = 2.80, 3.17, 2.95, and 2.89 for GM+, GM-, NI, and commercially milled rice, respectively). Carcass traits (adjusted for final BW) did not differ (P = 0.10) among treatments (hot carcass yield = 73.5, 72.6, 72.6, and 73.2%; 10th-rib backfat = 23.0, 22.7, 21.3, and 23.8 mm; LM area = 38.6, 38.0, 38.2, and 38.1 cm(2); carcass fat-free lean = 50.5, 50.5, 51.2, and 50.0%). Gilts grew slower (P0.05) and were leaner (P0.05) than barrows. Responses to type of rice did not differ between barrows and gilts, with no evidence of a diet x gender interaction (P = 0.50) for any trait. The results indicate that the glufosinate herbicide-tolerant rice was similar in composition and nutritional value to conventional rice for growing-finishing pigs.

The majority of patients with breast carcinoma receive chemotherapy as a component of multimodality treatment. Over the past decade, it has become increasingly more common to deliver chemotherapy first, but this has raised new questions within all disciplines of cancer management. However, the effect of cytotoxic treatment cannot be predicted on individually specific basis, then identification of tumor characteristics associated with tumor therapeutic response and outcome is then of great clinical interest. We studied 141 patients at Masaryk Memorial Cancer Institute, who received neoadjuvant chemotherapy and/or chemotherapy + radiotherapy (CHT/CHT+RT) between 1994-2002. Tumor samples were taken prior to and after neoadjuvant therapy. We quantified the response to therapy pathologically and determined histological and molecular tumor characteristics (steroid receptors, CEA, Ca 15-3). In addition to therapeutic response as immediate outcome, event free survival (EFS) was examined as more complex primary end-point of the study. Complete remission (CR) has been achieved in 6.5%, partial remission (PR) in 49.6%, stable disease (SD) in 26.2% and progression disease (PD) in 17.7% patients. Patients were divided into two groups according to the result of neoadjuvant therapy--responders (CR+PR+SD, who successfully underwent surgery), and risk group (patients with SD or PD, who could not undergo surgery). Responders to neoadjuvant CHT/CHT+RT regimens reached statistically significant better EFS than non-responders, low tumor size (T2) and stage (II) categories were confirmed as additional predictive factors not only for EFS but for therapeutic response as well. The study primarily examined predictive power of tumor markers as CEA, Ca 15-3, and steroid receptors (ER/PR) and searched for their role in the prospective evaluation of neoadjuvant therapy. We evaluated these factors as potential predictors of EFS, independent in predictive power on therapeutic response to neoadjuvant therapy. Diagnostically valuable cut off points were proposed in ROC analysis for all these markers. Responders to the neoadjuvant therapy with Ca 15-323.0 kU/l, CEA5.0 mg/l, estrogen receptors (ER)5.0 fmol/mg or both estrogen /progesterone receptors (ER/PR) positive had statistically significantly better EFS in comparison to patients with Ca 15-323.0 kU/l, CEA5.0 mg/l, ER5.0 fmol/mg, or other cases than patients double positive in ER/PR. Marker Ca 15-3 revealed significant predictive power even within the group of non- responders, these patients with Ca 15-323.0 kU/l had better EFS as compared to patients with Ca 15-323.0 kU/l. Tumor size and low stage proved predictive value for immediate response to neoadjuvant therapy. Risk parameters for neoadjuvant therapy were T4, stage III, namely if RT was necessary. Therapeutic response to neoadjuvant therapy was independent on investigated molecular parameters, but there was strong predictive association of Ca 15-3, CEA and ER/PR receptors with event free survival development. Diagnostically valuable cut-off points were proposed and validated for sensitivity and specificity in ROC analysis.

In general, the cancer incidence becomes stabilized in the Czech Republic during last years. However, the incidence of colorectal and renal cancers remains increasing and dominates also in European comparisons. A program of cancer prevention and early detection needs to be established at least for six so called preventable cancers as breast, lung, colorectal, cervical and prostatic carcinomas and malignant melanoma, which represent together 40 % of all oncological cases. The aim is reduction of cancer mortality as well as improved effectivity of cancer treatment and cost reduction. More efficient utilisation of the National Cancer Registry data for monitoring of the cancer management is suggested with an application of the project SVOD - the software system of visualisation of oncological data.

In a tidal marsh on the Savannah River (Georgia, USA), rate of plant community change along a salinity gradient was measured using a reciprocal transplant study. Donor sods were moved in all possible combinations from freshwater to brackish sites and from brackish to freshwater sites at four different locations. The reciprocal aspect of the experiment also allowed the determination of how the rate of plant community change is affected by the direction and level of displacement along the salinity gradient. Stem densities of each species were counted in each transplanted plot in June and October for a 30-month period. Plant community structure and composition changed by a significantly measurable amount within 6 to 18 months of a change in salinity. However, the time required for the transplanted sods to resemble their surrounding communities (at the p ≤ 0.05 level) ranged from 6 to more than 30 months, with some transplanted sods never resembling the surrounding plant communities during the study ...

We sought to assess whether the peak systolic and diastolic tricuspid annular velocities as indicators of the right ventricular systolic and diastolic function are of prognostic importance in patients with symptomatic heart failure.The study included 139 consecutive patients with symptomatic heart failure. Their mean left ventricular ejection fraction was 24% (range, 10-39%); 107 patients (77%) were in functional class III according to the New York Heart Association. All patients underwent clinical and laboratory examination, standard echocardiography completed by the Doppler tissue imaging of the tricuspid annular motion, and the right-sided heart catheterization. They were followed up for cardiac-related death and non-fatal cardiac events including the need for implantation of a cardioverter-defibrillator and hospitalization for heart failure. The median follow-up was 11 months (range, 1-48 months). There were 17 cardiac-related deaths and 23 non-fatal cardiac events. The multivariate stepwise Cox regression modelling revealed three effective predictors for both survival and event-free survival: aetiology of heart failure, left ventricular end-diastolic diameter, and the peak systolic tricuspid annular velocity (Sa). Patients with Sa10.8cms(-1) exhibited worse survival (P=0.048) and event-free survival (P0.001) compared with those having Sa/=10.8cms(-1). Risk values of Sa (10.8cms(-1)) and the left ventricular end-diastolic diameter (70mm) were found to be of additive simultaneous influence leading to a very poor prognosis, mainly if aetiology of heart failure was idiopathic dilated cardiomyopathy (P0.001).The Sa represents a significant independent predictor of survival and event-free survival in patients with symptomatic heart failure. Its combination with the left ventricular end-diastolic diameter provides a very powerful tool for patient risk stratification.

The immunological dysfunction associated with human cancer is well known phenomenon. It comprises number of pathological changes within immune network including imbalance in cytokines of Th1/Th2 origin. The objectives of our study were (i) to evaluate the abnormalities in serum levels of selected cytokines in malignant melanoma patients with regional lymph node metastases as compared to normal values, (ii) to examine the relationship between postoperative cytokine levels and disease progression and (iii) to correlate cytokine profile changes during IFN-alpha therapy with the disease progression and potential therapeutical response. Nine Th1/Th2 related cytokines and sIL-2R were determined in 26 malignant melanoma patients at clinical stage III prior and during adjuvant immunotherapy. Control group consisted of 26 healthy persons. Patients were treated with rIFN-alpha according to EORTC Melanoma group protocol 18952. Cytokines were quantified in patients sera using commercial ELISA kits. Majority of melanoma patients showed significantly lower values of IL-2 and IFN-gamma and pathologically elevated levels of IL-4, IL-6, IL-10 as compared to healthy subjects what indicates disease associated Th1/Th2 imbalance. In addition increased IL-12 and IL-15 values were noted in some patients (54% and 27%, respectively). All patients who manifested early relapse during immunotherapy had significantly lower pretreatment levels of IL-2 and IL-12 than those remaining without progression and probably benefiting from the treatment. Cytokine changes during immunotherapy disclosed that decreases in IL-2 and IL-12 and raises in IL-6 and IL-10 values occurred at least one month prior to relapse. Moreover, the continuous elevation of TNF-alpha and sIL-2R could be observed in patients who remained without progression during 10 months lasting immunotherapy. Our data illustrate that malignant melanoma associates with Th1/Th2 perturbances which are directed towards extended Th2 responses and that measurement of selected cytokines of Th1/Th2 category may be used as an early signal of disease deterioration and for evaluation of immunotherapy response.

Bst1/CD157 is a GPI-anchored transmembrane protein belonging to the ADP-ribosyl-cyclase family and it is expressed on some blood cells such as monocytes and neutrophils. Importantly, we demonstrated that this antigen is expressed in blast cells from almost 100% of Acute Myeloid Leukemia patients (either at primary diagnosis or at relapse). MEN1112 is a humanized, de-fucosylated antibody targeting the Bst1/CD157 antigen with high affinity and inducing potent in vitro and ex vivo Antibody Dependent Cell-mediated Cytotoxicity (ADCC) responses against AML cell lines and blasts, respectively. MEN1112 was discovered as a mouse Fab antibody from a phage display library raised against recombinant Bst1/CD157 protein. The Fab was selected base upon its ability to recognize recombinant Bst1/CD157 protein by ELISA and for its ability to recognize Bst1/CD157 positive endogenous cancer cell lines by FACS (fluorescence activated cell sorting). The Fab was also chosen based upon its ability to recognize cynomolgus Bst1/CD157 antigen on recombinant and endogenous cells. The selected Fab sequence was humanized and incorporated into the Biowa Potelligent cell line to produce a de-fucosylated full IgG1 version (MEN1112). The binding affinity of MEN1112 for the Bst1/CD157 antigen showed an EC50 of 1nM as assessed by flow cytometry (FACS) analysis using multiple cell lines. No binding was observed on antigen-negative cell lines demonstrating specificity of MEN1112. High affinity of MEN1112 for the recombinant antigen was confirmed in an ELISA assay (EC50 0.4 nM). Beyond the affinity for the antigen, it is of relevance for its ADCC activity that MEN1112 is characterized by an improved affinity for Fc receptors on effector cells over the parental antibody. In particular, MEN1112, lacking fucose residues in its Fc domain, showed an impressive high affinity binding to the Fc receptor CD16A both high affinity and low affinity alleles. Internalization studies demonstrate the slow internalization of the Bst1/CD157 antigen following binding to MEN1112 which favors the ADCC efficacy of the antibody. Overall our results indicate that MEN1112 has the potential to exert anti-leukemia actions through a powerful ADCC in view of: (i) superior affinity for blast cell membrane antigen Bst1/CD157, (ii) enhanced affinity for all variants of CD16A Fc receptor expressed on effector cells and (iii) minimal internalization following antigen binding. Disclosures Aud: Oxford BioTherapeutics: Employment. Dusek:Oxford BioTherapeutics: Employment. Bisht:Oxford BioTherapeutics: Employment. Swaminithan:Oxford BioTherapeutics: Employment. Awdew:Oxford BioTherapeutics: Employment. Trang:Oxford BioTherapeutics: Employment. Lin Lou:Oxford BioTherapeutics: Employment. Manzini:Menarini Ricerche SpA: Employment. Martinez Mogarra:Menarini Biotech srl: Employment. Bressan:Menarini Ricerche SpA: Employment. Binaschi:Menarini Ricerche SpA: Employment.

Antibody-based immunotherapy represents a promising strategy to target and eliminate acute myeloid leukemia (AML) tumor cells. We evaluated BST1/CD157, a novel, slow internalizing surface antigen, for its suitability as immunotherapeutic target in AML. An Fc-optimized antibody against BST1/CD157 was developed (MEN1112/OBT357NF), which binds to the Fc-receptor on natural killer (NK) cells with enhanced affinity. The target antigen expression profile of BST1/CD157 on AML bulk cells as well as on leukemic stem cells (LSC) was analyzed with flow cytometry using a commercially available antibody. BST1/CD157 expression was detected in > 97% of AML patients at primary diagnosis (n=81) and at time of relapse (n=20) using specific fluorescence intensity (SFI, positivity: SFI > 1. 5). Importantly, BST1/CD157 was also expressed on CD34+/CD38-cells (n=20), the compartment with a high percentage of LSCs. Functional titration experiments of MEN1112/OBT357NF showed antibody-mediated lysis of U937 cells in the low picomolar range (EC50 = 30–140 pM) and demonstrated superior ADCC activity compared to its non Fc-engineered parental analogue. To evaluate the additive effect of the complement cascade, healthy donor (HD) monocytes were co-incubated with autologous NK cells and MEN1112/OBT357NF in the presence or absence of 5% donor serum. After 20 hours of incubation, a significantly enhanced lysis efficacy by MEN1112/OBT357NF through the addition of serum compared to control cultures without serum (p=0.02) was demonstrated. For further functional characterization of MEN1112/OBT357NF standard chromium release assays using AML cell lines and NK cells from HDs were performed. In this setting, efficient target cell lysis (30–50%) at various effector cell:target (E:T) ratios (50:1–6:1) was observed. Compared to Rituximab-mediated lysis of RAJI cells, MEN1112/OBT357NF triggered more efficient target cell lysis at much lower effector cell concentrations (33% lysis of OCI-AML3 cells vs. 11% lysis of RAJI cells at E:T 6:1). Furthermore, the cytotoxic potential of NK cells from AML patients after intense double induction chemotherapy on AML cell lines was tested. The results were highly variable with efficient lysis in about one third of samples tested (n=10). As a positive control NK cells from HDs were used which showed superior lysis as compared to patient-derived NK cells. In an autologous set-up using NK cells from either primary diagnosis or at time of remission, we could show efficient lysis of primary AML cells in one of two patient samples (patient in complete remission) in the presence of MEN1112/OBT357NF. In summary, our analysis demonstrates that BST1/CD157 is a promising target antigen for antibody-based therapy in AML. The effective in-vitro ADCC activity supports further development of MEN1112/OBT35NF as an immunotherapy for patients with AML. Disclosures Krupka: Oxford BioTherapeutics Ltd: Research Funding. Jansen:Oxford BioTherapeutics Ltd: Research Funding. Aud:Oxford BioTherapeutics Ltd: Employment. Dusek:Oxford BioTherapeutics Ltd: Employment. Bisht:Oxford BioTherapeutics Ltd: Employment. Pombo-Villar:Oxford BioTherapeutics Ltd: Employment, Equity Ownership. Rohlff:Oxford BioTherapeutics Ltd: Employment. Subklewe:Oxford BioTherapeutics Ltd: Research Funding.

With the successes of Kadcyla and Adcetris, and the emerging data from early phase trials of many other ADCs our understanding of the critical attributes for target selection and ADC development has improved significantly. Clinical experience indicates that the dose-limiting toxicities observed are predominately off-target and thus are similar across ADCs using the same linker and drug combinations and independent of the target antigen. Furthermore, the maximum tolerated doses (MTDs) in humans, monkeys, and mice for many ADCs seem to be very similar regardless of the protein being targeted. Thus, the therapeutic index of new ADCs using the current drug/linker technologies (tubulin and DNA targeting toxins) will be driven predominately by efficacy, specifically the ability to achieve antitumor activity at exposure levels below the MTD. Therefore, the focus of future target selection should be on efficacy within the therapeutic window rather than on antigen-dependent (i.e. on-target) toxicity arising from normal tissue expression. We have selected targets and toxins for ADC development based on the likelihood of robust potency against cancer cells. The properties favored are : 1) high expression and high prevalence in selected malignancies, 2) normal tissue expression profiles known to be tolerable for ADCs ( e.g. her2neu, gpnmb, nectin4), 3) targets enabling rapid intracellular delivery of ADC and release of active toxin, 4) clinical indications sensitive to the toxin of choice. This process and its success are demonstrated here through the development of two ADCs. Firstly, Ox-1476 for triple negative breast cancer (TNBC). The target was selected based on consistent high expression in TNBC, the MAb selected from a large screen of greater than 1000 candidates based on activity as an actual ADC, and the toxin selected based on the positive experience with maytansine in breast cancer (Kadcyla) and the preclinical data presented here. The Ox-1476 ADC shows greater and broader activity than Kadcyla in vitro and an initial toxicity profile consistent with pursuing clinical development. Secondly, Ox-1425 is being developed for small cell lung cancer (SCLC). The target and MAb were selected by the same processes but for Ox-1425 the toxin screen resulted in the selection of a DNA alkylating agent. Our proteomics database has provided a unique data set of candidate cell surface targets for the development of antibodies compatible with the current state of the art ADC payloads. The selected targets show high and prevalent expression in cancers, are in protein families shown to internalize efficiently, and have normal tissue expression profiles similar to other proteins already being targeted by clinical stage ADCs. The preclinical safety and activity data shown here is supportive of our strategy for selecting ADC targets. Citation Format: Jonathan A. Terrett, Rachel Dusek, Dee Aud, Rahel Awdew, Sudha Swaminathan, San Lin Lou, Michael Trang, Arnima Bisht, Mary Do, Jim Ackroyd, Robert Boyd, Lindsey Hudson, Phuoc Pham, Nickolas Attanasio, Ami Antani, Carmel Lynch, Christian Rohlff. Proteomics and selecting the right combination of target and toxin for antibody-drug-conjugate (ADC) development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 661. doi:10.1158/1538-7445.AM2014-661

Recent findings of the role of the immunity in eradication of residual tumour tissue after autologous transplantation rejection leading to extensive studies on T-cell mediated specific antitumor effects or nonspecific NL-cell mediated anticancer effects. We have evaluated on the methods of adoptive cell therapy--IL-2 activation of autologous graft in the preclinical conditions. In laboratory conditions we have manipulated with autologous grafts form patients suffering with chronic myelocytic leukemia and patients suffering with multiple myeloma.Autologous graft was activated with IL-2 during 24-hours cultivation period in X-Vivo 10 medium with heparine, glutamine and Dnase. Quality of grafts after cultivation, contamination and activation of T and NK cell were evaluated. No significant differences between IL-2 activated graft and control were found. Results of autologous graft quality (CD34+, CFU-GM) were comparable with already published results. Quality of final product allowed starting of clinical experimental trials.We have proved the possibility to use IL-2 activated autologous graft in the clinical conditions. Based on our preclinical results experimental clinical trials have been initiated in patients suffering from chronic myelocytic leukemia and multiple myeloma.