Cytoreduction and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal metastases from colorectal cancer in the Czech Republic in 2018.

BACKGROUND: For highly selected patients with peritoneal metastases (PM) from colorectal cancer (CRC), an aggressive surgical approach with intraperitoneal chemotherapy may be beneficial. This management may prolong overall survival, which is well documented by the results of a number of clinical trials. In the Czech Republic, five specialized centers of surgical oncology are able to perform cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC). All of these centers provided accurate information on the number of CRS procedures in 2018 in the PM CRC indication. The estimation of the prevalence of peritoneal metastases from CRC is based on data from the Czech National Cancer Registry. PURPOSE: To determine the number of cytoreductive procedures performed in patients with peritoneal metastases from CRC in the Czech Republic in 2018, and to compare it with the number of patients who could hypothetically benefit from this procedure according to statistical data. RESULTS: Twenty-five CRS/HIPEC procedures were performed on patients with peritoneal metastases from CRC in 2018 in the Czech Republic. However, based on the prevalence of peritoneal metastases from CRC in the Czech Republic, cytoreduction with intraperitoneal chemotherapy (CRS/HIPEC) could probably bring benefit to a minimum of 150 patients a year in the Czech Republic. CONCLUSION: In the Czech Republic in 2018, the cytoreduction and HIPEC procedures for peritoneal metastases from CRC were performed in significantly fewer cases than would correspond to the estimated number of potentially curable patients.To increase the awareness of this issue and improve the number of potentially curative cytoreductive procedures, there will be necessary better awareness and closer cooperation among specialized centers, general surgeons, and clinical oncologists.

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies. Patients and methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review. Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated. ClinicalTrials.gov number: NCT02149108 (LUME-Colon 1).

[Immunotherapy of Colorectal and Anal Carcinoma]. / Imunoterapie nádoru dolní cásti trávicí trubice.

BACKGROUND: The lower part of the digestive tract includes the large intestine, rectum and anus. Treatment algorithms of cancers in these localities have significant differences in both early and advanced stages. The vast majority of metastatic cases are incurable. A few years ago, it was generally accepted that gastrointestinal tumors are poorly immunogenic and modern immunotherapy would not work in gastrointestinal cancers. The breakthrough has become the recognition of the mismatch repair system (MMR) that affects the microsatellite instability (MSI) and its role in the development of colorectal carcinoma (CRC). Metastatic colorectal carcinoma (mCRC) with defect MMR (dMMR) and MSI-H, resp. is immunogenic and can be a target of modern imunotherapy directed on the PD1/PD-L1 axis. Such a treatment can improve prognosis and life quality od patients with mCRC MSI-H. Immunotherapy effectiveness was shown also in a subgroup of patients with a BRAF mutation where the effectiveness of existing systemic treatment is low. The proven predictive factor is dMMR/MSI-H. PD-1 expression does not have this significance. Results of clinical studies with nivolumab and pembrolizumab result in the inclusion of these drugs in mCRC treatment algorithms. Phase II study shows nivolumab effectiveness also in pretreated metastatic anal cancer. PURPOSE: An overview of basic information on the possibilities of immunotherapy in CRC and anal cancers.Key words: cancer immunotherapy - checkpoint inhibitors - colorectal cancer - anal cancer - nivolumab - pembrolizumab Supported by MH CZ - DRO (MMCI, 00209805) I declare that, in connection with the abovementioned contribution, which I am an author, I have a conflict of interest with the following companies: BMS, Roche, Merck, Amgem and Bayer. The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 7. 9. 2017Accepted: 5. 11. 2017.

[Malignant tumors of the small bowel]. / Maligní nádory tenkého streva.

INTRODUCTION: Malignant tumors of the small bowel are relatively uncommon neoplasms; their incidence is around 1.5 per 100,000 inhabitants in the Czech Republic. METHOD: 104 patients underwent a resection of the small bowel because of a primary or secondary tumor over the 10-year period between 20062015 at the Masaryk Memorial Cancer Institute. Data from these patients was reviewed retrospectively. Survival rates were analyzed using the Kaplan-Meier method. RESULTS: We observed 45 primary and 59 secondary tumors. The group of primary malignancies included 12 adenocarcinomas, 14 cases of GIST and 19 cases of NET. Neuroendocrine tumors showed the best prognosis with a 62% probability of five-year survival. Patients with gastrointestinal stromal tumors had a 39% probability of five-year survival and those with adenocarcinomas had a 32% probability of five-year survival. Secondary tumors were caused mostly by metastatic colorectal carcinoma (22 times), malignant melanoma (11 times) and ovarian cancer (10 times). The probability of five-year survival was 15% in the group of secondary tumors. CONCLUSION: Malignant tumors of the small intestine are rare, but their incidence has increased in the last decades. The main prognostic factors include advancement of the tumor and radicality of surgical resection.Key words: small bowel tumors - adenocarcinoma - sarcoma - NET - GIST - lymphoma.

[Anticoagulation and Thrombembolism During Bevacizumab Treatment--To Be Careful or Fearful?]. / Antikoagulacní lécba a trombembolizmus pri lécbe bevacizumabem--opatrnost, ci obavy?

Inhibition of angiogenesis is a valid approach in today's medicine. Besides oncology, it is used in ophthalmology, as well. In oncology, angiogenesis inhibition has become a routine and accessible method. A combination of angiogenesis inhibition and other therapies, including anticoagulation and antiaggregation is common in many cases. Bevacizumab is the most used antiangiogenic agent and has been in use for the longest period of time. A concomitant administration of angiogenesis inhibitors and anticoagulation may be feared by oncologists. From the available literature it is obvious that concomitant administration of bevacizumab and anticoagulation is safe. Also, use of antiaggregation and bevacizumab is safe. The risk of venous and arterial thromboembolism is real during the treatment with bevacizumab. Therefore, concomitant anticoagulation is not only possible but also may be desirable.

[Risks and complications of urological surgical procedures in elderly patients]. / Rizika a komplikace operacních výkonu u urologických pacientu ve vyssím veku.

INTRODUCTION: Surgical procedures in elderly patients are associated with a higher risk of complications. The main goal of this study was to evaluate the results and complications of urological surgeries in elderly patients. MATERIAL AND METHODS: A retrospective study was completed, evaluating the perioperative and early postoperative complications in patients over the age of 75. In total, 221 patients that underwent urological surgery between January 2011 and December 2012 were evaluated. The mean age of the patients was 78. RESULTS: The patient cohort that was evaluated experienced 48 (22%) complications; one death (<0.5%) and 4 (<2%) underwent repeat surgery due to serious complications. Infection was the most common complication: sepsis or surgical site infection. Other complications included respiratory insufficiency, delirium, bleeding etc. CONCLUSION: Urological surgery in patients above the age of 75 is safe, provided all pre-op procedures are executed correctly and prevention of possible complications is dealt with appropriately. Based on our results, the risk of complications falls within an acceptable range.

[The current approach to the treatment of the patients with metastatic colorectal cancer]. / Soucasný prístup k lécbe pacientu s metastatickým kolorektálním karcinomem.

Colorectal cancer is one of the most common malignant tumors. Despite the constant promotion of prevention remains around 20- 30% of cases dia-gnosed in the metastatic stage and approximately 50- 60% of patients developed the late dissemination. In 80- 90% of them we can find already unresectable metastases. Although surgical treatment is basic modality of therapy, with using mo-dern targeted therapy in combination with chemotherapy we can achieve longterm complete remission in the cases of advanced tumor and we can significantly prolonged the life of patients with this disease now. About 40- 50% patients in advanced stages who underwent metastasectomy survives 5-years and 10year survival rate is up to 25%. When administered systemic treatment median overall survival in these cases reaches around 24 months.

[Malignant melanoma treated with radical chemotherapy, resemblance histology of melanoma to soft tissue sarcomas, case report]. / Maligní melanom lécený intenzivní chemoterapií, podobnost histologického obrazu maligního melanomu a nádoru mekkých tkání, kazuistika pacientky.

BACKGROUND: Malignant melanoma is considered to be highly resistant to chemotherapy, radiotherapy, hormonotherapy and standard immunotherapy (interleukin 2, interferon alpha). Radical surgery in the early stages of the disease is still the most efficient method. Since the development of immunotherapy and targeted therapy, the role of palliative chemotherapy for advanced disease may be changing. CASE: A case report regarding 44-year-old woman with extensive tumor of the pectoral wall with contralateral axillary lymphadenopathy is presented. On the basis of imaging methods, histology and immunohistochemistry, the tumor was defined as a sarcoma. Due to PAX7-FKHR fusion gene positivity, rhabdomyosarcoma was the most probable classification. The patient was treated with radical chemotherapy including iphosphamide, vincristine, actinomycin D and doxorubicin with the effect of partial regression of the tumor. This enabled radical surgery of the chest wall tumor. Pathology proved 70% necrosis of the tumor. A contralateral axillary dissection was performed with a finding of two lymph nodes infiltrated with melanoma. The immunohistochemistry markers S100, HMB-45 and Melan A were positive. This resulted in a reclassification of the chest wall tumor to malignant melanoma. The following PET/CT scan was negative. A massive progression of the disease occurred after 5 months. B-RAF mutation leads to a plan of targeted therapy with vemurafenib. CONCLUSION: The case demonstrates the limits of the sensitivity and specificity of immunohistochemical markers of melanoma and the ability of this tumor to imitate various tumors including soft tissue sarcomas. A rare -PAX7-FKHR fusion gene positivity considered specific for rhabdomyosarcoma was found. An extraordinary response to radical chemotherapy with surgical resection led to an improvement of the quality of life and to a prolonged survival comparable with the effect of new targeted treatment for malignant melanoma.

Clinical impact of PAI 1 4G/5G gene polymorphism in colorectal carcinoma patients.

Plasminogen activator ihnibitor (PAI 1) belongs to the plasminogen activator system, which is part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumors. Its plasma level is normally low but 4G/4G homozygotes have higher concentrations of PAI 1. This genotype may be associated with worse prognosis and proximal location of colorectal cancer than 5G/5G homozygotes. In our prospective evaluation we examined plasma level PAI 1 (using photometric microplate method ELISA) pre-surgery and, subsequently, 6-8 weeks later, from 80 patients. For the PAI 1 rs1799889 -675 4G/5G polymorphism test the PCR amplification was used.Analysis of collected data was confirmed that significantly higher plasma levels of PAI 1 were found in patients before starting therapy, which decreased (p=0.004) after initiation of treatment. Patients with higher plasma level PAI 1 before (p=0.013) and after therapy (p=0.004) had significantly shorter survival. We found no relationship between polymorphisms of PAI 1 (-675 4G/5G) in relation to stage, survival or tumor location. PAI 1 is useful as a negative marker of prognosis and could be advantageous when planning adjuvant treatment of patients with colorectal carcinoma. Although opinions on the importance of polymorphisms of PAI 1 in relation to the prognosis are not uniform, it does seem that their role in the prognosis of patients with colorectal cancer is not essential.

[Analysis of prognostic factors in osteosarcoma adult patients, a single institution experience]. / Prognostické faktory konvencního osteosarkomu dospelých pacientu

BACKGROUND: The objective of this report was to estimate long-term outcome and prognostic factors in adult patients with high-grade osteosarcoma. The intended therapeutic strategy included preoperative and/or postoperative chemotherapy as well as surgery of all operable lesions. PATIENTS AND METHODS: We reviewed the clinical data of 36 newly diagnosed adult patients (aged 19-82, average 37.5, median 28.5 years) with high-grade osteosarcoma of the trunk or limbs evaluated by a multidisciplinary team and treated between 1999 and 2010 in Brno. Forty-five percent of patients were over thirty, more than 36% over forty. Thirty-one percent of patients had metastasis at the time of diagnosis. Demographic parameters, tumor-related and treatment-related variables included possible prognostic factors and their impact on response, overall survival (OS) and event-free survival (EFS) were analyzed. RESULTS: All the patients were followed up after treatment. Seventy-three percent of patients were poor responders to chemotherapy. Sixteen patients are alive, and twenty patients died. The survival time ranged from 2 to 177 months (average 45 months, median survival 23 months). The 5-year OS of all patients was 52.4%. OS of patients without metastasis was 68.12%, while 2-year OS with metastasis was 26% only. 5-year EFS was 38.7%. Univariate analysis revealed that the prognosis of adult osteosarcoma patients was significantly related to distant metastasis (p = 0.006), surgical stage (p = 0.00582), serum alkaline phosphatase (ALP) level (p = 0.00841) and serum lactatdehydrogenase (LD) level (p = 0.047). The other analyzed prognostic factors including age had no statistically significant influence on outcome of osteosarcoma in adult patients. CONCLUSION: The prognosis of osteosarcoma in adult patients was significantly correlated to surgical stage, distant metastasis, serum ALP and LD.

[Significance of urokinase and its inhibitors in the invasiveness and metastasing of malignant tumors]. / Význam urokinázy a jejích inhibitoru pro invazi a metastazování zhoubných nádoru

Fibrinolysis is process, which leads to the degradation of fibrin to fibrin monomers. Fibrinolysis helps to regulate hemostasis and prevents the creation of inappropriately large thrombus, which could reduce blood flow to the bloodstream. The main enzyme involved in fibrinolysis is plasmin. Tissue plasminogen activator (tPA) and urokinase (uPA) are agents converting plasminogen into active plasmin, together with urokinase receptor (uPAR) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) form plasminogen activator system (PAS) which is among others also part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumours. In contrast to tPA that is fundamental in fibrinolysis, uPA plays an essential role in tissue degradation as part of physiological and pathological processes. uPAR is a GPI (glycosylphosphatidylinositol)-anchored protein. The binding of uPA to uPAR results in activation of protein tyrosine kinase, protein kinase C and MAP kinase. At the same time, direct signalling pathway via Jak/STAT cascade utilising signalling transduction of Scr-like protein tyrosine kinase have also been described. uPAR expression is regulated by many growth factors, e.g. EGF, FGF-2 and HGF. It seems that individual PAS factors are involved in the process of rendering malignant tumors invasive. To what degree this influence is essential to specific malignancies, should be answered by further research. In the article the authors present a summary of findings about the interaction of fibrinolysis and tumor process, especially on the effects of urokinase and other activators and their inhibitors in metastasis of malignant tumors. The text contains information on the factors theirs introduction into practice is still the subject of numerous discussions, but in the future, individual PAS factors could play an important role in planning treatment strategies and also could become targets of targeted therapy.

[Liver function assessment in oncology practice]. / Hodnocení jaterní funkce v onkologické praxi.

The overall condition and prognosis of a patient can be affected by impaired liver function. It applies to anticancer pharmacotherapy, liver surgery and radiological interventions. The liver condition is usually assessed by common laboratory tests and clinical examination in daily practice. Liver tests consist of aminotransferases - alanine transaminase, aspartate transaminase, bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase, lactate dehydrogenase, albumin and prothrombin time, less frequently prealbumin and cholinesterase. The alkaline phosphatase and aspartate transaminase are markers of a liver damage, the alkaline phosphatase and gamma glutamyl transpeptidase are most useful as markers for cholestatic liver injury. Albumin, prealbumin, cholinesterase and prothrombin time are the markers of synthetic liver function. Bilirubin and bile acids are related to the liver transport and excretory capacity. The Child-Pugh score is used to assess prognosis of chronic liver disease, mainly cirrhosis. The examination of liver function using indocyanine green helps to determinate the extent of possible liver resection. A mathematical analysis of dynamic cholescintigraphy and a calculation of hepatic extraction fraction enables quantification of liver function. Other liver function tests are of little use in oncology.

Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients.

Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, and together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. In our project we examined the expression of uPA, uPAR, PAI 1 and PAI 2 in tumor tissue and we also studied the plasma levels of PAI 1 before and after the initiation of therapy in patients with colorectal carcinoma in relationship to grade of tumor and the treatment response. In our prospective evaluation we included 80 patients treated for adenocarcinoma of the colon and rectum. Analysis of collected data revealed statistically significant evidence of a relationship between the level of PAI 1 in plasma before treatment and grade of the tumor, which increases with tumor grade (p=0.025). We demonstrated that there exists a statistically significant relationship between the expression of PAI 2 (p<0.001) and uPAR (p=0.031) and grade of tumor. We also confirmed a statistically significant relationship between soluble levels of PAI 1 before treatment and therapeutic response (p=0.021). In our group of patients the expression of uPA, uPAR, PAI 1 and 2 in tumor tissue in relation to response to treatment was also assessed. Our results suggest that the greater expression of these parameters in tumor tissue is linked to a worse response to therapy. In conclusion, PAS factors help as a prognostic indicators and could also act as a predictive factor in colorectal carcinoma.

[Plasminogen activator system and its clinical significance in patients with a malignant disease]. / Plazminogen aktivátor systém a jeho klinický význam u pacientu s nádorovým onemocnením.

Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, a serine protease participating in the activation of matrixmetaloproteinases, latent elastases, growth factors and cytokines involved in the degradation of extracellular matrix elements. Together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI-1, PAI-2, PAI-3 and protease nexin), it forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. Plasminogen activator inhibitor 1 inhibits uPA-dependent invasiveness of some cancer cell lines. The vitronectin-PAI-1 complex inhibits migration of smooth muscle cells by binding alpha(v)beta3 integrin to vitronectin. PAI-1 or its deficiency interferes with signalling pathways such as PI3K/Akt and JAK/STAT and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death. PAI-1 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways. The individual components of PAS undoubtedly play an important role in angiogenesis and metastasising of malignant tumours. In the near future, results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and, at the same time, could serve as the goal for targeted therapies.

Bile duct malignancies.

Bile duct malignancies include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gall bladder carcinoma (GC) and carcinoma of Vater's ampulla (ampulloma). Bile duct neoplasms are rare tumours with overall poor prognosis. The overall incidence affects up to 12.5 per 100,000 persons in the Czech Republic. The mortality rate has risen recently to 9.5 per 100,000 persons. The incidence and mortality have been remarkably stable over the past 3 decades. The survival rate of patients with these tumours is poor, usually not exceeding 12 months. The diagnostic process is complex, uneasy and usually late. Most cases are diagnosed when unresectable, and palliative treatment is the main approach of medical care for these tumours. The treatment remains very challenging. New approaches have not brought much improvement in this field. Standards of palliative care are lacking and quality of life assessments are surprisingly not common. From the scarce data it seems, however, that multimodal individually tailored treatment can prolong patients'survival and improve the health-related quality of life. The care in specialized centres offers methods of surgery, interventional radiology, clinical oncology and high quality supportive care. These methods are discussed in the article in greater detail. Improvements in this field can be sought in new diagnostic methods and new procedures in surgery and interventional radiology. Understanding the tumour biology on the molecular level could shift the strategy to a more successful one, resulting in more cured patients. Further improvements in palliative care can be sought by defining new targets and new drug development. The lack of patients with bile duct neoplasms has been the limiting factor for any improvements. A new design of larger randomized international multicentric clinical trials with prompt data sharing could help to overcome this major problem. Defining standards of palliative care is a necessity. Addressing health-related quality of life could help to assess the real benefit of palliative treatment.

[Current methods in diagnostics and monitoring of patients with hereditary polyposis syndromes. Investigation of the small intestine]. / Soucasné vysetrovací metody v diagnostice a sledování familiárních polypóz. vysetrení tenkého streva.

BACKGROUNDS: Familial polypous syndromes include, in particular, familial adenomatous polyposis, Peutz-Jeghers syndrome and familial juvenile polyposis. The cumulative risk of developing cancer of the small intestine is higher and ranges between 5 to 13%. Close follow-up is therefore very important in the prevention of both malignant and benign complications of the basic disease. Currently there are many methods that can be offered to follow up patients with hereditary polyposis syndromes.The anatomy of the gastrointestinal tract can be investigated by endoscopy or double-contrast radiological techniques. The part of the small intestine between the duodenum and terminal ileum is difficult to reach by standard endoscopy and can only be judged by radiological enteroclysis, which has the disadvantage of exposing the patient to X-rays, moreover, it is impossible to examine the pathological findings histologically. However, new and more accurate enteroscopical (single and double-balloon, including intraoperative) methods and capsule enteroscopy have recently started to be used in routine clinical practice: Capsule endoscopy is an endoscopical method that enables us to examine the whole small intestine.This technology consists of swallowing a capsule the size of a bean that is later moved by motility of the gastrointestinal tract distally. A doctor then evaluates the record. Intraoperative enteroscopy is ever more often substituted by balloon enteroscopy. However, it remains a possibility when traditional double-balloon enteroscopy does not solve the patient's problems definitely; this occurs mainly in patients with intestinal adhesions or multiple lesions of the small intestine, endoscopically insolvable. Balloon enteroscopy is a modern endoscopic method that is used to examine the whole small intestine that also enables therapeutic efforts to be carried out when routine endoscopy is not successful. In some indications it has substituted intraoperative enteroscopy. CONCLUSION: These three methods are complementary, are connected in the examination algorithm and cannot be replaced by each other. Some authors consider them the golden standard in investigating the small intestine.

[Systemic and paraneoplastic manifestations of malignant diseases]. / Systémové a paraneoplastické projevy maligních onemocnení.

Timely diagnosis of malignant diseases largely depends on attention being given to early symptoms and on timely start of an extensive diagnostic process. Only this way can a tumour be diagnosed in its initial stage, and better effect of therapy can be achieved. The following overview provides a list of systemic (paraneoplastic - distant) manifestations of a tumour, and of symptoms related to local tumour expansion. The objective of the overview is to draw attention to all early symptoms of malignant diseases in patients, and to contribute to timely diagnosis and treatment.

Decreased expression of smooth muscle alpha-actin results in decreased contractile function of the mouse bladder.

PURPOSE: Smooth muscle alpha-actin (SMalphaA) is an important actin isoform for functional contractility in the mouse bladder. Alterations in the expression of SMalphaA have been associated with a variety of bladder pathological conditions. Recently, a SMalphaA-null mouse was generated and differences in vascular tone and contractility were observed between wild-type and SMalphaA-null mice suggesting alterations in function of vascular smooth muscle. We used SMalphaA-null mice to explore the hypothesis that SMalphaA is necessary for normal bladder function. MATERIALS AND METHODS: Reverse transcriptase polymerase chain reaction, Western blotting and immunohistochemical staining were used to confirm the absence of SMalphaA transcript and protein in the bladder of SMalphaA-null mice. In vitro bladder contractility compared between bladder rings harvested from wild-type and SMalphaA-null mice was determined by force measurement following electrical field stimulation (EFS), and exposure to chemical agonists and antagonists including KCl, carbachol, atropine and tetrodotoxin. Resulting force generation profiles for each tissue and agent were analyzed. RESULTS: There was no detectable SMalphaA transcript and protein expression in the bladder of SMalphaA-null mice. Nine wild-type and 9 SMalphaA-null mice were used in the contractility study. Bladders from SMalphaA-null mice generated significantly less force than wild-type mice in response to EFS after KCl. Similarly, bladders from SMalphaA-null mice generated less force than wild-type mice in response to pretreatment EFS, and EFS after carbachol and atropine, although the difference was not significant. Surprisingly, the bladders in SMalphaA-null mice appeared to function normally and showed no gross or histological abnormalities. CONCLUSIONS: SMalphaA appears to be necessary for the bladder to be able to generate normal levels of contractile force. No functional deficits were observed in the bladders of these animals but no stress was placed on these bladders. To our knowledge this study represents the first report to demonstrate the importance of expression of SMalphaA in force generation in the bladder.