RESUMO
INTRODUCTION: A large number of preventable adverse events are encountered during hospital admission and in particular around surgical procedures. Checklists may well be effective in surgery to prevent errors and adverse events. We developed, validated and evaluated a SURgical PAtient Safety System (SURPASS) checklist. METHODS: A prototype checklist was constructed based on literature on surgical errors and adverse events, and on human-factors literature. The items on the theory-based checklist were validated by comparison with process deviations (safety risk events) during real-time observation of the surgical pathway. Subsequently, the usability of the checklist was evaluated in daily clinical practice. RESULTS: The multidisciplinary SURPASS checklist accompanies the patient during each step of the surgical pathway and is completed by different members of the team. During 171 high-risk surgical procedures, 593 process deviations were observed. Of the deviations suitable for coverage by a checklist, 96% corresponded to an item on the checklist. Users were generally positive about the checklist, but a number of logistic improvements were suggested. CONCLUSION: The SURPASS checklist covers the vast majority of process deviations suitable for checklist assessment and can be applied in clinical practice relatively simply. SURPASS is the first validated patient safety checklist for the entire surgical pathway.
Assuntos
Lista de Checagem , Garantia da Qualidade dos Cuidados de Saúde/métodos , Procedimentos Cirúrgicos Operatórios/normas , Humanos , Erros Médicos/prevenção & controle , Desenvolvimento de Programas , Gestão da SegurançaRESUMO
Surgical adverse events remain a considerable problem: over 50% of in-hospital adverse events are related to a surgical procedure. The WHO, in its 'Safe surgery saves lives' campaign, propose what is essentially an expanded time-out procedure, including a debriefing. In recent years, this type of procedure has been widely advocated and implemented. While it is valuable, it has one major drawback: it is limited to the operating room. We recently observed 170 patients undergoing surgery. Over 50% of the incidents observed occurred outside the operating room, before and/or after surgery. Many near misses can be intercepted before entering the operating room. We therefore developed and validated a multidisciplinary checklist that covers the entire surgical patient pathway, instead of just the operative phase. The implementation of the so-called 'Surgical patient safety system' (SURPASS) checklist is currently underway. The effectiveness of the checklist in reducing adverse events and improving patient safety is being studied.
Assuntos
Salas Cirúrgicas/estatística & dados numéricos , Salas Cirúrgicas/normas , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Humanos , Satisfação do Paciente , Gestão da SegurançaRESUMO
INTRODUCTION: Adverse events in hospitals constitute a serious problem with grave consequences. Many studies have been conducted to gain an insight into this problem, but a general overview of the data is lacking. We performed a systematic review of the literature on in-hospital adverse events. METHODS: A formal search of Embase, Cochrane and Medline was performed. Studies were reviewed independently for methodology, inclusion and exclusion criteria and endpoints. Primary endpoints were incidence of in-hospital adverse events and percentage of preventability. Secondary endpoints were adverse event outcome and subdivision by provider of care, location and type of event. RESULTS: Eight studies including a total of 74 485 patient records were selected. The median overall incidence of in-hospital adverse events was 9.2%, with a median percentage of preventability of 43.5%. More than half (56.3%) of patients experienced no or minor disability, whereas 7.4% of events were lethal. Operation- (39.6%) and medication-related (15.1%) events constituted the majority. We present a summary of evidence-based interventions aimed at these categories of events. CONCLUSIONS: Adverse events during hospital admission affect nearly one out of 10 patients. A substantial part of these events are preventable. Since a large proportion of the in-hospital events are operation- or drug-related, interventions aimed at preventing these events have the potential to make a substantial difference.
Assuntos
Hospitais , Erros Médicos/estatística & dados numéricos , Interpretação Estatística de Dados , Pesquisa sobre Serviços de Saúde , Hospitais/normas , Humanos , Erros Médicos/prevenção & controle , Gestão de Riscos/métodosRESUMO
Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model.
Assuntos
Neoplasias do Colo/patologia , Fator V/genética , Neoplasias Hepáticas/secundário , Mutação/genética , Trombofilia/complicações , Animais , Neoplasias do Colo/irrigação sanguínea , Citoplasma/patologia , Células Endoteliais/patologia , Fibrina/metabolismo , Fibrinogênio/metabolismo , Homozigoto , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Transporte Proteico , Carga TumoralRESUMO
The non-pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD) comprises a large number of related components. Active case-finding is advocated in (ex-)smokers above the age of 40 who either cough or have 2 respiratory-tract infections per year. Structured self-management programmes may have positive effects; follow-up is of importance to prevent relapse of unhealthy behaviour. Patients with COPD must not smoke. Exercise training is essential in all stages of COPD; an exercise test should be done first, especially in severe COPD. Exercise training should preferably be incorporated in a pulmonary-rehabilitation programme if other components of such a programme are also indicated. Certain breathing exercises may be considered in patients that feel anxious or tense. Nutritional support combined with exercise training should be considered in patients with severe COPD and underweight, involuntary weight loss or a deficiency of fat-free mass. There are limited indications that psychosocial interventions may have a positive effect on the well-being and psychosocial function of patients with COPD. An exercise test to assess the maximum tolerated energy expenditure is indicated in COPD patients that experience limitations on their physical capabilities during work. Maintenance therapy with supplemental oxygen should be considered in case of hypoxia (PaO2 < 7.3 kPa) and if the PaO2 = 7.3-8.0 kPa combined with indications of pulmonary hypertension, peripheral oedema or a haematocrit > 0.55. A yearly influenza vaccination is indicated.
Assuntos
Exercício Físico/fisiologia , Fenômenos Fisiológicos da Nutrição , Doença Pulmonar Obstrutiva Crônica/terapia , Abandono do Hábito de Fumar , Humanos , Vacinas contra Influenza/administração & dosagem , Países Baixos , Doença Pulmonar Obstrutiva Crônica/prevenção & controleRESUMO
The reported incidence of concomitant cancer in patients with idiopathic venous thromboembolism (IVTE) varies between 4 and 24%, while the mean incidence of cancer within 3 years thereafter approximates 9%. Baseline investigations of patients with IVTE have been recommended. We evaluated the clinical practice regarding the screening of these patients according to these recommendations in two teaching hospitals. Medical history and physical examination were done reasonably exhaustively, except for investigations of the urogenital tract. Laboratory and imaging investigations were performed incompletely in a substantial proportion of the patients. The clinical evaluation regarding cancer, performed in patients with IVTE, could be improved. The implementation of a protocol should be considered.
Assuntos
Programas de Rastreamento/normas , Neoplasias/diagnóstico , Tromboembolia/complicações , Trombose Venosa/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Laboratório Clínico/normas , Feminino , Hospitais de Ensino/normas , Humanos , Masculino , Anamnese/normas , Pessoa de Meia-Idade , Neoplasias/etiologia , Países Baixos , Exame Físico/normas , Guias de Prática Clínica como Assunto , Tromboembolia/etiologia , Trombose Venosa/etiologiaRESUMO
Patients with cancer are frequently treated with anticoagulants, including heparins, to treat or to prevent thrombosis. Recent randomized trials that compared low molecular weight heparin to unfractionated heparin for the treatment of deep vein thrombosis have indicated that heparins affect survival of patients with cancer. Experimental studies support the hypothesis that cancer progression can be influenced by heparins, but results of these studies are not conclusive. Heparins are negatively charged polysaccharides that can bind to a wide range of proteins and molecules and affect their activity. As a consequence, heparins have a wide variety of biological activities other than their anticoagulant effects, which may interfere with the malignant process. In the present systematic review, we critically evaluate experimental studies in which heparins have been tested as anti-cancer drugs. All animal studies, published between 1960 and 1999, that report effects of heparins on growth of subcutaneously implanted tumors, spontaneous metastasis or experimentally induced metastasis are reviewed. In addition, we discuss mechanisms by which heparins potentially exert their activity on various steps in cancer progression and malignancy related processes. It is shown that heparins can affect proliferation, migration, and invasion of cancer cells in various ways and that heparins can interfere with adherence of cancer cells to vascular endothelium. Moreover, heparins can affect the immune system and have both inhibitory and stimulatory effects on angiogenesis. Because of the wide variety of activities of heparins, it is concluded that the ultimate effect of heparin treatment on cancer progression is uncertain.
Assuntos
Anticoagulantes/farmacologia , Antineoplásicos/farmacologia , Heparina/farmacologia , Metástase Neoplásica/prevenção & controle , Neoplasias/patologia , Animais , Antineoplásicos/uso terapêutico , Progressão da Doença , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , HumanosAssuntos
Anticoagulantes/uso terapêutico , Neoplasias/mortalidade , Trombofilia/prevenção & controle , Vitamina K/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/mortalidade , Ensaios Clínicos como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Heparina/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias/sangue , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Razão de Chances , Trombofilia/etiologia , Trombofilia/mortalidadeAssuntos
Antineoplásicos/uso terapêutico , Heparina/uso terapêutico , Neoplasias Experimentais/terapia , Neovascularização Patológica/prevenção & controle , Animais , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/crescimento & desenvolvimento , Heparina/metabolismo , Humanos , CamundongosRESUMO
Cancer patients treated for venous thromboembolism with low molecular weight heparin (LMWH) have a better survival rate than patients treated with unfractionated heparin (UFH). Because fibrin-associated angiogenesis is an important determinant in the progression and metastasis of many solid tumors, the effects of heparins on in vitro angiogenesis were investigated. Both UFH and LMWH inhibited bFGF-induced proliferation of human microvascular endothelial cells (hMVECs) to the same the extent (36-60%). VEGF165-induced proliferation was inhibited to a to a lesser extent (19-33%). Turbidity measurements and electron microscopy showed that the presence of LMWH during polymerization of the fibrin matrix led to a more transparent rigid network with thin fibrin bundles, whereas the presence of UFH resulted in a more opaque more porous network with thick fibrin fibers. We used a human in vitro angiogenesis model, which consisted of hMVECs seeded on top of a fibrin matrix, and stimulated the cells with basic fibroblast growth factor plus tumor necrosis factor a to induce capillary-like tubular structures. The formation of capillary-like tubular structures was retarded with matrices polymerized in the presence of LMWH (46% inhibition compared with a control matrix for both 1.5 and 10 units/ml LMWH), whereas matrices polymerized in the presence of UFH facilitated tubular structure formation (72 and 36% stimulation compared with a control matrix for 1.5 and 10 units/ml UFH, respectively). Similar results were obtained for cells stimulated with vascular endothelial growth factor plus tumor necrosis factor alpha. These data demonstrate the inhibitory effect of heparins on proliferation of hMVECs and provide a novel mechanism by which LMWH may affect tumor progression, namely reduced ingrowth of microvascular structures in a fibrinous stroma matrix by rendering it less permissive for invasion.
Assuntos
Fibrina/metabolismo , Fibrinolíticos/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Heparina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/crescimento & desenvolvimento , HumanosRESUMO
It is well documented that cancer patients undergoing surgery are at a sufficiently high risk of developing venous thromboembolism (VTE) to justify the routine use of prophylactic anticoagulant therapy. However, despite many studies showing an increased incidence of VTE associated with the use of chemotherapy in patients with breast carcinoma and with the use of indwelling venous access catheters in patients with various kinds of cancer, thromboprophylactic strategies are not yet widely used.
Assuntos
Neoplasias/epidemiologia , Trombofilia/etiologia , Trombose Venosa/prevenção & controle , Antineoplásicos/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Cateterismo Venoso Central/efeitos adversos , Terapia Combinada , Feminino , Glioma/complicações , Glioma/tratamento farmacológico , Glioma/cirurgia , Humanos , Incidência , Linfoma/complicações , Linfoma/tratamento farmacológico , Masculino , Neoplasias/sangue , Neoplasias/terapia , Estudos Prospectivos , Medição de Risco , Trombose Venosa/epidemiologia , Trombose Venosa/etiologiaRESUMO
Clinical and experimental studies have suggested that unfractionated heparin (UFH) effects malignancy progression. We reviewed all published clinical reports concerning the effects of UFH, as compared to no treatment on survival of cancer patients. Studies were classified on methodological strength and subdivided as to whether therapeutic or prophylactic dosages of UFH were used. Mortality rates after 3 years were extracted or calculated. One randomized study that evaluated the use of UFH in therapeutic dosages in patients with small cell lung carcinoma reported on an improved survival (odds ratio (OR) 0.64; 95% confidence interval (CI): 0.25 to 1.62). A detrimental effect was observed in 2 randomized studies which investigated the effects of intraportal UFH treatment in a prophylactic dose after surgery for gastrointestinal cancer (OR 1.66; 95% CI: 1.02 to 2.71). In contrast, level 2 studies in which either therapeutic or prophylactic dosages of UFH on mortality of patients with gastrointestinal cancer were evaluated, showed OR of 0.58 (95% CI; 0.11-3.13) and 0.65 (95% CI 0.51 to 0.84), respectively. We conclude that there is no convincing evidence of either positively or negatively effects of UFH on survival of patients with malignancy.
Assuntos
Anticoagulantes , Heparina , Neoplasias , Humanos , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Heparina/efeitos adversos , Heparina/uso terapêutico , Metanálise como Assunto , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaAssuntos
Anticoagulantes/uso terapêutico , Heparina/uso terapêutico , Neoplasias/mortalidade , Trombose/tratamento farmacológico , Anticoagulantes/farmacologia , Heparina/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Metástase Neoplásica , Neoplasias/complicações , Neoplasias/patologia , Trombose/complicaçõesRESUMO
Patients with malignant disease constitute a significant subgroup among patients with venous thromboembolism. Current results suggest that cancer patients are not only at an increased risk for thromboembolic events, particularly during chemotherapy treatment or after surgery, they also have an increased risk for bleeding complications while receiving oral anticoagulant treatment. The exact incidences of venous thromboembolic complications for the various types of cancer, however, are not well determined. Recent studies have indicated that subcutaneous low-molecular-weight heparin (LMWH) is as safe and effective as intravenous unfractionated heparin (UFH) in the initial treatment of venous thromboembolism. Moreover, a meta-analysis has provided preliminary evidence that, compared with UFH, LMWH treatment may prolong survival in cancer patients. Initiation of LMWH treatment in these patients is, therefore, recommended. Prospective randomized clinical trials to assess the optimum dose and duration of therapy are called for.
Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina/uso terapêutico , Neoplasias/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Heparina/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Recent randomized trials have suggested that treatment with low molecular weight heparin (LMWH) improves survival of cancer patients with venous thromboembolism, as compared to treatment with unfractionated heparin (UFH). Experimental studies have shown that UFH has activities besides its anticoagulant function which may affect progression of malignancy, including stimulation of new blood vessel formation. In contrast, LMWH has been suggested to inhibit angiogenesis. In the present study, we compared quantitatively the effects of treatment with UFH, LMWH or placebo on the development of experimentally induced colon carcinoma metastases in rat liver and on tumor-associated angiogenesis. It is shown that UFH and LMWH in therapeutic dosages neither affect development of metastases nor tumor blood vessel formation in this animal model. These results indicate that heparins do not affect colon cancer metastasis in liver. Further studies in other animal models are required to establish the mechanisms by which heparins potentially affect cancer.
Assuntos
Anticoagulantes/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina/uso terapêutico , Neovascularização Patológica , Animais , Anticoagulantes/efeitos adversos , Neoplasias do Colo/irrigação sanguínea , Heparina/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Metástase Neoplásica/prevenção & controle , RatosRESUMO
The effects of omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs on the development of experimentally induced colon carcinoma metastasis in rat liver were investigated quantitatively in vivo. Rats were kept on either a low-fat diet or on a fish oil (omega-3 PUFAs) or safflower oil (omega-6 PUFAs) diet for 3 weeks before the administration of colon cancer cells to the portal vein, until they were sacrificed at 1 or 3 weeks after tumor transplantation. At 1 week after transplantation, the fish oil diet had induced 7-fold more metastases (in terms of number and size) than had the low-fat diet, whereas the safflower oil diet had not affected the number and total volume of metastases. At 3 weeks after tumor transplantation, the fish oil diet and the safflower oil diet had induced, respectively, 10- and 4-fold more metastases (number) and over 1000- and 500-fold more metastases (size) than were found in the livers of rats on the low-fat diet. These differences were sex independent. Immunohistochemical analysis revealed that the immune system in the liver (Kupffer cells, pit cells, T cells, newly recruited macrophages, and the activation state of macrophages) did not play a significant role in this diet-dependent outgrowth of tumors. In conclusion, omega-3 and omega-6 PUFAs promote colon cancer metastasis in the liver without down-regulating the immune system. This finding has serious implications for the treatment of cancer patients with fish oil diet to fight cachexia.
Assuntos
Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Ácidos Graxos Ômega-3/toxicidade , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/secundário , Animais , Apresentação de Antígeno/imunologia , Divisão Celular/fisiologia , Neoplasias do Colo/imunologia , Dieta , Ácidos Graxos Ômega-6 , Ácidos Graxos Insaturados/toxicidade , Feminino , Células Matadoras Naturais/imunologia , Células de Kupffer/imunologia , Fígado/citologia , Fígado/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Masculino , Ratos , Ratos Endogâmicos , Linfócitos T/imunologiaRESUMO
Resection of liver metastases in patients with colon cancer increases survival but success depends on removal of all tumour tissue. For this purpose, understanding of spatial relationships between metastases and liver architecture is essential. Because metastatic cancer growth is essentially a three-dimensional (3D) event, we decided to apply 3D reconstruction techniques to study these spatial relationships between metastases and liver structures such as blood vessels, stroma and the liver capsule (Glisson's capsule). Colon carcinoma metastases were experimentally induced in rat liver by injection of colon cancer cells (CC531) into the portal vein. Three weeks later, livers from these animals and control livers were removed and immediately frozen in liquid nitrogen. Thirty-seven to 110 consecutive sections were used for each 3D reconstruction of 26 metastases in eight livers. Contours of different structures were stained by (immuno)histochemical means, traced in each section and stored in a database. From the contour model, a volume model was generated. Among the 26 metastases, seven were found to grow distantly from the liver capsule. They were small and consisted of well-differentiated cancer cells that were totally surrounded by a basement membrane and stroma which was always connected with adjacent blood vessels of a portal tract. The remaining 19 metastases showed a more advanced pattern of development. Infiltration of poorly differentiated colon cancer cells progressed through the stroma at various sites and areas of direct contact between cancer cells and hepatocytes were frequently found. This type of outgrowth of cancer cells was only found when metastases had made contact with the liver capsule. However, some areas in sections of these advanced stages still resembled small metastases. On the basis of these findings, we conclude that stroma-affects the differentiation pattern of cancer cells and has at least a dual role in tumour growth. On the one hand it limits invasion of cancer cells in the surrounding host tissue. On the other hand, stroma formation at the capsule, which consists mainly of granulation tissue, facilitates outgrowth of the tumours. Furthermore, our 3D reconstructions demonstrate the spatial heterogeneity of larger metastases and the importance of a 3D approach to understand growth and development of metastases in general and colon cancer metastases in the liver in particular.
Assuntos
Neoplasias do Colo/patologia , Processamento de Imagem Assistida por Computador , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/secundário , Animais , Ratos , Células Tumorais CultivadasRESUMO
The present study was performed to investigate processes involved in circumvention of the immune system by advanced stages of tumor growth in the liver. The efficacy of Kupffer cells and pit cells against cancer cells was tested in vivo in an experimental model of colon carcinoma metastasis in rat liver. Liver tumors were induced by administration of CC531 colon cancer cells into the vena portae. After 3 weeks, livers were obtained and partly fixed for electron microscopic procedures or frozen in liquid nitrogen for enzyme and immunohistochemistry at the light microscope level. The activation status of Kupffer cells was studied by expression of Ia-antigen (MHC class II) and by measurement of glucose-6-phosphate dehydrogenase (G6PDH) activity in the cells in situ as a measure of production of reactive oxygen species. Large numbers of Kupffer cells were found in liver parenchyma surrounding colon carcinomas when compared with levels in control livers, but these cells were not activated. Large numbers of activated monocytes and macrophages, cytotoxic T cells but only a few pit cells were found to be recruited to the boundary between liver parenchyma and tumors or their stroma. In those areas where cancer cells invaded liver parenchyma, only newly recruited macrophages and some Kupffer cells were present but few cytotoxic T cells or pit cells were found. The low activation status of Kupffer cells both in terms of production of reactive oxygen species and Ia-antigen expression and the absence of significant numbers of pit cells at tumor sites suggest that Kupffer cells and pit cells do not play a significant role in advanced stages of tumor growth. High levels of prostaglandin E2 were detected in the parenchyma of livers containing tumors and transforming growth factor beta was detected in the stroma of the tumors, therefore suggest that cytotoxicity of newly recruited monocytes, macrophages and cytotoxic T cells may be limited in these stages because of local production of these immunosuppressive factors.
Assuntos
Carcinoma/secundário , Neoplasias do Colo/patologia , Células Matadoras Naturais/fisiologia , Células de Kupffer/fisiologia , Neoplasias Hepáticas Experimentais/secundário , Animais , Carcinoma/patologia , Dinoprostona/análise , Modelos Animais de Doenças , Células Matadoras Naturais/imunologia , Células de Kupffer/imunologia , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Macrófagos/patologia , Masculino , Microscopia Eletrônica , Monócitos/patologia , Ratos , Ratos Endogâmicos , Linfócitos T/patologia , Fator de Crescimento Transformador beta/análise , Células Tumorais CultivadasRESUMO
Localization and production of alpha2-macroglobulin (alpha2M), a multifunctional binding protein with protease and cytokine scavenging properties, was studied in situ in rat livers containing experimentally induced colon carcinoma metastases by means of immunocytochemistry and in situ hybridization methods. The study was performed to investigate whether alpha2M production by hepatocytes plays a role in the defense against the growth of metastases on the basis of its protease inhibiting capacity. It was found that colon cancer cells in all developmental stages of the metastases contained large amounts of messenger RNA (mRNA) of alpha2M but hardly any alpha2M protein. Cancer cells in culture contained large amounts of both mRNA and protein of alpha2M. In contrast, stromal cells and liver cells did not show positivity for alpha2M mRNA above background levels. The exception was a few layers of hepatocytes around the latest stage of metastases. Hepatocytes contained both alpha2M mRNA and protein only when Kupffer cells were present, indicating that alpha2M mRNA production was induced via Kupffer cells. On the other hand, alpha2M protein was found in high amounts in the sinusoids and stroma of all metastases, irrespective of their developmental stage. Increased levels of alpha2M could not be detected in serum in all but one rat tested (n=8). It is concluded that production of alpha2M by hepatocytes occurs only around the latest developmental stage of metastases and that alpha2M does not play a significant role in the defense against metastatic cancer growth in rat liver. In contrast, cancer cells produce and secrete large amounts of alpha2M, which seems to be linked with their tumorigenicity. We suggest that this alpha2M captures cytokines rather than proteases by complex formation. These complexes were observed using immunocytochemical staining for alpha2M protein indicating that it was captured by either stromal cells, sinusoidal cells, or hepatocytes that are in direct contact with cancer cells, Therefore, changes in serum levels of alpha2M were limited, indicating that these levels do not reflect local production and effects of alpha2M.