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BACKGROUND: The advent of elexacaftor/tezacaftor/ivacaftor (ETI) resulted in unprecedented clinical benefits for eligible adults with CF. As a result, the question of whether chronic treatments can be safely stopped or adapted to this new situation has become a matter of great interest. Our objective was to derive a consensus among Italian experts on the impact of ETI on the current clinical management of CF lung disease. METHODS: From December 2021 to April 2022 a panel of Italian experts endorsed by the national CF scientific society derived and graded a set of statements on the pulmonary management of adults with cystic fibrosis through a modified Delphi methodology. RESULTS: The panel produced 13 statements exploring possible modifications in the fields of inhaled antibiotics and mucoactives; airway clearance and physical activity; chronic macrolides and bronchodilators; and lung transplant referral. The areas that the experts considered most urgent to explore were the impact of ETI on the role of inhaled antibiotics and lung transplant. CONCLUSIONS: The list of priorities that emerged from this study could be useful to guide and inform clinical research on the most urgent area of impact of ETI on CF lung disease and its clinical management.
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Fibrose Cística , Adulto , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Consenso , Técnica Delphi , Antibacterianos/uso terapêutico , MutaçãoRESUMO
BACKGROUND: Lung transplantation is a complex but effective treatment of end-stage pulmonary disease. Among the post-operative complications, phrenic nerve injury, and consequent diaphragmatic dysfunction are known to occur but are hitherto poorly described. We aimed to investigate the effect of lung transplantation on diaphragmatic function with a multimodal approach. METHODS: A total of 30 patients were studied at 4 time points: pre-operatively, at discharge after surgery, and after approximately 6 and subsequently 12 months post surgery. The diaphragmatic function was studied in terms of geometry (assessed by the radius of the diaphragmatic curvature delineated on chest X-ray), weakness (considering changes in forced vital capacity when the patient shifted from upright to supine position), force (maximal pressure during sniff), mobility (excursion of the dome of the diaphragm delineated by ultrasound), contractility (thickening fraction assessed by ultrasound), electrical activity (latency and area of compound muscle action potential during electrical stimulation of phrenic nerve), and kinematics (relative contribution of the abdominal compartment to tidal volume). RESULTS: Despite good clinical recovery (indicated by spirometry and 6 minutes walking test), a reduction of the diaphragmatic function was detected at discharge; it persisted 6 months later to recover fully 1 year after transplantation. Diaphragmatic dysfunction was demonstrated in terms of force, weakness, electrical activity, and kinematics. Our data suggest that the dysfunction was caused by phrenic nerve neurapraxia or moderate axonotmesis, potentially as a consequence of the surgical procedure (i.e., the use of ice and pericardium manipulation). CONCLUSIONS: The occurrence of diaphragmatic dysfunction in patients with a good clinical recovery indicates that the evaluation of diaphragmatic function should be included in the post-operative assessment after lung transplantation.
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Diafragma/fisiopatologia , Transplante de Pulmão/métodos , Pulmão/fisiopatologia , Adulto , Diafragma/inervação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nervo Frênico/fisiopatologia , Período Pós-Operatório , Estudos Prospectivos , Espirometria/métodos , Capacidade Vital/fisiologia , Adulto JovemRESUMO
Although the literature demonstrates that cardiac autonomic control (CAC) might be impaired in patients with chronic pulmonary diseases, the interplay between CAC and disease severity in end-stage lung disease has not been studied yet. We investigated the effects of end-stage lung disease on CAC through the analysis of heart rate variability (HRV) among patients awaiting lung transplantation. Forty-nine patients on the waiting list for lung transplantation (LTx; 19 men, age 38 ± 15 years) and 49 healthy non-smoking controls (HC; 22 men, age 40 ± 16 years) were enrolled in a case-control study at Policlinico Hospital in Milan, Italy. LTx patients were divided into two groups, according to disease severity evaluated by the Lung Allocation Score (LAS). To assess CAC, electrocardiogram (ECG) and respiration were recorded at rest for 10 min in supine position and for 10 min during active standing. Spectral analysis identified low and high frequencies (LF, sympathetic, and HF, vagal). Symbolic analysis identified three patterns, i.e., 0V% (sympathetic) and 2UV% and 2LV% (vagal). Compared to HCs, LTx patients showed higher markers of sympathetic modulation and lower markers of vagal modulation. However, more severely affected LTx patients, compared to less severely affected ones, showed an autonomic profile characterized by loss of sympathetic modulation and predominant vagal modulation. This pattern can be due to a loss of sympathetic rhythmic oscillation and a subsequent prevalent respiratory modulation of heart rate in severely affected patients.
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Respiratory physiotherapy and rehabilitation are important therapeutic options in non-cystic fibrosis bronchiectasis (NCFB). The aims of this review of clinical trials were to evaluate the safety and the effects on physiologic and clinical outcomes of airway clearance techniques (ACTs) and rehabilitation in NCFB patients, in comparison to usual care. The search was performed on March 2018 by using PubMed and PeDro databases. 33 studies were selected. The use of ACTs for NCFB were effective in increasing sputum volume although no benefit in quality of life (QoL) or pulmonary exacerbations were observed. There were no differences in effectiveness between the several techniques used. Humidification and saline inhalation were able to aid airway clearance. Hypertonic solution (HS) was more effective than isotonic solutions (IS) in improving expectoration and sputum viscosity. Pulmonary rehabilitation (PR) was found to be associated with short term benefits in exercise capacity, dyspnea and fatigue. Exercise training seems to improve quality of life and lower exacerbation rate, but long-term data are not available. Further studies are necessary to identify the most feasible long-term outcomes such as QoL and exacerbation rate.
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Bronquiectasia/terapia , Fibrose Cística/terapia , Modalidades de Fisioterapia/estatística & dados numéricos , Terapia Respiratória/métodos , Administração por Inalação , Manuseio das Vias Aéreas/métodos , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Fibrose Cística/fisiopatologia , Progressão da Doença , Humanos , Umidificadores , Modalidades de Fisioterapia/tendências , Qualidade de Vida , Segurança , Solução Salina/administração & dosagem , Escarro , Resultado do TratamentoRESUMO
Bronchiectasis is a heterogeneous chronic disease. Heterogeneity characterises bronchiectasis not only in the stable state but also during exacerbations, despite evidence on clinical and biological aspects of bronchiectasis, exacerbations still remain poorly understood.Although the scientific community recognises that bacterial infection is a cornerstone in the development of bronchiectasis, there is a lack of data regarding other trigger factors for exacerbations. In addition, a huge amount of data suggest a primary role of neutrophils in the stable state and exacerbation of bronchiectasis, but the inflammatory reaction involves many other additional pathways. Cole's vicious cycle hypothesis illustrates how airway dysfunction, airway inflammation, infection and structural damage are linked. The introduction of the concept of a "vicious vortex" stresses the complexity of the relationships between the components of the cycle. In this model of disease, exacerbations work as a catalyst, accelerating the progression of disease. The roles of microbiology and inflammation need to be considered as closely linked and will need to be investigated in different ways to collect samples. Clinical and translational research is of paramount importance to achieve a better comprehension of the pathophysiology of bronchiectasis, microbiology and inflammation both in the stable state and during exacerbations.
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Bronquiectasia/complicações , Bronquiectasia/microbiologia , Bronquiectasia/patologia , Progressão da Doença , HumanosRESUMO
BACKGROUND: Regional analysis by computed tomography (CT) is an attractive technique to interpret lung patterns after transplantation (LTx). We evaluated the application of CT functional mask derived parameters to determine whether development of primary graft dysfunction (PGD) is associated with short and/or long-term postoperative evidences of pulmonary function alterations. METHODS: A total of 38 patients who underwent bilateral LTx were evaluated at 24, 48 and 72 hours after the end of surgery to establish PGD occurrence and grading. CT scans at 3 and 12 months after LTx were analyzed to measure specific gas volume (SVg) changes normalized on expiratory SVgEXP of the whole lung (ΔSVg/SVgEXP) and to obtain functional masks of density variation, namely maps of low ventilation (LV), consolidation (C), air trapping (AT) and healthy parenchyma (H). RESULTS: Our main result was the evidence of a marked decrease in ΔSVg/SVgEXP in all subjects, irrespectively on PGD, at each time point after LTx, indicating a high degree of ventilation defects versus healthy. High percentages of LV were found in all subjects while percentages of AT and C were negligible. CONCLUSIONS: We demonstrate that quantification of ventilation defects by CT functional mask offers insights into the correlation between PGD and pulmonary function after LTx at short and mid-term.
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OBJECTIVES: Donation after circulatory death (DCD) potentially provides transplantable lungs suitable for a transplant, but in Italy, the need for 20 min of a no-touch period after cardiac arrest for legal declaration of death poses real challenges to organ preservation. METHODS: This is a single-institution, retrospective study using data collected prospectively between October and December 2017. After the approval of the multidisciplinary DCD study group of Regione Lombardia, Maastricht category III DCD donors became eligible for combined procurement of lungs and abdominal organs. Our group subsequently established a dedicated technical protocol. Our protocol consists of a non-rapid normothermic open-lung procurement process that takes place during abdominal normothermic regional perfusion, namely without pleural topical cooling before the start of pneumoplegia. After the lung is procured according to the technique described in the article, lung function is evaluated by ex vivo lung perfusion, which is run with the low-flow, open atrium, low haematocrit technique. RESULTS: During the study, we managed 5 controlled DCDs. In 3 cases, the lungs were successfully transplanted. All 3 patients are alive after 1 year, with good respiratory function. CONCLUSIONS: Our approach resulted in adequate lung preservation and successful transplants without detrimental effects on abdominal organ procurement, confirming the possibility of overcoming the obstacle of a long no-touch period in a DCD setting.
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Isquemia , Transplante de Pulmão/métodos , Pulmão/irrigação sanguínea , Preservação de Órgãos/métodos , Perfusão/métodos , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Adulto , Circulação Extracorpórea , Feminino , Humanos , Pulmão/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF. In this context, NE seems to be a predictor of long-term clinical outcomes and a possible target of treatment. In order to better evaluate the role of NE in bronchiectasis, a systematic search of scientific evidence was performed.Two investigators independently performed the search on PubMed and included studies published up to May 15, 2017 according to predefined criteria. A final pool of 31 studies was included in the systematic review, with a total of 2679 patients. For each paper data of interest were extracted and reported in table.In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment. NE has also been associated with risk of exacerbation, time to next exacerbation and all-cause mortality. This study reviews also the role of NE as a specific target of treatment in bronchiectasis. Inhibition of NE is at a very early stage and future interventional studies should evaluate safety and efficacy for new molecules and formulations.
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Bronquiectasia/diagnóstico , Bronquiectasia/enzimologia , Elastase de Leucócito/metabolismo , Biomarcadores/metabolismo , Estudos Transversais , Humanos , Escarro/metabolismoRESUMO
It is estimated that about 60-70% of Cystic Fibrosis patients develop Pseudomonas aeruginosa chronic infection, with progressive loss of lung function, as well as increased antibiotic resistance and mortality. The current strategy is to maintain lung function by chronic suppressive antipseudomonas antibiotic therapy. Tobramycin inhalation solution was the first approved aerosolised antibiotic to be used against P. aeruginosa; inhalatory tobramycin frequency of administration is twice daily and inhalation time is estimated to be 15 to 20 min. From the pharmacokinetic point of view, aminoglycosides are dose-dependent antibiotics and therefore once-daily dosing intravenous regimens have shown to be superior to the conventional multiple daily dosing. Therefore, there is no pharmacological reason to prefer the b.i.d administration as it is usually performed in current clinical practice. Should this be confirmed also for inhalatory route, the use of once-daily dosed aerosolized tobramycin could be an important step in making treatment burden easier in CF patients. The aim of this proof of concept study was to explore the effectiveness of treatment with once daily inhaled tobramycin in reducing P. aeruginos a density in sputum of chronically infected patients.
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PURPOSE: The aim of our study is to investigate if lung carbon monoxide diffusing capacity (DLCO) measured during effort is able to detect early respiratory functional impairment. METHODS: We enrolled 25 very light smokers and 20 healthy non smokers. Subjects underwent plethysmography, DLCO (single breath technique) and calculated effective pulmonary blood flow (Qc) by rebreathing method. During exercise by cycle ergometer (duration 10±2min; recovery 11±3min) DLCO and Qc were calculated at 25% and 50% of theoretical maximum workload. RESULTS: At baseline lung function and Qc did not differ between groups. DLCO and DLCO/Qc measured during exercise were significantly greater in non smokers (p<0.001); Qc was not statistically different. In very light smokers, DLCO, DLCO/Qc measured during exercise significantly correlated with the number of pack years (r=-0.60 p<0.001; r=-0.58 p<0.05; r=-0.55 p<0.05, respectively). CONCLUSIONS: In very light smokers there is lung function impairment and our data show that DLCO during exercise may reveal this underlying early damage.
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Teste de Esforço , Pneumopatias/diagnóstico , Pneumopatias/fisiopatologia , Pulmão/fisiopatologia , Capacidade de Difusão Pulmonar , Fumar/fisiopatologia , Adulto , Monóxido de Carbono/metabolismo , Exercício Físico/fisiologia , Feminino , Humanos , Pneumopatias/etiologia , Masculino , Pletismografia , Fluxo Sanguíneo Regional , Tabagismo/complicações , Tabagismo/fisiopatologiaRESUMO
OBJECTIVES: A large number of transplantation centres consider extracorporeal membrane oxygenation as an inappropriate option for bridging critical patients to lung transplantation. Technical improvements such as the introduction of a polymethylpentene membrane, new centrifugal pumps and heparin-coated circuits have led to a safer application of extracorporeal membrane oxygenation, and an increasing number of centres are reporting their positive experiences. The aim of this study was to review our practice in bridging critical candidates to lung transplantation with extracorporeal membrane oxygenation, by comparing patients with invasive mechanical ventilation with patients with spontaneous breathing. METHODS: The records of candidates for lung transplantation treated with extracorporeal membrane oxygenation have been revised. RESULTS: From February 2008 to 2012, 11 patients who experienced an abrupt worsening of their respiratory conditions were treated with extracorporeal membrane oxygenation; mean age: 33.9 ± 13.2 years, male/female ratio: 5/6, 6 patients were affected by cystic fibrosis, 2 had chronic rejection after transplantation, 2 had pulmonary fibrosis and 1 had systemic sclerosis. Seven patients were awake, while 4 patients received invasive mechanical ventilation. The sequential organ failure assessment score significantly increased during bridging time and this increase was significantly higher in the intubated patients. All the patients had bilateral lung transplantation. Spontaneously breathing patients showed a tendency to require a shorter duration of invasive mechanical ventilation, intensive care unit stay and hospital stay after transplantation. One-year survival rate was 85.7% in patients with spontaneous breathing vs 50% in patients with invasive mechanical ventilation. CONCLUSIONS: Extracorporeal membrane oxygenation in spontaneously breathing patients is a feasible, effective and safe bridge to lung transplantation.
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Oxigenação por Membrana Extracorpórea , Pneumopatias/terapia , Transplante de Pulmão , Respiração Artificial , Respiração , Adulto , Estado Terminal , Oxigenação por Membrana Extracorpórea/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Unidades de Terapia Intensiva , Estimativa de Kaplan-Meier , Tempo de Internação , Pneumopatias/diagnóstico , Pneumopatias/mortalidade , Pneumopatias/fisiopatologia , Pneumopatias/cirurgia , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Respiração Artificial/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Patients with Chronic Obstructive Pulmonary Disease (COPD) and tracheostomy are at high risk for exacerbations and hospitalizations. Macrolide treatment has shown to reduce exacerbations in moderate-to-severe COPD. To evaluate the safety and the efficacy of long-term azithromycin use in outpatients with severe COPD and tracheostomy. A multicenter, randomized, uncontrolled, pilot trial evaluating the safety and the efficacy of azithromycin 500 mg three day-a-week for 6 months (AZI) vs. standard of care (SC) in severe COPD outpatients with tracheostomy. Patients were monitored for six months of treatment plus six months of follow up. The primary outcome was the reduction in the number of exacerbations and hospitalizations. A total of 22 patients was randomized (11 to SC and 11 to AZI). Patients in AZI had a significant lower cumulative number of exacerbations after the first 3 months of treatment when compared to patients in SC (p = 0.001), as well as hospitalizations (p = 0.02). Kaplan-Meier survival curves for time to first exacerbation showed a significant reduction in AZI of the rates of first exacerbation when compared to SC (log rank test = 12.14, p < 0.001), as well as to first hospitalization (log-rank = 4.09, p = 0.04). Azithromycin significantly improved the quality of life in comparison to SC. No serious adverse events in the AZI group were reported. Long-term azithromycin treatment seems to be safe and effective in severe COPD outpatients with tracheostomy in reducing exacerbations, hospitalizations, as well as in improving quality of life.
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Azitromicina/uso terapêutico , Macrolídeos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Traqueostomia , Idoso , Idoso de 80 Anos ou mais , Azitromicina/efeitos adversos , Índice de Massa Corporal , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Macrolídeos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Doença Pulmonar Obstrutiva Crônica/mortalidade , Qualidade de Vida , Índice de Gravidade de Doença , FumarRESUMO
BACKGROUND: It has been reported that Chlamydophila (C.) pneumoniae is involved in the initiation and promotion of asthma and chronic obstructive pulmonary diseases (COPD). Surprisingly, the effect of C. pneumoniae on airway function has never been investigated. METHODS: In this study, mice were inoculated intranasally with C. pneumoniae (strain AR39) on day 0 and experiments were performed on day 2, 7, 14 and 21. RESULTS: We found that from day 7, C. pneumoniae infection causes both a sustained airway hyperresponsiveness and an inflammation. Interferon-gamma (IFN-gamma) and macrophage inflammatory chemokine-2 (MIP-2) levels in bronchoalveolar lavage (BAL)-fluid were increased on all experimental days with exception of day 7 where MIP-2 concentrations dropped to control levels. In contrast, tumor necrosis factor-alpha (TNF-alpha) levels were only increased on day 7. From day 7 to 21 epithelial damage and secretory cell hypertrophy was observed. It is suggested that, the inflammatory cells/mediators, the epithelial damage and secretory cell hypertrophy contribute to initiation of airway hyperresponsiveness. CONCLUSION: Our study demonstrates for the first time that C. pneumoniae infection can modify bronchial responsiveness. This has clinical implications, since additional changes in airway responsiveness and inflammation-status induced by this bacterium may worsen and/or provoke breathlessness in asthma and COPD.
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Hiper-Reatividade Brônquica/microbiologia , Infecções por Chlamydophila/complicações , Chlamydophila pneumoniae , Pulmão/microbiologia , Pneumonia Bacteriana/microbiologia , Animais , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/microbiologia , Quimiocina CXCL2/metabolismo , Infecções por Chlamydophila/metabolismo , Infecções por Chlamydophila/microbiologia , Infecções por Chlamydophila/patologia , Infecções por Chlamydophila/fisiopatologia , Cílios/microbiologia , Cílios/ultraestrutura , Modelos Animais de Doenças , Hipertrofia , Interferon gama/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/patologia , Pneumonia Bacteriana/fisiopatologia , Testes de Função Respiratória , Mucosa Respiratória/microbiologia , Mucosa Respiratória/ultraestrutura , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This review summarizes the present concepts regarding the biological processes that mediate intrinsic and innate host defense against microbial invasion of the lung. Innate immunity is the first line of defense of the higher organisms towards invading pathogens. It accomplishes a wide variety of activities including recognition and effector functions. The innate responses use phagocytic cells (macrophages, monocytes, and neutrophils), cells that release inflammatory mediators (basophils, mast cells, and eosinophils), and natural killer cells. The molecular component of innate responses includes complement, acute-phase proteins, and cytokines. Recognition of pathogen-associated molecular patterns is mediated by the pathogen receptors of the innate immune system, among these molecules toll-like receptors have emerged as fundamental components in the innate immune responses to infection, and a link between innate and adaptive immunity. Additional protection comes from polypeptide mediators of the innate host defense, such as the defensins and other antibiotic peptides. In view of the considerable burden in terms of mortality and morbidity that severe infections still pose worldwide, a better understanding of the biological basis of host-pathogen interactions opens stimulating future treatment perspectives.
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Bactérias/imunologia , Sistema Imunitário/imunologia , Fagocitose/imunologia , Pneumonia Bacteriana/imunologia , Animais , Bactérias/patogenicidade , Humanos , Imunidade Celular , Imunidade Inata , Fagócitos/imunologia , Pneumonia Bacteriana/microbiologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/microbiologiaRESUMO
The association between cancer and thromboembolic disease is a well-known phenomenon and can contribute significantly to the morbidity and mortality of cancer patients. The spectrum of thromboembolic manifestations in cancer patients includes deep vein thrombosis, pulmonary embolism, but also intravascular disseminated coagulation and abnormalities in the clotting system in the absence of clinical manifestations. Unfractionated heparin (UFH) and particularly low molecular weight heparins (LMWH-s) are widely used for the prevention and treatment of thromboembolic manifestations that commonly accompany malignancies. Malignant growth has also been linked to the activity of heparin-like glycosaminoglycans, to neoangiogenesis, to protease activity, to immune function and gene expression. All these factors contribute in the proliferation and dissemination of malignancies. Heparins may play a role in tumour cell growth and in cancer dissemination. The aims of the study are to review the efficiency of heparins in the prevention and treatment of cancer-related thromboembolic complications, and review the biological effects of heparins. Heparins are effective in reducing the frequency of thromboembolic complications in cancer patients. Meta-analyses comparing unfractionated heparins and LMWH-s for the treatment of deep vein thrombosis have shown better outcome with a reduction of major bleeding complications in patients treated with LMWH-s. LMWH have antitumour effects in animal models of malignancy: heparin oligosaccharides containing less than 10 saccharide residues have been found to inhibit the biological activity of basic fibroblast growth factor (bFGF), whereas heparin fragments with less than 18 saccharide residues have been reported to inhibit the binding of vascular endothelial growth factor (VEGF) to its receptors on endothelial cells. It has been shown that LMWH, in contrast with UFH, can hinder the binding of growth factors to their high-affinity receptors as a result of its smaller size. In vitro heparin fragments of less than 18 saccharide residues reduce the activity of VEGF, and fragments of less than 10 saccharide residues inhibit the activity of bFGF. Small molecular heparin fractions have also been shown to inhibit VEGF- and bFGF-mediated angiogenesis in vivo, in contrast with UFH. Moreover, heparin may influence malignant cell growth through other different interrelated mechanisms: inhibition of (1) heparin-binding growth factors that drive malignant cell growth; (2) tumour cell heparinases that mediate tumour cell invasion and metastasis; (3) cell surface selectin-mediated tumour cell metastasis and blood coagulation. The above evidence, together with favourable pharmaco-properties and with a reduction in major bleeding complications, suggests an important role for LMWH-s in thromboprophylaxis and in the therapy of venous thromboembolism in cancer patients. There is sufficient experimental data to suggest that heparins may interfere with various aspects of cancer proliferation, angiogenesis, and metastasis formation. Large-scale clinical trials are required to determine the clinical impact of the above activities on the natural history of the disease.