Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

The incidence of pulmonary embolism during deep vein thrombosis.

Among life-threatening cardiovascular diseases, pulmonary embolism (PE) is the third most common after myocardial infarction and stroke. PE is a manifestation of venous thromboembolism (VTE). PE shares risk factors with deep vein thrombosis (DVT) and is regarded as a consequence of DVT rather than a separate clinical entity. Risk factors for VTE include major surgery, major trauma, high age, myocardial infarction, chronic heart failure, prolonged immobility, malignancy, thrombophilia and prior VTE. It is, however, important to recognize that these factors are not equally important and not equally common in patients with PE and DVT, respectively. Compared with DVT, PE is more often associated with major surgery, major trauma, high age, myocardial infarction and chronic heart failure, whereas malignancy and thrombophilia primarily are clinical predictors of DVT. In patients with prior VTE the initial clinical manifestation strongly predicts the manifestation of recurrent episodes, i.e. patients with previous PE are more likely to develop recurrent PE than DVT while patients with DVT predominantly are at risk of recurrent DVT.

Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines.

Three guidelines have recently been published for the diagnosis and treatment of disseminated intravascular coagulation (DIC) in adults. This communication seeks to harmonize the recommendations in these guidelines using a modified GRADE system. The scoring system for diagnosis of DIC using global coagulation tests is known to correlate with key clinical observations and outcomes (Moderate quality). The cornerstone of DIC treatment is the treatment of the underlying condition (Moderate quality). In general, transfusion of platelets or plasma (components) in patients with DIC should be reserved for patients who are bleeding (Low quality). Therapeutic doses of heparin should be considered in cases of DIC where clinical features of thrombosis predominate. Heparin is not recommended in those patients with a high risk of bleeding, (Moderate quality). However, prophylactic doses of unfractionated heparin or low molecular we ight heparin is recommended in critically ill and non-bleeding patients with DIC for prevention of venous thromboembolism (Moderate to High quality). Although further prospective evidence from randomized controlled trials is required, administration of antithrombin or recombinant thrombomodulin may be considered in certain patients with DIC. In general, patients with DIC should not be treated with antifibrinolytic agents (Low quality). However those who present with severe bleeding, that is characterized by a markedly hyperfibrinolytic state such as leukemia (Low quality) and trauma (Moderate quality), may be treated with antifibrinolytic agents. © 2013 International Society on Thrombosis and Haemostasis.

Clustered mixed nonhomogeneous Poisson process spline models for the analysis of recurrent event panel data.

A flexible semiparametric model for analyzing longitudinal panel count data arising from mixtures is presented. Panel count data refers here to count data on recurrent events collected as the number of events that have occurred within specific follow-up periods. The model assumes that the counts for each subject are generated by mixtures of nonhomogeneous Poisson processes with smooth intensity functions modeled with penalized splines. Time-dependent covariate effects are also incorporated into the process intensity using splines. Discrete mixtures of these nonhomogeneous Poisson process spline models extract functional information from underlying clusters representing hidden subpopulations. The motivating application is an experiment to test the effectiveness of pheromones in disrupting the mating pattern of the cherry bark tortrix moth. Mature moths arise from hidden, but distinct, subpopulations and monitoring the subpopulation responses was of interest. Within-cluster random effects are used to account for correlation structures and heterogeneity common to this type of data. An estimating equation approach to inference requiring only low moment assumptions is developed and the finite sample properties of the proposed estimating functions are investigated empirically by simulation.

Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study.

BACKGROUND: Patients undergoing major abdominal surgery carry a high risk of venous thromboembolism (VTE), but the optimal duration of postoperative thromboprophylaxis is unknown. OBJECTIVES: To evaluate the efficacy and safety of thromboprophylaxis with the low molecular weight heparin (dalteparin), administered for 28 days after major abdominal surgery compared to 7 days' treatment. PATIENTS/METHODS: A multicenter, prospective, assessor-blinded, open-label, randomized trial was performed in order to evaluate prolonged thromboprophylaxis after major abdominal surgery. In total, 590 patients were recruited, of whom 427 were randomized and received at least 1 day of study medication, and 343 reached an evaluable endpoint. The primary efficacy endpoint was objectively verified VTE occurring between 7 and 28 days after surgery. All patients underwent bilateral venography at day 28. RESULTS: The cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012). The number that needed to be treated to prevent one case of VTE was 12 (95% confidence interval 7-44). Bleeding events were not increased with prolonged compared with short-term thromboprophylaxis. CONCLUSIONS: Four-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis.

Improving on nature's defenses: optimization & high throughput screening of antimicrobial peptides.

Antimicrobial peptides (AMPs) are ubiquitous in nature where they play important roles in host defense and microbial control. Despite their natural origin, antimicrobial spectrum and potency, the lead peptide candidates that so far have entered pharmaceutical development have all been further optimized by rational or semi-rational approaches. In recent years, several high throughput screening (HTS) systems have been developed to specifically address optimization of AMPs. These include a range of computational in silico systems and cell-based in vivo systems. The in silico-based screening systems comprise several computational methods such as Quantitative Structure/Activity Relationships (QSAR) as well as simulation methods mimicking peptide/membrane interactions. The in vivo-based systems can be divided in cis-acting and trans-acting screening systems. The cis-acting pre-screens, where the AMP exerts its antimicrobial effect on the producing cell, allow screening of millions or even billions of lead candidates for their basic antimicrobial or membrane-perturbating activity. The trans-acting screens, where the AMP is secreted or actively liberated from the producing cell and interacts with cells different from the producing cell, allow for screening under more complex and application-relevant conditions. This review describes the application of HTS systems employed for AMPs and lists advantages as well as limitations of these systems.

Randomised controlled trial of a shared care programme for newly referred cancer patients: bridging the gap between general practice and hospital.

OBJECTIVE: To determine the effect of a shared care programme on the attitudes of newly referred cancer patients towards the healthcare system and their health related quality of life and performance status, and to assess patients' reports on contacts with their general practitioner (GP). SETTING: Department of Oncology at Aarhus University Hospital and general practices. DESIGN: Randomised controlled trial in which patients completed questionnaires at three time points. The shared care programme included transfer of knowledge from the oncologist to the GP, improved communication between the parties, and active patient involvement. PARTICIPANTS: 248 consecutive cancer patients recently referred to the department. MAIN OUTCOME MEASURES: Patients' attitudes towards the healthcare services, their health related quality of life, performance status, and reports on contacts with their GPs. RESULTS: The shared care programme had a positive effect on patient evaluation of cooperation between the primary and secondary healthcare sectors. The effect was particularly significant in men and in younger patients (18-49 years) who felt they received more care from the GP and were left less in limbo. Young patients in the intervention group rated the GP's knowledge of disease and treatment significantly higher than young patients in the control group. The number of contacts with the GP was significantly higher in the intervention group. The EORTC quality of life questionnaire and performance status showed no significant differences between the two groups. CONCLUSIONS: An intersectoral shared care programme in which GPs and patients are actively involved has a positive influence on patients' attitudes towards the healthcare system. Young patients and men particularly benefit from the programme.

The effect of low-dose acetylsalicylic acid on bleeding after transurethral prostatectomy--a prospective, randomized, double-blind, placebo-controlled study.

OBJECTIVE: An increase in the loss of blood after ingestion of acetylsalicylic acid (ASA) has been reported after several types of surgery, but randomized placebo-controlled studies have exclusively been performed after coronary artery bypass surgery. The reported effects of ASA on bleeding after transurethral prostatectomy (TURP) have been conflicting. We have studied the effect of low doses of ASA (150 mg) on bleeding after TURP in a prospective, randomized, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Patients were randomized to receive either 150 mg ASA (n = 26) or placebo (n = 27) 10 days before surgery. The weight of resected tissue, operation time and blood loss, transfusion requirements and complications were recorded. RESULTS: There was no significant difference in the median operative blood loss between the groups (p = 0.528), but postoperatively the blood loss in the ASA group (median 284; quartiles 196-660 ml) was significantly higher than in the placebo group (median 144; quartiles 75-379 ml), (p = 0.011). No significant difference was observed between the groups regarding the amount of resected tissue (p = 0.209) or the operating time (p = 0.297). In both groups the operative blood loss was significantly related to the amount of resected tissue (p < 0.005) and the operating time (p < 0.005). No significant difference in transfusion requirements (p = 0.280), time to catheter removal (p = 0.455) and hospital stay (p = 0.820) were observed between the groups. CONCLUSION: Long-term low-dose ASA therapy is associated with a significant increase in the postoperative blood loss after TURP, and although no significant difference in transfusion requirements was observed more units of blood were used in the ASA group. We advise that ASA therapy should be withdrawn 10 days before TURP.

[Anticoagulant treatment]. / Antikoagulationsbehandling.

In 1998, the sale of vitamin K antagonists (VKA) in Denmark corresponded to the amount used for treatment of more than 20,000 patients for one year. This is more than three times more than ten years earlier. The reasons for the increasing use of VKA are new indications for permanent anticoagulant treatment, especially chronic atrial fibrillation and venous thromboembolism associated with permanent thromboembolic risk factors. The risk of bleeding is higher in the introductory phase of anticoagulant treatment than later on. It is now recommended to commence anticoagulant therapy without a loading dose. This seems to hasten a good estimate of the maintenance dose. The metabolism of VKA depends on a number of genetic and acquired factors. Knowledge of these factors is crucial for optimal regulation of the treatment, and it is important that patients at start of treatment are thoroughly informed about these factors in order to minimize the risk of complications.

[Acquired factor VIII deficiency treated with cyclosporine]. / Erhvervet faktor VIII-mangel behandlet med ciclosporin.

The treatment of acquired factor VIII inhibitors remains controversial, and no standard therapy exists. We describe a case story of successful treatment with prednisolone and cyclosporine of an 83-year old female with severe bleeding disorder due to an acquired factor VIII inhibitor. The patient had complete remission, and no side effects were observed. We recommend that treatment of acquired factor VIII inhibitor with cyclosporine is further investigated.

[Cross-sectorial cooperation regarding cancer patients in a recently started care program. Ideas and themes based on focus group interviews with general practitioners and oncologists]. / Tvaersektorielt samarbejde omkring kraeftpatienter i nystartede behandlingsforløb. Ideer og temaer udsprunget af fokusgruppeinterview med praktiserende laeger og onkologer.

This study identified ideas for an improved collaboration between general practitioners and oncologists regarding patients with cancer. A qualitative research-method with focused group interviews was chosen. The results demonstrated that both oncologists and general practitioners would like the general practitioners to take more active part in the total care programme for cancer patients. Some of the needed improvements were more detailed referral letters including description of treatment plans, information about what the patient had been told and general information about the specific cancer disease. Both parts desire bilateral information exchange and a dialogue about the distribution of tasks. Both parts are willing to collaborate but this is at present restricted due to lack of knowledge of each others' working areas and the oncologists' impression that general practitioners need more medical knowledge regarding specific aspects of cancer. A randomized intervention study using ideas from this study may clarify if it is possible to improve the collaboration and thereby the cancer patients' satisfaction with care.

Bleeding and activation of coagulation during and after transurethral prostatectomy: importance of the acute-phase response and prostate specific antigen?

OBJECTIVE: To evaluate the importance of coagulation activation in patients with benign prostatic hyperplasia, undergoing transurethral prostatic resection (TURP) and to examine whether changes in activity are related to blood loss, the circulatory entry of prostate specific antigen (PSA), operative trauma (resected tissue weight) and the inflammatory response, as assessed by C-reactive protein (CRP). PATIENTS AND METHODS: TURP was performed in 24 men and the weight of resected tissue and blood loss determined. The activation of coagulation was followed using new sensitive and specific assays, and the changes related to blood loss, the release of PSA, operative trauma and the acute-phase response. The area under the curve (AUC) for the measured quantities was used in correlation analysis. RESULTS: TURP was followed by a marked activation in coagulation. There was no correlation between the markers of coagulation and the operative blood loss, but the latter correlated with the weight of resected tissue (P=0.001). Postoperatively, the blood loss correlated with prothrombin fragment (F1+2; P=0.010), with thrombin-antithrombin complexes (TAT; P=0.024), and with the PSA concentrations (P=0.016) but not with fibrinogen. Serum concentrations of PSA increased significantly and the AUC in the operative period correlated with F1+2 (P=0.003) and TAT (P<0. 005), but postoperatively only with F1+2 (P=0.013). The weight of resected tissue correlated operatively with PSA (P=0.012) but not with the concentrations of F1+2 or TAT. Postoperatively, there was a correlation with the acute-phase proteins, CRP (P=0.005), fibrinogen (P=0.012) and with PSA (P=0.020). CONCLUSION: The operative blood loss is caused by surgical factors and the observed postoperative hypercoagulable state can be explained as a physiological response to bleeding, i.e. to secure haemostasis. The activity of coagulation was unrelated to operative trauma, but the acute-phase proteins were. The release of PSA into the circulation probably has an effect on blood coagulation.

Safety of low-molecular-weight heparin in pregnancy: a systematic review.

Unfractionated heparin (UFH) remains the anticoagulant of choice during pregnancy. Low-molecular-weight heparins (LMWH) are an attractive alternative to UFH due to their logistic advantages and their association with a lower incidence of osteoporosis and HIT. We reviewed all published clinical reports concerning the use of LMWH during pregnancy. In addition, participants of an international interest group contributed a cohort of pregnant women treated with LMWH. Pregnancies were divided into two groups; those with and those without maternal comorbid conditions. The number of adverse fetal outcomes and the occurrence of maternal complications were evaluated in the two groups. In the group of women with comorbid conditions (n = 290), 13.4% of the pregnancies were associated with an adverse fetal outcome. In contrast, in the group of women without comorbid conditions (n = 196), 3.1% were associated with an adverse outcome, which is comparable to that seen in the normal population. We conclude that LMWH appear to be a safe alternative to unfractionated heparin as an anticoagulant during pregnancy.

Quality of reinfused drainage blood after total knee arthroplasty.

Reinfusion of postoperative wound drainage blood has become an attractive alternative in primary total knee and hip arthroplasty. Quality of the drainage blood was studied with respect to content of extracellular bioactive substances and coagulation split products. Using the HandyVac ATS autotransfusion system, drainage blood was collected and reinfused within 6 hours postoperatively from 10 patients undergoing primary total knee arthroplasty. Blood samples were collected from the patients immediately after and 1 hour after opening of the tourniquet and after reinfusion of drainage blood. Samples were also collected from the drainage blood immediately before and at the end of reinfusion. The leukocyte-derived and platelet-derived bioactive substances histamine, eosinophil cationic protein (ECP), eosinophil protein X (EPX), myeloperoxidase (MPO), plasminogen activator inhibitor type 1 (PAI-1), and activated complement factor C3(C3a) and various coagulation factors and split products were analyzed in patient and drainage blood samples. None of the patients received additional predonated autologous blood or allogeneic blood components during the study period. Within 6 hours postoperatively, 250 to 1,000 mL drainage blood was collected and reinfused. Histamine, ECP, EPX, MPO, PAI-1, and C3a content was significantly increased in drainage blood immediately before and at the end of reinfusion. Reinfusion did not change the concentration of these substances in samples from the patients. Coagulation factors and various split products showed that drainage blood was defibrinated. Reinfusion of drainage blood did not change the coagulative capacity of the patients. Drainage blood appears to be defibrinated and contains various extracellular leukocyte-derived and platelet-derived bioactive substances. Reinfusion does not change the coagulative capacity or the concentration of bioactive substances of patients.

[Cross-sectional therapeutic programs--an example of a cooperative health care system. A review with comments]. / Tvaersektorielle behandlingsprogrammer--et eksempel på det samarbejdende sundhedsvaesen. En kommenteret oversigt.

There is no tradition for sharing the responsibility for episodes of care between the primary and secondary sectors in the Danish health care system. Concurrently with increased international experience with shared care programmes, there is also a growing interest in Denmark in cooperation between the sectors. Based on literature research, shared care programmes are presented as a method of ensuring continuity and quality in treatment of chronic diseases. Experiences in the areas of diabetes, asthma, rheumatoid arthritis, and cancer are described. It is concluded that the Danish health care system is well prepared for the implementation of shared care programmes; there are only few sources of payment in the system, and an extensive continuing medical education system ensures that general practitioners can participate in relevant education. The implementation of shared care programmes in Denmark should be followed by scientific evaluation and documentation of the quality of the treatment programmes.

The effect of antithrombin on the systemic inflammatory response in disseminated intravascular coagulation.

Sepsis and major trauma are the two most common causes of disseminated intravascular coagulation (DIC) and are characterized by a sudden increase in inflammatory mediators. In general, the outcome of the patient is determined by the degree of the inflammatory response. In severe cases of sepsis and trauma, cascade systems, such as the coagulation, fibrinolytic and complement systems, are activated beyond the capacity of the autoregulatory mechanisms. During DIC, plasma levels of antithrombin (AT)--a serine protease inhibitor that acts mainly on the serine proteases of the coagulation system--decrease due to the formation and subsequent elimination of complexes between AT and activated coagulation factors. The consumption of AT may start a vicious circle by facilitating further intravascular fibrin formation, followed by ischaemic tissue injury and accelerated activation of blood coagulation. Infusion of AT has an anti-inflammatory effect through its ability to counteract microvascular thrombosis. Furthermore, AT induces the release of prostacyclin from the vessel wall by binding to glycosaminoglycans on the surface of endothelial cells. Prostacyclin has a marked anti-inflammatory effect as a result of its inhibitory effect on neutrophils, monocytes and platelets.

An Insertion/Deletion polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene is associated with plasma levels but not with stroke risk in the elderly.

The purpose of the present study was to examine the effects of an insertion/deletion (ins/del) polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene on plasma PAI-1 antigen and activity levels and on stroke risk in the elderly. The ins/del genotype and PAI-1 antigen and activity plasma levels were determined in 177 patients with ischemic stroke (mean age, 75 years) and 93 healthy elderly subjects (mean age, 74 years). There was no difference in the frequencies of the ins and del alleles between stroke patients and healthy elderly subjects. The del/del genotype was associated with the highest plasma PAI-1 antigen levels in the healthy subjects: those with the ins/ins genotype had 36% lower plasma PAI-1 antigen levels than those with the del/del genotype (effect of genotype, P=0.3). In contrast, the ins/del genotype was not associated with plasma PAI-1 antigen and activity levels in 89 patients who had a stroke less than 10 days before blood sampling. However, an association of ins/del genotype with plasma PAI-1 activity levels could be demonstrated in 88 other patients more than 5 months after the stroke. This may suggest that PAI-1 metabolism is temporarily perturbed after a stroke. The present data suggest that an ins/del polymorphism in the PAI-1 promoter region affects plasma PAI-1 levels but has little or no effect on stroke risk in the elderly.