Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase 3 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 3 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 (IQR 59-71). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% CI 16.0-22.2) compared to 20.1 months (95% CI 17.0-25.1) 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. CONCLUSION: 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.

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.

Hypoglycemia and hemostatic parameters in juvenile-onset diabetes.

Hypoglycemia was induced by intravenous infusion of insulin in six juvenile-onset diabetic subjects. Hemostatic parameters were assessed before insulin infusion and 0, 1, and 2 h after discontinuation of insulin infusion. The onset of hypoglycemia coincided with an enhancement of ADP-induced platelet aggregation in five of the patients; platelet aggregation returned to normal levels during the next 2 h. The recalcification time was significantly shortened at the onset of hypoglycemia and continued to decrease for the next 2 h despite the return of serum glucose to normal levels. Correspondingly, a significant increase in fibrinogen was found. The ethanol gelation test was positive in two patients 2 h after stopping insulin infusion. Platelet counts decreased significantly after stopping insulin infusion. Thus, insulin-induced hypoglycemia markedly affects hemostatic balance and may potentially lead to intravascular coagulation in juvenile-onset diabetic patients.

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.

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 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.

Internal fixation of femoral shaft fractures in children and adolescents: a ten- to twenty-one-year follow-up of 52 fractures.

In a long-term follow-up (mean 16 years) of 52 femoral shaft fractures treated by internal fixation in 50 children and adolescents, we noted a mean overgrowth of 1 mm after plating and a mean undergrowth or relative shortening of 2 and 9 mm after nailing with broad (IMN) and slender (flexible rods: IMR) intramedullary nails, respectively. The mean overgrowth was 8 mm in children, but adolescents had a mean undergrowth of 5 mm (p < 0.01). Excessive overgrowth tended to occur less frequently after intramedullary nailing than after plating (p = 0.1). Undergrowth tended to occur with increasing frequency with increasing age and attained troublesome levels in three patients with severe trauma. Three cases of moderate valgus deformity of the hip and one case of late arthrosis of the hip occurred after intramedullary nailing with IMN introduced through the greater trochanter. We conclude that this method should not be used in patients with open physes.

[Low molecular weight heparin versus unfractionated heparin in the treatment of deep venous thrombosis--a meta-analysis]. / Lavmolekylaert heparin versus ufraktioneret heparin ved behandling af dyb venetrombose--en metaanalyse.

A review based on 17 randomised studies on low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) in the treatment of objectively verified deep venous thrombosis (DVT) is presented. Long-term treatment with LMWH was compared with long-term UFH in two studies and with warfarin in one study. In the rest of the studies LMWH and UFH were used during initiation of oral anticoagulant therapy, and these studies were included in a meta-analysis. The relative risk of progression of DVT during LMWH treatment compared with UFH was 0.63 (95% confidence interval: 0.39-1.00) and the relative risk of major bleeding was 0.41 (95% confidence interval: 0.24-0.70). There was no significant difference in the reduction of Marder score during treatment (LMWH 5.0 versus UFH 3.8) or in the frequency of new symptomatic, scintigraphically or angiographically verified pulmonary embolism (LMWH 0.6% versus UFH 1.1%). The frequency of complications seemed independent of whether LMWH was administered once or twice daily. Monitoring of LMWH treatment is not considered necessary but determination of anti-factor Xa in plasma is recommended if bleeding occurs during treatment with LMWH.

[Shunt-nephritis]. / Shunt-nephritis.

Infection in ventriculo-atrial shunts implanted for relief of raised intracranial pressure may, in rare cases, result in glomerulonephritis (shunt-nephritis). Most frequently, infection with low-virulent bacteria is concerned. This results in mild or subclinical symptoms with the subsequent risk that the condition is overlooked. The glomerular damage is considered to be precipitated by deposition of immune complexes in the kidneys and subsequent activation of the complement system. The renal manifestations consist of varying degrees of proteinuria, haematuria and reduction of renal function. Treatment consists of removal of the shunt. If continued relief of pressure in the ventricular system is necessary, a ventriculo-peritoneal shunt should be implanted. Normally, the prognosis of the renal disease is good. If the diagnosis and treatment are delayed, irreversible renal damage may result. Regular control of urine (proteinuria, haematuria) and blood (Hb, serumcreatinine and serum complement) are recommended in the follow up control of patients with ventriculo-atrial shunts.

[Bacteriological urine analysis as part of check-ups on children. A retrospective study from general practice]. / Bakteriologiske urinanalyser i forbindelse med profylaktiske børneundersøgelser. En retrospektiv undersøgelse fra almen praksis.

This paper presents a retrospective study of asymptomatic bacteriuria from general practice. The general practitioner had screened children's urine specimens for asymptomatic bacteriuria at the eight regular health examinations during preschool age. The urine was collected in special adhesive bags or as a midstream clean catch and investigated by stix and culture at the practitioner's. When significant bacteriuria was noted, a new urine sample was collected for analysis. If asymptomatic bacteriuria was again noted, the culture plates were sent to a microbiological hospital department for determination of bacterial type and antibiotic resistance. The children were subsequently treated with a relevant antibiotic. The material collected during 12 years consisted of 658 urine samples obtained from 1295 examinations of 208 children. Thirty-five samples (5.3%) were positive, and 30 of the children presented at least one positive sample (14.2%). Most of the positive samples were obtained during the first two years. However, the material is too small to obtain statistically positive results and must due to its retrospective nature be interpreted with care. Nevertheless, the high rate of infection in our study motivates the initiation of a regular prospective study.

[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.

[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.

[Use of fibrinolytics in the treatment of acute myocardial infarction in Denmark. A questionnaire study]. / Anvendelse af fibrinolytika ved behandling af akut myokardieinfarkt i Danmark. En spørgeskemaundersøgelse.

Questionnaires were sent to all Danish departments admitting patients with acute myocardial infarction (AMI) in order to investigate the attitudes of the departments to thrombolytic therapy in AMI. Two questionnaires were used: one with few questions which was answered by all 68 departments, and a more comprehensive questionnaire which was answered by 51 departments. The study shows that thrombolytic therapy now is use in all departments as opposed to 25% two years ago. In connection with introduction of thrombolytic therapy scientific studies are performed in 75% of the departments. In all departments, streptokinase (SK) is the drug of first choice and recombinant tissue plasminogen activator (rt-PA) is used in 2/3 of the departments in cases where SK-antibodies are suspected.

[Treatment of unstable angina pectoris. A questionnaire study]. / Behandling af ustabil angina pectoris. En spørgeskemaundersøgelse.

Questionnaires about therapy in unstable angina pectoris were sent to 63 Danish medical departments and were answered by 52 departments (82.5%). Nitroglycerin is commonly used but only in half of the departments is Nitroglycerin administered intravenously. Calcium-receptor-blockers are used in more departments (65%) than beta-receptor-blockers (35%) (p less than 0.05). Five departments use thrombolytic therapy along local guidelines. All recommend aspirin as prophylaxis against thrombosis and 63% recommend the therapy to be continued for life. An exercise test is always performed during hospital stay in 1/3 of the departments while the rest of the departments often wait till after the patient has been discharged. The estimate of frequency of coronary angiography varied considerably: from less than 5% to 100%. The frequency of coronary angiography was stated to be higher in Copenhagen and Aarhus (median 50%, interval 10-100%) than in the rest of the country (median 15%, interval less than 5-75%) (p less than 0.01).

[Standardized prothrombin time determinations and optimal anticoagulant therapy]. / Den standardiserede protrombintidsbestemmelse og optimal antikoagulansbehandling.

WHO and other international organizations have recommended the introduction of a standardized prothrombin time determination. This would allow a universal scale for the intensity of oral anticoagulation therapy to be used. A prerequisite is the use of thromboplastin, calibrated against the international reference thromboplastin, standardized methodology etc. This permits every prothrombin time determination to be expressed as International Normalized Ratio (INR). The introduction of INR facilitates the implementation of optimal oral anticoagulation as defined by larged international studies.

[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.

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.