Susanne M. Smorenburg

The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy

PURPOSE Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Kupffer cells and pit cells are not effective in the defense against experimentally induced colon carcinoma metastasis in rat liver

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 la-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 β 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.

Association between Acute Geriatric Syndromes and Medication-Related Hospital Admissions

BACKGROUND Elderly patients are at a 4-fold higher risk of adverse drug events (ADEs) and drug-related hospitalization. Hospitalization of an elderly patient is often preceded by geriatric syndromes, like falls or delirium. OBJECTIVES The primary aim of this study was to investigate whether geriatric syndromes were associated with ADEs in acutely admitted elderly patients. METHODS Consecutive medical patients, aged 65 years or more, who were acutely admitted, were enrolled. An initial multidisciplinary evaluation was completed and baseline characteristics were collected. A fall before admission was retrieved from medical charts. Delirium was determined by the Confusion Assessment Method. RESULTS A total of 641 patients were included. Over 25% had an ADE present at admission, 26% presented with delirium and 12% with a fall. Delirium was associated with the use of antidepressants, antipsychotics and antiepileptics. In all ADEs (n = 167), ADEs were associated with a fall, with non-steroidal anti-inflammatory drugs or diuretics, but not with pre-existing functioning, delirium or older age. For ADEs involving psychoactive medication (n = 35), an association was found between delirium, falls, opioids and antipsychotics in bivariate analyses. A fall just before hospitalization (odds ratio [OR] 3.69 [95% CI 1.41, 9.67]), antipsychotics (OR 3.70 [95% CI 1.19, 11.60]) and opioids (OR 14.57 [95% CI 2.02, 105.30]) remained independently associated with an ADE involving psychoactive medication. CONCLUSION This prospective study demonstrated that, in a cohort of elderly hospital patients, a fall before admission and prevalent delirium are associated with several pharmacological groups and/or with ADE-related hospital admission.

Three-dimensional reconstruction of colon carcinoma metastases in liver

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.

Application of the Bow-Tie Model in Medication Safety Risk Analysis: Consecutive Experience in Two Hospitals in the Netherlands

AbstractBackground: To improve medication safety effectively, one should systematically analyse and assess the risks for medication errors and determine the possible causes. So far, no risk-analysis instrument exists in healthcare that can be used to analyse and visualize risks, causes and consequences of potential adverse events in a prospective manner. In high-risk industries such as petrochemistry and aviation, the Bow-Tie model is frequently used. This model combines causes, errors, preventive and recovery measures, and consequences in one model and gives insight into the magnitude and causes of existing safety risks. The aim of our project was to study the usefulness of the Bow-Tie model in the hospital setting for prospective analysis of risks in the medication process in order to develop a practicable method. Methods: The model was first adapted to the clinical setting. Thereafter, the risk-analysis model was applied in a large tertiary teaching hospital in multi-disciplinary sessions. The sessions and risk-analysis method were evaluated on the following aspects: applicability, comprehensibility, creation of awareness in and motivation of participants, and the capability of the ‘system approach’ (the approach taken by the Bow-Tie model, which focuses on the conditions under which individuals work and tries to build defences to avert errors or mitigate their effects, in contrast to a ‘person approach’, which focuses on errors of individuals, blaming them for forgetfulness, inattention etc.). Based on this evaluation, the risk analysis method was adjusted and consecutively applied in a general teaching hospital. After evaluation of the sessions in the second hospital a recommended method for risk analysis with the Bow-Tie model was defined. Results: The risk-analysis method with the Bow-Tie model in the first hospital gave insight into many medication safety-related risks. However, the method was insufficient on comprehensibility and on the creation of awareness and motivation owing to a great number of determined risks which made thorough analysis, drawing of Bow-Ties and prioritizing difficult. The adjusted method in the second hospital focused more on the in-depth analysis of a small number of important safety issues of a department with specific attention for underlying causes. This approach was considered better in applicability, comprehensibility and the creation of awareness. Furthermore, by analyzing underlying causes, more attention could be paid to latent conditions (which can translate into error-provoking conditions) within the system. Conclusion: We found the Bow-Tie to be an appropriate model for prospective risk analysis of medication safety in a hospital. By applying the model in two hospitals consecutively we developed a feasible method for risk-analysis sessions. Key factors of this recommended method are a focus on the prioritized selection of safety issues and specific attention to latent conditions within the system by analysing these safety issues in depth to the root causes with the help of the Bow-Tie model.

Risk Assessment and Prophylaxis of Venous Thromboembolism in Non-Surgical Patients: Cancer as a Risk Factor

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.

In vivo treatment of rats with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) does not affect experimentally induced colon carcinoma metastasis

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.

Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation.

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.

How nurses and physicians judge their own quality of care for deteriorating patients on medical wards: Self-assessment of quality of care is suboptimal

Objective:To describe how nurses and physicians judge their own quality of care for deteriorating patients on medical wards compared with the judgment of independent experts. Design:Cross-sectional study using interviews of care-providers regarding their perceived quality of care for clinically deteriorating patients compared with retrospective judgment by independent experts. Setting:Academic Medical Center of Amsterdam, the Netherlands. Patients:Between April and July 2009, all patients with cardiopulmonary arrests and unplanned intensive care unit admissions from six medical nursing wards were included. The care-providers (nurses and physicians) taking care of these patients in the previous 12 hrs were included. Measurements and Main Results:Forty-seven events and 198 interviews were analyzed. Skill and knowledge level regarding the recognition of a deteriorating patient were rated on a scale of 1–10 with means (SD) of 7.9 (0.8) and 7.7 (0.9), respectively. Nurses and residents attributed coordination of care largely to themselves (74% and 76%, respectively). Communication, cooperation, and coordination were graded in a positive manner (medians between 7.3 and 8), whereas the medical staff graded these factors higher compared to the grading by nurses and residents. Negative predictive values regarding the presence of a delay compared with an expert panel was 37% for nurses and 38% for residents and specialists. Conclusions:Care-providers mostly rate their care provided to patients in the hours preceding a life-threatening adverse event as good. In contrast, independent experts had a more critical appraisal of the provided care in regards to timely recognition. These findings may partly explain the reluctance of care-providers to implement patient safety initiatives.

Should patients with venous thromboembolism and cancer be treated differently

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.