Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion.

Gene expression-based classification systems have identified an aggressive colon cancer subtype with mesenchymal features, possibly reflecting epithelial-to-mesenchymal transition (EMT) of tumor cells. However, stromal fibroblasts contribute extensively to the mesenchymal phenotype of aggressive colon tumors, challenging the notion of tumor EMT. To separately study the neoplastic and stromal compartments of colon tumors, we have generated a stroma gene filter (SGF). Comparative analysis of stromahigh and stromalow tumors shows that the neoplastic cells in stromahigh tumors express specific EMT drivers (ZEB2, TWIST1, TWIST2) and that 98% of differentially expressed genes are strongly correlated with them. Analysis of differential gene expression between mesenchymal and epithelial cancer cell lines revealed that hepatocyte nuclear factor 4α (HNF4α), a transcriptional activator of intestinal (epithelial) differentiation, and its target genes are highly expressed in epithelial cancer cell lines. However, mesenchymal-type cancer cell lines expressed only part of the mesenchymal genes expressed by tumor-derived neoplastic cells, suggesting that external cues were lacking. We found that collagen-I dominates the extracellular matrix in aggressive colon cancer. Mimicking the tumor microenvironment by replacing laminin-rich Matrigel with collagen-I was sufficient to induce tumor-specific mesenchymal gene expression, suppression of HNF4α and its target genes, and collective tumor cell invasion of patient-derived colon tumor organoids. The data connect collagen-rich stroma to mesenchymal gene expression in neoplastic cells and to collective tumor cell invasion. Targeting the tumor-collagen interface may therefore be explored as a novel strategy in the treatment of aggressive colon cancer.

Rap1 Spatially Controls ArhGAP29 To Inhibit Rho Signaling during Endothelial Barrier Regulation.

The small GTPase Rap1 controls the actin cytoskeleton by regulating Rho GTPase signaling. We recently established that the Rap1 effectors Radil and Rasip1, together with the Rho GTPase activating protein ArhGAP29, mediate Rap1-induced inhibition of Rho signaling in the processes of epithelial cell spreading and endothelial barrier function. Here, we show that Rap1 induces the independent translocations of Rasip1 and a Radil-ArhGAP29 complex to the plasma membrane. This results in the formation of a multimeric protein complex required for Rap1-induced inhibition of Rho signaling and increased endothelial barrier function. Together with the previously reported spatiotemporal control of the Rap guanine nucleotide exchange factor Epac1, these findings elucidate a signaling pathway for spatiotemporal control of Rho signaling that operates by successive protein translocations to and complex formation at the plasma membrane.

[Summary of the practice guideline 'Asthma in children' (second revision) from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'astma bij kinderen' (tweede herziening) van het Nederlands Huisartsen Genootschap.

A number of important changes have been made in the second revision of the guideline 'Asthma in children' from the Dutch College of General Practitioners. In children under the age of 6 years, the symptoms stuffiness and recurrent cough are no longer considered part of the symptomatic diagnosis of asthma. Wheezing has become the key symptom of asthma. In children aged 6 years or more, spirometry is the optimal method for both diagnosis and monitoring. This method is preferred over peak flow measurement. Inhalation allergies should be investigated in children under the age of 6 years because the presence of an inhalation allergy may influence the management approach. Starting asthma medication in children under the age of 6 years should always be considered a therapeutic trial, and its effect should always be evaluated. The prescription of allergen-resistant mattresses and bed coverings is only effective when it is one component of a set of allergen reduction measures. At this time, the Dutch Health Council recommends influenza vaccination in children with asthma.

Computed critiquing integrated into daily clinical practice affects physicians' behavior--a randomized clinical trial with AsthmaCritic.

OBJECTIVE: We developed AsthmaCritic, a non-inquisitive critiquing system integrated with the general practitioners' electronic medical records. The system is based on the guidelines for asthma and chronic obstructive pulmonary disease (COPD) as issued by the Dutch College of General Practitioners. This paper assesses the effect of AsthmaCritic on monitoring and treatment of asthma and COPD by Dutch general practitioners in daily practice. METHODS: A randomized clinical trial in 32 practices (40 Dutch general practitioners) using electronic patient records. An intervention group was given the use of AsthmaCritic, a control group continued working in the usual manner. Both groups had the disposal of the asthma and COPD guidelines routinely distributed by the Dutch College of General Practitioners. We measured the average number of contacts, FEV 1 (forced expiratory volume), and peak-flow measurements per asthma/COPD patient per practice; and, the average number of antihistamine, cromoglycate, deptropine, and oral bronchodilator prescriptions per asthma/COPD patient per practice. RESULTS: The number of contacts increased in the age group of 12-39 years. The number of FEV1 , peak-flow measurements, and the ratio of coded measurements increased, whereas the number of cromoglycate prescriptions decreased in the age group of 12-39 years. CONCLUSIONS: Our study shows that the guideline-based critiquing system AsthmaCritic changed the manner in which the physicians monitored their patients and, to a lesser extent, their treatment behavior. In addition, the physicians changed their data-recording habits.

[Terminal sedation: consultation with a second physician as is the case in euthanasia and assisted suicide]. / Terminale sedatie: consultatie van een tweede arts zoals bij euthanasie of hulp bij zelfdoding.

In terminally-ill patients in the Netherlands deep sedation by means of a continuous subcutaneous infusion with midazolam occurs more frequently than euthanasia and assisted suicide. Deep terminal sedation is applied to relieve symptoms during the phase of dying, but in contrast to euthanasia and assisted suicide, does not hasten death. In three terminally-ill patients, a 65-year-old man suffering from pulmonary carcinoma, a 94-year-old woman with general malaise, nausea and anorexia, and a 79-year-old woman in the final stage of ovarian carcinoma, a general-practitioner advisor was consulted about an end-of-life decision--deep terminal sedation versus euthanasia or assisted suicide. The first two patients were given deep sedation until death, in both cases a day and a half later. The third patient's request for euthanasia was considered to meet the legal criteria for euthanasia. Compliance with the Dutch statutory criteria for due care in euthanasia and assisted suicide might also be helpful when deciding about terminal deep sedation, but the role and responsibility of the attending physician may differ. However, the radical effects of sedation on the terminally-ill patient and the rapid changes in the clinical situation of the patient when the decision to sedate is taken, both emphasize the need for consultation with another physician.

Efficacy of fluticasone on cough: a randomised controlled trial.

Cough may be the consequence of bronchial hyperresponsiveness (BHR) and inflammation. This study was designed to investigate the short-term effects of an inhaled steroid (fluticasone propionate (FP)) on cough, and to determine the effects of smoking, BHR, allergy and forced expiratory volume in one second (FEV1) on the efficacy of FP. In a community-based primary healthcare centre, 135 previously healthy adults suffering from cough for > or =2 weeks were enrolled in a randomised, double-blind, placebo-controlled trial of inhaled FP 500 microg b.i.d. for 2 weeks. Participants completed daily diary cards of lower respiratory tract symptoms. The primary outcome measure was the decrease in mean total daily cough score (0-6) during the second week of treatment. In the FP group, the cough score decreased from 3.8 at baseline to mean+/-SEM 1.4+/-0.2 during the second week. In the placebo group, this decrease was from 3.8 to 1.9+/-0.1 and was statistically significantly less. A favourable effect of FP was only detectable in nonsmokers, in whom the score was 0.9 points lower compared with placebo. The clinical relevance of this finding has to be established further. Allergy, FEV1 and BHR at baseline did not affect the efficacy of FP. In conclusion, anti-inflammatory treatment with the inhaled steroid fluticasone propionate reduces cough in otherwise healthy adults who do not smoke.

[Postcoital test--a useful aid for the family physician]. / Post-coitumtest bruikbaar hulpmiddel voor de huisarts.

Gynaecologists still debate the usefulness of the postcoital test. However, in general practice the duration of infertility may be shorter than in infertility outpatient clinic patients. In a primary care subfertility population (mean duration of infertility 20.7 months) it was shown that an abnormal postcoital test is associated with triple reduction in live birth prognosis. The guideline 'Subfertility' of the Dutch College of General Practitioners recommends primary investigations by the general practitioners to start when spontaneous pregnancy has not occurred after one year. Postcoital testing by the general practitioner appears to be useful.

Simulating an integrated critiquing system.

OBJECTIVE: To investigate factors that determine the feasibility and effectiveness of a critiquing system for asthma/COPD that will be integrated with a general practitioner's (GP's) information system. DESIGN: A simulation study. Four reviewers, playing the role of the computer, generated critiquing comments and requests for additional information on six electronic medical records of patients with asthma/COPD. Three GPs who treated the patients, playing users, assessed the comments and provided missing information when requested. The GPs were asked why requested missing information was unavailable. The reviewers reevaluated their comments after receiving requested missing information. MEASUREMENTS: Descriptions of the number and nature of critiquing comments and requests for missing information. Assessment by the GPs of the critiquing comments in terms of agreement with each comment and judgment of its relevance, both on a five-point scale. Analysis of causes for the (un-)availability of requested missing information. Assessment of the impact of missing information on the generation of critiquing comments. RESULTS: Four reviewers provided 74 critiquing comments on 87 visits in six medical records. Most were about prescriptions (n = 28) and the GPs' workplans (n = 27). The GPs valued comments about diagnostics the most. The correlation between the GPs' agreement and relevance scores was 0.65. However, the GPs' agreements with prescription comments (complete disagreement, 31.3%; disagreement, 20.0%; neutral, 13.8%; agreement, 17.5%; complete agreement, 17.5%) differed from their judgments of these comments' relevance (completely irrelevant, 9.0%; irrelevant, 24.4%; neutral, 24.4%; relevant, 32.1%; completely relevant, 10.3%). The GPs were able to provide answers to 64% of the 90 requests for missing information. Reasons available information had not been recorded were: the GPs had not recorded the information explicitly; they had assumed it to be common knowledge; it was available elsewhere in the record. Reasons information was unavailable were: the decision had been made by another; the GP had not recorded the information. The reviewers left 74% of the comments unchanged after receiving requested missing information. CONCLUSION: Human reviewers can generate comments based on information currently available in electronic medical records of patients with asthma/COPD. The GPs valued comments regarding the diagnostic process the most. Although they judged prescription comments relevant, they often strongly disagreed with them, a discrepancy that poses a challenge for the presentation of critiquing comments for the future critiquing system. Requested additional information that was provided by the GPs led to few changes. Therefore, as system developers faced with the decision to build an integrated, non-inquisitive or an inquisitive critiquing system, the authors choose the former.

[Deliberation between physician and patient concerning active euthanasia at the patient's home]. / Overleg tussen huisarts en patiënt over actieve levensbeëindiging in de thuissituatie.

Three patients, one man aged 68 and two aged 67, with terminal incurable cancer, requested euthanasia. It was performed in two, the third patient eventually died without having repeated his request. There are three phases in euthanasia: orientation (the patient asks the physician whether he would be willing to assist should the need arise), organisation (the physician ensures that the necessary prerequisites are fulfilled, i.e. the patient's request must be voluntary, mature and longlasting, his suffering must be longlasting, unbearable and incurable, and another physician must have been consulted and must have prepared a written report), and the phase entered after the definitive decision to perform euthanasia has been taken. The physician should not be reluctant to bring up the subject at an early stage, as it may set the patient's mind at rest to have expressed a wish concerning suffering and the end of life.

[The role of the consulting physician in situations of active euthanasia]. / De rol van de consulent bij actieve levensbeëindiging in de thuissituatie.

The cases are reported of two patients, a man aged 69 with a metastasized bronchial carcinoma and a woman aged 65 with a frontotemporal glioblastoma no longer responding to irradiation. Both requested active euthanasia. In both cases, euthanasia was performed by injection, after a general practitioner from the same locum group had acted as consultant. The requirements of meticulousness in handling a request for active euthanasia are concerned with the request (which has to be voluntary, thoroughly considered and constant), the suffering (which has to be protracted, unbearable and incurable), consultation and the written report. The consulting or second physician in cases of active euthanasia confirms that the requirements of meticulousness have been met. In addition, the second physician may assist the general practitioner in the detection of factors that may impair correct decision-making by the doctor or the patient. The second physician will be aided in performing these tasks if he is a member of the same locum group as the treating physician. However, if he considers himself too involved, a physician outside the locum group should be available at all times.