Genomewide copy number alteration screening of circulating plasma DNA: potential for the detection of incipient tumors.

Background: Early cancer diagnosis might improve survival rates. As circulating tumor DNA (ctDNA) carries cancer-specific modifications, it has great potential as a noninvasive biomarker for detection of incipient tumors. Patients and methods: We collected cell-free DNA (cfDNA) samples of 1002 elderly without a prior malignancy, carried out whole-genome massive parallel sequencing and scrutinized the mapped sequences for the presence of (sub)chromosomal copy number alterations (CNAs) predictive for a malignancy. When imbalances were detected, 6-monthly clinical follow-up was carried out. Results: In 3% of participants chromosomal imbalances were detected. Follow-up analyses, including whole-body MRI screening, confirmed the presence of five hematologic malignancies: one Hodgkin lymphoma (HL), stage II; three non-HL (type chronic lymphocytic leukemia, Rai I-Binet A; type SLL, stage III; type mucosa-associated lymphoid tissue, stage I) and one myelodysplastic syndrome with excess blasts, stage II. The CNAs detected in cfDNA were tumor-specific. Furthermore, one case was identified with monoclonal B-cell lymphocytosis, a potential precursor of B-cell malignancy. In 24 additional individuals, CNAs were identified but no cancer diagnosis was made. For 9 of them, the aberrant cfDNA profile originated from peripheral blood cells. For 15 others the origin of aberrations in cfDNA remains undetermined. Conclusion(s): Genomewide profiling of cfDNA in apparently healthy individuals enables the detection of incipient hematologic malignancies as well as clonal mosaicism with unknown clinical significance. CNA screening of cellular DNA of peripheral blood in elderly has established that clonal mosaicism for these chromosomal anomalies predicts a 5- to 10-fold enhanced risk of a subsequent cancer. We demonstrate that cfDNA screening detects CNAs, which are not only derived from peripheral blood, but even more from other tissues. Since the clinical relevance of clonal mosaics in other tissues remains unknown, long-term follow-up is warranted. Taken together, this study demonstrates that genomewide cfDNA analysis has potential as an unbiased screening approach for hematological malignancies and premalignant conditions.

Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.

[The treatment of acute diarrhea]. / Quand ça va trop vite ... Les antidiarrhéiques sous la loupe.

Racecadotril has sufficient proven efficacy in the treatment of acute diarrhea in children. Treatment outcomes in adults are less convincing. The place of gelatin tannate is unclear. Some sources point to potential hepatotoxicity and diminished iron absorption, with a concomitant risk of anemia, at least in case of excessive or prolonged use. Loperamide still has a prominent place in the treatment of acute and chronic diarrhea. Attention should be payed to correct dosing and some well-known contra-indications. Probiotics are indicated in children, as well as in the prevention of antibiotics-induced diarrhea. There is no evidence to support their use in the treatment of acute diarrhea in adults. Up till now publications disagree on the efficacy in the prevention of travelers' diarrhea. Astringents and absorbents are no longer supported in guidelines. Oral rehydration systems have a part to play in pediatric treatment.

[Does 5-methyltetrahydrofolate offer any advantage over folic acid?]. / Le 5-méthyltétrahydrofolate a-t-il des avantages par rapport a l'acide folique?

Almost half of the women do not follow the guidelines around folate suppletion before and during pregnancy, despite the proven benefit in the prevention of neural tube defects, miscarriages and premature births. The Belgian Superior Health Council recommends a minimum of 400 micrograms of folic acid or folate suppletion per day from 4 weeks before conception to 8 weeks thereafter. Many studies point to the importance of a wider intake period, more particularly at least 3 months before conception and throughout pregnancy and lactation. In high-risk women 4 mg is recommended until after the first 3 months of pregnancy. Afterwards the usual dose of 400 micrograms is sufficient. About half of the European population appears to have a gene mutation on the gene coding for the production of methylenetetrahydrofolate reductase, the enzyme that is involved in the formation of 5-methyltetrahydrofolate, which is, in his turn, responsible for the conversion of the toxic homocysteine in methionine. Women with such a gene polymorphism have a significantly higher risk to have a miscarriage or a baby with neural tube defects. For this reason, a search for an alternative form of synthetic folic acid supplement "pteroylmonoglutamic acid (PMG)" was conducted, particularly the calcium salt of 5-methyltetrahydrofolate (Metafolin). This offers the possibility to deliver the reduced folate immediately, which no longer needs to be converted by the reductase enzyme. Furthermore, this avoids free PMG in the circulation, lowers the risk for drug interactions and a vitamin B2 deficiency will not be masked. Despite clear guidelines regarding dietary supplements before and during pregnancy, their implementation is poor. Not only gynecologists but also GPs and pharmacists, should make more efforts to provide women of childbearing age with personal information. Especially risk groups such as adolescents, low-skilled or less well-off women and immigrants deserve special attention.

[Consumer study on the use of patient information leaflets]. / D'abord lire, puis guérir... Etude sur l'utilisation des notices destinées aux patients.

The aim of this study was to get a clear idea of the reading frequency of the patient information leaflet (PIL) and to set up a profile of the reader in specific. Apart from that, we also wanted to evaluate the impact of the internet in the patient's search for information on health and medication. Do patients consult the digital PIL and is the FAGG website known by common people? In order to answer these research questions, a specific inquiry was performed in 800 respondents. Some interesting conclusions can be drawn: only one out of four participants reads the full PIL when purchasing a medicine they never used before. People who always read the PIL are mainly older than 65. However, the largest amount of people who never reads the PIL is also situated in the plus 65 scale. In general, men show little interest in reading the PIL unlike woman, who read clearly more often the PIL. The parts of the PIL most often read by patients are the sections on dosage (section 3) and side effects (section 4). Unfortunately, too little attention is paid to the section 2, which contains the most warnings, such as contra-indications. The most important reason why the PIL is not read is because patients believe they get sufficient information from the doctor and the pharmacist. Another remark is that the internet is used by more than half of the respondents to search for health-related information. There is also a remarkable difference between men and woman, men rarely search for health information or information on medicines on the internet. The number of respondents searching for leaflets on the internet is quite limited. Additionally, the Federal Agency Medicines and Health Products (FAMHP) website is unknown to most internet users. We can conclude that the actual PIL is read too little. In order to make the PIL more appealing and even more patient friendly than it is actually, taking patients' needs into account should be a priority. The digital leaflet should be drawn attention to in order for patients to make more use of the information that is available to them.

[Drug related problems pharmacists encounter when a patient is discharged from hospital]. / Problématique des médicaments à prendre par les patients sortant de l'hôpital: etude réalisée auprès de pharmaciens d'officine flamands.

AIMS: To explore drug related problems a community pharmacist encounters when a patient is discharged from hospital. The study also investigates which information from the hospital reaches the community pharmacy. METHODS: A validated survey was presented, by community pharmacists, to patients or their family after hospital discharge, between the 1st of December 2007 and the 29th of February 2008. The survey contained questions on 4 items: patient characteristics--discharge medication--information received from the hospital--drug related problems and pharmacists interventions. Analyses were done with SPSS 16.0. MAIN RESULTS: 82 community pharmacists participated. 261 patients were included. Only 25% of the patients collected their medication from the pharmacy themselves. On discharge, patients on average received two additional drugs, compared to the pre-hospital situation. 69% received a medication chart, but less than half of them brought this chart along when visiting the pharmacy. Only 9% got computer-generated prescriptions from the hospital and < 3% received a letter of referral addressed to their pharmacist. In 33% of the cases the pharmacists noticed one or more problems concerning the medication prescribed after hospital discharge. The chance to detect a problem increased significantly when the chart was brought to the pharmacy (p=0.033). In case of observed problems, the community pharmacist succeeded to reach the treating specialist by phone in less than one third of those cases. CONCLUSION: The results foster the discussion on the need for a better seamless care and the role clinical and community pharmacists could play in this care model.

Teaching and counselling behaviour: an applied study with community pharmacists.

Continuing education aims at improving practice. In this article, three main research questions are addressed: Which methodology is optimal to improve counselling behaviour? Are learning outcomes influenced by learning style? Does knowing imply doing? Four educational methods, transferring information on cough medicines, are assessed: a lecture, an interactive workshop, an audiocassette and a textbook. Attendants of the first three methods also received the textbook. Pharmacists completed a learning-style inventory in addition to a pretest. After the instruction phase, they were interviewed by telephone (post-test). We also evaluated the counseling behaviour by an 'incognito' visit to participants as well as to controls. Seventy-eight pharmacists participated. Their learning-style cannot be related to the results of pre- or posttest. Each educational method improved the level of knowledge significantly, but none of them proved to be better than the others. The pharmacists who in addition read the textbook, acquired more knowledge than those who did not. Self-study at home led to more fundamental rather than practical knowledge. Improving knowledge does not result in better counselling: 75% of the pharmacists asked only one question, especially concerning the type of cough. However 9 out of 10 mentioned how to use the drug. About half of the pharmacists told the patient about the action of the medicine. Other items were hardly ever mentioned. There was no difference in counselling behaviour between the intervention group and a group of pharmacists who did not attend the course. This investigation does not reveal any particular method of in-service training as being more efficient. Active use of self-study materials helps to improve pharmacological knowledge. Implementing educational strategies to improve counselling behaviour remains a future aim.

[Treatment of pain at a community pharmacy]. / Le traitement de la douleur dans le cadre de l'officine.

The first part of this article deals with the physiology of pain. We focus on the different pathways of pain. Two main mechanisms of pain control are described, namely peripheral control, by the supraspinal gate and central or supra-medular control. Three different mechanisms can induce pain. We focus on pain perception by excess of stimuli and desafferent ways of pain. The following part deals with the different kinds of pain presented to the community pharmacist. At the end we discuss the treatment of pain, describing the pharmacological aspects of the three most important "Over The Counter" molecules, namely paracetamol, aspirin and ibuprofen. Also some combinations of analgesic agents and adjuvants are discussed.