Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer.

Both somatostatin (SST) and somatostatin receptors (SSTRs) are proteins with important functions in both physiological tissue and in tumors, particularly in neuroendocrine tumors (NETs). NETs are frequently characterized by high SSTRs expression levels. SST analogues (SSAs) that bind and activate SSTR have anti-proliferative and anti-secretory activity, thereby reducing both the growth as well as the hormonal symptoms of NETs. Moreover, the high expression levels of SSTR type-2 (SSTR2) in NETs is a powerful target for therapy with radiolabeled SSAs. Due to the important role of both SST and SSTRs, it is of great importance to elucidate the mechanisms involved in regulating their expression in NETs, as well as in other types of tumors. The field of epigenetics recently gained interest in NET research, highlighting the importance of this process in regulating the expression of gene and protein expression. In this review we will discuss the role of the epigenetic machinery in controlling the expression of both SSTRs and the neuropeptide SST. Particular attention will be given to the epigenetic regulation of these proteins in NETs, whereas the involvement of the epigenetic machinery in other types of cancer will be discussed as well. In addition, we will discuss the possibility to target enzymes involved in the epigenetic machinery to modify the expression of the SST-system, thereby possibly improving therapeutic options.

Prognostic factors in infective endocarditis in general hospitals in the Netherlands.

INTRODUCTION: Despite advances in treatment, infective endocarditis (IE) still ranks amongst the most lethal infectious diseases. We sought to determine prognostic factors in general hospitals in the Netherlands as research in this setting is scarce. RESULTS: Between 2004 and 2011, we identified 216 cases of IE, 30.1 % of which were prosthetic valve IE. This leads to an annual incidence of IE of 5.7 new cases per 100,000 persons per year. Women were less likely to undergo surgical intervention (OR = 1.96, 95 % CI 1.06-3.61, p = 0.031). Also, ageing was an independent prognostic factor for not receiving surgery in a multivariate analysis (annual OR = 1.04, 95 % CI 1.02-1.06, p < 0.001). Female sex was a prognostic factor for mortality (OR = 2.35, 95 % CI 1.29-4.28, p = 0.005). Age was also an independent prognostic factor for mortality (OR = 1.05, 95% CI 1.03-1.08, p < 0.001). Conservative treatment was a prognostic factor for mortality (OR = 3.39, 95 % CI 1.80-6.38, p < 0.001) whereas surgical intervention was an independent prognostic factor for adverse events (OR = 3.03, 95% CI 1.64-5.55, p < 0.001). Staphylococcus aureus was an independent prognostic factor for adverse events (OR = 2.05, 95 % CI 1.10-3.84, p = 0.024) but not for mortality. CONCLUSION: This study shows that endocarditis in general hospitals has a high rate of morbidity and mortality. Even when treated, it ranks as one of the most lethal infectious diseases in the Netherlands, especially in women and the elderly.

Perceived determinants of cardiovascular risk management in primary care: disconnections between patient behaviours, practice organisation and healthcare system.

BACKGROUND: Although conditions for high quality cardiovascular risk management in primary care in the Netherlands are favourable, there still remains a gap between practice guideline recommendations and practice. The aim of the current study was to identify determinants of cardiovascular primary care in the Netherlands. METHODS: We performed a qualitative study, using semi-structured interviews with healthcare professionals and patients with established cardiovascular diseases or at high cardiovascular risk. A framework analysis was used to cluster the determinants into seven domains: 1) guideline factors, 2) individual healthcare professional factors, 3) patient factors, 4) professional interaction, 5) incentives and recourses, 6) mandate, authority and accountability, and 7) social, political and legal factors. RESULTS: Twelve healthcare professionals and 16 patients were interviewed. Healthcare professionals and patients mentioned a variety of factors concerning all seven domains. Determinants of practice according to the health care professionals were related to communication between healthcare professionals, patients' lack of knowledge and self-management, time management, market mechanisms in the Dutch healthcare system and motivational interviewing skills of healthcare professionals. Patients mentioned determinants related to their knowledge of risk factors for cardiovascular diseases, medication adherence and self-management as key determinants. A key finding is the mismatch between healthcare professionals' and patients' views on patient's knowledge and self-management. CONCLUSIONS: Perceived determinants of cardiovascular risk management were mainly related to patient behaviors and (but only for health professionals) to the healthcare system. Though health care professionals and patients agree upon the importance of patients' knowledge and self-management, their judgment of the current state of knowledge and self-management is entirely different.

KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients.

BACKGROUND: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (CRC). KRAS mutation analysis is usually performed on primary tumour tissue because metastatic tissue is often not available. However, controversial data are available on the concordance of test results between primary tumours and corresponding metastases. We assessed the concordance of KRAS mutation status in a study of 305 primary colorectal tumours and their corresponding liver metastases. METHODS: Patients with histologically confirmed CRC who underwent surgical resection of the primary tumour and biopsy or surgical resection of the corresponding liver metastasis were included. KRAS mutation analysis was performed for codons 12 and 13. RESULTS: KRAS mutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), we found a discordance between primary tumour and metastasis: 5 primary tumours had a KRAS mutation with a wild-type metastasis, 1 primary tumour was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a different KRAS mutation. CONCLUSION: We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6-98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7-4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis.

[Supporting patients in self-management: moving to a personalised approach]. / Ondersteuning van patiënten bij zelfmanagement.

OBJECTIVE: The aim of this research was to assess the effect of providing personalised self-management support on patient activation (knowledge, skills, self-efficacy) and self-management behaviour. DESIGN: Cluster randomised trial in 15 general practices (Dutch Trial Register No.: NTR 3960). METHOD: Patients aged 18 years or older with a chronic condition were invited to participate in the study. The Self-Management Screening (SeMaS) questionnaire - which illustrates barriers to self-management - was used as a tool for personalised self-management support. Nurse practitioners in the intervention practices were trained for 2 hours in using SeMaS and personalising self-management support on the basis of the SeMaS profile. At baseline and after 6 months, patients filled in questionnaires on patient activation (PAM-13) and lifestyle. Using data from the questionnaires and medical records, the use of individual care plans, referrals to self-management interventions, self-monitoring and healthcare use were assessed. We used a multiple multilevel regression model for data analysis. RESULTS: After 6 months, no difference was found in patient activation between the control group (n = 348) and the intervention group (n = 296). 29.4% of the patients in the intervention group performed self-monitoring, versus 15.2% in the control group (regression coefficient r = 0.9, p = 0.01). In the per-protocol analysis (control n = 348; intervention n = 136), the number of individual care plans (r = 1.3, p = 0.04) and the number of patients performing self-monitoring (r = 1.0; p = 0.01) were higher in the intervention group. CONCLUSION: Personalised self-management support with the use of the SeMaS method stimulates self-monitoring and the use of individual care plans. The intervention had no effect on patient activation or lifestyle. Given the positive secondary outcomes, the further potential of the tool should be researched.

Regional implementation of the NWC guideline on ST-elevation myocardial infarction: Report from the Task Force Prehospital Triage Zuidoost Brabant (PHT ZoB).

BACKGROUND: The NVVC guideline on ST-elevation myocardial infarction forms the basis for the regional prehospital triage (PHT) project in Zuidoost Brabant. In this project diagnosis and treatment strategies are determined in the ambulance. AIM: To summarise quality assessment and clinical results after one year. METHODS: We evaluated the protocol and patient record form, the patient's call, assignment of tasks, diagnosis, treatment, time intervals, information to hospitals, cooperation and data transmission. Time delays were compared with time delays in a regional dry run before the start of the project and with time delays reported in the literature. RESULTS: Patients still wait over one hour before seeking medical attention. The GP received the majority (65%) of patient calls. In half of all cases (51%), GPs call the ambulance centre only after they have seen the patient. When the patient calls the ambulance centre (35%), information to the GP is either prompt or absent. In 77% of calls to 112 it remains unclear whether the GP was informed at all. The treatment strategy was correct in 97% of cases. Time between symptoms and call decreased in comparison with our local preliminary investigation. Quality assessment after one year shows protocol deviations that are either logical procedural improvements or correctable flaws with no substantial negative influence. CONCLUSION: Short-term clinical results are good, but structured follow-up is needed to reduce mortality in the long term, especially after thrombolysis. A guideline is a snapshot of a dynamic process. The PHT project allows rapid adaptations to be made to new paradigms.

[Benign prostatic hyperplasia; recommendations for transmural care. Working Group, Dutch College of General Practitioners and Netherlands College of Urologists]. / Benigne prostaathyperplasie; aanbevelingen voor transmurale zorg.

Both the Netherlands College of Urologists (NVU) and the Dutch General Practice College (NHG) in recent years published guidelines for the management of benign hypertrophy of the prostate (BPH). The two differ in a number of respects and are not always consistent. The differences between the GP's and urologists' guidelines are mostly to be attributed to the difference in the patient populations visiting the GP and the urologist, respectively. In order to arrive a better adjustment concerning BPH patients between general practice and specialists, a team composed of NVU and NHG has drawn up 'Recommendations for transmural care'. These recommendations concern four subjects: diagnosis of micturition abnormalities, indication for examination of cancer of the prostate, drug treatment, indications for referring and re-referring of patients with micturition problems.

[Educational plans as control instruments in youth care in the Netherlands]. / Erziehungspläne als Steuerungsinstrumente der Jugendhilfe in den Niederlanden.

The significance, development, and different forms of educational plans and the special role of mentors and case managers in youth care in the Netherlands are presented.

[Summary of the NHG practice guideline 'Lower urinary tract symptoms in men']. / Samenvatting van de NHG-standaard 'Mictieklachten bij mannen'.

In general practice, lower urinary tract symptoms (LUTS) in men are usually not attributable to specific disorders. Prostate cancer is rarely the cause of LUTS. Education, counselling, and non-pharmaceutical advice form the basis for treatment of LUTS. Only when these measures do not relieve the patient's symptoms sufficiently, drug therapy could be considered. Alpha-blockers are the drugs of first choice and are also recommended when transurethral catheterization is needed for acute urinary retention. The effect of medication on LUTS is limited and largely based on placebo effect. The effectiveness of prostate cancer screening is a subject of debate; therefore patients asking for a PSA test should be informed about the benefits and harms of measuring PSA before having a test. A PSA value > 4 ng/ml, or abnormal results on digital rectal examination should prompt further diagnostic evaluation.

[Dutch College of General Practitioners' practice guideline 'Peripheral facial paralysis': a summary]. / De NHG-standaard 'Perifere aangezichtsverlamming': samenvatting.

The practice guideline 'Peripheral facial paralysis' of the Dutch College of General Practitioners provides the general practitioner with guidelines for diagnosis and management of patients with a peripheral facial paralysis. In about two-thirds of cases of peripheral facial paralysis no cause can be found. The diagnosis of this so-called idiopathic peripheral facial paralysis is based on the patient's history and physical examination; additional investigations are not indicated. The natural course is usually good: without treatment 65-85% of patients will regain normal function of the facial muscles. Treatment with corticosteroids is recommended for all patients with an idiopathic peripheral facial paralysis, irrespective of the degree of the paralysis. This increases the chance of complete recovery by approximately 10%. Antiviral treatment is not recommended.

The effect of transrectal ultrasonography (TRUS) including digital rectal examination (DRE) of the prostate on the level of prostate specific antigen (PSA).

OBJECTIVE: To study the effect of transrectal ultrasonography (TRUS) including digital rectal examination (DRE) of the prostate on serum prostate specific antigen (PSA). PATIENTS AND METHODS: In a diagnostic centre for general practitioners serum PSA was determined in patients before, immediately after, and one week after TRUS including DRE. In a small group of patients PSA was determined at various times after DRE and TRUS. RESULTS: The PSA levels showed a statistically significant rise of 20% immediately after DRE and TRUS. After 7 days the PSA levels had returned to their initial levels. This decrease appeared to occur within the first 24 h. CONCLUSION: When applying the diagnostic triad PSA, DRE and TRUS blood samples for PSA should preferably be taken before DRE and TRUS. If blood samples are taken afterwards, it is safe to do so after seven days.