Impact of the new rectal cancer definition on multimodality treatment and interhospital variability:Results from a nationwide cross-sectional study

Aim: This study aimed to determine the consequences of the new definition of rectal cancer for decision-making in multidisciplinary team meetings (MDT). The new definition of rectal cancer, the lower border of the tumour is located below the sigmoid take-off (STO), was implemented in the Dutch guideline in 2019 after an international Delphi consensus meeting to reduce interhospital variations. Method: All patients with rectal cancer according to the local MDT, who underwent resection in 2016 in the Netherlands were eligible for this nationwide collaborative cross-sectional study. MRI-images were rereviewed, and the tumours were classified as above or on/below the STO. Results: This study registered 3107 of the eligible 3178 patients (98%), of which 2784 patients had an evaluable MRI. In 314 patients, the tumour was located above the STO (11%), with interhospital variation between 0% and 36%. Based on TN-stage, 175 reclassified patients with colon cancer (6%) would have received different treatment (e.g., omitting neoadjuvant radiotherapy, candidate for adjuvant chemotherapy). Tumour location above the STO was independently associated with lower risk of 4-year locoregional recurrence (HR 0.529; p = 0.030) and higher 4-year overall survival (HR 0.732; p = 0.037) compared to location under the STO. Conclusion: By using the STO, 11% of the prior MDT-based diagnosis of rectal cancer were redefined as sigmoid cancer, with potential implications for multimodality treatment and prognostic value. Given the substantial interhospital variation in proportion of redefined cancers, the use of the STO will contribute to standardisation and comparability of outcomes in both daily practice and trial settings.</p

Frequency, nature and determinants of pharmacy compounded medicines in Dutch community pharmacies

Item does not contain fulltextAIMS: To examine the frequency, nature and determinants of pharmacy compounded medicines in Dutch community pharmacies. METHODS: A prospective nested case-control study comparing prescriptions for pharmacy compounded medicines (cases) with non-pharmacy compounded medicines (controls) was carried out in 79 Dutch community pharmacies. 991 Prescriptions for compounded medicines (cases), dispensed by the pharmacy on a predetermined day in a specific period (29 March until 11 April 2001), and 993 prescriptions for non-compounded medicines (controls) randomly selected on the same day, were studied. The nature and frequency of compounded medicines as well as patient, drug and prescriber related determinants were assessed. In addition, some organisational characteristics, like compounding site and use of protocols, were investigated. Also, the value of compounded medicines in terms of the availability of an industrially compounded equivalent and patient specific reasons, as perceived by the participating pharmacists, was evaluated. RESULTS: The overall frequency of prescriptions for pharmacy compounded medicines in relation to the total number of prescriptions was 3.4%. This means 12.5 compounded medicines per pharmacy per day on average, but there was a large variation between pharmacies. Excluding the products purchased from specialised compounding companies (28.4%) and the small part of medicines coming from other pharmacies (5.2%), we found an overall frequency of 2.3% of actual compounding in the pharmacy itself. On average, approximately one employee was needed for compounding activities with a large variation between pharmacies. More than 13% of the pharmacists stated that they delivered more than 25% of their compounded medicines to other pharmacies. In 2 pharmacies (2.6%) no actual compounding took place. For 58% of the products manufactured in the pharmacy itself or coming from other pharmacies a (semi-) standardised protocol was used. Compared to non-compounded medicines we found a huge share of dermatological dosage forms among compounded medicines (62.1% versus 5.3%). Oral solutions and ear-nose-throat (ENT) products were also found relatively often. While no ATC class was very pronounced in the control group, the group of dermatologicals was prominently present in the case group (57%) followed by CNS agents (8.4%). The dermatologist was a very strong determinant of compounded medicines compared to GPs (ORadj 12.2 [6.3-23.6]). Patients of 12 years or younger received a significantly higher rate of compounded medicines than persons older than 12 years of age (ORadj 3.4 [2.5-4.8]). Compounding occurred almost twice as often when a medicine was prescribed for the first time compared to a repeat prescription (ORadj 1.8 [1.5-2.2]). In about 63% of the cases the pharmacist judged that an industrially produced medicine could not substitute for the compounded medicine. In about 33% of the compounded products they indicated a patient specific reason. In about 10% this reason concerned a strictly defined pharmaceutical care issue. CONCLUSIONS: Based upon our research, all Dutch community pharmacies compound more than 13,000 medicines per day (2.3% of all prescriptions). They consist mainly of dermatological preparations. Younger children (< 12 yr) receive a significantly higher rate of compounded medicines than other people. At least 1.2 compounded prescriptions per pharmacy per day have a specific pharmaceutical care reason according to the pharmacists

Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident

In order to maintain a stable karyotype, the eukaryotic cell cycle is coordinated such that only one round of S phase precedes each mitosis, and mitosis is not initiated until DNA replication is completed. Several checkpoints and regulatory proteins have been defined in lower eukaryotes that govern this coordination, but little is known about the proteins that are involved in mammalian cells. Previously, we have shown that the winged-helix transcription factor Trident - also known as HFH-11, FKL16 and WIN [1] [2] [3] - is exclusively expressed in cycling cells and is phosphorylated during mitosis [1] [4]. The cellular function of Trident has yet to be described, however. Here, we have shown that disruption of the Trident gene in mice resulted in postnatal death, most probably because of circulatory failure. Histological analysis of Trident -/- embryos from embryonic day 10 (E10) onwards revealed a specific, characteristic defect in the developing myocardium. The orientation of the myocytes was highly irregular and the nuclei of these disorganized cardiomyocytes were clearly polyploid with up to a 50-fold increase in DNA content. Polyploidy was also observed in embryonic hepatocytes. Our results indicate that expression of Trident is required to prevent multiple rounds of S phase in the heart and the liver. Trident therefore appears to have a role in preventing DNA re-replication during the G2 and M phases

Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.

OBJECTIVE: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aorta dilatation in the Fbn1C1039G/+ MFS mouse model. APPROACH AND RESULTS: Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2. Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor kappaB dependent. CONCLUSIONS: Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS

Implementation and outcome of minor and major minimally invasive liver surgery in the Netherlands

Background: While most of the evidence on minimally invasive liver surgery (MILS) is derived from expert centers, nationwide outcomes remain underreported. This study aimed to evaluate the implementation and outcome of MILS on a nationwide scale.Methods: Electronic patient files were reviewed in all Dutch liver surgery centers and all patients undergoing MILS between 2011 and 2016 were selected. Operative outcomes were stratified based on extent of the resection and annual MILS volume.Results: Overall, 6951 liver resections were included, with a median annual volume of 50 resections per center. The overall use of MILS was 13% (n = 916), which varied from 3% to 36% (P = 20 MILS annually, major MILS was associated with less conversions (14 (11%) versus 41 (30%), P < 0.001), shorter operating time (184 (117- 239) versus 200 (139-308) minutes, P = 0.010), and less overall complications (37 (30%) versus 58 (42%), P = 0.040).Conclusion: The nationwide use of MILS is increasing, although large variation remains between centers. Outcomes of major MILS are better in centers with higher volumes.Transplant surger

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

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