Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants

Aims Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. Methods A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m(2) every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. Results In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. Conclusion Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments

Should jaundice preclude resection in patients with gallbladder cancer? Results from a nation-wide cohort study

Background: It is controversial whether patients with gallbladder cancer (GBC) presenting with jaundice benefit from resection. This study re-evaluates the impact of jaundice on resectability and survival. Methods: Data was collected on surgically explored GBC patients in all Dutch academic hospitals from 2000 to 2018. Survival and prognostic factors were assessed. Results: In total 202 patients underwent exploration and 148 were resected; 124 non-jaundiced patients (104 resected) and 75 jaundiced patients (44 resected). Jaundiced patients had significantly (P < 0.05) more pT3/T4 tumors, extended (≥3 segments) liver- and organ resections, major post-operative complications and margin-positive resection. 90-day mortality was higher in jaundiced patients (14% vs. 0%, P < 0.001). Median overall survival (OS) was 7.7 months in jaundiced patients (2-year survival 17%) vs. 26.1 months in non-jaundiced patients (2-year survival 39%, P < 0.001). In multivariate analysis, jaundice (HR1.89) was a poor prognostic factor for OS in surgically explored but not in resected patients. Six jaundiced patients did not develop a recurrence; none had liver- or common bile duct (CBD) invasion on imaging. Conclusion: Jaundice is associated with poor survival. However, jaundice is not an independent adverse prognostic factor in resected patients. Surgery should be considered in patients with limited disease and no CBD invasion on imaging

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Alcohol's impact on fine motor skills: Insights from minimally invasive surgical simulation

Background: Alcohol misuse among medical professionals poses a significant concern, and there is a lack of clarity in (inter)national guidelines regarding alcohol use during work. Moreover, there exists an insufficient body of research on the specific impact of alcohol on fine motor skills within the medical sector, specifically surgery. This study aims to investigate the impact of alcohol on fine motor skills in a minimally invasive surgical setting. Methods: A cross-sectional study was conducted at Lowland Science on August 19th, 20th, and 21st, 2022, during the Lowlands music festival in Biddinghuizen, the Netherlands. Participants were divided into five groups based on measured alcohol consumption. Exclusion criteria included drug use, prior surgical experience, being underage, and previous participation. The main outcomes were the number of correctly transferred rings during the PEG transfer task and the number of errors. Blood alcohol concentration (BAC) was measured using a breathalyser. Results: A total of 1056 participants were included in the study. The results indicated an inverse relationship between BAC levels and surgical performance, with higher alcohol levels associated with a decrease in performance (p = 0.023). However, there was no significant difference in the number of errors among the five groups (p = 0.597). The group with the highest alcohol consumption (BAC >0.08 %) exhibited significantly worse performance compared to the group with a BAC of 0.0 % (p = 0.002). Conclusion: This study uncovers a negative impact of increased alcohol intake on fine motor skills in a minimally invasive surgery simulation exercise. While there was no effect on the occurrence of errors. Professional medical organizations should reconsider and explicate their position on alcohol use in (surgical) healthcare

Objective assessment for open surgical suturing training by finger tracking can discriminate novices from experts

ABSTRACTIt is difficult, time consuming and expensive to assess manual skills in open surgery. The aim of this study is to investigate the construct validity of a low-cost, easily accessible tracking technique for basic open suturing tasks. Medical master students, surgical residents, and surgeons at the Radboud University Medical Center were recruited between September 2020 until September 2021. The participants were divided, according to experience, in a novice group (≤10 sutures performed) and an expert group (>50 sutures performed). For objective tracking, a tablet with SurgTrac software was used, which tracked a blue and a red tag placed on respectively their left and right index finger. The participants executed four basic tasks on a suturing model: 1) knot tying by hand, 2) transcutaneous suturing with an instrument knot, 3) ‘Donati’ (vertical mattress suture) with an instrument knot and 4) continuous intracutaneous suturing without a knot. In total 76 participants were included: 57 novices and 19 experts. All four tasks showed significant differences between the novice group and expert group for the parameters time (p<0.001), distance (p<0.001 for Task 1, 2 and 3 and p=0.034 for Task 4) and smoothness (p<0.001). Additionally, Task 3 showed a significant difference for the parameter handedness (p=0.006) and Task 4 for speed (p=0.033). Tracking index finger movements using SurgTrac software on a tablet while executing basic open suturing skills on a simulator shows excellent construct validity for time, distance and motion smoothness in all four suturing tasks

evidence

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Perioperative treatment and radical cystectomy for bladder cancer - A population based trend analysis of 10,338 patients in the Netherlands

Background In Europe, population-based data concerning perioperative treatment (PT) and radical cystectomy (RC) are lacking. We assessed temporal trends in PT (neoadjuvant chemotherapy [NAC], neoadjuvant radiotherapy [NAR], adjuvant chemotherapy [AC], adjuvant radiotherapy [AR]) and RC in the Netherlands and identified patients' and hospital characteristics associated with PT. Methods This nationwide, retrospective, population-based study included cTa/is, T1-4, N0-3, M0-1 bladder cancer patients from the Netherlands Cancer Registry who underwent RC with curative intent between 1995 and 2013. PT-administration over time was compared with chi-square tests. Multivariable logistic regression analyses were performed to identify characteristics associated with PT usage. The sub-groups cT2-4N0M0 and cT2-4, N0 or NX, M0 or MX were separately analysed. Results In total, 10,338 patients met inclusion criteria. Eighty-six percent did not receive PT, 7.0% received NAC (or induction chemotherapy [IC]), 3.2% NAR, 1.8% AC, and 2.1% AR. NAC usage increased from 0.6% in 1995 to 21% in 2013 (p < 0.001), application of NAR decreased from 15% to 0.4% (p < 0.001). Usage of AC and AR in 2013 was <1.5%. Comparable temporal trends were found in 6032 patients staged cT2-4N0M0. Multivariable logistic regression analysis revealed that younger age, ≥cT3, ≥cN1 and treatment in academic/teaching hospitals were associated with NAC or IC (all p < 0.05). Conclusions The increase in NAC administration in the Netherlands reflects a slow but steady adoption of evidence-based guidelines over the last two decades. Considerable variability in patients' and hospital characteristics in the likelihood of receiving NAC exists. Conversely, NAR, AR and AC are hardly administered anymore

Patients with Congenital Low-Flow Vascular Malformation Treated with Low Dose Sirolimus

Introduction: Patients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10–15 ng/ml were well tolerated; however, in a relative high percentage of patients sirolimus caused serious adverse events (AEs). Methods: A case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4–10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading. Results: An improvement in symptoms was seen in 92% (n = 11/12) of patients. In nine patients pain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus. Conclusions: Low dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition