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We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Background Increased awareness of gastric cancer risk, easy access to upper endoscopy, and high definition endoscopes with virtual chromoendoscopy may have led to the increase in early diagnosis of gastric cancer observed in recent years in Europe, which may be associated with improved survival. Currently, no data exist on the impact of early diagnosis on survival at a populational level in Europe. Our aim was to assess gastric cancer incidence, early diagnosis, and survival in northwestern and southern European countries with a low-to-moderate incidence of gastric cancer. Methods Data on 41 138 gastric cancers diagnosed in 2007–2016 were retrieved from national cancer registries of Belgium, the Netherlands, and northern Portugal. Age-standardized incidence and mortality rates were assessed and expressed per 100 000 person-years. Early diagnosis was defined as T1 tumors. Net survival estimates for 2007–2011 vs. 2012–2016 were compared. Results Age-standardized incidence and mortality decreased over time in Belgium, northern Portugal, and the Netherlands (relative incidence decrease 8.6 %, 4.5 %, and 46.8 %, respectively; relative mortality decrease 22.0 %, 30.9 %, and 50.0 %, respectively). Early gastric cancer diagnosis increased over time for all countries. Net 1-year survival improved significantly between the two time periods in all countries, and at 5 years in Belgium and Portugal. Conclusions This is the first study comparing trends (2007–2016) in gastric cancer incidence and mortality in some European countries. We found an increasing proportion of T1 gastric cancers and a decrease in age-standardized mortality over time, supporting the use of secondary prevention strategies.

Highlights • Results of a breast cancer planning study with 4 cases conducted in the Netherlands are reported. • A guideline for evaluation of breast cancer radiotherapy treatment plans has been established. • The dosimetric parameters D98%, Dmean and D2% are adopted for target volume dose evaluation. • For the heart and lungs, Dmean is adopted as the most important dosimetric parameter., Purpose The aim was to reach consensus in The Netherlands on which parameters should be used to evaluate breast cancer radiotherapy (RT) plans. Materials and methods A Benchmark Case with delineated planning target volumes (PTVs) and Organs At Risk (OARs) was sent to all Dutch radiotherapy centres in combination with a questionnaire, with the request to generate RT plans prescribing 15 times 2.67 Gy for four different treatment indications according to the institutional irradiation technique. The plans and accompanying questionnaire answers were analysed using descriptive statistics. These results, together with a harmonisation proposal, were sent to all centres. The proposal was discussed at a meeting of the Dutch Society of Radiation Oncology breast cancer platform. Distinct parameters were accepted if consensus on them was reached. Results 19 out of 20 Dutch departments participated in this study. PTV coverage varied considerably, with D98% between 63% and 99% for the breast and between 37% and 97% for the internal mammary nodes (IMN). Also substantial OAR dose differences were observed, with e.g. mean heart doses ranging between 1.85 Gy and 5.42 Gy in case the IMN were included in the PTV. For evaluation of the PTVs D98%, D2% and Dmean were chosen to report on, with target values of ≥ 95% (90% for the PTV_IMN), ≤ 107%, and 99–101%, respectively. For OARs, consensus was reached on the parameters to be evaluated, without target values: Dmean of the heart, Dmean and V5% of the lungs, and in case of periclavicular radiotherapy V30Gy of the thyroid gland. For patients younger than 40 years a contralateral mean breast dose of ≤ 1 Gy was agreed upon. Conclusion A new Dutch consensus guideline for evaluation of breast cancer RT plans has been established.

BACKGROUND: To report technical and clinical 30-day results following treatment with the Zenith Alpha™ abdominal stent graft from the ZEnith alPHa for aneurYsm Repair Registry (ZEPHYR).METHODS: Multicenter, nonrandomized, single arm, core laboratory-controlled, prospective registry collecting data on the Zenith Alpha Abdominal Endovascular Graft being used in subjects with abdominal aortic aneurysms (AAA) from sites in Germany, Belgium, and The Netherlands between December 2016 and December 2019. Inclusion criteria were non-ruptured AAAs with a maximum diameter ≥50 mm or enlargement >5 mm over 6 months with an AAA neck length ≥10 mm (site reported). Primary outcome measure was treatment success at 30 days. Treatment success was defined as a combined endpoint consisting of technical and clinical success. Technical success was defined as successful stent graft delivery and deployment as well as successful removal of the delivery system. Clinical success at 30 days was defined as freedom from type I and III endoleak, aneurysm rupture, conversion to open surgery and stent graft occlusion.RESULTS: Three hundred forty-seven subjects were included from 14 sites with a median age of 73.0 years (IQR 68.0-79.0). Thirty-four patients were female (9.8%). The median AAA diameter was 58.3 mm (IQR 55.0-63.5). The median proximal neck diameter was 23.6 mm (IQR 22.0-25.2) with a median proximal neck length of 24.4 mm (IQR 15.0-34.8) and a median infrarenal neck angulation of 24.5° (IQR 15.0-35.0). The right and left common iliac diameter were 16.1 mm (IQR 14.1-19.4) and 16.2 mm (IQR 14.1-19.1), respectively. The treatment success rate at 30 days was 94.8% (N = 329). Technical success was achieved in 333 patients (96.0%). The clinical success rate at 30 days was 98.8% (N = 343). Three patients had limb occlusions at 30 day follow up (0.9%). One patient had a type Ib endoleak (0.3%). Seventy percent of vascular access approaches were percutaneous. The reintervention rate was 1.7% (N = 6) within 30 days. Indications for reinterventions were a false aneurysm at puncture site (N = 1), limb complications (N = 2), stentgraft-associated renal artery occlusions (N = 2), and an external iliac artery thrombosis (N = 1).CONCLUSIONS: Endovascular aneurysm repair using the Zenith Alpha Abdominal Endovascular Graft is effective in the short term. Long term results will be reported in the future.

Background The aim of this nationwide observational study was to evaluate factors associated with multivisceral resection (MVR), margin status and overall survival in locally advanced colorectal cancer (CRC). Material and methods Patients with (y)pT4, cM0 CRC between 2006 and 2017 were selected from the Netherlands Cancer Registry. Cox-proportional hazards modelling was used for survival analysis, stratified for T4a and T4b. Annual hospital volume cut-off was 75 for colon and 40 for rectal resections. Results A total of 11.930 patients were included and 2410 patients (20.2%) underwent MVR. Factors associated with MVR for colon and rectal cancer besides cT4 category were more recent diagnosis (OR 3.61, CI 95% 3.06–4.25 (colon) and OR 2.72, CI 95% 1.82–4.08 (rectum)) and high hospital volume (OR 1.20, CI 95% 1.05–1.38 (colon) and OR 2.17, CI 95% 1.55–3.04 (rectum)). Patients ≥70 year were less likely to undergo MVR for colon cancer (OR 0.80, 95% CI 0.70–0.90). Risk factors for incomplete resection were cT4 (OR 3.08, CI 95% 2.35–4.04 (colon) and OR 1.82, CI 95% 1.13–2.94 (rectum)) and poor/undifferentiated tumors (OR 1.41, CI 95% 1.14–1.72 (colon) and OR 1.69, CI 95% 1.05–2.74 (rectum)). More recent diagnosis was independently associated with less incomplete resections in colon cancer (OR 0.58, CI 95% 0.40–0.76). Independent predictors of survival were age, resection margin, nodal status and adjuvant chemotherapy, but not MVR. Conclusion Treatment of locally advanced CRC with MVR at population level was influenced by year of diagnosis and hospital volume. Margin status in colon cancer improved substantially over time.

Purpose Little is known about the prevalence of occult lymph node metastases (LNM) in muscle-invasive bladder cancer (MIBC) patients with pathological downstaging of the primary tumor. We aimed to estimate the prevalence of occult LNM in patients without residual MIBC at radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or neoadjuvant radiotherapy (NAR), and to assess overall survival (OS). Methods Patients with cT2-T4aN0M0 urothelial MIBC who underwent RC plus pelvic lymph node dissection (PLND) with curative intent between January 1995–December 2013 (retrospective Netherlands Cancer Registry (NCR) cohort) and November 2017–October 2019 (prospective NCR-BlaZIB cohort (acronym in Dutch: BlaaskankerZorg In Beeld; in English: Insight into bladder cancer care)) were identified from the nationwide NCR. The prevalence of occult LNM was calculated and OS of patients with y)pT2N0 vs. y)pT2N+ disease was estimated by the Kaplan–Meier method. Results In total, 4657 patients from the NCR cohort and 760 patients from the NCR-BlaZIB cohort were included. Of 1374 patients downstaged to y)pT2, 4.3% (N = 59) had occult LNM 4.1% (N = 49) of patients with cT2-disease and 5.6% (N = 10) with cT3-4a-disease. This was 4.0% (N = 44) in patients without NAC or NAR, 4.5% (N = 10) in patients with NAC, and 13.5% (N = 5) in patients with NAR but number of patients treated with NAR and downstaged disease was small. The prevalence of y)pT2N+ disease was 4.2% (N = 48) in the NCR cohort and 4.6% (N = 11) in the NCR-BlaZIB cohort. For patients with y)pT2N+ and y)pT2N0, median OS was 3.5 years (95% CI 2.5–8.9) versus 12.9 years (95% CI 11.7–14.0), respectively. Conclusion Occult LNM were found in 4.3% of patients with cT2-4aN0M0 MIBC with (near-) complete downstaging of the primary tumor following RC plus PLND. This was regardless of NAC or clinical T-stage. Patients with occult LNM showed considerable worse survival. These results can help in counseling patients for bladder-sparing treatments.

Background Acute occlusion of renal bridging stent grafts after fenestrated/branched endovascular aortic repair (F/B-EVAR) is an acknowledged complication with high morbidity that often results in chronic dialysis dependence. The feasibility and effect of timely or late (≥6 hours of ischemia) renal artery revascularization has not been adequately reported. Methods We performed a retrospective, multicenter study across 11 tertiary institutions of all consecutive patients who had undergone revascularization of renal artery stent graft occlusions after complex EVAR. The end points were technical success, association between ischemia time and renal function salvage, interventional complications, mortality, and mid-term outcomes. Results From 2009 to 2019, 38 patients with 46 target vessels (TVs; eight bilateral occlusions) were treated for renal artery occlusions after complex EVAR (mean age, 63.5 ± 10 years; 63.2% male). Six patients had a solitary kidney (15.8%). Of the 38 patients, 16 (42.1%) had undergone FEVAR and 22 (57.9%) had undergone BEVAR. The technical success rate was 95.7% (44 of 46 TVs). The recanalization technique used was sole aspiration thrombectomy in 5.3%, aspiration thrombectomy and stent graft relining in 52.6%, and sole stent graft relining in 36.8%. The median renal ischemia time was 27.5 hours (range, 4-720 hours; interquartile range, 4-36 hours). Most patients (94.4%) had been treated after ≥6 hours of renal ischemia time, and 55.6% had been treated after 24 hours. In 14 patients (36.8%), renal function had improved after intervention (mean glomerular filtration rate improvement, 14.2 ± 9 mL/min/1.73 m2). However, 24 patients (63.2%) showed no improvement. Improvement of renal function did not correlate with the length of renal ischemia time. Of the 14 patients with bilateral renal artery occlusion or a solitary kidney, 9 experienced partial recovery of renal function and no longer required hemodialysis. In-hospital mortality was 2.6%. The cause of renal stent graft occlusion could not be identified in 50% of the TVs (23 of 46). However, in 19 (41.3%), significant stenosis or a kink of the renal stent graft was found. The median follow-up was 11 months (interquartile range, 0-28 months). The estimated 1-year patient survival and patency rate of the renal stent grafts was 97.4% and 83.8%, respectively. Conclusions Revascularization of occluded renal bridging stent grafts after F/B-EVAR is a safe and feasible technique and can lead to significant improvement of renal function, even after long ischemia times (>24 hours) of the renal parenchyma or bilateral occlusion, as long as residual perfusion of the renal parenchyma has been preserved. Also, the long-term patency rates justify aggressive management of renal artery occlusion after F/B-EVAR.

Purpose To investigate the association between smartphone use and refractive error in teenagers using the Myopia app. Design Cross-sectional population-based study. Participants A total of 525 teenagers 12 to 16 years of age from 6 secondary schools and from the birth cohort study Generation R participated. Methods A smartphone application (Myopia app; Innovattic) was designed to measure smartphone use and face-to-screen distance objectively and to pose questions about outdoor exposure. Participants underwent cycloplegic refractive error and ocular biometry measurements. Mean daily smartphone use was calculated in hours per day and continuous use as the number of episodes of 20 minutes on screen without breaks. Linear mixed models were conducted with smartphone use, continuous use, and face-to-screen distance as determinants and spherical equivalent of refraction (SER) and axial length-to-corneal radius (AL:CR) ratio as outcome measures stratified by median outdoor exposure. Main Outcome Measures Spherical equivalent of refraction in diopters and AL:CR ratio. Results The teenagers on average were 13.7 ± 0.85 years of age, and myopia prevalence was 18.9%. During school days, total smartphone use on average was 3.71 ± 1.70 hours/day and was associated only borderline significantly with AL:CR ratio (β = 0.008; 95% confidence interval [CI], –0.001 to 0.017) and not with SER. Continuous use on average was 6.42 ± 4.36 episodes of 20-minute use without breaks per day and was associated significantly with SER and AL:CR ratio (β = –0.07 [95% CI, –0.13 to –0.01] and β = 0.004 [95% CI, 0.001–0.008], respectively). When stratifying for outdoor exposure, continuous use remained significant only for teenagers with low exposure (β = –0.10 [95% CI, –0.20 to –0.01] and β = 0.007 [95% CI, 0.001–0.013] for SER and AL:CR ratio, respectively). Smartphone use during weekends was not associated significantly with SER and AL:CR ratio, nor was face-to-screen distance. Conclusions Dutch teenagers spent almost 4 hours per day on their smartphones. Episodes of 20 minutes of continuous use were associated with more myopic refractive errors, particularly in those with low outdoor exposure. This study suggested that frequent breaks should become a recommendation for smartphone use in teenagers. Future large longitudinal studies will allow more detailed information on safe screen use in youth.

OBJECTIVES This study aimed to compare long-term survival following minimally invasive esophagectomy (MIE) versus open esophagectomy (OE) for esophageal cancer using a nationwide propensity-score matched cohort. SUMMARY BACKGROUND DATA MIE provides lower postoperative morbidity and mortality, and similar short-term oncological quality compared to OE. METHODS Data was acquired from the Dutch Upper Gastrointestinal Cancer Audit. Patients undergoing minimally invasive or open, transthoracic or transhiatal esophagectomy for primary esophageal cancer between 2011-2015 were included. A propensity-score matching analysis for MIE versus OE was performed separately for transthoracic and transhiatal esophagectomies. RESULTS A total of 1036 transthoracic MIE and OE patients, and 582 transhiatal MIE and OE patients were matched. Long-term survival was comparable for MIE and OE for both transthoracic and transhiatal procedures (5-year overall survival: transthoracic MIE 49.2% vs. OE 51.1%, p 0.695; transhiatal MIE 48.4% vs. OE 50.7%, p 0.832). For both procedures, MIE yielded more lymph nodes (transthoracic median 21 vs. 18, p < 0.001; transhiatal 15 vs. 13, p 0.007). Post-operative morbidity was comparable after transthoracic MIE and OE (60.8% vs. 64.9%, p 0.177), with a reduced length of stay after transthoracic MIE (median 12 vs. 15 days, p < 0.001). After transhiatal MIE, more postoperative complications (64.9% vs. 56.4%, p 0.034) were observed, without subsequent difference in length of stay. CONCLUSION Long-term survival after minimally invasive esophagectomy was equivalent to open in both propensity-score matched cohorts of patients undergoing transthoracic or transhiatal esophageal resections. Transhiatal minimally invasive esophagectomy was accompanied with more post-operative morbidity. Both transthoracic and transhiatal minimally invasive esophagectomy resulted in a more extended lymphadenectomy.

BACKGROUND AND AIMS: Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics. METHOD: Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening. RESULTS: A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects. CONCLUSION: In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.

Background Biological sex and gender have been reported to affect incidence and overall survival (OS) of curatively treated gastroesophageal cancer. The aim of this study was to compare palliative treatment allocation and OS between women and men with advanced gastroesophageal cancer. Methods Patients with an unresectable or metastatic esophageal (including cardia) adenocarcinoma (EAC) or squamous cell carcinoma (ESCC) or gastric adenocarcinoma (GAC) diagnosed in 2015-2018 were identified in the Netherlands Cancer Registry. Treatment allocation was compared using χ2 tests and multivariable logistic regression analyses, and OS using the Kaplan-Meier method with log-rank test and Cox proportional hazards analysis. All statistical tests were 2-sided. Results Of patients with EAC (n = 3077), ESCC (n = 794), and GAC (n = 1836), 18.0%, 39.4%, and 39.1% were women, respectively. Women less often received systemic treatment compared with men for EAC (42.7% vs 47.4%, P = .045) and GAC (33.8% vs 38.8%, P = .03) but not for ESCC (33.2% vs 39.5%, P = .07). Women had a lower probability of receiving systemic treatment for GAC in multivariable analyses (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.62 to 1.00) but not for EAC (OR = 0.86, 95% CI = 0.69 to 1.06) and ESCC (OR = 0.81, 95% CI = 0.57 to 1.14). Median OS was lower in women with EAC (4.4 vs 5.2 months, P = .04) but did not differ after adjustment for patient and tumor characteristics and systemic treatment administration. Conclusions We observed statistically significant and clinically relevant gender differences in systemic treatment administration and OS in advanced gastroesophageal cancer. Causes of these disparities may be sex based (ie, related to tumor biology) as well as gender based (eg, related to differences in treatment choices).

This two-part preclinical study aims to evaluate prostate specific membrane antigen (PSMA) as a valuable target for expression-based imaging applications and to determine changes in target binding in function of varying apparent molar activities (MAapp) of [18F]AlF-PSMA-11. For the evaluation of PSMA expression levels, male NOD/SCID mice bearing prostate cancer (PCa) xenografts of C4-2 (PSMA+++), 22Rv1 (PSMA+) and PC-3 (PSMA−) were administered [18F]AlF-PSMA-11 with a medium MAapp (20.24 ± 3.22 MBq/nmol). SUVmean and SUVmax values were respectively 3.22 and 3.17 times higher for the high versus low PSMA expressing tumors (p app, C4-2 and 22Rv1 xenograft bearing mice underwent additional [18F]AlF-PSMA-11 imaging with a high (211.2 ± 38.9 MBq/nmol) and/or low MAapp (1.92 ± 0.27 MBq/nmol). SUV values showed a significantly increasing trend with higher MAapp. Significant changes were found for SUVmean and SUVmax between the high versus low MAapp and medium versus low MAapp (both p app (p = 0.055 and 0.25, respectively). The effect of varying MAapp was more pronounced in low expressing tumors and PSMA expressing tissues (e.g. salivary glands and kidneys). Overall, administration of a high MAapp increases the detection of low expression tumors while also increasing uptake in PSMA expressing tissues, possibly leading to false positive findings. In radioligand therapy, a medium MAapp could reduce radiation exposure to dose-limiting organs with only limited effect on radionuclide accumulation in the tumor.

OBJECTIVE: To evaluate changes in treatment and outcomes of esophagogastric cancer surgery after introduction of the DUCA. In addition, the presence of risk-averse behavior was assessed. SUMMARY OF BACKGROUND DATA: Clinical auditing is seen as an important quality improvement tool; however, its long-term efficacy remains largely unknown. In addition, critics claim that enhancements result from risk-averse behavior rather than positive effects of auditing. METHODS: DUCA data were used from registration start (1-1-2011) until 31-12-2018. Trends in patient, tumor, hospital and treatment characteristics were univariably assessed. Trends in short-term outcomes were investigated using multilevel multivariable logistic regression. Presence of risk aversion was described by the corrected proportion of patients undergoing surgery, using data from the Netherlands Cancer Registry. To evaluate the impact of centralization on time trends identified, the association between hospital volume and outcomes was investigated. RESULTS: This study included 6172 patients with esophageal and 3,690 with gastric cancer who underwent surgery. Pathological outcomes (lymph node yield, radicality) improved and futile surgery decreased over the years. In-hospital/30-day mortality decreased for esophagectomy (4.2% to 2.5%) and for gastrectomy (7.1% to 4.3%). Reinterventions, (minor) complications and readmissions increased. Risk aversion appeared absent. Between 2011-2018, annual median hospital volumes increased from 38 to 53 for esophagectomy and from 14 to 29 for gastrectomy. Higher hospital volumes were associated with several improved outcomes measures. CONCLUSIONS: During 8 years of auditing, outcomes improved, with no signs of risk-averse behavior. These improvements occurred in parallel with centralization. Feedback on postoperative complications remains the focus of the DUCA.

OBJECTIVE: This population-based study aimed to compare presentation, treatment allocation and survival of potentially curable esophageal cancer patients between Sweden and the Netherlands. SUMMARY OF BACKGROUND DATA: Identification of inter-country differences in treatment allocation and survival may be used for targeted esophageal cancer care improvement. METHODS: Nationwide datasets were acquired from a Swedish cohort study and the Netherlands Cancer Registry. Patients with potentially curable (cT1-T4a/Tx, cN0/+, cM0/x) esophageal adenocarcinoma or squamous cell carcinoma (SCC) diagnosed in 2011-2015 were included. Multivariable logistic regression provided odds ratios (OR) for treatment allocation, and multivariable Cox model provided hazard ratios (HR) for overall survival, all with 95% confidence intervals (CI), adjusted for age, sex, year, tumor sub-location and stage. RESULTS: Among 1980 Swedish and 7829 Dutch esophageal cancer patients, Swedish patients were older (71 vs 69 years, P

Objective To report the outcomes of redo fenestrated and/or branched endovascular aortic repair (F/BEVAR in FEVAR) to rescue previous failed FEVAR. Methods Retrospective review of all consecutive patients undergoing F/BEVAR in FEVAR at eight aortic centres including pre-, intra-, and post-operative data according to a pre-established protocol. Follow up consisted of at least yearly computed tomography angiography. Values are presented as median and interquartile range, and survival as estimate ± standard error in percentage. Results 18 male patients (76 years old; range 69 – 78 years) receiving FEVAR involving two (two or three) target vessels between 2006 and 2016 underwent F/BEVAR in FEVAR between 2012 and 2019 (aneurysm diameter of 63 mm; range 56 – 69 mm). Median interval between the procedures was 53 (29 – 103) months. The indication for F/BEVAR in FEVAR was type Ia endoleak in 16 cases (eight isolated and eight combined with graft migration), one graft migration without endoleak and one migration with significant proximal aortic expansion. F/BEVAR in FEVAR involved all patent renovisceral arteries and had an operating time of 260 (204 – 344) minutes. Technical success was achieved in 15 (83%) cases. There was a failure to bridge one renal artery, one renal capsular bleed with the subsequent need for renal artery embolisation within 24 hours and one persistent type Ib endoleak despite iliac extension. There was no peri- or in hospital death. Two patients developed spinal cord ischaemia, one transient paraparesis and one permanent paraplegia. The latter occurred in a non-staged procedure where spinal drainage was used. During a follow up of 27 (7 – 39) months, three (17%) patients underwent late re-interventions. Overall survival at 24 months was 70 ± 11% with no aneurysm related death and a secondary clinical success at 24 months of 84 ± 11%. Conclusion F/BEVAR in FEVAR is a technically challenging but feasible solution to rescue failed FEVAR. The outcomes are promising in many aortic centres but need to be confirmed by further studies with longer follow up.

Purpose Photo-optical TCpO2 (pTCpO2) has been proposed as a new method to determine the partial oxygen pressure of the lower extremity in patients with peripheral arterial disease. It is aimed to determine the level of agreement between pTCpO2 and the traditional electro-chemical transcutaneous oxygen tension measurement (eTCpO2). Methods Eighteen patients with intermittent claudication underwent simultaneous ankle-brachial index measurement, toe-pressure, pTCpO2 and eTCpO2 tests. Oxygen tension levels were measured on anterior chest and calf prior in rest (T0), during induced ischemia (T1) and after blood flow restoration (T2). TCpO2 agreement was assessed according to the principles of Bland and Altman. Results Absolute average TCpO2 values differed between eTCpO2 and pTCpO2 for calf in T2 (38,1 mmHg (σ 14,4) vs. 49,8 (σ 22.3) with P = 0.35). The Bland-Altman plots demonstrated eTCpO2 and pTCpO2 bias of 3,7 mmHg (σ 18,8), 11,6 mmHg (σ 17,6) and 6,7 mmHg (σ 23,5) for T0, T1 and T2 for the calf. Conclusion pTCpO2 is in agreement with eTCpO2 in measuring pO2 levels of the lower extremity in rest and during induced ischemia in patients with vascular claudication. The large variability between eTCpO2 and pTCpO2 should be accounted for, while pTCpO2 values have a tendency to demonstrate higher values in comparison to eTCpO2.

Purpose: Fenestrated endovascular aneurysm repair (FEVAR) is a well-established endovascular treatment option for pararenal abdominal aortic aneurysms in which balloon-expandable covered stents (BECS) are used to bridge the fenestration to the target vessels. This study presents midterm clinical outcomes and patency rates of the Advanta V12 BECS used as a bridging stent. Methods: All patients treated with FEVAR with at least 1 Advanta V12 BECS were included from 2 large-volume vascular centers between January 2012 and December 2015. Primary endpoints were freedom from all-cause reintervention, and freedom from BECS-associated complications and reintervention. BECS-associated complications included significant stenosis, occlusion, type 3 endoleak, or stent fracture. Secondary endpoints included all-cause mortality in-hospital and during follow-up. Results: This retrospective study included 194 FEVAR patients with a mean age of 72.2±8.0 years. A total of 457 visceral arteries were stented with an Advanta V12 BECS. Median (interquartile range) follow-up time was 24.6 (1.6, 49.9) months. The FEVAR procedure was technically successful in 93% of the patients. Five patients (3%) died in-hospital. Patient survival was 77% (95% CI 69% to 84%) at 3 years. Freedom from all-cause reintervention was 70% (95% CI 61% to 78%) at 3 years, and 33% of all-cause reinterventions were BECS associated. Complications were seen in 24 of 457 Advanta V12 BECSs: type 3 endoleak in 8 BECSs, significant stenosis in 4 BECSs, occlusion in 6 BECSs, and stent fractures in 3 BECSs. A combination of complications occurred in 3 BECSs: type 3 endoleak and stenosis, stent fracture and stenosis, and stent fracture and occlusion. The freedom from BECS-associated complications for Advanta V12 BECSs was 98% (95% CI 96% to 99%) at 1 year and 92% (95% CI 88% to 95%) at 3 years. The freedom from BECS-associated reinterventions was 98% (95% CI 95% to 100%) at 1 year and 94% (95% CI 91% to 97%) at 3 years. Conclusion: The Advanta V12 BECS used as bridging stent in FEVAR showed low complication and reintervention rates at 3 years. A substantial number of FEVAR patients required a reintervention, but most were not BECS related.

The management of inflammatory rheumatic diseases has substantially changed in recent years, as has the profile of patients. The advent of biotherapies has been a revolution in rheumatology and the impact of co-morbidities in the management of these patients is now becoming increasingly important. Metabolic syndrome (MetS) is one of the most frequent comorbidities, and hepatic complications of MetS are not uncommon. MetS is responsible for Non-alcoholic fatty liver disease (NAFLD), characterized by excessive hepatic fat accumulation. In extreme cases, progression to cirrhosis is possible. NAFLD ranks among the top three indications for liver transplantation. We review available data on the safety, especially the risk of infections, of TNF inhibitors (TNFi) in case of NAFLD and in case of liver cirrhosis, in patients with rheumatic disease. In cases of NAFLD without severe fibrosis, available data are reassuring and tend to show a beneficial effect of TNFi on hepatic tissue. In case of cirrhosis, data are conflicting. Further large, well-designed studies are needed to explore this specific issue.

Background: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown. Aims: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment. Methods: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM-85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end-point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent. Results: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68–1.69], p = 0.77). With the use of OM-85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p = 0.02). In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR = 0.71, 95%CI [0.39–1.26], p = 0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T cells, did not show differences between the groups. Conclusion: Although OM-85 may have immune-modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post hoc analysis showed a potential clinical benefit in patients with type 2 inflammation.

Background Bowel dysfunction after rectal cancer surgery is common, with some experiencing low anterior resection syndrome (LARS) is common after rectal cancer surgery. This study examined if transanal total mesorectal excision (TaTME) has a similar risk of LARS and altered quality of life (QoL) as patients who undergo low anterior resection (LAR). Methods Patients who underwent TaTME or traditionally approached total mesorectal excision in a prospective colorectal cancer cohort study (2014–2019) were propensity score matched in a 1 : 1 ratio. LARS and QoL scores were assessed before and after surgery with a primary endpoint of major LARS at 12 months analysed for possible association between factors by logistic regression. Results Of 61 TaTME and 317 LAR patients eligible, 55 from each group were propensity score matched. Higher LARS scores (30.6 versus 25.4, P = 0.010) and more major LARS (65 versus 42 per cent, P = 0.013; OR 2.64, 95 per cent c.i. 1.22 to 5.71) were reported after TaTME. Additionally, QoL score differences (body image, bowel frequency, and embarrassment) were worse in the TaTME group. Conclusions TaTME may be associated with more severe bowel dysfunction than traditional approaches to rectal cancer.

Objectives To describe the current methods usable to assess intestinal permeability in spondyloarthritis (SpA) and rheumatoid arthritis (RA), to analyze the available data on intestinal permeability in SpA and RA patients and the effects of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal permeability. Methods A systematic review was conducted. Medline, Embase, and Cochrane Library databases were searched. Studies published in the last 40 years (January 1980–September 2020) with patients with SpA and/or RA assessing the intestinal permeability were selected. Results A total of 2916 articles were collected, after discarding 1125 duplicate articles, we analyzed the titles and abstracts of 1791 studies. There were 459 articles that met the inclusion criteria and whose text was read. A total of 23 studies were included in the final analysis. Sample sizes ranged from 6 to 206 participants. In patients with spondyloarthritis, a large majority of studies reported an increase in intestinal permeability regardless of the method used. No increase in intestinal permeability was found in RA patients compared to healthy subject in half of the studies. NSAID treatment does not appear to influence intestinal permeability in SpA and seems to increase the intestinal permeability in RA patients as much as in healthy subjects. Conclusion The results of our review suggest the existence of increased intestinal permeability in SpA patients even in the absence of NSAIDs use and regardless of the method assessing the intestinal permeability. Studies in RA patients are more controversial.

Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases., PMOs (phosphorodiamidate morpholino oligomers) have huge potential for antisense therapy but complex and slow synthesis limits application. Here, the authors report the development of automated flow synthesis methods which reduce nucleobase coupling times from hours to minutes removing human errors and allow for high-throughput production.

Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with increased risk of developmental and mental disorders but detailed information on the psychiatric phenotype in hyperprolinemic patients is limited. Following PRISMA guidelines, we carried out a systematic review to clarify psychiatric phenotypes in patients with hyperprolinemia. We screened 1753 studies and included 35 for analysis, including 20 case reports and 15 case–control and cohort studies. From these studies, a common psychiatric phenotype is observed with a high prevalence of developmental delay, intellectual disability, autism spectrum disorders, and psychosis spectrum disorders. In most cases, a genetic cause of hyperprolinemia was known, these included mutations in the PRODH and ALDH4A1 genes and deletions of chromosome 22q11.2. No evidence for a biochemical phenotype-clinical phenotype correlation was found; that is, no association between higher proline levels and specific psychiatric phenotypes was observed. This suggests that genomic and environmental factors are likely to contribute to clinical outcomes. More studies are needed to clarify whether hyperprolinemia is a primary causal factor underlying the increased risk of developing psychiatric disorders seen in patients with hyperprolinemia, or whether hyperprolinemia and psychiatric disorders are both consequences of a shared underlying mechanism.

Introduction: Management of inflammatory rheumatic diseases has evolved based on improved treatment strategies and better management of comorbidities, specifically cardiovascular risk. Methotrexate is one of the first-line treatments in the management of inflammatory rheumatic diseases, but its cardiovascular effects are poorly understood. The purpose of this review is to assess the cardiovascular impact of methotrexate in inflammatory rheumatic disease.Areas covered: Current knowledge about the mechanism of action of methotrexate on cardiovascular tissue is presented. A review of the literature in the Medline, Cochrane and Embase databases was performed. Current data about the cardiovascular effects of methotrexate in rheumatoid arthritis, psoriatic arthritis, and psoriasis are presented.Expert opinion: Mechanism of action of methotrexate is based on the antagonism of purines. It reduces systemic inflammation and oxidative stress and improves the major cardiovascular risk factors. Methotrexate improves cardiovascular risk in rheumatoid arthritis, psoriasis and psoriatic arthritis, but the mechanisms involved are partially identified. Data are controversial regarding its effects on endothelial function and atherosclerosis. Conversely, in the general population and in patients with HIV infection, methotrexate does not modify cardiovascular outcomes. Thus, methotrexate only improves cardiovascular risk by reducing systemic inflammation, and should not be used to prevent cardiovascular events.

Contains fulltext : 234372.pdf (Publisher’s version ) (Open Access) We examined the response to a phonics through spelling intervention in 52 children with dyslexia by analyzing their phonological, morphological, and orthographical spelling errors both before and after the intervention whereas their spelling errors before the intervention were compared with those of 105 typically developing spellers. A possible compensatory role of semantics on the intervention effects was also investigated. Results showed that before the intervention, children with dyslexia and the typically developing children both made most morphological errors, followed by orthographic and phonological errors. Within each category, children with dyslexia made more errors than the typically developing children, with differences being largest for phonological errors. Children with dyslexia with better developed semantic representations turned out to make less phonological, morphological, and orthographic errors compared with children with dyslexia with less developed semantic representations. The intervention for children with dyslexia led to a reduction of all error types, mostly of the orthographic errors. In addition, semantics was related to the decline in phonological, morphological, and orthographic spelling errors. This study implicates that semantic stimulation could benefit the spelling development of children at risk for or with dyslexia. 20 p.

OBJECTIVES The aim of this study was to evaluate the effects of the coronavirus 2019 pandemic on elective and acute thoracic aortic surgery in the Netherlands. METHODS The Netherlands Heart Registration database was used to compare the volume of elective and acute surgery on the thoracic aorta in 2019 and 2020, starting from week 11 in both years. A sub-analysis was done to assess the impact of the pandemic on high-volume and low-volume aortic centres. RESULTS During the pandemic, the number of elective thoracic aortic operations declined by 18% [incidence rate ratio (IRR) 0.82 [0.73–0.91]; P < 0.01]. The decline in volume of elective surgery was significant in both high-volume (IRR 0.82 [0.71–0.94]; P < 0.01) and low-volume aortic centres (IRR 0.81 [0.68–0.98]; P = 0.03). The overall number of acute aortic operations during the pandemic remained similar to that in 2019 (505 vs 499; P = 0.85), but an increased share of these operations occurred at high-volume centres. The number of acute operations performed in high-volume centres increased by 20% (IRR 1.20 [1.01–1.42]; P = 0.04), while the number of acute operations performed in low-volume centres decreased by 17% (IRR 0.83 [0.69–1.00]; P = 0.04). CONCLUSIONS The coronavirus 2019 pandemic led to a significant decrease in elective thoracic aortic surgery but did not cause a change in the volume of acute thoracic aortic surgery in the Netherlands. Moreover, the pandemic led to a centralization of care for acute thoracic aortic surgery., The coronavirus disease 19 (COVID-19) pandemic has impacted the delivery of health care around the world.

Giving an overview of the current implementation and limitations of point-of-care ultrasound (POCUS) in Belgian Emergency Departments (EDs).A survey, consisting of questions regarding demographics, practice patterns, policies, difficulties of implementing ultrasound (US) and training of emergency physicians was sent out to all Belgian EDs (n = 109).Seventy-two percent of all the EDs responded. Eighty percent of these had an US device, 10% intended to have one in the near future whilst the remaining 10% had no intention of obtaining one. The main reasons for not having US were insufficient training (50%), no budget to purchase a device (31%), resistance from other specialties (31%), no return from investment (25%) and uncertainty about liability (19%).Eighty-four percent of the responding hospitals had a prehospital MUG (Mobiele Urgentiegroep) - team or SMUR (Service Mobile d'Urgence et de Réanimation). In 29% of these, prehospital US (PHUS) was used, 18% were in the process of purchasing a device whilst 53% had no intention of implementing PHUS. The main reasons for not implementing PHUS were short transfer times (38%), insufficient training (33%), the cost of a device (25%), no return from investment (19%), the assumption that PHUS delays administering urgent care (19%) and the uncertainty about liability (8%). Nationwide, 40% of all emergency physicians have had some form of US training.POCUS is regularly used in Belgian EDs for diagnostic and management purposes. Further implementation of POCUS will depend on how barriers are being addressed in the near future.

Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.

A case of ureteric metastasis of pancreatic carcinoma is discussed. Metastatic disease of the ureter is very rare and only 9 other cases of pancreatic carcinoma metastasizing to the ureter have been published. A lack of continuous longitudinal blood and lymphatic vasculature is a possible explanation for the low incidence. Diagnosis of ureteric metastasis can be difficult and a combination of radiographic imaging and histologic evaluation is often required. Treatment of ureteric metastasis depends on the primary tumor. Metastasectomy can be considered in a select number of patients. When urinary obstruction is caused by the ureteric mass, urine drainage can be considered.

Background Endovascular aortic aneurysm repair (EVAR) has become the treatment of choice for most patients with abdominal aortic aneurysm (AAA). Open aneurysm repair (OAR) is still being used in a number of patients for specific reasons. The aim of the present study was to investigate the reasons and perioperative outcomes of OAR in a high-volume endovascular center. Methods All patients who underwent OAR in a single center institution during the period April 2010 to July 2019 were retrospectively analyzed. Results During the study period, 222 patients underwent OAR. One hundred and forty-one (63.5%) patients underwent elective surgery, and eighty-one (36.5%) patients were treated acutely. The reasons for the decision to perform OAR instead of EVAR were as follows: anatomical in 89 (40.1%) cases, rupture in unstable patient in 57 (25.7%) cases, AAA with concomitant iliac arterial occlusive disease in 44 (19.8%) cases, previous EVAR with complications in 14 (6.3%) cases, large pararenal aneurysm considered risky to wait for a customized fenestrated stent graft in 7 (3.2%) cases, young patient age in 4 (1.8%) cases, the patient's preference in 3 (1.4%) cases, infected/mycotic AAA in 2 (0.9%) cases, and simultaneous OAR with colon cancer resection (n = 1, 0.5%) and renal transplantation (n = 1, n = 0.5). Thirty-day mortality in elective cases was 5% (7/141) and in acute cases 34.6% (28/81). Conclusions This study shows that OAR is still used for selected patients despite improvements in EVAR technology. The most common reason for OAR was an unsuitable anatomy for EVAR. Perioperative mortality of OAR both for acute and elective cases as observed in this study is in line with published outcomes of other centers.

Background and objective: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. Design: We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. Results: The cohort included 76 patients with a median retrospective follow-up period of 15 years (min -max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. Conclusion: Protein intake in excess of recommendations is frequent and is associated with poor outcome. 0 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

First reported in 1976, hepatic angiomyolipoma (HAML) is a rare mesenchymal liver tumor occurring mostly in middle-aged women. Diagnosis of the liver mass is often incidental on abdominal imaging due to the frequent absence of specific symptoms. Nearly 10% of HAMLs are associated with tuberous sclerosis complex. HAML contains variable proportions of blood vessels, smooth muscle cells and adipose tissue, which renders radiological diagnosis hazardous. Cells express positivity for HMB-45 and actin, thus these tumors are integrated into the group of perivascular epithelioid cell tumors. Typically, a HAML appears on magnetic resonance imaging (or computed tomography scan) as a hypervascular solid tumor with fatty areas and with washout, and can easily be misdiagnosed as other liver tumors, particularly hepatocellular carcinoma. The therapeutic strategy is not clearly defined, but surgical resection is indicated for symptomatic patients, for tumors showing an aggressive pattern (i.e., changes in size on imaging or high proliferation activity and atypical epithelioid pattern on liver biopsy), for large (> 5 cm) biopsy-proven HAML, and if doubts remain on imaging or histology. Conservative management may be justified in other conditions, since most cases follow a benign clinical course. In summary, the correct diagnosis of HAML is challenging on imaging and relies mainly on pathological findings.

The positive effects of physical activity in both rheumatoid arthritis and ankylosing spondylitis have been proven, but no clear data is yet published regarding psoriatic arthritis (PsA). The aims of this study were (i) to assess the level of physical activity (PA) in these patients and (ii) to review the effects of PA on articular disease, extra articular symptoms, and overall well-being.The research strategy was performed on Pubmed, Cochrane, PEDro databases using the following keywords: "psoriatic arthritis AND physical activity" without restriction. The PRISMA methodology was used to select and analyze articles. We searched for all studies published online and in English before January 2021.A total of 319 studies were retrieved by our search but only 13 could be included. Two reports showed that 17 and 68% of patients reported practicing regularly physical activity. Exercise improved the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), the general symptoms (pain and fatigue), and the quality of life. Muscle strength and some of cardiovascular comorbidities were also improved. While the studies concerning the risk of enthesitis or flare induced by physical activity are conflicting, recent clinical trials did not mention any adverse event. Finally, rehabilitation programs were associated with a reduction mainly of pain and fatigue.Studies show clear beneficial effects of exercise in PsA on disease activity, on well-being, and on comorbidities, and they seem to outweigh the risk of enthesitis induced by mechanical stress. Further investigations are necessary to confirm these results and to precise the modalities of exercise. Key Points • Psoriatic arthritis patients have a sedentary lifestyle • Physical activity has beneficial effects on disease activity, well-being and reduced some cardiovascular risk factor in psoriatic arthritis • Risk of enthesitis and flares is low with exercise in psoriatic arthritis.

Background: The majority of patients with uncontrolled severe CRSwNP, asthma and atopic dermatitis share a similar T helper 2 type inflammation linked to their underlying phenotype. This discovery has triggered new research around treatments targeting specific cytokines driving inflammation in CRSwNP like IL-4, IL-13, IL-5 and IgE. Biologicals are increasingly tested as additional tre- atment for patients suffering from severe chronic rhinosinusitis with nasal polyps (CRSwNP). Their efficacy has been demonstrated in multiple studies. All studies differ in terms of baseline characteristics of included patients and outcome parameters analysed. Aims: A comparative analysis of the efficacy of reported biologicals for CRSwNP based on the published data for phase 2 and 3 studies. The aim was to provide a comprehensive overview across the different biologicals and outcome parameters. Methods: In a first step we critically selected out of all available phase 2 and 3 clinical trials the ones containing the most rigorous and compatible study designs. Meaning studies that comply with a need for a clear definition of CRSwNP, at least two administra- tion doses, comparable timeframes and the same outcome parameters studied. This assessment was performed using a PRISMA search. We retained 7 studies with significant data for dupilumab, mepolizumab and omalizumab. In a second step the effect-sizes of treatment with those biologicals were compared for the most important outcome parameters both patient relevant (nasal con- gestion, smell loss and SNOT-22 scores) and patient irrelevant (CT scan Lund-Mackay, smell test and nasal polyp scores). Therapy duration of 16 to 25 weeks was chosen for evaluation of efficacy. Results: A direct comparison of efficacy between dupilumab, mepolizumab and omalizumab is challenging given differences in inclusion criteria, outcome parameters and time-points of analyses. We have been able to conclude that effect sizes of dupilumab, mepolizumab and omalizumab seem large enough to reflect a major reduction in symptom burden as experienced by patients suffering from refractory CRSwNP. The effect size of dupilumab on both patient relevant and patient irrelevant parameters of smell loss are clearly significant and reflect the clinical experience of major reduction of smell impairment in treated patients. Conclusion: Despite the heterogeneity of protocols, dosages and time-points of analyses of biological trials in CRSwNP, this over- view highlights outcomes of biological treatment in CRSwNP in a comprehensive way. Real-life registries, comparative trials and/ or endotype-driven treatment plans are needed to provide the answers to the multiple questions that are still open today.

In early 2020, the book "Breast cancer: Global Quality Care" was published by Oxford University Press. In the year since then, publications, interviews (by ecancer), presentations, webinars, and virtual congress have been organized to disseminate further the main message of the project: "A call for Fairer Breast Cancer Care for all Women in a Globalized World." Special attention is paid to increasing the "value-based healthcare" putting the patient in the center of the care pathway and sharing information on high-quality integrated breast cancer care. Specific recommendations are made considering the local resource facilities. The multidisciplinary breast conference is considered "the jewel in the crown" of the integrated practice unit, connecting multiple specializations and functions concerned with patients with breast cancer. Management and coordination of medical expertise, facilities, and their interfaces are highly recommended. The participation of two world-leading cancer research programs, the CONCORD program and Breast Health Global Initiative, in this project has been particularly important. The project is continuously under review with feedback from the faculty. The future plan is to arrive at an openaccess publication that is freely available to all interested people. This project is designed to help ease the burden and suffering of women with breast cancer across the globe.

Purpose To investigate feasibility and outcomes of endovascular repair for acute thoracoabdominal aortic aneurysms (TAAA). Materials and Methods Data from a single center were retrospectively analyzed. Patients who underwent endovascular repair for acute TAAA between January 2010 and April 2020 were included. Perioperative and mid-term follow-up outcomes were analyzed. Survival, freedom from reintervention, and target vessel patency were calculated by Kaplan–Meier analysis. Results A total of 30 patients (18 men, 67.5 ± 6.9 years) underwent endovascular repair for acute symptomatic (n = 15) or contained ruptured (n = 15) TAAA. An off-the-shelf four-branched stent-graft (T-Branch) was used in 19 (63.3%) patients, a custom-made device (CMD) with expedite order in 5 (16.7%) patients, a CMD with short anticipated delivery time in 3 (10.0%) patients, and a CMD available in the hospital in 3 (10.0%) patients. Technical success was 90.0% (n = 27). Thirty-day mortality was 10% (n = 3). There was no complete persistent paraplegia, but one (3.3%) patient suffered permanent limb weakness. Estimated survival at 1 and 2 years was 86.3% ± 6.4%, and 82.3% ± 7.2%, respectively. Estimated freedom from reintervention at 1 and 2 years was 81.4% ± 7.6% and 73% ± 8.8%. Estimated target vessel patency at 1 and 2 years was 96.6% ± 2% and 92.6% ± 2.9%. Conclusion Endovascular treatment of acute TAAA in this selected group of patients was associated with low early mortality and excellent mid-term survival. The off-the-shelf stent-graft option (T-Branch) was used in the majority of patients. Endovascular repair should be considered the first option for suitable acute TAAA.

PurposeTo investigate the dosimetric impact of breathing motion on robustly optimized proton therapy treatment plans for left-sided breast cancer patients with an indication for locoregional irradiation.Materials and methodsClinical Target Volumes (CTVs) (left-sided breast, level 1 to 4 axillary lymph nodes, interpectoral and internal mammary lymph node regions) and organs at risk were delineated on 4 D-CTs of ten female patients. After treatment planning to a prescribed dose of 40.05 Gy(RBE) in 15 fractions on the time-averaged CT, the dose was calculated on all ten phases of the breathing cycle. Robustness to setup (5 mm) and range errors (3%) was evaluated for those ten phases. Correlations were evaluated between the phases of the breathing cycle and the D98% of the CTV and the D-mean of the heart.ResultsCorrelations coefficients were between -0.12 and 0.29. At the most extreme values of the 28 robustness scenarios, the clinical goals were met for all but two patients. The mean heart dose was 0.41 Gy(RBE) with a standard deviation of 0.31 Gy(RBE) of proton therapy plans.ConclusionThe effect of breathing motion on the robustness of proton therapy treatment plans for this patient group is minor and not of clinical significance. Based on this patient group, a deep-inspiration breath hold seems to be unnecessary to improve robustness for these patients.

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

This retrospective study examines the outcomes of sclerotherapy in children with (veno)lymphatic malformations who received sclerotherapy between 2011 and 2016 (116 children, 234 procedures). Complication severity was classified using the Society of Interventional Radiology classification. Clinical response was rated on a scale of 0 (no change) to 3 (good improvement). The sclerosants used were bleomycin (n = 132; 56%), lauromacrogol (n = 42; 18%), doxycycline (n = 15; 6%), ethanol (n = 12; 5%), or a combination (n = 33; 14%). Four major and 25 minor complications occurred without significant differences between the agents. The median response rate per procedure was 2—some improvement—for all sclerosants. However, in pure LMs (67%), bleomycin and a combination of agents resulted in the best clinical response. On patient level, all had some or good clinical response. Mixed macrocystic and microcystic lesions showed a significantly lower clinical response (median 2 versus 3; p = 0.023 and p = 0.036, respectively) and required significantly more procedures (median 2 versus 1; p = 0.043 and p = 0.044, respectively) compared with lesions with one component.Conclusion: Sclerotherapy for (V)LMs in children is safe and effective. Bleomycin is the most frequently used agent in this clinic and seemed most effective for pure LMs. Mixed macrocystic and microcystic lesions are most difficult to treat effectively. What is Known:• A variety of agents can be used for sclerotherapy of lymphatic malformations in children.• Macrocystic lesions have favorable outcomes compared with microcystic and mixed lesions. What is New:• Bleomycin and a combination of agents seem to be most effective to treat lymphatic malformations in children.• Mixed macrocystic and microcystic lesions are more difficult to treat effectively compared with lesions with either one of these components.

The goals of this study were to examine whether machine-learning algorithms outperform multivariable logistic regression in the prediction of insufficient response to methotrexate (MTX), secondly, to examine which features are essential for correct prediction, and finally, to investigate whether the best performing model specifically identifies insufficient responders to MTX (combination) therapy. The prediction of insufficient response (3-month Disease Activity Score 28-Erythrocyte-sedimentation rate (DAS28-ESR) &gt, 3.2) was assessed using logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting (XGBoost). The baseline features of 355 rheumatoid arthritis (RA) patients from the &ldquo, treatment in the Rotterdam Early Arthritis CoHort&rdquo, (tREACH) and the U-Act-Early trial were combined for analyses. The model performances were compared using area under the curve (AUC) of receiver operating characteristic (ROC) curves, 95% confidence intervals (95% CI), and sensitivity and specificity. Finally, the best performing model following feature selection was tested on 101 RA patients starting tocilizumab (TCZ)-monotherapy. Logistic regression (AUC = 0.77 95% CI: 0.68&ndash, 0.86) performed as well as LASSO (AUC = 0.76, 95% CI: 0.67&ndash, 0.85), random forest (AUC = 0.71, 95% CI: 0.61 = 0.81), and XGBoost (AUC = 0.70, 95% CI: 0.61&ndash, 0.81), yet logistic regression reached the highest sensitivity (81%). The most important features were baseline DAS28 (components). For all algorithms, models with six features performed similarly to those with 16. When applied to the TCZ-monotherapy group, logistic regression&rsquo, s sensitivity significantly dropped from 83% to 69% (p = 0.03). In the current dataset, logistic regression performed equally well compared to machine-learning algorithms in the prediction of insufficient response to MTX. Models could be reduced to six features, which are more conducive for clinical implementation. Interestingly, the prediction model was specific to MTX (combination) therapy response.

Contains fulltext : 238665.pdf (Publisher’s version ) (Open Access) PURPOSE: To evaluate imaging, treatment, and outcomes in neonates with a lymphatic malformation (LM) adjacent to the airway and to evaluate risk factors that can predict outcome. METHODS: A retrospective case series was conducted of ten patients treated between January 2011 and July 2019. The main outcome measures included airway compromise and clinical response to sclerotherapy +/- surgery. Categorical data were compared using the Fisher's exact test. RESULTS: Ex-utero intrapartum therapy was performed in four cases, among whom one died due to sepsis. All patients underwent schlerotherapy, with surgical debulking in two. Four patients showed a good clinical response, and five started experimental systemic treatment. Patients with bilateral disease and patients with an LM with >180 degrees tracheal surrounding were significantly at risk for airway compromise (bilateral: n = 6/6 versus n = 0/4, p = 0.005; >180 degrees : n = 5/5 versus n = 1/5, p = 0.048). The need for LM treatment in the neonatal period was indicative of a poor clinical response ('non-responders' 5/6, 'responders' 0/4; p = 0.048). CONCLUSIONS: This study indicates that bilateral disease and >180 degrees tracheal surrounding are risk factors for airway compromise in neonates with an LM adjacent to the airway. In addition, the need for early treatment seems to be indicative of a poor clinical response.

BackgroundVaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients’ risk of recurrence based on molecular tumor characteristics.Primary objectivesTo compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapyStudy hypothesisAdjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs.Trial designA multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm).Major inclusion/exclusion criteriaWomen aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1).EndpointsThe primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs.Sample size500 eligible and evaluable patients.Estimated dates for completing accrual and presenting resultsEstimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023.Trial registrationThe trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

Inborn errors of metabolism (IEMs) comprise a diverse group of individually rare monogenic disorders that affect metabolic pathways. Mutations lead to enzymatic deficiency or dysfunction, which results in intermediate metabolite accumulation or deficit leading to disease phenotypes. Currently, treatment options for many IEMs are insufficient. Rarity of individual IEMs hampers therapy development and phenotypic and genetic heterogeneity suggest beneficial effects of personalized approaches. Recently, cultures of patient-own liver-derived intrahepatic cholangiocyte organoids (ICOs) have been established. Since most metabolic genes are expressed in the liver, patient-derived ICOs represent exciting possibilities for in vitro modelling and personalized drug testing for IEMs. However, the exact application range of ICOs remains unclear. To address this, we examined which metabolic pathways can be studied with ICOs and what the potential and limitations of patient-derived ICOs are to model metabolic functions. We present functional assays in patient ICOs with defects in branched-chain amino acid metabolism (methylmalonic acidemia), copper metabolism (Wilson disease) and transporter defects (cystic fibrosis). We discuss the broad range of functional assays that can be applied to ICOs, but also address the limitations of these patient-specific cell models. In doing so, we aim to guide the selection of the appropriate cell model for studies of a specific disease or metabolic process. This article is protected by copyright. All rights reserved.

Background The development of biological treatments has transformed the management of a broad spectrum of autoimmune/inflammatory diseases. However, little is known about their use in solid-organ transplant recipients. This study aimed to evaluate complications occurring with biologic treatments in solid-organ transplant recipients. Methods A systematic review of the literature was performed in the Medline, Embase and Cochrane databases, up to 01/10/2020, to identify published case reports or series reporting the use of biologic treatments in solid organ transplant recipients with chronic inflammatory diseases. We collected data on patient characteristics and reported complications. Results In total, 57 articles were included, totalling 187 patients (141 liver, 42 kidney, 3 heart, and 1 liver-kidney transplant recipients). Inflammatory bowel diseases represented the most common indication for biologic treatment initiation (80.7%), followed by rheumatic diseases (7.5%), hereditary periodic fever syndromes (5.9%) and psoriasis (4.8%). Anti-TNFα were mainly used (77.5%; mainly monoclonal antibodies (70%) compared to soluble receptor etanercept (7.5%)), followed by the anti-α4β7 integrin, vedolizumab (27.3%) and the anti-IL-1R, anakinra (6.9%). Median treatment duration was 12 months. Infections occurred in 54 patients (28.9%) through 88 recorded events. No therapeutic or demographic factors were associated with occurrence of infection. Sixteen patients (8.6%) developed malignancies, and acute graft rejections occurred in 5 patients (2.7%). Among the 187 patients, 9 deaths were reported (4.8%). Conclusions This review assembles the largest number of published reports regarding the use of biological treatments in solid organ transplant recipients, providing data about their safety. Further comparative studies are needed to assess the safety of biological treatments in transplanted patients.

Background Deep grey matter (DGM) atrophy in multiple sclerosis (MS) and its relation to cognitive and clinical decline requires accurate measurements. MS pathology may deteriorate the performance of automated segmentation methods. Accuracy of DGM segmentation methods is compared between MS and controls, and the relation of performance with lesions and atrophy is studied. Methods On images of 21 MS subjects and 11 controls, three raters manually outlined caudate nucleus, putamen and thalamus; outlines were combined by majority voting. FSL-FIRST, FreeSurfer, Geodesic Information Flow and volBrain were evaluated. Performance was evaluated volumetrically (intra-class correlation coefficient (ICC)) and spatially (Dice similarity coefficient (DSC)). Spearman's correlations of DSC with global and local lesion volume, structure of interest volume (ROIV), and normalized brain volume (NBV) were assessed. Results ICC with manual volumes was mostly good and spatial agreement was high. MS exhibited significantly lower DSC than controls for thalamus and putamen. For some combinations of structure and method, DSC correlated negatively with lesion volume or positively with NBV or ROIV. Lesion-filling did not substantially change segmentations. Conclusions Automated methods have impaired performance in patients. Performance generally deteriorated with higher lesion volume and lower NBV and ROIV, suggesting that these may contribute to the impaired performance.

Background: Data from recently published trials have provided practice-changing recommendations for the surgical approach to the axilla in breast cancer. Patients with T1-2 lesions, treated with breast conservation, who have not received neoadjuvant chemotherapy and have 1-2 positive sentinel nodes (Z0011-criteria) may avoid axillary lymph node dissection (ALND). We aim to describe the dissemination of this practice in Europe over an extended period of time. Methods: Our source of data was the eusomaDB, a central data warehouse of prospectively collected information of the European Society of Breast Cancer Specialists (EUSOMA). We identified cases fulfilling Z0011-criteria from 2005 to 2016 from 34 European breast centers and report trends in ALND. Data derived from Germany, Italy, Belgium, Switzerland, Austria, and Netherlands. Results: 6671 patients fulfilled Z0011-criteria. Rates of ALND showed a statistically significant decrease from 2010 (89%) to 2011 (73%), reaching 46% in 2016 (p < 0.001). After multivariable analysis, factors associated with higher probability of ALND were earlier year of surgery, younger age, increasing tumor size and grade, and being operated in Italy (p < 0.001). The minimum and maximal rates of ALND in the most recent two-year period (2015-2016) were 0% and 83% in two centers located in different countries (p < 0.001). Conclusion: Our study demonstrates, a decrease in rates of ALND that started after year 2010 through the end of the study period. Wide differences were observed among centers and countries indicating the need to spread unified clinical guidelines in Europe to allow for homogeneous evidence-based practice patterns. (C) 2019 Elsevier Ltd. All rights reserved.

BACKGROUND:The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.METHODS:In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.FINDINGS:Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.INTERPRETATION:This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.FUNDING:Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Contains fulltext : 229345.pdf (Publisher’s version ) (Closed access) PURPOSE: To evaluate treatment outcomes of embolization for peripheral arteriovenous malformations (AVMs) in a tertiary referral center where ethanol is the primary agent of choice. METHODS: A retrospective study was performed of 93 patients (median age, 31 years; range, 2-66 years) with peripheral AVMs treated with embolization (n = 442; median, 2 per patient; range, 1-82) between January 2010 and July 2016. Ethanol was used in most cases (n = 428; 97%). AVMs were classified as type I (n = 3), type II (n = 57), type IIIa (n = 5), type IIIb (n = 15), and type IV (n = 13) according to the Yakes classification system. Effectiveness of embolization was based on AVM devascularization on angiography: 100% (total), 90%-99% (near-total), 70%-90% (substantial), 30%-70% (partial), and 0%-30% (failure). Complications were graded according to the Society of Interventional Radiology classification. RESULTS: In 69% of patients, 70%-100% devascularization was achieved. Total and near-total occlusion of the nidus were more often achieved in AVMs of types I and IIIa (both 100%) than in AVMs of types II, IIIb, and IV (56%, 67%, and 39%, respectively; P = .019). A total of 109 complications were identified: 101 minor (22.9%) and 8 major (1.8%). Major complications included wounds (n = 5), false aneurysm (n = 1), finger contracture (n = 1), and severe pain (n = 1) requiring therapy. The patient complication risk was significantly affected by the number of procedures (relative risk = 2.0; P < .001). Age, AVM location, and angioarchitecture type did not significantly affect complication risk. CONCLUSIONS: AVM embolization resulted in 70%-100% devascularization in 69% of patients, with few major complications. This study indicates that the type of AVM angioarchitecture affects the number of procedures needed and the achievability of AVM devascularization.

Introduction Psoriatic arthritis (PsA) is a chronic inflammatory rheumatism characterized for a long time by a high degree of cardiovascular risk. Chronic inflammation is one of the mechanisms that explain this cardiovascular excess of risk through direct and indirect pathways. In recent years, epidemiological data have changed somewhat since the increasing use of bio-drugs that are effective in reducing this inflammation. The purpose of this review is to assess the current state of cardiovascular morbidity and mortality in PsA and thus to assess the cardiovascular risk in case of PsA. Method We conducted a literature review using Pubmed and Medline databases with the following keywords “Psoriatic Arthritis” AND “cardiovascular” including articles from the last three years. Results It appears that in case of PsA, there is an increased prevalence of high blood pressure, diabetes, obesity and dyslipidemia, and therefore of metabolic syndrome. Insulin resistance is closely linked to PsA. On the other hand, the data are more contrasted for active smoking. There is also arterial inflammation specific to PsA. Finally, at the therapeutic level, the impact of NSAIDs remains controversial, while methotrexate and bio-drugs are beneficial at the cardiovascular level. Conclusion PsA is characterized by an increase in cardiovascular morbidity in relation with insulin resistance. Current treatments seem to improve this risk with a decrease in cardiovascular mortality in comparison with patients with plaque psoriasis but this requires confirmation in larger prospective studies.

The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27-51 years), while the majority was infant or adolescent (range: 0-20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.