Non-invasive stereotactic arrhythmia radiotherapy for ventricular tachycardia: results of the prospective STARNL-1 trial.

AIMS: Stereotactic arrhythmia radiotherapy (STAR) is suggested as potentially effective and safe treatment for patients with therapy-refractory ventricular tachycardia (VT). However, the current prospective knowledge base and experience with STAR is limited. In this study we aimed to prospectively evaluate the efficacy and safety of STAR. METHODS AND RESULTS: The StereoTactic Arrhythmia Radiotherapy in the Netherlands no.1 was a pre-post intervention study to prospectively evaluate efficacy and safety of STAR. In patients with therapy-refractory VT, the pro-arrhythmic region was treated with a 25 Gy single radiotherapy fraction. The main efficacy measure was a reduction in the number of treated VT-episodes by ≥50%, comparing the 12 months before and after treatment (or end of follow-up, excluding a 6-week blanking period). The study was deemed positive when ≥50% of patients would meet this criterion. Safety evaluation included left ventricular ejection fraction, pulmonary function, and adverse events. Six male patients with an ischaemic cardiomyopathy were enrolled, and median age was 73 years (range 54-83). Median left ventricular ejection fraction was 38% (range 24-52). The median planning target volume was 187 mL (range 93-372). Four (67%) patients completed the 12-month follow-up, and two patients died (not STAR related) during follow-up. The main efficacy measure of ≥50% reduction in treated VT-episodes at the end of follow-up was achieved in four patients (67%). The median number of treated VT-episodes was reduced by 87%. No reduction in left ventricular ejection fraction or pulmonary function was observed. No treatment related serious adverse events occurred. CONCLUSIONS: STAR resulted in a ≥ 50% reduction in treated VT-episodes in 4/6 (67%) patients. No reduction in cardiac and pulmonary function nor treatment-related serious adverse events were observed during follow-up. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register-NL7510.

Patient-reported factors influencing the choice of their kidney replacement treatment modality.

BACKGROUND: Access to various kidney replacement therapy (KRT) modalities for patients with end-stage kidney disease differs substantially within Europe. METHODS: European adults on KRT filled out an online or paper-based survey about factors influencing and experiences with modality choice (e.g. information provision, decision-making and reasons for choice) between November 2017 and January 2019. We compared countries with low, middle and high gross domestic product (GDP). RESULTS: In total, 7820 patients [mean age 59 years, 56% male, 63% on centre haemodialysis (CHD)] from 38 countries participated. Twenty-five percent had received no information on the different modalities, and only 23% received information >12 months before KRT initiation. Patients were not informed about home haemodialysis (HHD) (42%) and comprehensive conservative management (33%). Besides nephrologists, nurses more frequently provided information in high-GDP countries, whereas physicians other than nephrologists did so in low-GDP countries. Patients from low-GDP countries reported later information provision, less information about other modalities than CHD and lower satisfaction with information. The majority of modality decisions were made involving both patient and nephrologist. Patients reported subjective (e.g. quality of life and fears) and objective reasons (e.g. costs and availability of treatments) for modality choice. Patients had good experiences with all modalities, but experiences were better for HHD and kidney transplantation and in middle- and high-GDP countries. CONCLUSION: Our results suggest European differences in patient-reported factors influencing KRT modality choice, possibly caused by disparities in availability of KRT modalities, different healthcare systems and varying patient preferences. Availability of home dialysis and kidney transplantation should be optimized.

Work status and work ability of patients receiving kidney replacement therapy: results from a European survey.

BACKGROUND: Employment is important for the quality of life and financial security of patients of working age receiving kidney replacement therapy (KRT). We aimed to examine self-reported work status and general, physical and mental work ability and to determine associations between demographic, disease-related, work-related and macroeconomic factors and employment. . METHODS: Europeans from 37 countries, ages 19-65 years, treated with dialysis or kidney transplantation, filled out the web-based or paper-based cross-sectional EDITH kidney patient survey between November 2017 and January 2019. We performed descriptive analyses and multivariable generalized logistic mixed models. RESULTS: Of the 3544 patients, 36.5% were employed and working [25.8% of dialysis patients, 53.9% of kidney transplant recipients (KTRs)]. The mean general work ability was 5.5 out of 10 (dialysis: 4.8, KTRs: 6.5). Non-working patients (all: 4.1, dialysis: 3.9, KTRs: 4.7) scored lower than working patients (all: 7.7, dialysis 7.3, KTRs: 8.0). Working dialysis patients scored lower on physical and mental work ability (7.1 and 8.1) than working KTRs (8.0 and 8.4; P < 0.001). Impaired physical work ability (42.7%) was more prevalent than impaired mental work ability (26.7%). Male sex, age 40-49 years, higher education, home dialysis or kidney transplantation as current treatment, treatment history including kidney transplantation, absence of diabetes mellitus, better general work ability and higher country gross domestic product were positively associated with employment (P < 0.05). CONCLUSIONS: Low employment rates and impaired work ability were prevalent among European patients receiving KRT. Demographic, disease-related, work-related and macro-economic factors were associated with employment.

Low dose cone beam CT for paediatric image-guided radiotherapy: Image quality and practical recommendations.

PURPOSE: Cone beam CT (CBCT) is used in paediatric image-guided radiotherapy (IGRT) for patient setup and internal anatomy assessment. Adult CBCT protocols lead to excessive doses in children, increasing the risk of radiation-induced malignancies. Reducing imaging dose increases quantum noise, degrading image quality. Patient CBCTs also include 'anatomical noise' (e.g. motion artefacts), further degrading quality. We determine noise contributions in paediatric CBCT, recommending practical imaging protocols and thresholds above which increasing dose yields no improvement in image quality. METHODS AND MATERIALS: Sixty CBCTs including the thorax or abdomen/pelvis from 7 paediatric patients (aged 6-13 years) were acquired at a range of doses and used to simulate lower dose scans, totalling 192 scans (0.5-12.8 mGy). Noise measured in corresponding regions of each patient and a 10-year-old phantom were compared, modelling total (including anatomical) noise, and quantum noise contributions as a function of dose. Contrast-to-noise ratio (CNR) was measured between fat/muscle. Soft tissue registration was performed on the kidneys, comparing accuracy to the highest dose scans. RESULTS: Quantum noise contributed <20% to total noise in all cases, suggesting anatomical noise is the largest determinant of image quality in the abdominal/pelvic region. CNR exceeded 3 in over 90% of cases ≥ 1 mGy, and 57% of cases at 0.5 mGy. Soft tissue registration was accurate for doses > 1 mGy. CONCLUSION: Anatomical noise dominates quantum noise in paediatric CBCT. Appropriate soft tissue contrast and registration accuracy can be achieved for doses as low as 1 mGy. Increasing dose above 1 mGy holds no benefit in improving image quality or registration accuracy due to the presence of anatomical noise.

Feasibility of Conebeam CT-based online adaptive radiotherapy for neoadjuvant treatment of rectal cancer.

BACKGROUND: Online adaptive radiotherapy has the potential to reduce toxicity for patients treated for rectal cancer because smaller planning target volumes (PTV) margins around the entire clinical target volume (CTV) are required. The aim of this study is to describe the first clinical experience of a Conebeam CT (CBCT)-based online adaptive workflow for rectal cancer, evaluating timing of different steps in the workflow, plan quality, target coverage and patient compliance. METHODS: Twelve consecutive patients eligible for 5 × 5 Gy pre-operative radiotherapy were treated on a ring-based linear accelerator with a multidisciplinary team present at the treatment machine for each fraction. The accelerator is operated using an integrated software platform for both treatment planning and delivery. In all directions for all CTVs a PTV margin of 5 mm was used, except for the cranial/caudal borders of the total CTV where a margin of 8 mm was applied. A reference plan was generated based on a single planning CT. After aligning the patient the online adaptive procedure started with acquisition of a CBCT. The planning CT scan was registered to the CBCT using deformable registration and a synthetic CT scan was generated. With the support of artificial intelligence, structure guided deformation and the synthetic CT scan contours were adapted by the system to match the anatomy on the CBCT. If necessary, these contours were adjusted before a new plan was generated. A second and third CBCT were acquired to validate the new plan with respect to CTV coverage just before and after treatment delivery, respectively. Treatment was delivered using volumetric modulated arc treatment (VMAT). All steps in this process were defined and timed. RESULTS: On average the timeslot needed at the treatment machine was 34 min. The process of acquiring a CBCT, evaluating and adjusting the contours, creating the new plan and verifying the CTV on the CBCT scan took on average 20 min. Including delivery and post treatment verification this was 26 min. Manual adjustments of the target volumes were necessary in 50% of fractions. Plan quality, target coverage and patient compliance were excellent. CONCLUSIONS: First clinical experience with CBCT-based online adaptive radiotherapy shows it is feasible for rectal cancer. Trial registration Medical Research Involving Human Subjects Act (WMO) does not apply to this study and was retrospectively approved by the Medical Ethics review Committee of the Academic Medical Center (W21_087 # 21.097; Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands).

Results of the European EDITH nephrologist survey on factors influencing treatment modality choice for end-stage kidney disease.

BACKGROUND: Access to forms of dialysis, kidney transplantation (Tx) and comprehensive conservative management (CCM) for patients with end-stage kidney disease (ESKD) varies across European countries. Attitudes of nephrologists, information provision and decision-making may influence this access and nephrologists may experience several barriers when providing treatments for ESKD. METHODS: We surveyed European nephrologists and kidney transplant surgeons treating adults with ESKD about factors influencing modality choice. Descriptive statistics were used to compare the opinions of professionals from European countries with low-, middle- and high-gross domestic product purchasing power parity (GDP PPP). RESULTS: In total, 681 professionals from 33 European countries participated. Respondents from all GDP categories indicated that ∼10% of patients received no information before the start of renal replacement therapy (RRT) (P = 0.106). Early information provision and more involvement of patients in decision-making were more frequently reported in middle- and high-GDP countries (P < 0.05). Professionals' attitudes towards several treatments became more positive with increasing GDP (P < 0.05). Uptake of in-centre haemodialysis was sufficient to 73% of respondents, but many wanted increased uptake of home dialysis, Tx and CCM. Respondents experienced different barriers according to availability of specific treatments in their centre. The occurrence of barriers (financial, staff shortage, lack of space/supplies and patient related) decreased with increasing GDP (P < 0.05). CONCLUSIONS: Differences in factors influencing modality choice when providing RRT or CCM to adults with ESKD were found among low-, middle- and high-GDP countries in Europe. Therefore a unique pan-European policy to improve access to treatments may be inefficient. Different policies for clusters of countries could be more useful.

Supplemented ERA-EDTA Registry data evaluated the frequency of dialysis, kidney transplantation, and comprehensive conservative management for patients with kidney failure in Europe.

The aims of this study were to determine the frequency of dialysis and kidney transplantation and to estimate the regularity of comprehensive conservative management (CCM) for patients with kidney failure in Europe. This study uses data from the ERA-EDTA Registry. Additionally, our study included supplemental data from Armenia, Germany, Hungary, Ireland, Kosovo, Luxembourg, Malta, Moldova, Montenegro, Slovenia and additional data from Israel, Italy, Slovakia using other information sources. Through an online survey, responding nephrologists estimated the frequency of CCM (i.e. planned holistic care instead of kidney replacement therapy) in 33 countries. In 2016, the overall incidence of replacement therapy for kidney failure was 132 per million population (pmp), varying from 29 (Ukraine) to 251 pmp (Greece). On 31 December 2016, the overall prevalence of kidney replacement therapy was 985 pmp, ranging from 188 (Ukraine) to 1906 pmp (Portugal). The prevalence of peritoneal dialysis (114 pmp) and home hemodialysis (28 pmp) was highest in Cyprus and Denmark respectively. The kidney transplantation rate was nearly zero in some countries and highest in Spain (64 pmp). In 28 countries with five or more responding nephrologists, the median percentage of candidates for kidney replacement therapy who were offered CCM in 2018 varied between none (Slovakia and Slovenia) and 20% (Finland) whereas the median prevalence of CCM varied between none (Slovenia) and 15% (Hungary). Thus, the substantial differences across Europe in the frequency of kidney replacement therapy and CCM indicate the need for improvement in access to various treatment options for patients with kidney failure.

Non-medical barriers reported by nephrologists when providing renal replacement therapy or comprehensive conservative management to end-stage kidney disease patients: a systematic review.

BACKGROUND: Large international differences exist in access to renal replacement therapy (RRT) modalities and comprehensive conservative management (CCM) for patients with end-stage kidney disease (ESKD), suggesting that some patients are not receiving the most appropriate treatment. Previous studies mainly focused on barriers reported by patients or medical barriers (e.g. comorbidities) reported by nephrologists. An overview of the non-medical barriers reported by nephrologists when providing the most appropriate form of RRT (other than conventional in-centre haemodialysis) or CCM is lacking. METHODS: We searched in EMBASE and PubMed for original articles with a cross-sectional design (surveys, interviews or focus groups) published between January 2010 and September 2018. We included studies in which nephrologists reported barriers when providing RRT or CCM to adult patients with ESKD. We used the barriers and facilitators survey by Peters et al. [Ruimte Voor Verandering? Knelpunten en Mogelijkheden Voor Verbeteringen in de Patiëntenzorg. Nijmegen: Afdeling Kwaliteit van zorg (WOK), 2003] as preliminary framework to create our own model and performed meta-ethnographic analysis of non-medical barriers in text, tables and figures. RESULTS: Of the 5973 articles screened, 16 articles were included using surveys (n = 10), interviews (n = 5) and focus groups (n = 1). We categorized the barriers into three levels: patient level (e.g. attitude, role perception, motivation, knowledge and socio-cultural background), level of the healthcare professional (e.g. fears and concerns, working style, communication skills) and level of the healthcare system (e.g. financial barriers, supportive staff and practice organization). CONCLUSIONS: Our systematic review has identified a number of modifiable, non-medical barriers that could be targeted by, for example, education and optimizing financing structure to improve access to RRT modalities and CCM.

Impact cratering in sand: comparing solid and liquid intruders.

How does the impact of a deformable droplet on a granular bed differ from that caused by a solid impactor of similar size and density? Here, we experimentally study this question and focus on the effect of intruder deformability on the crater shape. For comparable impact energies, we show that the crater diameter is larger for droplets than for solid intruders but that the impact of the latter results in deeper craters. Interestingly, for initially dense beds of packing fractions larger than 0.58, we find that the resultant excavated crater volume is independent of the intruder deformability, suggesting an impactor-independent dissipation mechanism within the sand for these dense beds.

Clinical aspects of a large group of adults with Angelman syndrome.

Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe the evolution of the clinical phenotypes of AS in adulthood, using clinical data from 95 individuals (mean age 31.6 years, median 29.0 years, range 18-83 years), with genetically confirmed AS. Data was collected through physical examination and inspection of medical records, combined with questionnaires and interviews. Adults with AS experience substantial debilitating health problems. Constipation, reflux, visual problems, scoliosis, behavioral and sleeping problems occurred frequently and require appropriate attention. Epilepsy was reported in 57% of adults, negatively affecting the level of functioning. Non-convulsive status epilepticus was not observed in the adults, however some individuals developed prolonged episodes of rhythmic shaking while awake. A decline in mobility was noted in the majority of adults. A minority of adults with AS showed microcephaly. Taken together, this first phenotypic study of adults with AS to include in person interviews with care-givers and physical examination of patients, including the eldest adult reported to date, provides important insight in the development of the syndrome into adulthood. This knowledge is required to improve care for adult individuals with AS and to evaluate future therapies for this group.

How to increase kidney transplant activity throughout Europe-an advocacy review by the European Kidney Health Alliance.

Kidney transplantation offers better outcomes and quality of life at lower societal costs compared with other options of renal replacement therapy. In this review of the European Kidney Health Alliance, the current status of kidney transplantation throughout Europe and suggestions for improvement of transplantation rates are reported. Although the European Union (EU) has made considerable efforts in the previous decade to stimulate transplantation activity, the discrepancies among European countries suggest that there is still room for improvement. The EU efforts have partially been neutralized by external factors such as economic crises or legal issues, especially the illicit manipulation of waiting lists. Hence, growth in the application of transplantation throughout Europe virtually remained unchanged over the last few years. Continued efforts are warranted to further stimulate transplantation rates, along with the current registration and data analysis efforts supported by the EU in the Effect of Differing Kidney Disease Treatment Modalities and Organ Donation and Transplantation Practices on Health Expenditure and Patient Outcomes project. Future actions should concentrate on organization, harmonization and improvement of the legal consent framework, population education and financial stimuli.

The Stability of Type D Personality in Dialysis Patients.

PURPOSE: Type D personality has been identified as an independent risk factor for survival in cardiovascular disease (CVD) patients. As CVD is present in about 50% of dialysis patients, it is of clinical interest to assess the prevalence of type D personality, the association with depressive and anxiety symptoms, and stability of type D personality in dialysis patients. METHODS: Data was used from two consecutive measurements of the DIVERS study, a prospective cohort study among chronic dialysis patients in the Netherlands. Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and the Type D Scale-14 (DS14) were used to assess depressive and anxiety symptoms and type D personality, respectively. The association of type D personality was assessed with analysis of variance F test. Stability of type D personality, depressive, and anxiety symptoms were determined by calculating Cohen's κ, and by determining the positive agreement. RESULTS: In total, 349 patients were included of which 249 patients had two measurement points. The prevalence of type D personality was 21% and type D personality was associated with depressive and anxiety symptoms (P < 0.01). Over a 6-month period, Cohen's κ was 0.52, 0.56, and 0.61 for type D personality, depressive, and anxiety symptoms, respectively. Sixty-one, 73, and 73% had a stable type-D personality, depressive, and anxiety symptoms, respectively. CONCLUSION: The presence of type D personality varies over time in dialysis patients. Therefore, type D personality is possibly more a state instead of a trait phenomenon.

Crater formation during raindrop impact on sand.

After a raindrop impacts on a granular bed, a crater is formed as both drop and target deform. After an initial, transient, phase in which the maximum crater depth is reached, the crater broadens outwards until a final steady shape is attained. By varying the impact velocity of the drop and the packing density of the bed, we find that avalanches of grains are important in the second phase and hence affect the final crater shape. In a previous paper, we introduced an estimate of the impact energy going solely into sand deformation and here we show that both the transient and final crater diameter collapse with this quantity for various packing densities. The aspect ratio of the transient crater is however altered by changes in the packing fraction.

Interfractional renal and diaphragmatic position variation during radiotherapy in children and adults: is there a difference?

BACKGROUND: Pediatric safety margins are generally based on data from adult studies; however, adult-based margins might be too large for children. The aim of this study was to quantify and compare interfractional organ position variation in children and adults. MATERIAL AND METHODS: For 35 children and 35 adults treated with thoracic/abdominal irradiation, 850 (range 5-30 per patient) retrospectively collected cone beam CT images were registered to the reference CT that was used for radiation treatment planning purposes. Renal position variation was assessed in three orthogonal directions and summarized as 3D vector lengths. Diaphragmatic position variation was assessed in the cranio-caudal (CC) direction only. We calculated means and SDs to estimate group systematic (Σ) and random errors (σ) of organ position variation. Finally, we investigated possible correlations between organ position variation and patients' height. RESULTS: Interfractional organ position variation was different in children and adults. Median 3D right and left kidney vector lengths were significantly smaller in children than in adults (2.8, 2.9 mm vs. 5.6, 5.2 mm, respectively; p < .05). Generally, the pediatric Σ and σ were significantly smaller than in adults (p < .007). Overall and within both subgroups, organ position variation and patients' height were only negligibly correlated. CONCLUSIONS: Interfractional renal and diaphragmatic position variation in children is smaller than in adults indicating that pediatric margins should be defined differently from adult margins. Underlying mechanisms and other components of geometrical uncertainties need further investigation to explain differences and to appropriately define pediatric safety margins.

Liquid-Grain Mixing Suppresses Droplet Spreading and Splashing during Impact.

Would a raindrop impacting on a coarse beach behave differently from that impacting on a desert of fine sand? We study this question by a series of model experiments, where the packing density of the granular target, the wettability of individual grains, the grain size, the impacting liquid, and the impact speed are varied. We find that by increasing the grain size and/or the wettability of individual grains the maximum droplet spreading undergoes a transition from a capillary regime towards a viscous regime, and splashing is suppressed. The liquid-grain mixing is discovered to be the underlying mechanism. An effective viscosity is defined accordingly to quantitatively explain the observations.

Plan selection strategy for rectum cancer patients: An interobserver study to assess clinical feasibility.

BACKGROUND AND PURPOSE: In radiotherapy for rectum cancer, the target volume is highly deformable. An adaptive plan selection strategy can mitigate the effect of these variations. The purpose of this study was to evaluate the feasibility of an adaptive strategy by assessing the interobserver variation in CBCT-based plan selection. MATERIAL AND METHODS: Eleven patients with rectum cancer, treated with a non-adaptive strategy, were selected. Five CBCT scans were available per patient. To simulate the plan selection strategy, per patient three PTVs were created by varying the anterior upper mesorectum margin. For each CBCT scan, twenty observers selected the smallest PTV that encompassed the target volume. After this initial baseline measurement, the gold standard was determined during a consensus meeting, followed by a second measurement one month later. Differences between both measurements were assessed using the Wilcoxon signed-rank test. RESULTS: In the baseline measurement, the concordance with the gold standard was 69% (range: 60-82%), which improved to 75% (range: 60-87%) in the second measurement (p=0.01). For the second measurement, 10% of plan selections were smaller than the gold standard. CONCLUSION: With a plan selection consistency between observers of 75%, a plan selection strategy for rectum cancer patients is feasible.

Potential dosimetric benefit of an adaptive plan selection strategy for short-course radiotherapy in rectal cancer patients.

PURPOSE: An adaptive plan selection strategy can account for daily target volume variations for radiotherapy in rectal cancer patients. The aim was to quantify the daily dosimetric consequences of plan selection compared to a non-adaptive approach. MATERIALS AND METHODS: Ten patients with rectal cancer, treated with 25Gy in five fractions to the mesorectum and pelvic lymph nodes, were selected. The adaptive strategy was simulated by creating three plans per patient, with varying upper ventral PTV margins, and selecting the smallest PTV covering the entire mesorectum on every daily CBCT scan. Subsequently, mesorectum, bladder, and bowel cavity were delineated on these scans. Daily dose-volume histograms were calculated for both the adaptive and non-adaptive plan, with a ventral PTV margin of 20mm. Coverage of the mesorectum, defined as V95%>99%, was calculated, as well as bladder and bowel cavity V95% and V15Gy. RESULTS: In one patient, mesorectum coverage improved. A reduction in bladder V95% and bowel cavity V15Gy was found, of 6.9% and 18.4cm(3) (p<0.01), respectively. CONCLUSION: Plan selection for radiotherapy in rectal cancer can improve coverage of the target volume. Overall dosimetric sparing of bladder and bowel cavity was limited but could be beneficial for individual patients.