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Abstract Introduction Allogeneic serum from blood donors is starting to be used to treat patients with dry eye disease (DED). However, the optimal dose is not known. We therefore aimed to evaluate the clinical efficaciousness and user-friendliness of micro-sized versus conventional-sized allogeneic serum eye drops (SEDs). Methods In a randomized trial, patients with DED first receive micro-sized SEDs (7 µl/unit) for 1 month, followed by a 1-month washout, before receiving conventional-sized SEDs (50 µl/unit) for 1 month; or vice versa. The primary endpoint was the Ocular Surface Disease Index (OSDI) score. Secondary endpoints were tear break-up time (TBT), tear production (TP), and presence of corneal punctate lesions (CP). The user-friendliness of both application systems was also compared. A linear mixed model for cross-over design was applied to compare both treatments. Results Forty-nine patients completed the trial. The mean OSDI score significantly improved from 52 ± 3 to 41 ± 3 for micro-sized SEDs, and from 54 ± 3 to 45 ± 3 for conventional-sized SEDs. Non-inferiority (margin = 6) of micro-sized SEDs was established. We demonstrate a significant improvement for TBT in case of conventional-sized SEDs and for CP in both treatment groups. TP trended towards an improvement in both treatment groups. The user-friendliness of the conventional drop system was significantly higher. Conclusions For the first time, non-inferiority of micro-sized allogeneic SEDs was established. The beneficial effect of both SED volumes was similar as measured by the OSDI score. Although user-friendliness of the micro drop system was significantly lower, it is an attractive alternative as it saves valuable donor serum. Trial Registration ClinicalTrials.gov (NCT03539159).

The roles and responsibilities of radiation therapists (RTTs) are many and varied. Professional expectations are influenced by the technology available, as well as the level of autonomy RTTs have in their daily practice. This professional range requires RTTs to possess a unique set of ever evolving skills, posing challenges from an educational perspective.Teaching these “advanced skills” has been the ambition the ESTRO Advanced Skills in Modern Radiotherapy course. In the 10th year of this course, the Faculty look back and reflect on how our programme has evolved and what it has achieved.

Background and purpose: Strategies to limit the impact of intra-fraction motion during treatment are common in radiotherapy. Margin recipes, however, are not designed to incorporate these strategies. This work aimed to provide a framework to determine how motion management strategies influence treatment margins. Materials and methods: Two models of intra-fraction motion were considered. In model 1 motion was instantaneous, before treatment starts and in model 2 motion was a continuous drift during treatment. Motion management strategies were modelled by truncating the underlying error distribution at cσ, with σ the standard deviation of the distribution and c a free parameter. Using Monte Carlo simulations, we determined how motion management changed the required margin. The analysis was performed for different number of treatment fractions and different standard deviations of the underlying random and systematic errors. Results: The required margin for a continuous drift was found to be well approximated by an average position of the target at ¾ of the drift. Introducing a truncation at cσ, the relative change in the margin was equal to 0.3c. This result held for both models, was independent of σ or the number of fractions and naturally generalizes to the situation with a residual (systematic) error. Conclusion: Treatment margins can be determined when motion management strategies are applied. Moreover, our analysis can be used to study the potential benefit of different motion management strategies. This allows to discuss and determine the most appropriate strategy for margin reduction.

Background/purpose: In daily plan adaptation the radiotherapy treatment plan is adjusted just prior to delivery. A simple approach is taking the planning objectives of the reference plan and directly applying these in re-optimization. Here we present a tested method to verify whether daily adaptation without tweaking of the objectives can maintain the plan quality throughout treatment. Materials/methods: For fifteen rectal cancer patients, automated treatment planning was used to generate plans mimicking manual reference plans on the planning scans. For 74 fraction scans (4–5 per patient) an automated plan and a daily adapted plan were generated, where the latter re-optimizes the reference plan objectives without any tweaking. To evaluate the robustness of the daily adaptation, the adapted plans were compared to the autoplanning plans. Results: Median differences between the autoplanning plans on the planning scans and the reference plans were between −1 and 0.2 Gy. The largest interquartile range (1 Gy) was seen for the Lumbar Skin D2%. For the daily scans the PTV D2% and D98% differences between autoplanning and adapted plans were within ±0.7 Gy, with mean differences within ±0.3 Gy. Positive differences indicate higher values were obtained using autoplanning. For the Bowelarea + Bladder and the Lumbar Skin the D2% and Dmean differences were all within ±2.6 Gy, with mean differences between −0.9 and 0.1 Gy. Conclusion: Automated treatment planning can be used to benchmark daily adaptation techniques. The investigated adaptation workflow can robustly perform high quality adaptations without daily adjusting of the patient-specific planning objectives for rectal cancer radiotherapy.

Abstract Purpose To determine PTV margins for intrafraction motion in MRI-guided online adaptive radiotherapy for rectal cancer and the potential benefit of performing a 2nd adaptation prior to irradiation. Methods Thirty patients with rectal cancer received radiotherapy on a 1.5 T MR-Linac. On T2-weighted images for adaptation (MRIadapt), verification prior to (MRIver) and after irradiation (MRIpost) of 5 treatment fractions per patient, the primary tumor GTV (GTVprim) and mesorectum CTV (CTVmeso) were delineated. The structures on MRIadapt were expanded to corresponding PTVs. We determined the required expansion margins such that on average over 5 fractions, 98% of CTVmeso and 95% of GTVprim on MRIpost was covered in 90% of the patients. Furthermore, we studied the benefit of an additional adaptation, just prior to irradiation, by evaluating the coverage between the structures on MRIver and MRIpost. A threshold to assess the need for a secondary adaptation was determined by considering the overlap between MRIadapt and MRIver. Results PTV margins for intrafraction motion without 2nd adaptation were 6.4 mm in the anterior direction and 4.0 mm in all other directions for CTVmeso and 5.0 mm isotropically for GTVprim. A 2nd adaptation, applied for all fractions where the motion between MRIadapt and MRIver exceeded 1 mm (36% of the fractions) would result in a reduction of the PTVmeso margin to 3.2 mm/2.0 mm. For PTVprim a margin reduction to 3.5 mm is feasible when a 2nd adaptation is performed in fractions where the motion exceeded 4 mm (17% of the fractions). Conclusion We studied the potential benefit of intrafraction motion monitoring and a 2nd adaptation to reduce PTV margins in online adaptive MRIgRT in rectal cancer. Performing 2nd adaptations immediately after online replanning when motion exceeded 1 mm and 4 mm for CTVmeso and GTVprim respectively, could result in a 30–50% margin reduction with limited reduction of dose to the bowel.

Purpose: Descemet's membrane endothelial keratoplasty (DMEK) is becoming the gold standard to treat corneal endothelial dysfunctions worldwide. Compared with conventional penetrating keratoplasty, infectious complications after DMEK are ill defined. We describe the clinical picture of 2 DMEK recipients, operated on the same day and in the same clinic, who developed atypical herpes simplex virus type 1 (HSV-1) infection in the transplant recipient eye within days post-DMEK. Because recipients received cornea tissue from 2 different donors prepared by the same eye bank, the likelihood of a common HSV-1 source was determined. Design: Case series. Participants: Two DMEK recipients who developed atypical intraocular HSV-1 disease shortly after surgery and surplus cornea specimens of 6 donors. Methods: Surplus cornea donor (pre-DMEK cornea remnants and conditioned cornea storage and transport media) and recipient samples (post-DMEK aqueous humor) were assayed for HSV-1 DNA and infectious virus by real-time polymerase chain reaction (RT-PCR) and cell culture, respectively. Target-enriched whole viral genome sequencing was performed on HSV-1 DNA–positive ocular specimens. Main Outcome Measures: Clinical picture of atypical intraocular HSV-1 infection post-DMEK and presence and homology of HSV-1 genomes between ocular specimens of DMEK donors and recipients. Results: Herpes simplex virus type 1 DNA was detected in aqueous humor and donor cornea specimens of both DMEK cases, but not in the cornea remnants of 6 randomly selected donors processed by the same eye bank. Infectious HSV-1 was isolated from the cornea remnant and corresponding culture medium of 1 cornea donor. Notably, whole-genome sequencing of virus DNA-positive specimens demonstrated exceptionally high genetic similarity between HSV-1 strains in recipient and donor specimens of both DMEK cases. Conclusions: Data indicate cross-contamination of cornea grafts during DMEK preparation with subsequent graft-to-host HSV-1 transmission that caused atypical sight-threatening herpetic eye disease shortly after DMEK. Ophthalmologists should be aware that HSV-1 transmission by DMEK is possible and can lead to atypical ocular disease, a condition that can easily be prevented by taking appropriate technical and clinical measures at both eye bank and surgical levels.

Introduction: During a course of radiotherapy for head-and-neck-cancer (HNC), non-rigid anatomical changes can be observed on daily Cone Beam CT (CBCT). To objectify responses to these changes, we use a decision support system (traffic light protocol). Action levels orange and red may lead to re-planning. The purpose of this study was to evaluate how often re-planning was done for non-rigid anatomical changes, which anatomical changes led to re-planning and in which subgroups of patients treatment adaptation was deemed necessary. Materials and methods: A consecutive series of 388 HNC patients were retrospectively selected using the digital log of CBCT scans. The logs were analyzed for the number of new plans on an original planning CT scan (O-pCT) or a new pCT scan (N-pCT). Reasons for re-planning were categorized into: target volume increase/decrease, body contour decrease/increase and local shift of target volume. Subgroup analysis was performed to investigate relative differences of re-planning between treatment modalities. Results: For 33 patients the treatment plan was adapted due to anatomical changes, resulting in 37 new plans in total. Re-planning on a N-pCT with complete re-delineation was done 22 times. In fifteen cases a new plan was created after adjustment of contours on the O-pCT. Main reasons for re-planning were target volume increase, body contour decrease and local shifts of target volume. Most re-planning (23%) was seen in patients treated with chemoradiotherapy. Conclusion: Visual detection of anatomical changes on CBCT during treatment of HNC, results in re-planning in 1 out of 10 patients. Keywords: Head and neck cancer, Cone beam CT, Image guided radiotherapy, Traffic light protocol, Anatomical changes, Adaptive delivery

Background and purpose: Automatic delineations are often used as a starting point in the radiotherapy contouring workflow, after which they are manually reviewed and adapted. The purpose of this work was to quantify the geometric differences between automatic and manually edited breast clinical target volume (CTV) contours and evaluate the dosimetric impact of such differences. Materials and methods: Eighty-seven automatically generated and manually edited contours of the left breast were retrieved from our clinical database. The automatic contours were obtained with a commercial auto-segmentation toolbox. The geometrical comparison was performed both locally and globally using the Dice score and the 95% Hausdorff distance (HD). Two treatment plans were generated for each patient and the obtained dosimetric differences were quantified using dose-volume histogram (DVH) parameters in the lungs, heart and planning target volume (PTV). An inter-observer variability study with four observers was performed on a subset of ten patients. Results: A median Dice score of 0.95 and a median 95% HD of 9.7 mm were obtained. Larger breasts were consistently under-contoured. Cranial under-contouring resulted in more than 5% relative decrease in PTV coverage in 15% of the patients while lateroposterior over-contouring increased the lung V20Gy by a maximum of 2%. The inter-observer variability of the PTV coverage was smaller than the difference between PTV coverage achieved by the automatic and the consensus contours. Conclusions: Cranial under-contouring resulted in under-treatment, while lateroposterior over-contouring resulted in an increased lung dosage that is clinically irrelevant, showing the need to consider dose distributions to assess the clinical impact of local geometrical differences. Keywords: Auto-contouring, Contour comparison, Dosimetric differences

Background and purpose: The scatter induced image quality degradation of cone-beam computed tomography (CBCT) prevents more advanced applications in radiotherapy. We evaluated the dose calculation accuracy on CBCT of various disease sites using different scatter mitigation strategies. Materials and methods: CBCT scans of two patient cohorts (C1, C2) were reconstructed using a uniform (USC) and an iterative scatter correction (ISC) method, combined with an anti-scatter grid (ASG). Head and neck (H&N), lung, pelvic region, and prostate patients were included. To achieve a high accuracy Hounsfield unit and physical density calibrations were performed. The dose distributions of the original treatment plans were analyzed with the γ evaluation method using criteria of 1%/2 mm using the planning CT as the reference. The investigated parameters were the mean γ (γmean), the points in agreement (Pγ≤1) and the 99th percentile (γ1%). Results: Significant differences between USC and ISC in C1 were found for the lung and prostate, where the latter using the ISC produced the best results with medians of 0.38, 98%, and 1.1 for γmean, Pγ≤1 and γ1%, respectively. For C2 the ISC with ASG showed an improvement for all imaging sites. The lung demonstrated the largest relative increase in accuracy with improvements between 48% and 54% for the medians of γmean, Pγ≤1 and γ1%. Conclusions: The introduced method demonstrated high dosimetric accuracy for H&N, prostate and pelvic region if an ASG is applied. A significantly lower accuracy was seen for lung. The ISC yielded a higher robustness against scatter variations than the USC. Keywords: Cone beam CT, Dose, Adaptive radiotherapy

Abstract Background Emergency department (ED) overcrowding is a potential threat for patient safety. We searched for independent determinants of prolonged ED length of stay (LOS) with the aim to identify factors which can be targeted to reduce ED LOS, which may help in preventing overcrowding. Methods This prospective cohort study included consecutive ED patients in a Dutch tertiary care centre. Multivariable logistic regression analysis was used to identify independent determinants of ED LOS > 4 h, including patient characteristics (demographics, referral type, acuity, (number of) presenting complaints and comorbidity), treating specialty, diagnostic testing, consultations, number of patients in the ED and disposition. Furthermore, we quantified the absolute time delays (measured in real-time) associated with the most important independent determinants of prolonged ED LOS. Results In 1434 included patients independent determinants of prolonged ED LOS were number and type of presenting complaints, specialty, laboratory/radiology testing and consultations, and ICU admission. Modifiable determinants with the largest impact were blood testing; Adjusted odds ratio (AOR (95%-CI)); 3.45 (1.95–6.11), urine testing; 1.79 (1.21–2.63), radiology imaging; 3.02 (2.13–4.30), and consultation; 5.90 (4.08–8.54). Combined with the laboratory/radiology testing and/or consultations (requested in 1123 (78%) patients) the decision-making and discharge process consumed between 74 (42%) and 117 (66%) minutes of the total ED LOS of 177 (IQR: 129–225) minutes. Conclusions In tertiary care EDs, ED LOS can be reduced if the process of laboratory/radiology testing and consulting is optimized and the decision-making and discharge procedures are accelerated.

Background & purpose: With the introduction of more conformal techniques for breast cancer radiation therapy (RT), motion management is becoming increasingly important. We studied the breast-shape variability during RT after breast-conserving surgery (BCS). Materials & Methods: Planning computed tomography (CT) and follow-up cone-beam CT (CBCT) scans were available for 71 fractions of 17 patients undergoing RT after BCS. First, the CT and the CBCT scans were registered on bones. Subsequently, breast-contour data were generated. The CBCT contours were analyzed in 3D in terms of deviations (mean and standard deviation) relative to the contour of the CT scan for the upper medial, lower medial, upper lateral, and lower lateral breast quadrants, and the axilla. Results: Regional systematic and random standard deviations of the breast quadrants varied between 1.5 and 2.1 mm and 1.0–1.6 mm, respectively, and were larger for the axilla (3.0 mm). An absolute average shape change of ≥4.0 mm in at least one region was present in 21/71 fractions (30%), predominantly in breast volumes > 800 cc (p =

Background and purpose: The clinical target volume (CTV) in radiotherapy of rectal cancer is subject to large deformations. With a plan library strategy, the treatment may be adapted to these deformations. The purpose of this study was to determine feasibility and consistency in plan selection for a plan library strategy in radiotherapy of rectal cancer. Material and methods: Thirty rectal cancer patients were included in this retrospective study with in total 150 CBCT scans. A library of CTVs was constructed with in-house built software using population statistics on daily rectal deformations. The library consisted of five plans based on: the original CTV, two larger, and two smaller CTVs. An inter-observer study (study-I) was performed to test the consistency in plan choices between four observers (all RTTs). After five months the observers were asked to re-evaluate (study-II) the same set of scans based on refined guidelines. Results: In study-I the observers reached accordance with the majority choice in 69% of cases. This improved to 87% in study-II. The consensus meeting revealed that inconsistency in choices mainly arose from inadequate instructions, which were later clarified and formulated more accurately. Conclusion: Plan selection based on daily CBCT scans for rectal cancer patients is feasible, and can be performed consistently by well-trained RTTs. Keywords: Plan library, Rectum, Adaptive radiotherapy, Inter-observer study

OBJECTIVE:Comparison of conventional Penetrating Keratoplasty (PKP), posterior mushroom PKP and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) regarding overall graft survival of primary corneal transplants for Fuchs´ endothelial dystrophy (FED), best spectacle-corrected visual acuity (BSCVA) and astigmatism. METHODS:Single centre study using prospectively collected data from the national database for follow-up of corneal transplants. Main outcome parameters: 10 years graft survival, astigmatism at 24 months, pre- and post-operative BSCVA. RESULTS:In total, 721 cases were included: PKP, n = 171; posterior mushroom PKP, n = 91; and DSAEK, n = 459. There was no significant difference in graft survival between PKP, posterior mushroom PKP and the DSAEK technique (log-rank test, P = 0.12). The overall post-operative BSCVA improvement in all treatment groups was significant (paired t-test, P

Purpose. To investigate the long-term anatomical and functional outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK). Methods. Prospective follow-up of 114 eyes (95 subjects) after DSAEK for endothelial dysfunction. Measurements included best spectacle-corrected visual acuity (BSCVA), straylight, endothelial cell density (ECD), and graft thickness. Results. The mean follow-up time was 5.1 ± 1.5 years. Four grafts ultimately failed (after 5 to 7 years). From baseline up to 1 year after DSAEK, mean BSCVA improved by 0.30 logMAR. This beneficial effect remained until the last follow-up (LFU). After DSAEK, straylight was reduced. ECD sharply dropped by 900 cells/mm2 (33%) immediately after surgery and, thereafter, steadily decreased at a rate of 11 cells/mm2 per month. No significant correlation was observed between graft thickness at 3 years and BSCVA. Conclusions. We observed a low graft failure rate and a normalization of graft thickness. Postoperative straylight remained elevated relative to the normal population. The sharp initial and the subsequent more gradual ECD decline are consistent with other studies. A significant and prolonged functional gain can be achieved by posterior lamellar grafting for endothelial dysfunction.