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Background: The use of stereotactic body radiotherapy (SBRT) to definitively treat oligometastases in prostate cancer has drawn large clinical and research interests within radiation oncology. However, the evidence is considered in its early stages and there is currently no systematic review of randomized controlled trials (RCTs) in this field. We aimed to evaluate the efficacy and safety of SBRT as metastasis-directed therapy (MDT) in oligometastatic prostate cancer (OMPC) compared to no MDT reported in RCTs., Methods: MEDLINE, Embase, CINAHL Complete, and Cochrane Library were searched on October 28, 2023. Eligible studies were RCTs comparing SBRT as MDT with no MDT in extracranial OMPC, without restrictions on follow-up time, publication status, language, or year. Participant subsets fulfilling the eligibility criteria were included. Critical outcomes were overall survival and grade ≥ 3 toxicity, and additional important outcomes were progression-free survival (PFS), local control, grade 5 toxicity, health-related quality of life, and systemic therapy-free survival. Meta-analyses were planned. Risk of bias was assessed using the Cochrane risk-of-bias tool version 2, and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation., Results: In total, 1825 unique study reports were identified and seven phase II RCTs with 559 eligible participants were included. Four trials included multiple types of primary cancer. Outcome definitions were heterogeneous except for overall survival and toxicity. For overall survival, only one study reported events in both arms. Meta-analysis of the grade ≥ 3 toxicity results from two trials showed no difference (pooled risk ratio 0.78, 95% confidence interval 0.37-1.65, p = 0.52). Four trials reported significantly longer PFS, with a pooled hazard ratio of 0.31 (95% confidence interval 0.21-0.45, p < 0.00001). Risk of bias was of some concerns or high. Quality of evidence was low or moderate., Conclusions: Phase II trials have shown promising improvements in PFS for several OMPC states without excess toxicity. Overall survival comparisons are immature. In future confirmatory phase III trials, adequately large sample sizes, blinding of outcome assessors, and/or increased adherence to assigned intervention could improve the quality of evidence. PROSPERO registration number: CRD42021230131., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: AEP: None. AH: None. LBL: Receipt of a travelling grant from MSD. MR: None. JS: None. PN: None. HT: None. AG: Receipt of honoraria for a lecture from Janssen-Cilag., (© 2024. The Author(s).)

Purpose: Coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB) is associated with myocardial ischemia-reperfusion injury (IRI), which may limit the benefit of the surgery. Both experimental and clinical studies suggest that Intralipid, a lipid emulsion commonly used for parenteral nutrition, can limit myocardial IRI. We therefore aimed to investigate whether Intralipid administered at reperfusion can reduce myocardial IRI in patients undergoing CABG on CPB., Methods: We conducted a randomized, double-blind, pilot trial in which 29 adult patients scheduled for CABG were randomly assigned (on a 1:1 basis) to receive either 1.5 ml/kg Intralipid 20% or Ringer's Lactate 3 min before aortic cross unclamping. The primary endpoint was the 72-h area under the curve (AUC) for troponin I., Results: Of the 29 patients randomized, 26 were included in the study (two withdrew consent and one was excluded before surgery). The 72-h AUC for troponin I did not significantly differ between the control and Intralipid group (546437 ± 205518 versus 487561 ± 115724 arbitrary units, respectively; P = 0.804). Other outcomes (including 72-h AUC for CK-MB, C-reactive protein, need for defibrillation, time to extubation, length of ICU and hospital stay, and serious adverse events) were similar between the two groups., Conclusion: In patients undergoing CABG on CPB, Intralipid did not limit myocardial IRI compared to placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT02807727 (registration date: 16 June 2016)., (© 2024. The Author(s).)

Background: Heart transplantation in South Africa faces numerous challenges related to organ scarcity and unequal access to advanced heart therapy. There is an urgent need to analyse the current transplant referral pathway to optimise equitable access to transplantation., Objectives: To provide an audit of heart transplant referrals to Groote Schuur Hospital, Cape Town, over a 23-year period, focusing on patient demographics, indications for referral, waiting-list dynamics, and transplant referral outcomes., Methods: The study utilised a retrospective patient folder review for the period 1 January 1997 - 31 December 2019 and audited the trends in heart transplant referrals and associated outcomes of the referral at a tertiary academic hospital., Results: A total of 625 recipients were referred for heart transplantation, with the majority being male (n=412; 65.9%), while gender was undocumented for 69 cases (11.0%). The mean age was 38.1 (14.6) years, and 153 (24.5%) were listed for transplant, while 215 (34.4%) were deemed ineligible for listing. Contraindications for listing included social (n=106; 49.3%), medical (n=83; 38.6%) and psychological (n=26; 12.0%) factors, while 134 patients (21.4%) were considered too well. Poor social circumstances (n=38; 39.6%), poor insight (n=28; 29.2%) and poor compliance (n=21; 21.9%) were the most common non-medical reasons for not listing recipients, while obesity (n=30; 31.3%) and smoking (n=23; 24.0%) were notable medical contraindications. Forty-nine patients (7.8%) died during work-up, while 130 (85.0%) of the listed patients received a heart transplant. Of the 429 donor referrals, 139 (32.4%) were accepted for organ procurement. Reasons for declining donors included unsuitability for transplantation (30.3%), lack of capacity (1.8%), and recipient-donor mismatch (66.9%)., Conclusion: Three-quarters of the referred patients were deemed unsuitable for heart transplantation for medical and/or social reasons. The ratio of referral to listing has decreased over time. However, once listed, the likelihood of receiving a transplant was high.

Background and Purpose: In magnetic resonance imaging (MRI) only radiotherapy computed tomography (CT) is excluded. The method relies entirely on synthetic CT images generated from MRI. This study evaluates the compatibility of a commercial synthetic CT (sCT) with an accelerated commercial deep learning reconstruction (DLR) in MRI-only prostate radiotherapy., Materials and Methods: For a group of 24 patients (cohort 1) the effects of DLR were studied in isolation. MRI data were reconstructed conventionally and with DLR from identical k-space data, and sCTs were generated for both reconstructions. The sCT quality, Hounsfield Unit (HU) and dosimetric impact were investigated. In another group of 15 patients (cohort 2) effects on sCT generation using accelerated MRI acquisition (40 % time reduction) reconstructed with DLR were investigated., Results: sCT images from both cohorts, generated from DLR MRI data, were of clinically expected image quality. The mean dose differences for targets and organs at risks in cohort 1 were <0.06 Gy, corresponding to a 0.1 % prescribed dose difference. Similar dose differences were observed in cohort 2. Gamma pass rates for cohort 1 were 100 % for criteria 3 %/3mm, 2 %/2mm and 1 %/1mm for all dose levels. Mean error and mean absolute error inside the body, between sCTs, averaged over all cohort 1 subjects, were -1.1 ± 0.6 [-2.4 0.2] and 2.9 ± 0.4 [2.3 3.9] HU, respectively., Conclusions: DLR was suitable for sCT generation with clinically negligible differences in HU and calculated dose compared to the conventional MRI reconstruction method. For sCT generation DLR enables scan time reduction, without compromised sCT quality., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CJG has received a speaker fee from GE Healthcare. Other authors declare that they have no competing interests., (© 2024 The Author(s).)

Deep learning (DL) models for radiation therapy (RT) image segmentation require accurately annotated training data. Multiple organ delineation guidelines exist; however, information on the used guideline is not provided with the delineation. Extraction of training data with coherent guidelines can therefore be challenging. We present a supervised classification method for pelvis structure delineations where bowel cavity, femoral heads, bladder, and rectum data, with two guidelines, were classified. The impact on DL-based segmentation quality using mixed guideline training data was also demonstrated. Bowel cavity was manually delineated on CT images for anal cancer patients (n = 170) according to guidelines Devisetty and RTOG. The DL segmentation quality from using training data with coherent or mixed guidelines was investigated. A supervised 3D squeeze-and-excite SENet-154 model was trained to classify two bowel cavity delineation guidelines. In addition, a pelvis CT dataset with manual delineations from prostate cancer patients (n = 1854) was used where data with an alternative guideline for femoral heads, rectum, and bladder were generated using commercial software. The model was evaluated on internal (n = 200) and external test data (n = 99). By using mixed, compared to coherent, delineation guideline training data mean DICE score decreased 3% units, mean Hausdorff distance (95%) increased 5 mm and mean surface distance (MSD) increased 1 mm. The classification of bowel cavity test data achieved 99.8% unweighted classification accuracy, 99.9% macro average precision, 97.2% macro average recall, and 98.5% macro average F1. Corresponding metrics for the pelvis internal test data were all 99% or above and for the external pelvis test data they were 96.3%, 96.6%, 93.3%, and 94.6%. Impaired segmentation performance was observed for training data with mixed guidelines. The DL delineation classification models achieved excellent results on internal and external test data. This can facilitate automated guideline-specific data extraction while avoiding the need for consistent and correct structure labels., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background and Purpose: For pelvic magnetic resonance imaging (MRI)-only radiotherapy the use of receiver coil bridges (CB) is recommended to avoid deformation of the patient. Development in coil technology has enabled lightweight, flexible coils. In this work we evaluate the effects of a lightweight coil in a pelvic MRI-only radiotherapy workflow., Materials and Methods: Twenty-one patients, referred to prostate MRI-only radiotherapy, were included. Images were acquired with and without CB. Anatomical deformation from the on-patient coil placement was measured in the anterior-posterior (AP) and left-right (LR) direction. The change in signal-to-noise ratio (SNR) was measured in phantom and in vivo.The clinical treatment plan, created on the image with CB, was transferred and recalculated on the image without the CB. Dose metrics for the targets (planning- and clinical target volume) and organs at risks (OAR) were analyzed., Results: There was a statistically significant increase in SNR in-vivo (median 21 %, p = 0.002) when removing the CB. Anatomical differences after removing the CB in patients were -1.5 mm in AP (median change) and + 2.5 mm in LR direction. Dosimetric differences for the target structures were clinically negligible, but statistically significant. The difference in target mean doses were 0.2 % (both p = 0.004) of the prescribed dose. No dosimetric differences were observed for the OAR, except for the penile bulb., Conclusions: We concluded that anatomical change and dosimetric differences, originating from scanning without CB were minor. The CB can thereby be removed from the workflow, enabling easier patient positioning and increased SNR when using lightweight coils., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Author CJG gave an oral presentation which included a presentation fee on an ESTRO GE lunch symposium, Copenhagen, Denmark 2022. Main topic was MRI-only prostate treatment and the preliminary results of this study. No other authors declare any financial interests or personal relationships that can be considered as potential competing interests., (© 2023 The Author(s).)

A 63-year-old man presented with two days of palpable purpura over the right anterior shin and calf with notable point tenderness on the distal mid-calf without any palpable deep abnormality. Localized right calf pain worsened with walking and was associated with headache, chills, fatigue, and low-grade fevers. A punch biopsy of the anterior right lower leg showed necrotizing neutrophilic vasculitis of superficial and deep vessels. Direct immunofluorescence showed non-specific focal granular deposition of C3 within vessel walls. Three days after presentation, a live spider was found and microscopically identified as a male hobo spider. The patient suspected the spider arrived via packages shipped from Seattle, Washington. The patient was treated with a prednisone taper with full resolution of his cutaneous symptoms. Given the unilaterality of his symptoms and otherwise unexplained etiology, the patient was diagnosed with acute unilateral vasculitis secondary to hobo spider bite. Microscopic examination is required for identification of hobo spiders. Although not deadly, there have been several reports of cutaneous and systemic reactions resulting from hobo spider bites. Our case illustrates the importance of considering hobo spider bites in areas outside of their native regions, as they are known to travel in packaged items.

Background and Purpose: The aim of this study was to analyze a magnetic resonance imaging (MRI)-only radiotherapy workflow from an economic perspective in terms of reduced time, costs and systematic uncertainties., Material/methods: A documented Swedish clinical implementation of MRI-only radiotherapy was used as template for cost assessments compared to a combined computed tomography (CT)/MRI workflow. The costs were taken from official regional price lists from 2021. MRI-only specific quality assurance (QA) was assumed necessary in an initial phase. Treatment plans for target volumes with margins of 5-10 mm were created for ten prostate cancer patients prescribed 78 Gy in 39 fractions. The risk of Grade ≥ 2 rectal toxicity or rectal bleeding was calculated using the QUANTEC recommended NTCP model and costs estimated based on subsequent diagnostic examinations., Results: The exclusion of the CT-examination and faster target delineation were the main contributors to cost reductions. Additional QA procedures limited the initial cost reduction to 14 EUR/patient. Long-term MRI-only reduced the costs by 209 EUR/patient. Reducing margins resulted in Grade ≥ 2 rectal toxicity or rectal bleeding probability of 9.7 % for 7 mm margin and 6.0 % for 5 mm margin. This margin reduction resulted in an additional cost reduction of 46 EUR/patient., Conclusion: An MRI-only workflow implementation is associated with reduced costs when the workflow tasks are more time efficient and side effects are reduced as a result of margin reduction. The short-term economic benefits are limited due to extra costs of QA procedures. The economic benefits of MRI-only will make impact first when the workflow is well established, and margin reduction has been included., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Patients with severe symptomatic aortic stenosis (AS) have traditionally been treated with surgical aortic valve replacement (sAVR). Transcatheter aortic valve implantation is a percutaneous option that has been shown to be at least as effective as sAVR in numerous subgroups of patients with severe AS. This is an update on the previous joint consensus statement and guideline on transcatheter aortic valve implantation (TAVI) in South Africa, published in 2016. It provides guidance on which patients should preferably be offered TAVI over sAVR, with special consideration of the resource-constrained environment in South Africa.

Background: Delineation of organs at risk (OAR) for anal cancer radiation therapy treatment planning is a manual and time-consuming process. Deep learning-based methods can accelerate and partially automate this task. The aim of this study was to develop and evaluate a deep learning model for automated and improved segmentations of OAR in the pelvic region., Methods: A 3D, deeply supervised U-Net architecture with shuffle attention, referred to as Pelvic U-Net, was trained on 143 computed tomography (CT) volumes, to segment OAR in the pelvic region, such as total bone marrow, rectum, bladder, and bowel structures. Model predictions were evaluated on an independent test dataset (n = 15) using the Dice similarity coefficient (DSC), the 95th percentile of the Hausdorff distance (HD 95 ), and the mean surface distance (MSD). In addition, three experienced radiation oncologists rated model predictions on a scale between 1-4 (excellent, good, acceptable, not acceptable). Model performance was also evaluated with respect to segmentation time, by comparing complete manual delineation time against model prediction time without and with manual correction of the predictions. Furthermore, dosimetric implications to treatment plans were evaluated using different dose-volume histogram (DVH) indices., Results: Without any manual corrections, mean DSC values of 97%, 87% and 94% were found for total bone marrow, rectum, and bladder. Mean DSC values for bowel cavity, all bowel, small bowel, and large bowel were 95%, 91%, 87% and 81%, respectively. Total bone marrow, bladder, and bowel cavity segmentations derived from our model were rated excellent (89%, 93%, 42%), good (9%, 5%, 42%), or acceptable (2%, 2%, 16%) on average. For almost all the evaluated DVH indices, no significant difference between model predictions and manual delineations was found. Delineation time per patient could be reduced from 40 to 12 min, including manual corrections of model predictions, and to 4 min without corrections., Conclusions: Our Pelvic U-Net led to credible and clinically applicable OAR segmentations and showed improved performance compared to previous studies. Even though manual adjustments were needed for some predicted structures, segmentation time could be reduced by 70% on average. This allows for an accelerated radiation therapy treatment planning workflow for anal cancer patients., (© 2022. The Author(s).)

Leaflet durability and costs restrict contemporary trans-catheter aortic valve replacement (TAVR) largely to elderly patients in affluent countries. TAVR that are easily deployable, avoid secondary procedures and are also suitable for younger patients and non-calcific aortic regurgitation (AR) would significantly expand their global reach. Recognizing the reduced need for post-implantation pacemakers in balloon-expandable (BE) TAVR and the recent advances with potentially superior leaflet materials, a trans-catheter BE-system was developed that allows tactile, non-occlusive deployment without rapid pacing, direct attachment of both bioprosthetic and polymer leaflets onto a shape-stabilized scallop and anchorage achieved by plastic deformation even in the absence of calcification. Three sizes were developed from nickel-cobalt-chromium MP35N alloy tubes: Small/23 mm, Medium/26 mm and Large/29 mm. Crimp-diameters of valves with both bioprosthetic (sandwich-crosslinked decellularized pericardium) and polymer leaflets (triblock polyurethane combining siloxane and carbonate segments) match those of modern clinically used BE TAVR. Balloon expansion favors the wing-structures of the stent thereby creating supra-annular anchors whose diameter exceeds the outer diameter at the waist level by a quarter. In the pulse duplicator, polymer and bioprosthetic TAVR showed equivalent fluid dynamics with excellent EOA, pressure gradients and regurgitation volumes. Post-deployment fatigue resistance surpassed ISO requirements. The radial force of the helical deployment balloon at different filling pressures resulted in a fully developed anchorage profile of the valves from two thirds of their maximum deployment diameter onwards. By combining a unique balloon-expandable TAVR system that also caters for non-calcific AR with polymer leaflets, a powerful, potentially disruptive technology for heart valve disease has been incorporated into a TAVR that addresses global needs. While fulfilling key prerequisites for expanding the scope of TAVR to the vast number of patients of low- to middle income countries living with rheumatic heart disease the system may eventually also bring hope to patients of high-income countries presently excluded from TAVR for being too young., Competing Interests: “Strait Access Technologies” (SAT) is a start-up company of the University of Cape Town. HA, DB, JSc, HC, DW, and PZ own shares in SAT. JV, RC, and RS are employed by SAT. KP, BB, and MC are former employees and shareholders of SAT. BJ is a former employee of SAT. CS is employed by Auto Tissue Berlin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Appa, Park, Bezuidenhout, van Breda, de Jongh, de Villiers, Chacko, Scherman, Ofoegbu, Swanevelder, Cousins, Human, Smith, Vogt, Podesser, Schmitz, Conradi, Treede, Schröfel, Fischlein, Grabenwöger, Luo, Coombes, Matskeplishvili, Williams and Zilla.)

Aims: To analyse dosimetric and clinical predictors for acute and late gastrointestinal toxicity following chemoradiotherapy of anal cancer., Materials and Methods: Consecutive patients with locally advanced (T2 ≥4 cm - T4 or N+) anal cancer were selected from an institutional database (n = 114). All received intensity-modulated radiotherapy with concomitant 5-fluorouracil and mitomycin C. Gastrointestinal toxicity was retrospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and bowel cavity, small bowel and large bowel were contoured. Dosimetric and clinical variables were tested for associations with acute grade ≥3 gastrointestinal toxicity and late grade ≥2 gastrointestinal toxicity using the Mann-Whitney test, area under receiver operating characteristic curve (AUC) and logistic regression., Results: The median follow-up was 40 months. Acute grade ≥3 gastrointestinal toxicity was seen in 51 (44.7%) of the patients; late grade ≥2 gastrointestinal toxicity was seen in 36 of the patients (39.6% of 91 patients with >1 year recurrence-free follow-up). Bowel cavity V30Gy was the best dosimetric predictor for acute gastrointestinal toxicity (AUC 0.633; P = 0.02). Large bowel V20Gy was the best dosimetric predictor for late gastrointestinal toxicity (AUC 0.698; P = 0.001) but showed no association with acute gastrointestinal toxicity. In multivariate logistic regression, increasing age was significantly associated with acute gastrointestinal toxicity; smoking and large bowel V20Gy were significantly associated with late gastrointestinal toxicity. Patients who experienced acute grade ≥3 gastrointestinal toxicity were not at an increased risk of late grade ≥2 gastrointestinal toxicity (odds ratio 1.3; P = 0.55)., Conclusions: Factors of importance for acute and late gastrointestinal toxicity were not the same. Bowel cavity V30Gy is a good metric to use for the prediction of acute gastrointestinal toxicity, but the results of our study indicate that individual large and small bowel loops need to be contoured for better prediction of late gastrointestinal toxicity. The role of the large bowel as an important organ at risk for late gastrointestinal toxicity merits further research., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Radiotherapy (RT) datasets can suffer from variations in annotation of organ at risk (OAR) and target structures. Annotation standards exist, but their description for prostate targets is limited. This restricts the use of such data for supervised machine learning purposes as it requires properly annotated data. The aim of this work was to develop a modality independent deep learning (DL) model for automatic classification and annotation of prostate RT DICOM structures. Delineated prostate organs at risk (OAR), support- and target structures (gross tumor volume [GTV]/clinical target volume [CTV]/planning target volume [PTV]), along with or without separate vesicles and/or lymph nodes, were extracted as binary masks from 1854 patients. An image modality independent 2D InceptionResNetV2 classification network was trained with varying amounts of training data using four image input channels. Channel 1-3 consisted of orthogonal 2D projections from each individual binary structure. The fourth channel contained a summation of the other available binary structure masks. Structure classification performance was assessed in independent CT (n = 200 pat) and magnetic resonance imaging (MRI) (n = 40 pat) test datasets and an external CT (n = 99 pat) dataset from another clinic. A weighted classification accuracy of 99.4% was achieved during training. The unweighted classification accuracy and the weighted average F1 score among different structures in the CT test dataset were 98.8% and 98.4% and 98.6% and 98.5% for the MRI test dataset, respectively. The external CT dataset yielded the corresponding results 98.4% and 98.7% when analyzed for trained structures only, and results from the full dataset yielded 79.6% and 75.2%. Most misclassifications in the external CT dataset occurred due to multiple CTVs and PTVs being fused together, which was not included in the training data. Our proposed DL-based method for automated renaming and standardization of prostate radiotherapy annotations shows great potential. Clinic specific contouring standards however need to be represented in the training data for successful use. Source code is available at https://github.com/jamtheim/DicomRTStructRenamerPublic., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background and Purpose: Inter-modality image registration between computed tomography (CT) and magnetic resonance (MR) images is associated with systematic uncertainties and the magnitude of these uncertainties is not well documented. The purpose of this study was to investigate the potential uncertainty of gold fiducial marker (GFM) registration for localized prostate cancer and to estimate the inter-observer bias in a clinical setting., Methods: Four experienced observers registered CT and MR images for 42 prostate cancer patients. Manual GFM identification was followed by a landmark-based registration. The absolute difference between observers in GFM identification and the displacement of the clinical target volume (CTV) was investigated. The CTV center of mass (CoM) vector displacements, DICE-index and Hausdorff distances for the observer registrations were compared against a clinical baseline registration. The time allocated for the manual registrations was compared., Results: Absolute difference in GFM identification between observers ranged from 0.0 to 3.0 mm. The maximum CTV CoM displacement from the clinical baseline was 3.1 mm. Displacements larger than or equal to 1 mm, 2 mm and 3 mm were 46%, 18% and 4%, respectively. No statistically significant difference was detected between observers in terms of CTV displacement. Median DICE-index and Hausdorff distance for the CTV, with their respective ranges were 0.94 [0.70-1.00] and 2.5 mm [0.7-8.7]., Conclusions: Registration of CT and MR images using GFMs for localized prostate cancer patients was subject to inter-observer bias on an individual patient level. A CTV displacement as large as 3 mm occurred for individual patients. These results show that GFM registration in a clinical setting is associated with uncertainties, which motivates the removal of inter-modality registrations in the radiotherapy workflow and a transition to an MRI-only workflow for localized prostate cancer., (© 2021. The Author(s).)

Background: Treatment-related white blood cell (WBC) toxicity has been associated with an inferior prognosis in different malignancies, including anal cancer. The aim of the present study was to investigate predictors of WBC grade ≥ 3 (G3+) toxicity during chemoradiotherapy (CRT) of anal cancer., Methods: Consecutive patients with locally advanced (T2 ≥ 4 cm-T4 or N+) anal cancer scheduled for two cycles of concomitant 5-fluorouracil and mitomycin C chemotherapy were selected from an institutional database (n = 106). All received intensity modulated radiotherapy (IMRT; mean dose primary tumor 59.5 Gy; mean dose elective lymph nodes 45.1 Gy). Clinical data were extracted from medical records. The highest-grade WBC toxicity was recorded according to CTCAE version 5.0. Pelvic bone marrow (PBM) was retrospectively contoured and dose-volume histograms were generated. The planning CT was used to measure sarcopenia. Dosimetric, anthropometric, and clinical variables were tested for associations with WBC G3+ toxicity using the Mann-Whitney test and logistic regression. Cox proportional hazard regression was used to assess predictors for overall survival (OS) and anal cancer specific survival (ACSS)., Results: WBC G3+ was seen in 50.9% of the patients, and 38.7% were sarcopenic. None of the dosimetric parameters showed an association with WBC G3+ toxicity. The most significant predictor of WBC G3+ toxicity was sarcopenia (adjusted OR 4.0; P = 0.002). Sarcopenia was also associated with an inferior OS (adjusted HR 3.9; P = 0.01), but not ACSS (P = 0.07). Sensitivity analysis did not suggest that the inferior prognosis for sarcopenic patients was a consequence of reduced doses of chemotherapy or a prolonged radiation treatment time. Patients who experienced WBC G3+ toxicity had an inferior OS and ACSS, even after adjustment for sarcopenia., Conclusions: Sarcopenia was associated with increased risks of both WBC G3+ toxicity and death following CRT for locally advanced anal cancer. In this study, radiation dose to PBM was not associated with WBC G3+ toxicity. However, PBM was not used as an organ at risk for radiotherapy planning purposes and doses to PBM were high, which may have obscured any dose-response relationships., (© 2021. The Author(s).)

Background: The rate of cardiac implantable electronic device (CIED) implantation in low- and middle-income countries is increasing. Patients recieving these devices are frequently older and with multiple co-morbidities, which may later lead to complications requiring CIED removal. CIED removals are associated with life-threatening complications. However, high sucesss rates are reported in high-income countries. The purpose of this study was to report on the experience of CIED removal in a resource-constrained setting., Methods: In this retrospective study, we included consecutive adult patients admitted to Groote Schuur Hospital and the University of Cape Town Private Academic Hospital for CIED removal from 1 January 2008 to 31 December 2019., Results: During the study period, 53 patients underwent CIED removal (26 extractions and 27 explants). The patients had a mean (standard deviation) age of 59.1 (16.0) years. A history of systemic hypertension was present in 50.9% of patients, diabetes mellitus in 30.2% and dilated cardiomyopathy in 47.2%. Complete heart block was the leading indication for CIED implantation (37.7%), and device infection was the leading indication for removal (69.2%). CIEDs were removed after a median (interquantile range) of 243 (53-831) days. There were 40 leads extracted and 35 explants. Lead extractions were perfomed in the cardiac catheterisation laboratory under general anaesthesia via a percutaneous transvenous superior approach. There was one major and one minor complication related to lead extraction., Conclusions: CIED infections were the primary indication for CIED removal in a tertiary referral centre in South Africa. Despite being a low-volume centre, we report a high percutaneous transvenous extraction success rate with low complication rate; results which are comparable to high-volume centres.

Background: This study investigates the patterns of PET-positive lymph nodes (LNs) in anal cancer. The aim was to provide information that could inform future anal cancer radiotherapy contouring guidelines., Methods: The baseline [18F]-FDG PET-CTs of 190 consecutive anal cancer patients were retrospectively assessed. LNs with a Deauville score (DS) of ≥3 were defined as PET-positive. Each PET-positive LN was allocated to a LN region and a LN sub-region; they were then mapped on a standard anatomy reference CT. The association between primary tumor localization and PET-positive LNs in different regions were analyzed., Results: PET-positive LNs (n = 412) were identified in 103 of 190 patients (54%). Compared to anal canal tumors with extension into the rectum, anal canal tumors with perianal extension more often had inguinal (P < 0.001) and less often perirectal (P < 0.001) and internal iliac (P < 0.001) PET-positive LNs. Forty-two patients had PET-positive LNs confined to a solitary region, corresponding to first echelon nodes. The most common solitary LN region was inguinal (25 of 42; 60%) followed by perirectal (26%), internal iliac (10%), and external iliac (2%). No PET-positive LNs were identified in the ischiorectal fossa or in the inguinal area located posterolateral to deep vessels. Skip metastases above the bottom of the sacroiliac joint were quite rare. Most external iliac PET-positive LNs were located posterior to the external iliac vein; only one was located in the lateral external iliac sub-region., Conclusions: The results support some specific modifications to the elective clinical target volume (CTV) in anal cancer. These changes would lead to reduced volumes of normal tissue being irradiated, which could contribute to a reduction in radiation side-effects.

Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22-72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.

Rheumatic heart disease (RHD) still affects more patients globally than degenerative valve disease. The vast majority of these patients live in low- to middle-income countries. Once symptomatic, they will need heart valve surgery. Unfortunately, prosthetic valves perform poorly in these patients given their young age, the high incidence of multi-valve disease, late diagnoses and often challenging socio-economic circumstances. Notwithstanding the fact that better valve designs would ideally be available, ill-informed decision making processes between bioprosthetic and mechanical valves are contributing to the poor results. In the absence of multicentred, randomised clinical trials, comparing the current generations of bioprostheses with mechanical valves across all age groups Western guidelines tend to be uncritically applied. As a consequence, mechanical valves are being implanted into patients who are often not able to deal with anticoagulation while bioprosthetic valves may be overly shunned for fear of reoperations. Almost sixty years after the advent of cardiac surgery heart valve prostheses have eventually undergone improvements and several potentially disruptive developments are on the horizon. Until they materialise, however, choices between contemporary valve prostheses need to be made on the basis of individual risk and life-expectancy rather than an uncritical implementation of guidelines that were derived for very different patients and under distinctly different conditions. Given the fast expansion of cardiac surgery in middle-income countries and a growing number of independently operating centres in low-income countries a critical appraisal of facts underlying the choice of heart valve prostheses for patients with RHD seems opportune., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Diagnostic imaging often outperforms the surgeon's ability to identify small structures during therapeutic procedures. Smart soft tissue markers that translate the sensitivity of diagnostic imaging into optimal therapeutic intervention are therefore highly warranted. This paper presents a unique adaptable liquid soft tissue marker system based on functionalized carbohydrates (Carbo-gel). The liquid state of these markers allows for high-precision placement under image guidance using thin needles. Based on step-by-step modifications, the image features and mechanical properties of markers can be optimized to bridge diagnostic imaging and specific therapeutic interventions. The performance of Carbo-gel is demonstrated for markers that (i) have radiographic, magnetic resonance, and ultrasound visibility; (ii) are palpable and visible; and (iii) are localizable by near-infrared fluorescence and radio guidance. The study demonstrates encouraging proof of concept for the liquid marker system as a well-tolerated multimodal imaging marker that can improve image-guided radiotherapy and surgical interventions, including robotic surgery., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC). Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables. Results : Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p <.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6-5.0%) and 7.7% (5.5-10%), respectively. Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Background: Anal cancer is a rare disease, which might be the reason for the "one size fits all" approach still used for radiotherapy target contouring. To refine and individualize future guidelines, detailed and contemporary pattern of recurrence studies are needed., Methods: Consecutive anal cancer patients, all treated with curative intent intensity-modulated radiotherapy (IMRT), were retrospectively studied (n = 170). Data was extracted from medical records and radiological images. Radiotherapy planning CT's and treatment plans were reviewed, and recurrences were mapped and categorized according to radiation dose., Results: The mean dose to the primary tumor was 59.0 Gy. With a median follow-up of 50 months (range 14-117 months), 5-year anal cancer specific survival was 86.1%. Only 1 of 20 local recurrences was located outside the high dose (CTVT) volume. More patients experienced a distant recurrence (n = 34; 20.0%) than a locoregional recurrence (n = 24; 14.1%). Seven patients (4.2%) had a common iliac and/or para-aortic (CI/PA) recurrence. External iliac lymph node involvement (P = 0.04), and metastases in ≥3 inguinal or pelvic lymph node regions (P = 0.02) were associated with a 15-18% risk of CI/PA recurrence. Following chemoradiotherapy, 6 patients with recurrent or primary metastatic CI/PA lymph nodes were free of recurrence at last follow-up. The overall rate of ano-inguinal lymphatic drainage (AILD) recurrence was 2 of 170 (1.2%), and among patients with inguinal metastases at initial diagnosis it was 2 of 65 (3.1%)., Conclusions: We conclude that other measures than increased margins around the primary tumor are needed to improve local control. Furthermore, metastatic CI/PA lymph nodes, either at initial diagnosis or in the recurrent setting, should be considered potentially curable. Patients with certain patterns of metastatic pelvic lymph nodes might be at an increased risk of harboring tumor cells also in the CI/PA lymph nodes.

Purpose of Review: Transesophageal echocardiography (TEE) has made its way into the cardiac surgery realm and spurred the development of many interventions. In the domain of minimally invasive cardiac surgery (MICS), TEE has become central to reducing cardiovascular complications., Recent Findings: Real-time three-dimensional TEE is a key contributor to the safe and precise deployment of the PASCAL mitral valve repair system, which is showing great potential in ongoing studies. The current data on outcomes of transcatheter aortic valve replacement show that preprocedural three-dimensional TEE and multidetector computed tomography (CT) perform similarly in aortic root assessment. Three-dimensional color Doppler TEE has been suggested to be more appropriate in quantifying residual mitral regurgitation and evaluating the success of surgical or percutaneous closure. A three-dimensional TEE-derived aortomitral angle may be valuable in predicting and detecting dynamic left ventricular outflow tract obstruction, thereby enhancing the safety of transcatheter mitral valve replacement., Summary: Advanced imaging modalities are essential for the sustained growth of MICS, particularly with the evolution of novel transcatheter systems. These techniques rely on exceptional imaging quality at all stages of the perioperative period to modify surgical-risk and improve patient outcomes. TEE has the additional benefit of providing real-time information on intrathoracic structures to guide intraoperative management.

Aims: Cardiac surgery in middle-income countries differs significantly from that in high-income countries regarding prevailing heart valve pathologies and access to cardiac surgery. Typically, rheumatic aortic regurgitation in the absence of calcification by far outweighs stenosis. As such, entirely different transcatheter aortic valve implantation (TAVI) concepts are required for these regions. The aim of the study was to evaluate the five-month performance of the SAT (Strait Access Technologies, Cape Town, South Africa) pericardial TAVI system in the orthotopic aortic position of juvenile sheep., Methods and Results: A self-homing, non-occlusive balloon-expandable TAVI system comprising a hollow balloon, stabilising locator trunks, a scalloped CoCr stent with elevating anchorage arms and decellularised, sandwich-crosslinked pericardium was compared with control surgical valves (Edwards PERIMOUNT) in sheep. The implantation period was five months. The tactile placement of the TAVI valves was accomplished without the need for rapid pacing. At termination, no structural degeneration was observed in either group. The TAVIs were well healed with the stent struts largely embedded in tissue. Correlating with sheep growth (weight gain of 40.4±13.0%) during the implantation period, mean transvalvular gradients increased from 3.08±1.95 mmHg to 8.50±5.38 mmHg (p=0.044) after five months., Conclusions: A single-stage, balloon-expandable, easy to place TAVI system with antigen-depleted and antigen-masked bioprosthetic leaflets promises to address the distinct needs of low- and middle-income countries with regard to TAVI better than conventional systems.

Objectives: Patients with locally advanced non-small cell lung cancer (NSCLC) were included in a prospective trial for radiotherapy in deep inspiration breath hold (DIBH). We evaluated DIBH compliance and target position reproducibility., Methods: Voluntary, visually guided DIBHs were performed with optical tracking. Patients underwent three consecutive DIBH CT scans for radiotherapy planning. We evaluated the intrafractional uncertainties in the position of the peripheral tumour, lymph nodes and differential motion between them, enabling PTV margins calculation. Patients who underwent all DIBH imaging and had tumour position reproducibility <8 mm were up-front DIBH compliant. Patients who performed DIBHs throughout the treatment course were overall DIBH compliant. Clinical parameters and DIBH-related uncertainties were validated against our earlier pilot study., Results: 69 of 88 included patients received definitive radiotherapy. 60/69 patients (87%) were up-front DIBH compliant. DIBH plan was not superior in seven patients and three lost DIBH ability during the treatment, leaving 50/69 patients (72%) overall DIBH compliant.The systematic and random errors between consecutive DIBHs were small but differed from the pilot study findings. This led to slightly different PTV margins between the two studies., Conclusions: DIBH compliance and reproducibility was high. Still, this validation study highlighted the necessity of designing PTV margins in larger, representative patient cohorts., Advances in Knowledge: We demonstrated high DIBH compliance in locally advanced NSCLC patients. DIBH does not eliminate but mitigates the target position uncertainty, which needs to be accounted for in treatment margins. Margin design should be based on data from larger representative patient groups.

Purpose: We propose and simulate a model-based methodology to incorporate heterogeneous treatment benefit of proton therapy (PrT) versus photon therapy into randomized trial designs. We use radiation-induced pneumonitis (RP) as an exemplar. The aim is to obtain an unbiased estimate of how predicted difference in normal tissue complications probability (ΔNTCP) converts into clinical outcome on the patient level., Materials and Methods: ΔNTCP data from in silico treatment plans for photon therapy and PrT for patients with locally advanced lung cancer as well as randomly sampled clinical risk factors were included in simulations of trial outcomes. The model used at point of analysis of the trials was an iQUANTEC model. Trial outcomes were examined with Cox proportional hazards models, both in case of a correctly specified model and in a scenario where there is discrepancy between the dose metric used for ΔNTCP and the dose metric associated with the "true" clinical outcome, that is, when the model is misspecified. We investigated how outcomes from such a randomized trial may feed into a model-based estimate of the patient-level benefit from PrT, by creating patient-specific predicted benefit probability distributions., Results: Simulated trials showed benefit in accordance with that expected when the NTCP model was equal to the model for simulating outcome. When the model was misspecified, the benefit changed and we observed a reversal when the driver of outcome was high-dose dependent while the NTCP model was mean-dose dependent. By converting trial results into probability distributions, we demonstrated large heterogeneity in predicted benefit, and provided a randomized measure of the precision of individual benefit estimates., Conclusions: The design allows for quantifying the benefit of PrT referral, based on the combination of NTCP models, clinical risk factors, and traditional randomization. A misspecified model can be detected through a lower-than-expected hazard ratio per predicted ΔNTCP., Competing Interests: Conflicts of Interest: Ivan R. Vogelius, PhD, DMSc, has received grants and educational fees from Varian Medical Systems. Johannes A. Langendijk, MD, PhD, received honoraria from IBA for a consulting and advisory role and from IBA Speakers' Bureau, paid to the UMCG Research B.V. No other author declares conflicts of interest., (© Copyright 2019 International Journal of Particle Therapy.)

Endovascular treatment of thoracic aortic pathologies has recently progressed towards more proximal pathologies, including those of the aortic arch and ascending aorta where there is a higher risk for stent-graft migration during the deployment or the moulding procedure due to the beating and ejecting heart. Typical measures to prevent dislodgement of the balloon or the stent-graft during the procedure are rapid pacing or pharmacologically induced hypotension. We present a circular and fully non-occlusive stent-graft moulding balloon that does not require any reduction of cardiac output or hypotension during inflation, moulding and deflation of the balloon., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background and Purpose: Motion management in the treatment of lung cancer is necessary to assure highest quality of the delivered radiation therapy. In this study, the breath-hold technique is experimentally investigated for pencil beam scanned (PBS) proton therapy, with respect to the dosimetric effect of residual breath-hold motion., Material and Methods: Three-dimensional (3D)-printed tumours extracted from CT scans of three patients were inserted into a dynamic anthropomorphic breathing phantom. The target was set up to move with the individual patient's tumour motion during breath-hold as previously assessed on fluoroscopy. Target dose was measured with radio-chromic film, and both single field uniform dose (SFUD) and intensity-modulated proton therapy (IMPT) plans were delivered. Experiments were repeated for each patient without any motion, to compute the relative dose deviation between static and breath-hold cases., Results: SFUD plans showed small dose deviations between static and breath-hold cases, as evidenced by the gamma pass rate (3%, 3 mm) of 85% or higher. Dose deviation was more evident for IMPT plans, with gamma pass rate reduced to 50-70%., Conclusions: The breath-hold technique is robust to residual intra-breath-hold motion for SFUD treatment plans, based on our experimental study. IMPT was less robust with larger detected dose deviations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Although the results of aortic valve replacement are well documented for industrialized countries, the outcome in patients with rheumatic aortic valve disease in low- to middle-income countries is less well explored. The aim of this study was to determine the long-term survival and clinical outcomes after isolated aortic valve replacement in patients with rheumatic heart disease in a Sub-Saharan country where follow-up of indigent patients is often challenging., Methods: A retrospective review of 969 aortic valve replacements performed between 2003 and 2013 was conducted at Cape Town's Groote Schuur Hospital. Patients who underwent concomitant procedures (n = 664) or had nonrheumatic valve pathology (n = 185) were excluded. The mean age of the rheumatic cohort (n = 121) was 43.1 ± 11.6 years with a mean follow-up period of 6.14 ± 3.44 years. The primary end points were survival and valve-related complications., Results: A 15% cardiac- or valve-related 10-year mortality after receiving a mechanical prosthesis corresponded with a significantly higher mortality rate than that of a matched population. Overall cumulative survival at 1, 5, and 10 years was 93.5% (87.0-96.9), 86.4% (78.4-91.8), and 78.1% (67.5-86.0), respectively, and the corresponding cumulative freedom from combined thromboembolism and bleeding was 94.4% (88.2-97.5), 87.4% (79.4-92.5), and 86.1% (77.9-91.6), respectively., Conclusions: In low- to middle-income countries, with their unique mix of indigent and "First World" patients, rheumatic heart disease still accounts for a significant proportion of patients requiring isolated aortic valve replacement. Although mechanical prostheses are often selected in these young adults, survival remains suboptimal. Major bleeding and thromboembolic events account for the majority (77%) of the reported valve-related complications., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate breathing-motion induced interplay effects for stereotactic body radiotherapy (SBRT) of liver tumours treated with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT). Ten patients previously treated with liver SBRT were included in this study. All patients had four-dimensional computed tomography (4DCT) scans acquired prior to treatment. The 4DCT was sorted into 8-10 phases covering an equal time interval. A FFF VMAT plan was created for one fraction in the mid-ventilation phase for each patient. To generate dose distributions including both interplay effects and dose blurring, a sub-plan was calculated for each phase. The total dose distributions were accumulated to the mid-ventilation phase using the deformed vector fields (DVF) from deformable image registration between the corresponding CT and the mid-ventilation phase CT. A blurred dose distribution, not including interplay effects, was also obtained by distributing the delivery of the whole plan uniformly on all phases, and was similarly accumulated to the mid-ventilation phase. To isolate interplay effects, this blurred dose distribution was subtracted from the total dose distribution with interplay effects. The near minimum dose (D 98% ), mean dose (D mean ), heterogeneity index (HI), and the near minimum dose difference (ΔD 98% ) between the accumulated dose distributions with and without interplay effects were calculated within the gross tumour volume (GTV) for each patient. Comparing the accumulated dose distributions with and without interplay effects, the D 98% decreased for nine of the ten patients and the HI increased for all patients. The median and minimum differences in D 98% were  -2.1% and  -5.0% (p  =  0.006), respectively, and the median HI significantly increased from 6.2% to 12.2% (p  =  0.002). The median ΔD 98% was  -4.0% (range  -7% to  -1.5%). In conclusion, statistically significant breathing-induced interplay effects were observed for a single fraction of FFF VMAT liver SBRT, resulting in heterogeneous dose distributions within the GTV.

More than 6 billion people live outside industrialized countries and have insufficient access to cardiac surgery. Given the recently confirmed high prevailing mortality for rheumatic heart disease in many of these countries together with increasing numbers of patients needing interventions for lifestyle diseases due to an accelerating epidemiological transition, a significant need for cardiac surgery could be assumed. Yet, need estimates were largely based on extrapolated screening studies while true service levels remained unknown. A multi-author effort representing 16 high-, middle-, and low-income countries was undertaken to narrow the need assessment for cardiac surgery including rheumatic and lifestyle cardiac diseases as well as congenital heart disease on the basis of existing data deduction. Actual levels of cardiac surgery were determined in each of these countries on the basis of questionnaires, national databases, or annual reports of national societies. Need estimates range from 200 operations per million in low-income countries that are nonendemic for rheumatic heart disease to >1,000 operations per million in high-income countries representing the end of the epidemiological transition. Actually provided levels of cardiac surgery range from 0.5 per million in the assessed low- and lower-middle income countries (average 107 ± 113 per million; representing a population of 1.6 billion) to 500 in the upper-middle-income countries (average 270 ± 163 per million representing a population of 1.9 billion). By combining need estimates with the assessment of de facto provided levels of cardiac surgery, it emerged that a significant degree of underdelivery of often lifesaving open heart surgery does not only prevail in low-income countries but is also disturbingly high in middle-income countries., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

During the past decade transcatheter aortic valve implantation (TAVI) has revolutionized our approach to heart valve disease. Although largely applied to patients with calcific aortic valve stenosis, there is an unmet clinical need to also treat patients with aortic valve insufficiency in patients with non-calcific aortic valve disorders. The following Techno-College tutorial demonstrates our pre-clinical experience with a novel non-occlusive, self-homing TAVI system, developed with Strait Access Technologies, that we hope will improve outcomes for treatment of non-calcific aortic valve insufficiency., (© The Author 2016. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

During the past 50 years, median sternotomy has been the gold standard approach in cardiac surgery with excellent long-term outcomes. However, since the 1990 s, minimally invasive cardiac surgery (MICS) has gained wide acceptance due to patient and economic demand. The advantages include less surgical trauma, less bleeding, less wound infections, less pain and faster recovery of the patients. One of these MICS approaches is the J-shaped upper ministernotomy which results in favourable long-term outcomes even in elderly and redo patients when compared with conventional sternotomy. Owing to its similarity to a full midline sternotomy, it has become the most popular MICS approach besides a mini-thoracotomy. It is a safe and feasible access, but certain recognized principles are mandatory to minimize complications. After identification of the landmarks, the 5-cm skin incision is performed in the midline between the second and fourth rib. The third or fourth right intercostal space is located and dissected laterally off the sternum. After osteotomy, the pericardium is pulled up with stay sutures which allow excellent exposure. The surgical procedures are performed in a standard fashion with central cannulation. Continuous CO2 insufflation is used to minimize the risk of air embolism. Epicardial pacing wires are placed before the removal of the aortic cross-clamp and one chest tube is used. Sternal closure is achieved with three to five stainless steel wires. The pectoral muscle, subcutaneous tissue and skin are adapted with resorbable running sutures. When performed properly, complications are rare (conversion, bleeding and wound infection) and well manageable., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: While transcatheter aortic valve implantation (TAVI) has rapidly evolved for the treatment of aortic valve disease, the currently used bioprostheses are prone to continuous calcific degeneration. Thus, autologous, cell-based, living, tissue-engineered heart valves (TEHVs) with regeneration potential have been suggested to overcome these limitations. We investigate the technical feasibility of combining the concept of TEHV with transapical implantation technology using a state-of-the-art transcatheter delivery system facilitating the exact anatomical position in the systemic circulation., Methods: Trileaflet TEHVs fabricated from biodegradable synthetic scaffolds were sewn onto self-expanding Nitinol stents seeded with autologous marrow stromal cells, crimped and transapically delivered into the orthotopic aortic valve position of adult sheep (n = 4) using the JenaValve transapical TAVI System (JenaValve, Munich, Germany). Delivery, positioning and functionality were assessed by angiography and echocardiography before the TEHV underwent post-mortem gross examination. For three-dimensional reconstruction of the stent position of the anatomically oriented system, a computed tomography analysis was performed post-mortem., Results: Anatomically oriented, transapical delivery of marrow stromal cell-based TEHV into the orthotopic aortic valve position was successful in all animals (n = 4), with a duration from cell harvest to TEHV implantation of 101 ± 6 min. Fluoroscopy and echocardiography displayed sufficient positioning, thereby entirely excluding the native leaflets. There were no signs of coronary obstruction. All TEHV tolerated the loading pressure of the systemic circulation and no acute ruptures occurred. Animals displayed intact and mobile leaflets with an adequate functionality. The mean transvalvular gradient was 7.8 ± 0.9 mmHg, and the mean effective orifice area was 1.73 ± 0.02 cm(2). Paravalvular leakage was present in two animals, and central aortic regurgitation due to a single-leaflet prolapse was detected in two, which was primarily related to the leaflet design. No stent dislocation, migration or affection of the mitral valve was observed., Conclusions: For the first time, we demonstrate the technical feasibility of a transapical TEHV delivery into the aortic valve position using a commercially available and clinically applied transapical implantation system that allows for exact anatomical positioning. Our data indicate that the combination of TEHV and a state-of-the-art transapical delivery system is feasible, representing an important step towards translational, transcatheter-based TEHV concepts.

Objectives: Atrial fibrillation (AF) is a significant risk factor for embolic stroke originating from the left atrial appendage (LAA). This is the first report of long-term safety and efficacy data on LAA closure using a novel epicardial LAA clip device in patients undergoing cardiac surgery., Methods: Forty patients with AF were enrolled in this prospective 'first-in-man' trial. The inclusion criterion was elective cardiac surgery in adult patients with AF for which a concomitant ablation procedure was planned. Intraoperative transoesophageal echocardiography (TEE) was used to exclude LAA thrombus at baseline and evaluate LAA perfusion after the procedure, while computed tomography (CT) was used for serial imagery workup at baseline, 3-, 12-, 24- and 36-month follow-up., Results: Early mortality was 10% due to non-device-related reasons, and thus 36 patients were included in the follow-up consisting of 1285 patient-days and mean duration of 3.5 ± 0.5 years. On CT, clips were found to be stable, showing no secondary dislocation 36 months after surgery. No intracardial thrombi were seen, none of the LAA was reperfused and in regard to LAA stump, none of the patients demonstrated a residual neck >1 cm. Apart from one unrelated transient ischaemic attack (TIA) that occurred 2 years after surgery in a patient with carotid plaque, no other strokes and/or neurological events demonstrated in any of the studied patients during follow-up., Conclusion: This is the first prospective trial in which concomitant epicardial LAA occlusion using this novel epicardial LAA clip device is 100% effective, safe and durable in the long term. Closure of the LAA by epicardial clipping is applicable to all-comers regardless of LAA morphology. Minimal access epicardial LAA clip closure may become an interesting therapeutic option for patients in AF who are not amenable to anticoagulation and/or catheter closure. Further data are necessary to establish LAA occlusion as a true and viable therapy for stroke prevention., Clinical Trial Registration: The trial is registered at www.ClinicalTrials.gov, reference: NCT00567515.

Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Surgical revascularization remains the standard of care for many patients. Off-pump coronary artery bypass grafting (OPCAB) without cardiopulmonary bypass (CPB) has evolved during the past 20 years, and as such can significantly reduce the occurrence of neurological complications. While avoiding the aortic cross-clamping required in conventional on-pump techniques, OPCAB results in a lower incidence of stroke. However, clamp-related risk of stroke remains if partial or side-biting clamps are applied for proximal anastomoses. Others and we have demonstrated that no-touch 'anaortic' approaches avoiding any clamping during off-pump procedures via complete in situ grafting result in significantly reduced stroke rates when compared with partial clamping. Therefore, OPCAB in situ grafting has been proposed as the 'standard of care' to reduce neurological complications. However, this technique may not be applicable to for every patient as the use of free grafts (arterial or venous) requiring proximal anastomosis is often still necessary to achieve complete revascularization. In these situations, proximal anastomosis can be performed without a partial clamp by using the HEARTSTRING device, and over the last few years, considerable evidence has arisen supporting the impact of HEARTSTRING-enabled anastomosis to significantly minimize atheroembolism and neurological complications when compared with partial- or side-bite clamping. This paper provides a systematic overview and technical information about the combination of OPCAB and clampless strategies using the HEARTSTRING for proximal anastomosis to reduce stroke to levels reported for percutaneous coronary intervention.

Background: Surgical revascularization is the most appropriate therapy for patients with significant left main coronary-artery disease (LMD). An incidence of perioperative stroke remains an issue when compared to the early outcomes to percutaneous coronary intervention (PCI). This study evaluates the safety and impact of standardized "clampless" OPCAB techniques, composed of either complete in situ grafting or "clampless" device enabled techniques for stroke reduction in patients undergoing surgical revascularization for LMD., Methods: Between 1999 and 2009, 1031 patients with LMD underwent myocardial-revascularization at our institution. Of these, 507 patients underwent "clampless" OPCAB and 524 patients underwent conventional on-pump CABG (ONCABG). Data-collection was performed prospectively and a propensity-adjusted regression-analysis was applied to balance patient characteristics. LMD was defined as a stenosis >50% and endpoints were mortality, stroke, a cardiac-composite (including death, stroke and myocardial-infarction); a non-cardiac composite and complete-revascularization., Results: In OPCAB patients, the cardiac composite (3.0% vs. 7.8%; propensity-adjusted (PA)OR=0.27; CI95% 0.12-0.65; p=0.003) as well as the occurrence of stroke (0.4% vs. 2.9%; PAOR=0.04; CI95% 0.003-0.48; p=0.012) were significantly lower while the mortality-rate was well comparable between groups (1.8% vs. 2.5%; PAOR=0.44; CI95% 0.11-1.71; p=0.24). The non-cardiac composite was also significantly decreased after OPCAB (8.9% vs. 19.7%; PAOR=0.55; CI95% 0.34-0.89; p=0.014) and complete revascularization was achieved for similar proportions in both groups (95.1% vs. 93.7%; p=0.35)., Conclusions: This study shows the superiority of OPCAB for patients with LMD with regards to risk-adjusted outcomes other than mortality. A "clampless OPCAB strategy", effectively reduces stroke yielding similar early outcomes as PCI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk., Objective: To identify clinical and periprocedural factors that may have an impact on clinical outcome., Design: Multi-centre longitudinal cohort study., Setting: Tertiary referral centres., Patients: Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate-severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%., Interventions: MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia., Main Outcome Measures: Clinical, echocardiographic and procedural data were prospectively collected., Results: Acute procedural success (APS, defined as successful clip implantation with residual MR grade ≤2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival., Conclusions: In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR.

Objectives: Different flow patterns and shear forces were shown to cause significantly more luminal narrowing and neointimal tissue proliferation in coronary than in infrainguinal vein grafts. As constrictive external mesh support of vein grafts led to the complete suppression of intimal hyperplasia (IH) in infrainguinal grafts, we investigated whether mesh constriction is equally effective in the coronary position., Methods: Eighteen senescent Chacma baboons (28.8 ± 3.6 kg) received aorto-coronary bypass grafts to the left anterior descending artery (LAD). Three groups of saphenous vein grafts were compared: untreated controls (CO); fibrin sealant-sprayed controls (CO + FS) and nitinol mesh-constricted grafts (ME + FS). Meshes consisted of pulse-compliant, knitted nitinol (eight needles; 50 μm wire thickness; 3.4 mm resting inner diameter, ID) spray attached to the vein grafts with FS. After 180 days of implantation, luminal dimensions and IH were analysed using post-explant angiography and macroscopic and histological image analysis., Results: At implantation, the calibre mismatch between control grafts and the LAD expressed as cross-sectional quotient (Qc) was pronounced [Qc = 0.21 ± 0.07 (CO) and 0.18 ± 0.05 (CO + FS)]. Mesh constriction resulted in a 29 ± 7% reduction of the outer diameter of the vein grafts from 5.23 ± 0.51 to 3.68 ± 0 mm, significantly reducing the calibre discrepancy to a Qc of 0.41 ± 0.17 (P < 0.02). After 6 months of implantation, explant angiography showed distinct luminal irregularities in control grafts (ID difference between widest and narrowest segment 74 ± 45%), while diameter variations were mild in mesh-constricted grafts. In all control grafts, thick neointimal tissue was present [600 ± 63 μm (CO); 627 ± 204 μm (CO + FS)] as opposed to thin, eccentric layers of 249 ± 83 μm in mesh-constricted grafts (ME + FS; P < 0.002). The total wall thickness had increased by 363 ± 39% (P < 0.00001) in CO and 312 ± 61% (P < 0.00001) in CO + FS vs 82 ± 61% in ME + FS (P < 0.007)., Conclusions: In a senescent non-human primate model for coronary artery bypass grafts, constrictive, external mesh support of saphenous veins with knitted nitinol prevented focal, irregular graft narrowing and suppressed neointimal tissue proliferation by a factor of 2.5. The lower degree of suppression of IH compared with previous infrainguinal grafts coincided with a lesser reduction of calibre mismatch in the coronary grafts.

Objective: Obesity is highly prevalent in modern patient populations. Several studies have published conflicting outcomes after minimally invasive surgery with regard to morbidity and mortality. Some instances consider obesity as a relative contraindication for this approach because of inadequate exposure of the surgical field. Our aim was to investigate the outcomes of minimally invasive mitral valve surgery through a right lateral minithoracotomy in patients with a body mass index (BMI) of 30 kg/m2 or greater., Methods: We conducted a retrospective database review between January 1, 2009, and December 31, 2011. Preoperative, intraoperative, postoperative, and follow-up data of 225 consecutive patients were collected., Results: The patients were stratified according to their BMI: 108 had a normal weight with a BMI of lower than 25 kg/m2 (18-24), 90 were overweight with a BMI of 25 to 29 kg/m2, and 27 were obese with a BMI of 30 kg/m2 (30-41) or greater. Statistical analysis showed significantly longer ventilation times in the obese group, whereas all other variables were similar. Survival, major adverse cardiac and cerebrovascular event-free survival, valve competency, and freedom from reoperation were also comparable., Conclusions: Our data suggest that obesity should not deter a surgeon from selecting a minimally invasive approach. Despite longer postoperative ventilation times, a BMI of 30 kg/m2 or greater does not influence short- and medium-term outcome. Obese patients may even benefit from this approach because it avoids the need for sternotomy and therefore reduces the risk for sternal wound infection.

Stem cells have been repeatedly suggested for cardiac regeneration after myocardial infarction (MI). However, the low retention rate of single cell suspensions limits the efficacy of current therapy concepts so far. Taking advantage of three dimensional (3D) cellular self-assembly prior to transplantation may be beneficial to overcome these limitations. In this pilot study we investigate the principal feasibility of intramyocardial delivery of in-vitro generated stem cell-based 3D microtissues (3D-MTs) in a porcine model. 3D-MTs were generated from iron-oxide (MPIO) labeled human adipose-tissue derived mesenchymal stem cells (ATMSCs) using a modified hanging-drop method. Nine pigs (33 ± 2 kg) comprising seven healthy ones and two with chronic MI in the left ventricle (LV) anterior wall were included. The pigs underwent intramyocardial transplantation of 16 × 10(3) 3D-MTs (1250 cells/MT; accounting for 2 × 10(7) single ATMSCs) into the anterior wall of the healthy pigs (n = 7)/the MI border zone of the infarcted (n = 2) of the LV using a 3D NOGA electromechanical mapping guided, transcatheter based approach. Clinical follow-up (FU) was performed for up to five weeks and in-vivo cell-tracking was performed using serial magnet resonance imaging (MRI). Thereafter, the hearts were harvested and assessed by PCR and immunohistochemistry. Intramyocardial transplantation of human ATMSC based 3D-MTs was successful in eight animals (88.8%) while one pig (without MI) died during the electromechanical mapping due to sudden cardiac-arrest. During FU, no arrhythmogenic, embolic or neurological events occurred in the treated pigs. Serial MRI confirmed the intramyocardial presence of the 3D-MTs by detection of the intracellular iron-oxide MPIOs during FU. Intramyocardial retention of 3D-MTs was confirmed by PCR analysis and was further verified on histology and immunohistochemical analysis. The 3D-MTs appeared to be viable, integrated and showed an intact micro architecture. We demonstrate the principal feasibility and safety of intramyocardial transplantation of in-vitro generated stem cell-based 3D-MTs. Multimodal cell-tracking strategies comprising advanced imaging and in-vitro tools allow for in-vivo monitoring and post-mortem analysis of transplanted 3D-MTs. The concept of 3D cellular self-assembly represents a promising application format as a next generation technology for cell-based myocardial regeneration., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI), key-questions regarding the in-vivo cell-fate remain unknown. While most available animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70-75 days) were included. Ten animals either received an intra-uterine induction of MI only (n = 4) or MI+intra-myocardial injection (IMI;n = 6) using micron-sized, iron-oxide (MPIO) labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n = 3) or the bone-marrow (BMMSCs;n = 3). Three animals received an intra-peritoneal injection (IPI;n = 3; ATMSCs;n = 2/BMMSCs;n = 1). All procedures were performed successfully and follow-up was 7-9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×10(5)-5×10(5) human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific β-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow-Cytometry detected the cells within spleen, lungs, kidneys, thymus, bone-marrow and intra-peritoneal lavage, but not within the heart. For the first time we demonstrate the feasibility of intra-uterine, intra-myocardial stem-cell transplantation into the pre-immune fetal-sheep after MI. Utilizing cell-tracking strategies comprising advanced imaging-technologies and in-vitro tracking-tools, this novel model may serve as a unique platform to assess human cell-fate after intra-myocardial transplantation without the necessity of immunosuppressive-therapy.

Mitral valve (MV) insufficiency is the second most common heart valve disease represented in cardiac surgery. The gold standard therapy is surgical repair of the valve. Today, most centers prefer a minimally invasive approach through a right-sided mini-thoracotomy. Despite the small access, there is still the need to use cardiopulmonary bypass (CPB), and the operation has to be performed on the arrested heart. New devices have been developed to optimize the results of surgical repair by implementing mechanisms for post-implantation adjustment on the beating heart or the avoidance of CPB. Early attempts with adjustable mitral annuloplasty rings go back to the early 1990s. Only a few devices are available on the market. Recently, a mitral valve adjustable annuloplasty ring was CE-marked and is under further clinical investigation. In addition, a sutureless annuloplasty band to be implanted on the beating heart is under preclinical and initial clinical investigation for transatrial and transfemoral transcatheter implantation. Furthermore, new neochord systems are being developed, which allow for functional length adjustment on the beating heart after implantation. Some devices were developed for percutaneous MV repair implanted into the coronary sinus to reshape the posterior MV annulus. Other percutaneous devices are directly fixed to the posterior annulus to alter its shape. Several disadvantages have been observed preventing a broad clinical use of some of these devices. There is a continuous effort to develop innovative techniques to optimize MV repair and to decrease invasiveness.