Staphylococcus lugdunensis infective endocarditis with perforation of the sinus of Valsalva: a case report.

Background: Staphylococcus lugdunensis endocarditis is a rare but fulminant disease. Case summary: A 74-year-old female with a history of asymptomatic severe aortic valve stenosis and permanent atrial fibrillation presented with acute onset of fever (39.0°C). Electrocardiogram showed diffuse ST-segment elevation. She was hospitalized for further analysis. All blood cultures were positive for Staphylococcus lugdunensis and antibiotic treatment was started. Transthoracic echocardiography (TTE) showed known aortic valve stenosis without clear signs of endocarditis. The following day, a transoesophageal echocardiogram (TEE) showed a new moderate aortic valve regurgitation, new pericardial effusion (PE), and a thickened sinus of Valsalva (SOV) consistent with endocarditis with paravalvular involvement. Positron emission tomography-computed tomography was consistent with aortic valve endocarditis with paravalvular expansion. The patient was transferred to a tertiary referral centre for surgical treatment. On admission, patient was in shock and a second TTE revealed a new systolic and diastolic flow through the SOV to the right ventricle indicating SOV perforation. Additionally, there was flow in the PE suggestive of perforation of one of the cardiac chambers or large vessels. Emergent surgery showed extended infection with SOV perforation and a large perforation of the right ventricle. Ultimately, patient died during the operation because of extensive infection and refractory shock. Conclusion: Staphylococcus lugdunensis endocarditis is a severe disease with poor response to conventional anti-microbial treatment, destructive complications requiring surgery, and has a high mortality risk.

Screening, diagnosis and follow-up of Brugada syndrome in children: a Dutch expert consensus statement.

Brugada syndrome (BrS) is a rare inherited arrhythmia syndrome. Affected children may experience life-threatening symptoms, mainly during fever. The percentage of SCN5A variant carriers in children is higher than in adults. Current diagnostic and follow-up policies for children with (a family history of) BrS vary between centres. Here, we present a consensus statement based on the current literature and expert opinions to standardise the approach for all children with BrS and those from BrS families in the Netherlands. In summary, BrS is diagnosed in patients with a spontaneous type 1 electrocardiogram (ECG) pattern or with a Shanghai score ≥ 3.5 including ≥ 1 ECG finding. A sodium channel-blocking drug challenge test should only be performed after puberty with a few exceptions. A fever ECG is indicated in children with suspected BrS, in children with a first-degree family member with definite or possible BrS according to the Shanghai criteria with a SCN5A variant and in paediatric SCN5A variant carriers. In-hospital rhythm monitoring during fever is indicated in patients with an existing type 1 ECG pattern and in those who develop such a pattern. Genetic testing should be restricted to SCN5A. Children with BrS and children who carry an SCN5A variant should avoid medication listed at www.brugadadrugs.org and fever should be suppressed. Ventricular arrhythmias or electrical storms should be treated with isoproterenol infusion.

The impact of implementing an endocarditis team in comparison to the classic heart team in a tertiary referral centre.

BACKGROUND: Infective endocarditis (IE) is a complex disease for which the European Society of Cardiology guideline recommends a dedicated multidisciplinary endocarditis team (ET) approach since 2015. It is currently unknown whether this ET approach is beneficial compared to a classic heart team approach including bedside consultation by an infectious disease specialist in Western Europe. METHODS: This retrospective single centre, observational cohort study was conducted at the Radboudumc, a tertiary referral centre in the Netherlands. Consecutive patients treated for IE were included from September 2017 to September 2018 before implementation of a dedicated ET and from May 2019 to May 2020 afterwards. RESULTS: In total, 90 IE patients (45 patients before and 45 patients after the implementation of the ET) were included. No significant differences were found in diagnostic workup, surgical treatment (surgery performed 69% vs. 71%, p = 0.82), time to surgery because of an urgent indication (median 4 vs. 6 days, p = 0.82), in-hospital complications (53% vs. 67%, p = 0.20), and 6-month mortality (11% vs. 13%, p = 0.75) between IE patients treated before and after the implementation of the ET. CONCLUSION: Formalization of the recommended multidisciplinary endocarditis team might not significantly improve the complication rate nor the short term outcome.

Comparison between myocardial function assessed by echocardiography during hospitalization for COVID-19 and at 4 months follow-up.

In patients hospitalized for corona virus infectious disease 19 (COVID-19) it is currently unknown whether myocardial function changes after recovery and whether this is related to elevated cardiac biomarkers. In this single center, prospective cohort study we consecutively enrolled hospitalized COVID-19 patients between 1 April and 12 May 2020. All patients underwent transthoracic echocardiography (TTE) evaluation during hospitalization and at a median of 131 days (IQR; 116-136) follow-up. Of the 51 patients included at baseline, 40 (age: 62 years (IQR; 54-68), 78% male) were available for follow-up TTE. At baseline, 68% of the patients had a normal TTE, regarding left ventricular (LV) and right ventricular (RV) volumes and function, compared to 83% at follow-up (p = 0.07). Median LV ejection fraction (60% vs. 58%, p = 0.54) and tricuspid annular plane systolic excursion (23 vs 22 mm, p = 0.18) were comparable between hospitalization and follow-up, but a significantly lower RV diameter (39 vs. 34 mm, p = 0.002) and trend towards better global longitudinal strain (GLS) (- 18.5% vs - 19.1%, p = 0.07) was found at follow-up. Subgroup analysis showed no relation between patients with and without elevated TroponinT and/or NT-proBNP during hospitalization and myocardial function at follow-up. Although there were no significant differences in individual myocardial function parameters at 4 months follow-up compared to hospitalisation for COVID-19, there was an overall trend towards normalization in myocardial function, predominantly due to a higher rate of normal GLS at follow-up.

Development of robustness evaluation strategies for enabling statistically consistent reporting.

Robustness evaluation of proton therapy treatment plans is essential for ensuring safe treatment delivery. However, available evaluation procedures feature a limited exploration of the actual robustness of the plan and generally do not provide confidence levels. This study compared established and more sophisticated robustness evaluation procedures, with quantified confidence levels. We have evaluated several robustness evaluation methods for 5 bilateral head-and-neck patients optimized considering spot scanning delivery and with a conventional CTV-to-PTV margin of 4 mm. Method (1) good practice scenario selection (GPSS) (e.g. +/- 4 mm setup error 3% range uncertainty); (2) statistically sound scenario selection (SSSS) either only on or both on and inside isoprobability hypersurface encompassing 90% of the possible errors; (3) statistically sound dosimetric selection (SSDS). In the last method, the 90% best plans were selected according to either target coverage quantified by D 95 (SSDS_D 95) or to an approximation of the final objective function (OF) used during treatment optimization (SSDS_OF). For all methods, we have considered systematic setup and systematic range errors. A mix of systematic and random setup errors were also simulated for SSDS, but keeping the same conventional margin of 4 mm. All robustness evaluations have been performed using the fast Monte Carlo dose engine MCsquare. Both SSSS strategies yielded on average very similar results. SSSS and GPSS yield comparable values for target coverage (within 0.5 Gy). The most noticeable differences were found for the CTV between GPSS, on the one hand, and SSDS_D 95 and SSDS_OF, on the other hand (average worst-case D 98 were 2.8 and 2.0 Gy larger than for GPSS, respectively). Simulating explicitly random errors in SSDS improved almost all DVH metrics. We have observed that the width of DVH-bands and the confidence levels depend on the method chosen to sample the scenarios. Statistically sound estimation of the robustness of the plan in the dosimetric space may provide an improved insight on the actual robustness of the plan for a given confidence level.

Cardiac function in relation to myocardial injury in hospitalised patients with COVID-19.

BACKGROUND: Previous studies have reported on myocardial injury in patients with coronavirus infectious disease 19 (COVID-19) defined as elevated cardiac biomarkers. Whether elevated biomarkers truly represent myocardial dysfunction is not known. The aim of this study was to explore the incidence of ventricular dysfunction and assess its relationship with biomarker analyses. METHODS: This cross-sectional study ran from April 1 to May 12, 2020, and consisted of all consecutively admitted patients to the Radboud university medical centre nursing ward for COVID-19. Laboratory assessment included high-sensitivity Troponin T and N­terminal pro-B-type natriuretic peptide (NT-proBNP). Echocardiographic evaluation focused on left and right ventricular systolic function and global longitudinal strain (GLS). RESULTS: In total, 51 patients were included, with a median age of 63 years (range 51-68 years) of whom 80% was male. Troponin T was elevated (>14 ng/l) in 47%, and a clinically relevant Troponin T elevation (10â€¯× URL) was found in three patients (6%). NT-proBNP was elevated (>300 pg/ml) in 24 patients (47%), and in four (8%) the NT-proBNP concentration was >1,000 pg/ml. Left ventricular dysfunction (ejection fraction <52% and/or GLS >-18%) was observed in 27%, while right ventricular dysfunction (TAPSE <17 mm and/or RV S' < 10 cm/s) was seen in 10%. There was no association between elevated Troponin T or NT-proBNP and left or right ventricular dysfunction. Patients with confirmed pulmonary embolism had normal right ventricular function. CONCLUSIONS: In hospitalised patients, it seems that COVID-19 predominantly affects the respiratory system, while cardiac dysfunction occurs less often. Based on a single echocardiographic evaluation, we found no relation between elevated Troponin T or NT-proBNP, and ventricular dysfunction. Echocardiography has limited value in screening for ventricular dysfunction.

Proton vs photon: A model-based approach to patient selection for reduction of cardiac toxicity in locally advanced lung cancer.

PURPOSE/OBJECTIVE: To use a model-based approach to identify a sub-group of patients with locally advanced lung cancer who would benefit from proton therapy compared to photon therapy for reduction of cardiac toxicity. MATERIAL/METHODS: Volumetric modulated arc photon therapy (VMAT) and robust-optimised intensity modulated proton therapy (IMPT) plans were generated for twenty patients with locally advanced lung cancer to give a dose of 70 Gy (relative biological effectiveness (RBE)) in 35 fractions. Cases were selected to represent a range of anatomical locations of disease. Contouring, treatment planning and organs-at-risk constraints followed RTOG-1308 protocol. Whole heart and ub-structure doses were compared. Risk estimates of grade⩾3 cardiac toxicity were calculated based on normal tissue complication probability (NTCP) models which incorporated dose metrics and patients baseline risk-factors (pre-existing heart disease (HD)). RESULTS: There was no statistically significant difference in target coverage between VMAT and IMPT. IMPT delivered lower doses to the heart and cardiac substructures (mean, heart V5 and V30, P < .05). In VMAT plans, there were statistically significant positive correlations between heart dose and the thoracic vertebral level that corresponded to the most inferior limit of the disease. The median level at which the superior aspect of the heart contour began was the T7 vertebrae. There was a statistically significant difference in dose (mean, V5 and V30) to the heart and all substructures (except mean dose to left coronary artery and V30 to sino-atrial node) when disease overlapped with or was inferior to the T7 vertebrae. In the presence of pre-existing HD and disease overlapping with or inferior to the T7 vertebrae, the mean estimated relative risk reduction of grade⩾3 toxicities was 24-59%. CONCLUSION: IMPT is expected to reduce cardiac toxicity compared to VMAT by reducing dose to the heart and substructures. Patients with both pre-existing heart disease and tumour and nodal spread overlapping with or inferior to the T7 vertebrae are likely to benefit most from proton over photon therapy.

KinCor, a national registry for paediatric patients with congenital and other types of heart disease in the Netherlands: aims, design and interim results.

OBJECTIVE: Studies in children with heart disease have been hampered by a lack of easily identifiable patient groups. Currently, there are few prospective population-based registries covering the entire spectrum of heart disease in children. KinCor is a Dutch national registry for children with heart diseases. This paper presents the aims, design and interim results of the KinCor project. METHODS: All children presenting at a Dutch university medical centre with a diagnosis of heart disease from 2012 onwards were eligible for registration in the KinCor database. Data entry is through a web-based portal. Entry codes have been synchronised with the European Paediatric Cardiac Coding system, allowing coupling with similar databases for adults, such as CONCOR. RESULTS: Between June 2012 and July 2015, 8421 patients were registered (76 % of those eligible). Median age of the patients was 9.8 years, 44.7 % were female; 6782 patients had morphological congenital heart disease. The most prevalent morphological congenital heart defects were ventricular septal defects (18 %), Tetralogy of Fallot (10 %) and transposition of great arteries (9 %). For 42 % of the patients additional diagnoses were registered. Sixty percent of patients had undergone at least one intervention (catheter intervention or surgery). CONCLUSION: The KinCor database has developed into a large registry of data of children with all types of heart disease and continues to grow. This database will provide the opportunity for epidemiological research projects on congenital and other types of heart disease in children. Entry codes are shared with the CONCOR database, which may provide a unique dataset.

Occurrence of pharmaceuticals and endocrine disrupting compounds in macroalgaes, bivalves, and fish from coastal areas in Europe.

The occurrence and levels of PhACs, Endocrine Disrupting and related Compounds (EDCs) in seafood from potential contaminated areas in Europe has been studied. Macroalgae (Saccharina latissima and Laminaria digitata), bivalves (Mytilus galloprovincialis, Mytilus spp., Chamalea gallina and Crassostrea gigas) and fish (Liza aurata and Platichthys flesus) from Portugal, Spain, Italy, Netherlands, and Norway were analysed following 4 different analytical protocols depending on the organism and target group of contaminants. The results revealed the presence of 4 pharmaceutical compounds in macroalgae samples, 16 in bivalves and 10 in fish. To the best of our knowledge, this is the first time that PhACs have been detected in marine fish and in macroalgae. Besides, this is also the first time that dimetridazole, hydrochlorothiazide and tamsulosin have been detected in biota samples. The highest levels of PhACs corresponded to the psychiatric drug velanfaxine (up to 36.1 ng/g dry weight (dw)) and the antibiotic azithromycin (up to 13.3 ng/g dw) in bivalves from the Po delta (Italy). EDCs were not detected in macroalgae samples, however, the analysis revealed the presence of 10 EDCs in bivalves and 8 in fish. The highest levels corresponded to the organophosphorus flame retardant tris(2-butoxyethyl)phosphate (TBEP) reaching up to 98.4 ng/g dw in mullet fish from the Tagus estuary. Bivalves, in particular mussels, have shown to be good bioindicator organisms for PhACs and fish for EDCs. Taking into consideration the concentrations and frequencies of detection of PhACs and EDCs in the seafood samples analysed, a list of candidates' compounds for priorization in future studies has been proposed.

Co-occurrence of musk fragrances and UV-filters in seafood and macroalgae collected in European hotspots.

In the last decades, awareness regarding personal care products (PCP), i.e. synthetic organic chemicals frequently used in cosmetic and hygienic products, has become a forward-looking issue, due to their persistency in the environment and their potential multi-organ toxicity in both human and wildlife. Seafood is one of the most significant food commodities in the world and, certainly, one of the most prone to bioaccumulation of PCP, what can consequently lead to human exposure, especially for coastal population, where its consumption is more marked. The aim of this work was to evaluate the co-occurrence of musk fragrances and UV-filters in both seafood and macroalgae collected in different European hotspots (areas with high levels of pollution, highly populated and near wastewater treatment plants). Despite the fact that UV-filters were detected in three different kind of samples (mussel, mullet, and clam), in all cases they were below the limit of quantification. Galaxolide (HHCB) and tonalide (AHTN) were the musk fragrances most frequently detected and quantified in samples from the European hotspots. Cashmeran (DPMI) was also detected in most samples but only quantified in two of them (flounder/herring and mullet). The highest levels of HHCB and AHTN were found in mussels from Po estuary.

Calibrating page sized Gafchromic EBT3 films.

PURPOSE: The purpose is the development of a novel calibration method for dosimetry with Gafchromic EBT3 films. The method should be applicable for pretreatment verification of volumetric modulated arc, and intensity modulated radiotherapy. Because the exposed area on film can be large for such treatments, lateral scan errors must be taken into account. The correction for the lateral scan effect is obtained from the calibration data itself. METHODS: In this work, the film measurements were modeled using their relative scan values (Transmittance, T). Inside the transmittance domain a linear combination and a parabolic lateral scan correction described the observed transmittance values. The linear combination model, combined a monomer transmittance state (T(0)) and a polymer transmittance state (T(∞)) of the film. The dose domain was associated with the observed effects in the transmittance domain through a rational calibration function. On the calibration film only simple static fields were applied and page sized films were used for calibration and measurements (treatment verification). Four different calibration setups were considered and compared with respect to dose estimation accuracy. The first (I) used a calibration table from 32 regions of interest (ROIs) spread on 4 calibration films, the second (II) used 16 ROIs spread on 2 calibration films, the third (III), and fourth (IV) used 8 ROIs spread on a single calibration film. The calibration tables of the setups I, II, and IV contained eight dose levels delivered to different positions on the films, while for setup III only four dose levels were applied. Validation was performed by irradiating film strips with known doses at two different time points over the course of a week. Accuracy of the dose response and the lateral effect correction was estimated using the dose difference and the root mean squared error (RMSE), respectively. RESULTS: A calibration based on two films was the optimal balance between cost effectiveness and dosimetric accuracy. The validation resulted in dose errors of 1%-2% for the two different time points, with a maximal absolute dose error around 0.05 Gy. The lateral correction reduced the RMSE values on the sides of the film to the RMSE values at the center of the film. CONCLUSIONS: EBT3 Gafchromic films were calibrated for large field dosimetry with a limited number of page sized films and simple static calibration fields. The transmittance was modeled as a linear combination of two transmittance states, and associated with dose using a rational calibration function. Additionally, the lateral scan effect was resolved in the calibration function itself. This allows the use of page sized films. Only two calibration films were required to estimate both the dose and the lateral response. The calibration films were used over the course of a week, with residual dose errors ≤2% or ≤0.05 Gy.

Psychological functioning and disease-related quality of life in pediatric patients with an implantable cardioverter defibrillator.

The objective of this multicenter study was to evaluate psychological functioning and disease-related quality of life (DRQoL) in pediatric patients with an implantable cardioverter defibrillator (ICD) in The Netherlands. Thirty patients were investigated; the mean age was 16.3 years, and the mean duration of implantation was 3.6 years. To assess psychological problems, three domains of the Symptom Checklist (SCL-90-R) were administered to the 25 patients[13 years old. DRQoL was assessed with a disease-specific pediatric questionnaire, the short-form 11-item Worries About (WA)ICDs Scale. Patients C13 years old scored significantly higher than the reference group on the domains of anxiety, depression, and sleeping problems of the SCL-90-R (T = 7.5, p\0.001; T = 5.4, p\0.001; and T = 7.8, p\0.001, respectively). Patients who had received an (in)appropriate shock reported more depressive symptoms (T = 2.1, p\0.03). Patients with [2 years implant duration (N = 19) or who had received an (in)appropriate shock (N = 13) showed lower DRQoL scores on the modified WAICD (T = 2.1, p\0.04; T = 2.1, p\0.5, respectively). Age at implantation or underlying disease did not influence psychological problems or DRQoL. Young ICD patients showed more anxiety, depression, and sleeping disorders. Worries were increased among patients with ICD shocks and in those who had their ICD implanted for[2 years. To determine psychological problems and help children to learn to cope with shocks, proper guidance and monitoring of young ICD patients are recommended.

TU-G-BRCD-03: Managing Patient and Organ Motion in Proton Therapy.

BACKGROUND: The advent of proton based therapy has provided excitement in the radiation oncology community. Not in the least due to the theoretically advantageous geometrical properties of the dose deposition by such charged particles. In this presentation I will discuss the some of the challenges, which can make this tool sub-optimal when used in clinical practice with actual patients. METHODOLOGY: Data and analysis on patient setup variations and organ movement, gathered from "classical" photon therapy is projected to this new modality. Inter and intra fractional movement will be covered as well as the notion of margin determination in order to provide adequate coverage and in what way this makes sense. In addition, the time frame with which these uncertainties occur implies that different measures need to be taken and the use of in room imaging might be needed. Further, the advent of scanning techniques again provide an advantage as well as a disadvantage as far as movement is concerned. CONCLUSIONS: Proton therapy is a promising technique and exciting on a clinical and scientific level. In order to show significant improvement, knowledge with regard to targfet determination, as well as positioning is more critical in comparison with the classical modalities. LEARNING OBJECTIVES: 1. Knowledge on patient and/or organ movements motion effects. 2. Categorizing the movement in time and space. 3. Reflections on the impact of movement on proton based treatments.

SU-E-J-138: Fast 2-D Fiducial Marker Detection on Sequential MV Projections in Arc Therapy.

PURPOSE: To automatically detect intrafraction motion during arc radiotherapy for prostate cancer patients by tracking fiducial markers in two-dimensional MV images acquired using the treatment beam, in order to adjust radiation dose accordingly. METHODS: Four fiducial gold markers are implanted in a patient's prostate. Patients are irradiated using a Varian Linac 2100 C/D with RapidArc upgrade (Varian Medical Systems, Palo Alto, CA). MV images (1024 × 768 pixels, 0.392 × 0.392 mm2 pixel size) acquired during a 360 degree gantry rotation at a one second interval (5 degrees) are preprocessed by subtracting a smoothed version of the image to retain only high image frequencies. Edge detection is then applied, followed by a one pixel wide dilation and erosion to transform the edges into contiguous regions. Next, our method searches the centers of visible markers (i.e. not covered by the MLC), constrained by marker estimates from the planning CT. This is done by finding all contiguous regions and maximizing a marker-region distance criterion for every visible marker. A two-dimensional estimate correction over consecutive projections is also implemented to improve marker estimates during gantry rotation. RESULTS: We applied our method on four treatment fractions of the same patient. As such, a total of 191 projections with manually indicated marker ends as ground truth were used as validation. Markers were indicated twice on all images, to include observer errors. Results show a mean detection error of less than 0.5 mm in the projection image (standard deviation 0.6 mm), with an execution time of less than one second per image in matlab. Undetected markers and false positives mostly occurred at moving leaf boundaries, where marker visibility was determined by the observer. CONCLUSIONS: Preliminary findings demonstrate that this method can be used to detect intrafraction motion during arc radiotherapy by only using projected MV images. Research sponsored by Varian Medical Systems, Palo Alto, CA.

Beam energy considerations for gold nano-particle enhanced radiation treatment.

A novel approach using nano-technology enhanced radiation modalities is investigated. The proposed methodology uses antibodies labeled with organically inert metals with a high atomic number. Irradiation using photons with energies in the kilo-electron volt (keV) range shows an increase in dose due to a combination of an increase in photo-electric interactions and a pronounced generation of Auger and/or Coster-Krönig (A-CK) electrons. The dependence of the dose deposition on various factors is investigated using Monte Carlo simulation models. The factors investigated include agent concentration, spectral dependence looking at mono-energetic sources as well as classical bremsstrahlung sources. The optimization of the energy spectrum is performed in terms of physical dose enhancement as well as the dose deposited by Auger and/or Coster-Krönig electrons and their biological effectiveness. A quasi-linear dependence on concentration and an exponential decrease within the target medium is observed. The maximal dose enhancement is dependent on the position of the target in the beam. Apart from irradiation with low-photon energies (10-20 keV) there is no added benefit from the increase in generation of Auger electrons. Interestingly, a regular 110 kVp bremsstrahlung spectrum shows a comparable enhancement in comparison with the optimized mono-energetic sources. In conclusion we find that the use of enhanced nano-particles shows promise to be implemented quite easily in regular clinics on a physical level due to the advantageous properties in classical beams.

Founder mutations in the Netherlands: SCN5a 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide.

In this part of a series on founder mutations in the Netherlands, we review a Dutch family carrying the SCN5a 1795insD mutation. We describe the advances in our understanding of the premature sudden cardiac deaths that have accompanied this family in the past centuries. The mutation carriers show a unique overlap of long-QT syndrome (type 3), Brugada syndrome and progressive cardiac conduction defects attributed to a single mutation in the cardiac sodium channel gene SCN5a. It is at present one of the largest and best-described families worldwide and we have learned immensely from the mouse strains with the murine homologue of the SCN5a 1795insD mutation (SCN5a 1798insD). From the studies currently performed we are about to obtain new insights into the phenotypic variability in this monogenic arrhythmia syndrome, and this might also be relevant for other arrhythmia syndromes and the general population. (Neth Heart J 2009;17:422-8.).

Cardiac resynchronisation therapy in paediatric and congenital heart disease: differential effects in various anatomical and functional substrates.

BACKGROUND: Cardiac resynchronisation therapy (CRT) is increasingly used in children in a variety of anatomical and pathophysiological conditions, but published data are scarce. OBJECTIVE: To record current practice and results of CRT in paediatric and congenital heart disease. DESIGN: Retrospective multicentre European survey. SETTING: Paediatric cardiology and cardiac surgery centres. PATIENTS: One hundred and nine patients aged 0.24-73.8 (median 16.9) years with structural congenital heart disease (n = 87), congenital atrioventricular block (n = 12) and dilated cardiomyopathy (n = 10) with systemic left (n = 69), right (n = 36) or single (n = 4) ventricular dysfunction and ventricular dyssynchrony during sinus rhythm (n = 25) or associated with pacing (n = 84). INTERVENTIONS: CRT for a median period of 7.5 months (concurrent cardiac surgery in 16/109). MAIN OUTCOME MEASURES: Functional improvement and echocardiographic change in systemic ventricular function. RESULTS: The z score of the systemic ventricular end-diastolic dimension decreased by median 1.1 (p<0.001). Ejection fraction (EF) or fractional area of change increased by a mean (SD) of 11.5 (14.3)% (p<0.001) and New York Heart Association (NYHA) class improved by median 1.0 grade (p<0.001). Non-response to CRT (18.5%) was multivariably predicted by the presence of primary dilated cardiomyopathy (p = 0.002) and poor NYHA class (p = 0.003). Presence of a systemic left ventricle was the strongest multivariable predictor of improvement in EF/fractional area of change (p<0.001). Results were independent of the number of patients treated in each contributing centre. CONCLUSION: Heart failure associated with ventricular pacing is the largest indication for CRT in paediatric and congenital heart disease. CRT efficacy varies widely with the underlying anatomical and pathophysiological substrate.

Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study.

OBJECTIVE: Increasing imbalance between proliferation and apoptosis is important in cervical carcinogenesis. The death ligands FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis by binding to their cognate cell-surface death receptors Fas or death receptor (DR) 4 and DR5. This study aims to examine if changes in death ligand and death receptor expression during different stages of cervical carcinogenesis are related to an imbalance between proliferation and apoptosis. METHODS: The immunohistochemical expression and localization of Fas/FasL and DR4/DR5/TRAIL were assessed in 11 normal cervices, 15 cervical intraepithelial neoplasia (CIN) grade I, 15 CIN II, 13 CIN III, and 25 (microinvasive) squamous cell cervical cancers. The number of apoptotic cells was determined by morphological criteria and the number of proliferating cells by counting Ki-67-positive cells. RESULTS: A marked increase in proliferation as well as apoptosis percentage was found with increasing severity of neoplasia. In normal cervix and CIN I samples, FasL, DR4, DR5, and TRAIL staining was mainly observed in the basal/parabasal layer, whereas Fas staining was localized in the superficial, more differentiated epithelial layer. Frequency of Fas-positive staining decreased with increasing severity of CIN. In contrast, homogeneous FasL, DR4, DR5, and TRAIL expression throughout the lesions was more frequently observed in CIN III and cervical cancer. FasL, DR4, DR5, and TRAIL staining patterns were correlated, although TRAIL expression was more intense in low-grade lesions. No association was found between death receptor or ligand expression with the percentage of apoptosis or proliferation. CONCLUSION: The loss of Fas and the deregulation of FasL, DR4, DR5, and TRAIL in the CIN-cervical cancer sequence suggest a possible functional role of these death ligands and receptors during cervical carcinogenesis. The frequent expression of DR4 and DR5 presents these receptors as promising targets for innovative therapy modalities in cervical cancer.