Refining Treatment Planning in STereotactic Arrhythmia Radioablation (STAR): Benchmark Results and Consensus Statement from the STOPSTORM.eu Consortium.

BACKGROUND AND PURPOSE: STereotactic Arrhythmia Radioablation (STAR) showed promising results in patients with refractory ventricular tachycardia (VT). However, clinical data is scarce and heterogeneous. The STOPSTORM.eu consortium was established to investigate and harmonize STAR in Europe. The primary goal of this benchmark study was to investigate current treatment planning practice within the STOPSTORM project as a baseline for future harmonization. METHODS: Planning target volumes (PTV) overlapping extra-cardiac organs-at-risk and/or cardiac substructures were generated for three STAR cases. Participating centers were asked to create single fraction treatment plans with 25 Gy dose prescription based on in-house clinical practice. All treatment plans were reviewed by an expert panel and quantitative crowd knowledge-based analysis was performed with independent software using descriptive statistics for ICRU report 91 relevant parameters and crowd dose-volume-histograms. Thereafter, treatment planning consensus statements were established using a dual-stage voting process. RESULTS: Twenty centers submitted 67 treatment plans for this study. In most plans (75%) Intensity Modulated Arc Therapy (IMAT) with 6 MV flattening-filter-free beams was used. Dose prescription was mainly based on PTV D95% (49%) or D96-100% (19%). Many participants preferred to spare close extra-cardiac organs-at-risk (75%) and cardiac substructures (50%) by PTV coverage reduction. PTV D0.035cm3 ranged 25.5-34.6 Gy, demonstrating a large variety of dose inhomogeneity. Estimated treatment times without motion compensation or setup ranged 2-80 minutes. For the consensus statements, strong agreement was reached for beam technique planning, dose calculation, prescription methods and trade-offs between target and extra-cardiac critical structures. No agreement was reached on cardiac substructure dose limitations and on desired dose inhomogeneity in the target. CONCLUSION: This STOPSTORM multi-center treatment planning benchmark study showed strong agreement on several aspects of STAR treatment planning, but also revealed disagreement on others. To standardize and harmonize STAR in the future, consensus statements were established, however clinical data is urgently needed for actionable guidelines for treatment planning.

Repeated deep-inspiration breath-hold CT scans at planning underestimate the actual motion between breath-holds at treatment for lung cancer and lymphoma patients.

PURPOSE/OBJECTIVE: Deep-inspiration breath-hold (DIBH) during radiotherapy may reduce dose to the lungs and heart compared to treatment in free breathing. However, intra-fractional target shifts between several breath-holds may decrease target coverage. We compared target shifts between four DIBHs at the planning-CT session with those measured on CBCT-scans obtained pre- and post-DIBH treatments. MATERIAL/METHODS: Twenty-nine lung cancer and nine lymphoma patients were treated in DIBH. An external gating block was used as surrogate for the DIBH-level with a window of 2 mm. Four DIBH CT-scans were acquired: one for planning (CTDIBH3) and three additional (CTDIBH1,2,4) to assess the intra-DIBH target shifts at scanning by registration to CTDIBH3. During treatment, pre-treatment (CBCTpre) and post-treatment (CBCTpost) scans were acquired. For each pair of CBCTpre/post, the target intra-DIBH shift was determined. For lung cancer, tumour (GTV-Tlung) and lymph nodes (GTV-Nlung) were analysed separately. Group mean (GM), systematic and random errors, and GM for the absolute maximum shifts (GMmax) were calculated for the shifts between CTDIBH1,2,3,4 and between CBCTpre/post. RESULTS: For GTV-Tlung, GMmax was larger at CBCT than CT in all directions. GMmax in cranio-caudal direction was 3.3 mm (CT)and 6.1 mm (CBCT). The standard deviations of the shifts in the left-right and cranio-caudal directions were larger at CBCT than CT. For GTV-Nlung and CTVlymphoma, no difference was found in GMmax or SD. CONCLUSION: Intra-DIBH shifts at planning-CT session are generally smaller than intra-DIBH shifts observed at CBCTpre/post and therefore underestimate the intra-fractional DIBH uncertainty during treatment. Lung tumours show larger intra-fractional variations than lymph nodes and lymphoma targets.

Perforation of the right cardiac ventricle as a late complication of a displaced sternal fracture following blunt trauma.

Cardiac tamponade is a rare but possibly fatal complication of blunt thoracic trauma complicated by a sternal fracture. A delayed presentation of cardiac tamponade days or weeks after initial trauma has been described in a few cases. In these cases, the presumed mechanism of cardiac tamponade is pericardial irritation, caused by osseous fragments of the fractured sternum. This case describes a direct mechanical perforation of the right ventricle, caused by a displaced sternal fracture, presenting 5 days after initial trauma. To our knowledge, this mechanism of late cardiac tamponade has not been described in recent literature.

Real-time segmentation of multiple implanted cylindrical liver markers in kilovoltage and megavoltage x-ray images.

Gold markers implanted in or near a tumor can be used as x-ray visible landmarks for image based tumor localization. The aim of this study was to develop and demonstrate fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in cone-beam CT (CBCT) projections, for real-time motion management. Thirteen patients treated with conformal stereotactic body radiation therapy in three fractions had 2-3 cylindrical gold markers implanted in the liver prior to treatment. At each fraction, the projection images of a pre-treatment CBCT scan were used for automatic generation of a 3D marker model that consisted of the size, orientation, and estimated 3D trajectory of each marker during the CBCT scan. The 3D marker model was used for real-time template based segmentation in subsequent x-ray images by projecting each marker's 3D shape and likely 3D motion range onto the imager plane. The segmentation was performed in intra-treatment kV images (526 marker traces, 92,097 marker projections) and MV images (88 marker traces, 22,382 marker projections), and in post-treatment CBCT projections (42 CBCT scans, 71,381 marker projections). 227 kV marker traces with low mean contrast-to-noise ratio were excluded as markers were not visible due to MV scatter. Online segmentation times measured for a limited dataset were used for estimating real-time segmentation times for all images. The percentage of detected markers was 94.8% (kV), 96.1% (MV), and 98.6% (CBCT). For the detected markers, the real-time segmentation was erroneous in 0.2-0.31% of the cases. The mean segmentation time per marker was 5.6 ms [2.1-12 ms] (kV), 5.5 ms [1.6-13 ms] (MV), and 6.5 ms [1.8-15 ms] (CBCT). Fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in CBCT projections was demonstrated for a large dataset.

A thousand pericardial valves in aortic position: risk factors for postoperative acute renal function impairment in elderly.

AIM: Postoperative renal dysfunction after aortic valve replacement is a serious complication. To minimize its occurrence, risk factors have to be identified, and if possible eliminated. METHODS: Of 1000 consecutive patients, who underwent AVR, a file study was performed chi(2)nd logistic regression analysis were performed to study the effect of 24 preoperative, 7 peroperative and 7 postoperative factors on the occurrence of 30-day postoperative worsening of renal function. RESULTS: Fifty-three patients had a 30-day postoperative decrease of renal function. Nine of these patients died, which is significantly more than the mortality without this complication (P<0.0001). In those nine patients, another complication (postoperative heart failure, thromboembolism or respiratory failure) was present. Thirteen factors were significant in an univariate analysis: preoperative renal dysfunction (P<0.001), age>80 (P<0.001), atrial fibrillation (P<0.001) , preoperative pulmonary edema (P=0.001), conduction defect (P=0.002), diabetes (P=0.006), myocardial infarction (P=0.006), postoperative heart failure (P=0.007), cross clamp time >75 min (P=0.015), previous coronary artery bypass grafting (CABG) (P=0.018), concomitant CABG (P=0.031), ejection fraction <50% (P=0.033) and CVA (P=0.035). Four factors were identified as independent predictors in a multivariate analysis: renal dysfunction (P<0.001, Odds ratio [OR] 5.5; 95% confidence interval [CI] 2.9-10.4), preoperative atrial fibrillation (P=0.010, OR=2.3, 95% CI=1.2-4.2), age>80 (P=0.014, OR=2.2, 95% CI=1.2-4.1) and myocardial infarction (P=0.022, OR=2.2, 95% CI=1.1-4.4). CONCLUSIONS: Few factors are liable for therapeutic intervention, especially in elderly and patients with comorbidity. In patients with risk factors, shortening of cross clamping time or installation of minimal extracorporeal circulation might be beneficial.

An in vitro examination of the antioxidant and anti-inflammatory properties of buckwheat honey.

OBJECTIVE: Hydroxyl radical and hypochlorite anion formed at the wound site from superoxide anion produced by activated polymorphonuclear neutrophils (PMNs) are considered important factors in impaired wound healing. Superoxide anion may also react with nitric oxide produced by macrophages to form peroxynitrite, a third strong oxidant that damages surrounding tissue. In order to select honey for use in wound-healing products, different samples were compared for their capacity to reduce levels of reactive oxygen species (ROS) in vitro. METHOD: Honey samples were tested in assays for inhibition of ROS production by activated human PMNs, antioxidant activity (scavenging of superoxide anion in a cell-free system) and inhibition of human complement (reducing levels of ROS by limiting formation of complement factors that attract and stimulate PMNs). For buckwheat honey (NewYork, US), moisture and free acid content were determined by refractive index measurement and potentiometric titration respectively. Honey constituents other than sugars were investigated by thin layer chromatography, using natural product reagent to detect phenolic compounds. Constituents with antioxidant properties were detected by spraying the chromatogram with DPPH. RESULTS: Although most honey samples were shown to be active, significant differences were observed, with the highly active honey exceeding the activities of samples with minor effects by factors of 4 to 30. Most pronounced activities were found for American buckwheat honey from the state of NewYork. Phenolic constituents of buckwheat honey were shown to have antioxidant activity. CONCLUSION: As buckwheat honey was most effective in reducing ROS levels, it was selected for use in wound-healing products. The major antioxidant properties in buckwheat honey derive from its phenolic constituents, which are present in relatively large amounts. Its phenolic compounds may also exert antibacterial activity, whereas its low pH and high free acid content may assist wound healing.

Single centre, single domain validation of the EuroSCORE on a consecutive sample of primary and repeat CABG.

OBJECTIVES: Intra- and interdepartmental benchmarking require scoring systems with excellent performance on several properties: discrimination (resolution), reliability (calibration) and stability over the complete spectrum of peri-procedural risk. This single centre, single domain study validates the European system for cardiac operative risk evaluation (EuroSCORE) on an independent sample of primary and repeat coronary artery bypass grafting (CABG) patients and will evaluate these different properties. METHODS: The study population is a consecutive series of 2051 isolated primary and repeat CABG patients, inclusive of patients in cardiogenic shock or resuscitation, operated on in a single institution from January 1997 to July 2000. The age of the patients was 66+/-9 years, 77% were males and 7% were repeat procedures. The EuroSCORE was 5.0+/-3%, with a range from 0 to 22. The studied event was in-hospital death, defined as mortality during hospital stay, which was unlimited in time and included a stay in a secondary hospital without discharge home. RESULTS: The EuroSCORE predicted 102 deaths versus 81 deaths observed (P=0.14, Fisher exact test). The EuroSCORE described only 20% of the variance of in-hospital mortality. The EuroSCORE created an area under the receiver operating characteristic curve of 0.83+/-0.03. The highest discriminative accuracy was obtained with 8% EuroSCORE risk (only 64% sensitivity and 87% specificity). Further exploration identified an over score in the EuroSCORE range 0-8 (57%, P<0.0001). There was an equal score (-2%, P=1) in the range 9-11, but an under score in the range 12-22 (-133%, P=0.003). CONCLUSIONS: On the condition that these single centre results could be extended to any European cardiac surgery centre, it can be concluded that the overall acceptable performance of the EuroSCORE is the result of an over score in the lower risk and insufficient correction in the higher risk spectrum. The EuroSCORE is probably refined enough for improved informed consent versus aggregated results but should only be used for inter-institutional benchmarking with great caution, preferably below the 12% risk pivot.

The challenge of departmental quality control in the reengineering towards off-pump coronary artery bypass grafting.

OBJECTIVE: Off pump coronary surgery is a major reengineering effort of the surgical systems. There are no perfect tools available to guide every centre in the confrontation with the complete spectrum of risk and the limited number of events. This study analyses the use of a hospital mortality risk-stratifying system in the complete shift towards off-pump CABG. METHODS: All 535 off-pump CABG patients from January 1997 till September 2000 underwent a comparison of their hospital mortality versus the EuroSCORE predictions. The mean risk predicted by the EuroSCORE was 4.5+/-3% (range 0-14) and the mean age was 65+/-10 years (range 36-89). The series includes 23 repeat procedures, also 77 patients with per oral or insulin-treated diabetes. The number of distal anastomoses was 2.5+/-1 and of arterial grafts 1.3+/-0.6. RESULTS: The observed hospital mortality was 15 patients, 2.8% (Fisher exact test P=0.19 versus the EuroSCORE). The 1 and 3 month Kaplan-Meier survival, irrespective from hospital discharge, was 97.4+/-0.7 and 97.2+/-0.7%, respectively. A cumulative risk-adjusted mortality plot is constructed. The area under the ROC curve was 0.886. A stepwise sampling of patients according to increasing risk identified the difference between the EuroSCORE-predicted and observed hospital mortality for the complete spectrum of risk. The P value of this difference was 0.06 for the grouping including all patients from 0-5% risk (78% reduction), 0.04 for the grouping 0-8% risk (61% reduction), and 0.05 for the grouping 0-11% risk (52% reduction of risk). The loss of statistical significant difference was due to the inclusion of the patients at extremely high risk. CONCLUSION: A hospital mortality risk-stratifying system can provide guidance but different and in depth approaches are mandatory to improve the insight, certainly in the presence of a large spectrum of risk.

Effects of methoxylation of apocynin and analogs on the inhibition of reactive oxygen species production by stimulated human neutrophils.

Owing to their multiple side effects, the use of steroidal drugs is becoming more and more controversial, resulting in an increasing need for new and safer anti-inflammatory agents. In the inflammatory process, reactive oxygen species produced by phagocytic cells are considered to play an important role. We showed that apocynin (4'-hydroxy-3'-methoxy-acetophenone or acetovanillone), a non-toxic compound isolated from the medicinal plant Picrorhiza kurroa, selectively inhibits reactive oxygen species production by activated human neutrophils. Apocynin proved to be effective in the experimental treatment of several inflammatory diseases such as arthritis, colitis and atherosclerosis. These features suggest that apocynin could be a prototype of a novel series of non-steroidal anti-inflammatory drugs (NSAIDs). So far, apocynin is mainly used in vitro to block NADPH oxidase-dependent reactive oxygen species generation by neutrophils. In order to get a better insight in what chemical features play a role in the anti-inflammatory effects of apocynin, a structure-activity relationship study with apocynin analogs was performed. We show here that especially substances with an additional methoxy group at position C-5 display enhanced anti-inflammatory activity in vitro. Our approach may lead to the development of more effective anti-inflammatory agents which are safe and which lack the side effects of steroids.

Immunomodulatory and anti-inflammatory activity of Picrorhiza scrophulariiflora.

Extracts of the rhizomes of Picrorhiza scrophulariiflora Pennell (Scrophulariaceae) were investigated for their in vitro and in vivo immunomodulatory properties. Diethyl ether extracts showed potent inhibitory activity towards the classical pathway of the complement system, the respiratory burst of activated polymorphonuclear leukocytes, and mitogen-induced proliferation of T-lymphocytes. Furthermore, such extracts showed anti-inflammatory activity towards carrageenan-induced paw edema. No effects were observed in experimentally induced arthritis in mice.

Apocynin inhibits peroxynitrite formation by murine macrophages.

Peroxynitrite (ONOO(-)) the highly reactive coupling product of nitric oxide and superoxide, has been implicated in the pathogenesis of an increasing number of (inflammatory) diseases. At present, however, selective peroxynitrite antagonizing agents with therapeutic potential are not available. Therefore, the NADPH-oxidase inhibitor apocynin (4-hydroxy-3-methoxy-acetophenone) was tested for its ability to inhibit peroxynitrite formation in vitro The murine macrophage cell-line J774A.1, stimulated with IFNgamma/LPS, was used as a model. Conversion of 123-dihydrorhodamine (123-DHR) to its oxidation product 123-rhodamine was used to measure peroxynitrite production. Stimulated peroxynitrite formation could be completely inhibited by apocynin, by the superoxide scavenger TEMPO as well as by the nitric oxide synthase inhibitor aminoguanidine. Apocynin and aminoguanidine specifically inhibited superoxide and nitric oxide formation respectively as confirmed by measuring lucigenin enhanced chemiluminescence and nitrite accumulation. It is concluded that J774A.1 macrophages produce significant amounts of peroxynitrite, which is associated with nitric oxide production and NADPH-oxidase dependent superoxide formation. The NADPH-oxidase inhibitor apocynin proved to be a potent inhibitor of both superoxide and peroxynitrite formation by macrophages, which may be of future therapeutic significance in a wide range of inflammatory disorders.

Apocynin, a plant-derived, cartilage-saving drug, might be useful in the treatment of rheumatoid arthritis.

OBJECTIVE: To investigate whether apocynin, 1-(4-hydroxy-3-methoxyphenyl)ethanone, is able to diminish inflammation-induced cartilage destruction in rheumatoid arthritis (RA), studied in a human in vitro model. METHODS: Apocynin was added to cultures of RA peripheral blood mononuclear cells (PBMNC). Cartilage-destructive activity was determined by addition of culture supernatant to tissue samples of human articular cartilage. In addition, the proliferation of PBMNC, their production of tumour necrosis factor alpha (TN-Falpha), interleukin (IL)-1 and IL-10, and T-cell production of interferon gamma (IFN-gamma) and IL-4, as measures for T1 and T2 cell activity, were determined. RESULTS: Apocynin was able to counteract RA PBMNC-induced inhibition of cartilage matrix proteoglycan synthesis, while no effect on inflammation-enhanced proteoglycan release was found. The effect was accompanied by a decrease in IL-1 and TNF-alpha production by the MNC. No effect on T-cell proliferation was found, but the production of IFN-gamma, IL-4 and T-cell-derived IL-10 was strongly diminished. Most important, apocynin did not show any direct adverse effects on chondrocyte metabolism; on the contrary, it diminished the release of proteoglycans from the cartilage matrix. CONCLUSION: Apocynin in vitro inhibits inflammation-mediated cartilage destruction without having adverse effects on cartilage. The latter may be an advantage of apocynin over many other non-steroidal anti-inflammatory drugs. Therefore, apocynin might have an added beneficial effect in protecting RA patients from joint destruction.

Role of lipoxygenase products in the effects of angiotensin II in the isolated aorta and perfused heart of the rat.

The objective of this study was to determine whether arachidonate metabolites are involved in the vasoconstrictive effects of angiotensin II in rats. In the isolated perfused heart, dexamethasone (4 mg/kg) significantly suppressed the maximal decreases in coronary flow induced by angiotensin II and vasopressin (reference drug). In the heart, the nonselective lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 1 muM) markedly suppressed the angiotensin II-induced decreases in coronary flow. NDGA (10 muM) inhibited both angiotensin II- and methoxamine- (reference drug) induced contractions in aortic rings with (in the presence of L-NAME) and without endothelium. In the heart, the leukotriene synthesis inhibitor MK-886 (0.3 muM) significantly reduced the maximal effects to angiotensin II, but the leukotriene antagonist FPL 55712 (0.1 and 0.3 muM) had no effect. We conclude that in the isolated perfused rat heart angiotensin II-induced decreases in coronary flow are in part mediated by Hpoxygenase products, which might be derived from the 5-Hpoxygenase pathway, but are probably not leukotrienes. Furthermore, endothelium independent Hpoxygenase products mediate part of the contractile responses to angiotensin II in the isolated rat aorta.