Imaging features of myxoid soft-tissue tumours.

Myxoid soft-tissue tumours are mesenchymal neoplasms, which are characterised by the production of abundant extracellular myxoid matrix. Imaging plays an important role in the diagnosis of these tumours as well as treatment planning. The imaging features as well as the clinical course for these lesions are highly variable, depending on both the anatomical location of the tumour and the histopathological subtype. This article, illustrated by histopathologically proven cases from our tertiary referral soft-tissue sarcoma centre, reviews the spectrum of imaging findings and characteristic signs seen with different types of benign and malignant myxoid soft-tissue neoplasms.

Conversion from calcineurin inhibitors to belatacept-based immunosuppressive therapy skews terminal proliferation of non-classical monocytes and lowers lymphocyte counts.

Belatacept, a modified form of CTLA-Ig that blocks CD28-mediated co-stimulation of T cells, is an immune-suppressant that can be used as an alternative to calcineurin inhibitors (CNIs). In kidney transplant recipients, belatacept has been associated with improved renal function and reduced cardiovascular toxicity. Monocytes as well as T-lymphocytes play causal roles in the pathophysiology of atherosclerotic disease. We hypothesized that the beneficial impact of the use of belatacept over CNIs on cardiovascular risk could be partly explained by the impact of belatacept therapy on these circulating leukocytes. Hence, we phenotyped circulating leukocytes in transplanted patients with a stable renal function that were randomized between either continuation of CNI or conversion to belatacept in two international studies in which we participated. In 41 patients, we found that belatacept-treated patients consistently showed lower numbers of B-lymphocytes, T-lymphocytes as well as CD14-negative monocytes (CD14NM), especially in non-diabetic patients. Our observation that this decrease was associated to plasma concentrations of TNFα is consistent with a model where CD14NM-production of TNFα is diminished by belatacept-treatment, due to effects on the antigen-presenting cell compartment.

Microvascular damage in type 1 diabetic patients is reversed in the first year after simultaneous pancreas-kidney transplantation.

Simultaneous pancreas-kidney transplantation (SPK) is an advanced treatment option for type 1 diabetes mellitus (DM) patients with microvascular disease including nephropathy. Sidestreamdarkfield (SDF) imaging has emerged as a noninvasive tool to visualize the human microcirculation. This study assessed the effect of SPK in diabetic nephropathy (DN) patients on microvascular alterations using SDF and correlated this with markers for endothelial dysfunction. Microvascular morphology was visualized using SDF of the oral mucosa in DN (n = 26) and SPK patients (n = 38), healthy controls (n = 20), DM1 patients (n = 15, DM ≥ 40 mL/min) and DN patients with a kidney transplant (KTx, n = 15). Furthermore, 21 DN patients were studied longitudinally up to 12 months after SPK. Circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and soluble thrombomodulin (sTM) were measured using ELISA. Capillary tortuosity in the DN (1.83 ± 0.42) and DM ≥ 40 mL/min (1.55 ± 0.1) group was increased and showed reversal after SPK (1.31 ± 0.3, p < 0.001), but not after KTx (1.64 ± 0.1). sTM levels were increased in DN patients and reduced in SPK and KTx recipients (p < 0.05), while the Ang-2/Ang-1 ratio was normalized after SPK and not after KTx alone (from 0.16 ± 0.04 to 0.08 ± 0.02, p < 0.05). Interestingly, in the longitudinal study, reversal of capillary tortuosity and decrease in Ang-2/Ang-1 ratio and sTM was observed within 12 months after SPK. SPK is effective in reversing the systemic microvascular structural abnormalities in DN patients in the first year after transplantation.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis.

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.

Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation.

Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL-mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation.

Human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets.

OBJECTIVE: The presence of kinase-insert domain-containing receptor (KDR) on circulating CD34+ cells is assumed to be indicative for the potential of these cells to support vascular maintenance and repair. However, in bone marrow and in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood, less than 0.5% of CD34+ cells co-express KDR. Therefore, we studied whether CD34+/KDR+ cells are generated in the peripheral circulation. METHODS AND RESULTS: Using an ex vivo flow model, we show that activated platelets enable CD34+ cells to home to sites of vascular injury and that upon immobilization, KDR is translocated from an endosomal compartment to the cell-surface within 15 minutes. In patients with diabetes mellitus type 2, the percentage of circulating CD34+ co-expressing KDR was significantly elevated compared to age-matched controls. When treated with aspirin, the patients showed a 49% reduction in the generation of CD34+/KDR+ cells, indicating that the level of circulating CD34+/KDR+ cells also relates to in vivo platelet activation. CONCLUSIONS: Circulating CD34+/KDR+ are not mobilized from bone marrow as a predestined endothelial progenitor cell population but are mostly generated from circulating multipotent CD34+ cells at sites of vascular injury. Therefore, the number of circulating CD34+/KDR+ cells may serve as a marker for vascular injury.

Inflammation, vascular injury and repair in rheumatoid arthritis.

The systemic pro-inflammatory state present in patients with rheumatoid arthritis (RA) accelerates the progression of atherosclerosis through chronic endothelial activation. Uncoupling of endothelial nitric oxide synthase plays a central role in the amplification of oxidative signalling pathways that chronically activate and, ultimately, injure the endothelium. Recent studies indicate that the resultant loss of endothelial integrity in patients with RA may also involve defects in the vascular regenerative potential provided by circulating endothelial progenitor cells (EPC). This is most likely the consequence of endothelial cell dysfunction in the bone marrow stroma, which hampers the mobilisation of these EPC to the circulation. In addition, mediators of systemic inflammation in RA can affect a second pathway of vascular regeneration. Under normal circumstances, myeloid CD14+ cells can adopt a pro-angiogenic phenotype that plays a key role in vascular remodelling and collateral formation. However, the chronic systemic inflammation observed in patients with RA may skew the differentiation of bone marrow and circulating CD14+ cells in such a way that these cells lose their capacity to support collateral formation, increasing the risk of cardiovascular disease. Taken together, in patients with RA, the impaired capacity of circulating cells to support vascular regeneration may comprise a novel pathway in the development of premature atherosclerosis.

A novel method for engineering autologous non-thrombogenic in situ tissue-engineered blood vessels for arteriovenous grafting.

The durability of prosthetic arteriovenous (AV) grafts for hemodialysis access is low, predominantly due to stenotic lesions in the venous outflow tract and infectious complications. Tissue engineered blood vessels (TEBVs) might offer a tailor-made autologous alternative for prosthetic grafts. We have designed a method in which TEBVs are grown in vivo, by utilizing the foreign body response to subcutaneously implanted polymeric rods in goats, resulting in the formation of an autologous fibrocellular tissue capsule (TC). One month after implantation, the polymeric rod is extracted, whereupon TCs (length 6 cm, diameter 6.8 mm) were grafted as arteriovenous conduit between the carotid artery and jugular vein of the same goats. At time of grafting, the TCs were shown to have sufficient mechanical strength in terms of bursting pressure (2382 ±â€¯129 mmHg), and suture retention strength (SRS: 1.97 ±â€¯0.49 N). The AV grafts were harvested at 1 or 2 months after grafting. In an ex vivo whole blood perfusion system, the lumen of the vascular grafts was shown to be less thrombogenic compared to the initial TCs and ePTFE grafts. At 8 weeks after grafting, the entire graft was covered with an endothelial layer and abundant elastin expression was present throughout the graft. Patency at 1 and 2 months was comparable with ePTFE AV-grafts. In conclusion, we demonstrate the remodeling capacity of cellularized in vivo engineered TEBVs, and their potential as autologous alternative for prosthetic vascular grafts.

Co-digestion of animal slurry can increase short-term nitrogen recovery by crops.

Co-digestion changes slurry characteristics and is supposed to increase short-term nitrogen (N) uptake by crops after application. A higher N uptake from slurry reduces the need for additional mineral N fertilizer. If farmers apply co-digested slurry (CS), a higher N recovery has to be taken into account to prevent losses to the environment. Since data on the effects of co-digestion on N recovery by crops are scarce, a pot experiment was performed. The apparent N recovery (ANR) of five different co-digested pig slurries was compared with their raw source slurries (RS) during 105 d after a single fertilization of ryegrass (Lolium perenne L.), grown under controlled conditions. Slurry was mixed with sandy soil and grass was cut every 35 d. The results show that co-digestion increased (p < 0.05) the ANR at first cut on average from 39 to 50%, at second cut from 7 to 9% (p < 0.05), and had no effect on ANR at third cut (3%). The ANR increase at first cut was likely due to an increase of the NH(4)-N/total N ratio along with a decrease of the organic C/total N ratio of slurry during co-digestion. Field application may under certain circumstances decrease N fertilizer value of CS, due to a higher NH(3) emission compared to RS. A potential ANR increase may then be reduced, absent, or even become a decrease. Under comparable NH(3) emissions, however, CS can in the short term be more valuable as an N fertilizer than RS, and fertilizer savings can likely be realized.

Magnetic Resonance Imaging only Workflow for Radiotherapy Simulation and Planning in Prostate Cancer.

Magnetic resonance imaging (MRI) is often combined with computed tomography (CT) in prostate radiotherapy to optimise delineation of the target and organs-at-risk (OAR) while maintaining accurate dose calculation. Such a dual-modality workflow requires two separate imaging sessions, and it has some fundamental and logistical drawbacks. Due to the availability of new MRI hardware and software solutions, CT examinations can be omitted for prostate radiotherapy simulations. All information for treatment planning, including electron density maps and bony anatomy, can nowadays be obtained with MRI. Such an MRI-only simulation workflow reduces delineation ambiguities, eases planning logistics, and improves patient comfort; however, careful validation of the complete MRI-only workflow is warranted. The first institutes are now adopting this MRI-only workflow for prostate radiotherapy. In this article, we will review technology and workflow requirements for an MRI-only prostate simulation workflow.

Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell phenotype.

OBJECTIVE: Bone marrow-derived progenitor cells play a role in vascular regeneration. However, their homing to areas of vascular injury is poorly understood. One of the earliest responses to an injury is the activation of coagulation and platelets. In this study we assessed the role of hemostatic components in the recruitment of CD34+ cells to sites of injury. METHODS AND RESULTS: Using an ex vivo injury model, representing endothelial cell (EC) injury or vessel denudation, we studied homing of CD34+ under flow. Platelet aggregates facilitated initial tethering and rolling of CD34+ cells through interaction of P-selectin expressed by platelets and P-selectin glycoprotein ligand-1 (PSGL-1), expressed by CD34+ cells. Ligation of PSGL-1 activated adhesion molecules on CD34+ cells, ultimately leading to firm adhesion of CD34+ cells to tissue factor-expressing ECs or to fibrin-containing thrombi formed on subendothelium. We also demonstrate that fibrin-containing thrombi can support migration of CD34+ cells to the site of injury and subsequent differentiation toward a mature EC phenotype. Additionally, intravenously injected CD34+ cells homed in vivo to denuded arteries in the presence of endogenous leukocytes. CONCLUSIONS: We provide evidence that hemostatic factors, associated with vascular injury, provide a regulatory microenvironment for re-endothelialization mediated by circulating progenitor cells.

Angiogenic murine endothelial progenitor cells are derived from a myeloid bone marrow fraction and can be identified by endothelial NO synthase expression.

OBJECTIVE: Endothelial progenitor cells (EPCs) contribute to postnatal neovascularization and are therefore of great interest for autologous cell therapies to treat ischemic vascular disease. However, the origin and functional properties of these EPCs are still in debate. METHODS AND RESULTS: Here, ex vivo expanded murine EPCs were characterized in terms of phenotype, lineage potential, differentiation from bone marrow (BM) precursors, and their functional properties using endothelial NO synthase (eNOS)-green fluorescent protein transgenic mice. Despite high phenotypic overlap with macrophages and dendritic cells, EPCs displayed unique eNOS expression, endothelial lineage potential in colony assays, and angiogenic characteristics, but also immunologic properties such as interleukin-12p70 production and low levels of T-cell stimulation. The majority of EPCs developed from an immature, CD31(+)Ly6C+ myeloid progenitor fraction in the BM. Addition of myeloid growth factors such as macrophage-colony-stimulating factor (M-CSF) and granulocyte/macrophage (GM)-CSF stimulated the expansion of spleen-derived EPCs but not BM-derived EPCs. CONCLUSIONS: The close relationship between EPCs and other myeloid lineages may add to the complexity of using them in cell therapy. Our mouse model could be a highly useful tool to characterize EPCs functionally and phenotypically, to explore the origin and optimize the isolation of EPC fractions for therapeutic neovascularization.

Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies.

Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers.

Effect of extracellular matrix glycation on endothelial cell adhesion and spreading: involvement of vitronectin.

Glycation of proteins of the vessel wall is thought to play an important role in the pathogenesis of vascular complications in diabetes by affecting structure and function of these proteins. Adhesive proteins in the extracellular matrix (ECM) of endothelial cells (ECs) are essential for attachment of ECs to the subintima. In this study, we investigated the effect of glycation of ECM and purified adhesive proteins on EC adhesion and spreading. ECM was incubated with the reactive sugar glucose-6-phosphate (0-500 mmol/l) for different time periods (0-14 days) at 37 degrees C. Degree of glycation, measured in an enzyme-linked immunosorbent assay using a monoclonal antibody specific for advanced glycation end products, increased in a time- and concentration-dependent manner. Glycation of ECM with 50 mmol/l glucose-6-phosphate resulted in increased coverage by ECs as measured in a cell adhesion assay and was the result of an increase in number of adhered cells, while cell size was unaffected. Glycation of ECM with higher concentrations of glucose-6-phosphate resulted in decreased coverage by ECs caused by both a reduction in number of adhered ECs and impaired spreading. Experiments with purified glycated matrix proteins indicate that the decrease in EC adhesion and spreading on glycated ECM may result from glycation of vitronectin. Impaired EC adhesion and spreading caused by vitronectin glycation may result in impaired endothelial function and contribute to vascular disease.

Environmental impacts of innovative dairy farming systems aiming at improved internal nutrient cycling: A multi-scale assessment.

Several dairy farms in the Netherlands aim at reducing environmental impacts by improving the internal nutrient cycle (INC) on their farm by optimizing the use of available on-farm resources. This study evaluates the environmental performance of selected INC farms in the Northern Friesian Woodlands in comparison to regular benchmark farms using a Life Cycle Assessment. Regular farms were selected on the basis of comparability in terms of milk production per farm and per hectare, soil type and drainage conditions. In addition, the environmental impacts of INC farming at landscape level were evaluated with the integrated modelling system INITIATOR, using spatially explicit input data on animal numbers, land use, agricultural management, meteorology and soil, assuming that all farms practised the principle of INC farming. Impact categories used at both farm and landscape levels were global warming potential, acidification potential and eutrophication potential. Additional farm level indicators were land occupation and non-renewable energy use, and furthermore all farm level indicators were also expressed per kg fat and protein corrected milk. Results showed that both on-farm and off-farm non-renewable energy use was significantly lower at INC farms as compared with regular farms. Although nearly all other environmental impacts were numerically lower, both on-farm and off-farm, differences were not statistically significant. Nitrogen losses to air and water decreased by on average 5 to 10% when INC farming would be implemented for the whole region. The impact of INC farming on the global warming potential and eutrophication potential was, however, almost negligible (<2%) at regional level. This was due to a negligible impact on the methane emissions and on the surplus and thereby on the soil accumulation and losses of phosphorus to water at INC farms, illustrating the focus of these farms on closing the nitrogen cycle.

A protocol for the reduction of systematic patient setup errors with minimal portal imaging workload.

PURPOSE: To evaluate a new off-line patient setup correction protocol that minimizes the required number of portal images and perform a comparison with currently applied protocols. METHODS AND MATERIALS: We compared two types of off-line protocols: (a) the widely applied shrinking action level (SAL) protocol, in which the setup error, averaged over the measured treatment fractions, is compared with a threshold that decreases with the number of measurements, to decide if a correction is necessary; and (b) a new "no-action-level" (NAL) protocol, which simply calculates the mean setup error over a fixed number of fractions, and always corrects for it. The performance of the protocols was evaluated by applying them to (a) a database of measured setup errors from 600 prostate patients (with, on average, 10 imaged fractions/patient) and (b) Monte Carlo-generated setup error distributions for various values of the population systematic and random errors. RESULTS: The NAL protocol achieved a significantly higher accuracy than the SAL protocol for a similar workload in terms of image acquisition and analysis, as well as in setup corrections. The SAL protocol required approximately three times more images than the NAL protocol to obtain the same reduction of systematic errors. Application of the NAL protocol to measured setup errors confirmed its efficacy in systematic error reduction in a real patient population. CONCLUSION: The NAL protocol performed much more efficiently than the SAL protocol for both actually measured and simulated setup data. The resulting decrease in required portal images not only reduces workload, but also dose to healthy tissue, if dedicated large fields are required for portal imaging (double exposure).

Inclusion of geometrical uncertainties in radiotherapy treatment planning by means of coverage probability.

PURPOSE: Following the ICRU-50 recommendations, geometrical uncertainties in tumor position during radiotherapy treatments are generally included in the treatment planning by adding a margin to the clinical target volume (CTV) to yield the planning target volume (PTV). We have developed a method for automatic calculation of this margin. METHODS AND MATERIALS: Geometrical uncertainties of a specific patient group can normally be characterized by the standard deviation of the distribution of systematic deviations in the patient group (Sigma) and by the average standard deviation of the distribution of random deviations (sigma). The CTV of a patient to be planned can be represented in a 3D matrix in the treatment room coordinate system with voxel values one inside and zero outside the CTV. Convolution of this matrix with the appropriate probability distributions for translations and rotations yields a matrix with coverage probabilities (CPs) which is defined as the probability for each point to be covered by the CTV. The PTV can then be chosen as a volume corresponding to a certain iso-probability level. Separate calculations are performed for systematic and random deviations. Iso-probability volumes are selected in such a way that a high percentage of the CTV volume (on average > 99%) receives a high dose (> 95%). The consequences of systematic deviations on the dose distribution in the CTV can be estimated by calculation of dose histograms of the CP matrix for systematic deviations, resulting in a so-called dose probability histogram (DPH). A DPH represents the average dose volume histogram (DVH) for all systematic deviations in the patient group. The consequences of random deviations can be calculated by convolution of the dose distribution with the probability distributions for random deviations. Using the convolved dose matrix in the DPH calculation yields full information about the influence of geometrical uncertainties on the dose in the CTV. RESULTS: The model is demonstrated to be fast and accurate for a prostate, cervix, and lung cancer case. A CTV-to-PTV margin size which ensures at least 95% dose to (on average) 99% of the CTV, appears to be equal to about 2Sigma + 0.7sigma for three all cases. Because rotational deviations are included, the resulting margins can be anisotropic, as shown for the prostate cancer case. CONCLUSION: A method has been developed for calculation of CTV-to-PTV margins based on the assumption that the CTV should be adequately irradiated with a high probability.

On-line set-up corrections during radiotherapy of patients with gynecologic tumors.

PURPOSE: Positioning of patients with gynecologic tumors for radiotherapy has proven to be relatively inaccurate. To improve the accuracy and reduce the margins from clinical target volume (CTV) to planning target volume (PTV), on-line set-up corrections were investigated. METHODS AND MATERIALS: Anterior-posterior portal images of 14 patients were acquired using the first six monitor units (MU) of each irradiation fraction. The set-up deviation was established by matching three user-defined landmarks in portal and simulator image. If the two-dimensional deviation exceeded 4 mm, the table position was corrected. A second portal image was acquired using 30 MU of the remaining dose. This image was analyzed off-line using a semiautomatic contour match to obtain the final set-up accuracy. To verify the landmark match accuracy, the contour match was retrospectively performed on the six MU images as well. RESULTS: The standard deviation (SD) of the distribution of systematic set-up deviations after correction was < 1 mm in left-right and cranio-caudal directions. The average random deviation was < 2 mm in these directions (1 SD). Before correction, all standard deviations were 2 to 3 mm. The landmark match procedure was sufficiently accurate and added on average 3 min to the treatment time. The application of on-line corrections justifies a CTV-to-PTV margin reduction to about 5 mm. CONCLUSIONS: On-line set-up corrections significantly improve the positioning accuracy. The procedure increases treatment time but might be used effectively in combination with off-line corrections.

Analysis and reduction of 3D systematic and random setup errors during the simulation and treatment of lung cancer patients with CT-based external beam radiotherapy dose planning.

PURPOSE: To determine the magnitude of the errors made in (a) the setup of patients with lung cancer on the simulator relative to their intended setup with respect to the planned treatment beams and (b) in the setup of these patients on the treatment unit. To investigate how the systematic component of the latter errors can be reduced with an off-line decision protocol for setup corrections. METHODS AND MATERIALS: For 39 patients with CT planning, digitally-reconstructed radiographs (DRRs) were calculated for anterior-posterior and lateral beams. Retrospectively, the position of the visible anatomy relative to the planned isocenter was compared with the corresponding position on the digitized simulator radiographs using contour match software. The setup accuracy at the treatment unit relative to the simulator setup was measured for 40 patients for at least 5 fractions per patient in 2 orthogonal beams with the aid of an electronic portal imaging device (EPID). Setup corrections were applied, based on an off-line decision protocol, with parameters derived from knowledge of the random setup errors in the studied patient group. RESULTS: The standard deviations (SD) of the simulator setup errors relative to the CT planning setup in the lateral, longitudinal, and anterior-posterior directions were 4.0, 2.8, and 2.5 mm, respectively. The SD of rotations around the anterior-posterior axis was 1.6 degrees and around the left-right axis 1.3 degrees. The setup error at the treatment unit had a small random component in all three directions (1 SD = 2 mm). The systematic components were larger, particularly in the longitudinal direction (1 SD = 3.6 mm), but were reduced with the decision protocol to 1 SD < 2 mm with, on average, 0.6 setup correction per patient. CONCLUSION: Setup errors at the simulator, which become systematic errors if the simulation defines the reference setup, were comparable to the systematic setup errors at the treatment unit in case no off-line protocol would have been applied. Hence, the omission of a separate simulation step can reduce systematic errors as efficiently as the application of an off-line correction protocol during treatment. The random errors were sufficiently small to make an off-line protocol feasible.

An analysis of anatomic landmark mobility and setup deviations in radiotherapy for lung cancer.

PURPOSE: To identify thoracic structures that exhibit little internal motion during irradiation and to determine setup variations in patients with lung cancer. METHODS AND MATERIALS: Intrafractional images were generated with an electronic portal-imaging device from the AP fields of 10 patients, during several fractions. To determine the intrafractional mobility of thoracic structures, visible structures were contoured in every image and matched with a reference image by means of a cross-correlation algorithm. Setup variations were determined by comparing portal images with the digitized simulator films using the stable structures as landmarks. RESULTS: Mobility was limited in the lateral direction for the trachea, thoracic wall, paraspinal line, and aortic notch, and in the craniocaudal direction for the clavicle, aortic notch, and thoracic.wall. Analysis of patient setup revealed random deviations of 2.0 mm (1 SD) in the lateral direction and 2.8 mm in the craniocaudal direction, while the systematic deviations were 2.5 and 2.0 mm (1 SD) respectively. CONCLUSIONS: We have identified thoracic structures that exhibit little internal motion in the frontal plane, and recommend that these structures be used for verifying patient setup during radiotherapy. The daily variation in the setup of lung cancer patients at our center appears to be acceptable.