Anders N. Pedersen

DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer

PURPOSE It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer. PATIENTS AND METHODS In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat. RESULTS A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease. CONCLUSION In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.

Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: National guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group

Abstract During the past decade planning of adjuvant radiotherapy (RT) of early breast cancer has changed from two-dimensional (2D) to 3D conformal techniques. In the planning computerised tomography (CT) scan both the targets for RT and the organs at risk (OARs) are visualised, enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs. To ensure uniform RT in the national prospective trials of the Danish Breast Cancer Cooperative Group (DBCG), a national consensus for the delineation of clinical target volumes (CTVs) and OARs was required. Material and methods. A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node (LN) dissection was used for delineation. During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT. Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a final consensus. The Dice similarity coefficient (DSC) was used to evaluate the delineation agreement before and after the consensus. Results. The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes. The consensus provides recommendations for target delineation in a standard patient both in case of breast conservation or mastectomy. Before the consensus, the average value of the DSC was modest for most volumes, but high for the breast CTV and the heart. After the consensus, the DSC increased for all volumes. Conclusion. The DBCG has provided the first national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer. The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement. This consensus will be used by the DBCG in our prospective trials.

ExStroke Pilot Trial of the effect of repeated instructions to improve physical activity after ischaemic stroke: a multinational randomised controlled clinical trial

Objectives To investigate if repeated verbal instructions about physical activity to patients with ischaemic stroke could increase long term physical activity. Design Multicentre, multinational, randomised clinical trial with masked outcome assessment. Setting Stroke units in Denmark, China, Poland, and Estonia. Participants 314 patients with ischaemic stroke aged ≥40 years who were able to walk—157 (mean age 69.7 years) randomised to the intervention, 157 (mean age 69.4 years) in the control group. Interventions Patients randomised to the intervention were instructed in a detailed training programme before discharge and at five follow-up visits during 24 months. Control patients had follow-up visits with the same frequency but without instructions in physical activity. Main outcome measures Physical activity assessed with the Physical Activity Scale for the Elderly (PASE) at each visit. Secondary outcomes were clinical events. Results The estimated mean PASE scores were 69.1 in the intervention group and 64.0 in the control group (difference 5.0 (95% confidence interval −5.8 to 15.9), P=0.36. The intervention had no significant effect on mortality, recurrent stroke, myocardial infarction, or falls and fractures. Conclusion Repeated encouragement and verbal instruction in being physically active did not lead to a significant increase in physical activity measured by the PASE score. More intensive strategies seem to be needed to promote physical activity after ischaemic stroke. Trial registration Clinical Trials NCT00132483

Tumor Tissue Concentrations of the Proteinase Inhibitors Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and Plasminogen Activator Inhibitor Type 1 (PAI-1) Are Complementary in Determining Prognosis in Primary Breast Cancer

The purpose of this study was to investigate the association between tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and prognosis in patients with primary breast cancer and to analyze whether measurement of TIMP-1 in tumor extracts added prognostic information to that obtained from measurements of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 (PAI-1). An established sandwich enzyme-linked immunosorbent assay was thoroughly validated for the measurement of total TIMP-1 in tumor tissue extracts and used to determine levels of total TIMP-1 in 341 detergent-extracted tumor tissue samples from patients with primary breast cancer. The median age of the patients was 56 years (range, 29–75 years), and 164 were lymph node-negative, and 177 were lymph node-positive. The median follow-up time of the patients was 8.5 years (range, 7.3–11.3 years), and during follow-up 153 patients experienced recurrence of disease, and 136 patients died. In univariate survival analysis, we found a significant association between tumor tissue TIMP-1 level and both shorter recurrence-free survival (p = 0.0004) and shorter overall survival (p = 0.03). In multivariate survival analysis, higher tumor tissue TIMP-1 levels significantly and independently predicted shorter recurrence-free survival (p < 0.05, hazard ratios >1, comparing quartiles II–IV with I). In addition, we found that measurement of TIMP-1 levels added prognostic information to that obtained from measurement of PAI-1. In conclusion, high levels of TIMP-1 in tumor tissue extracts are significantly associated with a poor prognosis in patients with primary breast cancer. Furthermore TIMP-1 adds prognostic information to that obtained from PAI-1. However, further validation in independent data sets is needed.

Interfractional changes in tumour volume and position during entire radiotherapy courses for lung cancer with respiratory gating and image guidance

Introduction. With the purpose of implementing gated radiotherapy for lung cancer patients, this study investigated the interfraction variations in tumour size and internal displacement over entire treatment courses. To explore the potential of image guided radiotherapy (IGRT) the variations were measured using a set-up strategy based on imaging of bony landmarks and compared to a strategy using in room lasers, skin tattoos and cupper landmarks. Materials and methods. During their six week treatment course of 60Gy in 2Gy fractions, ten patients underwent 3 respiratory gated CT scans. The tumours were contoured on each CT scan to evaluate the variations in volumes and position. The lung tumours and the mediastinal tumours were contoured separately. The positional variations were measured as 3D mobility vectors and correlated to matching of the scans using the two different strategies. Results. The tumour size was significantly reduced from the first to the last CT scan. For the lung tumours the reduction was 19%, p=0.03, and for the mediastinal tumours the reduction was 34%, p=0.0007. The mean 3D mobility vector and the SD for the lung tumours was 0.51cm (±0.21) for matching using bony landmarks and 0.85cm (±0.54) for matching using skin tattoos. For the mediastinal tumours the corresponding vectors and SDs were 0.55cm (±0.19) and 0.72cm (±0.43). The differences between the vectors were significant for the lung tumours p=0.004. The interfractional overlap of lung tumours was 80–87% when matched using bony landmarks and 70–76% when matched using skin tattoos. The overlap of the mediastinal tumours were 60–65% and 41–47%, respectively. Conclusions. Despite the use of gating the tumours varied considerably, regarding both position and volume. The variations in position were dependent on the set-up strategy. Set-up using IGRT was superior to set-up using skin tattoos.

The role of image guidance in respiratory gated radiotherapy

Respiratory gating for radiotherapy beam delivery is a widely available technique, manufactured and sold by most of the major radiotherapy machine vendors. Respiratory gated beam delivery is intended to limit the irradiation of tumours moving with respiration to selected parts of the respiratory cycle, and thereby enable dose escalation and/or reduction of dose to organs at risk. Without adequate use of respiratory correlated image guidance on a regular basis, respiratory beam gating may however have a detrimental effect on target coverage. Image guidance of tumour respiratory motion is therefore of utmost importance for the safe introduction of respiratory gating. In this short overview, suitable image guidance strategies for respiratory gated radiotherapy are reviewed for two cancer sites; breast cancer and lung tumours.

Level of Physical Activity in the Week Preceding an Ischemic Stroke

Background: Most observational studies investigating physical activity as a risk factor for stroke have concentrated on the years preceding a stroke event. In the present case control study we compared the reported level of physical activity performed during the week preceding an ischemic stroke with that of community controls. Furthermore we calculated the odds ratio for stroke based on the level of physical activity. Subjects and Methods: Patients with an ischemic stroke were recruited consecutively from hospitals covering Copenhagen City. Community controls were recruited among participants of the Copenhagen City Heart Study and matched according to age and gender. The level of physical activity was assessed using The Physical Activity Scale for the Elderly (PASE), which quantifies the amount of physical activity done in the last 7 days. Results: A total of 127 cases and 301 control subjects were included in the study. Mean (±SD) PASE scores for cases were 76.0 ± 46.2 and 119.7 ± 69.4 for controls (p < 0.001). For each 1-point increase in PASE score the odds ratio for ischemic stroke was 0.98 (0.98–0.99), equivalent to an odds ratio of 0.86 (95% CI: 0.82–0.90) for each 10-point increase. Conclusion: Stroke patients are less physically active in the week preceding an ischemic stroke when compared to age- and sex-matched controls. Increasing PASE score was inversely, log-linearly and significantly associated with odds ratio for ischemic stroke.

Loss of ELISA specificity due to biotinylation of monoclonal antibodies.

A significant degree of nonspecificity was found in ELISA determinations of soluble urokinase receptor (suPAR) in human blood plasma when biotinylated monoclonal antibodies (Mabs) were used for the detection layer. Surface plasmon resonance studies using both nonbiotinylated and biotinylated antibodies demonstrated that biotinylation reduced specific binding of the antibodies to their target antigen, suPAR. Furthermore, biotinylation produced a new interaction with unknown human plasma protein(s), unrelated to suPAR. Nonspecific interaction with plasma protein(s) was also observed after biotinylation of a Mab having no specific target antigen in human plasma and, in both cases, the level of nonspecific interaction was directly related to the degree of antibody biotinylation. These results reinforce earlier observations that biotinylation of antibodies can reduce the affinity of antibodies, but also indicate that, in addition, biotinylation can reduce the specificity of immunoassays for plasma proteins.

Reduced lung dose and improved inspiration level reproducibility in visually guided DIBH compared to audio coached EIG radiotherapy for breast cancer patients

Abstract Introduction. Patients with left-sided breast cancer with lymph node involvement have routinely been treated with enhanced inspiration gating (EIG) for a decade at our institution. In a transition from EIG to deep inspiration breath hold (DIBH) we compared the two techniques with focus on target coverage, dose to organs at risk and reproducibility of the inspiration level (IL). Material and methods. Twenty-four patients were computed tomography (CT) scanned with EIG and DIBH. For DIBH we used visual feedback and for EIG audio coaching, both during scan and treatment. Treatment plans for 50 Gy over 25 fractions were calculated. Seventeen of the patients were included in the analysis of reproducibility. They were audio coached for one minute before beam-on in DIBH at nine treatment sessions. These respiration curves were analysed with average maximum IL and standard deviation (SD) for the EIG part of the respiratory signal, and mean IL and SD for the DIBH. Comparison of dosimetric and respiration parameters were performed with the Wilcoxon signed rank-sum test. Results. In DIBH, the ipsilateral lung volume increased further compared to EIG (p < 0.0004, mean increase 11%). This lead to a 9% mean reduction (p = 0.002) of the ipsilateral lung volume receiving 20 Gy (V20 Gy). We found no other significant dosimetric differences between the two methods. The reproducibility of the IL was better with the DIBH method, observed as a significantly smaller SD in most patients (p < 0.04 for 16 of 17 patients). Conclusion. The DIBH method resulted in a significantly larger lung volume and lower ipsilateral lung V20 Gy compared to EIG. The IL for visually guided DIBH was more reproducible than audio-coached EIG. Based on these findings, the DIBH technique is our new breathing adaptation standard for radiotherapy of patients with left-sided breast cancer with lymph node involvement.

Can audio coached 4D CT emulate free breathing during the treatment course

Background. The image quality of 4DCT depends on breathing regularity. Respiratory audio coaching may improve regularity and reduce motion artefacts. We question the safety of coached planning 4DCT without coaching during treatment. We investigated the possibility of coaching to a more stable breathing without changing the breathing amplitude. The interfraction variation of the breathing cycle amplitude in free and coached breathing was studied as well as the possible impact of fatigue on longer coaching sessions. Methods. Thirteen volunteers completed respiratory audio coaching on 3 days within a 2 week period. An external marker system monitoring the motion of the thoraco-abdominal wall was used to track the respiration. On all days, free breathing and two coached breathing curves were recorded. We assumed that free versus coached breathing from day 1 (reference session) simulated breathing during an uncoached versus coached planning 4DCT, respectively, and compared the mean breathing cycle amplitude to the free versus coached breathing from day 2 and 3 simulating free versus coached breathing during treatment. Results. For most volunteers it was impossible to apply coaching without changes in breathing cycle amplitude. No significant decrease in standard deviation of breathing cycle amplitude distribution was seen. Generally it was not possible to predict the breathing cycle amplitude and its variation the following days based on the breathing in the reference session irrespective of coaching or free breathing. We found a significant tendency towards an increased breathing cycle amplitude variation with the duration of the coaching session. Conclusion. These results suggest that large interfraction variation is present in breathing amplitude irrespective of coaching, leading to the suggestion of daily image guidance for verification of respiratory pattern and tumour related motion. Until further investigated it is not recommendable to use coached 4DCT for planning of a free breathing treatment course.