BACKGROUND Radiofrequency catheter ablation (RFCA) for idiopathic right ventricular outflow tract (RVOT) arrhythmias is typically guided by local activation time (LAT) mapping and unipolar... Show moreBACKGROUND Radiofrequency catheter ablation (RFCA) for idiopathic right ventricular outflow tract (RVOT) arrhythmias is typically guided by local activation time (LAT) mapping and unipolar electrogram morphology (QS configuration). However, LAT mapping is limited by the large variation among patients, and the area demonstrating a QS configuration of the unipolar electrogram may be larger than the focal source. Reversed polarity has been proposed as a criterion for guiding RFCA. OBJECTIVE The purpose of this study was to investigate the value of reversed polarity of adjacent bipolar electrograms for predicting a successful ablation site in idiopathic RVOT arrhythmias. METHODS Twenty-five consecutive patients (12 men [ 48%], age 43 +/- 15 years) undergoing RFCA for RVOT arrhythmia were studied. Electrograms of ablation sites and of points within a 15-mm radius to the successful site were evaluated for LAT, unipolar electrogram morphology, and the presence of reversed polarity of adjacent bipolar electrograms. Electrogram characteristics of successful ablation sites were compared to those of nonsuccessful ablation sites. The spatial distribution of each electrogram characteristic was studied. RESULTS Successful ablation sites more often demonstrated reversed polarity and had an earlier LAT than nonsuccessful sites. A wide spatial distribution was observed for unipolar electrograms with a QS configuration around the successful ablation site. Mapping based on LAT and reversed polarity had a higher predictive value for a successful ablation site than mapping based on LAT and QS configuration. CONCLUSION The presence of reversed polarity has a high predictive value for successful ablation sites in focal idiopathic RVOT arrhythmias and is likely to reduce the number of RFCA applications. Show less
Coremans, I.; Wiggenraad, R.; Jong, M. de; Santvoort, J. van; Ages, D.; Putter, H.; ... ; Creutzberg, C. 2011
Near-infrared (NIR) fluorescence imaging has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. Indocyanine green (ICG) is currently the only clinically available... Show moreNear-infrared (NIR) fluorescence imaging has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. Indocyanine green (ICG) is currently the only clinically available fluorophore that can be used for SLN mapping. Preclinically, ICG adsorbed to human serum albumin (ICG:HSA) improves its performance as a lymphatic tracer in some anatomical sites. The benefit of ICG:HSA for SLN mapping of breast cancer has not yet been assessed in a clinical trial. We performed a double-blind, randomized study to determine if ICG:HSA has advantages over ICG alone. The primary endpoint was the fluorescence brightness, defined as the signal-to-background ratio (SBR), of identified SLNs. Clinical trial subjects were 18 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using (99m)Technetium-nanocolloid and patent blue. Patients were randomly assigned to receive 1.6 ml of 500 mu M ICG:HSA or ICG that was injected periareolarly directly after patent blue. The Mini-Fluorescence-Assisted Resection and Exploration (Mini-FLARE) imaging system was used for NIR fluorescence detection and quantitation. SLN mapping was successful in all patients. Patient, tumor, and treatment characteristics were equally distributed over the treatment groups. No significant difference was found in SBR between the ICG:HSA group and the ICG alone group (8.4 vs. 11.3, respectively, P = 0.18). In both groups, the average number of detected SLNs was 1.4 +/- A 0.5 SLNs per patient (P = 0.74). This study shows that there is no direct benefit of premixing ICG with HSA prior to injection for SLN mapping in breast cancer patients, thereby reducing the cost and complexity of the procedure. With these optimized parameters that eliminate the necessity of HSA, larger trials can now be performed to determine patient benefit. Show less
Lips, D.J.; Koebrugge, B.; Liefers, G.J.; Linden, J.C. van de; Smit, V.T.H.B.M.; Pruijt, H.F.M.; ... ; Bosscha, K. 2011
Denial is a well-known phenomenon in clinical oncology practice. Yet whether the impact of denial on patient well-being is beneficial or harmful remains unknown. The purpose of the current study is... Show moreDenial is a well-known phenomenon in clinical oncology practice. Yet whether the impact of denial on patient well-being is beneficial or harmful remains unknown. The purpose of the current study is to investigate the relationship between denial and social and emotional outcomes in a large sample of lung cancer patients over an extended time period. Denial and social and emotional outcomes were measured in 195 newly diagnosed lung cancer patients. Four assessments were conducted over 8 months. The level of denial was measured using the Denial of Cancer Interview. Patient-reported social and emotional outcomes were measured using the EORTC-QLQ-30 and the HADS. Patients with a moderate or increasing level of denial over time reported better social outcomes (role functioning: p = 0.0036, social functioning: p = 0.027) and less anxiety (p = 0.0001) and depression (p = 0.0019) than patients with a low level of denial. The overall quality of life was better among lung cancer patients who displayed either moderate or increasing levels of denial compared with those who displayed low levels of denial (p < 0.0001). A certain level of denial in lung cancer patients can have a protective effect on social and emotional outcomes. Clinicians should take this into account when providing information about the illness and its prognosis. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Show less
Purpose The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression... Show morePurpose The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. Patients and Methods Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. Results Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred < 4) and 77% were PgR-rich (Allred >= 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P = .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P < .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P = .002), and multivariate analyses (P < .001 and P = .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. Conclusion Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment. Show less
Stroma tissue surrounding cancer cells plays an important role in tumor development and behavior. In colorectal cancer, it has been found that the amount of stroma within the primary tumor is of... Show moreStroma tissue surrounding cancer cells plays an important role in tumor development and behavior. In colorectal cancer, it has been found that the amount of stroma within the primary tumor is of prognostic value. We therefore have evaluated the prognostic value of this tumor-stroma ratio for breast cancer. A cohort of 574 early breast cancer patients, primarily treated with surgery between 1985 and 1994 was analyzed for the tumor-stroma ratio. The percentage of stroma was visually estimated on Haematoxylin-Eosin (H&E) stained histological sections. Patients with more than 50% intra-tumor stroma were quantified as stroma rich and patients with less than 50% as stroma poor. For the total group of patients, stroma-rich tumors had a shorter relapse-free period (RFP) (P = 0.001) and overall survival (OS) (P = 0.025) compared to stroma-poor tumors. Tumor-stroma ratio was an independent prognostic parameter for the total group of patients (P < 0.001) and also in stratified analysis based on systemic treatment. Importantly, in the triple-negative cancer subpopulation, patients with stroma-rich tumors had a 2.92 times higher risk of relapse (P = 0.006) compared to those with stroma-poor tumors, independently of other clinico-pathological parameters. Five-year RFP-rates for triple-negative cancer patients with stroma-rich compared to stroma-poor tumors were 56 and 81%, respectively. Tumor-stroma ratio has proven to be an independent prognostic factor for RFP in breast cancer patients and especially in the triple-negative cancer subpopulation. Tumor-stroma ratio could be easily implemented in routine daily pathology diagnostics, as it is simple to determine, reproducible, and performed in quick time. Show less
In breast cancer, the prognostic impact of COX2 expression varies widely between studies. We examined the prognostic value of COX2 expression in a large cohort of breast cancer patients treated... Show moreIn breast cancer, the prognostic impact of COX2 expression varies widely between studies. We examined the prognostic value of COX2 expression in a large cohort of breast cancer patients treated with primary surgery between 1985 and 1994 and explained the variable results of COX2 expression found in the literature. A tissue microarray was constructed of available tumour material, and ER, PgR, HER2, Ki67 and COX2 were examined by immunohistochemistry. Median follow-up was 19 years. Fifty-five percent (n = 369/677) of patients received no systemic treatment. COX2 was scored using a weighted histoscore. Analysis of COX2 expression in two groups based on the median (148; below vs. above) showed an increased hazard ratio (HR) of 1.35 (95% CI 1.05-1.75, P = 0.021) for disease-free survival (DFS) and of 1.39 (95% CI 1.03-1.82, P = 0.016) for overall survival (OS). However, COX2 did not remain independent in multivariate analysis. In patients with hormone receptor positive tumours, COX2 expression had a negative influence on outcome (low vs. high: DFS: HR 1.37, 95% CI 1.07-1.76, P = 0.013). This effect disappeared when endocrine therapy was administered (low vs. high: DFS: HR 0.93, 95% CI 0.51-1.70, P = 0.811) while it remained statistically significant when endocrine therapy was omitted (low vs. high: DFS: HR 1.48, 95% CI 1.12-1.94, P = 0.005). Our results show that COX2 plays a role in hormonal pathways. Our results can explain the results found in previously published studies. Show less
Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both... Show moreBeing born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (<-1SDS; "SGA") with 75 individuals born preterm but with a birth weight appropriate for their gestational age (>-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; "AGA"). The SGA individuals were not only lighter at birth, but also had a smaller length (p = 3.3 × 10(-13)) and head circumference at birth (p = 4.1 × 10(-13)). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non-epigenetic mechanisms that may lead to similar later health outcomes. Show less
Vorst, J.R. van der; Hutteman, M.; Mieog, J.S.D.; Rooij, K.E. de; Kaijzel, E.L.; Lowik, C.W.G.M.; ... ; Vahrmeijer, A.L. 2011
BACKGROUND: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) is a promising technique to obtain real-time assessment of the extent and number of colorectal liver metastases... Show moreBACKGROUND: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) is a promising technique to obtain real-time assessment of the extent and number of colorectal liver metastases during surgery. The current study aims to optimize dosage and timing of ICG administration. MATERIALS AND METHODS: Liver tumors were induced in 18 male WAG/Rij rats by subcapsular inoculation of CC531 rat colorectal cancer cells into three distinct liver lobes. Rats were divided in two groups: imaging after 24 and 48 h or 72 and 96 h after intravenous ICG administration. In each time group, rats were allocated to three dose groups: 0.04, 0.08, or 0.16 mg ICG. Intraoperative imaging and ex vivo measurements were performed using the Mini-FLARE imaging system and confirmed by fluorescence microscopy. Fluorescence intensity was quantified using the Mini-FLARE software and the difference between tumor signal and liver signal (tumor-to-liver ratio; TLR) was calculated. RESULTS: In all 18 rats, all colorectal liver metastases (n = 34), some as small as 1.2 mm, were identified using ICG and the Mini-FLARE imaging system. Average tumor-to-liver ratio (TLR) over all groups was 3.0 ± 1.2. TLR was significantly higher in the 72 h time group compared with other time points. ICG dose did not significantly influence TLR, but a trend was found favoring the 0.08 mg dose group. Fluorescence microscopy demonstrated a clear fluorescent rim around the tumor. CONCLUSIONS: This study demonstrates that colorectal cancer liver metastases can be clearly identified during surgery using ICG and the Mini-FLARE imaging system, with optimal timing of 72 h post-injection and an optimal dose of 0.08 mg (0.25 mg/kg) ICG. NIR fluorescence imaging has the potential to improve intraoperative detection of micrometastases and, thus, the completeness of resection. Show less
There is a clear growing interest, at least in the statistical literature, in competing risks and multi-state models. With the rising interest in competing risks and multi-state models a number of... Show moreThere is a clear growing interest, at least in the statistical literature, in competing risks and multi-state models. With the rising interest in competing risks and multi-state models a number of software packages have been developed for the analysis of such models. The present special issue of the Journal of Statistical Software introduces a selection of R packages devoted to competing risks and multi-state models. This introduction to the special issue contains some background and highlights the contents of the contributions. Show less
Multi-state models are a very useful tool to answer a wide range of questions in survival analysis that cannot, or only in a more complicated way, be answered by classical models. They are suitable... Show moreMulti-state models are a very useful tool to answer a wide range of questions in survival analysis that cannot, or only in a more complicated way, be answered by classical models. They are suitable for both biomedical and other applications in which time-to-event variables are analyzed. However, they are still not frequently applied. So far, an important reason for this has been the lack of available software. To overcome this problem, we have developed the mstate package in R for the analysis of multi-state models. The package covers all steps of the analysis of multi-state models, from model building and data preparation to estimation and graphical representation of the results. It can be applied to non-and semi-parametric (Cox) models. The package is also suitable for competing risks models, as they are a special category of multi-state models. This article offers guidelines for the actual use of the software by means of an elaborate multi-state analysis of data describing post-transplant events of patients with blood cancer. The data have been provided by the EBMT (the European Group for Blood and Marrow Transplantation). Special attention will be paid to the modeling of different covariate effects (the same for all transitions or transition-specific) and different baseline hazard assumptions (different for all transitions or equal for some). Show less
BACKGROUND Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with... Show moreBACKGROUND Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). METHODS The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. FINDINGS 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. INTERPRETATION Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. FUNDING Pfizer. Show less
Taxis, C.F.B.V. van; Wijnmaalen, A.P.; Uijl, D.W. den; Gawrysiak, M.; Putter, H.; Schalij, M.J.; Zeppenfeld, K. 2011
BACKGROUND:: Radiofrequency catheter ablation (RFCA) for idiopathic right ventricular outflow tract (RVOT) arrhythmias is typically guided by local activation time (LAT) mapping and unipolar... Show moreBACKGROUND:: Radiofrequency catheter ablation (RFCA) for idiopathic right ventricular outflow tract (RVOT) arrhythmias is typically guided by local activation time (LAT) mapping and unipolar electrogram morphology (QS-configuration). However, LAT mapping is limited by the large variation among patients and the area demonstrating a QS-configuration of the unipolar electrogram may be larger than the focal source. Reversed polarity has been proposed as criterion to guide RFCA. OBJECTIVE:: The aim of this study was to investigate the value of reversed polarity of adjacent bipolar electrograms to predict a successful ablation site in idiopathic RVOT arrhythmias. METHODS:: Twenty-five consecutive patients (12 male [48%], 43±15 years) undergoing RFCA for RVOT arrhythmia were studied. Electrograms of ablation sites and of points within a 15mm radius to the successful site were evaluated for LAT, unipolar electrogram morphology and the presence of reversed polarity of adjacent bipolar electrograms. Electrogram characteristics of successful ablation sites were compared to non-successful ablation sites. The spatial distribution of each electrogram characteristic was studied. RESULTS:: Successful ablation sites more often demonstrated reversed polarity and had an earlier LAT than non-successful sites. A wide spatial distribution was observed for unipolar electrograms with a QS-configuration around the successful ablation site. Mapping based on LAT and reversed polarity had a higher predictive value for a successful ablation site than mapping based on LAT and QS-configuration. CONCLUSION:: The presence of reversed polarity has a high predictive value for successful ablation sites in focal idiopathic RVOT arrhythmias and is likely to reduce the number of RFCA applications. Show less
HIV dynamical models are often based on non-linear systems of ordinary differential equations (ODE), which do not have an analytical solution. Introducing random effects in such models leads to... Show moreHIV dynamical models are often based on non-linear systems of ordinary differential equations (ODE), which do not have an analytical solution. Introducing random effects in such models leads to very challenging non-linear mixed-effects models. To avoid the numerical computation of multiple integrals involved in the likelihood, a hierarchical likelihood (h-likelihood) approach, treated in the spirit of a penalized likelihood is proposed. The asymptotic distribution of the maximum h-likelihood estimators (MHLE) for fixed effects is given. The MHLE are slightly biased but the bias can be made negligible by using a parametric bootstrap procedure. An efficient algorithm for maximizing the h-likelihood is proposed. A simulation study, based on a classical HIV dynamical model, confirms the good properties of the MHLE. The method is applied to the analysis of a clinical trial. (C) 2010 Elsevier B.V. All rights reserved. Show less
