Biological-effective versus conventional dose volume histograms correlated with late genitourinary and gastrointestinal toxicity after external beam radiotherapy for prostate cancer: a matched pair analysis

BACKGROUND: To determine whether the dose-volume histograms (DVH's) for the rectum and bladder constructed using biological-effective dose (BED-DVH's) better correlate with late gastrointestinal (GI) and genitourinary (GU) toxicity after treatment with external beam radiotherapy for prostate cancer than conventional DVH's (C-DVH's). METHODS: The charts of 190 patients treated with external beam radiotherapy with a minimum follow-up of 2 years were reviewed. Six patients (3.2%) were found to have RTOG grade 3 GI toxicity, and similarly 6 patients (3.2%) were found to have RTOG grade 3 GU toxicity. Average late C-DVH's and BED-DVH's of the bladder and rectum were computed for these patients as well as for matched-pair control patients. For each matched pair the following measures of normalized difference in the DVH's were computed: (a) δ(AUC )= (Area Under Curve [AUC] in grade 3 patient – AUC in grade 0 patient)/(AUC in grade 0 patient) and (b) δ(V60 )= (Percent volume receiving = 60 Gy [V60] in grade 3 patient – V60 in grade 0 patient)/(V60 in grade 0 patient). RESULTS: As expected, the grade 3 curve is to the right of and above the grade 0 curve for all four sets of average DVH's – suggesting that both the C-DVH and the BED-DVH can be used for predicting late toxicity. δ(AUC )was higher for the BED-DVH's than for the C-DVH's – 0.27 vs 0.23 (p = 0.036) for the rectum and 0.24 vs 0.20 (p = 0.065) for the bladder. δ(V60 )was also higher for the BED-DVH's than for the C-DVH's – 2.73 vs 1.49 for the rectum (p = 0.021) and 1.64 vs 0.71 (p = 0.021) for the bladder. CONCLUSIONS: When considering well-established dosimetric endpoints used in evaluating treatment plans, BED-DVH's for the rectum and bladder correlate better with late toxicity than C-DVH's and should be considered when attempting to minimize late GI and GU toxicity after external beam radiotherapy for prostate cancer

MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients

Background: MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients. Methods: Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database. Results: MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non-expressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005). Conclusions: The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma

Where It’s at Really Matters: In Situ In Vivo Vascular Endothelial Growth Factor Spatially Correlates with Electron Paramagnetic Resonance pO2 Images in Tumors of Living Mice

Purpose: Tumor microenvironments show remarkable tumor pO_{2} heterogeneity, as seen in prior EPR pO_{2} images (EPROI). pO_{2} correlation with hypoxia response proteins is frustrated by large rapid pO2 changes with position. Procedures: To overcome this limitation, biopsies stereotactically located in the EPROI were used to explore the relationship between vascular endothelial growth factor A (VEGF) concentrations in living mouse tumors and the local EPROI pO_{2}. Results: Quantitative ELISA VEGF concentrations correlated (p = 0.0068 to 0.019) with mean pO_{2}, median pO_{2}, and the fraction of voxels in the biopsy volume with pO_{2} less than 3, 6, and 10 Torr. Conclusions: This validates EPROI hypoxic fractions at the molecular level and provides a new paradigm for the assessment of the relationship, in vivo, between hypoxia and hypoxia response proteins. When translated to human subjects, this will enhance understanding of human tumor pathophysiology and cancer response to therapy

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Calibration of Video Cameras to the Coordinate System of a Radiation Therapy Treatment Machine

There has been recent interest in using video cameras along with computer vision and photogrammetric techniques to aid in the daily positioning of patients for radiation therapy. We describe here a method to calibrate video cameras to the beam coordinate system of a radiation therapy treatment machine. Standard camera calibration relates the three-dimensional coordinate system of a calibration phantom to the two-dimensional image coordinates. Using a calibration phantom designed for simultaneous X-ray and video imaging, both types of images can be calibrated to a single coordinate system. A series of X-ray images of the calibration phantom is taken using the motion of the treatment machine. Camera calibration parameters derived from these images are used to find a transformation from the coordinate system of the calibration phantom to the beam coordinate system of the treatment machine

Region-of-interest image reconstruction with intensity weighting in circular cone-beam CT for image-guided radiation therapy

Imaging plays a vital role in radiation therapy and with recent advances in technology considerable emphasis has been placed on cone-beam CT (CBCT). Attaching a kV x-ray source and a flat panel detector directly to the linear accelerator gantry has enabled progress in target localization techniques, which can include daily CBCT setup scans for some treatments. However, with an increasing number of CT scans there is also an increasing concern for patient exposure. An intensity-weighted region-of-interest (IWROI) technique, which has the potential to greatly reduce CBCT dose, in conjunction with the chord-based backprojection-filtration (BPF) reconstruction algorithm, has been developed and its feasibility in clinical use is demonstrated in this article. A nonuniform filter is placed in the x-ray beam to create regions of two different beam intensities. In this manner, regions outside the target area can be given a reduced dose but still visualized with a lower contrast to noise ratio. Image artifacts due to transverse data truncation, which would have occurred in conventional reconstruction algorithms, are avoided and image noise levels of the low- and high-intensity regions are well controlled by use of the chord-based BPF reconstruction algorithm. The proposed IWROI technique can play an important role in image-guided radiation therapy