Feasibility of intensity-modulated and image-guided radiotherapy for functional organ preservation in locally advanced laryngeal cancer

Purpose: The study aims to assess the feasibility of intensity-modulated and image-guided radiotherapy (IMRT, and IGRT, respectively) for functional preservation in locally advanced laryngeal cancer. A retrospective review of 27 patients undergoing concurrent chemoradiation for locally advanced laryngeal cancers (8 IMRT, 19 IGRT) was undertaken. In addition to regular clinical examinations, all patients had PET imaging at 4 months and 10 months after radiotherapy, then yearly. Loco-regional control, speech quality and feeding-tube dependency were assessed during follow-up visits. Results: At a median follow-up of 20 months (range 6-57 months), four out of 27 patients (14.8%) developed local recurrence and underwent salvage total laryngectomy. One patient developed distant metastases following salvage surgery. Among the 23 patients who conserved their larynx with no sign of recurrence at last follow-up, 22 (95%) reported normal or near normal voice quality, allowing them to communicate adequately. Four patients (14.8%) had long-term tube feeding-dependency because of severe dysphagia (2 patients) and chronic aspiration (2 patients, with ensuing death from aspiration pneumonia in one patient). Conclusions and Clinical Relevance: Functional laryngeal preservation is feasible with IMRT and IGRT for locally advanced laryngeal cancer. However, dysphagia and aspiration remain serious complications, due most likely to high radiation dose delivery to the pharyngeal musculatures. © 2012 Nguyen et al

Pretargeted PET Imaging with a TCO-Conjugated Anti-CD44v6 Chimeric mAb U36 and [Zr-89]Zr-DFO-PEG(5)-Tz

The recent advances in the production of engineered antibodies have facilitated the development and application of tailored, target-specific antibodies. Positron emission tomography (PET) of these antibody-based drug candidates can help to better understand their in vivo behavior. In this study, we report an in vivo proof-ofconcept pretargeted immuno-PET study where we compare a pretargeting vs targeted approach using a new Zr-89-labeled tetrazine as a bio-orthogonal ligand in an inverse electron demand Diels-Alder (IEDDA) in vivo click reaction. A CD44v6-selective chimeric monoclonal U36 was selected as the targeting antibody because it has potential in immuno-PET imaging of head-and-neck squamous cell carcinoma (HNSCC). Zirconium-89 (t(1/2) = 78.41 h) was selected as the radionuclide of choice to be able to make a head-to-head comparison of the pretargeted and targeted approaches. [Zr-89]Zr-DFO-PEG S -Tz ([Zr-89]Zr-3) was synthesized and used in pretargeted PET imaging of HNSCC xenografts (VU-SCC-OE) at 24 and 48 h after administration of a trans-cyclooctene (TCO)-functionalized U36. The pretargeted approach resulted in lower absolute tumor uptake than the targeted approach (1.5 +/- 0.2 vs 17.1 +/- 3.0% ID/g at 72 h p.i. U36) but with comparable tumor-to-non-target tissue ratios and significantly lower absorbed doses. In conclusion, anti-CD44v6 monoclonal antibody U36 was successfully used for Zr-89-immuno-PET imaging of HNSCC xenograft tumors using both a targeted and pretargeted approach. The results not only support the utility of the pretargeted approach in immuno-PET imaging but also demonstrate the challenges in achieving optimal in vivo IEDDA reaction efficiencies in relation to antibody pharmacokinetics.Peer reviewe

Automatic Individual Arterial Input Functions Calculated From PCA Outperform Manual and Population-Averaged Approaches for the Pharmacokinetic Modeling of DCE-MR Images

[EN] Background: To introduce a segmentation method to calculate an automatic arterial input function (AIF) based on prin- cipal component analysis (PCA) of dynamic contrast enhanced MR (DCE-MR) imaging and compare it with individual manually selected and population-averaged AIFs using calculated pharmacokinetic parameters. Methods: The study included 65 individuals with prostate examinations (27 tumors and 38 controls). Manual AIFs were individually extracted and also averaged to obtain a population AIF. Automatic AIFs were individually obtained by applying PCA to volumetric DCE-MR imaging data and finding the highest correlation of the PCs with a reference AIF. Variability was assessed using coefficients of variation and repeated measures tests. The different AIFs were used as inputs to the pharmacokinetic model and correlation coefficients, Bland-Altman plots and analysis of variance tests were obtained to compare the results. Results: Automatic PCA-based AIFs were successfully extracted in all cases. The manual and PCA-based AIFs showed good correlation (r between pharmacokinetic parameters ranging from 0.74 to 0.95), with differences below the manual individual variability (RMSCV up to 27.3%). The population-averaged AIF showed larger differences (r from 0.30 to 0.61). Conclusion: The automatic PCA-based approach minimizes the variability associated to obtaining individual volume- based AIFs in DCE-MR studies of the prostate.Sanz Requena, R.; Prats-Montalbán, JM.; Marti Bonmati, L.; Alberich Bayarri, A.; García Martí, G.; Pérez, R.; Ferrer Riquelme, AJ. (2015). Automatic Individual Arterial Input Functions Calculated From PCA Outperform Manual and Population-Averaged Approaches for the Pharmacokinetic Modeling of DCE-MR Images. Journal of Magnetic Resonance Imaging. 42:477-487. doi:10.1002/jmri.24805S47748742Leach, M. O., Brindle, K. M., Evelhoch, J. L., Griffiths, J. R., Horsman, M. R., Jackson, A., … Workman, P. (2005). The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. British Journal of Cancer, 92(9), 1599-1610. doi:10.1038/sj.bjc.6602550Tofts, P. S., & Kermode, A. G. (1991). Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magnetic Resonance in Medicine, 17(2), 357-367. doi:10.1002/mrm.1910170208Parker, G. J. M., Roberts, C., Macdonald, A., Buonaccorsi, G. A., Cheung, S., Buckley, D. L., … Jayson, G. C. (2006). Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI. Magnetic Resonance in Medicine, 56(5), 993-1000. doi:10.1002/mrm.21066Meng, R., Chang, S. D., Jones, E. C., Goldenberg, S. L., & Kozlowski, P. (2010). Comparison between Population Average and Experimentally Measured Arterial Input Function in Predicting Biopsy Results in Prostate Cancer. Academic Radiology, 17(4), 520-525. doi:10.1016/j.acra.2009.11.006Loveless, M. E., Halliday, J., Liess, C., Xu, L., Dortch, R. D., Whisenant, J., … Yankeelov, T. E. (2011). A quantitative comparison of the influence of individual versus population-derived vascular input functions on dynamic contrast enhanced-MRI in small animals. Magnetic Resonance in Medicine, 67(1), 226-236. doi:10.1002/mrm.22988Shukla-Dave, A., Lee, N., Stambuk, H., Wang, Y., Huang, W., Thaler, H. T., … Koutcher, J. A. (2009). Average arterial input function for quantitative dynamic contrast enhanced magnetic resonance imaging of neck nodal metastases. BMC Medical Physics, 9(1). doi:10.1186/1756-6649-9-4Wang, Y., Huang, W., Panicek, D. M., Schwartz, L. H., & Koutcher, J. A. (2008). Feasibility of using limited-population-based arterial input function for pharmacokinetic modeling of osteosarcoma dynamic contrast-enhanced MRI data. Magnetic Resonance in Medicine, 59(5), 1183-1189. doi:10.1002/mrm.21432Rijpkema, M., Kaanders, J. H. A. M., Joosten, F. B. M., van der Kogel, A. J., & Heerschap, A. (2001). Method for quantitative mapping of dynamic MRI contrast agent uptake in human tumors. Journal of Magnetic Resonance Imaging, 14(4), 457-463. doi:10.1002/jmri.1207Singh, A., Rathore, R. K. S., Haris, M., Verma, S. K., Husain, N., & Gupta, R. K. (2009). Improved bolus arrival time and arterial input function estimation for tracer kinetic analysis in DCE-MRI. Journal of Magnetic Resonance Imaging, 29(1), 166-176. doi:10.1002/jmri.21624Shi, L., Wang, D., Liu, W., Fang, K., Wang, Y.-X. J., Huang, W., … Ahuja, A. T. (2013). Automatic detection of arterial input function in dynamic contrast enhanced MRI based on affinity propagation clustering. Journal of Magnetic Resonance Imaging, 39(5), 1327-1337. doi:10.1002/jmri.24259Kim, J.-H., Im, G. H., Yang, J., Choi, D., Lee, W. J., & Lee, J. H. (2011). Quantitative dynamic contrast-enhanced MRI for mouse models using automatic detection of the arterial input function. NMR in Biomedicine, 25(4), 674-684. doi:10.1002/nbm.1784Li, X., Welch, E. B., Arlinghaus, L. R., Chakravarthy, A. B., Xu, L., Farley, J., … Yankeelov, T. E. (2011). A novel AIF tracking method and comparison of DCE-MRI parameters using individual and population-based AIFs in human breast cancer. Physics in Medicine and Biology, 56(17), 5753-5769. doi:10.1088/0031-9155/56/17/018Fedorov, A., Fluckiger, J., Ayers, G. D., Li, X., Gupta, S. N., Tempany, C., … Fennessy, F. M. (2014). A comparison of two methods for estimating DCE-MRI parameters via individual and cohort based AIFs in prostate cancer: A step towards practical implementation. Magnetic Resonance Imaging, 32(4), 321-329. doi:10.1016/j.mri.2014.01.004Lin, Y.-C., Chan, T.-H., Chi, C.-Y., Ng, S.-H., Liu, H.-L., Wei, K.-C., … Wang, J.-J. (2012). Blind estimation of the arterial input function in dynamic contrast-enhanced MRI using purity maximization. Magnetic Resonance in Medicine, 68(5), 1439-1449. doi:10.1002/mrm.24144Roberts, C., Little, R., Watson, Y., Zhao, S., Buckley, D. L., & Parker, G. J. M. (2010). The effect of blood inflow andB1-field inhomogeneity on measurement of the arterial input function in axial 3D spoiled gradient echo dynamic contrast-enhanced MRI. Magnetic Resonance in Medicine, 65(1), 108-119. doi:10.1002/mrm.22593Jackson, J. E. (1991). A Use’s Guide to Principal Components. Wiley Series in Probability and Statistics. doi:10.1002/0471725331Prats-Montalbán, J. M., Sanz-Requena, R., Martí-Bonmatí, L., & Ferrer, A. (2013). Prostate functional magnetic resonance image analysis using multivariate curve resolution methods. Journal of Chemometrics, 28(8), 672-680. doi:10.1002/cem.2585Eyal, E., Bloch, B. N., Rofsky, N. M., Furman-Haran, E., Genega, E. M., Lenkinski, R. E., & Degani, H. (2010). Principal Component Analysis of Dynamic Contrast Enhanced MRI in Human Prostate Cancer. Investigative Radiology, 45(4), 174-181. doi:10.1097/rli.0b013e3181d0a02fTofts, P. S. (1997). Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. Journal of Magnetic Resonance Imaging, 7(1), 91-101. doi:10.1002/jmri.1880070113Donahue, K. M., Burstein, D., Manning, W. J., & Gray, M. L. (1994). Studies of Gd-DTPA relaxivity and proton exchange rates in tissue. Magnetic Resonance in Medicine, 32(1), 66-76. doi:10.1002/mrm.1910320110Taylor, J. S., & Reddick, W. E. (2000). Evolution from empirical dynamic contrast-enhanced magnetic resonance imaging to pharmacokinetic MRI. Advanced Drug Delivery Reviews, 41(1), 91-110. doi:10.1016/s0169-409x(99)00058-7Port, R. E., Knopp, M. V., & Brix, G. (2001). Dynamic contrast-enhanced MRI using Gd-DTPA: Interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors. Magnetic Resonance in Medicine, 45(6), 1030-1038. doi:10.1002/mrm.1137Dale, B. M., Jesberger, J. A., Lewin, J. S., Hillenbrand, C. M., & Duerk, J. L. (2003). Determining and optimizing the precision of quantitative measurements of perfusion from dynamic contrast enhanced MRI. Journal of Magnetic Resonance Imaging, 18(5), 575-584. doi:10.1002/jmri.10399Garpebring, A., Brynolfsson, P., Yu, J., Wirestam, R., Johansson, A., Asklund, T., & Karlsson, M. (2012). Uncertainty estimation in dynamic contrast-enhanced MRI. Magnetic Resonance in Medicine, 69(4), 992-1002. doi:10.1002/mrm.24328Onxley, J. D., Yoo, D. S., Muradyan, N., MacFall, J. R., Brizel, D. M., & Craciunescu, O. I. (2014). Comprehensive Population-Averaged Arterial Input Function for Dynamic Contrast–Enhanced vMagnetic Resonance Imaging of Head and Neck Cancer. International Journal of Radiation Oncology*Biology*Physics, 89(3), 658-665. doi:10.1016/j.ijrobp.2014.03.006Chen, Y.-J., Chu, W.-C., Pu, Y.-S., Chueh, S.-C., Shun, C.-T., & Tseng, W.-Y. I. (2012). Washout gradient in dynamic contrast-enhanced MRI is associated with tumor aggressiveness of prostate cancer. Journal of Magnetic Resonance Imaging, 36(4), 912-919. doi:10.1002/jmri.23723Vos, E. K., Litjens, G. J. S., Kobus, T., Hambrock, T., Kaa, C. A. H. de, Barentsz, J. O., … Scheenen, T. W. J. (2013). Assessment of Prostate Cancer Aggressiveness Using Dynamic Contrast-enhanced Magnetic Resonance Imaging at 3 T. European Urology, 64(3), 448-455. doi:10.1016/j.eururo.2013.05.045Yang, C., Karczmar, G. S., Medved, M., Oto, A., Zamora, M., & Stadler, W. M. (2009). Reproducibility assessment of a multiple reference tissue method for quantitative dynamic contrast enhanced-MRI analysis. Magnetic Resonance in Medicine, 61(4), 851-859. doi:10.1002/mrm.21912McGrath, D. M., Bradley, D. 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Feasibility of Tomotherapy-Based Image-Guided Radiotherapy for Locally Advanced Oropharyngeal Cancer

PURPOSE: The study aims to assess the feasibility of tomotherapy-based image-guided (IGRT) radiotherapy for locally advanced oropharyngeal cancer. A retrospective review of 33 patients undergoing concurrent chemoradiation for locally advanced oropharyngeal cancers was conducted. Radiotherapy planning, treatment toxicity and loco-regional control were assessed. RESULTS: At a median follow-up of 32 months (6-47 months), no patient developed loco-regional recurrence. Two patients (6%) developed distant metastases. Grade 3-4 acute toxicity was respectively 72% and 25% for mucositis and gastrointestinal toxicity. Two patients (6%) had long-term dependence on tube feedings. Dose-volume histogram demonstrated excellent target volume coverage and low radiation dose to the organs at risk for complications. CONCLUSIONS AND CLINICAL RELEVANCE: IGRT provides excellent loco-regional control but acute toxicity remains significant and needs to be addressed in future prospective trials. The feasibility of Tomotherapy to decrease radiation dose to the normal tissues merits further investigations

Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer

Background To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastases. Methods A retrospective review of 52 patients undergoing radiotherapy for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed. Results Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was, respectively, 14.1 Gy and 24.7 Gy for the SC and CC plans (p < 0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% (p < 0.0001) Conclusion Tomotherapy for head and neck cancer minimized radiotherapy dose to the contralateral parotid gland in patients undergoing elective node irradiation without sacrificing target coverage

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current LAS era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N=3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤ 45 years, p<0.0001), were less often smokers (35% vs. 46%, p<0.0001), had more often clear chest X-rays (82% vs. 72%, p<0.0001), had better donor oxygenation ratio's (20% vs. 26% with PaO /FiO ≤ 300 mmHg, p<0.0001) and had better lung donor score values (LDS) (28% vs. 17% with LDS=6, p<0.0001) compared to donors used for LTx in countries with low donation rate. Survival rates for the groups LDS =6 and ≥7 at 5 years were 69.7% and 60.9% (p=0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized

Pretargeted PET Imaging with a TCO-Conjugated Anti-CD44v6 Chimeric mAb U36 and [Zr-89]Zr-DFO-PEG(5)-Tz

The recent advances in the production of engineered antibodies have facilitated the development and application of tailored, target-specific antibodies. Positron emission tomography (PET) of these antibody-based drug candidates can help to better understand their in vivo behavior. In this study, we report an in vivo proof-ofconcept pretargeted immuno-PET study where we compare a pretargeting vs targeted approach using a new Zr-89-labeled tetrazine as a bio-orthogonal ligand in an inverse electron demand Diels-Alder (IEDDA) in vivo click reaction. A CD44v6-selective chimeric monoclonal U36 was selected as the targeting antibody because it has potential in immuno-PET imaging of head-and-neck squamous cell carcinoma (HNSCC). Zirconium-89 (t(1/2) = 78.41 h) was selected as the radionuclide of choice to be able to make a head-to-head comparison of the pretargeted and targeted approaches. [Zr-89]Zr-DFO-PEG S -Tz ([Zr-89]Zr-3) was synthesized and used in pretargeted PET imaging of HNSCC xenografts (VU-SCC-OE) at 24 and 48 h after administration of a trans-cyclooctene (TCO)-functionalized U36. The pretargeted approach resulted in lower absolute tumor uptake than the targeted approach (1.5 +/- 0.2 vs 17.1 +/- 3.0% ID/g at 72 h p.i. U36) but with comparable tumor-to-non-target tissue ratios and significantly lower absorbed doses. In conclusion, anti-CD44v6 monoclonal antibody U36 was successfully used for Zr-89-immuno-PET imaging of HNSCC xenograft tumors using both a targeted and pretargeted approach. The results not only support the utility of the pretargeted approach in immuno-PET imaging but also demonstrate the challenges in achieving optimal in vivo IEDDA reaction efficiencies in relation to antibody pharmacokinetics

Multidisciplinary Functional MR Imaging for Prostate Cancer

Various functional magnetic resonance (MR) imaging techniques are used for evaluating prostate cancer including diffusion-weighted imaging, dynamic contrast-enhanced MR imaging, and MR spectroscopy. These techniques provide unique information that is helpful to differentiate prostate cancer from non-cancerous tissue and have been proven to improve the diagnostic performance of MRI not only for cancer detection, but also for staging, post-treatment monitoring, and guiding prostate biopsies. However, each functional MR imaging technique also has inherent challenges. Therefore, in order to make accurate diagnoses, it is important to comprehensively understand their advantages and limitations, histologic background related with image findings, and their clinical relevance for evaluating prostate cancer. This article will review the basic principles and clinical significance of functional MR imaging for evaluating prostate cancer