Tumour perfusion measured using DCE-MRI is prognostic for ...

The prognostic value of dynamic contrast-enhanced MRI contrast agent transfer constant Ktrans in cervical cancer is explained by plasma flow rather than vessel permeability SHORT TITLE: Microvascular plasma flow predicts survival in cervical cancerBen R. Dickie1,2, Chris J. Rose3, Lucy E. Kershaw1,2, Stephanie B. Withey4, Bernadette M. Carrington5, Susan E Davidson5, Gillian Hutchison6, Catharine ML. West11Division of Molecular and Clinical Cancer Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK2Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, UK3Division of Informatics, Imaging, and Data Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK4RRPPS, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK5Department of Diagnostic Radiology, The Christie NHS Foundation Trust, Manchester, UK6Department of Radiology, Royal Bolton NHS Foundation Trust, Farnworth, UKKey words: cervix cancer, DCE-MRI, prognostic biomarker, plasma flow, Ktrans, permeability surface-area productCorresponding email: ben.dickie@manchester.ac.ukABSTRACT Background: The microvascular contrast agent transfer constant Ktrans has shown prognostic value in cervical cancer patients treated with chemoradiotherapy. This study aims to determine whether this is explained by the contribution to Ktrans of plasma flow (Fp), vessel permeability surface-area product (PS), or a combination of both.Methods: Pre-treatment dynamic contrast-enhanced MRI (DCE-MRI) data from 36 patients were analysed using the two-compartment exchange model. Estimates of Fp, PS, Ktrans, and fractional plasma and interstitial volumes (vp and ve) were made and used in univariate and multivariate survival analyses adjusting for clinicopathologic variables tumour stage, nodal status, histological subtype, patient age, tumour volume, and treatment type (chemoradiotherapy versus radiotherapy alone).Results: In univariate analyses, Fp (HR = 0.25, P = 0.0095) and Ktrans (HR = 0.20, P = 0.032) were significantly associated with disease-free survival while PS, vp and ve were not. In multivariate analyses adjusting for clinicopathologic variables, Fp and Ktrans significantly increased the accuracy of survival predictions (P = 0.0089). Conclusion: The prognostic value of Ktrans in cervical cancer patients treated with chemoradiotherapy is explained by microvascular plasma flow (Fp) rather than vessel permeability surface-area product (PS). INTRODUCTIONDynamic contrast-enhanced MRI (DCE-MRI) has been extensively used to study the relationship between pre-treatment microvascular function and treatment outcome in locally advanced cervix cancer ADDIN CSL_CITATION { "citationID" : "fBd31SoS", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zahra", "given" : "Mark A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Li Tee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Priest", "given" : "Andrew N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Graves", "given" : "Martin J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arends", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crawford", "given" : "Robin AF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brenton", "given" : "James D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lomas", "given" : "David J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sala", "given" : "Evis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology* Biology* Physics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "766\u2013773", "title" : "Semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging measurements predict radiation response in cervix cancer", "type" : "article-journal", "volume" : "74" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.ijrobp.2009.04.069", "ISBN" : "1879-355X", "ISSN" : "1879-355X", "PMID" : "19735887", "abstract" : "PURPOSE: To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. METHODS AND MATERIALS: Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. RESULTS: Pretherapy radiologic parameters and pharmacokinetic K(trans) correlated with response (p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. CONCLUSIONS: A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.", "author" : [ { "dropping-particle" : "", "family" : "Semple", "given" : "Scott I K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harry", "given" : "Vanessa N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parkin", "given" : "David E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gilbert", "given" : "Fiona J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International journal of radiation oncology, biology, physics", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "611-617", "title" : "A combined pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging predicts response to chemoradiation in locally advanced cervical cancer.", "type" : "article-journal", "volume" : "75" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.radonc.2012.11.007", "ISSN" : "01678140", "PMID" : "23333024", "abstract" : "Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: ABrix, k ep, kel, Tofts: Ktrans, \u03bde). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: ABrix, kel, and Ktrans were significantly (P < 0.05) positively associated with both clinical LRC and PFS, while \u03bde was significantly positively correlated with PFS only. kep showed no association with any endpoint. ABrix was positively correlated with Ktrans and \u03bde, and showed the strongest association with endpoint in the log-rank testing. k el and Ktrans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure. \u00a9 2012 Elsevier Ireland Ltd. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Andersen", "given" : "Erlend K F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hole", "given" : "KH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Lund", "given" : "Kjersti", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundf\u00f8r", "given" : "Kolbein", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kristensen", "given" : "Gunnar B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyng", "given" : "Heidi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malinen", "given" : "Eirik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Radiotherapy and Oncology", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "117-122", "title" : "Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome", "type" : "article-journal", "volume" : "107" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "ISSN" : "0360-3016", "abstract" : "PURPOSE: This study investigated sequential changes in tumor blood supply using magnetic resonance (MR) perfusion imaging and assessed their significance in the prediction of outcome of patients with advanced cervical cancer. The purpose of this project was to devise a simple, noninvasive method to predict early signs of treatment failure in advanced cervical cancer treated with conventional radiation therapy.\nMETHODS AND MATERIALS: Sixty-eight MR perfusion studies were performed prospectively in 17 patients with squamous carcinomas (14) and adenocarcinomas (3) of the cervix, Stages bulky IB (1), IIB (5), IIIA (1), IIIB (8), and IVA (1), and recurrent (1). Four sequential studies were obtained in each patient: immediately before radiation therapy (pretherapy), after a dose of 20-22 Gy/ approximately 2 weeks (early therapy), after a dose of 40-45 Gy/ approximately 4-5 weeks (midtherapy), and 4-6 weeks after completion of therapy (follow-up). Perfusion imaging of the tumor was obtained at 3-s intervals in the sagittal plane. A bolus of 0.1 mmol/kg of MR contrast material (gadoteridol) was injected intravenously 30 s after beginning image acquisition at a rate of 9 ml/s using a power injector. Time/signal-intensity curves to reflect the onset, slope, and relative signal intensity (rSI) of contrast enhancement in the tumor region were generated. Median follow-up was 8 months (range 3-18 months).\nRESULTS: Tumors with a higher tissue perfusion (rSI > or = 2.8) in the pretherapy and early therapy (20-22 Gy) studies had a lower incidence of local recurrence than those with a rSI of < 2.8, but this was not statistically significant (13% vs. 67%; p = 0.05). An increase in tumor perfusion early during therapy (20-22 Gy), particularly to an rSI of > or = 2.8, was the strongest predictor of local recurrence (0% vs. 78%; p = 0.002). However, pelvic examination during early therapy (20-22 Gy) commonly showed no appreciable tumor regression. The slope of the time/signal-intensity curve obtained before and during radiation therapy also correlated with local recurrence. Follow-up perfusion studies did not provide information to predict recurrence.\nCONCLUSION: These preliminary results suggest that two simple MR perfusion studies before and early in therapy can offer important information on treatment outcome within the first 2 weeks of radiation therapy before response is evident by clinical examination. High tumor perfusion before therapy and increasing or persistent hi\u2026", "author" : [ { "dropping-particle" : "", "family" : "Mayr", "given" : "N. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yuh", "given" : "W. T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magnotta", "given" : "V. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ehrhardt", "given" : "J. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wheeler", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sorosky", "given" : "J. I.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "C. S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wen", "given" : "B. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "D. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pelsang", "given" : "R. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buller", "given" : "R. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oberley", "given" : "L. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mellenberg", "given" : "D. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hussey", "given" : "D. H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology, Biology, Physics", "id" : "ITEM-4", "issue" : "3", "issued" : { "date-parts" : [ [ "1996", "10" ] ] }, "language" : "eng", "page" : "623-633", "title" : "Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay", "title-short" : "Tumor perfusion studies using fast magnetic resona", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1002/cncr.24822", "ISSN" : "1097-0142", "abstract" : "BACKGROUND:\nThe authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed.\nMETHODS:\nSixty-two cervical cancer patients underwent dynamic contrast-enhanced (DCE) MRI before and during early radiation/chemotherapy (2-2.5 weeks into treatment). Heterogeneous tumor perfusion was analyzed by signal intensity (SI) of each tumor voxel. Poorly perfused tumor regions were quantified as lower 10th percentile of SI (SI[10%]). DCE-MRI and 3-dimensional (3D) tumor volumetry MRI parameters were assessed as predictors of recurrence and cancer death (median follow-up, 4.1 years). Their discriminating capacity was compared with clinical prognostic factors (stage, lymph node status, histology) using sensitivity/specificity and Cox regression analysis.\nRESULTS:\nSI(10%) and 3D volume 2-2.5 weeks into therapy independently predicted disease recurrence (hazard ratio [HR], 2.6; 95% confidence interval [95% CI], 1.0-6.5 [P = .04] and HR, 1.9; 95% CI, 1.1-3.5 [P = .03], respectively) and death (HR, 1.9; 95% CI, 1.0-3.5 [P = .03] and HR, 1.9; 95% CI, 1.2-2.9 [P = .01], respectively), and were superior to clinical prognostic factors. The addition of MRI parameters to clinical prognostic factors increased sensitivity and specificity of clinical prognostic factors from 71% and 51%, respectively, to 100% and 71%, respectively, for predicting recurrence, and from 79% and 54%, respectively, to 93% and 60%, respectively, for predicting death.\nCONCLUSIONS:\nMRI parameters reflecting heterogeneous tumor perfusion and subtle tumor volume change early during radiation/chemotherapy are independent and better predictors of tumor recurrence and death than clinical prognostic factors. The combination of clinical prognostic factors and MRI parameters further improves early prediction of treatment failure and may enable a window of opportunity to alter treatment strategy. Cancer 2010. \u00a9 2010 American Cancer Society.", "author" : [ { "dropping-particle" : "", "family" : "Mayr", "given" : "Nina A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yuh", "given" : "William T. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jajoura", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Jian Z.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lo", "given" : "Simon S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montebello", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porter", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Dongqing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McMeekin", "given" : "D. Scott", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buatti", "given" : "John M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-5", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "2" ] ] }, "language" : "en", "page" : "903-912", "title" : "Ultra-early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1097/RLI.0b013e3181a64ce9", "ISSN" : "0020-9996", "abstract" : "Purpose\nTo assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival.\n\nMaterials and Methods\nThree MRI examinations were obtained in 101 patients before and during therapy (at 2\u20132.5 and 4\u20135 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional (3D) tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3D-volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t-test, Kaplan-Meier analysis and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 1.2\u201312.3 years).\n\nResults\nTumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2\u20132.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of \u226530 cm3 in the MRI obtained at 2\u20132.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, p=0.006) and disease-free-survival rate (47% vs. 79%, p=0.001), respectively.\n\nConclusions\nOur results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2\u20132.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation and the bulk of residual presumably therapy-resistant tumor, requires future study.", "author" : [ { "dropping-particle" : "", "family" : "Yuh", "given" : "William T.C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayr", "given" : "Nina A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jarjoura", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Dee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grecula", "given" : "John C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lo", "given" : "Simon S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Edwards", "given" : "Susan M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magnotta", "given" : "Vincent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sammet", "given" : "Steffen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Hualin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montebello", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fowler", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Knopp", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Jian Z.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Investigative radiology", "id" : "ITEM-6", "issue" : "6", "issued" : { "date-parts" : [ [ "2009", "6" ] ] }, "page" : "343-350", "title" : "Predicting Control of Primary Tumor and Survival by DCE MRI During Early Therapy in Cervical Cancer", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Zahra et al, 2009; Semple et al, 2009; Andersen et al, 2013; Mayr et al, 1996, 2010; Yuh et al, 2009)", "manualFormatting" : "(Mayr et al, 1996, 2010; Zahra et al, 2009; Yuh et al, 2009; Semple et al, 2009; Andersen et al, 2013)", "plainTextFormattedCitation" : "(Zahra et al, 2009; Semple et al, 2009; Andersen et al, 2013; Mayr et al, 1996, 2010; Yuh et al, 2009)", "previouslyFormattedCitation" : "(Zahra et al, 2009; Semple et al, 2009; Andersen et al, 2013; Mayr et al, 1996, 2010; Yuh et al, 2009)" }, "properties" : { "formattedCitation" : "{\\rtf [2\\uc0\\u8211{}7]}", "noteIndex" : 0, "plainCitation" : "[2\u20137]", "unsorted" : true }, "schema" : "" }(Mayr et al, 1996, 2010; Zahra et al, 2009; Yuh et al, 2009; Semple et al, 2009; Andersen et al, 2013). Greater uptake of contrast agent by tumour tissue measured using MRI signal enhancement or quantitative model-based parameters such as Ktrans ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/(SICI)1522-2586(199909)10", "ISBN" : "1053-1807 (Print)\\n1053-1807 (Linking)", "ISSN" : "1053-1807", "PMID" : "10508281", "abstract" : "We describe a standard set of quantity names and symbols related to\\n\\tthe estimation of kinetic parameters from dynamic contrast-enhanced\\n\\tT1-weighted magnetic resonance imaging data, using diffusable agents\\n\\tsuch as gadopentetate dimeglumine (Gd-DTPA). These include a) the\\n\\tvolume transfer constant Ktrans (min21); b) the volume of extravascular\\n\\textracellular space (EES) per unit volume of tissue ve (0 F ve F\\n\\t1); and c) the flux rate constant between EES and plasma kep (min21).\\n\\tThe rate constant is the ratio of the transfer constant to the EES\\n\\t(kep 5 Ktrans/ve). Under flow-limited conditions Ktrans equals the\\n\\tblood plasma flow per unit volume of tissue; under permeability-limited\\n\\tconditions Ktrans equals the permeability surface area product per\\n\\tunit volume of tissue. We relate these quantities to previously\\n\\tpublished work from our groups; our future publications will refer\\n\\tto these standardized terms, and we propose that these be adopted\\n\\tas international standards. J. Magn. Reson. Imaging 10: 223\u00f1232,\\n\\t1999. r 1999Wiley-Liss, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Tofts", "given" : "Paul S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brix", "given" : "Gunnar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "L Evelhoch", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Knopp", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Larsson", "given" : "Henrik B W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Ting-Yim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayr", "given" : "Nina a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parker", "given" : "Geoffrey J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Port", "given" : "Ruediger E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "June", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weisskoff", "given" : "Robert M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Magn Reson Imag", "id" : "ITEM-1", "issue" : "July", "issued" : { "date-parts" : [ [ "1999" ] ] }, "page" : "223-232", "title" : "Estimating Kinetic Parameters From Dynamic Contrast-Enhanced T1-Weighted\\tMRI of a Diffusable Tracer: Standardized Quantities and Symbols", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tofts et al, 1999)", "plainTextFormattedCitation" : "(Tofts et al, 1999)", "previouslyFormattedCitation" : "(Tofts et al, 1999)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Tofts et al, 1999), has been shown to be a positive prognostic factor ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0360-3016", "abstract" : "PURPOSE: This study investigated sequential changes in tumor blood supply using magnetic resonance (MR) perfusion imaging and assessed their significance in the prediction of outcome of patients with advanced cervical cancer. The purpose of this project was to devise a simple, noninvasive method to predict early signs of treatment failure in advanced cervical cancer treated with conventional radiation therapy.\nMETHODS AND MATERIALS: Sixty-eight MR perfusion studies were performed prospectively in 17 patients with squamous carcinomas (14) and adenocarcinomas (3) of the cervix, Stages bulky IB (1), IIB (5), IIIA (1), IIIB (8), and IVA (1), and recurrent (1). Four sequential studies were obtained in each patient: immediately before radiation therapy (pretherapy), after a dose of 20-22 Gy/ approximately 2 weeks (early therapy), after a dose of 40-45 Gy/ approximately 4-5 weeks (midtherapy), and 4-6 weeks after completion of therapy (follow-up). Perfusion imaging of the tumor was obtained at 3-s intervals in the sagittal plane. A bolus of 0.1 mmol/kg of MR contrast material (gadoteridol) was injected intravenously 30 s after beginning image acquisition at a rate of 9 ml/s using a power injector. Time/signal-intensity curves to reflect the onset, slope, and relative signal intensity (rSI) of contrast enhancement in the tumor region were generated. Median follow-up was 8 months (range 3-18 months).\nRESULTS: Tumors with a higher tissue perfusion (rSI > or = 2.8) in the pretherapy and early therapy (20-22 Gy) studies had a lower incidence of local recurrence than those with a rSI of < 2.8, but this was not statistically significant (13% vs. 67%; p = 0.05). An increase in tumor perfusion early during therapy (20-22 Gy), particularly to an rSI of > or = 2.8, was the strongest predictor of local recurrence (0% vs. 78%; p = 0.002). However, pelvic examination during early therapy (20-22 Gy) commonly showed no appreciable tumor regression. The slope of the time/signal-intensity curve obtained before and during radiation therapy also correlated with local recurrence. Follow-up perfusion studies did not provide information to predict recurrence.\nCONCLUSION: These preliminary results suggest that two simple MR perfusion studies before and early in therapy can offer important information on treatment outcome within the first 2 weeks of radiation therapy before response is evident by clinical examination. High tumor perfusion before therapy and increasing or persistent hi\u2026", "author" : [ { "dropping-particle" : "", "family" : "Mayr", "given" : "N. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yuh", "given" : "W. T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magnotta", "given" : "V. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ehrhardt", "given" : "J. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wheeler", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sorosky", "given" : "J. I.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "C. S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wen", "given" : "B. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "D. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pelsang", "given" : "R. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buller", "given" : "R. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oberley", "given" : "L. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mellenberg", "given" : "D. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hussey", "given" : "D. H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology, Biology, Physics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1996", "10" ] ] }, "language" : "eng", "page" : "623-633", "title" : "Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay", "title-short" : "Tumor perfusion studies using fast magnetic resona", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1002/cncr.24822", "ISSN" : "1097-0142", "abstract" : "BACKGROUND:\nThe authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed.\nMETHODS:\nSixty-two cervical cancer patients underwent dynamic contrast-enhanced (DCE) MRI before and during early radiation/chemotherapy (2-2.5 weeks into treatment). Heterogeneous tumor perfusion was analyzed by signal intensity (SI) of each tumor voxel. Poorly perfused tumor regions were quantified as lower 10th percentile of SI (SI[10%]). DCE-MRI and 3-dimensional (3D) tumor volumetry MRI parameters were assessed as predictors of recurrence and cancer death (median follow-up, 4.1 years). Their discriminating capacity was compared with clinical prognostic factors (stage, lymph node status, histology) using sensitivity/specificity and Cox regression analysis.\nRESULTS:\nSI(10%) and 3D volume 2-2.5 weeks into therapy independently predicted disease recurrence (hazard ratio [HR], 2.6; 95% confidence interval [95% CI], 1.0-6.5 [P = .04] and HR, 1.9; 95% CI, 1.1-3.5 [P = .03], respectively) and death (HR, 1.9; 95% CI, 1.0-3.5 [P = .03] and HR, 1.9; 95% CI, 1.2-2.9 [P = .01], respectively), and were superior to clinical prognostic factors. The addition of MRI parameters to clinical prognostic factors increased sensitivity and specificity of clinical prognostic factors from 71% and 51%, respectively, to 100% and 71%, respectively, for predicting recurrence, and from 79% and 54%, respectively, to 93% and 60%, respectively, for predicting death.\nCONCLUSIONS:\nMRI parameters reflecting heterogeneous tumor perfusion and subtle tumor volume change early during radiation/chemotherapy are independent and better predictors of tumor recurrence and death than clinical prognostic factors. The combination of clinical prognostic factors and MRI parameters further improves early prediction of treatment failure and may enable a window of opportunity to alter treatment strategy. Cancer 2010. \u00a9 2010 American Cancer Society.", "author" : [ { "dropping-particle" : "", "family" : "Mayr", "given" : "Nina A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yuh", "given" : "William T. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jajoura", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Jian Z.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lo", "given" : "Simon S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montebello", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porter", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Dongqing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McMeekin", "given" : "D. Scott", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buatti", "given" : "John M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "2" ] ] }, "language" : "en", "page" : "903-912", "title" : "Ultra-early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1097/RLI.0b013e3181a64ce9", "ISSN" : "0020-9996", "abstract" : "Purpose\nTo assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival.\n\nMaterials and Methods\nThree MRI examinations were obtained in 101 patients before and during therapy (at 2\u20132.5 and 4\u20135 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional (3D) tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3D-volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t-test, Kaplan-Meier analysis and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 1.2\u201312.3 years).\n\nResults\nTumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2\u20132.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of \u226530 cm3 in the MRI obtained at 2\u20132.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, p=0.006) and disease-free-survival rate (47% vs. 79%, p=0.001), respectively.\n\nConclusions\nOur results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2\u20132.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation and the bulk of residual presumably therapy-resistant tumor, requires future study.", "author" : [ { "dropping-particle" : "", "family" : "Yuh", "given" : "William T.C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayr", "given" : "Nina A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jarjoura", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Dee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grecula", "given" : "John C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lo", "given" : "Simon S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Edwards", "given" : "Susan M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magnotta", "given" : "Vincent A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sammet", "given" : "Steffen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Hualin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montebello", "given" : "Joseph F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fowler", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Knopp", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Jian Z.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Investigative radiology", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "2009", "6" ] ] }, "page" : "343-350", "title" : "Predicting Control of Primary Tumor and Survival by DCE MRI During Early Therapy in Cervical Cancer", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zahra", "given" : "Mark A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Li Tee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Priest", "given" : "Andrew N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Graves", "given" : "Martin J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arends", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crawford", "given" : "Robin AF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brenton", "given" : "James D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lomas", "given" : "David J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sala", "given" : "Evis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology* Biology* Physics", "id" : "ITEM-4", "issue" : "3", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "766\u2013773", "title" : "Semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging measurements predict radiation response in cervix cancer", "type" : "article-journal", "volume" : "74" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1016/j.ijrobp.2009.04.069", "ISBN" : "1879-355X", "ISSN" : "1879-355X", "PMID" : "19735887", "abstract" : "PURPOSE: To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. METHODS AND MATERIALS: Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. RESULTS: Pretherapy radiologic parameters and pharmacokinetic K(trans) correlated with response (p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. CONCLUSIONS: A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.", "author" : [ { "dropping-particle" : "", "family" : "Semple", "given" : "Scott I K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harry", "given" : "Vanessa N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parkin", "given" : "David E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gilbert", "given" : "Fiona J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International journal of radiation oncology, biology, physics", "id" : "ITEM-5", "issue" : "2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "611-617", "title" : "A combined pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging predicts response to chemoradiation in locally advanced cervical cancer.", "type" : "article-journal", "volume" : "75" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1016/j.radonc.2012.11.007", "ISSN" : "01678140", "PMID" : "23333024", "abstract" : "Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: ABrix, k ep, kel, Tofts: Ktrans, \u03bde). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: ABrix, kel, and Ktrans were significantly (P < 0.05) positively associated with both clinical LRC and PFS, while \u03bde was significantly positively correlated with PFS only. kep showed no association with any endpoint. ABrix was positively correlated with Ktrans and \u03bde, and showed the strongest association with endpoint in the log-rank testing. k el and Ktrans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure. \u00a9 2012 Elsevier Ireland Ltd. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Andersen", "given" : "Erlend K F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hole", "given" : "KH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Lund", "given" : "Kjersti", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundf\u00f8r", "given" : "Kolbein", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kristensen", "given" : "Gunnar B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyng", "given" : "Heidi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malinen", "given" : "Eirik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Radiotherapy and Oncology", "id" : "ITEM-6", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "117-122", "title" : "Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome", "type" : "article-journal", "volume" : "107" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Mayr et al, 1996, 2010; Semple et al, 2009; Yuh et al, 2009; Zahra et al, 2009; Andersen et al, 2013)", "plainTextFormattedCitation" : "(Mayr et al, 1996, 2010; Semple et al, 2009; Yuh et al, 2009; Zahra et al, 2009; Andersen et al, 2013)", "previouslyFormattedCitation" : "(Mayr et al, 1996, 2010; Semple et al, 2009; Yuh et al, 2009; Zahra et al, 2009; Andersen et al, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Mayr et al, 1996, 2010; Semple et al, 2009; Yuh et al, 2009; Zahra et al, 2009; Andersen et al, 2013). Increased uptake of contrast agent before treatment may reflect a tumour that is better oxygenated (improving radio-sensitivity) and more easily infiltrated with chemotherapy agents via the vasculature, thus improving the chances of treatment success and reducing the risk of recurrence.Uptake of contrast agent into tumour tissue depends on a number of microvascular factors. For example, a measurement of Ktrans depends on the delivery of contrast agent to the capillary bed (plasma flow; Fp) and exchange flow of contrast agent across the vessel wall (as measured by the permeability surface-area product; PS) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/(SICI)1522-2586(199909)10", "ISBN" : "1053-1807 (Print)\\n1053-1807 (Linking)", "ISSN" : "1053-1807", "PMID" : "10508281", "abstract" : "We describe a standard set of quantity names and symbols related to\\n\\tthe estimation of kinetic parameters from dynamic contrast-enhanced\\n\\tT1-weighted magnetic resonance imaging data, using diffusable agents\\n\\tsuch as gadopentetate dimeglumine (Gd-DTPA). These include a) the\\n\\tvolume transfer constant Ktrans (min21); b) the volume of extravascular\\n\\textracellular space (EES) per unit volume of tissue ve (0 F ve F\\n\\t1); and c) the flux rate constant between EES and plasma kep (min21).\\n\\tThe rate constant is the ratio of the transfer constant to the EES\\n\\t(kep 5 Ktrans/ve). Under flow-limited conditions Ktrans equals the\\n\\tblood plasma flow per unit volume of tissue; under permeability-limited\\n\\tconditions Ktrans equals the permeability surface area product per\\n\\tunit volume of tissue. We relate these quantities to previously\\n\\tpublished work from our groups; our future publications will refer\\n\\tto these standardized terms, and we propose that these be adopted\\n\\tas international standards. J. Magn. Reson. Imaging 10: 223\u00f1232,\\n\\t1999. r 1999Wiley-Liss, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Tofts", "given" : "Paul S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brix", "given" : "Gunnar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "L Evelhoch", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Knopp", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Larsson", "given" : "Henrik B W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Ting-Yim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayr", "given" : "Nina a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parker", "given" : "Geoffrey J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Port", "given" : "Ruediger E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "June", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weisskoff", "given" : "Robert M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Magn Reson Imag", "id" : "ITEM-1", "issue" : "July", "issued" : { "date-parts" : [ [ "1999" ] ] }, "page" : "223-232", "title" : "Estimating Kinetic Parameters From Dynamic Contrast-Enhanced T1-Weighted\\tMRI of a Diffusable Tracer: Standardized Quantities and Symbols", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Sourbron", "given" : "Steven P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic Resonance in Medicine", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "735\u2013745", "title" : "On the scope and interpretation of the Tofts models for DCE-MRI", "type" : "article-journal", "volume" : "66" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Tofts et al, 1999; Sourbron & Buckley, 2011)", "plainTextFormattedCitation" : "(Tofts et al, 1999; Sourbron & Buckley, 2011)", "previouslyFormattedCitation" : "(Tofts et al, 1999; Sourbron & Buckley, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Tofts et al, 1999; Sourbron & Buckley, 2011). It is therefore currently unknown whether perfusion, or vessel permeability surface area product, or both are responsible for the observed relationship between Ktrans and the survival of cervical cancer patients treated with chemoradiotherapy. Knowledge of this may open new avenues for targeted treatments and allow better stratification of patients into distinct prognostic groups.Improvements in the temporal resolution of DCE-MRI sequences ADDIN CSL_CITATION { "citationID" : "e29shorik", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Stollberger", "given" : "Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fazekas", "given" : "Franz", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Topics in Magnetic Resonance Imaging", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "245\u2013255", "title" : "Improved perfusion and tracer kinetic imaging using parallel imaging", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Stollberger & Fazekas, 2004)", "plainTextFormattedCitation" : "(Stollberger & Fazekas, 2004)", "previouslyFormattedCitation" : "(Stollberger & Fazekas, 2004)" }, "properties" : { "formattedCitation" : "[11]", "noteIndex" : 0, "plainCitation" : "[11]" }, "schema" : "" }(Stollberger & Fazekas, 2004) have facilitated independent measurement of plasma flow (Fp) and permeability surface area product (PS) using the two-compartment exchange (2CXM) ADDIN CSL_CITATION { "citationID" : "19noot5qs4", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Brix", "given" : "Gunnar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiessling", "given" : "Fabian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lucht", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Darai", "given" : "Susanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wasser", "given" : "Klaus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delorme", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griebel", "given" : "J\u00fcrgen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic Resonance in Medicine", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "420\u2013429", "title" : "Microcirculation and microvasculature in breast tumors: pharmacokinetic analysis of dynamic MR image series", "title-short" : "Microcirculation and microvasculature in breast tu", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Brix et al, 2004)", "plainTextFormattedCitation" : "(Brix et al, 2004)", "previouslyFormattedCitation" : "(Brix et al, 2004)" }, "properties" : { "formattedCitation" : "[12]", "noteIndex" : 0, "plainCitation" : "[12]" }, "schema" : "" }(Brix et al, 2004) and adiabatic approximation to the tissue homogeneity models ADDIN CSL_CITATION { "citationID" : "k5q26eihs", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/00004647-199812000-00011", "ISSN" : "0271-678X", "abstract" : "Using the adiabatic approximation, which assumes that the tracer concentration in parenchymal tissue changes slowly relative to that in capillaries, we derived a time-domain, closed-form solution of the tissue homogeneity model. This solution, which is called the adiabatic solution, is similar in form to those of two-compartment models. Owing to its simplicity, the adiabatic solution can be used in CBF experiments in which kinetic data with only limited time resolution or signal-to-noise ratio, or both, are obtained. Using computer simulations, we investigated the accuracy and the precision of the parameters in the adiabatic solution for values that reflect 2H-labeled water (D2O) clearance from the brain (see Part II). It was determined that of the three model parameters, (1) the vascular volume (Vi), (2) the product of extraction fraction and blood flow (EF), and (3) the clearance rate constant (kadb), only the last one could be determined accurately, and therefore CBF must be determined from this parameter only. From the error analysis of the adiabatic solution, it was concluded that for the D2O clearance experiments described in Part II, the coefficient of variation of CBF was approximately 7% in gray matter and 22% in white matter.", "author" : [ { "dropping-particle" : "", "family" : "St Lawrence", "given" : "K. S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "T. Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "1998", "12" ] ] }, "language" : "eng", "page" : "1365-1377", "title" : "An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: I. Theoretical derivation", "title-short" : "An adiabatic approximation to the tissue homogenei", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(St Lawrence & Lee, 1998)", "plainTextFormattedCitation" : "(St Lawrence & Lee, 1998)", "previouslyFormattedCitation" : "(St Lawrence & Lee, 1998)" }, "properties" : { "formattedCitation" : "[13]", "noteIndex" : 0, "plainCitation" : "[13]" }, "schema" : "" }(St Lawrence & Lee, 1998). This paper describes a prospective study in which the two-compartment exchange model is used to independently measure Fp and PS in 36 patients with locally advanced cervix cancer treated with chemoradiotherapy. It was hypothesised that survival is limited by the delivery of chemotherapy and oxygen via plasma flow rather than vessel permeability surface area product, and that plasma flow is therefore a more accurate prognostic factor than PS and Ktrans. Data and software for performing all analyses described in this paper are available at ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.5281/zenodo.1495211", "author" : [ { "dropping-particle" : "", "family" : "Dickie", "given" : "BR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Zenodo", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2017" ] ] }, "title" : "MRdep/Predicting-Survival-in-Cervical-Cancer-using-DCE-MRI: Predicting-Survival-in-Cervical-Cancer-using-DCE-MRI: Software and Data for Survival Analysis in Patients with Locally Advanced Cervical Cancer_v3 [Data set]", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dickie, 2017)", "plainTextFormattedCitation" : "(Dickie, 2017)", "previouslyFormattedCitation" : "(Dickie, 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dickie, 2017)MATERIALS AND METHODSStudy outlineThe study was prospective and received local research ethics committee approval from the South Manchester Research Ethics Committee (Ref: 05/Q1403/28). Eligible patients had biopsy proven locally advanced carcinoma of the cervix and planned treatment with radical concurrent chemoradiotherapy, followed by either a low dose rate brachytherapy or external beam radiotherapy boost. Exclusion criteria were age < 18 years and contraindication for MRI. Forty patients were recruited at a single centre between July 2005 and March 2010. All patients gave written informed consent prior to involvement in the study. Patients received DCE-MRI approximately 1 week before the first fraction of radiotherapy and received standard follow-up for detection of recurrence. Survival analysis was undertaken to infer the prognostic effect and predictive value of DCE-MRI and clinicopathologic variables. DCE-MRI data from four patients could not be analysed, leaving a total of thirty-six patients for inclusion in survival analyses. Supplementary Figure 1 shows a CONSORT diagram for the study ADDIN CSL_CITATION { "citationID" : "163ut83g14", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140-6736(00)04337-3", "ISSN" : "0140-6736", "abstract" : "Summary\nTo comprehend the results of a randomised controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through total transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by use of a checklist and flow diagram. The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect, or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrolment, intervention allocation, followup, and analysis). The diagram explicitly shows the number of participants, for each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have done an intentionto- treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.", "author" : [ { "dropping-particle" : "", "family" : "Moher", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schulz", "given" : "Kenneth F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Altman", "given" : "Douglas G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet", "id" : "ITEM-1", "issue" : "9263", "issued" : { "date-parts" : [ [ "2001", "4" ] ] }, "page" : "1191-1194", "title" : "The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials", "title-short" : "The CONSORT statement", "type" : "article-journal", "volume" : "357" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Moher et al, 2001)", "plainTextFormattedCitation" : "(Moher et al, 2001)", "previouslyFormattedCitation" : "(Moher et al, 2001)" }, "properties" : { "formattedCitation" : "[27]", "noteIndex" : 0, "plainCitation" : "[27]" }, "schema" : "" }(Moher et al, 2001). TreatmentEach patient received external beam radiotherapy to the whole pelvis (up to L4) with a dose of 40–45 Gy in 20 fractions. Cisplatin chemotherapy was administered concurrently in 2–4 cycles where tolerated. Brachytherapy boosts were administered in one fraction following EBRT (20–32 Gy). External beam radiotherapy boosts were delivered in 8–10 fractions (20–32 Gy).MRI protocolMRI was performed on a 1.5 T Siemens Magnetom Avanto scanner (Siemens Medical Solutions, Erlangen, Germany). MRI acquisition parameters have been described in detail previously ADDIN CSL_CITATION { "citationID" : "qhdc9jse1", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/mrm.22217", "ISBN" : "1522-2594 (Electronic)\\n0740-3194 (Linking)", "ISSN" : "07403194", "PMID" : "20187179", "abstract" : "The Tofts tracer kinetic models are often used to analyze dynamic contrast-enhanced MRI data. They are derived from a general two-compartment exchange model (2CXM) but assume negligible plasma mean transit time. The 2CXM estimates tissue plasma perfusion and capillary permeability-surface area; the Tofts models estimate the transfer constant K(trans), which reflects a combination of these two parameters. The aims of this study were to compare the 2CXM and Tofts models and report microvascular parameters in patients with cervical cancer. Thirty patients were scanned pretreatment using a dynamic contrast-enhanced MRI protocol with a 3 sec temporal resolution and a total scan duration of 4 min. Whole-tumor parameters were estimated with both models. The 2CXM provided superior fits to the data for all patients (all 30 P values < 0.005), and significantly different parameter estimates were obtained (P < 0.01). K(trans) (mean = 0.35 +/- 0.26 min(-1)) did not equal absolute values of tissue plasma perfusion (mean = 0.65 +/- 0.56 mL/mL/min) or permeability-surface area (mean = 0.14 +/- 0.09 mL/mL/min) but correlated strongly with tissue plasma perfusion (r = 0.944; P = 0.01). Average plasma mean transit time, calculated with the 2CXM, was 22 +/- 16 sec, suggesting the assumption of negligible plasma mean transit time is not appropriate in this dataset and the 2CXM is better suited for its analysis than the Tofts models. The results demonstrate the importance of selecting an appropriate tracer kinetic model in dynamic contrast-enhanced MRI.", "author" : [ { "dropping-particle" : "", "family" : "Donaldson", "given" : "Stephanie B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "West", "given" : "Catharine M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "Susan E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrington", "given" : "Bernadette M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hutchison", "given" : "Gillian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "Andrew P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sourbron", "given" : "Steven P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic Resonance in Medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "691-700", "title" : "A comparison of tracer kinetic models for T1-weighted dynamic contrast-enhanced MRI: Application in carcinoma of the cervix", "title-short" : "A comparison of tracer kinetic models for T1-weigh", "type" : "article-journal", "volume" : "63" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Donaldson et al, 2010)", "plainTextFormattedCitation" : "(Donaldson et al, 2010)", "previouslyFormattedCitation" : "(Donaldson et al, 2010)" }, "properties" : { "formattedCitation" : "[9]", "noteIndex" : 0, "plainCitation" : "[9]" }, "schema" : "" }(Donaldson et al, 2010). Briefly, a high spatial resolution 2D T2-weighted turbo spin echo scan (FOV = 240 x 320 mm2, 16 x 5 mm slices, voxel size = 0.63 x 0.63 mm2, TR = 5390 ms, TE = 118 ms, NSA = 2) was acquired for defining tumour regions of interest (ROIs). A 3D T1-weighted spoiled gradient-recalled echo (SPGR) volumetric interpolated breath-hold examination sequence, with the same field of view as T2-weighted scans but lower spatial resolution (voxel size = 2.5 x 2.5 x 5 mm3, TR/TE = 5.6/1.08 ms, SENSE factor = 2), was used for pre-contrast T1 mapping (flip angles: 5o, 10o, and 35o, NSA = 10) and dynamic imaging (flip angle: 25o, NSA = 1). Pre-contrast T1 was used to convert dynamic signal intensity into contrast agent concentration for tracer kinetic modelling. Dynamic imaging was performed with a temporal resolution of 3 s to facilitate measurement of plasma flow (Fp) and permeability surface area product (PS) using the 2CXM. A total of 80 dynamic volumes were acquired for a total DCE-MRI acquisition time of 4 minutes. A bolus of 0.1?mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist, Bayer-Schering Pharma AG, Berlin, Germany) was administered 15 seconds into the dynamic scan at 4 mL s-1 using a power injector through a cannula placed in the antecubital vein, followed by a 20 mL saline flush. Imaging was performed in the sagittal plane with the read encoding direction aligned along the superior-inferior direction to minimise inflow-enhancement effects ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/mrm.22217", "ISBN" : "1522-2594 (Electronic)\\n0740-3194 (Linking)", "ISSN" : "07403194", "PMID" : "20187179", "abstract" : "The Tofts tracer kinetic models are often used to analyze dynamic contrast-enhanced MRI data. They are derived from a general two-compartment exchange model (2CXM) but assume negligible plasma mean transit time. The 2CXM estimates tissue plasma perfusion and capillary permeability-surface area; the Tofts models estimate the transfer constant K(trans), which reflects a combination of these two parameters. The aims of this study were to compare the 2CXM and Tofts models and report microvascular parameters in patients with cervical cancer. Thirty patients were scanned pretreatment using a dynamic contrast-enhanced MRI protocol with a 3 sec temporal resolution and a total scan duration of 4 min. Whole-tumor parameters were estimated with both models. The 2CXM provided superior fits to the data for all patients (all 30 P values < 0.005), and significantly different parameter estimates were obtained (P < 0.01). K(trans) (mean = 0.35 +/- 0.26 min(-1)) did not equal absolute values of tissue plasma perfusion (mean = 0.65 +/- 0.56 mL/mL/min) or permeability-surface area (mean = 0.14 +/- 0.09 mL/mL/min) but correlated strongly with tissue plasma perfusion (r = 0.944; P = 0.01). Average plasma mean transit time, calculated with the 2CXM, was 22 +/- 16 sec, suggesting the assumption of negligible plasma mean transit time is not appropriate in this dataset and the 2CXM is better suited for its analysis than the Tofts models. The results demonstrate the importance of selecting an appropriate tracer kinetic model in dynamic contrast-enhanced MRI.", "author" : [ { "dropping-particle" : "", "family" : "Donaldson", "given" : "Stephanie B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "West", "given" : "Catharine M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "Susan E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrington", "given" : "Bernadette M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hutchison", "given" : "Gillian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "Andrew P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sourbron", "given" : "Steven P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic Resonance in Medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "691-700", "title" : "A comparison of tracer kinetic models for T1-weighted dynamic contrast-enhanced MRI: Application in carcinoma of the cervix", "title-short" : "A comparison of tracer kinetic models for T1-weigh", "type" : "article-journal", "volume" : "63" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Donaldson et al, 2010)", "plainTextFormattedCitation" : "(Donaldson et al, 2010)", "previouslyFormattedCitation" : "(Donaldson et al, 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Donaldson et al, 2010).DCE-MRI analysisTumour regions of interest (ROIs) were delineated on the high spatial resolution T2-weighted images by a radiologist (G.H., 7 years of experience) blinded to patient outcome and DCE-MRI data. To convert ROIs to the spatial resolution of T1 mapping and dynamic images, ROI masks were downsampled using MRIcro (Version 1.4, Chris Rorden, Columbia, SC, USA. ).Patient specific arterial input functions (AIFs) were measured from the DCE-MRI images by manually drawing an arterial ROI in the descending aorta. Each arterial ROI was drawn in the dynamic frame showing maximal enhancement and in a slice distal to inflowing spins to minimize inflow enhancement effects ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/mrm.22593", "ISBN" : "1522-2594", "ISSN" : "1522-2594", "PMID" : "20928889", "abstract" : "A major potential confound in axial 3D dynamic contrast-enhanced magnetic resonance imaging studies is the blood inflow effect; therefore, the choice of slice location for arterial input function measurement within the imaging volume must be considered carefully. The objective of this study was to use computer simulations, flow phantom, and in vivo studies to describe and understand the effect of blood inflow on the measurement of the arterial input function. All experiments were done at 1.5 T using a typical 3D dynamic contrast-enhanced magnetic resonance imaging sequence, and arterial input functions were extracted for each slice in the imaging volume. We simulated a set of arterial input functions based on the same imaging parameters and accounted for blood inflow and radiofrequency field inhomogeneities. Measured arterial input functions along the vessel length from both in vivo and the flow phantom agreed with simulated arterial input functions and show large overestimations in the arterial input function in the first 30 mm of the vessel, whereas arterial input functions measured more centrally achieve accurate contrast agent concentrations. Use of inflow-affected arterial input functions in tracer kinetic modeling shows potential errors of up to 80% in tissue microvascular parameters. These errors emphasize the importance of careful placement of the arterial input function definition location to avoid the effects of blood inflow.", "author" : [ { "dropping-particle" : "", "family" : "Roberts", "given" : "Caleb", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Little", "given" : "Ross", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watson", "given" : "Yvonne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhao", "given" : "Sha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parker", "given" : "Geoff J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "108-119", "title" : "The effect of blood inflow and B(1)-field inhomogeneity on measurement of the arterial input function in axial 3D spoiled gradient echo dynamic contrast-enhanced MRI.", "type" : "article-journal", "volume" : "65" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Roberts et al, 2011)", "plainTextFormattedCitation" : "(Roberts et al, 2011)", "previouslyFormattedCitation" : "(Roberts et al, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Roberts et al, 2011). Slices near the edge of the field of view were discounted to minimise the influence of transmit B1 field inhomogeneity. Arterial signal intensity was converted to contrast agent concentration using an assumed pre-contrast T1 value for blood of 1.2 s ADDIN CSL_CITATION { "citationID" : "1evidm8sdd", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISBN" : "978-99976-35-73-0", "abstract" : "This is the third edition of the reference for the subspeciality of MRI, continuing to provide the kind of comprehensive and authoritative coverage that the previous two successful editions have provided. It gives an exhaustive, encyclopaedic coverage with 2,800 bookpages and 7,320 images/illustrations (320 in colour). All chapters have been exhaustively revised, and the number of images has been increased. This edition will be much more manageable than the previous edition due to the fact that it will be presented in three volumes (the second edition was presented in two volumes), still continuing the logical organisation by body region that was followed in the first two editions. 'Volume 1', will cover physics and body, 'Volume 2', will cover musculoskeletal system, and 'Volume 3', will cover brain, head and neck, and spine. 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Experiments are carried out on rabbit head and human extremities. Depending on the field of view, the isotropic resolution is 1 mm or even less leading to cross-sectional images with a 1 mm slice thickness. In principle, FLASH imaging techniques are applicable to any MR system without the need of major hardware modifications. However, high-speed computers, large storage capacity, and rapid image display routines greatly facilitate an advantageous use of the 3D-FLASH variant.", "author" : [ { "dropping-particle" : "", "family" : "Frahm", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haase", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matthaei", "given" : "D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Computer Assisted Tomography", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1986", "4" ] ] }, "language" : "eng", "page" : "363-368", "title" : "Rapid three-dimensional MR imaging using the FLASH technique", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Frahm et al, 1986)", "plainTextFormattedCitation" : "(Frahm et al, 1986)", "previouslyFormattedCitation" : "(Frahm et al, 1986)" }, "properties" : { "formattedCitation" : "[16]", "noteIndex" : 0, "plainCitation" : "[16]" }, "schema" : "" }(Frahm et al, 1986). Blood contrast agent concentrations were converted to plasma concentrations using a literature value for haematocrit of 0.42 ADDIN CSL_CITATION { "citationID" : "2q72sv0kj0", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISBN" : "978-1-84076-070-5", "author" : [ { "dropping-particle" : "", "family" : "Sharma", "given" : "Sanjay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kaushal", "given" : "Rashmi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "edition" : "Second Edi", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2006", "6" ] ] }, "language" : "English", "number-of-pages" : "432", "publisher" : "CRC Press", "publisher-place" : "London", "title" : "Rapid Review of Clinical Medicine for MRCP Part 2", "title-short" : "Rapid Review of Clinical Medicine for MRCP Part 2,", "type" : "book" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sharma & Kaushal, 2006)", "plainTextFormattedCitation" : "(Sharma & Kaushal, 2006)", "previouslyFormattedCitation" : "(Sharma & Kaushal, 2006)" }, "properties" : { "formattedCitation" : "[17]", "noteIndex" : 0, "plainCitation" : "[17]" }, "schema" : "" }(Sharma & Kaushal, 2006). DCE-MRI images were co-registered using a rigid-body model-based approach ADDIN CSL_CITATION { "citationID" : "2qddbelopb", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Buonaccorsi", "given" : "Giovanni A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Connor", "given" : "James PB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caunce", "given" : "Angela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roberts", "given" : "Caleb", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cheung", "given" : "Sue", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watson", "given" : "Yvonne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Karen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hope", "given" : "Lynn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Alan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jayson", "given" : "Gordon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parker", "given" : "Geoffrey JM.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic Resonance in Medicine", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "1010\u20131019", "title" : "Tracer kinetic model\u2013driven registration for dynamic contrast-enhanced MRI time-series data", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Buonaccorsi et al, 2007)", "plainTextFormattedCitation" : "(Buonaccorsi et al, 2007)", "previouslyFormattedCitation" : "(Buonaccorsi et al, 2007)" }, "properties" : { "formattedCitation" : "[18]", "noteIndex" : 0, "plainCitation" : "[18]" }, "schema" : "" }(Buonaccorsi et al, 2007). The 2CXM parameters (plasma flow, Fp [mL min-1 mL-1]; permeability surface-area produce, PS [mL min-1 mL-1]; fractional interstitial volume, ve [mL mL-1]; and fractional plasma volume, vp [mL mL-1]) were estimated at each voxel by jointly fitting T1 mapping and dynamic signal models ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/mrm.26013", "ISSN" : "15222594", "PMID" : "26480291", "abstract" : "PURPOSE: To improve the accuracy and precision of tracer kinetic model parameter estimates for use in dynamic contrast enhanced (DCE) MRI studies of solid tumors.\\n\\nTHEORY: Quantitative DCE-MRI requires an estimate of precontrast T1 , which is obtained prior to fitting a tracer kinetic model. As T1 mapping and tracer kinetic signal models are both a function of precontrast T1 it was hypothesized that its joint estimation would improve the accuracy and precision of both precontrast T1 and tracer kinetic model parameters.\\n\\nMETHODS: Accuracy and/or precision of two-compartment exchange model (2CXM) parameters were evaluated for standard and joint fitting methods in well-controlled synthetic data and for 36 bladder cancer patients. Methods were compared under a number of experimental conditions.\\n\\nRESULTS: In synthetic data, joint estimation led to statistically significant improvements in the accuracy of estimated parameters in 30 of 42 conditions (improvements between 1.8% and 49%). Reduced accuracy was observed in 7 of the remaining 12 conditions. Significant improvements in precision were observed in 35 of 42 conditions (between 4.7% and 50%). In clinical data, significant improvements in precision were observed in 18 of 21 conditions (between 4.6% and 38%).\\n\\nCONCLUSION: Accuracy and precision of DCE-MRI parameter estimates are improved when signal models are fit jointly rather than sequentially. Magn Reson Med, 2015. \u00a9 2015 Wiley Periodicals, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Dickie", "given" : "Ben R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Banerji", "given" : "Anita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kershaw", "given" : "Lucy E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mcpartlin", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Choudhury", "given" : "Ananya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "West", "given" : "Catharine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rose", "given" : "Chris J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic Resonance in Medicine", "id" : "ITEM-1", "issue" : "October 2015", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "1270-1281", "title" : "Improved accuracy and precision of tracer kinetic parameters by joint fitting to variable flip angle and dynamic contrast enhanced MRI data", "type" : "article-journal", "volume" : "76" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Dickie et al, 2015)", "plainTextFormattedCitation" : "(Dickie et al, 2015)", "previouslyFormattedCitation" : "(Dickie et al, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Dickie et al, 2015) using the Levenberg-Marquardt least squares algorithm ADDIN CSL_CITATION { "citationID" : "9r0j8cphc", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Marquardt", "given" : "Donald W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the Society for Industrial & Applied Mathematics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1963" ] ] }, "page" : "431\u2013441", "title" : "An algorithm for least-squares estimation of nonlinear parameters", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Marquardt, 1963)", "plainTextFormattedCitation" : "(Marquardt, 1963)", "previouslyFormattedCitation" : "(Marquardt, 1963)" }, "properties" : { "formattedCitation" : "[20]", "noteIndex" : 0, "plainCitation" : "[20]" }, "schema" : "" }(Marquardt, 1963) in IDL 8.2.2 (Exelis Visual Information Solutions, Boulder, Colorado, USA). The contrast agent volume transfer constant, Ktrans [min-1] was computed from estimates of Fp and PS using the compartment model extraction fraction equation: Ktrans = EFp, where the first-pass extraction fraction E = PS/(Fp + PS) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/nbm.2940", "ISBN" : "0952-3480", "ISSN" : "09523480", "PMID" : "23674304", "abstract" : "Dynamic contrast-enhanced MRI (DCE-MRI) is a functional MRI method where T1 -weighted MR images are acquired dynamically after bolus injection of a contrast agent. The data can be interpreted in terms of physiological tissue characteristics by applying the principles of tracer-kinetic modelling. In the brain, DCE-MRI enables measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), blood-brain barrier (BBB) permeability-surface area product (PS) and the volume of the interstitium (ve ). These parameters can be combined to form others such as the volume-transfer constant K(trans) , the extraction fraction E and the contrast-agent mean transit times through the intra- and extravascular spaces. A first generation of tracer-kinetic models for DCE-MRI was developed in the early 1990s and has become a standard in many applications. Subsequent improvements in DCE-MRI data quality have driven the development of a second generation of more complex models. They are increasingly used, but it is not always clear how they relate to the models of the first generation or to the model-free deconvolution methods for tissues with intact BBB. This lack of understanding is leading to increasing confusion on when to use which model and how to interpret the parameters. The purpose of this review is to clarify the relation between models of the first and second generations and between model-based and model-free methods. All quantities are defined using a generic terminology to ensure the widest possible scope and to reveal the link between applications in the brain and in other organs. Copyright \u00a9 2013 John Wiley & Sons, Ltd.", "author" : [ { "dropping-particle" : "", "family" : "Sourbron", "given" : "Steven P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "NMR in Biomedicine", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1004-1027", "title" : "Classic models for dynamic contrast-enhanced MRI", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sourbron & Buckley, 2013)", "plainTextFormattedCitation" : "(Sourbron & Buckley, 2013)", "previouslyFormattedCitation" : "(Sourbron & Buckley, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Sourbron & Buckley, 2013). For input into survival modelling, voxel-wise 2CXM parameter estimates were summarised using the median.Clinicopathologic variablesClinicopathologic characteristics of the cohort are shown in Supplementary Table 1. The following variables were obtained for each patient: primary tumour (T) stage, nodal status, histological subtype, tumour volume, and patient age. Primary tumour stage was assessed using routine T1 and T2-weighted MRI scans against the American Joint Committee on Cancer staging criteria ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISBN" : "0387952713", "abstract" : "The AJCC Cancer Staging Manual and Handbook, prepared by the American Joint Committee on Cancer, are used by physicians and health care professionals throughout the world to facilitate the uniform description of neoplastic diseases. Proper classification and staging allow the physician to determine treatment more appropriately, evaluate results of management more reliably, and compare worldwide statistics reported from various institutions on a local, regional, and national basis more confidently. The fully revised and updated Sixth Edition of the AJCC Cancer Staging Manual brings together all currently available information on staging of cancer at various anatomic sites and incorporates newly acquired knowledge on the etiology and pathology of cancer. As more is learned, cancer staging must adapt to accommodate new information and this revised edition provides an evidence-based staging system based upon the established tenets of TNM classification. All of the TNM staging information included in the Sixth Edition is uniform between the AJCC and the UICC (International Union Against Cancer). Organized by disease site into 48 comprehensive chapters, the Sixth Edition features much-anticipated, major revisions to the chapters on melanoma and breast cancer. Numerous new line drawings illustrate key anatomic sites throughout the text. Additional user-friendly enhancements include: * a concise summary of changes in the TNM classification since the previous edition at the start of every chapter * color-coordinated page tabs for easy access between chapters * a CD-ROM packaged with each Manual containing printable copies of each of the book's 45 Staging Forms for both individual and institutional use * a comprehensive index The Sixth Edition of the AJCC Cancer Staging Manual and Handbook remains the essential reference for oncologists, pathologists, surgeons, cancer registrars, and medical professionals worldwide to assure that all those taking care of cancer patients will be trained in the language of cancer staging", "author" : [ { "dropping-particle" : "", "family" : "Frederick L", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2002" ] ] }, "number-of-pages" : "421", "publisher" : "Springer Science & Business Media", "title" : "AJCC Cancer Staging Manual, Volume 1", "type" : "book" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Frederick L, 2002)", "plainTextFormattedCitation" : "(Frederick L, 2002)", "previouslyFormattedCitation" : "(Frederick L, 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Frederick L, 2002). Involvement of pelvic and/or para-aortic lymph nodes was assessed on large field of view coronal and transverse T1-weighted and sagittal T2-weighted imaging. Tumour volumes were computed from the T2-weighted images by multiplying the number of voxels in the tumour region of interest (ROI) by the voxel volume.Patient follow-upFollowing treatment, patients attended clinic every 3 months in years one and two, and twice per year thereafter, unless symptomatic. Patients underwent clinical examination at each visit. MRI scans (sagittal, transverse and coronal T2-weighted turbo spin echo sequences) were used to confirm suspected recurrent disease. If disease was central and amenable to salvage surgery, biopsies were also taken as a definitive marker of recurrence. Treating physicians were blinded to DCE-MRI data.Survival analysisThe primary endpoint was disease-free survival (DFS). Events were classed as primary, local, or distant disease recurrence or death by any cause. Time to event was calculated from the first fraction of radiotherapy. If an event was not observed before the last recorded follow up date, the observation was right censored. Receiver operator characteristic (ROC) analysis was performed to determine the most appropriate cut-off value to dichotomise continuous variables (median DCE-MRI parameters, patient age, and tumour volume). Cut-off values were chosen using the Youden J index ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/bimj.200410135", "author" : [ { "dropping-particle" : "", "family" : "Fluss", "given" : "Ronen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Faraggi", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reiser", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "458-472", "title" : "Estimation of the Youden Index and its Associated Cutoff Point", "type" : "article-journal", "volume" : "47" }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "(Fluss et al, 2005)", "plainTextFormattedCitation" : "(Fluss et al, 2005)", "previouslyFormattedCitation" : "(Fluss et al, 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Fluss et al, 2005) which identifies the cut-off that satisfies max(sensitivity – specificity). Cut-offs were limited to the 30th-70th percentile range to ensure each risk group contained at least 10 patients. If the Youden J index lay outside this range the closest percentile within the allowed range was used. T stage was dichotomised as early (T1/T2a) versus advanced stage (T2b/T4); histological subtype as squamous cell carcinoma (SCC) versus all other subtypes; treatment as chemoradiotherapy versus radiotherapy alone; and nodal status as zero versus at least one involved node. For each variable, univariate Cox regression was used to estimate DFS hazard ratios (HRs). P-values and 95% confidence intervals (CI) for HRs were computed using a two-tailed Wald test. P-values < 0.05 were considered statistically significant. Kaplan-Meier survival curves were estimated to allow visual comparison of DFS between risk groups. The utility of clinicopathologic and DCE-MRI variables for predicting DFS was assessed in a multivariate setting using the random survival forest (RSF) algorithm ADDIN CSL_CITATION { "citationID" : "8s92nlcdi", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1932-6157", "abstract" : "We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. Computations for all examples were implemented using the freely available R-software package, randomSurvivalForest.", "author" : [ { "dropping-particle" : "", "family" : "Ishwaran", "given" : "Hemant", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kogalur", "given" : "Udaya B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blackstone", "given" : "Eugene H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lauer", "given" : "Michael S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Annals of Applied Statistics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "841-860", "title" : "Random Survival Forests", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ishwaran et al, 2008)", "plainTextFormattedCitation" : "(Ishwaran et al, 2008)", "previouslyFormattedCitation" : "(Ishwaran et al, 2008)" }, "properties" : { "formattedCitation" : "[21]", "noteIndex" : 0, "plainCitation" : "[21]" }, "schema" : "" }(Ishwaran et al, 2008). The RSF is a non-parametric ensemble tree algorithm that models the effect of multiple (possibly highly correlated) variables on the risk of recurrence/death with minimal assumptions ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1932-6157", "abstract" : "We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. Computations for all examples were implemented using the freely available R-software package, randomSurvivalForest.", "author" : [ { "dropping-particle" : "", "family" : "Ishwaran", "given" : "Hemant", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kogalur", "given" : "Udaya B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blackstone", "given" : "Eugene H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lauer", "given" : "Michael S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Annals of Applied Statistics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "841-860", "title" : "Random Survival Forests", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ishwaran et al, 2008)", "plainTextFormattedCitation" : "(Ishwaran et al, 2008)", "previouslyFormattedCitation" : "(Ishwaran et al, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ishwaran et al, 2008). To determine the relative prognostic value of each variable, accounting for possible confounding and variable interactions, an RSF model was trained using all clinicopathologic and 2CXM variables and the variable importance (VIMP) statistic computed ADDIN CSL_CITATION { "citationID" : "1iuu9p9cms", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1932-6157", "abstract" : "We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. Computations for all examples were implemented using the freely available R-software package, randomSurvivalForest.", "author" : [ { "dropping-particle" : "", "family" : "Ishwaran", "given" : "Hemant", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kogalur", "given" : "Udaya B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blackstone", "given" : "Eugene H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lauer", "given" : "Michael S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Annals of Applied Statistics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "841-860", "title" : "Random Survival Forests", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ishwaran et al, 2008)", "plainTextFormattedCitation" : "(Ishwaran et al, 2008)", "previouslyFormattedCitation" : "(Ishwaran et al, 2008)" }, "properties" : { "formattedCitation" : "[21]", "noteIndex" : 0, "plainCitation" : "[21]" }, "schema" : "" }(Ishwaran et al, 2008). Broadly speaking, this statistic evaluates how the removal of each variable affects the model prediction error on test data. A high VIMP is associated with a large detrimental effect on model predictions, reflecting high prognostic importance. Bootstrapping was used to calculate point estimates and Bonferroni-corrected 95% CIs on VIMP for each variable.Two further RSF models were built. A null model containing the six clinicopathologic variables and an alternative model containing the top six clinicopathologic and DCE-MRI variables ranked by median VIMP. Six variables were chosen such that the null and alternative model had the same number of independent variables, facilitating a like-for-like comparison. Predictions of recurrence risk were generated for both null and alternative models in a leave-one-out analysis. The discriminatory accuracy of each model was assessed using Harrell’s concordance index (c-index) ADDIN CSL_CITATION { "citationID" : "1ft419qjmg", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Harrell", "given" : "Frank E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Califf", "given" : "Robert M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pryor", "given" : "David B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Kerry L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosati", "given" : "Robert A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Jama", "id" : "ITEM-1", "issue" : "18", "issued" : { "date-parts" : [ [ "1982" ] ] }, "page" : "2543\u20132546", "title" : "Evaluating the yield of medical tests", "type" : "article-journal", "volume" : "247" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Harrell et al, 1982)", "plainTextFormattedCitation" : "(Harrell et al, 1982)", "previouslyFormattedCitation" : "(Harrell et al, 1982)" }, "properties" : { "formattedCitation" : "[26]", "noteIndex" : 0, "plainCitation" : "[26]" }, "schema" : "" }(Harrell et al, 1982) and the null hypothesis of no difference in c-indices was tested using a one-sided paired t-test with significance threshold P < 0.05. The ability of each model to separate left-out patients into distinct risk groupings was evaluated using Cox regression and Kaplan Meier curve analysis. Partial plots showing the effect of each variable in the alternative model towards risk of recurrence, adjusted for the effect of all other variables, were generated. All survival analyses were performed in R (Version 3.1, R Foundation for Statistical Computing, Vienna, Austria) using the ‘survival’, ‘survcomp’, and ‘randomForestSRC’ packages. RESULTSMedian follow-up time in surviving patients was 7.2 years (range 3.2–10.4 years). No patients were lost to follow-up. Table 1 shows results from the ROC analysis including the Youden cut-off values for each continuous variable. Supplementary Figure 2 shows the ROC curves for each continuous variable. Supplementary Table 2 shows univariate Cox model hazard ratios (HRs) and P-values for all variables. Figure 1 shows Kaplan-Meier (KM) DFS curve estimates for variables with hazard ratios that differed significantly from 1 (P < 0.05). Significant variables were treatment type (HR = 3.9, P = 0.0049), nodal status (HR = 2.9, P = 0.037), patient age (HR = 3.9, P = 0.019), tumour volume (HR = 2.6, P = 0.047), plasma flow (Fp; HR = 0.25, P = 0.0095), and contrast agent transfer constant (Ktrans; HR = 0.20, P = 0.032). Kaplan Meier curves for all other variables are shown in Supplementary Figure 3. While non-significant, high PS, high ve, and high vp were associated with increased DFS. Figure 2 highlights the differences in plasma flow maps for patients with short (0.78 - 1.1 years) and long (8.4 - 9.7 years) disease-free survival. Differences in Ktrans maps were not as pronounced as for Fp maps, reflecting a reduction in prognostic ability. PS maps appear very similar between short and long DFS groups reflecting low prognostic value. Results from multivariate random survival forest analyses are shown in Table 2, Figure 3 and Figure 4. Table 2 shows point estimates and 95% confidence intervals on median VIMP. The six most important prognostic variables in order of decreasing VIMP (and those selected for the alternative model): plasma flow (Fp), treatment, histological subtype, nodal status, patient age, and the transfer constant Ktrans. In leave-one-out analysis, the alternative model made statistically significantly more accurate predictions than the null model (c-indices of 0.70 versus 0.61, P = 0.0089). The alternative model was also better at assigning left-out patients into distinct risk groups (P = 0.029 versus P = 0.056). Figure 4 shows the prognostic effect of each variable in the alternative model after adjusting for the effect of all other variables in the model. Predicted risks differed significantly between the levels of all variables except for patient age and nodal status (see figure for P-values). DISCUSSIONPlasma flow and the contrast agent transfer constant were the only microvascular parameters statistically significantly associated with survival. All other microvascular parameters, including PS, showed non-significant ability to stratify patients into distinct risk groupings. In both univariate and multivariate analyses, Fp was shown to be a better predictor of DFS than Ktrans. These results support the hypothesis that Ktrans derives its prognostic value from its dependence on Fp but is less useful as a prognostic biomarker, due to its dependence on PS. Other work evaluating the prognostic value of plasma or blood flow in tumours has found confirmatory results. Using DCE-computed tomography in 108 head and neck cancer patients treated with radiotherapy, Hermans et al. showed high blood flow was associated with reduced risk of local recurrence ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0360-3016(03)00764-8", "ISBN" : "0360-3016 (Print)", "ISSN" : "03603016", "PMID" : "14630273", "abstract" : "Purpose: To investigate the value of CT-determined tumor perfusion as a predictive factor of local and regional failure and cause-specific survival in head-and-neck cancer treated by radiotherapy. Methods and Materials: In 105 patients, the perfusion of a primary head-and-neck squamous cell carcinoma was estimated using dynamic CT. A contrast agent bolus was rapidly injected i.v., while during the first pass a dynamic data acquisition was performed at the level of the largest axial tumor surface. The perfusion in the selected tumor region of interest was calculated by dividing the slope of the tumor-time density curve by the maximal value in arterial density. Primary and nodal tumor volume was calculated from the CT images. All patients were treated by radiotherapy with curative intent; in 15 patients, adjuvant concomitant chemotherapy was administered. Mean follow-up time was 2.2 years. Actuarial (life-table) statistical analysis was done; multivariate analysis was performed using the Cox proportional hazards model. Results: When the patients were stratified according to the median perfusion value (83.5 mL/min/100 g), those with the lower perfusion rate had a significantly higher local failure rate (p < 0.05). In the multivariate analysis, perfusion rate (p = 0.01) and T category (p = 0.03) were found to be the independent predictors of local failure. Perfusion rate had predictive value regarding neither regional control nor cause-specific survival. Conclusion: CT-determined tumor perfusion rate was found to be an independent predictor of local outcome in irradiated head-and-neck cancer. The results of this study confirm the hypothesis that less-perfused tumors respond poorly to radiotherapy. \u00a9 2003 Elsevier Inc.", "author" : [ { "dropping-particle" : "", "family" : "Hermans", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meijerink", "given" : "Martijn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Walter", "non-dropping-particle" : "Van Den", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rijnders", "given" : "Alexis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weltens", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lambin", "given" : "Philippe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology Biology Physics", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2003" ] ] }, "note" : "NULL", "page" : "1351-1356", "title" : "Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hermans et al, 2003)", "plainTextFormattedCitation" : "(Hermans et al, 2003)", "previouslyFormattedCitation" : "(Hermans et al, 2003)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hermans et al, 2003). Haldorsen et al. investigated the prognostic value DCE-MRI blood flow measurements in patients with endometrial cancer treated with surgery. While not related to response of tumours to chemoradiotherapy, low blood flow was associated with increased expression of microvascular proliferation markers and shorter survival times ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/bjc.2013.694", "ISSN" : "0007-0920", "abstract" : "Background:\nWe aimed to study the angiogenic profile based on histomorphological markers in endometrial carcinomas in relation to imaging parameters obtained from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) and to explore the potential value of these markers to identify patients with poor outcome.\n\nMethods:\nIn fifty-four surgically staged endometrial carcinoma patients, immunohistochemical staining with factor VIII and Ki67 allowed assessment of microvessel density (MVD) and microvascular proliferation reflecting tumour angiogenesis. In the same patients, preoperative pelvic DCE-MRI and DWI allowed the calculation of parameters describing tumour microvasculature and microstructure in vivo.\n\nResults:\nMicrovascular proliferation was negatively correlated to tumour blood flow (Fb) (r=\u22120.36, P=0.008), capillary permeability surface area product (PS) (r=\u22120.39, P=0.004) and transfer from the blood to extravascular extracellular space (EES) (Ktrans) (r=\u22120.40, P=0.003), and was positively correlated to tumour volume (r=0.34; P=0.004). High-tumour microvascular proliferation, low Fb and low Ktrans were all significantly associated with reduced progression/recurrence-free survival (P<0.05).\n\nConclusion:\nDisorganised angiogenesis with coexisting microvascular proliferation and low tumour blood flow is a poor prognostic factor supporting that hypoxia is associated with progression and metastatic spread in endometrial carcinomas.", "author" : [ { "dropping-particle" : "", "family" : "Haldorsen", "given" : "I S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stefansson", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gr\u00fcner", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Husby", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magnussen", "given" : "I J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Werner", "given" : "H M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salvesen", "given" : "\u00d8 O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bj\u00f8rge", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trovik", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taxt", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Akslen", "given" : "L A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salvesen", "given" : "H B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British Journal of Cancer", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "107-114", "title" : "Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas", "type" : "article-journal", "volume" : "110" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Haldorsen et al, 2014)", "plainTextFormattedCitation" : "(Haldorsen et al, 2014)", "previouslyFormattedCitation" : "(Haldorsen et al, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Haldorsen et al, 2014). All clinicopathologic factors displayed the expected prognostic trend ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1200/JCO.2011.37.5923", "ISSN" : "0732-183X, 1527-7755", "abstract" : "Purpose Our study aimed to develop a model to predict distant recurrence in locally advanced cervical cancer, which can be used to select high-risk patients in enriched clinical trials.\nPatients and Methods Our study was a retrospective analysis of a multi-institutional cohort of patients treated between 2001 and 2009. According to the order of data submission, data from three institutions were allocated to a model development cohort (n = 434), and data from the remaining two institutions were allocated to an external validation cohort (n = 115). Patient information including [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data and clinical outcome was modeled using competing risk regression analysis to predict 5-year cumulative incidence of distant recurrence.\nResults The competing risk analysis revealed that the following four parameters were significantly associated with distant recurrence: pelvic and para-aortic nodal positivity on FDG-PET, nonsquamous cell histology, and pretreatment serum squamous cell carcinoma antigen levels. This four-parameter model showed good discrimination and calibration, with a bootstrap-adjusted concordance index of 0.70. Also, the validation set showed good discrimination with a bootstrap-adjusted concordance index of 0.73. A user-friendly Web-based nomogram predicting 5-year probability of distant recurrence was developed.\nConclusion We have developed a robust model to predict the risk of distant recurrence in patients with locally advanced cervical cancer. Further, we discussed how the selective enrichment of the patient population could facilitate clinical trials of systemic chemotherapy in locally advanced cervical cancer.", "author" : [ { "dropping-particle" : "", "family" : "Kang", "given" : "Sokbom", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nam", "given" : "Byung-Ho", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Park", "given" : "Jeong-Yeol", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seo", "given" : "Sang-Soo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ryu", "given" : "Sang-Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Jae Weon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Seung-Cheol", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Park", "given" : "Sang-Yoon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nam", "given" : "Joo-Hyun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Clinical Oncology", "id" : "ITEM-1", "issue" : "19", "issued" : { "date-parts" : [ [ "2012", "7" ] ] }, "language" : "en", "page" : "2369-2374", "title" : "Risk assessment tool for distant recurrence after platinum-based concurrent chemoradiation in patients with locally advanced cervical cancer: a Korean gynecologic oncology group study", "title-short" : "Risk Assessment Tool for Distant Recurrence After ", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.jfma.2012.10.021", "ISSN" : "0929-6646", "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Chien-chih", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Lily", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Jin-ching", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jan", "given" : "Jian-sheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the Formosan Medical Association", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "231-237", "publisher" : "Elsevier Taiwan LLC", "title" : "The prognostic factors for locally advanced cervical cancer patients treated by intensity-modulated radiation therapy with concurrent chemotherapy", "type" : "article-journal", "volume" : "114" }, "uris" : [ "", "" ] }, { "id" : "ITEM-3", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Rose", "given" : "Peter G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bundy", "given" : "Brian N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watkins", "given" : "Edwin B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thigpen", "given" : "J. 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Treatment type was the strongest prognostic factor in both univariate and multivariate analyses, possibly reflecting the added cytotoxic effect of combined chemoradiotherapy ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Rose", "given" : "Peter G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bundy", "given" : "Brian N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watkins", "given" : "Edwin B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thigpen", "given" : "J. 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Nodal status and patient age were significant factors in univariate analyses but lost significance when adjusting for other factors (alternative model, Figure 4). Stratification of patients by T stage was not a significant prognostic factor in either univariate or multivariate methods. This was probably due to the small number of patients in the early stage group (T1-T2a) leading to low precision in the estimated hazard ratio. Biological interpretationPrevious studies across a range of tumour types have shown uptake of MRI contrast agent is associated with the degree of tissue hypoxia. In a melanoma xenograft model, Egeland et al. showed a strong relationship between pimonidazole stain fraction and Ktrans ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/mrm.23014", "author" : [ { "dropping-particle" : "", "family" : "Egeland", "given" : "Tormod A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gulliksrud", "given" : "Kristine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaustad", "given" : "Jon-vidar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mathiesen", "given" : "Berit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rofstad", "given" : "Einar K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "519-530", "title" : "Dynamic Contrast-Enhanced-MRI of Tumor Hypoxia", "type" : "article-journal", "volume" : "530" }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "(Egeland et al, 2012)", "plainTextFormattedCitation" : "(Egeland et al, 2012)", "previouslyFormattedCitation" : "(Egeland et al, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Egeland et al, 2012). Halle et al. observed a negative correlation between maximum amplitude of signal enhancement and HIF-α expression in cervix tumours ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1158/0008-5472.CAN-12-1085", "author" : [ { "dropping-particle" : "", "family" : "Halle", "given" : "Cathinka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Andersen", "given" : "Erlend", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lando", "given" : "Malin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aarnes", "given" : "Eva-katrine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasvold", "given" : "Grete", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holden", "given" : "Marit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Syljua", "given" : "Randi G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundf\u00f8r", "given" : "Kolbein", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kristensen", "given" : "Gunnar B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holm", "given" : "Ruth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malinen", "given" : "Eirik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyng", "given" : "Heidi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "page" : "5285-5295", "title" : "Hypoxia-Induced Gene Expression in Chemoradioresistant Cervical Cancer Revealed by Dynamic Contrast-Enhanced MRI", "type" : "article-journal" }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "(Halle et al)", "plainTextFormattedCitation" : "(Halle et al)", "previouslyFormattedCitation" : "(Halle et al)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Halle et al). Similarly, three cervix cancer studies have shown a strong correlation between tumour oxygen pressure measurements made using polarographic electrodes and maximum relative signal enhancement ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0167-8140", "PMID" : "11033189", "abstract" : "BACKGROUND AND PURPOSE: The Eppendorf pO(2) histograph is the 'gold standard' method for measuring tumour oxygenation. The method is not suitable for widespread application because its use is limited to accessible tumours. A non-invasive imaging technique would be an attractive alternative. Therefore, the relationships between tumour oxygenation and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters were investigated. MATERIALS AND METHODS: The study comprised 30 patients with carcinoma of the cervix. Tumour oxygenation was measured pre-treatment as median pO(2) and the proportion of values less than 5 mmHg (HP5) using a pO(2) histograph. Repeat measurements were obtained for nine patients following 40-45 Gy external beam radiotherapy giving a total of 39 measurements. Dynamic contrast-enhanced MRI using gadolinium was performed prior to obtaining the oxygenation data. Time/signal intensity curves were generated to obtain two standard parameters: maximum enhancement over baseline (SI-I) and the rate of enhancement (SI-I/s). RESULTS: Using the 39 measurements, there was a significant correlation between SI-I and both median pO(2) (r=0.59; P<0.001) and HP5 (r=-0. 49; P=0.002). There was a weak, borderline significant correlation between SI-I/s and both median pO(2) (r=0.29; P=0.071) and HP5 (r=-0. 34; P=0.037). There was a significant relationship between tumour size and SI-I (r=0.54; P<0.001), but not SI-I/s. In 29 tumours, where data were available, there was no relationship between histological assessment of tumour angiogenesis (intra-tumour microvessel density; IMD) and either MRI parameter. CONCLUSIONS: Tumour oxygenation levels measured using a pO(2) histograph correlate with dynamic contrast-enhanced MRI parameters. Therefore, non-invasive dynamic MRI may be a method for measuring hypoxia in human tumours.", "author" : [ { "dropping-particle" : "", "family" : "Cooper", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrington", "given" : "B M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loncaster", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Todd", "given" : "S M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "S E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Logue", "given" : "J P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luthra", "given" : "A D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "A P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stratford", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hunter", "given" : "R D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "West", "given" : "C M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2000" ] ] }, "page" : "53-59", "title" : "Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix.", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/S0360-3016(02)02972-3", "ISSN" : "0360-3016", "abstract" : "Purpose: To investigate whether analysis of MRI enhancement data using a pharmacokinetic model improved a previously found correlation between contrast enhancement and tumor oxygenation measured using Po2 histograph. To evaluate the prognostic value of gadolinium enhancement data for radiotherapy outcome, and to study the efficacy of combined enhancement and MRI volume data.\n\nMethods and materials: Fifty patients underwent dynamic gadolinium-enhanced MRI as part of their initial staging investigations before treatment. Gadolinium enhancement was analyzed using the Brix pharmacokinetic model to obtain the parameters amplitude and rate of contrast enhancement. Pretreatment tumor oxygen measurements (Eppendorf Po2 histograph) were available for 35 patients.\n\nResults: Both standard and pharmacokinetic-derived enhancement data correlated with tumor oxygenation measurements, and poorly enhancing tumors had low tumor oxygen levels. However, only the pharmacokinetic-analyzed data correlated with patient outcome and patients with poorly (amplitude less than median) vs. well-enhancing tumors had significantly worse disease-specific survival (p = 0.024). For the 50 patients studied, no relationship was found between enhancement and volume data. Combining MRI volume and enhancement information highlighted large differences in outcome (p = 0.0054). At the time of analysis, only 55% of patients with large, poorly enhanced tumors were alive compared with 92% of patients with small, well-enhanced tumors.\n\nConclusion: These preliminary results suggest that pharmacokinetic modeling of dynamic contrast-enhanced MRI provides data that reflect tumor oxygenation and yields useful prognostic information in patients with locally advanced carcinoma of the cervix. Combining MRI-derived enhancement and volume data delineates large differences in radiotherapy outcome.", "author" : [ { "dropping-particle" : "", "family" : "Loncaster", "given" : "Juliette A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrington", "given" : "Bernadette M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sykes", "given" : "Johnathan R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "Andrew P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Todd", "given" : "Susan M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cooper", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "Susan E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Logue", "given" : "John P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hunter", "given" : "Robin D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "West", "given" : "Catharine M. 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These relationships have subsequently been upheld for more recent measurements of blood flow in cervix and head and neck cancers ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Haider", "given" : "Masoom A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Milosevic", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fyles", "given" : "Anthony", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sitartchouk", "given" : "Igor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yeung", "given" : "Ivan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henderson", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lockwood", "given" : "Gina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Ting Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roberts", "given" : "Timothy PL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology* Biology* Physics", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "1100\u20131107", "title" : "Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Donaldson", "given" : "Stephanie B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Betts", "given" : "Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonington", "given" : "Suzanne C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Homer", "given" : "Jarrod J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Slevin", "given" : "Nick J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kershaw", "given" : "Lucy E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valentine", "given" : "Helen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "West", "given" : "Catharine ML", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buckley", "given" : "David L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Journal of Radiation Oncology* Biology* Physics", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "1176\u20131183", "title" : "Perfusion estimated with rapid dynamic contrast-enhanced magnetic resonance imaging correlates inversely with vascular endothelial growth factor expression and pimonidazole staining in head-and-neck cancer: a pilot study", "title-short" : "Perfusion estimated with rapid dynamic contrast-en", "type" : "article-journal", "volume" : "81" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Haider et al, 2005; Donaldson et al, 2011)", "plainTextFormattedCitation" : "(Haider et al, 2005; Donaldson et al, 2011)", "previouslyFormattedCitation" : "(Haider et al, 2005; Donaldson et al, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Haider et al, 2005; Donaldson et al, 2011). Since vessel walls pose little barrier to oxygen ADDIN CSL_CITATION { "citationID" : "2oi09idgkp", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0008-6363", "abstract" : "This review addresses the long-standing controversy over the principal mechanisms of transport of macromolecules through the endothelium of microvessels of 'normal' permeability. Two types of mechanism have been proposed: convective transport through 'large pores' in the endothelium: transport via vesicles (transcytosis). The different techniques for estimating microvascular permeability to macromolecules are described and values for microvascular permeability to serum albumin in different tissues are tabulated. Whereas the evidence for convective transport when obtained from experiments on perfused microvascular beds remains convincing, attention is drawn to recent measurements using the tracer uptake technique which suggest that transport in the intact circulation from blood to tissues may not be coupled to fluid movement. Direct evidence for the involvement of endothelial vesicles in transendothelial transport has been reported relatively recently but the mechanisms whereby macromolecules are conveyed through the vesicular system have yet to be established. The possibility of convective transport through transient transendothelial channels formed by the fusion of vesicles is discussed.", "author" : [ { "dropping-particle" : "", "family" : "Michel", "given" : "C. 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Survival analyses presented in this study support the hypothesis that plasma flow could be a more sensitive measure of tissue oxygenation compared to Ktrans and PS, however further work is needed to definitively test this hypothesis. The permeability surface area product measures the leakiness of vessels to the MRI contrast agent (i.e. Gd-DTPA) and approximates the permeability of vessels to molecules of similar size (i.e. such as cisplatin). The prognostic trend of PS observed in this study could reflect sensitivity to differences in chemotherapy drug delivery for those patients treated with chemoradiotherapy. Under this reasoning, the observed lack of statistical significance for PS could be due to inclusion of nine patients in the sample who received only radiotherapy and would therefore not be affected by PS. Alternatively, the difference in PS between patients may not be sufficient to cause a meaningful difference in the delivery rate of chemotherapy to tumour cells. 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The weak relationship between ve and DFS could reflect reduced tumour cell density (vcell ~ 1 - vb - ve, where vcell is the volume fraction of tumour cells). Plasma volume fraction was not prognostic despite a positive correlation with Fp (Pearson r = 0.6, data not shown). Simulation data from Luypaert et al. suggests 2CXM estimates of vp are less precise than Fp ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/0031-9155/55/21/006", "author" : [ { "dropping-particle" : "", "family" : "Luypaert", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ingrisch", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sourbron", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gill", "given" : "Andrew B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Black", "given" : "Richard T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowden", "given" : "David J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Phys. 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An obvious solution is to recruit more patients, but that approach has strong ethical, economic, and practical disincentives. To address this issue, we used a state-of-the-art survival model called the random survival forest (RSF). 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The model makes very few assumptions about the data (notably it does not depend on the proportional hazards assumption of the Cox model). It also facilitates reliable and objective automatic variable selection in the p ≈ n regime, as demonstrated by ADDIN CSL_CITATION { "citationID" : "275utr2ndb", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1932-6157", "abstract" : "We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. 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To control for possible confounding ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Rose", "given" : "Peter G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bundy", "given" : "Brian N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watkins", "given" : "Edwin B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thigpen", "given" : "J. 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Each institution should follow a consistent treatment policy when performing HDR brachytherapy, including complete documentation of treatment parameters and correlation with clinical outcome, such as pelvic control, survival, and complications. The goals are to treat Point A to at least a total low-dose-rate (LDR) equivalent of 80\u201385 Gy for early stage disease and 85\u201390 Gy for advanced stage. The pelvic sidewall dose recommendations are 50\u201355 Gy for early lesions and 55\u201365 Gy for advanced ones. The relative doses given by external beam radiation therapy (EBRT) vs. brachytherapy depend upon the initial volume of disease, the ability to displace the bladder and rectum, the degree of tumor regression during pelvic irradiation, and institutional preference. As with LDR brachytherapy, every attempt should be made to keep the bladder and rectal doses below 80 Gy and 75 Gy LDR equivalent doses, respectively. Interstitial brachytherapy should be considered for patients with disease that cannot be optimally encompassed by intracavitary brachytherapy. While recognizing that many efficacious HDR fractionation schedules exist, some suggested dose and fractionation schemes for combining the EBRT with HDR brachytherapy for each stage of disease are presented. These recommendations are intended only as guidelines, and the suggested fractionation schemes have not been thoroughly tested. The responsibility for the medical decisions ultimately rests with the treating radiation oncologist.\n\nConclusion: Guidelines are established for HDR brachytherapy for cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies. 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Given the small sample size, adjustment for the presence or absence of brachytherapy or external beam boosts was not made. 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Further work should also aim to correlate DCE-MRI Fp measurements with in-vivo Eppendorf electrode pO2 measurements and determine the extent to which Fp can be used as a biomarker of tumour oxygenation. Alternatively, development and validation of perfusion measurements using more readily available technologies such as contrast-enhanced (microbubble) transvaginal ultrasound may lead to cheaper and faster translation to the clinic. Ultimately, pre-treatment blood flow measurements may be useful to identify patients suitable for treatment modifications such as dose escalation, use of hypoxia-modifying treatments such as accelerated radiotherapy with carbogen and nicotinimide (ARCON ADDIN CSL_CITATION { "citationID" : "2ioj2d13jr", "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0167-8140", "PMID" : "10799722", "abstract" : "BACKGROUND: Since there is increasing evidence that both acute (perfusion-limited) and chronic (diffusion-limited) hypoxia, and tumor repopulation may prejudice the outcome of radiotherapy, the combination of carbogen (95% oxygen-5% carbon dioxide) and nicotinamide with accelerated radiotherapy (ARCON) should reduce the impact of these factors of radioresistance.\nAIM: This clinical study was aimed at determining the feasibility, as well as the qualitative and quantitative toxic effects of a therapeutic approach based on ARCON, and assessing the tumor response rates that can be achieved with this regime in patients with locally advanced tumors of the head and neck.\nMETHODS: A phase I/II study conducted between 1993 and 1996 by the Co-operative Group of Radiotherapy of the EORTC included three consecutive steps: accelerated fractionation (AF) combined with carbogen (11 analyzable patients), AF combined with the daily administration of nicotinamide (n=10), and AF with both carbogen and nicotinamide (n=17). Radiotherapy was based on an accelerated regime (72 Gy in 5.5 weeks). Nicotinamide was delivered 90 min before the first irradiation session, at a daily dose of 6 g. Carbogen breathing started 5 min before irradiation and lasted throughout the entire radiotherapy sessions.\nRESULTS: No significant difference in loco-regional toxicity was found among the three study steps, when carbogen and nicotinamide, either alone or in combination, were combined with AF. The feasibility of the ARCON protocol, as proposed in the present EORTC study, appears to be significantly impaired when nicotinamide is added, at a daily dose of 6 g, to AF and carbogen, in an unselected group of patients. More than 20% of patients experienced grade 2 or 3 emesis. It also demonstrates, in unselected groups of patients, no significant difference in tumor response and local control when carbogen and nicotinamide, either alone or in combination, are added to accelerated radiotherapy. The percentages of objective response at 2 months were 81, 70 and 87%, respectively.\nCONCLUSION: Future ARCON trials should target selected head and neck tumor localizations and stages, and a lower nicotinamide dose is needed to reduce severe upper gastro-intestinal toxicity.", "author" : [ { "dropping-particle" : "", "family" : "Bernier", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denekamp", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rojas", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Minatel", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horiot", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hamers", "given" : "H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Antognoni", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dahl", "given" : "O.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richaud", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glabbeke", "given" : "M.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pi\u00e9rart", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2000", "5" ] ] }, "language" : "eng", "page" : "111-119", "title" : "ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. 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