Chest Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Giesel, F. L.
Right arrow Articles by Knopp, M. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Giesel, F. L.
Right arrow Articles by Knopp, M. V.
(Chest. 2006;129:1570-1576.)
© 2006 American College of Chest Physicians

Dynamic Contrast-Enhanced MRI of Malignant Pleural Mesothelioma*

A Feasibility Study of Noninvasive Assessment, Therapeutic Follow-up, and Possible Predictor of Improved Outcome

Frederik L. Giesel, MD; Helge Bischoff, MD; Hendrik von Tengg-Kobligk, MD; Marc-André Weber, MD; Christian M. Zechmann, MD; Hans-Ulrich Kauczor, MD and Michael V. Knopp, MD, PhD

* From the German Cancer Research Center (Drs. Giesel, Tengg-Kobligk, Weber, Zechmann, and Kauczor), Department of Radiology, Heidelberg, Germany; Thoraxklinik (Dr. Bischoff), Heidelberg; and Department of Radiology (Dr. Knopp), The Ohio State University, Columbus, OH.

Correspondence to: Michael V. Knopp, MD, PhD, Professor of Radiology and Biomedical Informatics, Novartis Chair and Director of Imaging Research, Department of Radiology, The Ohio State University, University Hospitals, 657 Means Hall, 1654 Upham Dr, Columbus, OH 43210-1228; e-mail: Knopp.16{at}osu.edu

Abstract

Study objective: Dynamic contrast-enhanced MRI (DCE-MRI) followed by pharmacokinetic analysis has been successfully used in a variety of solid tumors. The aims of this study were to evaluate the feasibility of DCE-MRI in malignant pleural mesothelioma (MPM), to differentiate benign from pathologic tissue and compare pharmacokinetic with clinical parameters and survival in order to map out its microcirculation; and to compare pharmacokinetic with clinical parameter and survival in order to improve our understanding of the in vivo biology of this malignancy.

Methods: Nineteen patients with a diagnosis of MPM who were scheduled to receive chemotherapy with gemcitabine were enrolled in the study. DCE-MRI was performed before treatment (n = 19) and after the third cycle (n = 12) and sixth cycle (n = 7) of chemotherapy. An established pharmacokinetic two-compartment model was used to analyze DCE-MRI. Tumor regions were characterized by the pharmacokinetic parameters amplitude (Amp), redistribution rate constant (kep), and elimination rate constant (kel). Kinetic parameters of tumor tissue and normal tissue were compared using the Student t test. Patients were classified as clinical responders or nonresponders according to clinical outcome, and these groups were compared with the pharmacokinetic parameters derived from DCE-MRI.

Results: Normal and tumor tissue could be distinguished by the pharmacokinetic parameters Amp and kel (p ≤ 0.001). Clinical responders had a median kep value within the tumor of 2.6 min, while nonresponders showed a higher value (3.6 min), which coincided with longer survival (780 days vs 460 days).

Conclusions: DCE-MRI can be used in patients with MPM to assess tumor microvascular properties and to demonstrate tumor heterogeneity for therapy monitoring. High pretherapeutic values of kep within the tumor correlated with a poor overall response to therapy.

Key Words: angiogenesis • dynamic contrast enhanced MRI • malignant pleural mesothelioma • therapy monitoring

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that is usually fatal. Unfortunately, standard therapeutic regimens including surgery, chemotherapy, and radiation frequently yield unsatisfactory results (median survival, 6 to 12 months). While the use of single-agent or combined cytotoxic therapy protocols has been studied in numerous clinical trials123 without significantly affecting the prognosis, therapeutic options have increased with newer multitargeted drugs. Although the disease is relatively rare, it is estimated that > 80,000 new cases will occur during the next 20 years in North America alone.4 Therefore, it is essential to advance noninvasive imaging methodologies that can map out in vivo pathophysiologic characteristics of MPM, their homogeneity or heterogeneity, and to assess biological response to new therapies that might impact disease survival.

There is widespread agreement on the need to improve current treatment strategies and implement advanced cross-sectional imaging techniques for noninvasive functional assessment of tumor response. Traditional morphologic imaging techniques such as CT and MRI provide little insight into tumor metabolism and pathophysiology and are not well suited to assess early biological response.

Until now, CT has been widely used for the diagnosis, staging, and monitoring therapeutic response in MPM. The key structural findings include unilateral pleural effusion, nodular pleural thickening, interlobular fissure thickening, and tumor invasion of the chest wall, mediastinum or diaphragm.5 However, CT can be misleading in the evaluation of the extent of disease because it can underestimate early chest wall invasion and peritoneal involvement,6 and has well-known limitations in the evaluation of mediastinal lymph node metastases.7 Conventional MRI has been shown to be superior to CT. However, the identification of residual vital tumor tissue during therapy based on anatomic changes alone is difficult. Functional imaging methods that allow for a better understanding of tumor biology and provide more accurate prognostic and early response-to-therapy information are highly desirable. One functional modality with the potential to demonstrate metabolic activity within a tumor is fluorodeoxyglucose (FDG)-positron emission tomography (PET).789 It has been even demonstrated that FDG-PET is especially valuable for distinguishing between benign and malignant pleural processes.10

While PET using FDG-PET has been explored in the research setting, it has not achieved wide utilization in MPM9 because of its cost, limited availability, and lack of anatomic information. Recently, integrated PET and CT systems have allowed the advantages of high sensitivity (PET) to be combined with a high-resolution method (CT) in a single co-registered image. It has been shown that the integrated PET-CT scanning improves T staging and N staging of lung cancer in comparison to other imaging methods, but similar data are lacking for MRM.12 Niethammer et al8 demonstrated that integrated PET-CT identifies more accurately patients with MPM response than either CT or PET alone. However, PET-CT systems are expensive, and other functional imaging modalities, such as dynamic contrast-enhanced MRI (DCE-MRI), might be of benefit in this setting.

DCE-MRI has been successfully employed in patients with solid tumors for tumor characterization as well as to assess response to therapy.13 DCE-MRI involves the sequential acquisition of images during IV administration of a gadolinium chelate. The temporal passage of contrast media through tissue, including neoplastic (neoangiogenic) tissue, reflects its microcirculation and can be used to assess and map out differences in microcirculation and vascular permeability.131415 It has been shown in breast cancer that the pharmacokinetic analysis of DCE-MRI provides parameters that show significant correlation with angiogenesis. Moreover, this method has enabled an earlier prediction of response to chemotherapy in some trials13141516 when compared to assessment of morphologic changes. The purpose of this study was to evaluate the capabilities and feasibility of DCE-MRI to assess biological effects in patients with MPM undergoing chemotherapy by using pharmacokinetic parameters of contrast enhancement to characterize response to therapy. Assessing the enhancement profiles noninvasively might allow the characterization of biological aggressiveness of the tumors and help identify those that are unlikely to respond to standard regimens and who, therefore, should be directed to more aggressive therapy regimes or experimental clinical trials.

Materials and Methods

Patients and Diagnostic Evaluation
A total of 19 patients (17 men and 2 women; age range, 53 to 77 years; mean, 62.5 years) received a diagnosis of stage II (n = 9) or stage IV (n = 10) MPM, and subsequently were included in a prospective clinical trial with single-agent chemotherapy. All reported patients were enrolled under an investigational protocol that was approved by the investigational review board of the university clinics. Written informed consent was obtained from all patients. DCE-MRI was performed as an exploratory surrogate biomarker prior to therapy (n = 19) and after the third cycle (n = 12) and sixth cycle (n = 7) of chemotherapy. Only seven patients (stage II) were scanned successfully all three times. All patients underwent chemotherapy with six cycles of gemcitabine, 1,250 mg/m2, which was dose adjusted according to tolerance (2',2'-difluorodesoxycytidin).17 All patients underwent a pretreatment pleural biopsy that was evaluated with immunohistopathology18 Tumors were staged and classified according to World Health Organization/International Union Against Cancer staging criteria and MPM histopathologic classification of Butchart et al.19

Initial pharmacokinetic analysis of the MRI parameters were compared with survival. Retrospectively, the population was divided into responders (complete remission or partial responders, n = 4) and nonresponders (stable disease and progressive disease, n = 15). Pharmacokinetic values (amplitude [Amp], redistribution rate constant [kep]; elimination rate constant [kel]) of these two groups were correlated with survival prior to therapy.

MRI and Pharmacokinetic Analysis
DCE-MRI was performed using a standard clinical 1.5-T magnetic resonance system (Siemens; Erlangen, Germany) with a T1-weighted two-dimensional fat gradient-echo sequence (repetition time, 7.0 ms; echo time, 3.9 ms; matrix, 256 x 256; bandwidth, 260 Hz/s; 15 axial slices; 22 sequential repetitions). Gadolinium-diethylenetriamine penta-acetic acid was administered by slow injection (0.6 mL/s of 0.1 mmol/kg) after the third repetition using a power injector (Tomojet System; GE Healthcare; Buckinghamshire, UK). Imaging was acquired during shallow breathing. DCE-MRI source data were postprocessed using a pharmacokinetic two-compartment model on a personal computer as previously described.2021 Color maps reflecting pharmacokinetic parameters (Amp, kep) were generated. Regions of interest (ROIs) were generated from the color maps and evaluated for the whole tumor, adjacent normal tissue (muscle, liver, and spleen), as well as focal "hot spots" within the tumor. Tumor regions with pixels of colors purple, tortoise, green, yellow, and white were assigned to malignant tissue representing higher values for Amp and kep. Each ROI was placed after consensus had been reached between two experienced readers (F.L.G., M.V.K.). Three pharmacokinetic parameters—Amp, kep, and kel—were calculated for each ROI.

Technical Implementation
The thoracic location of MPM initially posed technical challenges due to physiologic motion of the lung and thoracic vessels that required optimization of acquisition parameters relative to standard breast DCE-MRI. The dynamic magnetic resonance sequence that was used in previous studies2021 for solid-tumor imaging was adjusted to thoracic imaging by reducing the repetition time from 40 to 7 ms. Shallow continuous breathing with a relative faster contrast media administration rate (0.6 mL/s vs 0.3 mL/s for breast DCE-MRI) was employed. Baseline pharmacokinetic color maps of the tumor area demonstrated most tumors to be heterogeneous, displaying a variety of contrast enhancement patterns depicted by characteristic signal-intensity time curves (Fig 1 ). The color-coded map readily displayed this heterogeneity of enhancement and was helpful in identifying the vascular tumor volume as well as hot spots that were evaluated separately.


Figure 1
View larger version (41K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Tumor heterogeneity demonstrated by DCE-MRI. Top, A: color-coded display demonstrates a left MRM with heterogenous enhancement. Different ROIs are drawn in green lines (muscle, tumor ROIs 2 to 5 [R5, R4, R3, R2], aorta). Bottom, B: signal-intensity curves of different tumor regions in MPM. Tumor ROI-2 and ROI-3 represent strong and fast enhancement followed by a moderate washout (hot spots). Tumor ROI-4 and ROI-5 display less vascular regions of the tumor. a.u. = arbitrary units; S/Spre = signal intensity/signal intensity prior to contrast media.

 
Statistical Analysis
Statistic analysis and graphic visualization were performed (SigmaPlot; SPSS; Chicago, IL). A Student t test was used to compare the value of kinetic parameters in normal and tumor tissue (level of significance, p = 0.05). The Pearson correlation was calculated comparing survival and kinetic parameters (Amp, kep, kel).

Results

Pretherapeutic pharmacokinetic quantification of the tumor area presented heterogeneous color maps with different contrast-enhancement patterns showing by characteristic signal-intensity time curves (Fig 1). The color-coded maps were very helpful to successfully guide semiautomated ROI analysis, separating normal from malignant tissue.

Subjects were classified as clinical nonresponders or responders. Nonresponders (n = 15) were characterized by short median survival (460 days). In contrast, responders (n = 4) demonstrated longer median survival (780 days) [Fig 2 ]. Nonresponders had significantly higher kep values than did responders (Fig 2). There was no correlation between the responder and nonresponder groups for the other two parameters (Amp and kel).


Figure 2
View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Median survival differentiated by kep per minute retrospectively between the responder group (n = 4) and nonresponder group (n = 15). The nonresponders demonstrate a higher kep, with a median of 3.6/min vs 2.6/min for responders.

 
Noninvasive pharmacokinetic tissue analysis enabled a classification of normal and tumor tissue based on differentiation by Amp, kep, and kel. A statistically significant difference between normal and neoplastic tissue was achieved with the parameters Amp and kel (p ≤ 0.001) [Fig 3 ]. The hot spots of the tumors demonstrated intense contrast enhancement, with high Amp, comparable to highly vascularized organs, ie, spleen (Fig 3). The hot spots within the tumor were also characterized by a rapid washout pattern (positive kel), whereas the remainder of the tumor typically showed a slowly rising pattern of enhancement represented by a negative kel.


Figure 3
View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. Differentiation of tumor, muscle, spleen and liver parenchyma using the pharmacokinetic parameters Amp (in arbitrary units and kel per minute). The ROI within the MPM tumor reveals a strong initial enhancement similar to spleen, followed by slow accumulation indicated by a negative kel. Pharmacokinetic clustering using Amp vs kel. See legend of Fig 1 for abbreviation not used in the text.

 
Four patients, all classified as clinical responders, demonstrated decreased contrast enhancement after therapy. The 15 nonresponding patients demonstrated elevated kep values at baseline that continued to increase during therapy. In three cases, the initial clinical response was followed by a relapse during chemotherapeutic intervention after the sixth cycle. This coincided with an increase of kep and increase in tumor size. Figure 4 presents one of these three cases; kep increased from 2.7/min prior to therapy up to 3.7/min after the sixth cycle. Chest pain and dyspnea developed within 2 months. The pharmacokinetic kep parameter after the third DCE-MRI examination increased to 4.3/min. Despite another six cycles of chemotherapy, the kep value continued to rise to 6.0/min, and the patient eventually succumbed to the disease.


Figure 4
View larger version (99K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. A patient with a partial response to gemcitabine therapy with one pretreatment DCE-MRI examination (top left, A) and three posttreatment DCE-MRI examinations (top right, B, bottom left, C, bottom right, D) is presented. Prior to therapy (top left, A), chest wall infiltration and encasement of the parenchyma are visible in the right lung. Color-coding maps display the heterogeneity of tumor microcirculation with an initial kep of 2.7/min based on total tumor ROI. After the sixth cycle, a decrease in tumor volume is noted, and an increased kep of 3.7/min was calculated (top right, B). The patient was classified clinically as a responder. The patient left the hospital and returned after 3 months with pain and massive tumor growth in the right lung (bottom left, C). The kep rose to 4.3/min. Despite further chemotherapy, the tumor progressed with a kep of 6.0/min (bottom right, D), and the patient died.

 
Discussion

This pilot feasibility study successfully demonstrates that parametric mapping based on DCE-MRI in MPM depicts not only the lesion and its extent but can map out the heterogeneity of microcirculation within the full thoracic extent of MPM. The pharmacokinetic parameters (Amp, kep, kel) enabled differentiation of normal and tumor tissue. In addition, the kinetic parameter kep may provide prognostic information with regard to therapeutic response.

MPM has been causally related to asbestos exposure and usually develops 20 to 50 years after such exposure.22 MPM has been increasing in incidence and is expected to reach its peak incidence within the next 2 decades. However, treatment results remain unsatisfactory. Although surgery,232425 radiotherapy, and chemotherapy (systemic and intrapleural)252627282930 have been proposed to improve outcome, none of them have yet documented improved survival. It is widely assumed that a more successful treatment of MPM will require a multitargeted approach. Until such an approach emerges, there have been continuing attempts to change prognosis using single-agent approaches.

Imaging may play an important role in identifying candidates for particular therapies and in documenting early responses. Conventional morphologic imaging methods such as plain chest radiography or multidetector CT can demonstrate pleural effusion, pleura thickening, rib destruction, encasement of the thorax, and mass extension typical of MPM.31 Therapy response or even clinical response prediction based on morphologic assessment without functional information is difficult and to our knowledge has not been described for MPM. Functional imaging with FDG-PET3233 to image the tumor metabolism in MPM has shown that most MPM demonstrate high metabolic tumor rate. Changes in FDG uptake reflect tumor aggressiveness and response to therapy.34 DCE-MRI is also a well-established imaging technique in clinical trials and is less time intensive and cost intensive. Reports31314151617 have described significant correlation of tumor histopathology, tumor angiogenesis, and pharmacokinetic results of DCE-MRI; these studies have largely focused on stationary organs such as the brain, breast, and cervix, leaving open the question whether the technique is applicable in more mobile organs such as lungs, liver, and kidneys.

To date, DCE-MRI has been limited by respiratory motion and heart pulsations during repetitive image acquisitions. However, by using shallow breathing, shortening the image acquisition time, and adapting the injection rate, pharmacokinetic analysis of the contrast-enhancement characteristics is feasible. This technique provides a noninvasive insight into tumor microcirculation and vascular permeability in a spatially resolved manner prior to and/or during therapy. Normal tissue has a distinctly different enhancement pattern compared with MPM. MPM was characterized by a rapid initial increase in signal followed by slower rise in signal over the duration of the DCE-MRI, which was very different pattern from that of normal tissue. Hot spots within the tumor demonstrated an even more rapid initial uptake of contrast but also had a rapid washout as well. These phenomena—which reflect different levels of neoangiogenesis and tumor vascular permeability—have been described for other tumors such as glioblastomas, cervix carcinomas, and breast cancer.31314151617 Tumor heterogeneity is often associated with therapy failure.3 Parametric mapping based on the DCE-MRI information of MPM demonstrated this characteristic. This finding suggests that a more heterogeneous MPM might not respond as well to chemotherapy, and consideration should be given to other, more aggressive treatment approaches in such patients.

Neovascularization has been shown to be necessary for tumor growth.835 Although some exceptions exist, many studies11 have confirmed the negative impact of elevated tumor vascularization on prognosis. Among the reported proangiogenic factors, vascular endothelial growth factor (VEGF) is the most well known.363738 A number of investigators36394041 have reported a significant relationship between vascular density and VEGF expression in a variety of tumors. Moreover, overexpression is associated with a poor prognosis in some neoplasms.42 Furthermore, studies35434445 confirm that high tumor expression of proangiogenetic factors (VEGF, VEGF type C) in MPM is associated with shorter survival. Because VEGF is known as a potent inducer of microvascular hyperpermeability, the pharmacokinetic kep may reflect the microvascular effects of this growth factor in vivo.45 New therapeutic interventions, ie, anti-VEGF antibody and other antivascular-targeted agents, require functional imaging to detect early biological effects in order to noninvasively assess response and enable individual treatment outside of clinical trials. In this study, kep values were predictive of treatment response and survival.

CT imaging is the major imaging modality of the chest but underestimates early chest wall invasion and peritoneal involvement6 as well as assessment of mediastinal lymph node metastases.7 A study46 using perfusion CT showed promising results in assessing metastatic lung nodules undergoing therapy. Although not relevant in this population, perfusion CT exposes the patient to substantial radiation that limits the ability to study it in the research setting, where strict limits are placed on nonclinical exposures. Similarly research PET studies are limited by radiation exposures, and so only one or two PET scans can be used during most clinical research studies before nonclinical exposure limits are reached.

This pilot study has several limitations. First, the sample population was relatively small because this was a single-center trial and MPM is relatively uncommon. Therefore, when several patients were unable to complete the full series of imaging due to progression of their disease, only a few patients actually completed all three scans. Additionally, the technique described here does not reflect the latest and most rapid MRI techniques available today, as we had to fix the technique for the duration of the study, which took several years to accrue. All these limitations can be readily overcome in new, multicenter trials using state-of-the-art equipment.

In summary, this pilot study demonstrates encouraging preliminary results including the feasibility and application of functional imaging parameters derived from the noninvasive DCE-MRI to characterize the microcirculation of MPM and its response to monotherapy. The kinetic contrast enhancement parameters were predictive of response although overall survival remained poor. This pilot study encourages further studies including DCE-MRI and pharmacokinetic analysis to assess MPM. As DCE-MRI continues to improve in temporal and spatial resolution, further increases in the accuracy of pharmacokinetic analysis are anticipated. Overall, this methodology could be widely available and would provide additive information by the direct mapping of functional and morphologic information to advance disease assessment and management.

Acknowledgements

We acknowledge the extensive review and comments by Peter L. Choyke, MD, from the National Cancer Institute Molecular Imaging Program.

Footnotes

Abbreviations: Amp = amplitude; DCE-MRI = dynamic contrast-enhanced MRI; FDG = fluorodeoxyglucose; kel = elimination rate constant; kep = redistribution rate constant; MPM = malignant pleural mesothelioma; PET = positron emission tomography; ROI = region of interest; VEGF = vascular endothelial growth factor

Received for publication August 11, 2005. Accepted for publication December 13, 2005.

References

  1. Antman, KH, Li, FP, Pass, HI, et al (1993) Benign and malignant mesothelioma. DeVita, VT, Jr Hellman, S Rosenberg, SA eds. Cancer: principles and practice of oncology 4th ed. ,1489-1508 Lippincott. Philadelphia, PA:
  2. Chahinian, AP Malignant mesothelioma. Holland, JF Frei, E Bast, RCet al eds. Cancer medicine 3rd ed. 1993,1337-1354 Lea & Febiger. Philadelphia, PA:
  3. Ruffie, P, Feld, R, Minkin, S, et al Current approach to malignant mesothelioma of the pleura. Chest 1995;107(6 Suppl),332S-344S
  4. Stewart, DJ, Edwards, JG, Smythe, WR, et al Malignant pleural mesothelioma: an update. Int J Occup Environ Health 2004;10,26-39[Medline]
  5. Steinert, DJ, Santos Dellea, MM, Burger, C, et al Therapy response evaluation in malignant pleural mesothelioma with integrated PET-CT imaging. Lung Cancer 2005;49(Suppl 1),S33-S35
  6. Rusch, VW, Godwin, JD, Shuman, WP, et al The role of computed tomography scanning in the initial assessment and the follow-up of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1988;96,171-177[Abstract]
  7. Benard, F, Sterman, D, Smith, RJ, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest 1998;114,713-722[Medline]
  8. Niethammer, AG, Xiang, R, Becker, JC, et al A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 2002;8,1369-1375[CrossRef][ISI][Medline]
  9. Haberkorn, U Positron emission tomography in the diagnosis of mesothelioma. Lung Cancer 2004;45(suppl),S73-S76[Medline]
  10. Schneider, DB, Clary-Macy, C, Challa, S, et al Positron emission tomography with f18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2000;129,128-133
  11. Jeswani, T, Padhani, AR Imaging tumor angiogenesis. Cancer Imaging 2005;5,131-138[Medline]
  12. Lardinois, D, Weder, W, Hany, TF, et al Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 2003;348,2500-2507[Abstract/Free Full Text]
  13. Choyke, PL, Dwyer, AJ, Knopp, MV Functional tumor imaging with dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 2003;17,509-520[CrossRef][Medline]
  14. Hawighorst, H, Knopp, MV, Debus, J, et al Pharmacokinetic MRI for assessment of malignant glioma response to stereotactic radiotherapy: initial results. J Magn Reson Imaging 1998;8,783-788[Medline]
  15. Knopp, MV, Weiss, E, Sinn, HP, et al Pathophysiologic basis of contrast enhancement in breast tumors. J Magn Reson Imaging 1999;10,260-266[CrossRef][ISI][Medline]
  16. Hall, GH, Atkin, SL, Turnbull, LW Use of dynamic contrast-enhanced MRI to assess the functional vascular pharmacokinetic parameters of normal human ovaries. J Reprod Med 2002;47,107-114[Medline]
  17. Kroep, JR, Peters, GJ, van Moorsel, CJ, et al Gemcitabine-cisplatin: a schedule finding study. Ann Oncol 1999;10,1503-1510[Abstract/Free Full Text]
  18. Kayser, K, Bohm, G, Blum, S, et al Glyco- and immunohistochemical refinement of the differential diagnosis between mesothelioma and metastatic carcinoma and survival analysis of patients. J Pathol 2001;193,175-180[Medline]
  19. Butchart, EG, Ashcroft, T, Barnsley, WC, et al Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: experience with 29 patients. Thorax 1976;31,15-24[Abstract]
  20. Brix, G, Semmler, W, Port, R, et al Pharmacokinetic parameters in CNS Gd-DTPA enhanced MR imaging. J Comput Assist Tomogr 1991;15,621-628[Medline]
  21. Hoffmann, U, Brix, G, Knopp, MV, et al Pharmacokinetic mapping of the breast: a new method for dynamic MR mammography. Magn Reson Med 1995;33,506-514[Medline]
  22. Peto, J, Hodgson, JT, Matthews, FE, et al Continuing increase in mesothelioma mortality in Britain. Lancet 1995;345,535-539[CrossRef][ISI][Medline]
  23. Boutin, C, Rey, F, Gouvernet, J Malignant mesothelioma: prognostic factors in a series of 125 patients studied from 1973 to 1987. Bull Acad Natl Med 1992;176,105-114[Medline]
  24. Butchart, EG Surgery of mesothelioma of the pleura. Roth, JA Ruckdeschel, JC Weinseinberger, TH eds. Thoracic oncology 1989,566-583 W. B. Saunders. Philadelphia, PA:
  25. Rusch, VW, Piantadosi, S, Holmes, EC The role of extrapleural pneumonectomy in malignant pleural mesothelioma: a Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 1991;102,1-9[Abstract]
  26. Mattson, K, Holsti, LR, Tammilehto, L, et al Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 1992;24,643-650[ISI][Medline]
  27. Gordon, W, Jr, Antman, KH, Greenberger, JS, et al Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982;8,19-25[ISI][Medline]
  28. Davis, SR, Tan, L, Ball, DL Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994;38,212-214[Medline]
  29. Ong, ST, Vogelzang, NJ Chemotherapy in malignant pleural mesothelioma: a review. J Clin Oncol 1996;14,1007-1017[Abstract/Free Full Text]
  30. Hasturk, S, Tastepe, I, Unlu, M, et al Combined chemotherapy in pleurectomized malignant pleural mesothelioma patients. J Chemother 1996;8,159-164[ISI][Medline]
  31. Marom, EM, Erasmus, JJ, Pass, HI, et al The role of imaging in malignant pleural mesothelioma. Semin Oncol 2002;29,26-35[Medline]
  32. Knopp, MV, Bischoff, H, Lorenz, WJ, et al PET imaging of lung tumours and mediastinal lymphoma. Nucl Med Biol 1994;21,749-757[Medline]
  33. Gerbaudo, VH, Britz-Cunningham, S, Sugarbaker, DJ, et al Metabolic significance of the pattern, intensity and kinetics of 18F-FDG uptake in malignant pleural mesothelioma. Thorax 2003;58,1077-1082[Abstract/Free Full Text]
  34. Detterbeck, FC, Vansteenkiste, JF, Morris, DE, et al Seeking a home for a PET, part 3: emerging applications of positron emission tomography imaging in the management of patients with lung cancer. Chest 2004;126,1656-1666[CrossRef][Medline]
  35. Folkman, J Tumor angiogenesis: therapeutic implications. N Engl J Med 1976;285,1182-1186
  36. Mattern, J, Koomagi, R, Volm, M Vascular endothelial growth factor expression and angiogenesis in non-small cell lung carcinomas. Int J Oncol 1995;6,1059
  37. Samoto, K, Ikezaki, K, Ono, M, et al Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 1995;55,1189-1193[Abstract/Free Full Text]
  38. Takahashi, Y, Kitadai, Y, Bucana, CD, et al Expression of vascular endothelial growth factor and its receptor KDR, correlation with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55,3964-3968[Abstract/Free Full Text]
  39. Weidner, N, Semple, JP, Welch, WR, et al Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 1991;324,1-8[Abstract]
  40. Macchiarini, P, Fontanini, G, Hardin, MJ, et al Relation of neovascularisation to metastasis on non-small cell lung cancer. Lancet 1991;340,145-146
  41. Toi, M, Hoshina, S, Takayagani, T Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res 1994;85,1045[CrossRef][ISI][Medline]
  42. Chodak, GW, Haudenschild, C, Gittes, RF Angiogenic activity as a marker of neoplasia and pre-neoplasia in lesions of the human bladder. Ann Surg 1980;192,762-771[ISI][Medline]
  43. Kumar-Singh, S, Vermeulen, PB, Weyler, J, et al Evaluation of tumour angiogenesis as a prognostic factor in malignant mesothelioma. J Pathol 1997;182,211-216[CrossRef][ISI][Medline]
  44. Ohta, Y, Shridhar, V, Bright, RK, et al VEGF and VEGF type C play an important role in angiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999;81,54-61[CrossRef][ISI][Medline]
  45. Knopp, MV, Weiss, E, Sinn, HP, et al Pathophysiologic basis of contrast enhancement in breast tumors. J Magn Reson Imaging 1999;10,260-266[CrossRef][ISI][Medline]
  46. Kiessling, F, Boese, J, Corvinus, C, et al Perfusion CT in patients with advanced bronchial carcinomas: a novel chance for characterization an treatment monitoring? Eur Radiol 2004;14,1226-1233[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Giesel, F. L.
Right arrow Articles by Knopp, M. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Giesel, F. L.
Right arrow Articles by Knopp, M. V.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS