Angiogenesis of uterine cervical carcinoma: characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement.

Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this project to: (a) examine the relationship between contrast-enhanced dynamic MRI-derived characteristics and histological microvessel density counts, a recognized surrogate of tumor angiogenesis, from primary or recurrent cancers of the uterine cervix; and (b) correlate these parameters with lymphatic involvement to characterize tumor aggressiveness in terms of lymphatic spread. Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21) were calculated from a contrast-enhanced dynamic MRI series in 55 patients (ages 25-72 years; mean, 50 years) with biopsy-proven primary (n = 42) or recurrent (n = 13) uterine cervical cancer. Both pharmacokinetic parameters were correlated to histologically determined microvessel density counts (factor VIII-related antigen) and other pathological tumor characteristics obtained from the operative specimens after radical surgery. In addition, the magnetic resonance and histological data were correlated to the presence or absence of lymphatic system involvement. Pharmacokinetic MRI-derived parameters (A and k21) increased with increasing histological microvessel density counts with r = 0.41 and 0.50, respectively. Lymphatic involvement was more comprehensibly assessed by the pharmacokinetic parameter k21 compared with histological microvessel density, resulting in a higher sensitivity, overall accuracy, and comparable specificity. Contrast-enhanced MRI parameters might prove to be applicable for estimation of tumor angiogenesis in uterine cervical cancer; thus, MRI may become an additional tool to characterize malignant progression in terms of lymphatic involvement in uterine cervical cancer.

[Detection of angiogenesis-dependent parameters by functional MRI: correlation with histomorphology and evaluation of clinical relevance as prognostic factor using cervix carcinoma as an example]. / Erfassung angiogeneseabhängiger Parameter mittels funktioneller MRT: Korrelation mit der Histomorphologie sowie Abklärung der klinischen Relevanz als Prognosefaktor am Beispiel des Zervixkarzinomes.

PURPOSE: Purpose of this study is to compare functional MRI parameters with histomorphological markers of tumor microvessel density (MVD) and permeability (vascular endothelial growth factor) and to determine the ultimate value of both approaches by correlation with disease outcome in patients with primary cancer of the uterine cervix. METHOD: Pharmacokinetic parameters were calculated from contrast-enhanced dynamic MR imaging series in 37 patients with biopsy-proven primary cervical cancer. On the operative whole mount specimens, histomorphological markers of tumor angiogenesis (MVD, VEGF) were compared with the MRI-derived parameters. For MRI and histomorphological data, Kaplan-Meier survival curves were calculated and compared using logrank statistics. RESULTS: Significant (p < 0.05-0.01) associations were found between MVD and dynamic MRI parameters. No significant relationships were observed between VEGF expression and dynamic MRI parameters. Disease outcome was better assessed with dynamic MRI parameters than with the histomorphological approach. CONCLUSIONS: It is concluded that 1) the pathophysiological basis for the amplitude A in dynamic MRI is MVD but not VEGF expression; and 2) a functional, dynamic MRI approach may be more suited to assess angiogenic activity in terms of patient survival than current histomorphological-based markers of tumor angiogenesis.

Damage to arterial and venous endothelial cells in bypass grafts induced by several solutions used in bypass surgery.

The purpose of our study was to evaluate the cytotoxicity of incubation solutions used in heart surgery to endothelial cells. The endothelial layer of human saphenous veins (HSV) and bovine internal mammary arteries (BMA) and veins (BMV) were studied after a two-hour storage interval and compared with control vessel segments prepared immediately after harvesting. To visualize the endothelial cell damage, specimens were stained with a silver nitrate technique. The surface covered by light-microscopically intact endothelial cells was computed in percent. In the control HSV segments 70.8 +/- 4.6% of the endothelium were found to be morphologically intact. The results for stored HSV segments were 50.0 +/- 4.2% (Bretschneider's solution), 14.8 +/- 4.5% (physiological saline), 0.45 +/- 0.1% (physiological saline with heparin), 16.7 +/- 4.7% (Ringer's lactate) and 37.2 +/- 5.3% (heparinized blood). Comparable values obtained with BMA specimens were 98.3 +/- 0.7% (controls), 78.1 +/- 4.7% (Bretschneider's solution), 39.2 +/- 3.3% (physiological saline), 8.4 +/- 2.0% (physiological saline with heparin), 11.3 +/- 1.7% (Ringer's lactate) and 67.8 +/- 6.2% (heparinized blood). A similar trend was found with BMV segments: 85.2 +/- 4.7% (controls), 75.6 +/- 6.0% (Bretschneider's solution), 49.5 +/- 8.9% (physiological saline), 5.95 +/- 0.7% (physiological saline with heparin), 6.2 +/- 0.7% (Ringer's lactate) and 54.3 +/- 5.1% (heparinized blood). In conclusion, Bretschneider's solution proved to be superior for storage of bypass grafts in comparison to all other tested solutions in this series.

Staging of invasive cervical carcinoma and of pelvic lymph nodes by high resolution MRI with a phased-array coil in comparison with pathological findings.

PURPOSE: Our goal was to stage invasive cervical carcinoma (pT1b-pT4a) and pelvic lymph nodes by high resolution MRI with a circularly polarized (cp) phased-array coil in correlation with the whole-mount specimen and the histopathological findings. METHOD: Thirty-three patients (20-68 years old; mean age 55 years) with biopsy-proven primary cancer of the cervix were prospectively examined on a 1.5 T scanner by using a cp body phased-array coil. The MR protocol consisted of high resolution T2-weighted turbo-SE (TSE) and pre- and postcontrast T1-weighted SE (SE) sequences. Slice thickness was 5-7 mm with a pixel size of 0.3-0.4 mm2. All MRI findings were matched to the whole-mount specimens and the histopathological findings. RESULTS: Pathological stages evaluated were pT1b (n = 5), pT2b (n = 16), and pT4a (n = 12). The overall accuracy rates for tumor staging were 79% for high resolution T2-weighted TSE and 76% for postcontrast T1-weighted SE images. The accuracy for high resolution T2-weighted TSE images in determining parametrial infiltration, pelvic side wall, and bladder and rectal wall infiltration was 84, 87, and 87%, respectively. In prospective analysis of the 1.0 cm criterion for diagnosis of a positive pelvic lymph node, MRI had a 72% accuracy, a 68% sensitivity, and a 78% specificity. CONCLUSION: High resolution MRI with a cp body phased-array coil provides excellent and robust high resolution images in patients with invasive cervical carcinoma. However, accuracy, specificity, and sensitivity for staging invasive cervical carcinoma and pelvic lymph nodes with correlation to whole-mount specimens and histopathological findings did not improve compared with the results in the literature using a body coil with thicker slices and a lower spatial resolution.

[Diagnosis of recurrence of cervix carcinoma using dynamic MRI: correlation of pharmacokinetic analysis and histopathology]. / Rezidivdiagnostik beim Zervixkarzinom mittels dynamischer MR:-Korrelation von pharmakokinetischer Analyse und Histopathologie.

PURPOSE: The aim of the study was to evaluate the value of dynamic magnetic resonance imaging (MRI) to classify suspect lesions into benign and malignant in patients previously treated for cancer of the cervix. MATERIALS AND METHODS: Eleven patients with 14 suspect lesions after treatment of cervical carcinoma were examined by dynamic contrast-enhanced MRI. The imaging findings were compared to the giant cross-section specimen as the reference standard. Computed tissue-specific enhancement parameters were obtained (pharmacokinetic mapping) and displayed as color-coded images. The regions of interest were retrospectively defined according to the pharmacokinetic images over the most suspect areas. Therein, the threshold values were determined that achieved the greatest overall accuracy and a low rate of false-positive results. RESULTS: Analysis of the lesions on T2-weighted images revealed sensitivity of 88%, specificity of 40%, and accuracy of 71%. Analysis of the dynamic MR data showed significantly shorter (p < 0.01) and stronger (p < 0.001) contrast media enhancement of malignant (n = 9) than benign lesions (n = 5). CONCLUSION: Pharmacokinetic mapping appears to yield important information for dividing suspect lesions into malignant and benign following treatment of cervical cancer.

Influence of several solutions used in bypass surgery on the permeability of the endothelium of carotid arteries in New Zealand rabbits.

BACKGROUND: Alteration of endothelial permeability by perfusion solutions used may influence the outcome of bypass grafts. METHOD: Carotid arteries of New Zealand rabbits were locally perfused in situ for 20 or 60 min with various solutions used in bypass surgery. After restoring normal circulation, horseradish peroxidase was injected in the ear vein. Endothelial permeability was measured by electronmicroscopy as the peroxidase accumulation in the subendothelial space during 6min circulation. RESULTS: The density indices (mean standard deviation) as a parameter for permeability in comparison to the control vessels were significantly greater than 100% for all solutions: for physiological saline 254+/-22% and 358+/-15%, for Ringer's lactate 206+/-26% and 302+/-17%, for St. Thomas' Hospital solution 163+/-15 % and 252+/-29%, and for Bretschneider's HTK solution 130+/-15% (p=0.003) and 169+/-26%, after 20 and 60 min perfusion. Addition of heparin (50IU/ml) caused a significant increase in endothelial permeability (p<0.05). CONCLUSIONS: Bretschneider's is the most suitable of the solutions studied as a graft storage medium in bypass and cardiothoracic surgery, but a solution causing even less damage is desireable.

[Invasive cervix carcinoma (pT2b-pT4a). Value of conventional and pharmacokinetic magnetic resonance tomography (MRI) in comparison with extensive cross sections and histopathologic findings]. / Invasives Zervixkarzinom (pT2b-pT4a). Wertigkeit der konventionellen und pharmakokinetischen Magnetresonanztomographie (MRT) im Vergleich zum Grossflächenschnitt und dem histopathologischen Befund.

PURPOSE: To compare staging of advanced primary cervical carcinoma (pT2b-pT4a) by conventional and pharmacokinetic magnetic resonance imaging (MRI) with the giant cross section specimen and histopathological findings. MATERIALS AND METHODS: Seventeen patients with biopsy-proven cancer of the cervix and clinically suspected invasive cancer (FIGO IIB-IVA) were prospectively examined by conventional (T2 and contrast-enhanced T1-weighted spin echo images) and pharmacokinetic MRI. All MRI findings were compared with the giant cross section specimen and histopathology as the standard of reference. For pharmacokinetic MRI, a saturation recovery TurboFLASH sequence was used with a high temporal resolution of 13 s per ten sections. Signal time changes were analyzed using a pharmacokinetic model and the computed parameter values were visualized by color-coded overlay. RESULTS: Analysis of parametrial invasion on T2-weighted images resulted in an accuracy of 85% and 73% on contrast-enhanced T1-weighted images and on pharmacokinetic MR images respectively. Accuracy of analysis of bladder and/or rectal wall invasion was significantly (P < 0.05) higher on pharmacokinetic MR images (88%) than on T2-weighted images (67%). Contrast-enhanced T1-weighted spin-echo images improved staging accuracy compared with T2-weighted images (76% vs 67%). CONCLUSION: At present, conventional T2-weighted SE images are superior to contrast-enhanced T1-weighted SE and pharmacokinetic MR images in depicting infiltration of the parametrium. However, suspected infiltration of the bladder and/or rectum (pT4a) is diagnosed more accurately on pharmacokinetic images than on conventional MR images.

Cervical carcinoma: comparison of standard and pharmacokinetic MR imaging.

PURPOSE: To stage advanced cervical carcinoma with conventional or pharmacokinetic magnetic resonance (MR) imaging by correlating imaging findings with whole-mount specimens and histopathologic findings. MATERIALS AND METHODS: Twenty-six adult patients with primary cervical cancer (stages IIB-IVA) underwent T2-weighted turbo spin-echo (SE) MR imaging; gadolinium-enhanced, T1-weighted SE MR imaging; and gadolinium-enhanced, saturation-recovery, turbo fast low-angle shot MR imaging. All imaging findings were correlated with the whole-mount specimens and histopathologic findings. Signal intensity changes versus time were analyzed by using a pharmacokinetic model and parameter values displayed as a color-coded overlay. RESULTS: Histopathologic stages were IIB (n = 9), IIIB (n = 1), and IVA (n = 16). The overall accuracy for tumor staging was 73% for T2-weighted, 81% for T1-weighted, and 92% for pharmacokinetic MR imaging. Pharmacokinetic MR imaging was accurate (90%) in the diagnosis of tumor extension into the bladder and/or rectal wall but inaccurate (69%) in that of parametrial invasion. T2-weighted images were most accurate (86%) in the assessment of parametrial tumor extension but less accurate (69%) in that of bladder or rectal invasion. CONCLUSION: T2-weighted turbo SE images are still superior to contract medium-enhanced T1-weighted SE or pharmacokinetic MR images in the diagnosis of parametrial infiltration by uterine cervical carcinoma. However, pharmacokinetic MR imaging is a promising method for demonstrating and staging IVA disease.

Pelvic lesions in patients with treated cervical carcinoma: efficacy of pharmacokinetic analysis of dynamic MR images in distinguishing recurrent tumors from benign conditions.

OBJECTIVES: Dynamic MR image series were analyzed with a pharmacokinetic two-compartment model. To preserve the spatial resolution of the dynamic MR images, the pharmacokinetic parameters were computed pixel by pixel, color coded, and superimposed on conventional MR images (pharmacokinetic mapping). The efficacies of pharmacokinetic mapping and conventional MR imaging in distinguishing between recurrent tumors and benign conditions in patients who have pelvic lesions after treatment of cervical carcinoma were compared. MATERIALS AND METHODS: Twenty-one women with 24 suspected pelvic lesions and a history of treated cervical carcinoma (stages IB-IIIA) were included in this study. Patients had been treated before MR imaging with surgery or irradiation alone (eight patients) or a combination of the two (13 patients). Patients were referred because of our findings from CT examinations and/or clinical examinations. Of 24 suspected lesions, 17 were histologically verified as tumor recurrences and seven were classified as benign masses (histologically diagnosed as fibrosis and granulation tissue). T1- and T2-weighted spin-echo images were interpreted by three observers. During and after constant-rate infusion of gadopentetate dimeglumine, the kinetics of lesion response were determined with a strongly T1-weighted saturation recovery turbo-fast low-angle shot sequence. The signal-time curves for the suspected lesions were analyzed within the framework of a pharmacokinetic two-compartment model and displayed as color-coded images. The calculated pharmacokinetic parameters (amplitude [A] and tissue distribution time [t21]) were evaluated retrospectively to obtain optimal threshold values for differentiating malignant lesions from benign lesions. RESULTS: Analysis of the pharmacokinetic mapping data showed significantly shorter (p < .005) and stronger (p < .001) contrast medium enhancement of malignant lesions (t21, 24 sec; A, 1.5 arbitrary units) than of benign lesions (t21, 65 sec; A, 0.7), resulting in a sensitivity of 100%, a specificity of 88%, and an accuracy of 96%. Interpretation of the lesions on conventional T2-weighted MR images resulted in a sensitivity of 90%, a specificity of 38%, and an accuracy of 74%. CONCLUSION: Analysis of color-coded pharmacokinetic maps is more effective than conventional MR imaging in distinguishing between malignant and benign conditions in patients who have pelvic lesions after treatment of cervical carcinoma.

[Angiogenesis of cervix carcinoma. Contrast enhanced dynamic MRI, histologic quantification of capillary density and lymphatic system infiltration]. / Angiogenese des Zervixkarzinomes. Kontrastverstärkte dynamische MRT, histologische Quantifizierung der Kapillardichte und Lymphsysteminfiltration.

PURPOSE: It was the aim of this project to examine (i) the relationships between contrast-enhanced dynamic MR imaging derived characteristics and histologic microvessel density counts--a recognized surrogate of tumor angiogenesis--from tumors in patients with primary or recurrent cancer of the uterine cervix, and (ii) to correlate these parameters with lymphatic involvement (i.e. lymphatic channels) to assess tumor biological aggressiveness in terms of lymphatic spread. MATERIAL AND METHODS: Pharmacokinetic MR imaging parameters (amplitude A, exchange rate constant k21) were derived from contrast-enhanced dynamic MR imaging in thirty-three patients with biopsy proven cancer of the uterine cervix. The pharmacokinetic MR imaging characteristics were correlated to histologic capillary density counts obtained from whole mount specimen. In addition, these data were correlated to the angiogenic activity as a marker for lymphatic system involvement. RESULTS: Pharmacokinetic MR imaging derived parameters (A, k21) showed a weak but significant (p < 0.05) correlation with microvessel density counts. Lymphatic involvement was more comprehensively assessed by the pharmacokinetic parameter k21 compared with histologic microvessel density, resulting in a significantly (p < 0.05) higher overall accuracy (85% vs. 64%), sensitivity (83% vs. 54%), and comparable specificity (89% vs. 89%), respectively. CONCLUSION: Our first results show that the signal-time curves measured by contrast-enhanced MR imaging are only in part influenced by microvessel density. In addition, MR imaging derived characteristics may assess tumor biological aggressiveness in terms of lymphatic spread (i.e. lymphatic channels) more comprehensively than histologic microvessel density in patients with primary or recurrent cancer of the uterine cervix.