Ivan Zuna

Pathophysiologic basis of contrast enhancement in breast tumors

While the diagnostic benefits of gadolinium (Gd)‐chelate contrast agents are firmly established in magnetic resonance imaging (MRI) of tumors, the pathophysiologic basis of the enhancement observed and its histopathologic correlate remained vague. Tumor angiogenesis is fundamental for growth and metastasis and also of interest in new therapeutic concepts. By correlative analysis of a) histology; b) vascular density (CD31); and c) vascular permeability (vascular permeability factor/vascular endothelial growth factor [VPF/VEGF]), we found a) significantly (P < 0.001) faster exchange rates in malignant compared with benign breast lesions; b) distinct differences in enhancement characteristics between the histologic types (invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ); and c) dependence of enhancement kinetics on the VPF/VEGF expression. The pathophysiologic basis for the differences in contrast enhancement patterns of tumors detectable by MRI is mainly due to vascular permeability, which leads to more characteristic differences than vascular density. MRI is able to subclassify malignant breast tumors due to their different angiogenetic properties. J. Magn. Reson. Imaging 1999;10:260–266.

In Situ Expression of Interleukin-10 in Noninflamed Human Gut and in Inflammatory Bowel Disease

A dysregulated secretion of contra-inflammatory cytokines such as interleukin-10 (IL-10) could play a role in the pathogenesis of inflammatory bowel disease (IBD). We have investigated the expression of IL-10 in gut tissues from patients with Crohns disease (CD), ulcerative colitis (UC) and controls by mRNA in situ hybridization and immunohistochemistry. Intestinal epithelial cells were found to express IL-10 mRNA and IL-10 protein in all of the tissues investigated without any major differences in the expression patterns. However, compared with noninflamed gut, significantly increased numbers of mononuclear cells (MNCs) producing IL-10 were present in inflamed gut, both in CD and UC. This cytokine was expressed most prominently by inflammatory infiltrates enriched in macrophages, although T cells seem to contribute to its production as well. Elevated IL-10 expression in IBD was mainly detected in the submucosa, whereas IL-10 production by lamina propria cells remained comparably low. In contrast, the expression of IL-1beta mRNA was preferentially increased in the lamina propria. Our data argue against a general deficiency in IL-10 production in IBD. The results suggest rather that the local production of IL-10 by mucosal MNCs in IBD is insufficient to down-regulate pro-inflammatory cytokines such as IL-1beta in the lamina propria compartment.

Preoperative Staging of Renal Cell Carcinoma With Inferior Vena Cava Thrombus Using Multidetector Ct and Mri: Prospective Study With Histopathological Correlation

Objective: To evaluate the accuracy of multidetector computed tomography (CT) and magnetic resonance imaging (MRI) in staging and estimating renal carcinomas with caval thrombus. Methods: Initially, 23 patients with suspected caval thrombi were admitted into this prospective study. Triphasic CT imaging was performed using a multidetector CT with a reconstructed slice thickness of 2 mm. 3D CT reconstructions were used to improve surgical planning. MRI protocol included: a transversal T1-weighted GE sequence with and without Gd-DTPA, a transversal T2-weighted respiratory-gated TSE, and a coronal T1-weighted GE sequence with Gd-DTPA and fat saturation. In addition, a multiphase 3D angiography was performed after Gd-DTPA injection. Patients were divided into 3 groups: caval thrombus below the insertion of the hepatic veins, within the intrahepatic vena cava, and intra-atrial extension. The results the tumor thrombus extension and staging results of 2 independent readers were correlated with surgical and histopathological staging. Results: Of the 23 patients admitted, CT and MR scans of 14/13 patients respectively were correlated with histopathological workup. CT thrombus detection sensitivity and specificity for both readers was 0.93 and 0.8 respectively. MRI sensitivity and specificity for both readers was 1.0/0.85 and 0.75. Readers I and II evaluated the uppermost extension of the cranial tumor thrombus by both CT and MRI. CT and MR accuracy was 78% and 72%, 88% and 76% respectively. Conclusion: In cases of a suspected tumor thrombus, MRI and multidetector CT imaging showed similar staging results. Consequently, these staging modalities can be used to assess the extension of the tumor thrombus.

Serum Antibodies Against Helicobacter pylori Proteins VacA and CagA Are Associated with Increased Risk for Gastric Adenocarcinoma

Infection with Helicobacter pylori is associatedwith the development of gastric cancer. To study whetherthe infection with H. pylori strains expressing thevacuolating cytotoxin (VacA) and/or thecytotoxin-associated protein (CagA) is associated with an increasedrisk of developing gastric adenocarcinoma, sera of 90patients with gastric cancer and 90 matched controlswith cardiovascular diseases were investigated for the presence of antibodies to VacA and CagA byimmunoblot. Although no significant difference in theoverall H. pylori seropositivity was found betweencancer patients and controls, antibodies against VacA or CagA were significantly more frequent incancer patients than in control subjects. Seventyfive(97.4%) of 77 H. pylori-positive patients in the cancergroup, but only 60 (84.5%) of 71 H. pylori-positive control patients had antibodies against eitherVacA or CagA (χ2 6.63; relative risk,2.00; 95% confidence interval, 1.18–3.39; P =0.01). The presence of antibodies against VacA or CagAalone was also associated with an increased cancer risk (92.2%vs 80.3%; χ2 = 5.30; relative risk, 1.74;95% confidence interval, 1.08–2.78; P = 0.021, forVacA; and 87.0% vs 74.6%; χ2 4.90;relative risk, 1.61; 95% confidence interval, 1.06–2.45; P =0.037, for CagA). The relative risk for gastric cancerwas mainly elevated in patients under 65 years, but notin patients at or over 65 years. There is evidence that infection with VacA- or CagA-producing H.pylori strains increases the risk of developing gastriccancer, especially in younger patients.

IX. MR tissue characterization of intracranial tumors by means of texture analysis

Tissue characterization of the human brain has been performed by texture analysis of proton relaxation time images using a standard MR whole body imager operating at 1.5 T. A combined CP/CPMG multi-echo, multislice sequence was used to measure T1 and T2 in each pixel with an uncertainty not exceeding 10%. In a prospective clinical study, 12 patients with histologically confirmed brain tumors were investigated. For each ROI in the calculated T1 and T2 parameter images, texture parameters originating from the grey level distribution, the gradient distribution, the grey level co-occurrence matrix, and the grey level runlength histogram were used for classification and discrimination between tissues. All regions corresponding to the normal brain tissue (white matter, grey matter, cerebrospinal fluid) were successfully discriminated from each other as well as from the pathological tissue parts (edema and tumor). The classification of 10 edematous and 8 tumorous tissue regions yielded only one misclassification. Together with additional rules, these discrimination rules formed the knowledge base of an expert system for segmentation of the brain images. In cases of tumors without Gd-DTPA contrast medium uptake or in cases of Gd-DTPA contraindication, segmentated images can help solve nontrivial diagnostical problems such as delineating the target volume in radiation therapy.

Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy

Abstract. The aim of this study was to evaluate whether regressive changes after neoadjuvant chemotherapy for breast cancer affect the accuracy of preoperative MRI measurements of tumor size. Thirty-one patients with breast cancer underwent MRI before and after neoadjuvant treatment. Besides pre- and post-contrast T1-weighted MRI, dynamic MRI with high temporal resolution (turbo-FLASH) was performed. Contrast enhancement in dynamic MRI was quantified using a pharmacokinetic two-compartment model, where two parameters, amplitude and kep, were calculated and color coded on transversal parameter maps. Considering the conventional MR images, tumor diameters were measured on the color maps and compared with histological tumor size. Histological regression was scored on a five-point scale regarding cytopathic effects, reactive changes, and tumor cell reduction. The correlation between tumor sizes measured by MRI and histopathology was 0.83 (p<0.0007) in 12 tumors without regressive changes (score 0), and 0.48 (p<0.051) in 17 tumors with regressive changes scored 1 or 2, without any tendency for systematic over- or underestimation. In two cases without residual tumor (score 4), MRI likewise showed no signs of persistent tumor. The decrease of the contrast enhancement parameters was significantly more marked in tumors with signs of histological regression than in those without. Whenever MRI is used to judge the response of breast cancer to chemotherapy, the reader must be aware that therapy-induced changes may cause significant over- or underestimation of tumor size. We saw a high precision only when there was either no response – according to histological criteria – or when the tumor had regressed completely.

Evaluation of neoadjuvant chemotherapeutic response of breast cancer using dynamic MRI with high temporal resolution.

Abstract. The aim of this study was to evaluate changes in both size and contrast enhancement of breast tumors during neoadjuvant chemotherapy, using dynamic MRI with high temporal resolution. Patients with advanced breast cancer (n=21) underwent a 1.5-T MRI scan prior to and following neoadjuvant chemotherapy with four cycles. Dynamic contrast enhancement was measured using a fast turbo-FLASH sequence and quantified using a two-compartment model with the parameters kep and amplitude. Image analysis was done on images overlayed with a color map of parameters. The correlation between tumor diameter measured by histopathology and MRI was 0.7 (p<0.003). A reduction of tumor size after chemotherapy of more than 25% was associated with a decrease of both analyzed contrast enhancement parameters (kep: p<0.002; amplitude: p<0.006), where kep began to drop already after the first cycle of chemotherapy (p<0.008). A clear reduction of tumor size was only noted after the third cycle (p<0.008). In patients without tumor regression there was also a trend towards an early reduction of contrast enhancement.We assume that MRI with high temporal resolution and color mapping is a novel tool to assess therapeutic effects of neoadjuvant chemotherapy in breast tumors, which deserves further prospective evaluation.

Assessment of irradiated brain metastases by means of arterial spin-labeling and dynamic susceptibility-weighted contrast-enhanced perfusion MRI: Initial results

Rationale and Objectives:To assess if preradiation and early follow-up measurements of relative regional cerebral blood flow (rrCBF) can predict treatment outcome in patients with cerebral metastases and to evaluate rrCBF changes in tumor and normal tissue after stereotactic radiosurgery using arterial spin-labeling (ASL) and first-pass dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MRI. Methods:In 25 patients with a total of 28 brain metastases, DSC MRI and ASL perfusion MRI using the Q2TIPS sequence were performed with a 1.5-T unit. Measurements were performed prior to and at 6 weeks, 12 weeks, and 24 weeks after stereotactic radiosurgery. Follow-up examinations were completely available in 25 patients for Q2TIPS and 17 patients with 18 metastases for DSC MRI. The rrCBF of the metastases and the normal brain tissue was determined by a region-of-interest analysis. rrCBF values were correlated with the treatment outcome that was classified according to tumor volume changes at 6 months. Results:The alteration of the rrCBF at the 6-week follow-up was highly predictive for treatment outcome. A decrease of the rrCBF value predicted tumor response correctly in all metastases for Q2TIPS and in 13 of 16 metastases for DSC MRI. The pretherapeutic rrCBF was not able to predict treatment outcome. The rrCBF values in normal brain tissue affected by radiation doses less than 0.5 Gy remained unchanged after therapy. Conclusion:These preliminary results suggest that ASL and DSC MRI techniques determining rrCBF changes in brain metastases after stereotactic radiosurgery allow the prediction of treatment outcome.

Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease

Abstract Abstract. To define mediator profiles in inflamed and noninflamed areas in inflammatory bowel disease (IBD) we analyzed the expression of 35 messenger-RNAs (mRNAs) encoding cytokines, chemokines, and some related molecules in transmural gut tissues (n=138) from patients with ulcerative colitis (UC), Crohns disease (CD), and inflammatory and normal controls by real-time quantitative reverse transcription polymerase chain reaction. Using sample collectives with a comparable degree of inflammation, most parameters investigated showed similarly increased mRNA expression levels in both active UC and CD. This included proinflammatory cytokines, but also interferon (IFN) γ and several IFN-γ inducible chemokines. Only macrophage inflammatory protein (MIP)-2α mRNA was expressed at higher levels in inflamed UC vs. CD. IH revealed that MIP-2α protein was produced mainly by intestinal epithelial cells. Importantly, in histologically noninflamed/inactive IBD samples mRNAs for several mediators were significantly enhanced, accompanied by elevated levels of migration-inhibition factor related protein (MRP) 14 transcripts. CD14 positive macrophages were found especially in noninflamed/inactive UC, many of which coexpressed the RFD-7 antigen. Our results indicate a substantial overlap in cytokine/chemokine mRNA expression in UC and CD. Elevated mediator expression is evident in noninflamed/inactive areas in both diseases. Local recruitment of MRP-14 positive leukocytes might contribute to this phenomenon. In inactive UC a phenotypically altered population of macrophages expressing CD14 might play an additional role.

Improved vascular opacification in cerebral computed tomography angiography with 80 kVp

Purpose:We sought to intraindividually compare computed tomography angiographies (CTAs) acquired at 80 kVp and 120 kVp with respect to vessel contrast, noise level, and radiation dose. Material and Methods:CTA was performed on a single-slice CT scanner using tube voltages of 80 kVp and 120 kVp in 29 patients with arteriovenous malformations. Mean Hounsfield Units (HU) were evaluated for different vessels and brain parenchyma. To determine contrast-to-noise ratios (CNRs), noise levels were estimated from phantom measurements. Results:The calculated effective dose to male/female patients was 0.4/0.5 mSv for 80 kVp and 0.7/0.8 mSv for 120 kVp. CT density in blood vessels was between 297 and 458 HU for 80 kVp and 152 and 229 HU for 120 kVp (P < 0.0001). Despite an increased noise level in the low-voltage images, the CNR was 26–59% higher at 80 kVp than at 120 kVp (P < 0.05). Conclusion:The use of a reduced tube potential leads to improved CNR in CTA of the cerebral vasculature and a markedly reduced radiation exposure to patients.