Axel Gossmann

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme

To evaluate the effects of a neutralizing anti‐vascular endothelial growth factor (anti‐VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model.

Quantitative gadopentetate-enhanced MRI of breast tumors: Testing of different analytic methods

This study assessed several proposed imaging strategies and analytic methods based on gadopentetate‐enhanced MRI to differentiate benign from malignant breast tumors in a blinded experimental animal study. Steady‐state dynamic MRI and first‐pass imaging, performed with either T1‐ or T*2‐ weighted sequences, were compared. Semiquantitative and quantitative analysis methods, based on empirical measures of the data or physiological models, were subsequently applied to the imaging datasets. Comparative measures provided pathologic distinction of benign from malignant tumors, tumor grading, and histologic determination of microvascular density. Of the eight tested methods, only one, an estimate of first‐pass perfusion using T *2‐weighted imaging, showed an almost significant (P = 0.05) difference between benign and malignant tumors and correlated almost significantly (r = .3, P = 0.06) with the tumor grade. All other tests, performed either with steady‐state imaging or with T1‐weighted first‐pass imaging, failed to differentiate benign from malignant tumors. In addition, they yielded poor correlations with tumor grade and microvascular density. Magn Reson Med 44:915–924, 2000.

Comparison of Gadomer-17 and gadopentetate dimeglumine for differentiation of benign from malignant breast tumors with MR imaging.

RATIONALE AND OBJECTIVES This study compared gadopentetate dimeglumine (molecular weight, 0.5 kD), a standard contrast medium, and Gadomer-17 (apparent molecular weight, approximately 35 kD), a new, clinically applicable, large-molecular contrast medium, with respect to their microvascular characterizations of experimentally induced breast tumors at magnetic resonance (MR) imaging. MATERIALS AND METHODS A spectrum of breast tumors, benign through highly malignant, was induced in Sprague-Dawley rats (n = 30) by intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), a potent carcinogen. All animals underwent three-dimensional spoiled gradient-recalled MR imaging, with precontrast imaging and dynamic postcontrast imaging after injection of gadopentetate dimeglumine (0.1 mmol/kg) and Gadomer-17 (0.03 mmol/kg), administered in a random order at a 24-hour interval. Several microvascular parameters were compared: the endothelial transfer coefficient (K(PS)), a measure of microvascular permeability; the fractional plasma volume (fPV), and the plasma equivalent volume. Each MR imaging parameter was correlated with histopathologic findings. RESULTS With Gadomer-17, the mean values for K(PS) and fPV were significantly greater in carcinomas than in fibroadenomas (P < .004 and .04, respectively). With gadopentetate dimeglumine, the mean values for fPV and PEV were significantly greater in carcinomas (P <. 004 and .02, respectively). Because of the high variability within both fibroadenoma and carcinoma groups, however, there were no significant correlations between K(PS), fPV, or PEV and histopathologic tumor grade as indicated by the Scarff-Bloom-Richardson score, for either agent. CONCLUSION Although the K(PS) and fPV estimates obtained from dynamic MR imaging data with Gadomer-17 enhancement offer some potential for characterizing breast tumors, none of the quantitative microvascular parameters derived with either agent were significantly correlated with histopathologic tumor grade.

Effects of the Anti-VEGF Monoclonal Antibody Bevacizumab in a Preclinical Model and in Patients With Refractory and Multiple Relapsed Hodgkin Lymphoma

No curative treatment is currently available for refractory or relapsed Hodgkin lymphoma (HL) after high-dose chemotherapy. Thus, new drugs with different modes of action are needed. Vascular endothelial growth factor (VEGF), a key regulator of tumor-angiogenesis, is elevated in sera of patients with HL. Hodgkin and Reed-Sternberg cells also express the growth-stimulating VEGF-R2 receptor suggesting that VEGF could contribute to the pathophysiology of this malignancy. We investigated the effects of the humanized anti-VEGF monoclonal antibody bevacizumab (BV) against human HL xenografts in severe combined immune deficiency mice and in a compassionate use program in HL patients with multiple relapsed and progressive diseases. After a 4-week run-in phase of single agent BV, combined gemcitabine and BV therapy was administered. In the animal model, BV delayed the growth of HL tumors significantly (P=0.0004). Out of 5 patients included, BV alone had biologic effects as determined by tumor size, blood flow, fluorodeoxyglucose-uptake, and serum markers CCL17/thymus and activation-related chemokine, and sCD30 in 4 patients. The combination of BV and gemcitabine led to partial or complete remission in 3 of 5 patients. Accordingly, VEGF deprivation by the anti-VEGF antibody BV has antitumor activity in established HL tumors in a preclinical model. Furthermore, BV single agent therapy has biologic effects in HL patients indicating clinical activity. On the basis of these results, a prospective clinical study has been initiated to further investigate the impact of this antiangiogenic approach in HL.

Real-time MR-guided Wire Localization of Breast Lesions by Using an Open 1.0-T Imager: Initial Experience

The purpose of this study was to prospectively evaluate technique and time factors for real-time magnetic resonance (MR) imaging-guided wire localization of suspicious breast lesions by using an open 1.0-T MR imager. It was conducted with institutional review board approval; informed consent was given by patients. Needle placement was monitored in 30 women (mean age, 50.5 years; range, 28-70 years) by using a dynamic balanced gradient-echo (single-shot turbo field-echo [TFE]) sequence with a temporal resolution of 0.5 second. In all patients, the tip of the needle was clearly identified during placement. Consistent with balanced TFE (BTFE) imaging, diagnostic MR imaging after the interventional procedure confirmed that the hookwires were placed 0-6 mm (mean, 3.3 mm) from the target lesions. The total procedure time ranged from 16-36 minutes. Results show that real-time MR-guided wire localization permits correction of the needle position during placement and reduces the interventional procedure time.

Image Quality of Digital Direct Flat-Panel Mammography Versus an Analog Screen-Film Technique Using a Phantom Model

OBJECTIVE The objective of our study was to compare the detection and distinguishability of microcalcifications on mammograms obtained with a digital direct flat-panel detector versus an analog system using an anthropomorphic breast phantom. MATERIALS AND METHODS Studies were performed with a digital mammography system (Selenia) and an analog mammography system (Mammomat 3). Sixty-five transparent films were used as test specimens. Randomly distributed round and heterogeneous silicate particles (diameter, 100-1,400 microm) and an anthropomorphic scatter body were applied to the films. All radiographs were taken at identical settings and exposures. Six radiologists rated the films and monitor-displayed images independently of each other in random order on a standardized electronic questionnaire. RESULTS Interpretations based on monitor reading produced superior results over those based on digital image reading and analog film reading. In 41.1% (95% CI, 38.7-43.5%) of all the monitor readings, 20.2% (18.2-22.2%) of all digital images, and 19.6% (17.6-21.6%) of all analog films, the number of detectable microcalcifications agreed with the gold standard method. The diameter of visible microcalcifications was interpreted correctly in 35.6% (33.2-38.0%) of monitor readings, 19.0% (17.1-21.0%) of digital images, and 21.0% (18.9-23.0%) of analog films; and microcalcification shape was interpreted correctly in 53.8% (51.4-56.3%) of monitor readings, 28.2% (26.0-30.4%) of digital images, and 28.3% (26.0-30.5%) of analog films. Microcalcification number and size were underestimated more frequently than overestimated. Regardless of display medium, accuracy increased proportionately with the diameter of the simulated microcalcifications for all evaluation variables. CONCLUSION Digital flat-panel mammography is superior to the analog screen-film method for the detection and morphologic characterization of microcalcifications larger than 200 microm in diameter when the display medium is a monitor.

Comparison of Magnetic Resonance Imaging and Computed Tomography of 8 Aortic Stent-Graft Models

Purpose: To report the systematic comparison of magnetic resonance imaging (MRI) with contrast-enhanced computed tomography (CT) for evaluating 8 different aortic stent-graft models. Methods: MR angiography (MRA) was performed using a 1.5-T whole body system within 2 days of a CT examination (4 detector row scanner) on 8 patients with one of these stent-graft models: AneuRx, Endofit, PowerLink, Excluder, LifePath, Talent, Vanguard, or Zenith. Using a 4-point scale (maximum score 112 points), 4 independent readers (1 vascular surgeon and 3 radiologists) rated the impact of stent-related artifacts on the diagnostic quality of each imaging method for 28 parameters: length, diameter, collateral aortic side branches, stent-graft prostheses, and contrast. Each examiner also scored his personal diagnostic confidence with each stent-graft model. Results: The scores for diagnostic confidence in the CT imaging were 4 points for each stent-graft, with the exception of the LifePath (3 points). The diagnostic confidence in the MR images was mainly poor, with a median score of only 1; however, 3 stent-grafts (AneuRx, Excluder, and Vanguard) received ≥3 points. The total scores for comparative assessment were significantly different (p<0.05) between CT imaging (111.5) and MR (58.5). CT studies of all stent-grafts received > 101 points, while only 3 devices acquired >80 points (AneuRx, Excluder, and Vanguard). Bland-Altman analysis showed that the reliability of the 4 readers was higher using the CT method. The total assessment scores of the stent-graft systems were related only on the different imaging methods (p<0.0001) and not to the different readers (p=0.983). Conclusions: CT and MRI are fast, reliable means of providing all relevant information for stent-graft surveillance. Of 8 different stent-graft models, only 3 could be adequately assessed by MRA. Therefore, the potential advantages of the MR technique (e.g., use of minimally nephrotoxic contrast media, lack of ionizing radiation) are available only to a small proportion of patients.

Percutaneous Embolization for Cervicofacial Neoplasms and Hemorrhages

Objective: To retrospectively assess the effectiveness of percutaneous embolization for curative, preoperative or palliative management of hypervascular neoplasms, vascular malformations and bleedings of the head and neck area. Methods: A retrospective 8-year analysis of outcomes in 85 patients undergoing preoperative embolization for tumors or vascular lesions of the head and neck or embolization for refractory tumor bleeding and epistaxis at our hospitals was performed by reviewing case records. Outcome of the preoperatively embolized patients was defined as successful if intraoperative bleeding was <500 ml and/or postinterventional angiogram showed complete occlusion of all tumor-feeding or bleeding vessels. Results: Complete preoperative tumor embolization was achieved in 83.5% of the patients. Partial embolization was possible in 10.5%. All tumor bleedings refractory to conservative therapy and bleedings from epistaxis showed a successful outcome. Conclusions: In vascular lesions and tumors of the head and neck, preoperative percutaneous embolization improved the surgical outcome, reduced intraoperative blood loss significantly and facilitated tumor resectability. Cervicofacial bleeding resulting from a tumor, vascular malformation or epistaxis can be managed effectively by endovascular techniques.

Can a small-molecular gadolinium contrast agent be applied successfully with dynamic MRI to quantitatively define brain tumor microvascular responses to angiogenesis inhibition?

Currently, there are intensive efforts to identify and develop imaging methods to characterize and grade tumors with respect to angiogenesis. Angiogenesis is essential for tumor growth and metastases and is mediated by signaling molecules elaborated by tumors and tumor-associated inflammatory cells. Vascular endothelial growth factor (VEGF) is one of those angiogenic factors considered to play a key role in the vascularization of both normal and neoplastic tissue. VEGF is a potent and specific mitogen for endothelial cells and stimulates the full cascade of events required for angiogenesis. The VEGF polypeptide is simultaneously a vascular permeability factor (VPF) having been shown to increase the permeability of microvessels to macromolecular solutes, including serum proteins, with a potency approximating 50,000 times that of histamine. Reported studies have demonstrated that systemic administration of anti-VEGF monoclonal antibody can inhibit the growth of tumor xenografts, reduce the rate of tumor metastases, reduce overall tumor vascularity, and reduce the permeability to macromolecular solutes of tumor microvessels. However, the macromolecular permeability response to anti-VEGF antibody has been demonstrated in xenografts from tumor types arising outside the central nervous system (CNS). Similar observations may or may not extend to CNS tumors. Furthermore, the CNS has unique vascular characteristics resulting in a relatively impermeable brain/blood barrier, at least for normal neural tissue. Accordingly, macromolecular contrast media that might be well suited for estimating tumor hyperpermeability in non-neural tissues may not be necessary or well suited for CNS evaluations, and vice versa. If shown feasible in an orthotopic glial brain tumor model, the use of quantitative dynamic MRI enhanced using a small molecular gadolinium contrast agent could be applied immediately to clinical testing of antiangiogenesis drugs and to the routine evaluation of patients.

Macromolecular contrast media. A new approach for characterising breast tumors with MR-mammography

SummeryThe value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of “blood-pool“-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed.ZusammenfassungDiese Übersicht stellt den Stellenwert makromolekularer Kontrastmittel (MMKM) für die MR-tomographische Charakterisierung von benignen und malignen Mammatumoren dar. Aufgrund experimenteller Studien lassen MMKM eine signifikante Verbesserung der Spezifität der dynamischen kontrastmittelunterstützten MR-Mammographie erwarten. Das differentialdiagnostische Konzept beruht auf der pathologischen Hyperpermeabilität von Kapillaren in Karzinomen, die einen MMKM-Austritt in das Tumorinterstitium bedingt, während die intakten Kapillaren benigner Tumoren nicht permeabel für MMKM sind. Diagnostische Möglichkeiten und Grenzen des MMKM-Prototyps, Albumin-Gd-DTPA (92 kD), werden dargestellt und mit dem niedermolekularen Standard-Kontrastmittel Gd-DTPA (500 D) verglichen. Erste Erfahrungen mit neuen, für die klinische Anwendung optimierten MMKM-Präparaten, wie das Kaskadenpolymer, Gd-DTPA-Polylysine und das MS-325 werden vorgestellt. Das Potential von Blood-pool-Eisenoxidpräparaten, z. B. AMI-227, für die Bestimmung von Tumorkapillarpermeabilitäten wird diskutiert.