Clinical Focus

  • Diagnostic Radiology
  • Musculoskeletal Radiology
  • Body Imaging

Academic Appointments

Administrative Appointments

  • Co-chief, Division of Musculoskeletal Radiology, Department of Radiology, Stanford School of Medicine (2018 - 2022)

Honors & Awards

  • Poster Award “summa cum laude” (co-author), Swiss Society of Radiology (2003)
  • Top 50 papers, • European Society of Gastrointestinal Radiology (2004)
  • “Jubiläumspreis” (award for the young researcher of the year), • 91. General Assembly of the Swiss Society of Radiology (2004)
  • Postdoctoral Research Fellowship, Swiss National Science Foundation (2006)
  • Research Scholarship, Holcim Foundation, Switzerland (2006)
  • New Horizons Keynote Lecture “Cellular Imaging in Rheumatoid Arthritis”, ECR (2006)
  • Postdoctoral Research Fellowship, Swiss National Science Foundation (2007)
  • Bronze Award (co-author), European Society of Gastrointestinal Radiology (2008)
  • Scholar Award, Marsha Rivkin Center for Ovarian Cancer Research (2009)
  • GU Paper Presenter Award, Society of Abdominal Radiology (2013)

Professional Education

  • Fellowship: Stanford University Radiology Fellowships (2009) CA
  • Board Certification: FMH Swiss Medical Association, Diagnostic Radiology (2006)
  • Medical Education: Albert Ludwigs Universitaet Freiburg (1998) Germany
  • Fellowship: Kantonal Hospital Frauenfeld (2006) Switzerland
  • Residency: University Hospital of Zurich (2005) Switzerland
  • Internship: University Hospital Freiburg (2000) Germany

Current Research and Scholarly Interests

Molecular imaging in oncology
Peripheral Nerve Imaging
Cellular imaging of musculoskeletal inflammatory diseases
Kinematic musculoskeletal imaging
Magnetic resonance imaging of hepatic disorders

Clinical Trials

  • A Pilot Trial Using BR55 Ultrasound Contrast Agent in the Assessment of Prostate Cancer Not Recruiting

    Pilot study to evaluate the ability of BR55 to identify prostate cancer lesions with Gleason Score ≥7 by ultrasound molecular imaging on the basis of a visual score in comparison with histopathology results

    Stanford is currently not accepting patients for this trial. For more information, please contact Phuong Pham, 650-725-9810.

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  • BR55 in Characterization of Ovarian Lesions Not Recruiting

    This is an exploratory phase II, single center, open label, prospective study of BR55 CEUS for characterization of ovarian lesions in subjects with suspected ovarian cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Aya Kamaya, 650-723-8463.

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  • Combined F-18 NaF and F-18 FDG PET/CT for Evaluation of Malignancy Not Recruiting

    Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool for cancer detection and monitoring response to therapy. Sodium Fluorine-18 (F-18) was used in the 1970s for bone scanning and can be used as a skeletal tracer in current PET/CT scanners. The combined administration of F-18 and F-18 FDG in a single PET/CT scan for cancer detection was not attempted to date. We hope to learn what is the best approach for detection of cancer and thus to improve cancer treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrei Iagaru, 650-736-2859.

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  • Optimal Timing of BR55 CEUS of the Ovaries Not Recruiting

    This is an exploratory, single center, open label, prospective study of BR55 to determine the optimal phase of the menstrual cycle for performing BR55 CEUS of the target ovary in premenopausal women scheduled to undergo preventative surgery because of high familial/hereditary or genetic risk for ovarian cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amelie Lutz, MD, 650-498-2911.

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  • Photoacoustic Imaging in Detecting Ovarian or Fallopian Tube Cancer Not Recruiting

    This pilot clinical trial studies how well photoacoustic imaging works in detecting ovarian or fallopian tube cancer. Photoacoustic imaging is an imaging method that uses lasers to light up tissue, and then converts the light information into ultrasound images. Photoacoustic imaging can provide images of the structure of tissues, as well as their function and the levels of molecules, such as the flow of blood in blood vessels and the level of oxygen in the blood. Photoacoustic imaging may help doctors determine whether a mass is benign (non-cancerous) or cancerous based on the molecular differences between cancer and normal tissue. It may be more accurate and less expensive than other imaging methods, and does not expose patients to radiation.

    Stanford is currently not accepting patients for this trial.

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  • Pilot 3D Contrast-Enhanced Ultrasound Imaging to Predict Treatment Response in Liver Metastases Not Recruiting

    Patients are invited to participate in a research study of liver perfusion (how blood flows to the liver over time). Researchers hope to learn whether perfusion characteristics of liver metastases may be predictive of response to treatment and whether liver perfusion characteristics can be used to follow response to treatment. Patients were selected as a possible participant in this study because they are identified as having liver metastases

    Stanford is currently not accepting patients for this trial. For more information, please contact Risa Jiron, 650-736-1598.

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2023-24 Courses

All Publications

  • MRI-based Neuropathy Score Reporting And Data System (NS-RADS): multi-institutional wider-experience usability study of peripheral neuropathy conditions among 32 radiology readers. European radiology Chhabra, A., Duarte Silva, F., Mogharrabi, B., Guirguis, M., Ashikyan, O., Rasper, M., Park, E., Walter, S. S., Umpierrez, M., Pezeshk, P., Thurlow, P. C., Jagadale, A., Bajaj, G., Komarraju, A., Wu, J. S., Aguilera, A., Cardoso, F. N., Souza, F., Chaganti, S., Antil, N., Manzano, W., Stebner, A., Evers, J., Petterson, M., Geisbush, T., Downing, C., Christensen, D., Horneber, E., Kim, J. M., Purushothaman, R., Mohanan, S., Raichandani, S., Vilanilam, G., Cabrera, C., Manov, J., Maloney, S., Deshmukh, S. D., Lutz, A. M., Fritz, J., Andreisek, G., Chalian, M., Wong, P. K., Pandey, T., Subhawong, T., Xi, Y. 2024


    To determine the inter-reader reliability and diagnostic performance of classification and severity scales of Neuropathy Score Reporting And Data System (NS-RADS) among readers of differing experience levels after limited teaching of the scoring system.This is a multi-institutional, cross-sectional, retrospective study of MRI cases of proven peripheral neuropathy (PN) conditions. Thirty-two radiology readers with varying experience levels were recruited from different institutions. Each reader attended and received a structured presentation that described the NS-RADS classification system containing examples and reviewed published articles on this subject. The readers were then asked to perform NS-RADS scoring with recording of category, subcategory, and most likely diagnosis. Inter-reader agreements were evaluated by Conger's kappa and diagnostic accuracy was calculated for each reader as percent correct diagnosis. A linear mixed model was used to estimate and compare accuracy between trainees and attendings.Across all readers, agreement was good for NS-RADS category and moderate for subcategory. Inter-reader agreement of trainees was comparable to attendings (0.65 vs 0.65). Reader accuracy for attendings was 75% (95% CI 73%, 77%), slightly higher than for trainees (71% (69%, 72%), p = 0.0006) for nerves and comparable for muscles (attendings, 87.5% (95% CI 86.1-88.8%) and trainees, 86.6% (95% CI 85.2-87.9%), p = 0.4). NS-RADS accuracy was also higher than average accuracy for the most plausible diagnosis for attending radiologists at 67% (95% CI 63%, 71%) and for trainees at 65% (95% CI 60%, 69%) (p = 0.036).Non-expert radiologists interpreted PN conditions with good accuracy and moderate-to-good inter-reader reliability using the NS-RADS scoring system.The Neuropathy Score Reporting And Data System (NS-RADS) is an accurate and reliable MRI-based image scoring system for practical use for the diagnosis and grading of severity of peripheral neuromuscular disorders by both experienced and general radiologists.• The Neuropathy Score Reporting And Data System (NS-RADS) can be used effectively by non-expert radiologists to categorize peripheral neuropathy. • Across 32 different experience-level readers, the agreement was good for NS-RADS category and moderate for NS-RADS subcategory. • NS-RADS accuracy was higher than the average accuracy for the most plausible diagnosis for both attending radiologists and trainees (at 75%, 71% and 65%, 65%, respectively).

    View details for DOI 10.1007/s00330-023-10517-2

    View details for PubMedID 38244046

    View details for PubMedCentralID 4266395

  • In Vivo Ultrasound Molecular Imaging in the Evaluation of Complex Ovarian Masses: A Practical Guide to Correlation with Ex Vivo Immunohistochemistry. Advanced biology Antil, N., Wang, H., Kaffas, A. E., Desser, T. S., Folkins, A., Longacre, T., Berek, J., Lutz, A. M. 2023: e2300091


    Ovarian cancer is the fifth leading cause of cancer-related deaths in women and the most lethal gynecologic cancer. It is curable when discovered at an early stage, but usually remains asymptomatic until advanced stages. It is crucial to diagnose the disease before it metastasizes to distant organs for optimal patient management. Conventional transvaginal ultrasound imaging offers limited sensitivity and specificity in the ovarian cancer detection. With molecularly targeted ligands addressing targets, such as kinase insert domain receptor (KDR), attached to contrast microbubbles, ultrasound molecular imaging (USMI) can be used to detect, characterize and monitor ovarian cancer at a molecular level. In this article, the authors propose a standardized protocol is proposed for the accurate correlation between in- vivo transvaginal KDR-targeted USMI and ex vivo histology and immunohistochemistry in clinical translational studies. The detailed procedures of in vivo USMI and ex vivo immunohistochemistry are described for four molecular markers, CD31 and KDR with a focus on how to enable the accurate correlation between in vivo imaging findings and ex vivo expression of the molecular markers, even if not the entire tumor could can be imaged by USMI, which is not an uncommon scenario in clinical translational studies. This work aims to enhance the workflow and the accuracy of characterization of ovarian masses on transvaginal USMI using histology and immunohistochemistry as reference standards, which involves sonographers, radiologists, surgeons, and pathologists in a highly collaborative research effort of USMI in cancer.

    View details for DOI 10.1002/adbi.202300091

    View details for PubMedID 37403275

  • Patellar Tracking: An Old Problem with New Insights. Radiographics : a review publication of the Radiological Society of North America, Inc Watts, R. E., Gorbachova, T., Fritz, R. C., Saad, S. S., Lutz, A. M., Kim, J., Chaudhari, A. S., Shea, K. G., Sherman, S. L., Boutin, R. D. 2023; 43 (6): e220177


    Patellofemoral pain and instability are common indications for imaging that are encountered in everyday practice. The authors comprehensively review key aspects of patellofemoral instability pertinent to radiologists that can be seen before the onset of osteoarthritis, highlighting the anatomy, clinical evaluation, diagnostic imaging, and treatment. Regarding the anatomy, the medial patellofemoral ligament (MPFL) is the primary static soft-tissue restraint to lateral patellar displacement and is commonly reconstructed surgically in patients with MPFL dysfunction and patellar instability. Osteoarticular abnormalities that predispose individuals to patellar instability include patellar malalignment, trochlear dysplasia, and tibial tubercle lateralization. Clinically, patients with patellar instability may be divided into two broad groups with imaging findings that sometimes overlap: patients with a history of overt patellar instability after a traumatic event (eg, dislocation, subluxation) and patients without such a history. In terms of imaging, radiography is generally the initial examination of choice, and MRI is the most common cross-sectional examination performed preoperatively. For all imaging techniques, there has been a proliferation of published radiologic measurement methods. The authors summarize the most common validated measurements for patellar malalignment, trochlear dysplasia, and tibial tubercle lateralization. Given that static imaging is inherently limited in the evaluation of patellar motion, dynamic imaging with US, CT, or MRI may be requested by some surgeons. The primary treatment strategy for patellofemoral pain is conservative. Surgical treatment options include MPFL reconstruction with or without osseous corrections such as trochleoplasty and tibial tubercle osteotomy. Postoperative complications evaluated at imaging include patellar fracture, graft failure, graft malposition, and medial patellar subluxation. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

    View details for DOI 10.1148/rg.220177

    View details for PubMedID 37261964

  • Charachterization of spatially mapped volumetric molecular ultrasound signals for predicting response to anti-vascular therapy. Scientific reports Keller, C. A., Zarkesh, S., Zhou, J., Lutz, A. M., Hristov, D., Kamaya, A., El Kaffas, A. 2023; 13 (1): 1686


    Quantitative three-dimensional molecular ultrasound is a promising technology for longitudinal imaging applications such as therapy monitoring; the risk profile is favorable compared to positron emission tomography and computed tomography. However, clinical translation of quantitative methods for this technology are limited in that they assume that tumor tissues are homogeneous, and often depend on contrast-destruction events that can produce unintended bioeffects. Here, we develop quantitative features (henceforth image features) that capture tumor spatial information, and that are extracted without contrast destruction. We compare these techniques with the contrast-destruction derived differential targeted enhancement parameter (dTE) in predicting response to therapy. We found thirty-three reproducible image features that predict response to antiangiogenic therapy, without the need for a contrast agent disruption pulse. Multiparametric analysis shows that several of these image features can differentiate treated versus control animals with comparable performance to post-destruction measurements, suggesting that these can potentially replace parameters such as the dTE. The highest performing pre-destruction image features showed strong linear correlations with conventional dTE parameters with less overall variance. Thus, our study suggests that image features obtained during the wash in of the molecular agent, pre-destruction, may replace conventional post-destruction image features or the dTE parameter.

    View details for DOI 10.1038/s41598-022-26273-0

    View details for PubMedID 36717575

  • Interobserver agreement between eight observers using IOTA simple rules and O-RADS lexicon descriptors for adnexal masses. Abdominal radiology (New York) Antil, N., Raghu, P. R., Shen, L., Tiyarattanachai, T., Chang, E. M., Ferguson, C. W., Ho, A. A., Lutz, A. M., Mariano, A. J., Morimoto, L. N., Kamaya, A. 2022


    PURPOSE: To evaluate interobserver agreement in assigning imaging features and classifying adnexal masses using the IOTA simple rules versus O-RADS lexicon and identify causes of discrepancy.METHODS: Pelvic ultrasound (US) examinations in 114 women with 118 adnexal masses were evaluated by eight radiologists blinded to the final diagnosis (4 attendings and 4 fellows) using IOTA simple rules and O-RADS lexicon. Each feature category was analyzed for interobserver agreement using intraclass correlation coefficient (ICC) for ordinal variables and free marginal kappa for nominal variables. The two-tailed significance level (a) was set at 0.05.RESULTS: For IOTA simple rules, interobserver agreement was almost perfect for three malignant lesion categories (M2-4) and substantial for the remaining two (M1, M5) with k-values of 0.80-0.82 and 0.68-0.69, respectively. Interobserver agreement was almost perfect for two benign feature categories (B2, B3), substantial for two (B4, B5) and moderate for one (B1) with k-values of 0.81-0.90, 0.69-0.70 and 0.60, respectively. For O-RADS, interobserver agreement was almost perfect for two out of ten feature categories (ascites and peritoneal nodules) with k-values of 0.89 and 0.97. Interobserver agreement ranged from fair to substantial for the remaining eight feature categories with k-values of 0.39-0.61. Fellows and attendings had ICC values of 0.725 and 0.517, respectively.CONCLUSION: O-RADS had variable interobserver agreement with overall good agreement. IOTA simple rules had more uniform interobserver agreement with overall excellent agreement. Greater reader experience did not improve interobserver agreement with O-RADS.

    View details for DOI 10.1007/s00261-022-03580-8

    View details for PubMedID 35763052

  • Neuropathy Score Reporting and Data System (NS-RADS): MRI Reporting Guideline of Peripheral Neuropathy Explained and Reviewed. Skeletal radiology Chhabra, A., Deshmukh, S. D., Lutz, A. M., Fritz, J., Sneag, D. B., Mogharrabi, B., Guirguis, M., Andreisek, G., Xi, Y., Ahlawat, S. 2022


    A standardized guideline and scoring system should be used for the MR imaging diagnosis of peripheral neuropathy. The MR imaging-based Neuropathy Score Reporting and Data System (NS-RADS) is a newly devised classification system (in press in AJR) that can be used to communicate both type and severity of peripheral neuropathy in the light of clinical history and examination findings. The spectrum of neuropathic conditions and peripheral nerve disorders covered in this system includes nerve injury, entrapment, neoplasm, diffuse neuropathy, and post-interventional states. This classification system also describes the temporal MR imaging appearances of regional muscle denervation changes. This review article is based on the multicenter validation study pre-published in American journal of Roentgenology and discusses technical considerations of optimal MR imaging for peripheral nerve evaluation and discusses the NS-RADS classification and its severity scales with illustration of conditions that fall under each classification. The readers can gain knowledge of the NS-RADS classification system and learn to apply it in their practices for improved inter-disciplinary communications and timely patient management.

    View details for DOI 10.1007/s00256-022-04061-1

    View details for PubMedID 35478047

  • A robust 3D fast spin-echo technique for fast examination of the brachial plexus. Skeletal radiology Yoon, D., Antil, N., Biswal, S., Lutz, A. M. 2022


    To introduce a 3D fast spin-echo (FSE) sequence technique that may replace conventional clinical 2D FSE sequences for examining the brachial plexus.A 3D FSE sequence with motion-sensitized driven equilibrium magnitude preparation, triple-echo Dixon, and outer-volume suppression techniques, dubbed as MSDE-CUBE-fTED, was compared with clinical 2D T2-weighted and T1-weighted FSE sequences on the conventional brachial plexus exam of 14 volunteers. The resulting images were evaluated by two radiologists for fat suppression, blood flow suppression, nerve visualization, scalene muscle shape, surrounding fat planes, and diagnostic confidence. The inter-rater agreement of the reviewers was also measured. In addition, the signal magnitude ratios and contrast-to-noise ratios between nerve-to-vessel, nerve-to-muscle, and fat-to-muscle were compared.The MSDE-CUBE-fTED sequence scored significantly higher than the T2-weighed FSE sequence in all visualization categories (P < 0.05). Its score was not significantly different from that of the T1-weighted FSE in muscle and fat visualization (P ≥ 0.5). The inter-rater agreements were substantial (Gwet's agreement coefficient ≥ 0.7). The signal magnitude and contrast ratios were significantly higher in the MSDE-CUBE-fTED sequence (P < 0.05).Our results suggest that the MSDE-CUBE-fTED sequence can make a potential alternative to standard T2- and T1-weighted FSE sequences for examining the brachial plexus.

    View details for DOI 10.1007/s00256-022-04021-9

    View details for PubMedID 35347408

  • Contrast Enhanced Ultrasound Molecular Imaging of Spontaneous Chronic Inflammatory Bowel Disease in an Interleukin-2 Receptor alpha-/- Transgenic Mouse Model Using Targeted Microbubbles. Nanomaterials (Basel, Switzerland) Wang, H., Vilches-Moure, J. G., Bettinger, T., Cherkaoui, S., Lutz, A., Paulmurugan, R. 1800; 12 (2)


    Inflammatory bowel disease (IBD) is a lifelong inflammatory disorder with relapsing-remission cycles, which is currently diagnosed by clinical symptoms and signs, along with laboratory and imaging findings. However, such clinical findings are not parallel to the disease activity of IBD and are difficult to use in treatment monitoring. Therefore, non-invasive quantitative imaging tools are required for the multiple follow-up exams of IBD patients in order to monitor the disease activity and determine treatment regimens. In this study, we evaluated a dual P- and E-selectin-targeted microbubble (MBSelectin) in an interleukin-2 receptor alpha deficient (IL-2Ralpha-/-) spontaneous chronic IBD mouse model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI). We used IL-2Ralpha-/- (male and female on a C57BL/6 genetic background; n = 39) and C57BL/6 wild-type (negative control; n = 6) mice for the study. USMI of the proximal, middle, and distal colon was performed with MBSelectin using a small animal scanner (Vevo 2100) up to six times in each IL-2Ralpha-/- mouse between 6-30 weeks of age. USMI signals were compared between IL-2Ralpha-/- vs. wild-type mice, and sexes in three colonic locations. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E-stained sections and for selectin expression by immunofluorescence staining. We successfully detected spontaneous chronic colitis in IL-2Ralpha-/- mice between 6-30 weeks (onset at 6-14 weeks) compared to wild-type mice. Both male and female IL-2Ralpha-/- mice were equally (p = 0.996) affected with the disease, and there was no significant (p > 0.05) difference in USMI signals of colitis between the proximal, middle, and distal colon. We observed the fluctuating USMI signals in IL-2Ralpha-/- mice between 6-30 weeks, which might suggest a resemblance of the remission-flare pattern of human IBD. The ex vivo H&E and immunostaining further confirmed the inflammatory changes, and the high expression of P- and E-selectin in the colon. The results of this study highlight the IL-2Ralpha-/- mice as a chronic colitis model and are suitable for the long-term assessment of treatment response using a dual P- and E-selectin-targeted USMI.

    View details for DOI 10.3390/nano12020280

    View details for PubMedID 35055297

  • Automating Scoliosis Measurements in Radiographic Studies with Machine Learning: Comparing Artificial Intelligence and Clinical Reports. Journal of digital imaging Ha, A. Y., Do, B. H., Bartret, A. L., Fang, C. X., Hsiao, A., Lutz, A. M., Banerjee, I., Riley, G. M., Rubin, D. L., Stevens, K. J., Wang, E., Wang, S., Beaulieu, C. F., Hurt, B. 2022


    Scoliosis is a condition of abnormal lateral spinal curvature affecting an estimated 2 to 3% of the US population, or seven million people. The Cobb angle is the standard measurement of spinal curvature in scoliosis but is known to have high interobserver and intraobserver variability. Thus, the objective of this study was to build and validate a system for automatic quantitative evaluation of the Cobb angle and to compare AI generated and human reports in the clinical setting. After IRB was obtained, we retrospectively collected 2150 frontal view scoliosis radiographs at a tertiary referral center (January 1, 2019, to January 1, 2021, ≥ 16 years old, no hardware). The dataset was partitioned into 1505 train (70%), 215 validation (10%), and 430 test images (20%). All thoracic and lumbar vertebral bodies were segmented with bounding boxes, generating approximately 36,550 object annotations that were used to train a Faster R-CNN Resnet-101 object detection model. A controller algorithm was written to localize vertebral centroid coordinates and derive the Cobb properties (angle and endplate) of dominant and secondary curves. AI-derived Cobb angle measurements were compared to the clinical report measurements, and the Spearman rank-order demonstrated significant correlation (0.89, p < 0.001). Mean difference between AI and clinical report angle measurements was 7.34° (95% CI: 5.90-8.78°), which is similar to published literature (up to 10°). We demonstrate the feasibility of an AI system to automate measurement of level-by-level spinal angulation with performance comparable to radiologists.

    View details for DOI 10.1007/s10278-022-00595-x

    View details for PubMedID 35149938

  • Neuropathy Score Reporting and Data System: A Reporting Guideline for MRI of Peripheral Neuropathy With a Multicenter Validation Study. AJR. American journal of roentgenology Chhabra, A., Deshmukh, S. D., Lutz, A. M., Fritz, J., Andreisek, G., Sneag, D. B., Subhawong, T., Singer, A. D., Wong, P. K., Thakur, U., Pandey, T., Chalian, M., Mogharrabi, B., Guirguis, M., Xi, Y., Ahlawat, S. 2022


    Background: A standardized guideline and scoring system would improve evaluation and reporting of peripheral neuropathies on MRI. Objective: The objective of this study was to create and validate a neuropathy classification and grading system, which we named the Neuropathy Score Reporting and Data System (NS-RADS). Methods: This retrospective study included 100 patients with nerve imaging studies and known clinical diagnoses. Experts crafted NS-RADS using mutually agreed-upon qualitative criteria for the classification and grading of peripheral neuropathies. Different classes were created to account for the spectrum of underlying pathologies: unremarkable (U), injury (I), neoplasia (N), entrapment (E), diffuse neuropathy (D), not otherwise specified (NOS), and postintervention state (PI). Subclasses were established to describe the severity or extent of the lesions. Validation testing was performed by 11 readers from multiple institutions with experience levels ranging from 3 to 18 years after residency. After initial reader training, cases were presented to readers, who were blinded to final clinical diagnoses. Interobserver agreement was assessed using correlation coefficients and the Conger kappa, and accuracy testing was performed. Results: Final clinical diagnoses included normal (n = 5), nerve injury (n = 25), entrapment (n = 15), neoplasia (n = 33), diffuse neuropathy (n = 18), and persistent neuropathy after intervention (n = 4). The miscategorization rate for NS-RADS classes was 1.8%. Final diagnoses were correctly identified by readers in 71-88% of cases. Excellent interreader agreement was found on the NS-RADS pathology categorization (kappa = 0.96; 95% CI, 0.93-0.98) as well as muscle pathology categorization (kappa = 0.76; 95% CI, 0.68-0.82]. The accuracy for determining milder versus more severe categories per radiologist ranged from 88% to 97% for nerve lesions and from 86% to 94% for muscle abnormalities. Conclusion: The proposed NS-RADS classification is accurate and reliable across different reader experience levels and a spectrum of peripheral neuropathy conditions. Clinical Impact: NS-RADS can be used as a standardized guideline for reporting peripheral neuropathies and improved multidisciplinary communications.

    View details for DOI 10.2214/AJR.22.27422

    View details for PubMedID 35234483

  • Elbow Imaging: Variants and Asymptomatic Findings. Seminars in musculoskeletal radiology Antil, N., Stevens, K. J., Lutz, A. M. 2021; 25 (4): 546-557


    One of the key principles in the interpretation of radiology images is the ability to differentiate between normal and abnormal findings. This article provides a comprehensive overview of normal structures and anatomical variants occurring around the elbow including potential diagnostic pitfalls. We discuss frequently observed anatomical variants found in routine clinical practice associated with osseous, ligamentous, musculotendinous, and neurovascular structures at the elbow that may simulate pathology or predispose to symptoms under specific circumstances.

    View details for DOI 10.1055/s-0041-1729960

    View details for PubMedID 34706384

  • Using Dual-Energy CT for Painful Hip Arthroplasties. Radiology Lutz, A. M. 2021: 211272

    View details for DOI 10.1148/radiol.2021211272

    View details for PubMedID 34227889

  • Patient-Reported Outcomes and Knee Mechanics Correlate With Patellofemoral Deep Cartilage UTE-T2* 2 Years After Anterior Cruciate Ligament Reconstruction. The American journal of sports medicine Williams, A. A., Erhart-Hledik, J. C., Asay, J. L., Mahtani, G. B., Titchenal, M. R., Lutz, A. M., Andriacchi, T. P., Chu, C. R. 2021: 363546520982608


    Patellofemoral joint degeneration and dysfunction after anterior cruciate ligament reconstruction (ACLR) are increasingly recognized as contributors to poor clinical outcomes.To determine if greater deep cartilage matrix disruption at 2 years after ACLR, as assessed by elevated patellofemoral magnetic resonance imaging (MRI) ultrashort echo time-enhanced T2* (UTE-T2*), is correlated with (1) worse patient-reported knee function and pain and (2) gait metrics related to patellofemoral tracking and loading, such as greater external rotation of the tibia at heel strike, reduced knee flexion moment (as a surrogate of quadriceps function), and greater knee flexion angle at heel strike.Cross-sectional study; Level of evidence, 3.MRI UTE-T2* relaxation times in patellar and trochlear deep cartilage were compared with patient-reported outcomes and ambulatory gait metrics in 60 patients with ACLR at 2 years after reconstruction. ACLR gait metrics were compared with those of 60 uninjured reference patients matched by age, body mass index, and sex. ACLR UTE-T2* values were compared with those of 20 uninjured reference patients.Higher trochlear UTE-T2* values were associated with worse Knee injury and Osteoarthritis Outcome Scores (KOOS) Sport/Recreation subscale scores (rho = -0.32; P = .015), and showed a trend for association with worse KOOS Pain subscale scores (rho = -0.26; P = .045). At 2 years after ACLR, greater external rotation of the tibia at heel strike was associated with higher patellar UTE-T2* values (R = 0.40; P = .002); greater knee flexion angle at heel strike was associated with higher trochlear UTE-T2* values (rho = 0.39; P = .002); and greater knee flexion moment showed a trend for association with higher trochlear UTE-T2* values (rho = 0.30; P = .019). Patellar cartilage UTE-T2* values, knee flexion angle at heel strike, and external rotation of the tibia at heel strike were all elevated in ACLR knees as compared with reference knees (P = .029, .001, and .044, respectively).Patellofemoral deep cartilage matrix disruption, as assessed by MRI UTE-T2*, was associated with reduced sports and recreational function and with gait metrics reflective of altered patellofemoral loading. As such, the findings provide new mechanistic information important to improving clinical outcomes related to patellofemoral dysfunction after ACLR.

    View details for DOI 10.1177/0363546520982608

    View details for PubMedID 33507800

  • Characteristics of Patients With Complex Limb Pain Evaluated Through an Interdisciplinary Approach Utilizing Magnetic Resonance Neurography Frontiers in Pain Research Johnson, E. M., Yoon, D., Biswal, S., Curtin, C., Fox, P., Wilson, T. J., Carroll, I., Lutz, A., Tawfik, V. 2021
  • Toward the Clinical Development and Validation of a Thy1-Targeted Ultrasound Contrast Agent for the Early Detection of Pancreatic Ductal Adenocarcinoma. Investigative radiology Bam, R. n., Daryaei, I. n., Abou-Elkacem, L. n., Vilches-Moure, J. G., Meuillet, E. J., Lutz, A. n., Marinelli, E. R., Unger, E. C., Gambhir, S. S., Paulmurugan, R. n. 2020


    Early detection of pancreatic ductal adenocarcinoma (PDAC) represents the most significant step toward the treatment of this aggressive lethal disease. Previously, we engineered a preclinical Thy1-targeted microbubble (MBThy1) contrast agent that specifically recognizes Thy1 antigen overexpressed in the vasculature of murine PDAC tissues by ultrasound (US) imaging. In this study, we adopted a single-chain variable fragment (scFv) site-specific bioconjugation approach to construct clinically translatable MBThy1-scFv and test for its efficacy in vivo in murine PDAC imaging, and functionally evaluated the binding specificity of scFv ligand to human Thy1 in patient PDAC tissues ex vivo.We recombinantly expressed the Thy1-scFv with a carboxy-terminus cysteine residue to facilitate its thioether conjugation to the PEGylated MBs presenting with maleimide functional groups. After the scFv-MB conjugations, we tested binding activity of the MBThy1-scFv to MS1 cells overexpressing human Thy1 (MS1Thy1) under liquid shear stress conditions in vitro using a flow chamber setup at 0.6 mL/min flow rate, corresponding to a wall shear stress rate of 100 seconds, similar to that in tumor capillaries. For in vivo Thy1 US molecular imaging, MBThy1-scFv was tested in the transgenic mouse model (C57BL/6J - Pdx1-Cre; KRas; Ink4a/Arf) of PDAC and in control mice (C57BL/6J) with L-arginine-induced pancreatitis or normal pancreas. To facilitate its clinical feasibility, we further produced Thy1-scFv without the bacterial fusion tags and confirmed its recognition of human Thy1 in cell lines by flow cytometry and in patient PDAC frozen tissue sections of different clinical grades by immunofluorescence staining.Under shear stress flow conditions in vitro, MBThy1-scFv bound to MS1Thy1 cells at significantly higher numbers (3.0 ± 0.8 MB/cell; P < 0.01) compared with MBNontargeted (0.5 ± 0.5 MB/cell). In vivo, MBThy1-scFv (5.3 ± 1.9 arbitrary units [a.u.]) but not the MBNontargeted (1.2 ± 1.0 a.u.) produced high US molecular imaging signal (4.4-fold vs MBNontargeted; n = 8; P < 0.01) in the transgenic mice with spontaneous PDAC tumors (2-6 mm). Imaging signal from mice with L-arginine-induced pancreatitis (n = 8) or normal pancreas (n = 3) were not significantly different between the two MB constructs and were significantly lower than PDAC Thy1 molecular signal. Clinical-grade scFv conjugated to Alexa Fluor 647 dye recognized MS1Thy1 cells but not the parental wild-type cells as evaluated by flow cytometry. More importantly, scFv showed highly specific binding to VEGFR2-positive vasculature and fibroblast-like stromal components surrounding the ducts of human PDAC tissues as evaluated by confocal microscopy.Our findings summarize the development and validation of a clinically relevant Thy1-targeted US contrast agent for the early detection of human PDAC by US molecular imaging.

    View details for DOI 10.1097/RLI.0000000000000697

    View details for PubMedID 32569010

  • Ovarian Cancer - Current Status of Blood Biomarker and Imaging Screening Strategies Medical Research Archives Lutz, A., Antil, N. 2020; 8 (6)

    View details for DOI 10.18103/mra.v8i6.2116

  • Efficacy of affibody-based ultrasound molecular imaging of vascular B7-H3 for breast cancer detection. Clinical cancer research : an official journal of the American Association for Cancer Research Bam, R. n., Lown, P. S., Stern, L. A., Sharma, K. n., Wilson, K. E., Bean, G. R., Lutz, A. M., Paulmurugan, R. n., Hackel, B. J., Dahl, J. n., Abou-Elkacem, L. n. 2020


    Human B7-H3 (hB7-H3) is a promising molecular imaging target differentially expressed on the neovasculature of breast cancer and has been validated for pre-clinical ultrasound (US) imaging with anti-B7-H3-antibody functionalized microbubbles (MB). However, smaller ligands such as affibodies (ABY) are more suitable for the design of clinical-grade targeted-MB.Binding of ABYB7-H3 was confirmed with soluble and cell-surface B7-H3 by flow-cytometry. MB were functionalized with ABYB7-H3 or anti-B7-H3-antibody (AbB7-H3). Control and targeted-MB were tested for binding to hB7-H3-expressing cells (MS1hB7-H3) under shear stress conditions. US imaging was performed with MBABY-B7-H3 in an orthotopic mouse model of human MDA-MB-231 co-implanted with MS1hB7-H3 or control MS1WT cells and a transgenic mouse model of breast cancer development.ABYB7-H3 specifically binds to MS1hB7-H3 and murine-B7-H3-expressing monocytes. MBABY-B7-H3 (8.5 ± 1.4 MB/cell) and MBAb-B7-H3 (9.8 ± 1.3 MB/cell) showed significantly higher (p<0.0001) binding to the MS1hB7-H3 cells compared to control MBNon-targeted (0.5 ± 0.1 MB/cell) under shear stress conditions. In vivo, MBABY-B7-H3 produced significantly higher (p<0.04) imaging signal in orthotopic tumors co-engrafted with MS1hB7-H3 (8.4 ± 3.3 a.u.) compared to tumors with MS1WT cells (1.4 ± 1.0 a.u.). In the transgenic mouse tumors, MBABY-B7-H3 (9.6 ± 2.0 a.u.) produced higher (p<0.0002) imaging signal compared to MBNon-targeted (1.3 ± 0.3 a.u.), while MBABY-B7-H3 signal in normal mammary glands and tumors with B7-H3-blocking significantly reduced (p<0.02) imaging signal.MBABY-B7-H3 enhances B7-H3 molecular signal in breast tumors, improving cancer detection, while offering the advantages of a small size ligand and easier production for clinical imaging.

    View details for DOI 10.1158/1078-0432.CCR-19-1655

    View details for PubMedID 31924738

  • Do not forget the brachial plexus-prevalence of distal brachial plexus pathology on routine shoulder MRI. European radiology Antil, N. n., ElGuindy, Y. n., Lutz, A. M. 2020


    Most of the shoulder magnetic resonance imaging (MRI) examination focuses on internal joint structures but disregarding other structures like the distal brachial plexus, which may miss important findings. Hereby, we attempt to evaluate the prevalence of distal brachial plexus abnormalities and/or muscular denervation changes seen on routine shoulder MRI examinations and discuss common pathologies affecting the distal brachial plexus.A total of 701 routine shoulder MRI studies were evaluated. The evaluation of each exam was focused on the visualized brachial plexus elements and musculature abnormalities in each case. If any abnormalities of plexus and/or musculature were found, potential underlying etiologies such as paralabral or spinoglenoid notch cysts, infiltrative/primary masses on imaging, history of prior viral illness, and radiation therapy were searched. It was then confirmed whether the abnormal findings were mentioned in the exam reports or not.Thirty-four cases (4.85%) demonstrated abnormal findings of the visualized brachial plexus cords or branches and/or musculature. It was observed that in 35.3% of exam reports these findings were not mentioned, mainly missing subtle nerve abnormalities, but correctly reporting and interpreting the encountered muscle abnormalities.The distal brachial plexus and its branches should be included in the search pattern for shoulder MRI examinations.• Normal T2 signal of the brachial plexus is iso- to slightly hyperintense to muscle but less signal intense than fluid. • Diffuse, geographic muscle edema is an indirect sign of brachial plexus pathology. • Increased T2-weighted nerve signal with or without caliber or course change should be reported and followed up to find the underlying etiology.

    View details for DOI 10.1007/s00330-020-07476-3

    View details for PubMedID 33236205

  • The Stieda fracture revisited. Skeletal radiology Stevens, K. J., Albtoush, O. M., Lutz, A. M. 2020


    This study aimed to evaluate injury patterns associated with Stieda avulsion fractures of the medial femoral condyle at the attachment of the proximal MCL.Knee radiographs and MRI scans of 11 patients with Stieda fractures were evaluated by two fellowship-trained MSK radiologists for fracture origin, integrity of the deep and superficial components of the MCL, medial retinacular structures, posterior oblique ligament, other ligamentous injuries, meniscal tears, and osteochondral injuries. The mechanism of injury and subsequent clinical management were recorded.Eight Stieda fractures only involved the meniscofemoral fibers of the deep MCL, two larger Stieda fractures related to both superficial and deep layers, and one fracture only involved the superficial layer. Posteromedial retinacular structures and posterior oblique ligament were injured in all cases. Eight had high-grade ACL injuries, but none had high-grade PCL nor FCL injuries. The proximal anterolateral ligament was injured in seven, including two with associated Segond fractures. Other injuries included posterolateral corner injuries in six, meniscal injuries in seven, and additional fractures in nine, most commonly ACL-associated impaction fractures in the lateral tibiofemoral compartment. None had high-grade chondral injury. None of the Stieda fractures were treated surgically, but four underwent subsequent ACL reconstruction.Stieda fractures most commonly involved the deep fibers of the MCL and were accompanied by moderate-to-high-grade injury of other MCL components. There was a high association with other ligamentous injuries, particularly the posterior medial retinacular structures, posterior oblique ligament, and ACL, and many were associated with additional fractures.

    View details for DOI 10.1007/s00256-020-03645-z

    View details for PubMedID 33034705

  • Ultrasound and microbubble mediated therapeutic delivery: Underlying mechanisms and future outlook. Journal of controlled release : official journal of the Controlled Release Society Chowdhury, S. M., Abou-Elkacem, L. n., Lee, T. n., Dahl, J. n., Lutz, A. M. 2020


    Beyond the emerging field of oncological ultrasound molecular imaging, the recent significant advancements in ultrasound and contrast agent technology have paved the way for therapeutic ultrasound mediated microbubble oscillation and has shown that this approach is capable of increasing the permeability of microvessel walls while also initiating enhanced extravasation and drug delivery into target tissues. In addition, a large number of preclinical studies have demonstrated that ultrasound alone or combined with microbubbles can efficiently increase cell membrane permeability resulting in enhanced tissue distribution and intracellular drug delivery of molecules, nanoparticles, and other therapeutic agents. The mechanism behind the enhanced permeability is the temporary creation of pores in cell membranes through a phenomenon called sonoporation by high-intensity ultrasound and microbubbles or cavitation agents. At low ultrasound intensities (0.3-3 W/cm2), sonoporation may be caused by microbubbles oscillating in a stable motion, also known as stable cavitation. In contrast, at higher ultrasound intensities (greater than 3 W/cm2), sonoporation usually occurs through inertial cavitation that accompanies explosive growth and collapse of the microbubbles. Sonoporation has been shown to be a highly effective method to improve drug uptake through microbubble potentiated enhancement of microvascular permeability. In this review, the therapeutic strategy of using ultrasound for improved drug delivery are summarized with the special focus on cancer therapy. Additionally, we discuss the progress, challenges, and future of ultrasound-mediated drug delivery towards clinical translation.

    View details for DOI 10.1016/j.jconrel.2020.06.008

    View details for PubMedID 32554041

  • Chronic Model of Inflammatory Bowel Disease in IL-10(-/-) Transgenic Mice: Evaluation with Ultrasound Molecular Imaging THERANOSTICS Wang, H., Vilches-Moure, J. G., Cherkaoui, S., Tardy, I., Alleaume, C., Bettinger, T., Lutz, A., Paulmurugan, R. 2019; 9 (21): 6031–46

    View details for DOI 10.7150/thno.37397

    View details for Web of Science ID 000481603700001

  • Is it painful to be different? Sciatic nerve anatomical variants on MRI and their relationship to piriformis syndrome EUROPEAN RADIOLOGY Bartret, A. L., Beaulieu, C. F., Lutz, A. M. 2018; 28 (11): 4681–86
  • US Molecular Imaging of Acute Ileitis: Anti-Inflammatory Treatment Response Monitored with Targeted Microbubbles in a Preclinical Model RADIOLOGY Wang, H., Hyvelin, J., Felt, S. A., Guracar, I., Vilches-Moure, J. G., Cherkaoui, S., Bettinger, T., Tian, L., Lutz, A. M., Willmann, J. K. 2018; 289 (1): 90–100
  • Pharmacokinetic Modeling of Targeted Ultrasound Contrast Agents for Quantitative Assessment of Anti-Angiogenic Therapy: a Longitudinal Case-Control Study in Colon Cancer. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Turco, S., El Kaffas, A., Zhou, J., Lutz, A. M., Wijkstra, H., Willmann, J. K., Mischi, M. 2018


    PURPOSE: To evaluate quantitative and semi-quantitative ultrasound molecular imaging (USMI) for antiangiogenic therapy monitoring in human colon cancer xenografts in mice.PROCEDURES: Colon cancer was established in 17 mice by injection of LS174T (Nr=9) or CT26 (Nn=8) cancer cells to simulate clinical responders and non-responders, respectively. Antiangiogenic treatment (bevacizumab; Nrt=Nnt=5) or control treatment (saline; Nrc=4, Nnc=3) was administered at days 0, 3, and 7. Three-dimensional USMI was performed by injection at days 0, 1, 3, 7, and 10 of microbubbles targeted to the vascular endothelial growth factor receptor 2 (VEGFR2). Microbubble binding rate (kb), estimated by first-pass binding model fitting, and semi-quantitative parameters late enhancement (LE) and differential targeted enhancement (dTE) were compared at each day to evaluate their ability to assess and predict the response to therapy. Correlation analysis with the ex-vivo immunohistological quantification of VEGFR2 expression and the percentage blood vessel area was also performed.RESULTS: Significant changes in the USMI parameters during treatment were observed only in the responders treated with bevacizumab (p-value <0.05). Prediction of the response to therapy as early as 1day after treatment was achieved by the quantitative parameter kb (p-value <0.01), earlier than possible by tumor volume quantification. USMI parameters could significantly distinguish between clinical responders and non-responders (p-value <<0.01) and correlated well with the ex-vivo quantification of VEGFR2 expression and the percentage blood vessels area (p-value <<0.01).CONCLUSION: USMI (semi)quantitative parameters provide earlier assessment of the response to therapy compared to tumor volume, permit early prediction of non-responders, and correlate well with ex-vivo angiogenesis biomarkers.

    View details for DOI 10.1007/s11307-018-1274-z

    View details for PubMedID 30225758

  • Anatomical Road Mapping Using CT and MR Enterography for Ultrasound Molecular Imaging of Small Bowel Inflammation in Swine. European radiology Wang, H. n., Felt, S. A., Guracar, I. n., Taviani, V. n., Zhou, J. n., Sigrist, R. M., Zhang, H. n., Liau, J. n., Vilches-Moure, J. G., Tian, L. n., Saenz, Y. n., Bettinger, T. n., Hargreaves, B. A., Lutz, A. M., Willmann, J. K. 2018; 28 (5): 2068–76


    To evaluate the feasibility and time saving of fusing CT and MR enterography with ultrasound for ultrasound molecular imaging (USMI) of inflammation in an acute small bowel inflammation of swine.Nine swine with ileitis were scanned with either CT (n = 3) or MR (n = 6) enterography. Imaging times to load CT/MR images onto a clinical ultrasound machine, fuse them to ultrasound with an anatomical landmark-based approach, and identify ileitis were compared to the imaging times without anatomical road mapping. Inflammation was then assessed by USMI using dual selectin-targeted (MBSelectin) and control (MBControl) contrast agents in diseased and healthy control bowel segments, followed by ex vivo histology.Cross-sectional image fusion with ultrasound was feasible with an alignment error of 13.9 ± 9.7 mm. Anatomical road mapping significantly reduced (P < 0.001) scanning times by 40%. Localising ileitis was achieved within 1.0 min. Subsequently performed USMI demonstrated significantly (P < 0.001) higher imaging signal using MBSelectin compared to MBControl and histology confirmed a significantly higher inflammation score (P = 0.006) and P- and E-selectin expression (P ≤ 0.02) in inflamed vs. healthy bowel.Fusion of CT and MR enterography data sets with ultrasound in real time is feasible and allows rapid anatomical localisation of ileitis for subsequent quantification of inflammation using USMI.• Real-time fusion of CT/MRI with ultrasound to localise ileitis is feasible. • Anatomical road mapping using CT/MRI significantly decreases the scanning time for USMI. • USMI allows quantification of inflammation in swine, verified with ex vivo histology.

    View details for PubMedID 29170798

  • Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging ANGIOGENESIS Zhou, J., Zhang, H., Wang, H., Lutz, A. M., El Kaffas, A., Tian, L., Hristov, D., Willmann, J. K. 2017; 20 (4): 547–55


    Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment (P = 0.005), but not in CT26 tumors (P > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors (P < 0.001), but not in treated versus control CT26 tumors (P = 0.796). Early decrease in both PE and AUC by 45-50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes.

    View details for PubMedID 28721500

    View details for PubMedCentralID PMC5660665

  • Detection and prevalence of variant sciatic nerve anatomy in relation to the piriformis muscle on MRI SKELETAL RADIOLOGY Varenika, V., Lutz, A. M., Beaulieu, C. F., Bucknor, M. D. 2017; 46 (6): 751-757


    To determine whether known variant anatomical relationships between the sciatic nerve and piriformis muscle can be identified on routine MRI studies of the hip and to establish their imaging prevalence.Hip MRI studies acquired over a period of 4 years at two medical centers underwent retrospective interpretation. Anatomical relationship between the sciatic nerve and the piriformis muscle was categorized according to the Beaton and Anson classification system. The presence of a split sciatic nerve at the level of the ischial tuberosity was also recorded.A total of 755 consecutive scans were reviewed. Conventional anatomy (type I), in which an undivided sciatic nerve passes below the piriformis muscle, was identified in 87% of cases. The remaining 13% of cases demonstrated a type II pattern in which one division of the sciatic nerve passes through the piriformis whereas the second passes below. Only two other instances of variant anatomy were identified (both type III). Most variant cases were associated with a split sciatic nerve at the level of the ischial tuberosity (73 out of 111, 65.8%). By contrast, only 6% of cases demonstrated a split sciatic nerve at this level in the context of otherwise conventional anatomy.Anatomical variations of the sciatic nerve course in relation to the piriformis muscle are frequently identified on routine MRI of the hips, occurring in 12-20% of scans reviewed. Almost all variants identified were type II. The ability to recognize variant sciatic nerve courses on MRI may prove useful in optimal treatment planning.

    View details for DOI 10.1007/s00256-017-2597-6

    View details for Web of Science ID 000399447500004

    View details for PubMedID 28280851

  • A Model-Based Personalized Cancer Screening Strategy for Detecting Early-Stage Tumors Using Blood-Borne Biomarkers CANCER RESEARCH Hori, S. S., Lutz, A. M., Paulmurugan, R., Gambhir, S. S. 2017; 77 (10): 2570-2584


    An effective cancer blood biomarker screening strategy must distinguish aggressive from non-aggressive tumors at an early, intervenable time. However, for blood-based strategies to be useful, the quality and quantiy of the biomarker shed into the blood and its relationship to tumor growth or progression must be validated. To study how blood biomarker levels correlate with early-stage viable tumor growth in an mouse model of human cancer, we monitored early tumor growth of engineered human ovarian cancer cells (A2780) implanted orthotopically into nude mice. Biomarker shedding was monitored by serial blood sampling, while tumor viability and volume was monitored by bioluminescence imaging and ultrasound imaging. From these metrics we developed a mathematical model of cancer biomarker kinetics in different compartments that accounts for biomarker shedding from tumor and healthy cells, biomarker entry into vasculature, biomarker elimination from plasma and subject-specific tumor growth. We validated the model in a separate set of mice where subject-specific tumor growth rates were accurately predicted. To illustrate clinical translation of this strategy, we allometrically scaled model parameters from mouse to human and used parameters for PSA shedding and prostate cancer. In this manner, we found that blood biomarker sampling data alone was capable of enabling the detection and discrimination of simulated aggressive (2-month tumor doubling time) and non-aggressive (18-month tumor doubling time) tumors as early as 7.2 months and 8.9 years before clinical imaging, respectively. Our model and screening strategy offer broad impact in their applicability to any solid cancer and the biomarkers they shed, thereby allowing a distinction between aggressive vs. non-aggressive tumors using blood biomarker sampling data alone.

    View details for DOI 10.1158/0008-5472.CAN-16-2904

    View details for Web of Science ID 000401252900003

    View details for PubMedID 28283654

  • Ultrasound Molecular Imaging With BR55 in Patients With Breast and Ovarian Lesions: First-in-Human Results. Journal of clinical oncology Willmann, J. K., Bonomo, L., Carla Testa, A., Rinaldi, P., Rindi, G., Valluru, K. S., Petrone, G., Martini, M., Lutz, A. M., Gambhir, S. S. 2017: JCO2016708594-?


    Purpose We performed a first-in-human clinical trial on ultrasound molecular imaging (USMI) in patients with breast and ovarian lesions using a clinical-grade contrast agent (kinase insert domain receptor [KDR] -targeted contrast microbubble [MBKDR]) that is targeted at the KDR, one of the key regulators of neoangiogenesis in cancer. The aim of this study was to assess whether USMI using MBKDR is safe and allows assessment of KDR expression using immunohistochemistry (IHC) as the gold standard. Methods Twenty-four women (age 48 to 79 years) with focal ovarian lesions and 21 women (age 34 to 66 years) with focal breast lesions were injected intravenously with MBKDR (0.03 to 0.08 mL/kg of body weight), and USMI of the lesions was performed starting 5 minutes after injection up to 29 minutes. Blood pressure, ECG, oxygen levels, heart rate, CBC, and metabolic panel were obtained before and after MBKDR administration. Persistent focal MBKDR binding on USMI was assessed. Patients underwent surgical resection of the target lesions, and tissues were stained for CD31 and KDR by IHC. Results USMI with MBKDR was well tolerated by all patients without safety concerns. Among the 40 patients included in the analysis, KDR expression on IHC matched well with imaging signal on USMI in 93% of breast and 85% of ovarian malignant lesions. Strong KDR-targeted USMI signal was present in 77% of malignant ovarian lesions, with no targeted signal seen in 78% of benign ovarian lesions. Similarly, strong targeted signal was seen in 93% of malignant breast lesions with no targeted signal present in 67% of benign breast lesions. Conclusion USMI with MBKDR is clinically feasible and safe, and KDR-targeted USMI signal matches well with KDR expression on IHC. This study lays the foundation for a new field of clinical USMI in cancer.

    View details for DOI 10.1200/JCO.2016.70.8594

    View details for PubMedID 28291391

  • [Tumors of peripheral nerves]. Der Radiologe Ho, M., Lutz, A. M. 2017; 57 (3): 204-212


    Differentiation between malignant and benign tumors of peripheral nerves in the early stages is challenging; however, due to the unfavorable prognosis of malignant tumors early identification is required.To show the possibilities for detection, differential diagnosis and clinical management of peripheral nerve tumors by imaging appearance in magnetic resonance (MR) neurography.Review of current literature available in PubMed and MEDLINE, supplemented by the authors' own observations in clinical practice.Although not pathognomonic, several imaging features have been reported for a differentiation between distinct peripheral nerve tumors.The use of MR neurography enables detection and initial differential diagnosis in tumors of peripheral nerves. Furthermore, it plays an important role in clinical follow-up, targeted biopsy and surgical planning.

    View details for DOI 10.1007/s00117-017-0215-1

    View details for PubMedID 28188347

  • Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer. Radiology Wang, H., Lutz, A. M., Hristov, D., Tian, L., Willmann, J. K. 2017; 282 (2): 443-452


    Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction-replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. (©) RSNA, 2016 Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.2016160032

    View details for PubMedID 27490690

  • Feasibility of 7T MRI for Imaging Fascicular Structures of Peripheral Nerves. Muscle & nerve Yoon, D. n., Biswal, S. n., Rutt, B. n., Lutz, A. n., Hargreaves, B. n. 2017


    Evaluation of the nerve fascicular structure can be useful in diagnosing nerve damage, but it is a very challenging task with 3T MRI due to limited resolution. In this pilot study, we present the feasibility of high-resolution 7T MRI for examining the nerve fascicular structure.A 3D gradient-spoiled sequence was used for imaging peripheral nerves in extremities. Images acquired with different in-plane resolutions (0.42 x 0.42mm vs. 0.12 x 0.12mm), and different main field strengths (7T vs. 3T) were compared.The individual nerve fascicles were identified at 0.12 x 0.12mm resolution in both field strengths, but not at 0.42 x 0.42mm resolution. The fascicular structure was more sharply depicted in 7T images than in 3T images.High-resolution 3D imaging with 7T MRI demonstrated feasibility in imaging nerve fascicular structures. This article is protected by copyright. All rights reserved.

    View details for PubMedID 29211916

  • VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer. Cancer research Zhou, J., Wang, H., Zhang, H., Lutz, A. M., Tian, L., Hristov, D., Willmann, J. K. 2016; 76 (14): 4081-4089


    Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081-9. ©2016 AACR.

    View details for DOI 10.1158/0008-5472.CAN-15-3271

    View details for PubMedID 27206846

  • OVEREXERTION-RELATED FOCAL ULNAR NEUROPATHY MUSCLE & NERVE Muppidi, S., Orengo, J. P., Lutz, A. 2016; 53 (6): 989–91

    View details for DOI 10.1002/mus.25011

    View details for Web of Science ID 000379023200026

    View details for PubMedID 26663314

  • Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent RADIOLOGY Wang, H., Felt, S. A., Machtaler, S., Guracar, I., Luong, R., Bettinger, T., Tian, L., Lutz, A. M., Willmann, J. K. 2015; 276 (3): 809-817


    Purpose To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin-targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. Materials and Methods The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin-targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 10(8) MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. Results Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 10(8) MB/kg and plateaued between a dose of 10 and a dose of 20 × 10(8) MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). Conclusion Quantitative measurements of inflammation obtained by using dual-selectin-targeted US are reproducible and correlate well with the extent of inflammation at histologic examination in a porcine acute ileitis model as a next step toward clinical translation. (©) RSNA, 2015 Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.2015142478

    View details for PubMedID 25965901

  • Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging. Cancer research Bachawal, S. V., Jensen, K. C., Wilson, K. E., Tian, L., Lutz, A. M., Willmann, J. K. 2015; 75 (12): 2501-2509


    Ultrasound complements mammography as an imaging modality for breast cancer detection, especially in patients with dense breast tissue, but its utility is limited by low diagnostic accuracy. One emerging molecular tool to address this limitation involves contrast-enhanced ultrasound using microbubbles targeted to molecular signatures on tumor neovasculature. In this study, we illustrate how tumor vascular expression of B7-H3 (CD276), a member of the B7 family of ligands for T-cell coregulatory receptors, can be incorporated into an ultrasound method that can distinguish normal, benign, precursor, and malignant breast pathologies for diagnostic purposes. Through an IHC analysis of 248 human breast specimens, we found that vascular expression of B7-H3 was selectively and significantly higher in breast cancer tissues. B7-H3 immunostaining on blood vessels distinguished benign/precursors from malignant lesions with high diagnostic accuracy in human specimens. In a transgenic mouse model of cancer, the B7-H3-targeted ultrasound imaging signal was increased significantly in breast cancer tissues and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence. Our findings offer a preclinical proof of concept for the use of B7-H3-targeted ultrasound molecular imaging as a tool to improve the diagnostic accuracy of breast cancer detection in patients. Cancer Res; 75(12); 2501-9. ©2015 AACR.

    View details for DOI 10.1158/0008-5472.CAN-14-3361

    View details for PubMedID 25899053

    View details for PubMedCentralID PMC4470725

  • Detection of Osseous Metastasis by 18F-NaF/18F-FDG PET/CT Versus CT Alone. Clinical nuclear medicine Sampath, S. C., Sampath, S. C., Mosci, C., Lutz, A. M., Willmann, J. K., Mittra, E. S., Gambhir, S. S., Iagaru, A. 2015; 40 (3): e173-7


    Sodium fluoride PET (F-NaF) has recently reemerged as a valuable method for detection of osseous metastasis, with recent work highlighting the potential of coadministered F-NaF and F-FDG PET/CT in a single combined imaging examination. We further examined the potential of such combined examinations by comparing dual tracer F-NaF/F-FDG PET/CT with CT alone for detection of osseous metastasis.Seventy-five participants with biopsy-proven malignancy were consecutively enrolled from a single center and underwent combined F-NaF/F-FDG PET/CT and diagnostic CT scans. PET/CT as well as CT only images were reviewed in blinded fashion and compared with the results of clinical, imaging, or histological follow-up as a truth standard.Sensitivity of the combined F-NaF/F-FDG PET/CT was higher than that of CT alone (97.4% vs 66.7%). CT and F-NaF/F-FDG PET/CT were concordant in 73% of studies. Of 20 discordant cases, F-NaF/F-FDG PET/CT was correct in 19 (95%). Three cases were interpreted concordantly but incorrectly, and all 3 were false positives. A single case of osseous metastasis was detected by CT alone, but not by F-NaF/F-FDG PET/CT.Combined F-NaF/F-FDG PET/CT outperforms CT alone and is highly sensitive and specific for detection of osseous metastases. The concordantly interpreted false-positive cases demonstrate the difficulty of distinguishing degenerative from malignant disease, whereas the single case of metastasis seen on CT but not PET highlights the need for careful review of CT images in multimodality studies.

    View details for DOI 10.1097/RLU.0000000000000560

    View details for PubMedID 25140557

  • Correlation of plasma biomarker levels with early-stage tumor viability in an orthotopic ovarian cancer mouse model Hori, S. S., Lutz, A. M., Paulmurugan, R., Gambhir, S. S. AMER ASSOC CANCER RESEARCH. 2014
  • Ultrasound Molecular Imaging in a Human CD276 Expression-Modulated Murine Ovarian Cancer Model. Clinical cancer research Lutz, A. M., Bachawal, S. V., Drescher, C. W., Pysz, M. A., Willmann, J. K., Gambhir, S. S. 2014; 20 (5): 1313-1322


    To develop a mouse ovarian cancer model that allows modulating the expression levels of human vascular targets in mouse xenograft tumors and to test whether expression of CD276 during tumor angiogenesis can be visualized by molecularly targeted ultrasound in vivo.CD276-expressing MILE SVEN 1 (MS1) mouse endothelial cells were engineered and used for coinjection with 2008 human ovarian cancer cells for subcutaneous xenograft tumor induction in 15 nude mice. Fourteen control mice were injected with 2008 cells only. After confirming their binding specificity in flow chamber cell attachment studies, anti-CD276 antibody-functionalized contrast microbubbles were used for in vivo CD276-targeted contrast-enhanced ultrasound imaging.CD276-targeted ultrasound imaging signal was significantly higher (P = 0.006) in mixed MS1/2008 tumors than in control tumors. Compared with control microbubbles, the ultrasound signal using CD276-targeted microbubbles was significantly higher (P = 0.002), and blocking with purified anti-CD276 antibody significantly decreased (P = 0.0096) the signal in mixed MS1/2008 tumors. Immunofluorescence analysis of the tumor tissue confirmed higher quantitative immunofluorescence signal in mixed MS1/2008 tumors than in control 2008 only tumors, but showed not significantly different (P = 0.54) microvessel density.Our novel small animal model allows for modulating the expression of human tumor-associated vascular endothelial imaging targets in a mouse host and these expression differences can be visualized noninvasively by ultrasound molecular imaging. The animal model can be applied to other human vascular targets and may facilitate the preclinical development of new imaging probes such as microbubbles targeted at human vascular markers not expressed in mice. Clin Cancer Res; 20(5); 1313-22. ©2014 AACR.

    View details for DOI 10.1158/1078-0432.CCR-13-1642

    View details for PubMedID 24389327

    View details for PubMedCentralID PMC3965293

  • MR imaging of the brachial plexus. Neuroimaging clinics of North America Lutz, A. M., Gold, G., Beaulieu, C. 2014; 24 (1): 91-108


    Continuous improvements in magnetic resonance scanner, coil, and pulse sequence technology have resulted in the ability to perform routine, high-quality imaging of the brachial plexus. With knowledge of the anatomy of the plexus, and a familiarity with common pathologic conditions affecting this area, radiologists can provide valuable imaging evaluation of patients with brachial plexus pathologies.

    View details for DOI 10.1016/j.nic.2013.03.024

    View details for PubMedID 24210315

  • Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology Foygel, K., Wang, H., Machtaler, S., Lutz, A. M., Chen, R., Pysz, M., Lowe, A. W., Tian, L., Carrigan, T., Brentnall, T. A., Willmann, J. K. 2013; 145 (4): 885-894 e3


    Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.

    View details for DOI 10.1053/j.gastro.2013.06.011

    View details for PubMedID 23791701

  • Molecular Imaging of Inflammation in Inflammatory Bowel Disease with a Clinically Translatable Dual-Selectin-targeted US Contrast Agent: Comparison with FDG PET/CT in a Mouse Model. Radiology Wang, H., Machtaler, S., Bettinger, T., Lutz, A. M., Luong, R., Bussat, P., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 267 (3): 818-829


    Purpose: To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model. Materials and Methods: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis. Results: MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ≤ .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (ρ = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014). Conclusion: US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging. © RSNA, 2013 Supplemental material:

    View details for DOI 10.1148/radiol.13122509

    View details for PubMedID 23371306

  • Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model CANCER RESEARCH Bachawal, S. V., Jensen, K. C., Lutz, A. M., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 73 (6): 1689-1698


    While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MB(VEGFR2)) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MB(VEGFR2) than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R(2) = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women.

    View details for DOI 10.1158/0008-5472.CAN-12-3391

    View details for Web of Science ID 000316187500006

    View details for PubMedID 23328585

    View details for PubMedCentralID PMC3602408

  • Antiangiogenic and Radiation Therapy Early Effects on In Vivo Computed Tomography Perfusion Parameters in Human Colon Cancer Xenografts in Mice INVESTIGATIVE RADIOLOGY Ren, Y., Fleischmann, D., Foygel, K., Molvin, L., Lutz, A. M., Koong, A. C., Jeffrey, R. B., Tian, L., Willmann, J. K. 2012; 47 (1): 25-32


    To assess early treatment effects on computed tomography (CT) perfusion parameters after antiangiogenic and radiation therapy in subcutaneously implanted, human colon cancer xenografts in mice and to correlate in vivo CT perfusion parameters with ex vivo assays of tumor vascularity and hypoxia.Dynamic contrast-enhanced CT (perfusion CT, 129 mAs, 80 kV, 12 slices × 2.4 mm; 150 μL iodinated contrast agent injected at a rate of 1 mL/min intravenously) was performed in 100 subcutaneous human colon cancer xenografts on baseline day 0. Mice in group 1 (n=32) received a single dose of the antiangiogenic agent bevacizumab (10 mg/kg body weight), mice in group 2 (n=32) underwent a single radiation treatment (12 Gy), and mice in group 3 (n=32) remained untreated. On days 1, 3, 5, and 7 after treatment, 8 mice from each group underwent a second CT perfusion scan, respectively, after which tumors were excised for ex vivo analysis. Four mice were killed after baseline scanning on day 0 for ex vivo analysis. Blood flow (BF), blood volume (BV), and flow extraction product were calculated using the left ventricle as an arterial input function. Correlation of in vivo CT perfusion parameters with ex vivo microvessel density and extent of tumor hypoxia were assessed by immunofluorescence. Reproducibility of CT perfusion parameter measurements was calculated in an additional 8 tumor-bearing mice scanned twice within 5 hours with the same CT perfusion imaging protocol.The intraclass correlation coefficients for BF, BV, and flow extraction product from repeated CT perfusion scans were 0.93 (95% confidence interval: 0.78, 0.97), 0.88 (0.66, 0.95), and 0.88 (0.56, 0.95), respectively. Changes in perfusion parameters and tumor volumes over time were different between treatments. After bevacizumab treatment, all 3 perfusion parameters significantly decreased from day 1 (P ≤ 0.006) and remained significantly decreased until day 7 (P ≤ 0.008); tumor volume increased significantly only on day 7 (P=0.04). After radiation treatment, all 3 perfusion parameters decreased significantly on day 1 (P < 0.001); BF and flow extraction product increased again on day 3 and 5, although without reaching statistically significant difference; and tumor volumes did not change significantly at all time points (P ≥ 0.3). In the control group, all 3 perfusion parameters did not change significantly, whereas tumor volume increased significantly at all the time points, compared with baseline (P ≤ 0.04). Ex vivo immunofluorescent staining showed good correlation between all 3 perfusion parameters and microvessel density (ρ=0.71, 0.66, and 0.69 for BF, BV, and flow extraction product, respectively; P < 0.001). There was a trend toward negative correlation between extent of hypoxia and all 3 perfusion parameters (ρ=-0.53, -0.47, and -0.40 for BF, BV, and flow extraction product, respectively; P ≥ 0.05).CT perfusion allows a reproducible, noninvasive assessment of tumor vascularity in human colon cancer xenografts in mice. After antiangiogenic and radiation therapy, BF, BV, and flow extraction product significantly decrease and change faster than the tumor volume.

    View details for DOI 10.1097/RLI.0b013e31823a82f6

    View details for Web of Science ID 000298400100006

    View details for PubMedID 22178893

  • Quantification and Monitoring of Inflammation in Murine Inflammatory Bowel Disease with Targeted Contrast-enhanced US RADIOLOGY Deshpande, N., Lutz, A. M., Ren, Y., Foygel, K., Tian, L., Schneider, M., Pai, R., Pasricha, P. J., Willmann, J. K. 2012; 262 (1): 172-180


    To evaluate ultrasonography (US) by using contrast agent microbubbles (MBs) targeted to P-selectin (MB(P-selectin)) to quantify P-selectin expression levels in inflamed tissue and to monitor response to therapy in a murine model of chemically induced inflammatory bowel disease (IBD).All procedures in which laboratory animals were used were approved by the institutional administrative panel on laboratory animal care. Binding affinity and specificity of MB(P-selectin) were tested in cell culture experiments under flow shear stress conditions and compared with control MBs (MB(Control)). In vivo binding specificity of MB(P-selectin) to P-selectin was tested in mice with trinitrobenzenesulfonic acid-induced colitis (n = 22) and control mice (n = 10). Monitoring of anti-tumor necrosis factor α antibody therapy was performed over 5 days in an additional 30 mice with colitis by using P-selectin-targeted US imaging, by measuring bowel wall thickness and perfusion, and by using a clinical disease activity index score. In vivo targeted contrast material-enhanced US signal was quantitatively correlated with ex vivo expression levels of P-selectin as assessed by quantitative immunofluorescence.Attachment of MB(P-selectin) to endothelial cells was significantly (P = .0001) higher than attachment of MB(Control) and significantly (ρ = 0.83, P = .04) correlated with expression levels of P-selectin on endothelial cells. In vivo US signal in mice with colitis was significantly higher (P = .0001) with MB(P-selectin) than with MB(Control). In treated mice, in vivo US signal decreased significantly (P = .0001) compared with that in nontreated mice and correlated well with ex vivo P-selectin expression levels (ρ = 0.69; P = .04). Colonic wall thickness (P ≥ .06), bowel wall perfusion (P ≥ .85), and clinical disease activity scoring (P ≥ .06) were not significantly different between treated and nontreated mice at any time.Targeted contrast-enhanced US imaging enables noninvasive in vivo quantification and monitoring of P-selectin expression in inflammation in murine IBD.

    View details for DOI 10.1148/radiol.11110323

    View details for Web of Science ID 000298611500021

    View details for PubMedID 22056689

    View details for PubMedCentralID PMC3244669

  • Early Diagnosis of Ovarian Carcinoma: Is a Solution in Sight? RADIOLOGY Lutz, A. M., Willmann, J. K., Drescher, C. W., Ray, P., Cochran, F. V., Urban, N., Gambhir, S. S. 2011; 259 (2): 329-345


    Ovarian cancer is the most lethal of the gynecologic malignancies. Because ovarian cancer symptoms are subtle and nonspecific, the diagnosis is often delayed until the disease is well advanced. Overall 5-year survival is a rather dismal 50% but can be improved to greater than 90% if the disease is confined to the ovary at the time of diagnosis (generally in fewer than 25% of patients). Effective screening tools are currently not available. Owing to the rather low incidence of the disease in the general population, potential screening tests must provide very high specificity to avoid unnecessary interventions in false-positive cases. This article reviews currently available serum biomarkers and imaging tests for the early detection of ovarian cancer and provides an outlook on the potential improvements in these noninvasive diagnostic tools that may lead to successful implementation in a screening program. Supplemental material:

    View details for DOI 10.1148/radiol.11090563

    View details for Web of Science ID 000289667300006

    View details for PubMedID 21502390

  • Targeted Contrast-Enhanced Ultrasound Imaging of Tumor Angiogenesis with Contrast Microbubbles Conjugated to Integrin-Binding Knottin Peptides JOURNAL OF NUCLEAR MEDICINE Willmann, J. K., Kimura, R. H., Deshpande, N., Lutz, A. M., Cochran, J. R., Gambhir, S. S. 2010; 51 (3): 433-440


    Targeted contrast-enhanced ultrasound imaging is increasingly being recognized as a powerful imaging tool for the detection and quantification of tumor angiogenesis at the molecular level. The purpose of this study was to develop and test a new class of targeting ligands for targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with small, conformationally constrained peptides that can be coupled to the surface of ultrasound contrast agents.Directed evolution was used to engineer a small, disulfide-constrained cystine knot (knottin) peptide that bound to alpha(v)beta(3) integrins with a low nanomolar affinity (Knottin(Integrin)). A targeted contrast-enhanced ultrasound imaging contrast agent was created by attaching Knottin(Integrin) to the shell of perfluorocarbon-filled microbubbles (MB-Knottin(Integrin)). A knottin peptide with a scrambled sequence was used to create control microbubbles (MB-Knottin(Scrambled)). The binding of MB-Knottin(Integrin) and MB-Knottin(Scrambled) to alpha(v)beta(3) integrin-positive cells and control cells was assessed in cell culture binding experiments and compared with that of microbubbles coupled to an anti-alpha(v)beta(3) integrin monoclonal antibody (MB(alphavbeta3)) and microbubbles coupled to the peptidomimetic agent c(RGDfK) (MB(cRGD)). The in vivo imaging signals of contrast-enhanced ultrasound with the different types of microbubbles were quantified in 42 mice bearing human ovarian adenocarcinoma xenograft tumors by use of a high-resolution 40-MHz ultrasound system.MB-Knottin(Integrin) attached significantly more to alpha(v)beta(3) integrin-positive cells (1.76 +/- 0.49 [mean +/- SD] microbubbles per cell) than to control cells (0.07 +/- 0.006). Control MB-Knottin(Scrambled) adhered less to alpha(v)beta(3) integrin-positive cells (0.15 +/- 0.12) than MB-Knottin(Integrin). After blocking of integrins, the attachment of MB-Knottin(Integrin) to alpha(v)beta(3) integrin-positive cells decreased significantly. The in vivo ultrasound imaging signal was significantly higher after the administration of MB-Knottin(Integrin) than after the administration of MB(alphavbeta3) or control MB-Knottin(Scrambled). After in vivo blocking of integrin receptors, the imaging signal after the administration of MB-Knottin(Integrin) decreased significantly (by 64%). The imaging signals after the administration of MB-Knottin(Integrin) were not significantly different in the groups of tumor-bearing mice imaged with MB-Knottin(Integrin) and with MB(cRGD). Ex vivo immunofluorescence confirmed integrin expression on endothelial cells of human ovarian adenocarcinoma xenograft tumors.Integrin-binding knottin peptides can be conjugated to the surface of microbubbles and used for in vivo targeted contrast-enhanced ultrasound imaging of tumor angiogenesis. Our results demonstrate that microbubbles conjugated to small peptide-targeting ligands provide imaging signals higher than those provided by a large antibody molecule.

    View details for DOI 10.2967/jnumed.109.068007

    View details for Web of Science ID 000275133100026

    View details for PubMedID 20150258

  • Focal Liver Lesions: Detection and Characterization at Double-Contrast Liver MR Imaging with Ferucarbotran and Gadobutrol versus Single-Contrast Liver MR Imaging RADIOLOGY Heilmaier, C., Lutz, A. M., Bolog, N., Weishaupt, D., Seifert, B., Willmann, J. K. 2009; 253 (3): 724-733


    To retrospectively compare, in a multiobserver study, double-contrast-material (sequential administration of ferucarbotran and gadobutrol) magnetic resonance (MR) imaging with single-contrast-material ferucarbotran-enhanced and dynamic postferucarbotran gadobutrol-enhanced MR imaging for the detection and characterization of benign and malignant focal liver lesions.This study was institutional review board approved, and the requirement for informed patient consent was waived. Eighty-nine patients with a total of 128 focal liver lesions underwent double-contrast liver MR imaging (nonenhanced, ferucarbotran-enhanced, and dynamic postferucarbotran gadobutrol-enhanced MR imaging performed during one session). Four readers independently reviewed the data sets during three reading sessions focused on focal liver lesion detection and characterization: In session 1, the nonenhanced and dynamic postferucarbotran gadobutrol-enhanced images obtained at double-contrast MR imaging were analyzed. In session 2, the nonenhanced and ferucarbotran-enhanced images were analyzed. In session 3, all MR images were analyzed together. The diagnostic performance of each MR technique and each reader was evaluated by using receiver operating characteristic (ROC) analysis; differences between postferucarbotran gadobutrol-enhanced, ferucarbotran-enhanced, and double-contrast MR imaging were assessed at Wilcoxon signed rank testing; and interreader agreement was assessed at Cohen kappa analysis. Histopathologic confirmation or an unchanged clinical course or MR finding was the reference standard.The four readers' detection of the benign and malignant lesions was not significantly different (P > or = .11) between the three MR techniques. The benign and malignant focal liver lesions were differentiated with significantly higher confidence (P < or = .01) on the double-contrast (area under ROC curve [A(z)] = 0.988) and ferucarbotran-enhanced (A(z) = 0.985) MR images than on the dynamic gadobutrol-enhanced images (A(z) = 0.963). Accuracy in the diagnosis of hepatocellular carcinoma (HCC) was highest (P = .02) and confidence in the final diagnosis of HCC (P = .001) or metastasis (P = .049) was significantly higher with double-contrast imaging.In select cases, double-contrast MR imaging can improve diagnostic accuracy and increase confidence in characterizing focal liver lesions as HCC or metastasis.

    View details for DOI 10.1148/radiol.2533090161

    View details for Web of Science ID 000272247300019

    View details for PubMedID 19789232

  • MR angiography with parallel acquisition for assessment of the visceral arteries: comparison with conventional MR angiography and 64-detector-row computed tomography EUROPEAN RADIOLOGY Sutter, R., Heilmaier, C., Lutz, A. M., Weishaupt, D., Seifert, B., Willmann, J. K. 2009; 19 (11): 2679-2688


    The purpose of the study was to retrospectively compare three-dimensional gadolinium-enhanced magnetic resonance angiography (conventional MRA) with MRA accelerated by a parallel acquisition technique (fast MRA) for the assessment of visceral arteries, using 64-detector-row computed tomography angiography (MDCTA) as the reference standard. Eighteen patients underwent fast MRA (imaging time 17 s), conventional MRA (29 s) and MDCTA of the abdomen and pelvis. Two independent readers assessed subjective image quality and the presence of arterial stenosis. Data were analysed on per-patient and per-segment bases. Fast MRA yielded better subjective image quality in all segments compared with conventional MRA (P = 0.012 for reader 1, P = 0.055 for reader 2) because of fewer motion-induced artefacts. Sensitivity and specificity of fast MRA for the detection of arterial stenosis were 100% for both readers. Sensitivity of conventional MRA was 89% for both readers, and specificity was 100% (reader 1) and 99% (reader 2). Differences in sensitivity between the two types of MRA were not significant for either reader. Interobserver agreement for the detection of arterial stenosis was excellent for fast (kappa = 1.00) and good for conventional MRA (kappa = 0.76). Thus, subjective image quality of visceral arteries remains good on fast MRA compared with conventional MRA, and the two techniques do not differ substantially in the grading of arterial stenosis, despite the markedly reduced acquisition time of fast MRA.

    View details for DOI 10.1007/s00330-009-1473-8

    View details for Web of Science ID 000270838000016

    View details for PubMedID 19526242

  • Imaging Gene Expression in Human Mesenchymal Stem Cells: From Small to Large Animals RADIOLOGY Willmann, J. K., Paulmurugan, R., Rodriguez-Porcel, M., Stein, W., Brinton, T. J., Connolly, A. J., Nielsen, C. H., Lutz, A. M., Lyons, J., Ikeno, F., Suzuki, Y., Rosenberg, J., Chen, I. Y., Wu, J. C., Yeung, A. C., Yock, P., Robbins, R. C., Gambhir, S. S. 2009; 252 (1): 117-127


    To evaluate the feasibility of reporter gene imaging in implanted human mesenchymal stem cells (MSCs) in porcine myocardium by using clinical positron emission tomography (PET)-computed tomography (CT) scanning.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Transduction of human MSCs by using different doses of adenovirus that contained a cytomegalovirus (CMV) promoter driving the mutant herpes simplex virus type 1 thymidine kinase reporter gene (Ad-CMV-HSV1-sr39tk) was characterized in a cell culture. A total of 2.25 x 10(6) transduced (n = 5) and control nontransduced (n = 5) human MSCs were injected into the myocardium of 10 rats, and reporter gene expression in human MSCs was visualized with micro-PET by using the radiotracer 9-(4-[fluorine 18]-fluoro-3-hydroxymethylbutyl)-guanine (FHBG). Different numbers of transduced human MSCs suspended in either phosphate-buffered saline (PBS) (n = 4) or matrigel (n = 5) were injected into the myocardium of nine swine, and gene expression was visualized with a clinical PET-CT. For analysis of cell culture experiments, linear regression analyses combined with a t test were performed. To test differences in radiotracer uptake between injected and remote myocardium in both rats and swine, one-sided paired Wilcoxon tests were performed. In swine experiments, a linear regression of radiotracer uptake ratio on the number of injected transduced human MSCs was performed.In cell culture, there was a viral dose-dependent increase of gene expression and FHBG accumulation in human MSCs. Human MSC viability was 96.7% (multiplicity of infection, 250). Cardiac FHBG uptake in rats was significantly elevated (P < .0001) after human MSC injection (0.0054% injected dose [ID]/g +/- 0.0007 [standard deviation]) compared with that in the remote myocardium (0.0003% ID/g +/- 0.0001). In swine, myocardial radiotracer uptake was not elevated after injection of up to 100 x 10(6) human MSCs (PBS group). In the matrigel group, signal-to-background ratio increased to 1.87 after injection of 100 x 10(6) human MSCs and positively correlated (R(2) = 0.97, P < .001) with the number of administered human MSCs.Reporter gene imaging in human MSCs can be translated to large animals. The study highlights the importance of co-administering a "scaffold" for increasing intramyocardial retention of human MSCs.

    View details for DOI 10.1148/radiol.2513081616

    View details for Web of Science ID 000268362900015

    View details for PubMedID 19366903

    View details for PubMedCentralID PMC2702468

  • USPIO-enhanced magnetic resonance imaging of the knee in asymptomatic volunteers EUROPEAN RADIOLOGY Reiner, C. S., Lutz, A. M., Tschirch, F., Froehlich, J. M., Gaillard, S., Marincek, B., Weishaupt, D. 2009; 19 (7): 1715-1722


    The aim of this study was to compare signal characteristics of the synovium in knees of asymptomatic volunteers before and after intravenous administration of ultrasmall superparamagnetic iron oxide particles (USPIO). Ten knees of 10 asymptomatic volunteers were examined before and 36 h after intravenous administration of USPIO on a 1.5-T MR system using T1-weighted spin-echo, T2-weighted fast spin-echo, T2*-weighted gradient-echo (GRE), and short inversion time inversion-recovery sequences. In addition, synovial perfusion was measured using Gd-enhanced GRE imaging during the first imaging session. Images were analyzed qualitatively for any visual changes before and after USPIO administration. Signal-to-noise ratios (SNR) of the synovium were determined on unenhanced and USPIO-enhanced sequences. All MR images were reviewed for presence of any degenerative changes. Qualitative image analysis revealed no visually detectable changes of any knee joint before and after USPIO administration. The SNR values of the synovium on T1w, T2w, and T2*w images before and after USPIO administration showed no significant difference (T1, P = 0.86; T2, P = 0.95; T2*, P = 0.86). None of the volunteers showed any relevant degenerative changes of the knee and synovial perfusion was within normal limits. In knees of asymptomatic volunteers without any relevant degenerative changes and normal synovial perfusion neither visual changes nor changes of SNR values of the synovium can be depicted after USPIO administration. This means that USPIO-enhanced MRI may be used for assessment of knee disorders with increased macrophage activity.

    View details for DOI 10.1007/s00330-009-1343-4

    View details for Web of Science ID 000266780800022

    View details for PubMedID 19330333

  • Targeted microbubbles for imaging tumor angiogenesis: Assessment of whole-body biodistribution with dynamic micro-PET in mice RADIOLOGY Willmann, J. K., Cheng, Z., Davis, C., Lutz, A. M., Schipper, M. L., Nielsen, C. H., Gambhir, S. S. 2008; 249 (1): 212-219


    To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Lipid-shell perfluorocarbon-filled MBs, targeted to VEGFR2 via anti-VEGFR2 antibodies, were radiolabeled by conjugating the radiofluorination agent N-succinimidyl-4-[(18)F]fluorobenzoate (SFB) to the anti-VEGFR2 antibodies. These MBs were then injected intravenously into nude mice (n = 4) bearing angiosarcomas, and the whole-body biodistribution of these probes was assessed for 60 minutes by using dynamic micro-PET. Results were compared with ex vivo gamma counting (n = 6) and immunofluorescence staining (n = 6). Control studies in angiosarcoma-bearing mice were performed with injection of the radiolabeled antibodies alone (n = 3) or free SFB (n = 3). A mixed-effects regression of MB accumulation on fixed effects of time and tissue type (tumor or muscle) and random effect of animal was performed.VEGFR2-targeted MBs rapidly cleared from the blood circulation (50% blood clearance after approximately 3.5 minutes) and accumulated in the liver (mean, 33.4% injected dose [ID]/g +/- 13.7 [standard deviation] at 60 minutes) and spleen (mean, 9.3% ID/g +/- 6.5 at 60 minutes) on the basis of micro-PET imaging. These findings were confirmed with ex vivo gamma counting. Uptake of targeted MBs was significantly higher (P < .0001) in tumor than in adjacent skeletal muscle tissue. Immunofluorescence staining demonstrated accumulation of the targeted MBs within hepatic Kupffer cells and splenic macrophages. Biodistribution of the radiolabeled antibodies and free SFB differed from the distribution of the targeted MBs.Dynamic micro-PET allows assessment of in vivo biodistribution of VEGFR2-targeted MBs.

    View details for DOI 10.1148/radiol.2491072050

    View details for Web of Science ID 000259505200025

    View details for PubMedID 18695212

    View details for PubMedCentralID PMC2657857

  • Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo RADIOLOGY Willmann, J. K., Lutz, A. M., Paulmurugan, R., Patel, M. R., Chu, P., Rosenberg, J., Gambhir, S. S. 2008; 248 (3): 936-944


    To develop and validate a dual-targeted ultrasonographic (US) imaging agent with microbubbles (MBs) that attaches to both vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and alpha(v)beta(3) integrin and to compare the US imaging signal obtained from dual-targeted MBs (MB(D)) with that from single-targeted MBs (MB(S)) in a murine model of tumor angiogenesis.Animal protocols were approved by the institutional Administrative Panel on Laboratory Animal Care. Single- and dual-targeted US imaging agents were prepared by attaching anti-VEGFR2, anti-alpha(v)beta(3) integrin, or both antibodies to the shell of perfluorocarbon-filled MBs. Binding specificities of targeted MBs compared with isotype-matched immunoglobulin G-labeled control MBs (MB(C)) and nontargeted nonlabeled MBs (MB(N)) were tested with VEGFR2-positive and alpha(v)beta(3) integrin-positive cells (mouse SVR cells) and control cells (mouse 4T1 cells). In vivo imaging signals of contrast material-enhanced US by using anti-VEGFR2-targeted MBs (MB(V)), anti-alpha(v)beta(3) integrin-targeted MBs (MB(I)), MB(D), and MB(C) were quantified in 49 mice bearing SK-OV-3 tumors (human ovarian cancer). Tumor tissue was stained for VEGFR2, alpha(v)beta(3) integrin, and CD31.Attachment of MB(D) to SVR cells (mean, 0.74 MBs per cell +/- 0.05 [standard deviation]) was significantly higher than attachment to 4T1 cells (mean, 0.04 +/- 0.03), and attachment to SVR cells was higher for MB(D) than for MB(V) (mean, 0.58 +/- 0.09), MB(I) (mean, 0.42 +/- 0.21), MB(C) (mean, 0.11 +/- 0.13), and MB(N) (mean, 0.01 +/- 0.01) (P < .05). Imaging signal in the murine tumor angiogenesis model was significantly higher (P < .001) for MB(D) (mean, 16.7 +/- 7.2) than for MB(V) (mean, 11.3 +/- 5.7), MB(I) (mean, 7.8 +/- 5.3), MB(C) (mean, 2.8 +/- 0.9), and MB(N) (mean, 1.1 +/- 0.4). Immunofluorescence confirmed expression of VEGFR2 and alpha(v)beta(3) integrin on tumor vasculature.Dual-targeted contrast-enhanced US directed at both VEGFR2 and alpha(v)beta(3) integrin improves in vivo visualization of tumor angiogenesis in a human ovarian cancer xenograft tumor model in mice.

    View details for DOI 10.1148/radiol.2483072231

    View details for Web of Science ID 000258541500031

    View details for PubMedID 18710985

    View details for PubMedCentralID PMC2798094

  • Cancer screening: A mathematical model relating secreted blood biomarker levels to tumor sizes PLOS MEDICINE Lutz, A. M., Willmann, J. K., Cochran, F. V., Ray, P., Gambhir, S. S. 2008; 5 (8): 1287-1297


    Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3) and 3,610.14 mm(3) for CA125 and between 0.21 mm(3) and 131.51 mm(3) for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm(3) and 1.52 x 10(6) mm(3) for CA125 and between 27 mm(3) and 3.45 x 10(5) mm(3) for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.

    View details for DOI 10.1371/journal.pmed.0050170

    View details for Web of Science ID 000258739200018

    View details for PubMedID 18715113

    View details for PubMedCentralID PMC2517618

  • Dynamic MRI of the liver with parallel acquisition technique: characterization of focal liver lesions and analysis of the hepatic vasculature in a single MRI session ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN Heilmaier, C., Sutter, R., Lutz, A. M., Seifert, B., Willmann, J. K. 2008; 180 (5): 440-448


    To retrospectively evaluate the performance of breath-hold contrast-enhanced 3D dynamic parallel gradient echo MRI (pMRT) for the characterization of focal liver lesions (standard of reference: histology) and for the analysis of hepatic vasculature (standard of reference: contrast-enhanced 64-detector row computed tomography; MSCT) in a single MRI session.Two blinded readers independently analyzed preoperative pMRT data sets (1.5T-MRT) of 45 patients (23 men, 22 women; 28 - 77 years, average age, 48 years) with a total of 68 focal liver lesions with regard to image quality of hepatic arteries, portal and hepatic veins, presence of variant anatomy of the hepatic vasculature, as well as presence of portal vein thrombosis and hemodynamically significant arterial stenosis. In addition, both readers were asked to identify and characterize focal liver lesions. Imaging parameters of pMRT were: TR/TE/matrix/slice thickness/acquisition time: 3.1 ms/ 1.4 ms/ 384 x 224 / 4 mm/ 15 - 17 s. MSCT was performed with a pitch of 1.2, an effective slice thickness of 1 mm and a matrix of 512 x 512.Based on histology, the 68 liver lesions were found to be 42 hepatocellular carcinomas (HCC), 20 metastases, 3 cholangiocellular carcinomas (CCC) as well as 1 dysplastic nodule, 1 focal nodular hyperplasia (FNH) and 1 atypical hemangioma. Overall, the diagnostic accuracy was high for both readers (91 - 100 %) in the characterization of these focal liver lesions with an excellent interobserver agreement (kappa-values of 0.89 [metastases], 0.97 [HCC] and 1 [CCC]). On average, the image quality of all vessels under consideration was rated good or excellent in 89 % (reader 1) and 90 % (reader 2). Anatomical variants of the hepatic arteries, hepatic veins and portal vein as well as thrombosis of the portal vein were reliably detected by pMRT. Significant arterial stenosis was found with a sensitivity between 86 % and 100 % and an excellent interobserver agreement (kappa = 0.85).Diagnostic image quality remains good or excellent in most cases when the data acquisition time is accelerated by means of parallel imaging in dynamic MRI. It allows reliable detection and characterization of focal liver lesions as well as the depiction of hepatic vascular variants, portal vein thrombosis, and arterial stenosis. Introducing pMRT in routine liver MRI may be another step towards a simplified diagnostic work-up prior to liver surgery.

    View details for DOI 10.1055/s-2008-1027279

    View details for Web of Science ID 000256025800009

    View details for PubMedID 18438745

  • US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice RADIOLOGY Willmann, J. K., Paulmurugan, R., Chen, K., Gheysens, O., Rodriguez-Porcel, M., Lutz, A. M., Chen, I. Y., Chen, X., Gambhir, S. S. 2008; 246 (2): 508-518


    To prospectively evaluate contrast material-enhanced ultrasonography (US) with microbubbles targeted to vascular endothelial growth factor receptor type 2 (VEGFR2) for imaging tumor angiogenesis in two murine tumor models.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. A US contrast agent, consisting of encapsulated gaseous microbubbles, was developed specifically to bind to VEGFR2 (by using anti-VEGFR2 antibodies and biotin-streptavidin interaction) which is up-regulated on endothelial cells of tumor blood vessels. VEGFR2-targeted microbubbles (MB(V)), control microbubbles (MB(C)), and nonlabeled microbubbles (MB(N)) were tested for binding specificity on cells expressing VEGFR2 (mouse angiosarcoma SVR cells) and control cells (mouse skeletal myoblast C2C12 cells). Expression of mouse VEGFR2 in culture cells was tested with immunocytochemical and Western blot analysis. Contrast-enhanced US imaging with MB(V) and MB(C) was performed in 28 tumor-bearing nude mice (mouse angiosarcoma, n = 18; rat malignant glioma, n = 10). Differences were calculated by using analysis of variance.In cell culture, adherence of MB(V) on SVR cells (2.1 microbubbles per SVR cell) was significantly higher than adherence of control microbubbles (0.01-0.10 microbubble per SVR cell; P < .001) and significantly more MB(V) attached to SVR cells than to C2C12 cells (0.15 microbubble per C2C12 cell; P < .001). In vivo, contrast-enhanced US imaging showed significantly higher average video intensity when using MB(V) compared with MB(C) for angiosarcoma and malignant glioma tumors (P < .001). Results of immunohistochemical analysis confirmed VEGFR2 expression on vascular endothelial cells of both tumor types.US imaging with contrast microbubbles targeted to VEGFR2 allows noninvasive visualization of VEGFR2 expression in tumor vessels in mice.

    View details for DOI 10.1148/radio1.2462070536

    View details for Web of Science ID 000252796300021

    View details for PubMedID 18180339

  • Mapping of hepatic vascular anatomy: Dynamic contrast-enhanced parallel MR Imaging compared with 64-detector row CT RADIOLOGY Heilmaier, C., Sutter, R., Lutz, A. M., Seifert, B., Weishaupt, D., Marincek, B., Willmann, J. K. 2007; 245 (3): 872-880


    The study was approved by the institutional review board, and informed consent was obtained from all patients. The purpose of this study was to retrospectively evaluate the feasibility, reliability, and accuracy of breath-hold dynamic contrast material-enhanced parallel gradient-echo (GRE) magnetic resonance (MR) imaging for mapping the hepatic vascular anatomy, with contrast-enhanced 64-detector row computed tomography (CT) as the reference standard. The parallel GRE MR data sets of 100 patients acquired at 1.5 T were evaluated independently by two blinded readers with respect to (a) image quality for depiction of the hepatic arteries and the portal and hepatic veins and (b) presence of arterial stenosis and variant hepatic vasculature. The readers rated image quality to be good or excellent for 91.1%-100% of the vessels. At parallel GRE MR imaging, the readers diagnosed variant hepatic vessels and arterial stenosis with 94%-100% accuracy. They concluded that parallel GRE MR imaging, as compared with 64-detector row CT, is feasible for hepatic vascular mapping and enables reliable and accurate detection of variant hepatic vasculature and diagnosis of arterial stenosis. Supplemental material:

    View details for DOI 10.1148/radiol.2453062103

    View details for Web of Science ID 000251070700030

    View details for PubMedID 17954617

  • Assessment of aortoiliac and renal arteries: MR angiography with parallel acquisition versus conventional MR angiography and digital subtraction angiography RADIOLOGY Sutter, R., Nanz, D., Lutz, A. M., Plammatter, T., Seifert, B., Struwe, A., Heilmaier, C., Weishaupt, D., Marincek, B., Willmann, J. K. 2007; 245 (1): 276-284


    To prospectively compare the image quality, sensitivity, and specificity of three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography accelerated by parallel acquisition (ie, fast MR angiography) with MR angiography not accelerated by parallel acquisition (ie, conventional MR angiography) for assessment of aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the reference standard.The study was approved by the institutional review board; informed consent was obtained from all patients. Forty consecutive patients (33 men, seven women; mean age, 63 years) suspected of having aortoiliac and renal arterial stenoses and thus examined with DSA underwent both fast (mean imaging time, 17 seconds) and conventional (mean imaging time, 29 seconds) MR angiography. The arterial tree was divided into segments for image analysis. Two readers independently evaluated all MR angiograms for image quality, presence of arterial stenosis, and renal arterial variants. Image quality, sensitivity, and specificity were analyzed on per-patient and per-segment bases for multiple comparisons (with Bonferroni correction) and for dependencies between segments (with patient as the primary sample unit). Interobserver agreement was evaluated by using kappa statistics.Overall, the image quality with fast MR angiography was significantly better (P=.001) than that with conventional MR angiography. At per-segment analysis, the image quality of fast MR angiograms of the distal renal artery tended to be better than that of conventional MR angiograms of these vessels. Differences in sensitivity for the detection of arterial stenosis between the two MR angiography techniques were not significant for either reader. Interobserver agreement in the detection of variant renal artery anatomy was excellent with both conventional and fast MR angiography (kappa=1.00).Fast MR angiography and conventional MR angiography do not differ significantly in terms of arterial stenosis grading or renal arterial variant detection.

    View details for DOI 10.1148/radiol.2451062081

    View details for Web of Science ID 000249577500032

    View details for PubMedID 17717331

  • 2-Deoxy-2-[F-18]fluoro-D-glucose accumulation in ovarian carcinoma cell lines MOLECULAR IMAGING AND BIOLOGY Lutz, A. M., Ray, P., Willmann, J. K., Drescher, C., Gambhir, S. S. 2007; 9 (5): 260-266


    To evaluate 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) accumulation in human ovarian carcinoma cell lines compared with control tumor cell lines known to accumulate FDG.FDG accumulation assays were performed in 15 different ovarian carcinoma cell lines at 1, 2, and 3 hours after incubation with 1 microCi of FDG. Results were compared with FDG accumulation in six different control tumor cell lines. 2-deoxy-2-[F-18]fluoro-D-glucose accumulation was expressed as counts per minute (cpm) in cells and normalized to initial cpm in medium and total protein content of cell lysates.FDG accumulation in all 15 ovarian carcinoma cell lines was equal to or higher than 0.0005 +/- 8.6 10(-5) cpm in cells/cpm in medium/mug protein at all three different time points. In two ovarian carcinoma cell lines (ES-2, poorly differentiated clear cell carcinoma, and OVCAR-3, poorly differentiated papillary adenocarcinoma), FDG accumulation was not statistically, significantly different compared to the control cell line with the highest FDG accumulation (LS 174T human colorectal adenocarcinoma) at two or more time points (P > or = 0.07). In 2 of 15 (13%) ovarian carcinoma cell lines (OVCAR5 epithelial carcinoma and SKOV3 clear cell carcinoma), FDG accumulation was lower than that in the control cell line with the lowest FDG accumulation (HT-29 human colorectal adenocarcinoma) at one or more time points (P < 0.05).Most human ovarian carcinoma cell lines showed comparable FDG accumulations with control cell lines known to accumulate FDG. This study lays the foundations for further comparisons with other ovarian cancer cell lines and for other positron emission tomography tracers.

    View details for DOI 10.1007/s11307-007-0105-4

    View details for Web of Science ID 000248865200002

    View details for PubMedID 17610017

  • Assessment of the abdominal aorta and its visceral branches by contrast-enhanced dynamic volumetric hepatic parallel magnetic resonance imaging: feasibility, reliability and accuracy EUROPEAN RADIOLOGY Werder, R., Nanz, D., Lutz, A. M., Weishaupt, D., McCormack, L., Seifert, B., Marincek, B., Willmann, J. K. 2007; 17 (2): 541-551


    The purpose of this study was to evaluate a new three-dimensional gradient-echo (GRE) MR sequence performed with a parallel acquisition technique to shorten breath-hold times (parallel GRE MRI) in the detection of arterial variants and stenosis of the abdominal aorta and its visceral branches. A total of 102 patients underwent dynamic parallel GRE MRI, timed to the arterial phase by a test bolus (mean breath-hold time, 17 s). For both quantitative and qualitative analysis, the abdominal aorta and its visceral branches were divided into 13 arterial segments. In a subanalysis of 55/102 patients, the accuracy of parallel GRE MRI compared to MDCT in the detection arterial variants and stenosis was calculated for two independent readers. Mean SNRs and CNRs were 47.2 and 35.6, respectively. Image quality was rated good or excellent in 1,234/1,326 segments (93%). Hepatic and renal arterial variants were identified with an accuracy of 93 and 95%, respectively (reader 1) and 98 and 100%, respectively (reader 2). Both readers detected arterial stenosis with an accuracy of 98%. Interobserver agreement was good to excellent for the detection of hepatic (kappa=0.69) and renal (kappa=0.92) variants and for the diagnosis of stenosis (kappa=0.96). Dynamic three-dimensional parallel GRE MRI is feasible and allows a reliable and accurate diagnosis of arterial variants and stenosis of the abdominal aorta and its visceral branches in a short breath-hold-time.

    View details for DOI 10.1007/s00330-006-0384-1

    View details for Web of Science ID 000243604500025

    View details for PubMedID 16947013

  • Prospective intraindividual comparison between respiratory-triggered balanced steady-state free precession and breath-hold gradient-echo and time-of-flight magnetic resonance imaging for assessment of portal and hepatic veins EUROPEAN RADIOLOGY Willmann, J. K., Goepfert, K., Lutz, A. M., Nanz, D., McCormack, L., Petrowsky, H., Seifert, B., Hervo, P., Marincek, B., Weishaupt, D. 2007; 17 (1): 229-240


    The purpose of this study was to compare respiratory-triggered balanced steady-state free precession (bSSFP) with breath-hold contrast-enhanced dynamic two-dimensional (2D) gradient-echo (GRE) and time-of-flight (TOF) magnetic resonance imaging (MRI) for portal and hepatic vein visualization and assessment of portal and hepatic venous variants. Sixty patients with liver disease underwent nonenhanced bSSFP and contrast-enhanced GRE, bSSFP, and TOF imaging. Contrast-to-noise ratios (CNRs) for portal and hepatic veins were measured. Two readers rated the quality of portal and hepatic vein visualization on a 5-point Likert scale. The diagnostic performance of each MRI series in the detection of portal and hepatic venous variants was assessed in 40/60 patients who also underwent contrast-enhanced multidetector-row computed tomography (MDCT). CNRs for portal and hepatic veins were highest on contrast-enhanced bSSFP images. Image quality of portal and hepatic veins was rated higher for nonenhanced bSSFP than for contrast-enhanced GRE (p<0.03) and TOF (p<0.003) and higher for contrast-enhanced than for nonenhanced bSSFP (p<0.003). Compared with MDCT, portal and hepatic venous variants were identified with an accuracy of 99% on bSSFP images, with an excellent interobserver agreement (kappa=0.97). Compared with MDCT, presence of surgically important portal and hepatic venous anatomical variants can be predicted with high accuracy on bSSFP images.

    View details for DOI 10.1007/s00330-006-0305-3

    View details for Web of Science ID 000243396700027

    View details for PubMedID 16703307

  • USPIO-enhanced MR imaging for visualization of synovial hyperperfusion and detection of synovial macrophages: Preliminary results in an experimental model of antigen-induced arthritis JOURNAL OF MAGNETIC RESONANCE IMAGING Lutz, A. M., Goepfert, K., Jochum, W., Nanz, D., Froehlich, J. M., Weishaupt, D. 2006; 24 (3): 657-666


    To evaluate whether ultrasmall superparamagnetic iron particles (USPIO)-enhanced MRI is capable of assessing both synovial perfusion characteristics and the presence of synovial macrophages in a model of antigen-induced arthritis.Unilateral arthritis was induced in six knees of six rabbits. The contralateral knees of the rabbits served as control knees. After onset of arthritis, all 12 knees were scanned prior to and immediately following intravenous administration of USPIO using a multiphase T1-weighted (T1w) fast gradient-echo (FGRE) sequence, and T1w spin-echo (SE), T2-weighted (T2w) FSE, T2*w GRE, and short-tau inversion recovery (STIR) sequences prior to and 24 hours following USPIO administration. SI-vs.-time curves (STCs) and the early enhancement rate during the first 56 seconds (REE(56)) were calculated from SI measurements within the synovial tissue of all knees on dynamic T1w images. MR findings were correlated to histopathology.REE(56) was significantly higher in the synovial tissue of arthritic knees than in the control knees (P < 0.01). Significant T1-, T2-, and T2* effects (P = 0.03-0.04) and multiple synovial vessels were visually detectable within the arthritic synovial tissue 24 hours after administration of USPIO, whereas no signal changes or synovial vessels were seen in the control knees. Histopathology revealed widened synovial blood vessels in the arthritic knees, and confirmed iron uptake by macrophages in the arthritic knees.USPIO-enhanced MRI is capable of both assessing synovial hyperperfusion and detecting macrophages in antigen-induced arthritis in rabbits.

    View details for DOI 10.1002/jmri.20667

    View details for Web of Science ID 000240300800024

    View details for PubMedID 16878310

  • Uptake of F-18-fluorocholine, F-18-fluoro-ethyl-L-tyrosine and F-18-fluoro-2-deoxyglucose in F98 gliomas in the rat EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Spaeth, N., Wyss, M. T., Pahnke, J., Biollaz, G., Lutz, A., Goepfert, K., Westera, G., Treyer, V., Weber, B., Buck, A. 2006; 33 (6): 673-682


    The positron emission tomography (PET) tracers (18)F-fluoro-ethyl-L: -tyrosine (FET), (18)F-fluorocholine (N,N-dimethyl-N-[(18)F]fluoromethyl-2-hydroxyethylammonium (FCH]) and (18)F-fluoro-2-deoxyglucose (FDG) are used in the diagnosis of brain tumours. The aim of this study was threefold: (a) to assess the uptake of the different tracers in the F98 rat glioma, (b) to evaluate the impact of blood-brain barrier (BBB) disruption and microvessel density (MVD) on tracer uptake and (c) to compare the uptake in the tumours to that in the radiation injuries (induced by proton irradiation of healthy rats) of our previous study.F98 gliomas were induced in 26 rats. The uptake of FET, FCH and FDG was measured using autoradiography and correlated with histology, disruption of the BBB and MVD.The mean FET, FCH and FDG standardised uptake values (SUVs) in the tumour and the contralateral normal cortex (in parentheses) were 4.19+/-0.86 (1.32+/-0.26), 2.98+/-0.58 (0.51+/-0.11) and 11.02+/-3.84 (4.76+/-1.77) respectively. MVD was significantly correlated only with FCH uptake. There was a trend towards a negative correlation between the degree of BBB disruption and FCH uptake and a trend towards a positive correlation with FET uptake. The ratio of the uptake in tumours to that in the radiation injuries was 1.97 (FCH), 2.71 (FET) and 2.37 (FDG).MVD displayed a significant effect only on FCH uptake. The degree of BBB disruption seems to affect the accumulation of FET and FCH, but not FDG. Mean tumour uptake for all tracers was significantly higher than the accumulation in radiation injuries.

    View details for DOI 10.1007/s00259-005-0045-7

    View details for Web of Science ID 000238023000007

    View details for PubMedID 16538503

  • Uptake of 18F-fluorocholine, 18F-fluoro-ethyl-L: -tyrosine and 18F-fluoro-2-deoxyglucose in F98 gliomas in the rat. Eur J Nucl Med Mol Imaging Spaeth N, Wyss MT, Pahnke J, Biollaz G, Lutz A, Goepfert K, Westera G, Treyer V, Weber B, Buck A 2006; 33 (6): 673-82
  • Characteristics of displaceable and nondisplaceable meniscal tears at kinematic MR imaging of the knee RADIOLOGY Boxheimer, L., Lutz, A. M., Zanetti, M., Treiber, K., Labler, L., Marincek, B., Weishaupt, D. 2006; 238 (1): 221-231


    To prospectively determine if kinematic magnetic resonance (MR) imaging of the knee may demonstrate displacement of menisci with tears and, if so, to characterize displaceable and nondisplaceable meniscal tears.The study was approved by the hospital's review board, and informed consent was obtained. Forty-two patients (30 men, 12 women; mean age, 36.9 years) with 43 arthroscopically documented meniscal tears visible at 1.5-T MR imaging underwent kinematic MR imaging with an open-configuration 0.5-T MR imager with their knees in supine neutral, supine with 90 degrees flexion and external or internal rotation, and upright weight-bearing positions. Analysis of meniscal movement was performed in different knee positions in the coronal MR imaging plane. Meniscal displacement--that is, meniscal movement of 3 mm or more (in the medial direction for the medial meniscus, in the lateral direction for the lateral meniscus)--was compared with the patient's pain level as assessed with a visual analog scale by using analysis of variance.Between the different knee positions, meniscal displacement of 3 mm or more (displaceable meniscal tears) was noted in 18 (42%) of 43 menisci with tears. Simultaneous occurrence of grade II or III ipsilateral collateral ligament lesions was present in all 18 displaceable meniscal tears, whereas a normal-appearing collateral ligament or collateral ligament lesion (grade I) was present in 22 of 25 nondisplaceable tears (P < .05). Displaced menisci most commonly had complex, radial, or longitudinal tear configurations (16 of 18, 89%). Patients with displaceable meniscal tears had significantly more pain than did patients with nondisplaceable meniscal tears (P < .001), independent of the concomitant knee abnormalities.Displaceable meniscal tears usually have longitudinal, radial, or complex configurations; such tears are associated with substantial ipsilateral collateral ligament lesions and pain.

    View details for Web of Science ID 000234271600027

    View details for PubMedID 16373770

  • Hepatocellular carcinoma in cirrhosis: Enhancement patterns at dynamic gadolinium-and superparamagnetic iron oxide-enhanced T1-weighted MR imaging RADIOLOGY Lutz, A. M., Willmann, J. K., Goepfert, K., Marincek, B., Weishaupt, D. 2005; 237 (2): 520-528


    To prospectively compare intraindividual differences in enhancement patterns between gadolinium- and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging in patients with histologically proved hepatocellular carcinoma (HCC).Institutional review board approval and informed consent were obtained. Twenty-two patients (18 men, four women; mean age, 58.9 years) with 36 pathologically proved HCC lesions underwent contrast material-enhanced dynamic T1-weighted gradient-echo MR imaging twice. Gadopentetate dimeglumine was used at the first session. After a mean interval of 5 days, a second session was performed with a bolus-injectable SPIO agent, ferucarbotran. Qualitative analysis of contrast enhancement patterns with each agent during hepatic arterial, portal venous, and equilibrium phases was performed by two readers who classified lesions as isointense, hypointense, or hyperintense compared with surrounding liver parenchyma and searched for presence of hyperintense peritumoral ring enhancement. Results of signal intensity analysis during different vascular phases at both sessions were compared by using the McNemar test, and kappa statistic was used to evaluate agreement between signal intensity and enhancement pattern of lesions during different vascular phases.On gadolinium-enhanced hepatic arterial phase images, HCC lesions (n = 36) were hyperintense in 21 (58%) cases, hypointense in 10 (28%), and isointense in five (14%). On ferucarbotran-enhanced hepatic arterial phase images, HCC lesions were isointense in 18 (50%) cases, hypointense in 11 (31%), and hyperintense in seven (19%). On gadolinium-enhanced portal venous and equilibrium phase images, respectively, HCC lesions were hypointense in 17 (47%) and 21 (58%) cases, hyperintense in 10 (28%) cases and one (3%) case, and isointense in nine (25%) and 14 (39%) cases. On ferucarbotran-enhanced portal venous and equilibrium phase images, respectively, HCC lesions were hypointense in 15 (42%) and 11 (31%) cases, hyperintense in three (8%) and three (8%) cases, and isointense in 18 (50%) and 22 (61%) cases.For HCC, contrast enhancement pattern on T1-weighted gradient-echo MR images shows marked variability with gadolinium or SPIO contrast agents.

    View details for DOI 10.1148/radiol.2372041183

    View details for Web of Science ID 000232743300020

    View details for PubMedID 16192317

  • Imaging of macrophages in soft-tissue infection in rats: Relationship between ultrasmall superparamagnetic iron oxide dose and MR signal characteristics RADIOLOGY Lutz, A. M., Weishaupt, D., Persohn, E., Goepfert, K., Froehlich, J., Sasse, B., Gottschalk, J., Marincek, B., Kaim, A. H. 2005; 234 (3): 765-775


    To describe dose-dependent signal intensity (SI) characteristics of experimentally induced soft-tissue abscesses on 1.5-T T1- and T2*-weighted magnetic resonance (MR) images obtained 24 hours after administration of ultrasmall superparamagnetic iron oxide (USPIO) and to describe the relationship between SI and amount of USPIO uptake and macrophage iron content.Local institutional review committee on animal care approved the experiments, which were performed according to the guidelines of the National Institutes of Health and the committee on animal research at our institution. Unilateral calf muscle abscesses were induced in 21 rats with an injection of a Staphylococcus aureus suspension. The rats were divided into three groups of seven animals each: low USPIO dose (50 micromol of iron per kilogram of body weight), high USPIO dose (150 micromol Fe/kg), and control (saline solution). All rats were imaged before and 24 hours after USPIO administration at 1.5 T (transverse T1-weighted spin-echo, T2*-weighted fast gradient-echo, and short inversion time inversion-recovery sequences). Images were analyzed quantitatively and qualitatively with regard to SI and signal pattern. Temporal variation of calculated contrast-to-noise ratios was analyzed with the Wilcoxon signed rank test. MR findings were correlated with histopathologic findings, including those of electron microscopy.Twenty-four hours after USPIO administration in the high-dose group, susceptibility effects were present in abscess periphery on postcontrast T2*-weighted images (P=.04), and SI enhancement was noted on postcontrast T1-weighted images within both abscess wall and abscess center (P=.04 for both). In the low-dose group, SI enhancement was noted in entire abscess on T1-weighted postcontrast images (P=.03). Neither significant SI loss (P=.09) nor susceptibility effects were detected in periphery or center of any abscess on postcontrast T2*-weighted images. There was no obvious difference in total amount of macrophages among the groups, but there was a clear difference with regard to individual iron content of iron-positive macrophages between the USPIO dose groups.At 1.5 T, SI characteristics of abscesses on T1- and T2*-weighted images obtained 24 hours after USPIO injection strongly depend on administered dose of the contrast agent. At low doses, T1 effects were stronger than T2* effects.

    View details for DOI 10.1148/radiol.2343031172

    View details for Web of Science ID 000227145900016

    View details for PubMedID 15665219

  • Uptake of F-18-fluorocholine, F-18-fluoroethyl-L-tyrosine, and F-18-FDG in acute cerebral radiation injury in the rat: Implications for separation of radiation necrosis from tumor recurrence JOURNAL OF NUCLEAR MEDICINE Spaeth, N., Wyss, M. T., Weber, B., Scheidegger, S., Lutz, A., Verwey, J., Radovanovic, Pahnke, J., Wild, D., Westera, G., Weishaupt, D., Hermann, D. M., Kaser-Hotz, B., Aguzzi, A., Buck, A. 2004; 45 (11): 1931-1938


    Differentiation between posttherapy radiation necrosis and recurrent tumor in humans with brain tumor is still a difficult diagnostic task. The new PET tracers (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluorocholine (N,N-dimethyl-N-(18)F-fluoromethyl-2-hydroxyethylammonium [FCH]) have shown promise for improving diagnostic accuracy. This study assessed uptake of these tracers in experimental radiation injury.In a first model, circumscribed lesions were induced in the cortex of 35 rats using proton irradiation of 150 or 250 Gy. After radiation injury developed, uptake of (18)F-FET, (18)F-FCH, and (18)F-FDG was measured using autoradiography and correlated with histology and disruption of the blood-brain barrier as determined with Evans blue. In a second model, uptake of the tracers was assessed in acute cryolesions, which are characterized by the absence of inflammatory cells.Mean (18)F-FET, (18)F-FCH, and (18)F-FDG standardized uptake values in the most active part of the radiation lesion and the contralateral normal cortex (in parentheses) were 2.27 +/- 0.46 (1.42 +/- 0.23), 2.52 +/- 0.42 (0.61 +/- 0.12), and 6.21 +/- 1.19 (4.35 +/- 0.47). The degree of uptake of (18)F-FCH and (18)F-FDG correlated with the density of macrophages. In cryolesions, (18)F-FET uptake was similar to that in radiation lesions, and (18)F-FCH uptake was significantly reduced.Comparison of tracer accumulation in cryolesions and radiation injuries demonstrates that (18)F-FET uptake is most likely due to a disruption of the blood-brain barrier alone, whereas (18)F-FCH is additionally trapped by macrophages. Uptake of both tracers in the radiation injuries is generally lower than the published uptake in tumors, suggesting that (18)F-FET and (18)F-FCH are promising tracers for separating radiation necrosis from tumor recurrence. However, the comparability of our data with the literature is limited by factors such as different species and acquisition protocols and modalities. Thus, more studies are needed to settle this issue. Nevertheless, (18)F-FCH and (18)F-FET seem superior to (18)F-FDG for this purpose.

    View details for Web of Science ID 000225086000028

    View details for PubMedID 15534065

  • Detection of synovial macrophages in an experimental rabbit model of antigen-induced arthritis: Ultrasmall superparamagnetic iron oxide-enhanced MR imaging RADIOLOGY Lutz, A. M., Seemayer, C., Corot, C., GAY, R. E., Goepfert, K., Michel, B. A., Marincek, B., GAY, S., Weishaupt, D. 2004; 233 (1): 149-157


    To evaluate intravenously administered ultrasmall superparamagnetic iron oxide (USPIO) as a marker of macrophage activity in an experimental rabbit model of antigen-induced arthritis.Unilateral arthritis was induced by means of intraarticular injection of methylated bovine serum albumin in 10 knees of 10 rabbits that had been presensitized to the same antigen. The contralateral knees in these rabbits, as well as six knees in three other rabbits, served as controls. After onset of arthritis, all knees were imaged prior to and 24 hours after administration of USPIO. The magnetic resonance (MR) imaging protocol included T1-weighted spin-echo, T2-weighted fast spin-echo, T2*-weighted gradient-echo, and short inversion time inversion-recovery sequences. Images were analyzed quantitatively and qualitatively with regard to signal characteristics and pattern. MR findings were correlated with histopathologic findings. Wilcoxon signed rank test was used to compare results of signal-to-noise ratio calculations before and after USPIO administration.All knees with intraarticular injection of antigen suspension developed unilateral arthritis, whereas no signs of arthritis occurred in the control knees. On USPIO-enhanced images obtained 24 hours after contrast agent administration, significant T1 (P =.03) and more predominantly T2* (P =.02) and T2 effects (P =.01) were evident in the synovium of all 10 arthritic knees, which reflected USPIO uptake by macrophages in the synovial tissue. To a lesser extent, T2* effects were present also within the joint effusion (P =.01). No significant changes in signal characteristics were detected in the 10 nonarthritic knees in the antigen-injected group or the six knees in the control group (P =.06-.91). Histologic examination confirmed uptake of iron in the macrophages of arthritic knees. Changes in MR signal characteristics within the arthritic synovium and synovial effusion were visually detectable after intravenous administration of USPIO.MR imaging at 1.5 T can depict USPIO uptake in phagocytic-active macrophages in an antigen-induced arthritis animal model.

    View details for Web of Science ID 000224075000020

    View details for PubMedID 15333767

  • Assessment of skeletal muscle perfusion by contrast medium first-pass magnetic resonance imaging: Technical feasibility and preliminary experience in healthy volunteers JOURNAL OF MAGNETIC RESONANCE IMAGING Lutz, A. M., Weishaupt, D., Amann-Vesti, B. R., Pfammatter, T., Goepfert, K., Marincek, B., Nanz, D. 2004; 20 (1): 111-121


    To probe the potential and pitfalls of contrast medium first-pass skeletal muscle perfusion imaging under reproducible stress conditions.Magnetic resonance (MR) signal dynamics in calf muscle and lower-leg arteries of 20 healthy volunteers were analyzed under postarterial occlusion reactive hyperemia and concurrent contrast medium first pass, using a saturation recovery spoiled gradient-echo type sequence without heartbeat synchronization. The signal vs. time curves were analyzed descriptively and by two-compartment deconvolution analysis.Highly significant changes in calf muscle signal dynamics in the hyperemic leg vs. those in the contralateral leg at rest were found in phenomenological and deconvolution analysis. Although a distortion of the arterial signal derived input function by inflow effects was found to cause large variations of the deconvolution results, the magnitude of the observed effects suggested a potential for immediate visual detection of areas with reduced tissue perfusion.The first-pass approach appeared promising for visual evaluation. However, a disentanglement of inflow and contrast medium-induced effects on arterial signal intensity was deemed a prerequisite for input function-based numerical assessment.

    View details for DOI 10.1002/jmri.20092

    View details for Web of Science ID 000222411900015

    View details for PubMedID 15221816

  • MR imaging of the knee: Position related changes of the menisci in asymptomatic volunteers INVESTIGATIVE RADIOLOGY Boxheimer, L., Lutz, A. M., Treiber, K., Goepfert, K., Crook, D. W., Marincek, B., Weishaupt, D. 2004; 39 (5): 254-263


    To evaluate position related changes of the menisci in asymptomatic volunteers based on MR imaging of the knee in different positions.Twenty-two knees from 22 asymptomatic volunteers with no history of knee injury and no evidence of meniscal tears were examined with a 0.5-T open-configuration MR system. Sagittal and coronal images were obtained with the knee supine in neutral, supine in 90-degree flexion with external and internal rotation, as well as in upright weight-bearing positions. The position of the menisci from the outer inferior edge of the meniscus to the outermost edge of the articular cartilage of the tibial plateau was measured, and meniscal movement was calculated. The Wilcoxon signed-rank test was used for statistical analysis.Meniscal movement in the sagittal plane was greatest in the anterior horn of the medial meniscus upon position change from supine neutral to supine in 90-degree flexion with external rotation (mean, 10.5 millimeters). The least meniscal movement was observed in the anterior horn of the lateral meniscus when changing from the supine neutral to the upright knee position (mean, 0.6 millimeters). Meniscal protrusion (ie, protrusion of any part of the meniscus beyond the tibial plateau) was noted most frequently for the anterior horn of the medial meniscus (14/22 instances; 63.6%) in the sagittal plane with the knee in neutral position (mean, 2.6 millimeters, range, 1.8-2.8 millimeters). In the coronal plane, medial meniscal protrusion was most frequently present in the upright weight-bearing position (11/22 instances (50%; mean, 2 millimeters; range, 1.2-2.6 millimeters).: Meniscal movement is most prominent in the anterior horn of the medial meniscus with the knee in the supine position in 90-degree flexion with external rotation. Meniscal protrusion is more frequently present in the medial meniscus and averaged less than 3 millimeters in normal volunteers in either the sagittal or coronal MR imaging plane.

    View details for DOI 10.1097/01.rli.0000116895.04239.84

    View details for Web of Science ID 000220990600002

    View details for PubMedID 15087719

  • Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence J Nucl Med Spaeth N, Wyss MT, Weber B, Scheidegger S, Lutz A, Verwey J, Radovanovic I, Pahnke J, Wild D, Westera G, Weishaupt D, Hermann DM, Kaser-Hotz B, Aguzzi A, Buck A 2004; 45 (11): 1931-8
  • Resovist for imaging of hepatocellular carcinoma in the cirrhotic liver Schering Lunch Symposium on Resovist held at the ESGAR Congress Weishaupt, D., Willmann, J. K., Lutz, A. M., Marincek, B. SPRINGER. 2004: C5–C6

    View details for DOI 10.1007/s00330-003-2150-y

    View details for Web of Science ID 000188874400004

    View details for PubMedID 15113059

  • Contrast-enhanced MR angiography for differentiation between perigastric and submucosal gastric fundal varices ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN Willmann, J. K., Bauerfeind, P., Boehm, T., Lutz, A. M., Gopfert, K., Marincek, B., Weishaupt, D. 2003; 175 (4): 507-514


    To evaluate contrast-enhanced MR angiography for the distinction between perigastric and submucosal fundal varices.Nineteen consecutive patients with clinically suspected fundal varices underwent contrast-enhanced MR angiography and endoscopic ultrasound (EUS) within one week. Diagnostic confidence for the detection of perigastric and submucosal fundal varices was compared between MR angiography (two radiologists) and EUS (one gastroenterologist), and the agreement of size and location was evaluated.Both MR angiography and EUS detected perigastric varices in all 19 patients and submucosal fundal varices in 14 of the 19 patients. The interobserver reliability of MR angiography was good for measuring the variceal diameter (kappa = 0.76) and excellent for localizing the varices (kappa = 1.0). EUS and MR angiography agreed in 12 of 14 patients (86 %) in determining variceal diameter and location.Contrast-enhanced MR angiography is comparable to endoscopic ultrasound in the detection and characterization of gastric fundal varices.

    View details for Web of Science ID 000182382400009

    View details for PubMedID 12677506

  • Evaluation of aortoiliac aneurysm before endovascular repair: Comparison of contrast-enhanced magnetic resonance angiography with multidetector row computed tomographic angiography with an automated analysis software tool JOURNAL OF VASCULAR SURGERY Lutz, A. M., Willmann, J. K., Pfammatter, T., Lachat, M., Wildermuth, S., Marincek, B., Weishaupt, D. 2003; 37 (3): 619-627


    The purpose of this study was to assess accuracy and reliability of a volumetric analysis of abdominal aneurysms on the basis of multidetector row computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) with a commercially available automated vessel analysis software program.Twenty patients with abdominal aortic aneurysms underwent preoperative CTA and MRA before endovascular repair. Postdeployment CTA was performed in 15 of these 20 patients (75%). All preoperative CTA and MRA and postdeployment CTA data sets were analyzed with an automated software tool. The length of the stent grafts on postdeployment CTA was measured and compared with the true length of the primary component. Two readers independently evaluated 13 vessel parameters on preoperative CTA and MRA, which are considered to be important in planning stent graft deployment.With the automated analysis software tool, all measurements could be performed on either CTA or MRA data sets. There was no statistically significant difference between postdeployment measurements of stent graft length on CTA and the true dimensions of the implanted stent grafts. Interobserver agreement for all of the measurements with either CTA or MRA was good to excellent (interclass coefficient, 0.71 to 0.99) with only minimal mean differences of measured dimensions between both readers (range, -2.0 to +2.3 mm, Bland-Altman). Intermodality agreement between CTA and MRA was good to excellent (interclass coefficient, 0.62 to 0.98) with small mean differences of measured dimensions between both methods (range, -4.1 to +2.1 mm, Bland-Altman).Volumetric measurement with an automated analysis software tool allows a fast, precise, and reliable noninvasive preoperative determination of all aortic dimensions on the basis of either CTA or MRA data sets.

    View details for DOI 10.1067/mva.2003.143

    View details for Web of Science ID 000181364400023

    View details for PubMedID 12618702

  • Bone mineral density and quantitative ultrasound in adults with cystic fibrosis EUROPEAN JOURNAL OF ENDOCRINOLOGY Flohr, F., Lutz, A., App, E. M., Matthys, H., Reincke, M. 2002; 146 (4): 531-536


    With increasing life span osteoporosis becomes a more recognized problem in patients with cystic fibrosis (CF). The aim of this cross-sectional study in 75 adult patients with CF (mean age 25.3 years) was to assess the prevalence of low bone mineral density (BMD) by dual-energy x-ray absorptiometry (DEXA) and, for the first time, by quantitative ultrasound (QUS), and to identify predicting factors.Bone status was assessed at the lumbar spine (L2-L4) and the femoral neck by DEXA, and at the calcaneus by QUS (stiffness index). These data were correlated with a variety of clinical and anthropomorphic variables. Biochemical markers of bone turnover such as osteocalcin, bone-specific alkaline phosphatase, crosslinks in urine, 25-hydroxy vitamin D (25-OH vitamin D), parathyroid hormone, calcium and free testosterone were determined by standard assays.The mean BMD T score (+/-s.e.m.) was -1.4+/-0.17 at the lumbar spine, and -0.54+/-0.16 at the femoral neck. The mean T score of the calcaneal stiffness index was -0.83+/-0.19. Based on a lumbar spine T score <-2.5 by DEXA, 27% of the patients had osteoporosis. Multiple regression analysis showed that the forced expiratory volume in one second (FEV1) and the use of oral glucocorticoids were independent predictors of low lumbar spine BMD, whereas body mass index (BMI) and the use of oral glucocorticoids were independent predictors of low femoral neck BMD. The stiffness index correlated moderately with BMD (0.49-0.62, P<0.0001). QUS had a sensitivity and specificity of only 57% and 89% respectively for diagnosing 'osteoporosis' (based on a femoral neck T score <-2.5 by DEXA). Positive and negative predictive values were 36% and 95% respectively.Low BMD is frequent in adults with CF and is most strongly correlated with disease severity (BMI, FEV1) and the use of glucocorticoids. Calcaneal QUS might help to screen out patients with a normal BMD, but sensitivity and specificity were not sufficiently high to replace DEXA in these patients.

    View details for Web of Science ID 000178743000012

    View details for PubMedID 11916622

  • Adrenocortical function in patients with macrometastases of the adrenal gland EUROPEAN JOURNAL OF ENDOCRINOLOGY Lutz, A., Stojkovic, M., Schmidt, M., Arlt, W., Allolio, B., Reincke, M. 2000; 143 (1): 91-97


    Metastases of the adrenal gland are a frequent finding in patients with malignant tumors like bronchogenic carcinoma or breast cancer. Only limited and conflicting data on adrenocortical function in these patients are available.Cross-sectional study.We investigated the impact of adrenal macrometastases on adrenocortical function in a series of 28 tumor patients using the ACTH(1-24) stimulation test and dexamethasone suppression test. Seven normal controls (Con), eleven patients without adrenal metastases (No Met), eight patients with unilateral (Uni Met) and nine patients with bilateral adrenal metastases (Bil Met) were investigated.The prevalence of adrenal insufficiency was low in our study population, with only two of nine patients with bilateral metastases having subclinical adrenocortical insufficiency. In the remaining patients with uni- or bilateral metastases, baseline and stimulated cortisol concentrations were higher than in controls and cancer patients without metastases (baseline cortisol (in nmol/l): Con: 307+/-33.2 vs Uni Met: 440+/-53.5, and Bil Met: 637.6+/-92.1, P=0.04 by ANOVA; cortisol 60 min after ACTH(1-24): Con: 794.6+/-41.2 vs Uni Met: 990.8+/-92.9, and Bil Met: 1151.4+/-155.5, P=0.03 by ANOVA). Simultaneously, baseline and stimulated serum aldosterone concentrations were significantly blunted in the tumor groups.Adrenal insufficiency is infrequent and develops only in patients with bilateral metastases. However, the majority of patients have activation of the hypothalamic-pituitary-adrenal axis despite adrenal metastases with strongly elevated cortisol concentrations.

    View details for Web of Science ID 000088162000012

    View details for PubMedID 10870036

  • Worsening enterocolitis in neonates: diagnosis by CT examination of urine after enteral administration of iohexol PEDIATRIC RADIOLOGY Patton, W. L., Willmann, J. K., Lutz, A. M., Rencken, I. O., Gooding, C. A. 1999; 29 (2): 95-99


    Perforation, a severe complication of necrotizing enterocolitis (NEC), has a high mortality rate. Recently, we presented a new technique for evaluation of NEC: measuring the CT attenuation coefficient of urine after oral administration of iohexol. We present three cases of neonates with NEC who demonstrated serial increases in urine CT attenuation coefficients, all of whom subsequently deteriorated clinically and radiographically. Surgery in all three cases confirmed severe necrosis and/or perforation. These three cases suggest that the CT attenuation coefficient of urine after oral administration of iohexol may be a more sensitive indicator of NEC severity, progression, and perforation than clinical evaluation and radiography. More investigation is necessary, but eventually, this noninvasive technique may be able to decrease morbidity and mortality by predicting the need for surgical intervention or more aggressive medical management of NEC before perforation occurs.

    View details for Web of Science ID 000078689500006

    View details for PubMedID 9933327

  • Systemic spread of meconium peritonitis PEDIATRIC RADIOLOGY Patton, W. L., Lutz, A. M., Willmann, J. K., Callen, P., Barkovich, A. J., Gooding, C. A. 1998; 28 (9): 714-716


    Meconium peritonitis is a chemical peritonitis which occurs following bowel perforation during fetal life. It is generally looked upon as benign, resulting in no long-term sequelae. We present a case of a newborn infant with meconium peritonitis who developed infarcts in several organs. At autopsy the infarcts proved to be caused by emboli as a result of intravascular dissemination of meconium. To our knowledge, this is the first reported case of systemic spread of meconium peritonitis in the literature and suggests that meconium peritonitis may have more serious implications than generally thought.

    View details for Web of Science ID 000076131500014

    View details for PubMedID 9732503