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J Wittenberg

Publications and source records attributed to J Wittenberg.

At least 19 recordsLinked to original sources
PubMed1992

Receptor-directed contrast agents for MR imaging: preclinical evaluation with affinity assays.

In this study, the target-specific behavior of magnetic resonance (MR) imaging contrast agents directed at human hepatic asialoglycoprotein (ASG) receptors was evaluated in vitro with use of two novel assays: relaxation time measurements of incubated human cell membrane solutions and iron staining of biopsy samples. Specific uptake of ASG receptor-directed agents was demonstrated in human samples of normal liver tissue, areas of hepatitis, regenerating nodules, areas of focal nodular hyperplasia, and hepatic adenomas. A conventional iron oxide preparation not directed at ASG receptors failed to demonstrate specific uptake in these tissues. Attachment of the ASG receptor-directed agents was competitively blocked with a receptor agonist (D(+)-galactose) in these tissues. No attachment of conventional or receptor agents was seen in areas of hepatocellular carcinoma, cholangiocarcinoma, or liver metastases. The studies indicate that in vitro receptor assays are useful in predicting the affinity of new receptor-directed MR imaging contrast agents in human tissue prior to clinical trials.

Asialoglycoprotein Receptor↗
PubMed1991

Lymph nodes: microstructural anatomy at MR imaging.

High-resolution microscopic magnetic resonance (MR) images of rodent lymph nodes were directly correlated with sections obtained for histologic study to determine the microstructural anatomy of lymph nodes seen at MR imaging and to evaluate signal intensity changes induced by a novel intravenous lymphotropic MR contrast agent (ultrasmall superparamagnetic iron oxide [USPIO]). High-resolution T2-weighted images of unenhanced lymph nodes demonstrated medullary sinus as regions of low signal intensity and follicles as high-intensity structures. After a single intravenous administration of USPIO (160 mumol/kg), both T1-weighted and T2-weighted images showed areas of focal signal intensity loss in medullary sinuses corresponding to the distribution of uptake by macrophages. Lymph follicles appeared unchanged in signal intensity, as they are largely devoid of macrophages. This model of microscopic MR imaging should provide the basis for (a) understanding differences between patterns of contrast-enhanced normal lymph nodes and those of diseased ones and (b) guiding the development of targeting strategies for novel pharmaceuticals at the cellular level.

Animals↗
PubMed1991

Asialoglycoprotein receptor function in benign liver disease: evaluation with MR imaging.

An arabinogalactan-coated ultrasmall superparamagnetic iron oxide (AG-USPIO) preparation specific for asialoglycoprotein (ASG) receptors on hepatocytes was used as a magnetic resonance (MR) imaging contrast agent in the evaluation of a spectrum of benign liver diseases in animal models. The activity of hepatocyte ASG receptors, which directly reflects liver function, was directly assessed by measuring liver relaxation times in vitro and MR signal intensity in vivo. The following measurements allowed three-dimensional assessment of liver function: (a) liver relaxation time, (b) native MR signal intensities of liver, (c) response of liver to the AG-USPIO probe (percentage decrease of liver signal intensity after intravenous administration of 10 mumol/kg of AG-USPIO: normal liver 55%, fatty liver 57%, acute hepatitis 36%, chronic hepatitis 29%, and cirrhosis 46%), and (d) redistribution of hepatocyte-specific AG-USPIO to the spleen (present in hepatitis and cirrhosis but not in normal liver and fatty liver). The results of this study indicate that cellular hepatic abnormalities can be detected and quantitated with MR receptor imaging.

Animals↗
PubMed1991

Bone marrow: ultrasmall superparamagnetic iron oxide for MR imaging.

An ultrasmall superparamagnetic iron oxide (USPIO) preparation was evaluated as a potential intravenous contrast agent for magnetic resonance (MR) imaging of bone marrow. One hour after administration of USPIO (40, 80, and 160 mumols of iron per kilogram body weight) in rats and rabbits, T1 and T2 relaxation times were, respectively, approximately 30%, 50%, and 65% lower than precontrast relaxation times. Maximum decrease in relaxation times of marrow occurred within 1-24 hours after intravenous administration; thereafter, relaxation times slowly returned to normal within 7 days. In vivo MR imaging of rabbits and rats confirmed that USPIO decreases signal intensity of red and yellow marrow. The decrease was most marked with gradient echo pulse sequences. An animal model of intramedullary tumor demonstrated the potential of USPIO to enable differentiation between tumor and normal red marrow. USPIO-enhanced MR imaging improves detection of smaller tumors and allows differentiation of tumor deposits from islands of hyperplastic or normal red marrow.

Animals↗
PubMed1991

Experimental hepatocellular carcinoma: MR receptor imaging.

Relaxation time measurements and magnetic resonance (MR) imaging were performed in three different animal models of hepatocellular carcinoma (HCC). After intravenous administration of asialoglycoprotein-directed arabinogalactan-stabilized ultrasmall superparamagnetic iron oxide (10 mumol Fe/kg receptor agent), T2 of normal liver decreased from 41.6 msec +/- 1.0 to 19.4 msec +/- 1.7 (P less than .05) in rats. T2 of HCC implanted in normal liver or liver with chronic hepatitis was essentially unchanged. These results were similar to those obtained by administration of a reticuloendothelial cell-directed conventional iron oxide; however, the required dose of receptor agent was lower. MR imaging in a woodchuck model of virally induced HCC confirmed the distribution of the hepatocyte-directed agent to regions of functioning and differentiated hepatocytes but not to malignant tumor tissue. The results suggest that MR receptor imaging may play a role in the differentiation between primary liver tumor and functional liver tissue such as that in normal liver hepatitis or regenerating nodules.

Animals↗
PubMed1990

Preoperative staging and assessment of resectability of pancreatic cancer.

To study the accuracy of preoperative staging techniques for assessing resectability of pancreatic and ampullary adenocarcinoma, we entered 88 consecutive candidates into a prospective study of contrast-enhanced computed tomography, magnetic resonance imaging, angiography, and laparoscopy. Resectability was proved in 16 (29%) of 55 patients for the head of the pancreas, 1 (6%) of 17 for the body and tail of the pancreas, and 14 (88%) of 16 for the ampulla. The combined findings of computed tomography and angiography showed that more than 87% of pancreatic head tumors were unresectable because of vascular encasement, but neither modality sufficed alone. Small liver and peritoneal metastases were found in 15 (27%) of 55 cancers of the head of the pancreas, 11 (65%) of 17 cancers of the body and tail of the pancreas, and 1 (6%) of 16 cancers of the ampulla; computed tomography missed all but 2 of these instances of metastasis, but laparoscopy with biopsy identified 22 (96%) of 23 instances. Magnetic resonance imaging findings did not differ significantly from computed tomography and conferred no added benefit. Ninety percent of unresectable tumors were identified. Seventy-eight percent of pancreatic head cancers were resectable when all test results were negative vs 5% (2/37) when any test result was positive. This study demonstrates that accurate and efficient triage is possible for patients with cancer of the pancreas and ampulla.

Angiography↗
PubMed1990

Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging.

An ultrasmall superparamagnetic iron oxide (USPIO) preparation was developed that is small enough to migrate across the capillary wall, a prerequisite in the design of targetable particulate pharmaceuticals. Seventy percent of particles were smaller than 10 nm; 26%, smaller than 5 nm. The blood half-life of USPIO in rats was 81 minutes, considerably longer than that of larger superparamagnetic iron oxide preparations such as AMI-25 (6 minutes). Electron microscopy demonstrated that USPIO particles transmigrate the capillary wall by means of vesicular transport and through interendothelial junctions. Twenty-four hours after intravenous administration, 3.6% of the injected dose per gram of tissue was found in lymph nodes, 2.9% per gram in bone marrow, 6.3% per gram in liver, and 7.1% per gram in spleen. The major potential applications for USPIO are as (a) an intravenous contrast agent for the lymphatic system, (b) a bone marrow contrast agent, (c) a long-half-life perfusion agent for brain and heart, and (d) the magnetic moiety in organ-targeted superparamagnetic contrast agents for magnetic resonance imaging.

Animals↗
PubMed1990

Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging.

An ultrasmall superparamagnetic iron oxide (USPIO) preparation was evaluated as a potential intravenous contrast agent for lymph nodes. Relaxation time measurements and magnetic resonance (MR) imaging were performed in rats with normal lymph nodes and in rats with lymph node metastases. In normal animals, lymph node relaxation times decreased maximally within 24-48 hours after intravenous administration of USPIO. Twenty-four hours after administration, the T2 of normal lymph nodes had decreased from 74 msec +/- 2.2 to 30 msec +/- 0.7 (USPIO, 40 mumol of iron per kilogram) or 15 msec +/- 0.0 (200 mumol Fe/kg), whereas the T2 of metastatic nodes did not change. MR imaging of the animal model of nodal metastases confirmed the hypothesis that intravenously administered USPIO decreases signal intensity of normal but not metastatic nodes. A single intravenous administration of USPIO may allow detection of nodal metastases on the basis of signal intensity characteristics rather than the currently used, insensitive size characteristics.

Animals↗
PubMed1990

Hepatic tumors: quantitative tissue characterization with MR imaging.

To determine which quantitative methods of image analysis are most suitable for the differential diagnosis of benign and malignant hepatic lesions, the authors analyzed magnetic resonance images obtained at 0.6 T in 42 patients with proved hepatic cavernous hemangioma and 63 patients with various hepatic malignancies. The lesion-liver signal-intensity ratio for images obtained with a repetition time of 2,350 msec and echo time of 180 msec was most helpful in distinguishing hemangiomas from cancer (area under the receiving operator characteristic curve [ROC] = 0.99 +/- 0.005). All 38 lesions with lesion-liver signal-intensity ratios greater than 3.5 were hemangiomas, whereas all 57 hepatic tumors with a ratio less than 2.5 were malignant neoplasms. A specificity of 93% and sensitivity of 89% can be achieved with use of quantitative signal-intensity data only. The authors conclude that in conjunction with heavily T2-weighted pulse sequences, signal-intensity ratios are an important adjunct to morphologic analysis in the differential diagnosis of hepatic neoplasms.

Adult↗
PubMed1990

Receptor imaging: application to MR imaging of liver cancer.

A new contrast agent for magnetic resonance (MR) imaging, directed to asialoglycoprotein (ASG) receptors on hepatocytes, was used for detection of liver cancer in rats. Ultrasmall superparamagnetic (mean size, 12 nm) particles of iron oxide (USPIOs) were targeted to ASG receptors by coating particles with arabinogalactan (AG). Liver T2 relaxation times decreased more effectively after a single intravenous administration of AG-USPIO than after an equal dose of a conventional superparamagnetic liver MR contrast agent (AMI-25; mean size, 72 nm). Receptor affinity studies demonstrated that receptor-mediated attachment and subsequent cellular endocytosis do not occur in primary malignant (hepatocellular carcinoma) or metastatic (adenocarcinoma) tumors, because the surface ASG receptors are lost during malignant dedifferentiation. In vitro relaxation and in vivo MR imaging experiments of liver tumors show that targeting USPIO to hepatocytes rather than to the mononuclear phagocytic system allows a considerable dose reduction, increases tumor-liver contrast, and potentially allows distinction of ASG-positive (benign hepatocellular) and ASG-negative (malignant hepatocellular) tumors.

Animals↗
PubMed1990

Detection of hepatic metastases: comparison of contrast-enhanced CT, unenhanced MR imaging, and iron oxide-enhanced MR imaging.

Diagnostic accuracy of contrast-enhanced CT, unenhanced MR imaging, and MR images enhanced with superparamagnetic iron oxide was evaluated in 10 patients with histologically proved hepatic metastases. First, diagnostic performance of the imaging technique with respect to the ability of radiologists to recognize the presence or absence of a metastasis was measured by using receiver-operating-characteristic (ROC) analysis of single images. Second, the total number of lesions (N = 108) detected by "complete" CT and MR examinations was counted. Finally, lesion-liver contrast-to-noise ratios (CNR) were measured in all MR sequences. The area under the ROC curve was .67 +/- .03 for contrast-enhanced CT, .81 +/- .07 for the unenhanced SE 260/14 sequence, and .92 +/- .01 for the iron oxide-enhanced SE 1500/40 sequence. The enhanced SE 1500/40 sequence yielded significantly (p less than .005) greater accuracy than did contrast-enhanced CT. The same sequence detected significantly (p less than .05) more lesions than all other imaging techniques (19% more than the best unenhanced MR sequence and 36% more than contrast-enhanced CT). The enhanced SE 1500/40 sequence also yielded the highest CNR value (19.5 +/- 10.2) of all MR sequences. These results indicate that iron oxide-enhanced MR imaging is a superior imaging technique for the detection of hepatic lesions.

Adult↗
PubMed1990

MR receptor imaging: ultrasmall iron oxide particles targeted to asialoglycoprotein receptors.

Previously we have reported that ultrasmall superparamagnetic iron oxide (USPIO) particles migrate across capillary endothelium, a prerequisite for the design of particulate pharmaceuticals for MR receptor imaging. In the current study, USPIO particles are directed specifically to asialoglycoprotein (ASG) receptors by coupling galactose terminals in the form of arabinogalactan (AG) to these particles. Biodistribution data showed that ASG-directed, AG-coated USPIO (AG-USPIO) particles selectively accumulate in the liver but not in other organs. Electron microscopy of liver showed electron-dense iron oxide particles bound to hepatocyte cell-surface membranes and in large numbers within intracellular lysosomes. The specificity of AG-USPIO for asialoglycoprotein receptors was confirmed by incubation experiments with and without ASG-blocking agents such as D(+)galactose and asialofetuin. In vivo MR imaging in rats showed a significant decrease in liver signal intensity at low doses (2 mumol Fe/kg); no significant changes were observed in the spleen. This decrease in signal intensity is larger than that observed with conventional iron oxides at equal doses. These initial data suggest that, for the first time, superparamagnetic agents can be directed to specific sites for MR imaging by strategies such as receptor targeting.

Animals↗
PubMed1989

Clinical use of a nonferromagnetic needle for magnetic resonance-guided biopsy.

Five patients who had liver lesions detected by magnetic resonance (MR) and/or computed tomography (CT) were biopsied using MR guidance with a specially designed nonferromagnetic needle. The 20-gauge needle was constructed from Type 316 stainless steel in order to maximize needle visibility and minimize needle-tip artifact. In all cases adequate tissue was obtained for diagnosis and no side effects were observed during the biopsy or on clinical follow-up despite the fact that the needle was within the patient in MR for an average of 30 min.

Biopsy, Needle↗
PubMed1989

Central scars in primary liver tumors: MR features, specificity, and pathologic correlation.

Tumor scars were identified at pathologic study and magnetic resonance (MR) imaging in ten of 17 (59%) primary liver tumors (nine hepatocellular carcinomas, four giant hemangiomas, two hepatic adenomas, and two cases of focal nodular hyperplasia). Histopathologic examination revealed three types of scar tissue. Inflammatory scars (n = 4), with edema, necrosis, hypercellularity, and loose fibrous tissue, appeared hypointense relative to liver on T1-weighted images and hyperintense on T2-weighted images. Vascular scars (n = 3), predominantly composed of vascular channels traversing collagenous tissue, showed MR features similar to those of inflammatory scars. Collagenous scars (n = 3) appeared hypointense relative to liver on both T1-weighted and T2-weighted images. Central tumor scars are a frequent but nonspecific feature of both benign and malignant primary liver tumors.

Adult↗
PubMed1989

Forty-millisecond MR imaging of the abdomen at 2.0 T.

The ability of an ultrafast magnetic resonance (MR) imaging technique to provide abdominal MR images free of motion artifacts was studied. Individual T2-weighted transverse MR images were acquired in as little as 40 msec on a whole-body system operating at 2.0 T. Clinical evaluation was undertaken with fat-suppressed images in which only protons of water molecules contributed to image signal intensity. The ultrafast MR images were compared with conventional MR images obtained at 0.6 T. In 22 patients and two healthy volunteers, ultrafast MR images were of diagnostic quality and free of motion artifacts. Images obtained at an echo time (TE) of 30 msec (imaging time, 40 msec) had liver signal-to-noise ratios of 56.3 +/- 22.6 (n = 19). Because of a smaller data matrix, ultrafast MR images had soft-tissue interfaces that were less sharp than those of the highest-quality conventional MR images in which no motion artifacts were present. However, ultrafast MR images demonstrated high T2-dependent soft-tissue contrast, and pathologic and normal anatomies were readily detected with both imaging techniques. This ultrafast imaging technique has significant promise in whole-body MR imaging, in which motion artifacts often degrade image quality.

Abdomen↗
PubMed1989

AIDS in infancy: diagnostic, therapeutic, and ethical problems.

Congenital AIDS is on the rise and will pose multiple problems to society and to health care workers in particular, as more infants develop the disorder. Differentiation of AIDS from infantile grief reactions is of critical importance, as infants at risk for AIDS lose their mothers who have AIDS. Team approaches are optimal and should include psychiatric perspectives. Issues of diagnosis, maladaptive psychological reactions and ethical dilemmas are discussed and illustrated in a case history.

Acquired Immunodeficiency Syndrome↗