Standards of quality in medical research: who decides?
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Biomedical subjects
Publications and source records attributed to D D Stark.
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Superparamagnetic iron oxide (ferrite), a novel, reticuloendothelial cell-specific contrast agent used for magnetic resonance imaging (MRI), was evaluated in the detection of liver and spleen tumors in animal models and in phase I and II clinical trials in 33 patients. The initial results obtained in experimental cancer models showed a dramatic improvement in tumor detection. Our first clinical trials confirmed the experimental results and showed that ferrite-enhanced MRI significantly (p less than 0.05) increases the detection of individual lesions. Furthermore, the threshold of detectable tumor size decreased significantly, to 3 mm, when standard MR spin echo imaging techniques were used.
This paper presents an analysis of signal-to-noise and contrast-to-noise ratios from small tip angle, gradient reversal (FLASH) imaging. Analytic and numerical techniques are used to determine the delay times and tip angles that maximize signal-to-noise per unit time from a single tissue. Similar procedures are used to determine the delay times and tip angles that maximize both T1-induced and T-2*-induced contrast-to-noise per unit time for a pair of tissues as a function of tissue characteristics and pulse sequence sampling times. The advantage of optimized FLASH imaging over optimized spin-echo imaging is quantitated by comparing signal-to-noise and contrast-to-noise ratios per unit time from the two sequences. Images are used to confirm these numerical results, to compare noise levels resulting from gradient reversals versus 180 degrees rephasing pulses and to assess the possible adverse effects of static magnetic field inhomogeneities on FLASH imaging.
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The potential of superparamagnetic ferrite particles as a contrast agent for magnetic resonance (MR) imaging was studied by in vitro MR spectroscopy and in vivo MR imaging in laboratory animals. After aqueous preparations of ferrite particles were administered intravenously, MR spectroscopy showed greatly decreased T2 relaxation times of liver and spleen, with only minimally altered T1, and no changes in lung, kidney, or muscle. Effects occurred within 30 minutes of injection and persisted for more than 6 months. MR imaging with pulse sequences that provide T2-dependent contrast demonstrated that ferrite produced profound signal loss from liver, spleen, and bone marrow. Sequestration of ferrite particles in hepatic reticuloendothelial cells was confirmed by means of light and electron microscopy. Because ferrite has a potent effect on MR signal and exhibits tissue-specific localization, it warrants further study as a contrast agent for MR imaging of the reticuloendothelial system (i.e., liver, spleen, and bone marrow).
The potential of superparamagnetic ferrite particles to enhance detection of liver carcinoma at magnetic resonance (MR) imaging was studied with in vitro MR spectroscopy and in vivo MR imaging in animal models. After intravenous administration of ferrite, MR spectroscopy showed selective shortening of T2 relaxation times in normal liver but not in tumor. MR imaging showed that ferrite produced profound signal loss only from normal liver and not tumor; thus, differences in signal intensity between liver and tumor were greatly enhanced, especially on pulse sequences with T2-dependent contrast. Motion artifacts were reduced as well because of less signal from liver. Microscopic analysis showed sequestration of ferrite particles in hepatic reticuloendothelial cells but not in hepatocytes or tumor tissue, and there was no evidence of cellular injury. Ferrite particles efficiently and predictably enhance signal differences between normal liver and tumor and permit considerable latitude in selection of pulse sequence and timing parameters. Thus, they have considerable promise as a tissue-specific MR contrast agent for improved detection of liver carcinoma.
The influence of signal averaging (n), repetition time (TR), and echo delay (TE) on systematic noise (cardiac, vascular, respiratory, and peristaltic ghost artifacts) and statistical noise (thermal effects) was determined in eight healthy volunteers and 57 patients. Systematic noise was the dominant factor degrading abdominal magnetic resonance (MR) images. Signal averaging was the primary determinant of both statistical and systematic image noise, fitting a power function (n)b with b = 0.44 and -0.42, respectively, close to the expected b = -0.5 power function. All types of ghosting showed the same sensitivity to signal averaging. Normalized systematic noise increased slightly with TR (b = 0.16) and increased markedly with TE (b = 0.40). These data indicate that the short TR, short TE technique is a powerful method for reducing motion artifacts on breathhold images and can be combined with signal averaging to further suppress artifacts, improve signal-to-noise ratio, and maximize anatomic resolution.
Diverse materials with varying physical and magnetic properties have been evaluated as gastrointestinal contrast agents for magnetic resonance (MR) imaging. Uniform marking of the small bowel remains the greatest challenge. Ferrites are magnetically active iron oxide particles that are miscible with water and cause loss of signal on MR images. The decrease in MR signal intensity produced by ferrites occurs with a wide range of iron concentrations (0.1-10 mM) and with both T1- and T2-weighted pulse sequences. These effects of ferrites are explained by predominant T2 shortening with negligible T1 effects. The ferrite preparation used in this study was stable in vitro, with little iron solubilized by acid. Intragastric administration of ferrite (5 mg of iron per kg in 6 ml) routinely marked the small bowel of rats. The authors conclude that ferrites represent a promising new class of contrast agents for gastrointestinal MR imaging.
Twenty-four patients with acute sigmoid diverticulitis and associated pelvic fluid collections seen on computed tomographic scans underwent percutaneous catheter drainage as an adjunct to surgical therapy. Fourteen of the 24 underwent a single-stage surgical procedure within 10 days of drainage. Five patients required two-stage surgical procedures because localized inflammatory changes precluded a primary resection despite the absence of a residual abscess at surgery. Two of the three remaining patients initially had no surgery, but they had recrudescences of their symptoms that required surgical drainage within 8 months. One patient in whom surgical resection was deferred remained asymptomatic 10 months after percutaneous drainage. A retrospective review of 87 patients undergoing surgery for diverticulitis suggested that the percentage of two-stage surgical procedures has decreased in the last 5-10 years, but there remains a substantial number of patients who might benefit from percutaneous catheter drainage of diverticular abscess of the sigmoid colon.
To determine the accuracy of magnetic resonance (MR) imaging relative to computed tomography (CT) in the diagnosis of liver metastases, a randomized, controlled study was conducted of 135 subjects, including 57 with cancer metastatic to the liver, 27 with benign cysts or hemangiomas, and 51 without focal liver disease. The sensitivity of MR imaging for detecting individual metastatic deposits was 64%, significantly greater than 51% for CT (P less than .001); the difference in sensitivity for identifying patients with one or more hepatic metastases was less (82% for MR imaging vs. 80% for CT). In patients without hepatic metastases, the specificity of MR imaging was 99% versus 94% for CT. Significant differences were found between individual MR pulse sequences in detection of individual lesions. The sensitivity of both T1-weighted spin-echo (SE) (64%) and inversion-recovery (IR) (65%) pulse sequences was significantly (P less than .001) greater than either the TE (echo time) 60 msec (43%) or TE 120 msec (43%) T2-weighted pulse sequences. Overall, the accuracy of a single T1-weighted (10-minute) pulse sequence was superior to that of contrast-enhanced CT.
Magnetic resonance images were obtained before and after treatment in 17 patients with 29 amebic liver abscesses. Pretreatment T1-weighted images showed a sharply circumscribed, heterogeneous, low-signal-intensity mass, devoid of normal hepatic tissue and corresponding to the abscess cavity as measured sonographically. T2-weighted images showed the abscess cavity as a hyperintense region and also showed a larger region of hyperintensity extending from the cavity margins to the liver surface, corresponding to edematous but morphologically normal liver tissue. After treatment, the abscess cavity became homogeneously hypointense on T1-weighted images, corresponding to liquefaction of the abscess center. With successful treatment, concentric rings corresponding to (a) an inner margin of inflamed granulation tissue, (b) bands of type I collagen, and (c) the outer margin of atrophic and/or mildly inflamed liver tissue became prominent on T1- and T2-weighted images. T2-weighted images showed rapid resolution of the perifocal hepatic edema.
Extracranial hematomas have variable CT appearances and may be confused with other entities. MR imaging of 12 patients with intraabdominal or intrapelvic hemorrhages showed that intraabdominal hematomas develop a unique MR appearance after 3 weeks. Nine hematomas imaged after this time all showed a characteristic concentric-ring configuration, with a thin, dark peripheral rim on all pulse sequences and a bright inner ring most distinctive on T1-weighted images. Six hematomas imaged during the first 3 weeks failed to show this architecture. The concentric rings in MR images of chronic hematomas allowed a tissue-specific diagnosis.
High-frequency, high-resolution sonography was used to detect recurrent thyroid carcinoma in 73 patients with papillary carcinoma, 16 with medullary carcinoma, 10 with follicular carcinoma, and one with small-cell carcinoma. Of the 36 patients with negative sonograms, 35 had no other evidence of recurrence, while one had surgical proof of recurrence. Of 25 patients with positive sonograms, confirmed with surgery or radioactive iodine (I131) scanning (sonographic sensitivity 96%, specificity 83%), palpation was negative in 17 (palpation sensitivity 32%, specificity 100%). Thirty-two patient with positive sonographic findings had no objective clinical proof of recurrence. There were seven false-positive studies. This study suggests that sonography may be the method of choice for earliest detection and localization of recurrent carcinoma of the thyroid.
One hundred eighty-seven diagnostic and therapeutic interventional procedures in the pleural space were performed by using sonographic guidance. These consisted of diagnostic aspiration (118), drainage of malignant and nonmalignant effusions (41), empyema drainage (17), pleural sclerotherapy with tetracycline or bleomycin (7), and pleural biopsy (4). Diagnostic aspiration was performed with 20-gauge needles, and therapeutic and empyema drainages were performed by trocar technique with either a 7-French Sacks catheter or a specially designed empyema drainage catheter. Pneumothoraces were seen in 3% of the patients, and most of these were treated by the radiologist with placement of a Heimlich valve. We conclude that the use of sonography allows rapid localization of pleural fluid collections and instant monitoring of drainage of noninfected fluid collections and empyemas.
Detection of intrasplenic neoplasms using sonography, CT, and scintigraphy is limited by poor inherent tumor-spleen contrast relative to image noise. Despite the wide range of contrast parameters available for MR imaging, similar limitations have been found with this technique. Magnetopharmaceuticals have the ability to enhance tumor-spleen contrast and improve lesion detectability. In this study, a rodent model of cancer metastasized to the spleen was used to evaluate the potential of superparamagnetic ferrite particles as a tissue-specific reticuloendothelial contrast agent. Other studies have shown ferrite to have little or no toxicity. Without contrast material, metastatic adenocarcinoma of the spleen could not be distinguished from normal splenic parenchyma on in vivo MR images. At a dose of 50 mumol Fe/kg, the T2 relaxation time of spleen decreased by 77%, while tumor T2 was essentially unchanged (p less than .005). Intrasplenic tumors 4-6 mm in size became readily detectable on in vivo MR images after the administration of ferrite particles. Lesion conspicuity, quantitated by the tumor-spleen contrast-to-noise ratio, showed a 43-fold increase. Ferrite particles show great promise as a contrast agent to enhance the detection of focal splenic lesions.
The purpose of this investigation was to define the potential of unenhanced and ferrite-enhanced MR to detect hepatic lymphoma. Rats were implanted with diffuse and focal hepatic lymphoma. Both in vitro measurements of relaxation times and in vivo MR imaging of normal liver and of diffuse and focal hepatic lymphoma were compared. Diffuse infiltrative hepatic lymphoma showed increased T1 (45%) and T2 (41%) relaxation times in vitro, but could not be distinguished from normal control livers on in vivo spin echo (SE) images with a repetition time of 500 msec and an echo time of 30 msec (SE 500/30) or SE 1500/60 images. Focal hepatic lymphoma showed increased T1 (185%) and T2 (115%) relaxation times relative to normal liver tissue. Focal hepatic lymphoma was undetectable on unenhanced SE 500/30 MR images (contrast-to-noise ratio, C/N = 0.4) and was slightly hyperintense on SE 1500/60 images (C/N = 1.1). Ferrite (50 mumol Fe/kg) was administered to improve tissue contrast. In normal control animals, T2 of liver in vitro decreased from 29.3 +/- 3.3 msec to 11.1 +/- 1.2 msec, and image signal-to-noise ratio (S/N) of liver in vivo decreased from 16.1 +/- 2.4 to 2.8 +/- 0.3 (p less than .005). Ferrite-enhanced diffuse hepatic lymphoma showed in vitro T2 values and in vivo MR image S/N values indistinguishable from those of normal control animals. The T2 of focal hepatic lymphoma was essentially unaltered by ferrite. On SE 500/30 images, focal hepatic lymphoma became readily detectable, quantitated by a 35-fold increase in tumor-liver C/N. We conclude that clinical studies are warranted to determine the value of ferrite enhanced MR as a technique for the enhanced detection of focal hepatic lymphoma.
Seven patients with internal jugular and/or subclavian vein thrombosis were studied with real-time sonography and venography. High-resolution real-time sonography was used to tabulate morphologic parameters (venous size, shape, intraluminal echoes, and presence of collateral veins), as well as physiologic parameters (mobile venous valves, distention, compressibility, pulsation). Chronic venous thrombosis was characterized by the presence of collateral veins, spread of the thrombus to other major veins, and loss of normal vascular landmarks with poor visualization of the actual thrombus, the "cut-off sign." Acute catheter-induced thrombosis was confined to one vessel, and the thrombus was seen clearly in all cases. Two new signs of thrombosis, the absence of the beating venous valve and the "cut-off sign," are particularly useful in the sonographic diagnosis of internal jugular vein thrombosis.
Intravenous administration of ferrite particles may be useful as contrast agents for magnetic resonance (MR) imaging of the liver. We studied several sensitive biochemical parameters of hepatocellular function and toxicity in rats after intravenous ferrite injections to determine whether there was any evidence of iron-induced hepatotoxicity. Light microscopy and iron determinations were performed on the liver, spleen, lung, and kidney. Forty-eight hours after a massive (250 mg iron per kilogram) ferrite injection, liver, spleen, and lung nonheme iron concentrations were markedly increased. Microscopy showed this iron to be entirely in reticuloendothelial cells. Despite the large increase in hepatic iron concentration, we found no evidence of hepatic mitochondrial or microsomal lipid peroxidation or organelle dysfunction, sensitive biochemical indicators of iron-induced hepatocellular injury. At 10 to 11 weeks after administration of ferrite in smaller doses (30 mg iron per kilogram), results of all biochemical and morphologic studies were normal. Furthermore, quantitative iron determinations and microscopic studies suggest that ferrite particles may be partially degraded and that iron is cleared from the liver during a 3-month period. Because ferrite particles are taken up by reticuloendothelial cells, hepatocellular function is not impaired and iron-induced hepatocellular injury does not occur.