A Novel Protozoa Parasite-Derived Protein Adjuvant Is Effective in Immunization with Cancer Cells to Activate the Cancer-Specific Protective Immunity and Inhibit the Cancer Growth in a Murine Model of Colorectal Cancer.

Cancer-specific CD8+ cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8+ cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense granule protein 6 (GRA6Nt) of Toxoplasma gondii, an intracellular protozoan parasite, to activate IFN-γ production of microglia, a tissue-resident macrophage population. Therefore, in the present study, we examined whether recombinant GRA6Nt protein (rGRA6Nt) functions as an effective adjuvant to potently activate cancer-specific protective immunity using a murine model of MC38 colorectal cancer (CRC). When mice were immunized with non-replicable (either treated with mitomycin C or irradiated by X-ray) MC38 CRC cells in combination with rGRA6Nt adjuvant and received a challenge implantation of replication-capable MC38 tumor cells, those mice markedly inhibited the growth of the implanted tumors in association with a two-fold increase in CD8+ T cell density within the tumors. In addition, CD8+ T cells of the immunized mice secreted significantly increased amounts of granzyme B, a key mediator of the cytotoxic activity of CD8+ T cells, and IFN-γ in response to MC38 CRC cells in vitro when compared to the T cells from unimmunized mice. Notably, the protective effects of the immunization were specific to MC38 CRC cells, as the immunized mice did not exhibit a significantly inhibited growth of EL4 lymphoma tumors. These results indicate that rGRA6Nt is a novel and effective protein adjuvant when used in immunizations with non-replicable cancer cells to potently activate the protective immunity specifically against the cancer cells employed in the immunization.

Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration.

BACKGROUND AND PURPOSE: Nephrogenic systemic fibrosis following administration of intravenous gadobenate during MR imaging is rare. This study aimed to analyze any nephrogenic systemic fibrosis-related risks and quantify skin gadolinium levels in patients with impaired renal function but without nephrogenic systemic fibrosis who had received gadobenate. MATERIALS AND METHODS: In this retrospective study with a prospective skin biopsy phase, patients with estimated glomerular filtration rates of <60 mL/min/1.73 m2 undergoing contrast-enhanced MR imaging from July 2007 through June 2014 were screened for nephrogenic systemic fibrosis using a questionnaire. This was highly sensitive but not specific and reliably excluded nephrogenic systemic fibrosis if responses to at least 6 of the 8 questions were negative. If no nephrogenic systemic fibrosis was detected, a skin biopsy was requested. RESULTS: Of 2914 patients who met these criteria, 1988 were excluded for various reasons. Of the remaining 926 patients, 860 were screened negative for nephrogenic systemic fibrosis. Of these, 17 (2%) had estimated glomerular filtration rates of <15 mL/min/1.73 m2, 51 (6%) had levels of 15 < 30 mL/min/1.73 m2, 234 (27%) had levels of 30 < 45 mL/min/1.73 m2, and 534 (62%) had levels of 45 < 60 mL/min/1.73 m2. Of the 66 who were not cleared of nephrogenic systemic fibrosis by the questionnaire, 6 patients were evaluated by a dermatologist and confirmed not to have nephrogenic systemic fibrosis (no biopsy required). CONCLUSIONS: A diagnosis of nephrogenic systemic fibrosis was excluded in 860 patients with impaired renal function who were followed up and received gadobenate during MR imaging. In 14 such patients who underwent at least 1 gadobenate-enhanced MR imaging examination and did not have nephrogenic systemic fibrosis, gadolinium levels in the skin were exceedingly low.

T1-weighted parenchyma attenuated inversion recovery: A novel sequence that improves contrast ratio of enhancing brain lesions.

PURPOSE: The purpose of this study was to develop and test a parenchyma attenuated T1-weighted inversion recovery MR sequence (PAIR) that increases the contrast between enhancing and non-enhancing tissues in the brain and to compare the contrast ratio of enhancing brain tumors on this sequence compared to spin echo magnetization transfer (SEMT). PATIENTS AND METHODS: PAIR sequence parameters were developed to reduce signal from gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) in a healthy adult volunteer. Forty-one patients (17 men and 24 women) with a mean age of 55±13 (SD) years (range: 21-78years) with known or suspected brain tumors underwent PAIR and SEMT imaging after intravenous administration of gadobenate dimeglumine. In patients with confirmed tumors, PAIR and SEMT images were compared for contrast ratio of tumor-to-WM, tumor-to-GM, and tumor-to-CSF. RESULTS: A total of 23 enhancing neoplastic lesions were found in 14/41 patients. All tumors were visualized on both contrast enhanced PAIR and SEMT images. PAIR images showed a 2.5 fold increase in maximum tumor-to-GM contrast ratio (P<0.0001), a 1.4 fold increase in maximum tumor-to-WM contrast ratio (P=0.0007) and a 5-fold increase in maximum tumor-to-CSF contrast ratio (P<0.0001). CONCLUSION: PAIR provides improved lesion-to-background contrast ratio compared to SEMT and may be useful as an added sequence in tumor evaluation.

Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia.

A 52-year-old Caucasian male was followed with Mattis and 31P MRS examinations every 6 months for 33 months. At entry into the study, the subject had a normal clinical examination and normal Mattis scores but had alterations in MRS measures of membrane phospholipid and high-energy phosphate metabolism indistinguishable from those previously reported in mildly demented AD patients. After 33 months of follow-up, the subject had clinical and Mattis findings suggestive of possible incipient dementia and after 46 months of follow-up there was sufficient cognitive decline to make the diagnosis of dementia with a frontal lobe preponderance. The findings in this subject support the contention that alterations in brain membrane phospholipid and high-energy metabolism can be noninvasively detected by 31P MRS years before any clinical manifestations of the disease.

Conversion to neoral for neurotoxicity after primary adult liver transplantation under tacrolimus.

BACKGROUND: Neurological complications after orthotopic liver transplantation (OLTX) have remained a major concern in a small proportion of patients. The etiology of these complications is often thought to be multifactorial: the influence of calcineurin inhibitors is occasionally thought to play an important role. When neurotoxicity occurs after OLTX under tacrolimus, it is usually a minor complication and responds readily to a reduction in the dosage of or a temporary withdrawal of tacrolimus. However, neurotoxic complications occasionally do not respond to this conventional process. Neoral is a microemulsion formulation of cyclosporine. It has more consistent pharmacokinetic parameters and improved bioavailability when compared with conventional cyclosporine. The aim of the present report was to evaluate the role of Neoral in OLTX recipients with neurotoxic complication who failed to respond to a reduction in the dosage of tacrolimus. METHOD: Between August 1995 and November 1997, 330 adults (age >18 years) received primary OLTX under tacrolimus-based immunosuppression (mean age 52.6+/-11.4 years). There were 190 men and 140 women. Twenty-three (7%) patients (mean age 53.2+/-11.8 years; 17 men, 6 women) were converted to Neoral (mean 35+/-41 days after OLTX). These patients were followed until June 1998 (mean follow-up 22.7+/-7.8 months). RESULTS: Four (17.4%) patients died during the follow-up period, and two patients underwent retransplantation. Neurological symptoms improved in all patients who survived. Adequate trough concentrations were achieved in all patients with p.o. Neoral. Nine (39%) patients experienced rejection episodes after conversion. Six (26.1%) patients were converted back to tacrolimus because of ongoing rejection (n=3), retransplantation (n=2), or persistent nausea and vomiting (n=1) without recurrence of the original neurological complication. CONCLUSION: Neurological complications after OLTX disorders that occur under tacrolimus and that fail to respond to a reduction in the dosage can be treated safely by conversion to Neoral. However, the rate of rejection is up to 39%, and patients can often be converted back to tacrolimus without recurrence of the original neurological complication.

Ferrioxamine as a magnetic resonance contrast agent. Preclinical studies and phase I and II human clinical trials.

The preclinical and clinical trial experience with ferrioxamine (S-FDF; Salutar, Inc.) as a contrast agent for magnetic resonance imaging (MRI) is summarized. The results in 44 patients or subjects show that the drug is safe and well tolerated when given intravenously. In certain conditions, early results show that the use of this contrast agent provides more information than can be obtained with MRI alone.

A clinical comparison of the safety and efficacy of MultiHance (gadobenate dimeglumine) and Omniscan (Gadodiamide) in magnetic resonance imaging in patients with central nervous system pathology.

RATIONALE AND OBJECTIVES: The safety and diagnostic efficacy of MultiHance (gadobenate dimeglumine) in the central nervous system (CNS) were evaluated in a double-blind, multicenter, phase III clinical trial. METHODS: Two hundred five patients highly suspected of having a CNS lesion (by previous imaging exam) were enrolled at 16 sites in the United States. Patients were randomized to one of three incremental dosing regimens. Magnetic resonance imaging with Omniscan (gadodiamide) at doses of 0.1 and 0.3 mmol/kg was compared with MultiHance (gadobenate dimeglumine) at doses of 0.05 and 0.15 mmol/kg and at 0.1 and 0.2 mmol/kg. RESULTS: Compared with predose images alone, efficacy was demonstrated in each of the gadobenate dimeglumine and gadodiamide groups (single and cumulative doses) as indicated by the level of diagnostic information, number of lesions detected, and contrast-to-noise ratio measurements. The level of diagnostic information from gadobenate dimeglumine at 0.1 mmol/kg was equivalent to that with gadodiamide at the same dose. One of the two blinded reviewers found equivalence between the gadobenate dimeglumine 0.05 mmol/kg dose and gadodiamide at 0.1 mmol/kg. Both reviewers found the level of diagnostic information to be equivalent after the second dose of contrast for all three dosing regimens. The cumulative doses of gadobenate dimeglumine were well tolerated and as safe as gadodiamide. CONCLUSIONS: Gadobenate dimeglumine is comparable to gadodiamide in terms of safety and efficacy for imaging of CNS lesions, with a possible advantage in imaging applications owing to enhanced T1 relaxivity.

Magnetic resonance imaging in patients with central nervous system pathology: a comparison of OptiMARK (Gd-DTPA-BMEA) and Magnevist (Gd-DTPA).

RATIONALE AND OBJECTIVES: The objective of the two pivotal phase 3 studies was to evaluate the safety and efficacy of OptiMARK (Gd-DTPA-bis(methoxyethylamide) [Gd-DTPA-BMEA]) compared with Magnevist (Gd-DTPA) in magnetic resonance imaging of the central nervous system. METHODS: Two multicenter, randomized, double-blind, parallel group studies were conducted in 395 patients with known or suspected central nervous system pathology. Subjects were randomized to receive a single 0.1 mmol/kg intravenous injection of either Gd-DTPA-BMEA or Gd-DTPA. The safety of Gd-DTPA-BMEA and Gd-DTPA was monitored for up to 72 hours after study drug administration. Precontrast and postcontrast administration magnetic resonance scans were acquired using identical imaging planes and techniques. RESULTS: No deaths or unexpected adverse events were reported in either group. A comparison of adverse events by intensity and relation demonstrated no statistically significant differences between the two groups. Gd-DTPA-BMEA and Gd-DTPA were equivalent with respect to confidence in diagnosis, conspicuity, and border delineation. CONCLUSIONS: Gd-DTPA-BMEA and Gd-DTPA demonstrated comparable efficacy profiles, and the safety profiles were considered similar.

Computer-based tutorial in MR imaging.

PURPOSE: To test the effectiveness of customized software as a teaching tool to help the novice understand basic physics concepts underlying the creation of MR images via various pulse sequences. METHODS: The authors have developed animating graphic and highly interactive electronic MR audiovisual software for the Macintosh computer in the C programming language, and have integrated it into the classroom setting for teaching MR imaging physics concepts such as T1, T2, T2*, proton density, RF excitation, TR, TE, TI, flip angle, static magnetic field strength, gradient magnetic fields, section thickness, number of phase-encoding gradients, number of excitations, field of view, intersection gap, receiver bandwidth, contrast agent(s), etc. The program interactively demonstrates the effects of these variables upon such imaging objectives as voxel dimensions, section quantity, total scanned volume, signal-to-noise ratio, contrast, contrast-to-noise ratios, resolving power, and scan acquisition time. Partial saturation, gradient echo, inversion recovery, and fat-saturation imaging techniques are included. Written posttests on the syllabus covered in our basic MR course were administered to three groups: 43 student professionals (technologist/physicist/radiologist) (control professional group) before, 149 student professionals (exposed professional group) after the addition of the tutorial software into the MR course as an integral part of the teaching process, and a group of 200 pharmaceutical sales staff with little to no prior MR or scientific background (exposed pharmaceutical group). The scores were then evaluated and compared among the groups. One hundred ten students exposed to this software also anonymously rated the software on a 1 to 5 scale (harmful to very helpful, respectively) as to their feeling regarding its role in their MR educational experience and the ease with which they were able to understand the material covered in the basic MR course curriculum. RESULTS: Mean test scores were statistically significantly lower in the Control Professional Group (60%, +/- 2.59 standard error of the mean (SEM)) than in either the Exposed Pharmaceutical (73% +/- 0.75 SEM) or Exposed Professional Groups (77% +/- 0.99 SEM). The mean subjective assessment score regarding the software was 4.8 (scale 1 to 5). CONCLUSION: This custom-developed interactive MR tutorial software is demonstrated to be effective in assisting even those new to MR imaging in understanding the concepts underlying MR imaging physics in a manner that is felt to be significantly more palatable than lectures, articles, and/or textbooks alone.

MR findings in listerial rhombencephalitis.

We describe a case of listerial rhombencephalitis in a previously healthy 40-year-old man. The diagnosis was based on the clinical findings, results of cerebrospinal fluid analysis, blood culture, and MR imaging findings. The treatment was started before culture results were available, and the patient had a full clinical recovery.

Vertebral mass resulting from a chronic-contained rupture of an abdominal aortic aneurysm repair graft.

We describe a case of a 63-year-old man with chronic-contained rupture of an abdominal aortic aneurysm at the site of prior graft repair of the aneurysm. Initially misinterpreted as osteomyelitis on the basis of CT findings, this chronic-contained rupture of the abdominal aorta eroding the vertebrae was preoperatively diagnosed at MR imaging and confirmed at surgery. A conventional angiogram failed to show the pseudoaneurysm. Owing to a major difference in the management of a contained aortic aneurysm rupture versus that for osteomyelitis, MR imaging with CT or MR angiography is recommended before any operative or invasive procedure.

T2-weighted MR characteristics of internal auditory canal masses.

PURPOSE: To determine whether masses of the internal auditory canal are hypointense relative to cerebrospinal fluid, and therefore visible, on fast spin-echo T2-weighted MR images. METHODS: Forty-six patients had 50 masses of the internal auditory canal, identified initially on contrast-enhanced MR images, that were evaluated retrospectively for signal intensity of the mass with respect to cerebrospinal fluid and for visibility of the neural elements within the internal auditory canal on T2-weighted images. RESULTS: Forty-seven of 50 masses were clearly identified on T2-weighted images. Three small abnormalities (2 to 4 mm) were not seen with confidence on T2-weighted images. However, on close inspection of these three masses, the small abnormality on contrast-enhanced MR images corresponded to a hypointense focus on T2-weighted images. All 50 masses were hypointense relative to cerebrospinal fluid on T2-weighted images. CONCLUSION: All masses of the internal auditory canal in this study were hypointense relative to cerebrospinal fluid on T-2 weighted images, and were therefore visible.

Chronic acquired hepatic failure: MR imaging of the brain at 1.5 T.

The results of MR imaging of the brain at 1.5 T in 42 adults with non-Wilsonian chronic hepatic failure are reported. T1-weighted images demonstrated increased signal in the globus pallidus in 30 patients and in the putamen in 21, while T2-weighted images demonstrated no corresponding alteration in signal intensity. Symmetric low intensity in the central portion of the globus pallidus on spin-density and T2-weighted images in two patients correlated with regions of calcification on CT scans. Increased intensity on T1-weighted images also occurred in the mesencephalon surrounding the red nucleus (17/42) and in the quadrigeminal plate (4/42). Three patients demonstrated increased intensity in the pons on T2-weighted images unassociated with clinical brainstem dysfunction. Increased intensity on T1-weighted images was seen in the anterior pituitary in 28 of 35 patients. Alterations in signal intensity were not demonstrated in the cerebral cortex or cerebellum. MR findings did not correlate with laboratory indices of hepatic or thyroid function, with histologic liver diagnosis, or with neurologic status at the time of MR evaluation. Increased signal intensity in the basal ganglia, pituitary gland, and mesencephalon surrounding the red nuclei is characteristic of chronic hepatocellular dysfunction. Deposition of an as yet unidentified paramagnetic substance or altered intracellular water relaxation associated with the proliferation of astrocyte cytoplasmic organelles is postulated as the likely mechanism for this previously undescribed MR manifestation of chronic acquired hepatic failure.

Acquired hepatocerebral degeneration: MR and pathologic findings.

Acquired (non-Wilsonian) hepatocerebral degeneration (AHD) is a rare irreversible neurologic syndrome that occurs in patients with chronic liver disease associated with multiple metabolic insults. The pathophysiology and the locations of the cerebral injuries are incompletely understood. We describe a patient with fatal hepatic cirrhosis and AHD in whom MR images showed abnormalities in the brachium pontis bilaterally. Neuropathologic evaluation disclosed multiple regions of subcortical spongiform white matter changes.

Reversible ischemia determined by xenon-enhanced CT after 90 minutes of complete basilar artery occlusion.

Intraarterial thrombolytic therapy decreases mortality in the treatment of acute basilar artery occlusion. An acute decrease in cerebral blood flow (CBF) (<12 mL/100 g per minute) has been reported to invariably result in infarction. We report a case of acute basilar artery occlusion, recanalized within 90 minutes, with reversal of CBF of less than 6 mL/100 g per minute. After reperfusion, areas with persistent CBF of 6 mL/100 g per minute resulted in infarctions on subsequent CT studies. Parenchymal viability is possible after 90 minutes of posterior CBF of 6 mL/100 g per minute.

Multicenter trial of gadoteridol, a nonionic gadolinium chelate, in patients with suspected head and neck pathology.

PURPOSE: To evaluate the safety and efficacy of gadoteridol as an MR contrast agent in patients with suspected head and neck pathology. METHODS: One hundred thirty-three adult patients were studied with MR at 12 clinical trial sites before and after the intravenous administration of 0.10 mmol/kg gadoteridol. After enrollment, patients underwent a complete physical examination. Patient monitoring included vital signs, laboratory tests, and recording of the incidence and duration of adverse events. To evaluate efficacy, postcontrast T1-weighted images were compared with precontrast T1- and T2-weighted images. Investigators having clinical information evaluated 129 studies for efficacy; two readers blinded to clinical information subsequently evaluated 122 studies using the same criteria as the investigators. RESULTS: Eight patients (6.0%) experienced mild adverse events possibly or probably related to contrast administration, all of which resolved without treatment. Two clinically significant laboratory abnormalities considered related or possibly related to the administration of gadoteridol were reported in two patients. Enhancement of pathology was seen in 82.9% of cases evaluated by investigators at the study site and in 78.7% of cases subsequently evaluated by the blinded readers. Postcontrast images were judged by investigators to provide additional diagnostic information over precontrast images in 68.9% of studies. The additional diagnostic information available on postcontrast studies most often consisted of improved visualization of pathology and better definition of lesion borders. The use of this information might have contributed to a change in patient diagnosis in 18.6% of the cases evaluated by the investigators and in 16.4% of the cases reviewed by the blinded readers. CONCLUSIONS: Preliminary results show gadoteridol to be a safe and efficacious contrast agent for enhanced MR study of extracranial and extraspinal head and neck pathology.

Orbital imaging: factors determining magnetic resonance imaging appearance.

This article addresses the dependence of the image characteristics in MR imaging of the orbit. Among the variables discussed are signal-to-noise (SNR), field of view (FOV), spatial resolution, and their interdependence. It is further shown how image contrast can be controlled by judicious choice of pulse timing parameters and how contrast depends on the intrinsic tissue MR parameters T1, T2, and proton density.

Magnetic resonance imaging of spinal dysraphism.

MR imaging has become the definitive diagnostic procedure for the evaluation of suspected spinal dysrhaphic processes. Techniques for spinal MR imaging are discussed and MR findings in patients with surgically verified dysrhaphic spinal lesions are reviewed.

Pediatric musculoskeletal magnetic resonance imaging.

MRI has demonstrated clinical applicability and improved diagnostic capability in the musculoskeletal system to a degree rivaling its success in the neurologic system. For certain regions such as the joints, the superficial nature of these structures is ideal for the application of localized radiofrequency coils, enabling considerably improved signal, spatial resolution, and detectable contrast. The multiplanar capability is often invaluable in assessing such regions as the weight-bearing surfaces of the hips. It has been shown to be the most sensitive single test for diagnosing avascular necrosis, and has yielded very high resolution images of the internal architecture of the joints and soft tissues in an entirely noninvasive manner and without the need for the administration of exogenous contrast agents. Short TE images are quite useful in evaluating fatty background regions of interest, such as the bone marrow and subcutaneous tissue, whereas long TR and TE studies are frequently more suitable for soft tissue pathology. The lack of ionizing radiation and the continued failure of intensive research to disclose any deleterious effects at the levels used for clinical diagnostic imaging make this tool especially appealing for application to the pediatric population. With the continual development of new pulsing sequences, contrast agents, and further advances in imaging/spectroscopic correlation, magnetic resonance imaging of the musculoskeletal system is ensured of a solid role in the clinical diagnostic evaluation of the pediatric population.

Stereotactic magnetic resonance angiography for targeting in arteriovenous malformation radiosurgery.

Because conventional stereotactic angiography provides only two-dimensional information for dose planning, we studied the accuracy and usefulness of stereotactic magnetic resonance angiography (sMRA) for arteriovenous malformation (AVM) radiosurgery in 28 consecutive patients. We hypothesized that the multidimensional data set provided by sMRA and the opportunity to image both blood vessels and brain parenchyma would improve the accuracy of AVM irradiation and improve the safety of radiosurgery. Twenty-eight patients with AVMs in different brain locations and with a variety of AVM sizes (range, 15-31 mm mean diameter) had sMRA followed by stereotactic angiography. The sMRA images only were used to construct an initial radiosurgical plan. This plan was then used to outline the AVM volume defined by conventional angiography. In 24 patients, sMRA information equaled that of conventional angiography. In 3 patients, sMRA was better, because conventional angiography overestimated the size of the AVM nidus. In one patient, the conventional angiogram showed a second separate nidus (10-mm diameter) that was not as well defined on MRA. There were no complications with any procedure. In 16 patients (57%), sMRA provided critical information on AVM shape that was not provided by conventional angiography alone. Stereotactic MRA is a fast, noninvasive, inexpensive, multidimensional imaging method for AVM radiosurgery that provides information on vascular and parenchymal brain anatomy important for optimal dose planning. We believe that it can be used with confidence as the sole imaging method for medium-size, compact-nidus AVMs.