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.

Advancing pharmacovigilance through academic-legal collaboration: the case of gadolinium-based contrast agents and nephrogenic systemic fibrosis-a Research on Adverse Drug Events and Reports (RADAR) report.

OBJECTIVE: To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts. METHODS: The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration. RESULTS: The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA. CONCLUSION: Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA. ADVANCES IN KNOWLEDGE: This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.

Gadolinium contrast agents for CNS imaging: current concepts and clinical evidence.

SUMMARY: The aim of this article was to review the properties of the various gadolinium-based contrast agents used for CNS imaging along with the clinical evidence and published data that highlight the impact these different properties can have on diagnostic performance. In addition, approaches to optimizing image acquisition that take into account the different properties of specific gadolinium-based contrast agents and an extensive review of the safety profiles of the various agents are presented.

Application of a semiautomated contour segmentation tool to identify the intervertebral nucleus pulposus in MR images.

BACKGROUND AND PURPOSE: Accurate identification of the NP in MR images is crucial to properly and objectively assess the intervertebral disk. Therefore, computerized segmentation of the NP in T2WI is necessary to produce repeatable and accurate results with minimal user input. MATERIAL AND METHODS: A semiautomated CS method was developed to identify the NP in T2WI on the basis of intensity differences compared with the AF. The method was validated by segmenting computer-generated images with a known ROI. The method was tested by using 63 MR images of rabbit lumbar disks, which were segmented to detect disk degeneration. An ICC was used to assess the repeatability of this method compared with manual segmentation. RESULTS: The error in the detected area of the rabbit NP by using CS was -3.49% ± 4.4% (mean ± SD) compared with 22.36% ± 5.55% by using manual segmentation. Moreover, the method was capable of detecting disk degeneration in a known rabbit puncture model of disk degeneration. Finally, this method had an ICC of 0.97 and 0.99 in regard to segmenting the area and calculating the MR imaging index of the NP, deeming it highly repeatable. CONCLUSIONS: The CS method is a semiautomated computer method able to segment the NP of the rabbit disk and detect disk degeneration. In addition, it could assist in clinical detection, assessment, and monitoring of early degeneration in human disks.

Nephrogenic systemic fibrosis: risk factors suggested from Japanese published cases.

The aim of this article is to review the published cases of nephrogenic systemic fibrosis (NSF) in Japan. The Japanese medical literature database and MedLine were searched using the keywords NSF and nephrogenic fibrosing dermopathy (January 2000 to March 2009). Reports in peer-reviewed journals and meeting abstracts were included, and cases with biopsy confirmation were selected. 14 biopsy-verified NSF cases were found. In seven of eight patients reported after the association between gadolinium-based contrast agent (GBCA) and NSF was proposed, GBCA administration was documented: five received only gadodiamide; two received both gadodiamide and gadopentetate dimeglumine. In four cases, the amounts of contrast agent were registered: two received only a single dose (0.1 mmol kg(-1) body weight) whereas the other two received 7-15 ml (the body weight was not disclosed) for each MR examination. Five patients had multiple injections of GBCA before NSF developed. Except for one patient in whom renal assessment was not reported, none of the patients had an estimated glomerular filtration rate >30 ml min(-1) 1.73 m(-2) and all received dialysis. 5 of the 8 patients (63%) in whom GBCA exposure was confirmed were treated with peritoneal dialysis. Skin lesion of the lower extremity was the first symptom in 12 patients (86%), whereas 2 patients had primarily symptoms from the upper extremity. In three cases, GBCA was administered even after onset of the NSF symptoms because of the physicians' lack of knowledge about the possible association between GBCA and NSF. NSF is found among Japanese end-stage renal failure patients even after examinations using a single dose.

A serial dilution study of gadolinium-based MR imaging contrast agents.

BACKGROUND AND PURPOSE: With the approval of gadobenate dimeglumine, higher relaxivity MR contrast agents were introduced into the clinical environment, and multiple in vivo studies compared the efficacy and safety with the previously approved agents. An in vitro study was conducted to demonstrate differences between the various agents to confirm published values and for imaging-sequence optimization. MATERIALS AND METHODS: A contrast phantom was made with serial dilutions of commercially available formulations of 5 US Food and Drug Administration-approved gadolinium-based MR imaging contrast agents in human serum substitute. Dilution factors ranging from 1:8 to 1:4096 were included in the phantom. Spin-echo sequences were performed at 1.5T and 3T with varying TRs and TEs. RESULTS: At physiologic concentrations and by using short TRs and TEs, gadobenate demonstrated the highest signal intensities, confirming greater R1 relaxivity. At higher concentrations and with longer TR and TE values, the greatest signal intensity loss was appreciated for gadobenate, confirming greater R2 relaxivity. CONCLUSION: Using rigorous in vitro methodology and serial dilution techniques, this study confirms the reported higher R1 and R2 relaxivities of gadobenate relative to the other agents at 1.5T and 3T.

Gadolinium-induced nephrogenic systemic fibrosis in a patient with an acute and transient kidney injury.

Nephrogenic systemic fibrosis (NSF) describes a characteristic fibrosing disorder which typically presents with indurated plaques on the trunk and extremities of patients with advanced renal disease. We present a case of biopsy-confirmed NSF in a patient with severe acute kidney injury with no prior history of renal disease. A 64-year-old man with an acute and severe decrease in glomerular filtration rate underwent magnetic resonance imaging studies with gadolinium contrast (Omniscan) and subsequently developed NSF. His renal disease had normalized at the time his skin disease developed. Skin biopsies revealed findings of NSF and scanning electron microscopy with energy-dispersive X-ray spectroscopy confirmed insoluble gadolinium within lesional tissue.

Granulomatous amebic encephalitis in a multivisceral transplant recipient.

A 40-year-old man with multivisceral allograft developed acutely right-sided numbness 9 months after transplantation. Cranial magnetic resonance imaging (MRI) showed a small left parietal lesion, and cerebrospinal fluid analysis was unremarkable. Stereotactic brain biopsy was non-diagnostic. The patient continued to deteriorate, developed cerebral edema and died at 13 days after the onset of symptoms. Unexpectedly, autopsy demonstrated acanthamebic encephalitis. This case highlights diagnostic difficulties encountered with amebic encephalitis and expands the spectrum of opportunistic central nervous system (CNS) infections in solid and visceral organ transplant recipients.

Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates.

Malignant glioma is a fatal human cancer in which surgery, chemo- and radiation therapies are ineffective. Therapeutic gene transfer used in combination with current treatment methods may augment their effectiveness with improved clinical outcome. We have shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma. Here, we report safety and biodistribution studies of NUREL-C2 using rhesus macaques as a model host. Increasing total doses (1 x 10(7) to 1 x 10(9) plaque forming units (PFU)) of NUREL-C2 were delivered into the cortex with concomitant delivery of ganciclovir (GCV). The animals were evaluated for changes in behavior, alterations in blood cell counts and chemistry. The results showed that animal behavior was generally unchanged, although the chronic intermediate dose animal became slightly ataxic on day 12 postinjection, a condition resolved by treatment with aspirin. The blood chemistries were unremarkable for all doses. At 4 days following vector injections, magnetic resonance imaging showed inflammatory changes at sites of vector injections concomitant with HSV-TK and TNFalpha expression. The inflammatory response was reduced at 14 days, resolving by 1 month postinjection, a time point when transgene expression also became undetectable. Immunohistochemical staining following animal killing showed the presence of a diffuse low-grade gliosis with infiltrating macrophages localized to the injection site, which also resolved by 1 month postinoculation. Viral antigens were not detected and injected animals did not develop HSV-neutralizing antibodies. Biodistribution studies revealed that vector genomes remained at the site of injection and were not detected in other tissues including contralateral brain. We concluded that intracranial delivery of 1 x 10(9) PFU NUREL-C2, the highest anticipated patient dose, was well tolerated and should be suitable for safety testing in humans.

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.

Infectious aneurysm clipping by an MRI/MRA wand-guided protocol. A case report and technical note.

Infectious aneurysms are potentially deadly sequelae of multiple etiologies, typically associated with subacute bacterial endocarditis (SBE). Since these aneurysms tend to be distal, there are no consistent landmarks by which to localize them, in contrast to more typical aneurysms that occur on the circle of Willis or proximal, large cerebral vessel bifurcations. In addition, they tend to be extremely friable and may be obscured by blood if intracranial hemorrhage (ICH) has already occurred. These factors make clipping these aneurysms technically difficult, and searching for easily ruptured aneurysms without standard landmarks adds risk to the procedure. In this report, we describe the case of a 9-year-old boy with SBE and subsequent ICH secondary to a mycotic aneurysm. This aneurysm was localized to within millimeters by the MRI protocol described herein. The aneurysm was excised and the patient recovered without incident. Thus, MRI/MRA-guided frameless stereotaxy may be useful for localizing distal mycotic aneurysms, improving patient outcome by decreasing morbidity and mortality.

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.

Imaging the trigeminal nerve and pons before and after surgical intervention for trigeminal neuralgia.

OBJECTIVE: To study the various imaging changes occurring in the trigeminal nerve and brainstem in patients before or after trigeminal neuralgia surgery. METHODS: During a 7-year period, 275 patients with trigeminal neuralgia underwent high-resolution, contrast-enhanced magnetic resonance imaging (MRI) of the pons during gamma knife radiosurgery. Ninety-seven patients had no previous surgical intervention for trigeminal neuralgia, and 178 patients had undergone one or more previous procedures. Two independent observers, one of whom was blinded to patients' clinical details, reviewed MRI scans retrospectively. The analysis of the independent observers was then correlated with all previous therapeutic interventions. RESULTS: One hundred one MRI scans demonstrated no radiological changes related to trigeminal neuralgia, and 174 MRI scans exhibited some radiological abnormality. The average axial plane diameter of the nerve for all patients was 4 mm (range, 2-6 mm). In the group that had not undergone previous surgery, 65 patients (67%) exhibited vascular compression. In the 88 patients who had undergone previous microvascular decompression, 21 (24%) had evidence of a pontine infarction. Twenty-six patients experienced facial sensory loss, 22 (88%) of whom had undergone previous surgery with evidence of a pontine infarction (n = 11) or perineural scarring (n = 6). CONCLUSION: The majority of patients who had undergone previous trigeminal neuralgia surgery demonstrated readily identifiable abnormalities of the trigeminal nerve or brainstem. The frequency of such changes correlated with the type and number of procedures. Evidence of vascular compression was detected in the majority of patients. Most patients with postoperative facial sensory loss demonstrate changes in the nerve or pons on MR images.

Implantable pulse generators (pacemakers) and electrodes: safety in the magnetic resonance imaging scanner environment.

Static magnetic fields, time-varying electric and magnetic fields, and electromagnetic interference within the magnetic resonance imaging scanner environment can cause the implantable pulse generator (pacemaker) to malfunction and render the electrodes hazardous to the patient. This article provides a review of the literature and of international regulatory guidance concerning safety considerations when these implantable devices are exposed to magnetic resonance imaging.

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.

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.