Current Updates and Unmet Needs of Brain MRI-Based Artificial Intelligence Software for Patients With Neurodegenerative Diseases in the Republic of Korea

In aging societies, incidences of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are increasing. Neurodegenerative diseases are bringing main challenges to the healthcare system in today’s world. Analyzing characteristic imaging patterns of patients with neurodegenerative diseases is important. Since objective and reliable imaging assessments and precise analyses can lead to early diagnosis of neurodegenerative diseases, imaging patterns are being increasingly investigated. Artificial intelligence (AI) analyzing brain MRI has been applied to neurodegenerative diseases, providing added value in early diagnosis. MRI-based AI software has been developed and studied worldwide, with some AI-based software already being used in actual clinical care. Currently, there are MRI-based volumetry and segmentation software available. There is also an unmet demand for the application of AI in neurodegenerative diseases. Here, we review current status and unmet needs for application of AI in neurodegenerative diseases. We also discuss current limitations of AI, suggestion for AI-based software, and how it can be clinically applied in the future.

Brain MRI-Based Artificial Intelligence Software in Patients with Neurodegenerative Diseases: Current Status

and reliable assessment and precise detection are important for the early diagnosis of neurodegenerative diseases. Artificial intelligence (AI) using brain MRI applied to the study of neurodegenerative diseases could promote early diagnosis and optimal decisions for treatment plans. MRI-based AI software have been developed and studied worldwide. Representatively, there are MRI-based volumetry and segmentation software. In this review, we present the development process of brain volumetry analysis software in neurodegenerative diseases, currently used and developed AI software for neurodegenerative disease in the Republic of Korea, probable uses of AI in the future, and AI software limitations.

Diagnostic Yield of Diffusion-Weighted Brain Magnetic Resonance Imaging in Patients with Transient Global Amnesia: A Systematic Review and Meta-Analysis

Objective@#To investigate the diagnostic yield of diffusion-weighted imaging (DWI) in patients with transient global amnesia (TGA) and identify significant parameters affecting diagnostic yield. @*Materials and Methods@#A systematic literature search of the MEDLINE and EMBASE databases was conducted to identify studies that assessed the diagnostic yield of DWI in patients with TGA. The pooled diagnostic yield of DWI in patients with TGA was calculated using the DerSimonian-Laird random-effects model. Subgroup analyses were also performed of slice thickness, magnetic field strength, and interval between symptom onset and DWI. @*Results@#Twenty-two original articles (1732 patients) were included. The pooled incidence of right, left, and bilateral hippocampal lesions was 37% (95% confidence interval [CI], 30–44%), 42% (95% CI, 39–46%), and 25% (95% CI, 20–30%) of all lesions, respectively. The pooled diagnostic yield of DWI in patients with TGA was 39% (95% CI, 27–52%). The Higgins I2 statistic showed significant heterogeneity (I2 = 95%). DWI with a slice thickness ≤ 3 mm showed a higher diagnostic yield than DWI with a slice thickness > 3 mm (pooled diagnostic yield: 63% [95% CI, 53–72%] vs. 26% [95% CI, 16–40%], p 24 to 96 hours could increase the diagnostic yield.

Neuroimaging Findings in Patients with COVID-19: A Systematic Review and Meta-Analysis

Objective@#Central nervous system involvement in coronavirus disease 2019 (COVID-19) has been increasingly reported. We performed a systematic review and meta-analysis to evaluate the incidence of radiologically demonstrated neurologic complications and detailed neuroimaging findings associated with COVID-19. @*Materials and Methods@#A systematic literature search of MEDLINE/PubMed and EMBASE databases was performed up to September 17, 2020, and studies evaluating neuroimaging findings of COVID-19 using brain CT or MRI were included. Several cohort-based outcomes, including the proportion of patients with abnormal neuroimaging findings related to COVID-19 were evaluated. The proportion of patients showing specific neuroimaging findings was also assessed. Subgroup analyses were also conducted focusing on critically ill COVID-19 patients and results from studies that used MRI as the only imaging modality. @*Results@#A total of 1394 COVID-19 patients who underwent neuroimaging from 17 studies were included; among them, 3.4% of the patients demonstrated COVID-19-related neuroimaging findings. Olfactory bulb abnormalities were the most commonly observed (23.1%). The predominant cerebral neuroimaging finding was white matter abnormality (17.6%), followed by acute/subacute ischemic infarction (16.0%), and encephalopathy (13.0%). Significantly more critically ill patients had COVID-19-related neuroimaging findings than other patients (9.1% vs. 1.6%; p = 0.029). The type of imaging modality used did not significantly affect the proportion of COVID-19-related neuroimaging findings. @*Conclusion@#Abnormal neuroimaging findings were occasionally observed in COVID-19 patients. Olfactory bulb abnormalities were the most commonly observed finding. Critically ill patients showed abnormal neuroimaging findings more frequently than the other patient groups. White matter abnormalities, ischemic infarctions, and encephalopathies were the common cerebral neuroimaging findings.

Diagnostic Yield of Diffusion-Weighted Brain Magnetic Resonance Imaging in Patients with Transient Global Amnesia: A Systematic Review and Meta-Analysis

Objective@#To investigate the diagnostic yield of diffusion-weighted imaging (DWI) in patients with transient global amnesia (TGA) and identify significant parameters affecting diagnostic yield. @*Materials and Methods@#A systematic literature search of the MEDLINE and EMBASE databases was conducted to identify studies that assessed the diagnostic yield of DWI in patients with TGA. The pooled diagnostic yield of DWI in patients with TGA was calculated using the DerSimonian-Laird random-effects model. Subgroup analyses were also performed of slice thickness, magnetic field strength, and interval between symptom onset and DWI. @*Results@#Twenty-two original articles (1732 patients) were included. The pooled incidence of right, left, and bilateral hippocampal lesions was 37% (95% confidence interval [CI], 30–44%), 42% (95% CI, 39–46%), and 25% (95% CI, 20–30%) of all lesions, respectively. The pooled diagnostic yield of DWI in patients with TGA was 39% (95% CI, 27–52%). The Higgins I2 statistic showed significant heterogeneity (I2 = 95%). DWI with a slice thickness ≤ 3 mm showed a higher diagnostic yield than DWI with a slice thickness > 3 mm (pooled diagnostic yield: 63% [95% CI, 53–72%] vs. 26% [95% CI, 16–40%], p 24 to 96 hours could increase the diagnostic yield.

Optimized Image-Based Surrogate Endpoints in Targeted Therapies for Glioblastoma: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

OBJECTIVE: We aimed to determine the optimized image-based surrogate endpoints (IBSEs) in targeted therapies for glioblastoma through a systematic review and meta-analysis of phase III randomized controlled trials (RCTs).MATERIALS AND METHODS: A systematic search of OVID-MEDLINE and EMBASE for phase III RCTs on glioblastoma was performed in December 2017. Data on overall survival (OS) and IBSEs, including progression-free survival (PFS), 6-month PFS (6moPFS), 12-month PFS (12moPFS), median PFS, and objective response rate (ORR) were extracted. Weighted linear regression analysis for the hazard ratio for OS and the hazard ratios or odds ratios for IBSEs was performed. The associations between IBSEs and OS were evaluated. Subgroup analyses according to disease stage (newly diagnosed glioblastoma versus recurrent glioblastoma), types of test treatment, and types of response assessment criteria were performed.RESULTS: Twenty-three phase III RCTs published between 2000 and 2017, including 8387 patients, met the inclusion criteria. OS showed strong correlations with PFS (standardized β coefficient [R] = 0.719), 6moPFS (R = 0.647), and 12moPFS (R = 0.638). OS showed no correlations with median PFS and ORR. In subgroup analysis according to types of therapies, PFS showed the highest correlations with OS in targeted therapies for cell cycle pathways (R = 0.913) and growth factor receptors and their downstream pathways (R = 0.962). 12moPFS showed the highest correlation with OS in antiangiogenic therapy (R = 0.821). The response assessment in neuro-oncology criteria provided higher correlation coefficients between OS and IBSEs than the Macdonald criteria.CONCLUSION: Overall, PFS is an optimized IBSE in targeted therapies for glioblastoma; however, 12moPFS is optimal in antiangiogenic therapy.

Cigarette Smoking Preferentially Affects Intracranial Vessels in Young Males: A Propensity-Score Matching Analysis / 신경중재치료의학

PURPOSE: Cigarette smoking (CS) is one of the major risk factors of cerebral atherosclerotic disease, however, its level of contribution to extracranial and intracranial atherosclerotic stenosis (ECAS and ICAS) was not fully revealed yet. The purpose of our study was to assess the association of CS to cerebral atherosclerosis along with other risk factors. MATERIALS AND METHODS: All consecutive patients who were angiographically confirmed with severe symptomatic cerebral atherosclerotic disease between January 2002 and December 2012 were included in this study. Multivariate logistic regression analyses were performed to identify risk factors for ECAS and ICAS. Thereafter, CS group were compared to non-CS group in the entire study population and in a propensity-score matched population with two different age-subgroups. RESULTS: Of 1709 enrolled patients, 794 (46.5%) had extracranial (EC) lesions and the other 915 (53.5%) had intracranial (IC) lesions. CS group had more EC lesions (55.8% vs. 35.3%, P<0.001) whereas young age group (<50 years) had more IC lesion (84.5% vs. 47.6%, P<0.001). In multivariate analysis, seven variables including CS, male, old age, coronary heart disease, higher erythrocyte sedimentation rate, multiple lesions, and anterior lesion were independently associated with ECAS. In the propensity-score matched CS group had significant more EC lesion compared to non-CS group (65.7% vs. 47.9%) only in the old age subgroup. CONCLUSION: In contrast to a significant association between CS and severe symptomatic ECAS shown in old population, young patients did not show this association and showed relatively higher preference of ICAS.

Carotid Arterial Calcium Scoring Using Upper Airway Computed Tomography in Patients with Obstructive Sleep Apnea: Efficacy as a Clinical Predictor of Cerebrocardiovascular Disease

OBJECTIVE: To evaluate the value of airway computed tomography (CT) in patients with obstructive sleep apnea (OSA) as a predictor of cerebrocardiovascular disease (CCVD) clinically, by quantitatively analyzing carotid arterial calcification (CarAC). MATERIALS AND METHODS: This study included 287 patients aged 40–80 years, who had undergone both polysomnography (PSG) and airway CT between March 2011 and October 2015. The carotid arterial calcium score (CarACS) was quantified using the modified Agatston method on each upper airway CT. The OSA severity was categorized as normal, mild, moderate, and severe using the PSG results. Clinical characteristics, comorbid diseases, and lipid profiles of all patients were analyzed, and the prevalence of CCVDs was investigated during the follow up period (52.2 ± 16.0 months). RESULTS: CCVD occurred in 27 patients (9.3%) at the end of follow-up, and the CCVD-present groups showed a significantly older mean age (57.5 years vs. 54.2 years), higher prevalence of hypertension (59% vs. 34%) and CarAC (51.9% vs. 20.8%), whereas sex, other comorbid diseases, and severity of OSA were not significantly different from the CCVD-absent group. A univariate analysis showed that age, hypertension, incidence of CarAC, and CarACS were risk factors for the occurrence of CCVD events. In a multivariate analysis, the incidence of CarAC was the only independent risk factor for CCVD. CONCLUSION: CarAC is an independent risk factor for CCVD, whereas the severity of OSA is not a contributory risk factor in patients with OSA. Therefore, additional analysis of CarACS based on airway CT scans may be useful for predicting CCVD.

Coexistence of Intracranial Squamous Cell Carcinoma and Epidermoid Cyst: a Case with Consecutive Imaging Findings

In contrast to well-known imaging findings of intracranial epidermoid cysts on magnetic resonance imaging, those of intracranial squamous cell carcinoma (SqCC) are relatively unknown. We present a case of coexistence of intracranial SqCC and epidermoid cyst, with consecutive follow up over 14 months. Based on our case, a solid enhancing portion adjacent to a typically-looking epidermoid cyst may become a clue for coexistence of intracranial SqCC. An initial contrast enhancement and/or heterogeneous signal on diffusion weighted imaging may become a useful diagnostic clue, but more importantly, sudden rapid growth is important in formulating diagnosis.

Depiction of Acute Stroke Using 3-Tesla Clinical Amide Proton Transfer Imaging: Saturation Time Optimization Using an in vivo Rat Stroke Model, and a Preliminary Study in Human

PURPOSE: To optimize the saturation time and maximizing the pH-weighted difference between the normal and ischemic brain regions, on 3-tesla amide proton transfer (APT) imaging using an in vivo rat model. MATERIALS AND METHODS: Three male Wistar rats underwent middle cerebral artery occlusion, and were examined in a 3-tesla magnetic resonance imaging (MRI) scanner. APT imaging acquisition was performed with 3-dimensional turbo spin-echo imaging, using a 32-channel head coil and 2-channel parallel radiofrequency transmission. An off-resonance radiofrequency pulse was applied with a Sinc-Gauss pulse at a B(1,rms) amplitude of 1.2 µT using a 2-channel parallel transmission. Saturation times of 3, 4, or 5 s were tested. The APT effect was quantified using the magnetization-transfer-ratio asymmetry at 3.5 ppm with respect to the water resonance (APT-weighted signal), and compared with the normal and ischemic regions. The result was then applied to an acute stroke patient to evaluate feasibility. RESULTS: Visual detection of ischemic regions was achieved with the 3-, 4-, and 5-s protocols. Among the different saturation times at 1.2 µT power, 4 s showed the maximum difference between the ischemic and normal regions (-0.95%, P = 0.029). The APTw signal difference for 3 and 5 s was -0.9% and -0.7%, respectively. The 4-s saturation time protocol also successfully depicted the pH-weighted differences in an acute stroke patient. CONCLUSION: For 3-tesla turbo spin-echo APT imaging, the maximal pH-weighted difference achieved when using the 1.2 µT power, was with the 4 s saturation time. This protocol will be helpful to depict pH-weighted difference in stroke patients in clinical settings.

Depiction of Acute Stroke Using 3-Tesla Clinical Amide Proton Transfer Imaging: Saturation Time Optimization Using an in vivo Rat Stroke Model, and a Preliminary Study in Human

PURPOSE: To optimize the saturation time and maximizing the pH-weighted difference between the normal and ischemic brain regions, on 3-tesla amide proton transfer (APT) imaging using an in vivo rat model. MATERIALS AND METHODS: Three male Wistar rats underwent middle cerebral artery occlusion, and were examined in a 3-tesla magnetic resonance imaging (MRI) scanner. APT imaging acquisition was performed with 3-dimensional turbo spin-echo imaging, using a 32-channel head coil and 2-channel parallel radiofrequency transmission. An off-resonance radiofrequency pulse was applied with a Sinc-Gauss pulse at a B(1,rms) amplitude of 1.2 µT using a 2-channel parallel transmission. Saturation times of 3, 4, or 5 s were tested. The APT effect was quantified using the magnetization-transfer-ratio asymmetry at 3.5 ppm with respect to the water resonance (APT-weighted signal), and compared with the normal and ischemic regions. The result was then applied to an acute stroke patient to evaluate feasibility. RESULTS: Visual detection of ischemic regions was achieved with the 3-, 4-, and 5-s protocols. Among the different saturation times at 1.2 µT power, 4 s showed the maximum difference between the ischemic and normal regions (-0.95%, P = 0.029). The APTw signal difference for 3 and 5 s was -0.9% and -0.7%, respectively. The 4-s saturation time protocol also successfully depicted the pH-weighted differences in an acute stroke patient. CONCLUSION: For 3-tesla turbo spin-echo APT imaging, the maximal pH-weighted difference achieved when using the 1.2 µT power, was with the 4 s saturation time. This protocol will be helpful to depict pH-weighted difference in stroke patients in clinical settings.

Pediatric Vascular Surgery Review with a 30-Year-Experience in a Tertiary Referral Center

Pediatric vascular disease is rare, and remains a big challenge to vascular surgeons. In contrast to adults, surgery for pediatric vascular disease is complicated by issues related to small size, future growth, and availability of suitable vascular conduit. During the last 30 years, 131 major vascular operations were performed in a tertiary referral center, Seoul National University Hospital, including aortoiliac aneurysm, acute or chronic arterial occlusion, renovascular hypertension, portal venous hypertension, trauma, tumor invasion to major abdominal vessels, and others. Herein we review on the important pediatric vascular diseases and share our clinical experiences on these rare diseases.

Diagnostic Clue of Meningeal Melanocytoma: Case Report and Review of Literature

In this report, the patient was pre-diagnosed as meningioma before surgery, which turned out to be meningeal melanocytoma. Hence, we will discuss the interpretation of imaging and neurological statuses that may help avoid this problem. A 45-year-old man had increasing pain around the neck 14 months prior to admission. His cervical spine MR imaging revealed a space-occupying, contrast-enhancing mass within the dura at the level of C1. The neurologic examination revealed that the patient had left-sided lower extremity weakness of 4+, decreased sensation on the right side, and hyperreflexia in both legs. Department of Neuroradiology interpreted CT and MR imaging as meningiom. The patient underwent decompression and removal of the mass. We confirmed diagnosis as meningeal melanocytoma through pathologic findings. Afterwards, we reviewed the patient's imaging work-up, which showed typical findings of meningeal melanocytoma. However, it was mistaken as meningioma, since the disease is rare.

Improved Diagnostic Accuracy of Alzheimer's Disease by Combining Regional Cortical Thickness and Default Mode Network Functional Connectivity: Validated in the Alzheimer's Disease Neuroimaging Initiative Set

OBJECTIVE: To identify potential imaging biomarkers of Alzheimer's disease by combining brain cortical thickness (CThk) and functional connectivity and to validate this model's diagnostic accuracy in a validation set. MATERIALS AND METHODS: Data from 98 subjects was retrospectively reviewed, including a study set (n = 63) and a validation set from the Alzheimer's Disease Neuroimaging Initiative (n = 35). From each subject, data for CThk and functional connectivity of the default mode network was extracted from structural T1-weighted and resting-state functional magnetic resonance imaging. Cortical regions with significant differences between patients and healthy controls in the correlation of CThk and functional connectivity were identified in the study set. The diagnostic accuracy of functional connectivity measures combined with CThk in the identified regions was evaluated against that in the medial temporal lobes using the validation set and application of a support vector machine. RESULTS: Group-wise differences in the correlation of CThk and default mode network functional connectivity were identified in the superior temporal (p < 0.001) and supramarginal gyrus (p = 0.007) of the left cerebral hemisphere. Default mode network functional connectivity combined with the CThk of those two regions were more accurate than that combined with the CThk of both medial temporal lobes (91.7% vs. 75%). CONCLUSION: Combining functional information with CThk of the superior temporal and supramarginal gyri in the left cerebral hemisphere improves diagnostic accuracy, making it a potential imaging biomarker for Alzheimer's disease.

Effects of Arbuscular Mycorrhizal Fungi and Soil Conditions on Crop Plant Growth

We investigated the effects on various crops of inoculation with species of arbuscular mycorrhizal fungi (AMF) in soils from different sources and selected AMF species suitable for domestic environment-friendly farming. Effects on plants varied with the AMF species used. In carrot, Scutellospora heterogama, Acaulospora longula, and Funneliformis mosseae had a positive effect on growth of the host, whereas AMF had only weak effects on the growth of red pepper and leek. AMF inoculation had positive effects on the growth of carrot and sorghum. The results of this study indicate the nature of the relationship between soil, plants, and AMF; this study therefore has important implications for the future use of AMF in environment-friendly agriculture.

Pre-Operative Perfusion Skewness and Kurtosis Are Potential Predictors of Progression-Free Survival after Partial Resection of Newly Diagnosed Glioblastoma

OBJECTIVE: To determine whether pre-operative perfusion skewness and kurtosis derived from normalized cerebral blood volume (nCBV) histograms are associated with progression-free survival (PFS) of patients after partial resection of newly diagnosed glioblastoma. MATERIALS AND METHODS: A total of 135 glioblastoma patients who had undergone partial resection of tumor (resection of < 50% of pre-operative tumor volume or surgical biopsy) confirmed with immediate postsurgical MRI and examined with both conventional MRI and dynamic susceptibility contrast (DSC) perfusion MRI before the surgery were retrospectively reviewed in this study. They had been followed up post-surgical chemoradiotherapy for tumor progression. Using histogram analyses of nCBV derived from pre-operative DSC perfusion MRI, patients were sub-classified into the following four groups: positive skewness and leptokurtosis (group 1); positive skewness and platykurtosis (group 2); negative skewness and leptokurtosis (group 3); negative skewness and platykurtosis (group 4). Kaplan-Meier analysis and multivariable Cox proportional hazards regression analysis were performed to determine whether clinical and imaging covariates were associated with PFS or overall survival (OS) of these patients. RESULTS: According to the Kaplan-Meier method, median PFS of group 1, 2, 3, and 4 was 62, 51, 39, and 41 weeks, respectively, with median OS of 82, 77, 77, and 72 weeks, respectively. In multivariable analyses with Cox proportional hazards regression, pre-operative skewness/kurtosis pattern (hazard ratio: 2.98 to 4.64; p < 0.001), Karnofsky performance scale score (hazard ratio: 1.04; p = 0.003), and post-operative tumor volume (hazard ratio: 1.04; p = 0.02) were independently associated with PFS but not with OS. CONCLUSION: Higher skewness and kurtosis of nCBV histogram before surgery were associated with longer PFS in patients with newly diagnosed glioblastoma after partial tumor resection.

Surgical Treatment of Infected Aortoiliac Aneurysm

PURPOSE: Infected aneurysms of the abdominal aorta or iliac artery (IAAA) are rare but fatal and difficult to treat. The purpose of this study was to review the clinical presentations and outcomes of IAAA and to establish a treatment strategy for optimal treatment of IAAA. MATERIALS AND METHODS: Electronic medical records of 13 patients treated for IAAA at Seoul National University Hospital between March 2004 and December 2012 were retrospectively reviewed. RESULTS: Mean age was 64.2 (median 70, range 20-79) years. Aneurysms were located in the infrarenal aorta (n=7), iliac arteries (n=5), and suprarenal aorta (n=1). Seven patients underwent excision and in situ interposition graft, 3 underwent extra-anatomical bypass, and 1 underwent endovascular repair. One patient with endovascular repair in an outside hospital refused resection, and only debridement was done, which revealed tuberculosis infection. One staphylococcal infection was caused by iliac stenting. Mycobacterium was the most common pathogen, followed by Klebsiella, Salmonella, and Staphylococcus. There were 3 in-hospital mortalities and the causes were sepsis in 2 and aneurysm rupture in 1. The 3 extra-anatomic bypasses were all patent after 5-year follow-up. CONCLUSION: IAAA develops from various causes and various organisms. IAAA cases with gross pus were treated with extra-anatomic bypass, which was durable. In situ reconstruction is favorable for long term-safety and efficacy, but extensive debridement is essential.

Effects of MR Parameter Changes on the Quantification of Diffusion Anisotropy and Apparent Diffusion Coefficient in Diffusion Tensor Imaging: Evaluation Using a Diffusional Anisotropic Phantom

OBJECTIVE: To validate the usefulness of a diffusional anisotropic capillary array phantom and to investigate the effects of diffusion tensor imaging (DTI) parameter changes on diffusion fractional anisotropy (FA) and apparent diffusion coefficient (ADC) using the phantom. MATERIALS AND METHODS: Diffusion tensor imaging of a capillary array phantom was performed with imaging parameter changes, including voxel size, number of sensitivity encoding (SENSE) factor, echo time (TE), number of signal acquisitions, b-value, and number of diffusion gradient directions (NDGD), one-at-a-time in a stepwise-incremental fashion. We repeated the entire series of DTI scans thrice. The coefficients of variation (CoV) were evaluated for FA and ADC, and the correlation between each MR imaging parameter and the corresponding FA and ADC was evaluated using Spearman's correlation analysis. RESULTS: The capillary array phantom CoVs of FA and ADC were 7.1% and 2.4%, respectively. There were significant correlations between FA and SENSE factor, TE, b-value, and NDGD, as well as significant correlations between ADC and SENSE factor, TE, and b-value. CONCLUSION: A capillary array phantom enables repeated measurements of FA and ADC. Both FA and ADC can vary when certain parameters are changed during diffusion experiments. We suggest that the capillary array phantom can be used for quality control in longitudinal or multicenter clinical studies.

Effect of imatinib mesylate and rapamycin on the preformed intimal hyperplasia in rat carotid injury model

PURPOSE: Intimal hyperplasia (IH) is the main cause of restenosis or occlusion after vascular procedures. Imatinib mesylate and rapamycin are known to prevent IH. The purpose of this study was to evaluate the effect of these drugs on the regression of preformed IH in rat carotid injury model. METHODS: IH was established in rat carotid arteries using a balloon catheter. The drug effects were assessed in vitro on proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMC) in the neointima. And in vivo studies were carried out in 4 groups: imatinib, rapamycin, combined, and no medication. After 2-week oral medication, morphometric analysis evaluated the number and density of neointimal cells, intima-to-media (I/M) ratio and cross-sectional area. Cell proliferation, apoptosis, and collagen changes were also investigated by immunohistochemical staining (IHCS). RESULTS: Imatinib and rapamycin significantly inhibited VSMC proliferation and migration, and promoted apoptosis in vitro. In morphometric analysis, the number and density of neointimal cells decreased significantly in all medication groups compared with control group (P < 0.01). However, there was no significant difference in neointimal cross-sectional area and I/M ratio among groups. In IHCS, imatinib and rapamycin inhibited neointimal cell proliferation significantly. However, there was no significant change in cell apoptosis and collagen composition. CONCLUSION: Combined treatment of with imatinib and rapamycin induced reduction of cell mass in preformed intimal hyperplasia, but failed to induce regression of intimal mass in this short-term medication study. Further studies will be needed with additional strategies of inducing lysis of the extracellular matrix.

Increase in Anti-Gal IgM Level is Associated With Early Graft Failure in Intraportal Porcine Islet Xenotransplantation

BACKGROUND: Anti-Gal is a major antibody induced in non-human primates (NHPs) after xenotransplantation. To understand the mechanism of graft rejection, we investigated the association between anti-Gal responses and graft failure in NHP recipients of porcine islet transplantation (PITx). METHODS: Intraportal PITx was performed in 35 diabetic NHPs, and graft function was monitored. Early graft failure (EGF) was defined as loss of graft function within a month after PITx. Seven, 19, nine NHPs received immunosuppression (IS) without CD40 pathway blockade (Group I), with anti-CD154 (Group II), and with anti-CD40 (Group III), respectively. The anti-Gal levels on day 0 and day 7 of PITx were measured by ELISA. RESULTS: The frequency of EGF was significantly lower in Group II (26.3%) than in Group I (100%, P=0.0012) and Group III (77.8%, P=0.0166). While levels of anti-Gal IgG in Group I and anti-Gal IgM in Group III increased on day 7 compared with day 0 (P=0.0156 and 0.0273), there was no increase in either on day 7 in Group II. The ratio of anti-Gal IgM or IgG level on day 7 to that on day 0 (Ratio7/0) was significantly higher in recipients with EGF than without EGF (P=0.0009 and 0.0027). ROC curve analysis of anti-Gal IgM Ratio7/0 revealed an area under the curve of 0.789 (P=0.0003). CONCLUSIONS: IS with anti-CD154 suppressed anti-Gal responses and prevented EGF in PITx. Anti-Gal IgM Ratio7/0, being associated with EGF, is a predictive marker for EGF.