Impact of Portal Hypertension on Adverse Events after Splenic Arterial Aneurysm Embolization.

PURPOSE: To evaluate the outcomes of splenic artery aneurysm (SAA) embolization and compare adverse event (AE) rates after embolization in patients with and without portal hypertension (PHTN). MATERIALS AND METHODS: A retrospective review of all patients who underwent embolization of SAAs at 2 institutions was performed (34 patients from institution 1 and 7 patients from institution 2). Baseline demographic characteristics, preprocedural imaging, procedural techniques, and postprocedural outcomes were evaluated. Thirty-day postprocedural severe and life-threatening AEs were evaluated using the Society of Interventional Radiology guidelines. Thirty-day mortality and readmission rates were also evaluated. t test, χ2 test, and/or Fisher exact test were used for the statistical analysis. RESULTS: There was no statistically significant difference between patients with and without PHTN in the location, number, and size of SAA(s). All procedures were technically successful. There were 13 (32%) patients with and 28 (68%) patients without PHTN. The 30-day mortality rate (31% vs 0%; P = .007), readmission rates (61% vs 7%; P < .001), and severe/life-threatening AE rates (69% vs 0%; P < .001) were significantly higher in patients with PHTN than in those without PHTN. CONCLUSIONS: There was a significantly higher mortality and severe/life-threatening AE rate in patients with PHTN than in those without PHTN. SAAs in patients with PHTN need to be managed very cautiously, given the risk of severe/life-threatening AEs after embolization.

Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia.

CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell-derived factor-1 (SDF-1α). There is evidence that bone marrow-derived CXCR4-expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF-1α. We have previously found that transforming growth factor-ß (TGFß) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFß/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGFß/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60-fold; protein, 4-fold) in TGFß-treated, Smad3-expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGFß/Smad3 treatment also markedly enhanced SDF-1α-induced ERK1/2 phosphorylation as well as SMC migration in a CXCR4-dependent manner. Adenoviral expression of Smad3 in balloon-injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC-specific depletion of CXCR4 in the wire-injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGFß/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis. Stem Cells 2016;34:2744-2757.

Retrievable IVC Filters: Comprehensive Review of Device-related Complications and Advanced Retrieval Techniques.

Use of retrievable inferior vena cava filters (RIVCFs) has grown exponentially since their introduction into clinical practice, but many of these devices are not retrieved. Some are not retrieved due to poor clinical follow-up, but other devices remain in situ for extended periods because they present significant technical challenges during retrieval. Because of these and other factors, many of these devices were thus left in place permanently. However, recent data have placed a renewed emphasis on device retrieval due to increased risk of RIVCF-related complications, which are positively correlated with filter dwell time. Development of advanced filter retrieval techniques has had a significant impact on the removal of embedded RIVCFs, permitting retrieval of the majority of devices. The purpose of this article is to present an imaging and data review of the dominant device-related factors that complicate RIVCF retrieval and to describe the relevant advanced retrieval techniques to manage these factors. RIVCF imaging is frequently encountered in daily clinical practice via various imaging modalities. Therefore, diagnostic radiologists can play a vital role in identifying filter-related issues. Familiarity with the context for managing these issues in the interventional suite is essential for improving triage and care of patients with RIVCFs. © RSNA, 2017.

Quantitative susceptibility mapping of the motor cortex in amyotrophic lateral sclerosis and primary lateral sclerosis.

OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) is often difficult because of a lack of disease biomarkers. The purpose of this study was to investigate quantitative susceptibility mapping (QSM) of the motor cortex as a potential quantitative biomarker for the diagnosis of ALS and PLS. MATERIALS AND METHODS: From a retrospective database, QSM images of 16 patients with upper motor neuron disease (nine men [56%], seven women; mean age, 56.3 years; 12 with ALS, four with PLS) and 23 control patients (13 men [56%], 10 women; mean age, 56.6 years) were reviewed. Two neuroradiologists, blinded to diagnosis, qualitatively assessed QSM, T2- and T2*-weighted, and T2-weighted FLAIR images. Relative motor cortex susceptibility was calculated by subtraction of adjacent white matter and CSF signal intensity from mean motor cortex susceptibility on the axial image most representative of the right- or left-hand lobule, and ROC analysis was performed. The Fisher exact and Student t tests were used to evaluate for statistical differences between the groups. RESULTS: Qualitatively, QSM had greater diagnostic accuracy than T2-weighted, T2*-weighted, or T2-weighted FLAIR imaging for the diagnosis of ALS and PLS. Quantitatively, relative motor cortex susceptibility was found to be significantly greater in patients with motor neuron disease than in control patients (46.0 and 35.0 ppb; p < 0.001). ROC analysis showed an AUC of 0.88 (p < 0.0001) and an optimal cutoff value of 40.5 ppb for differentiating control patients from patients with ALS or PLS (sensitivity, 87.5%; specificity, 87.0%). CONCLUSION: QSM is a sensitive and specific quantitative biomarker of iron deposition in the motor cortex in ALS and PLS.

Safety and Diagnostic Efficacy of Image-Guided Biopsy of Small Renal Masses.

INTRODUCTION: Image-guided renal mass biopsy is gaining increased diagnostic acceptance, but there are limited data concerning the safety and diagnostic yield of biopsy for small renal masses (≤4 cm). This study evaluated the safety, diagnostic yield, and management after image-guided percutaneous biopsy for small renal masses. METHODS: A retrospective IRB-approved study was conducted on patients who underwent renal mass biopsy for histopathologic diagnosis at a single center from 2015 to 2021. Patients with a prior history of malignancy or a renal mass >4 cm were excluded. Descriptive statistics were used to summarize patient demographics, tumor size, the imaging modality used for biopsy, procedure details, complications, pathological diagnosis, and post-biopsy management. A biopsy was considered successful when the specimen was sufficient for diagnosis without need for a repeat biopsy. Complications were graded according to the SIR classification of adverse events. A chi-squared test (significance level set at p ≤ 0.05) was used to compare the success rate of biopsies in different lesion size groups. RESULTS: A total of 167 patients met the inclusion criteria. The median age was 65 years (range: 26-87) and 51% were male. The median renal mass size was 2.6 cm (range: one-four). Ultrasound was solely employed in 60% of procedures, CT in 33%, a combination of US/CT in 6%, and MRI in one case. With on-site cytopathology, the median number of specimens obtained per procedure was four (range: one-nine). The overall complication rate was 5%. Grade A complications were seen in 4% (n = 7), consisting of perinephric hematoma (n = 6) and retroperitoneal hematoma (n = 1). There was one grade B complication (0.5%; pain) and one grade D complication (0.5%; pyelonephritis). There was no patient mortality within 30 days post-biopsy. Biopsy was successful in 88% of cases. A sub-group analysis showed a success rate of 85% in tumors <3 cm and 93% in tumors ≥3 cm (p = 0.01). Pathological diagnoses included renal cell carcinoma (65%), oncocytoma (18%), clear cell papillary renal cell tumors (9%), angiomyolipoma (4%), xanthogranulomatous pyelonephritis (1%), lymphoma (1%), high-grade papillary urothelial carcinoma (1%), and metanephric adenoma (1%), revealing benign diagnosis in 30% of cases. The most common treatment was surgery (40%), followed by percutaneous cryoablation (22%). In total, 37% of patients were managed conservatively, and one patient received chemotherapy. CONCLUSION: This study demonstrates the safety and diagnostic efficacy of image-guided biopsy of small renal masses. The diagnostic yield was significantly higher for masses 3-4 cm in size compared to those <3 cm. The biopsy results showed a high percentage of benign diagnoses and informed treatment decisions in most patients.

Local drug delivery to prevent restenosis.

INTRODUCTION: Despite significant advances in vascular biology, bioengineering, and pharmacology, restenosis remains a limitation to the overall efficacy of vascular reconstructions, both percutaneous and open. Although the pathophysiology of intimal hyperplasia is complex, a number of drugs and molecular tools have been identified that can prevent restenosis. Moreover, the focal nature of this process lends itself to treatment with local drug administration. This article provides a broad overview of current and future techniques for local drug delivery that have been developed to prevent restenosis after vascular interventions. METHODS: A systematic electronic literature search using PubMed was performed for all accessible published articles through September 2012. In an effort to remain current, additional searches were performed for abstracts presented at relevant societal meetings, filed patents, clinical trials, and funded National Institutes of Health awards. RESULTS: The efficacy of local drug delivery has been demonstrated in the coronary circulation with the current clinical use of drug-eluting stents. Until recently, however, drug-eluting stents were not found to be efficacious in the peripheral circulation. Further pursuit of intraluminal devices has led to the development of balloon-based technologies, with a recent surge in trials involving drug-eluting balloons. Early data appear encouraging, particularly for treatment of superficial femoral artery lesions, and several devices have recently received the Conformité Européene mark in Europe. Investigators have also explored the periadventitial application of biomaterials containing antirestenotic drugs, an approach that could be particularly useful for surgical bypass or endarterectomy. In the past, systemic drug delivery has been unsuccessful; however, there has been recent exploration of intravenous delivery of drugs designed specifically to target injured or reconstructed arteries. Our review revealed a multitude of additional interesting strategies, including >65 new patents issued during the past 2 years for approaches to local drug delivery focused on preventing restenosis. CONCLUSIONS: Restenosis after intraluminal or open vascular reconstruction remains an important clinical problem. Success in the coronary circulation has not translated into solutions for the peripheral arteries. However, our literature review reveals a number of promising approaches, including drug-eluting balloons, periadventitial drug delivery, and targeted systemic therapies. These and other innovations suggest that the future is bright and that a solution for preventing restenosis in peripheral vessels will soon be at hand.

Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling.

OBJECTIVE: Apoptosis of smooth muscle cells (SMCs) is a prominent pathological characteristic of abdominal aortic aneurysm (AAA). We have previously shown that SMC apoptosis stimulates proinflammatory signaling in a mouse model of AAA. Here, we test whether protein kinase C-δ (PKCδ), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals. METHODS AND RESULTS: Mouse experimental AAA is induced by perivascular administration of CaCl(2). Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKCδ to the aortic wall of PKCδ(-/-) mice restores aneurysm, whereas overexpression of a dominant negative PKCδ mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKCδ(-/-) aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKCδ(-/-) mice restores inflammatory response and aneurysm development. CONCLUSIONS: PKCδ is an important signaling mediator for SMC apoptosis and inflammation in a mouse model of AAA. By stimulating monocyte chemoattractant protein-1 expression in aortic SMCs, upregulated PKCδ exacerbates the inflammatory process, in turn perpetuating elastin degradation and aneurysmal dilatation. Inhibition of PKCδ may serve as a potential therapeutic strategy for AAA.

TGF-ß and Smad3 modulate PI3K/Akt signaling pathway in vascular smooth muscle cells.

Transforming growth factor-ß (TGF-ß) is upregulated at the time of arterial injury; however, the mechanism through which TGF-ß enhances the development of intimal hyperplasia is not clear. Recent studies from our laboratory suggest that in the presence of elevated levels of Smad3, TGF-ß stimulates smooth muscle cell (SMC) proliferation. This is a novel phenomenon in that TGF-ß has traditionally been known as a potent inhibitor of cellular proliferation. In these studies we explore the signaling pathways through which TGF-ß mediates its proliferative effect in vascular SMCs. We found that TGF-ß phosphorylates and activates Akt in a time-dependent manner, and this effect is significantly enhanced by overexpression of Smad3. Furthermore, both chemical and molecular inhibition of Smad3 can reverse the effect of TGF-ß on Akt. Although we found numerous signaling pathways that might function as intermediates between Smad3 and Akt, p38 appeared the most promising. Overexpression of Smad3 enhanced p38 phosphorylation and inhibition of p38 with a chemical inhibitor or a small interfering RNA blocked TGF-ß-induced Akt phosphorylation. Moreover, TGF-ß/Smad3 enhancement of SMC proliferation was blocked by inhibition of p38. Phosphorylation of Akt by TGF-ß/Smad3 was not dependent on gene expression or protein synthesis, and immunoprecipitation studies revealed a physical association among p38, Akt, and Smad3 suggesting that activation requires a direct protein-protein interaction. Our findings were confirmed in vivo where overexpression of Smad3 in a rat carotid injury model led to enhancement of p-p38, p-Akt, as well as SMC proliferation. Furthermore, inhibition of p38 in vivo led to decreased Akt phosphorylation and SMC proliferation. In summary, our studies reveal a novel pathway whereby TGF-ß/Smad3 stimulates SMC proliferation through p38 and Akt. These findings provide a potential mechanism for the substantial effect of TGF-ß on intimal hyperplasia and suggest new targets for chemical or molecular prevention of vascular restenosis.

Accelerated aneurysmal dilation associated with apoptosis and inflammation in a newly developed calcium phosphate rodent abdominal aortic aneurysm model.

OBJECTIVE: The calcium chloride (CaCl(2)) model is a widely accepted rodent model for abdominal aortic aneurysms (AAAs). Calcium deposition, mainly consisting of calcium phosphate (CaPO(4)) crystals, has been reported to exist in human and experimental aneurysms. CaPO(4) crystals have been used for in vitro DNA transfection by mixing CaCl(2) and phosphate-buffered saline (PBS). Here, we describe accelerated aneurysm formation resulting from a modification of the CaCl(2) model. METHODS: A modified CaCl(2) model, the CaPO(4) model, was created by applying PBS onto the mouse infrarenal aorta after CaCl(2) treatment. Morphologic, histologic, and immunohistochemical analyses were performed on arteries treated with the CaPO(4) model and the conventional CaCl(2) model as the control. In vitro methods were performed using a mixture of CaCl(2) and PBS to create CaPO(4) crystals. CaPO(4)- induced apoptosis of primary cultured mouse vascular smooth muscle cells (VSMCs) was measured by DNA fragmentation enzyme-linked immunosorbent assay. RESULTS: The CaPO(4) model produces AAA, defined as an increase of ≥50% in the diameter of the aorta, faster than in the CaCl(2) model. The CaPO(4) model showed significantly larger aneurysmal dilation at 7, 28, and 42 days, as reflected by a maximum diameter (measured in mm) fold-change of 1.69 ± 0.07, 1.99 ± 0.14, and 2.13 ± 0.09 vs 1.22 ± 0.04, 1.48 ± 0.07, and 1.68 ± 0.06 in a CaCl(2) model, respectively (n = 6; P < .05). A semiquantitative grading analysis of elastin fiber integrity at 7 days revealed a significant increase in elastin degradation in the CaPO(4) model compared with the CaCl(2) model (2.7 ± 0.2 vs 1.5 ± 0.2; n = 6; P < .05). A significantly higher level of apoptosis occurred in the CaPO(4) model (apoptosis index at 1, 2, and 3 days postsurgery: 0.26 ± 0.14, 0.37 ± 0.14, and 0.33 ± 0.08 vs 0.012 ± 0.10, 0.15 ± 0.02, and 0.12 ± 0.05 in the conventional CaCl(2) model; n = 3; P < .05). An enhancement of macrophage infiltration and calcification was also observed at 3 and 7 days in the CaPO(4) model. CaPO(4) induced approximately 3.7 times more apoptosis in VSMCs than a mixture of CaCl(2) (n = 4; P < .0001) in vitro. CONCLUSIONS: The CaPO(4) model accelerates aneurysm formation with the enhancement of apoptosis, macrophage infiltration, and calcium deposition. This modified model, with its rapid and robust dilation, can be used as a new model for AAAs.

Transforming growth factor-ß increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinases pathways.

INTRODUCTION: We have previously demonstrated that transforming growth factor-ß (TGF-ß) in the presence of elevated levels of Smad3, its primary signaling protein, stimulates rat vascular smooth muscle cell (VSMC) proliferation and intimal hyperplasia. The mechanism is partly through the nuclear exportation of phosphorylated cyclin-dependent kinase inhibitor p27. The objective of this study is to clarify the downstream pathways through which Smad3 produces its proliferative effect. Specifically, we evaluated the role of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) in TGF-ß-induced VSMC proliferation. METHODS: Cultured rat aortic VSMCs were incubated with TGF-ß at varying concentrations and times, and phosphorylated ERK was measured by Western blotting. Smad3 was enhanced in VSMCs using an adenovirus expressing Smad3 or inhibited with small interfering RNA (siRNA). For in vivo experiments, male Sprague-Dawley rats underwent carotid balloon injury, followed by intraluminal infection with an adenovirus expressing Smad3. Arteries were harvested at 3 days and subjected to immunohistochemistry for Smad3, phospho-ERK MAPK, and proliferating cell nuclear antigen. RESULTS: In cultured VSMCs, TGF-ß induced activation and phosphorylation of ERK MAPK in a time-dependent and concentration-dependent manner. Overexpression of the signaling protein Smad3 enhanced TGF-ß-induced activation of ERK MAPK, whereas inhibition of Smad3 with a siRNA blocked ERK MAPK phosphorylation in response to TGF-ß. These data suggest that Smad3 acts as a signaling intermediate between TGF-ß and ERK MAPK. Inhibition of ERK MAPK activation with PD98059 completely blocked the ability of TGF-ß/Smad3 to stimulate VSMC proliferation, demonstrating the importance of ERK MAPK in this pathway. Immunoprecipitation of phospho-ERK MAPK and blotting with Smad3 revealed a physical association, suggesting that activation of ERK MAPK by Smad3 requires a direct interaction. In an in vivo rat carotid injury model, overexpression of Smad3 resulted in an increase in phosphorylated ERK MAPK as well as increased VSMC proliferation as measured by proliferating cell nuclear antigen. CONCLUSIONS: Our findings demonstrate a mechanism through which TGF-ß stimulates VSMC proliferation. Although TGF-ß has been traditionally identified as an inhibitor of proliferation, our data suggest that TGF-ß enhances VSMC proliferation through a Smad3/ERK MAPK signaling pathway. These findings at least partly explain the mechanism by which TGF-ß enhances intimal hyperplasia. Knowledge of this pathway provides potential novel targets that may be used to prevent restenosis.

Internal pudendal artery embolization for management of a traumatic labial hematoma.

Non-obstetric perineal injuries often occur as a result of blunt trauma from sport or vehicular accidents. Due to the rich vascular supply of the vulva, this region is susceptible to hematoma formation. Traumatic arterial injury usually involves emergency embolization, typically utilizing coils or microspheres. This case describes an incidence of the utilization of gelfoam for temporary embolization to prevent vulvar and labial necrosis in a patient with an actively expanding hematoma.

Idiopathic pyometra in a postmenopausal patient.

Pyometra is a rare gynecological condition most commonly seen in elderly, postmenopausal women. Malignancy should always be considered as the primary etiology until proven otherwise in the investigation of an intrauterine infection. Clinical signs and symptoms can be vague or nonexistent, and thorough investigation with ultrasound and cross-sectional imaging may be necessary to understand the extent of the disease and best course of treatment. We describe a case of idiopathic pyometra in a postmenopausal woman, as well as review the pathophysiology, investigation, and management of pyometra.

Acute Portal Vein Thrombosis: Current Trends in Medical and Endovascular Management.

Acute portal vein thrombosis (PVT) is a relatively rare diagnosis with a nonspecific clinical presentation. Imaging plays an important role in establishing the diagnosis as well as the etiology and complications of acute PVT. Prompt diagnosis is essential to prevent catastrophic short-term complications including bowel infarction, sepsis, and possible death; missed diagnosis can also result in the long-term sequelae of portal hypertension. Differentiation of acute from chronic PVT is crucial as management strategies differ. Currently, guidelines for treating acute PVT recommend immediate initiation of systemic anticoagulation. Catheter-directed therapy may be used in combination with systemic anticoagulation in the setting of bowel ischemia or as an adjunct in patients with a contraindication to systemic anticoagulation. In this review article, we discuss the diagnosis and clinical features of acute PVT, focusing on current medical and endovascular management strategies including mechanical thrombectomy and fibrinolytic therapy.

TGF-ß/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.

Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-ß and its downstream signaling protein Smad3 ∶ 1) are up-regulated following vascular injury, 2) together drive smooth muscle cell (SMC) proliferation and migration and 3) enhance the development of intimal hyperplasia. In order to determine a mechanism through which TGF-ß/Smad3 promote these effects, Affymetrix gene expression arrays were performed on primary rat SMCs infected with Smad3 and stimulated with TGF-ß or infected with GFP alone. More than 200 genes were differentially expressed (>2.0 fold change, p<0.05) in TGF-ß/Smad3 stimulated SMCs. We then performed GO term enrichment analysis using the DAVID bioinformatics database and found that TGF-ß/Smad3 activated the expression of multiple genes related to either development or cell differentiation, several of which have been shown to be associated with multipotent stem or progenitor cells. Quantitative real-time PCR confirmed up-regulation of several developmental genes including FGF1, NGF, and Wnt11 (by 2.5, 6 and 7 fold, respectively) as well as stem/progenitor cell associated genes CD34 and CXCR4 (by 10 and 45 fold, respectively). In addition, up-regulation of these factors at protein levels were also confirmed by Western blotting, or by immunocytochemistry (performed for CXCR4 and NGF). Finally, TGF-ß/Smad3 down regulated transcription of SMC contractile genes as well as protein production of smooth muscle alpha actin, calponin, and smooth muscle myosin heavy chain. These combined results suggest that TGF-ß/Smad3 stimulation drives SMCs to a phenotypically altered state of de-differentiation through the up-regulation of developmental related genes.

Preferential secretion of collagen type 3 versus type 1 from adventitial fibroblasts stimulated by TGF-ß/Smad3-treated medial smooth muscle cells.

Restenosis, or arterial lumen re-narrowing, occurs in 30-50% of the patients undergoing angioplasty. Adaptive remodeling is the compensatory enlargement of the vessel size, and has been reported to prevent the deleterious effects of restenosis. Our previous studies have shown that elevated transforming growth factor (TGF-ß) and its signaling protein Smad3 in the media layer induce adaptive remodeling of angioplastied rat carotid artery accompanying an increase of total collagen in the adventitia. In order to gain insights into a possible role of collagen in Smad3-induced adaptive remodeling, here we have investigated a mechanism of cell-cell communication between medial smooth muscle cells (SMCs) and adventitial fibroblasts in regulating the secretion of two major collagen subtypes. We have identified a preferential collagen-3 versus collagen-1 secretion by adventitial fibroblasts following stimulation by the conditioned medium from the TGF-ß1-treated/Smad3-expressing medial smooth muscle cells (SMCs), which contained higher levels of CTGF and IGF2 as compared to control medium. Treating the TGF-ß/Smad3-stimulated SMCs with an siRNA to either CTGF or IGF2 reversed the effect of conditioned media on preferential collagen-3 secretion from fibroblasts. Moreover, recombinant CTGF and IGF2 together stimulated adventitial fibroblasts to preferentially secrete collagen-3 versus collagen-1. This is the first study to identify a preferential secretion of collagen-3 versus collagen-1 from adventitial fibroblasts as a result of TGF-ß/Smad3 stimulation of medial SMCs, and that CTGF and IGF2 function together to mediate this signaling communication between the two cell types.

Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

OBJECT: The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. METHODS: A total of 30 patients with recurrent malignant glioma were included in the current study. RESULTS: The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. CONCLUSIONS: The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.