Jovan N. Markovic

Characterization of Osteopontin Binding Kinetics in MDA-MB231 Breast and SK-Hep-1 Liver Cancer Cells

Osteopontin (OPN) is a secreted phosphoprotein whic h plays a critical role in metastasis of colon, liver , and breast cancers. The canonical pathway for OPN signaling fo cuses on its binding interactions with integrin and CD44 cell surface receptors. However, the binding characteri stics of OPN to integrin and CD44 receptors has not been pre vi- ously examined. In this paper, using MDA-MB231 brea st cancer and SK-Hep-1 liver cancer cells, we determin e the relative binding characteristics of the OPN ligand to its integrin and CD44 cell surface receptors. The appar ent K D ’s for binding to CD44 was 56 μ M and 49 μ M and to integrin was 18 μ M and 17 μ M, in SK-Hep-1 and MDA- MB231, respectively. The CD44/Integrin ratio of OP N bound was 1.3 and 3.8 in SK-Hep-1 and MDA-MB231, respectively. Our results indicate that OPN binds t o it rec- ognized receptors with substantially different affi nities, receptor expression varies between cell types, and signifi- cant OPN cell surface interactions that are integri n- and CD44-independent. These uncharacterized interaction s may reveal important insights into OPN’s role in ca ncer metastasis.

Update on Radiofrequency Ablation

The two currently available methods to achieve ablation of incompetent veins using radiofrequency energy are radiofrequency ablation (VNUS Closure Plus(tm)) and radiofrequency powered segmental ablation (VNUS Closure Fast(tm)). Both treatment modalities expose vascular endothelium to high-frequency alternating current. This results in contraction of venous wall collagen with subsequent fibrotic endoluminal obliteration which eliminates hydrostatic and hydrodynamic pressures as the main hemodynamic mechanisms for varicosities. Radiofrequency segmental ablation has become available relatively recently, but increasing amount of clinical data and patients satisfaction support this technique as a reasonable therapy for superficial reflux disease. Although initial experience with Closure Fasttm catheter documented substantially decreased average procedural time, little postoperative discomfort and short-term occlusion rates that approximated 100%, larger clinical trials are needed before this modification of traditional radiofrequency ablation can be accurately evaluated in the treatment of superficial reflux disease.

Genomics of varicose veins and chronic venous insufficiency

Recent sequencing of the human genome has opened up new areas of investigation for genetic aberrations responsible for the pathogenesis of many human diseases. To date, there have been no studies that have investigated the entire human genome for the genetic underpinnings of chronic venous insufficiency (CVI). Utilizing Gene Chip Arrays we analyzed the relative expression levels of more than 47,000 transcripts and variants and approximately 38,500 well-characterized genes from each of 20 patients (N (CVI)=10; N (Control Group)=10). Relative gene expression profiles significantly differed between patients with CVI and patients unaffected by CVI. Regulatory genes of mediators of the inflammatory reaction and collagen production were up-regulated and down-regulated, respectively in CVI patients. DNA microarray analysis also showed that relative gene expression of multiple genes which function remains to be elucidated was significantly different in CVI patients. Fundamental advancements in our knowledge of the human genome and understanding of the genetic basis of CVI represents an opportunity to develop new diagnostic, prognostic, preventive and therapeutic modalities in the management of CVI.

A 6-year experience treating vascular malformations with foam sclerotherapy.

In this study, the authors present an analysis of the outcomes of 105 low-flow vascular malformation patients treated over a 6-year period and report specific lesion characteristics that correlate with those vascular malformations that will benefit from sodium tetradecyl sulfate foam sclerotherapy (STS FS) versus surgical resection as well as morphological characteristics of vascular malformations that are associated with a poor response to FS treatment. Improvement in symptoms was documented in 92.9% of patients treated with STS FS. There were no complications. Low-flow vascular malformations that were morphologically characterized by microcystic, septated vessels did not respond to FS, and these vascular malformations are best treated with surgical resection. Primary surgical resection is also the treatment of choice for localized, microcystic, and superficial low-flow vascular malformations. Symptomatic, diffuse, extensive, macrocystic malformations that involve multiple tissue planes and vital structures are best treated with FS.

Multidisciplinary treatment of extremity arteriovenous malformations

Congenital vascular malformations (CVMs) are a complex group of lesions that arise by embryologic dysmorphogenesis without increased endothelial proliferation that leads to structural and functional anomalies of the vascular system characterized by a wide range of presenting symptoms and often unpredictable clinical course. A recent advancement in the diagnostic and treatment modalities has resulted in a better understanding of the pathophysiology and natural history of CVMs and improved management of these lesions. The multidisciplinary approach and diagnostic algorithm used to distinguish high-flow (HFVM) from low-flow vascular malformations (LFVM) have been validated as clinically applicable for making an accurate anatomic and hemodynamic diagnosis of CVMs; they serve as a basis for proper treatment selection and significantly facilitate communication among different medical specialists. Dynamic contrast-enhanced magnetic resonance imaging is able to definitively distinguish HFVM from LFVM with accuracy of approximately 84%. In inconclusive cases, confirmatory angiography is required. Symptomatic, diffuse, extensive, macrocystic LFVMs and LFVMs that involve multiple tissue planes and vital structures are best treated with foam sclerotherapy. Primary surgical resection is the treatment of choice for localized, septated, and microcystic LFVMs. The management of HFVMs is characterized by multimodal treatment including preoperative embolization followed by complete surgical resection or sclerotherapy of the remaining venous component. Treatment of extensive CVMs is palliative and goal oriented. Implementation of the proposed diagnostic protocols and therapeutic algorithms in a multidisciplinary setting results in favorable outcomes with acceptable complication rates in this challenging patient population.

The impact of diabetes mellitus and renal insufficiency on the outcome of endovascular abdominal aortic aneurysm repair.

The purpose of this study was to determine the effects of diabetes mellitus (DM) and renal insufficiency (RI) on outcomes following endovascular abdominal aneurysms repair (EVAR). The surgical outcomes associated with endovascular repair in 12 451 patients are reported. After adjusting for confounders, DM and RI were analyzed against the primary outcome variables of mortality, major complications, length of stay, treatment cost, and routine discharge rates. This study shows that RI has a greater negative influence on the outcome of EVAR than previously suspected and that a conservative approach to the use of EVAR in patients with RI is warranted. While DM has negative impact on outcomes following open repair of abdominal aortic aneurysms, this study shows that it may confer less of a risk than previously thought, when confounders are controlled for, and that EVAR might be a favorable treatment modality for patients with abdominal aortic aneurysm and coexisting DM.

Emerging role of contrast-enhanced MRI in diagnosing vascular malformations

Vascular malformations comprise a diverse and rare group of lesions which generally pose a formidable treatment challenge. Requisite for optimal surgical planning are imaging modalities capable of delineating involved anatomy and malformation flow characteristics. In this regard, we and others have purported the advantages of contrast-enhanced MRI. Here, we review the current body of literature regarding the emerging of role of contrast enhanced MRI for the management of vascular malformations.

Endovenous Laser Ablation: Strategies for Treating Multilevel Disease

Since its introduction in 1999 and FDA approval in 2002, endovenous laser ablation has been widely accepted to effectively treat superficial venous reflux, with minimal side effects. Anatomically, any combination of superficial, perforator and deep venous disease can result in various stages of chronic venous insufficiency. In general, when multiple levels of venous disease are involved the manifestations of venous insufficiency increase in severity. Given that one patient with significant reflux in deep system will have no resultant symptoms, while another patient may progress to an active ulceration from a saphenous reflux alone, individual treatment strategies in the patient with multilevel reflux disease should be based on a thorough clinical and duplex evaluation to determine their specific anatomy and pathology. A basic understanding of mechanism of laser-tissue interaction, venous pathophysiology and the relationship of deep to superficial reflux disease assists in refining procedural techniques and strategies.

Lymphatic Malformation (LM) (Extratruncular): Lymphangioma

Lymphatic malformations (LMs) as a subgroup of congenital vascular malformations (CVMs) are localized or diffused abnormalities of lymphogenesis which lead to true structural and/or functional anomalies of the lymphatic system [1, 2]. Most clinicians – from primary care doctors to subspecialists (including vascular surgeons) – consider the management of LMs a difficult task reserved for referral centers with specialized expertise in this area. The main reason why expertise for LMs management is centralized to major clinics is the low frequency at which CVMs occur in general, the confusing nomenclature, and the lack of a uniform classification system which traditionally characterized majority of the literature discussing LMs, as well as the absence of established guidelines for their management [3, 4]. Consequently, a significant number of LM patients have been discouraged by the lack of correct diagnosis and proper treatment despite numerous visits to different clinics.

Contemporary Diagnosis: MRI and MRA

Historically, the diagnosis and treatment of congenital vascular malformations (CVMs) have been hampered by the complex nature of these vascular lesions, the persistence of outdated and often inconsistent terminology, as well as the absence of defined imaging protocols and therapeutic algorithms [1–5]. As vascular malformations range in severity from trivial to life-threatening, from focal to diffuse and extensive, and vary significantly with regard to composition, the ability to use a single imaging modality to distinguish between high-flow and low-flow lesions is essential when the goal is to avoid noncontributory and/or invasive imaging modalities, select proper treatment modality, avoid unnecessary invasive catheter-based procedures, and avoid potentially life-threatening side effects [6–9].