Rahmi Oklu

Angiogenesis and Current Antiangiogenic Strategies for the Treatment of Cancer

Angiogenesis is a complex process critical for embryonic development and for survival. It is also a critical player in many pathologic processes, most notably in neoplasia. The cell signaling pathways involved in angiogenesis have become key targets for drug design, with more than 2,500 clinical trials currently under way. This review summarizes the essential features of angiogenesis and discusses therapeutic strategies that have been applied to specific diseases known to be associated with perturbation of normal angiogenic control.

Bioprinting the Cancer Microenvironment

Cancer is intrinsically complex, comprising both heterogeneous cellular compositions and microenvironmental cues. During the various stages of cancer initiation, development, and metastasis, cell-cell interactions (involving vascular and immune cells besides cancerous cells) as well as cell-extracellular matrix (ECM) interactions (e.g., alteration in stiffness and composition of the surrounding matrix) play major roles. Conventional cancer models both two- and three-dimensional (2D and 3D) present numerous limitations as they lack good vascularization and cannot mimic the complexity of tumors, thereby restricting their use as biomimetic models for applications such as drug screening and fundamental cancer biology studies. Bioprinting as an emerging biofabrication platform enables the creation of high-resolution 3D structures and has been extensively used in the past decade to model multiple organs and diseases. More recently, this versatile technique has further found its application in studying cancer genesis, growth, metastasis, and drug responses through creation of accurate models that recreate the complexity of the cancer microenvironment. In this review we will focus first on cancer biology and limitations with current cancer models. We then detail the current bioprinting strategies including the selection of bioinks for capturing the properties of the tumor matrices, after which we discuss bioprinting of vascular structures that are critical toward construction of complex 3D cancer organoids. We finally conclude with current literature on bioprinted cancer models and propose future perspectives.

ALK Molecular Phenotype in Non–Small Cell Lung Cancer: CT Radiogenomic Characterization

PURPOSE To present a radiogenomic computed tomographic (CT) characterization of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) (ALK+). MATERIALS AND METHODS In this HIPAA-compliant institutional review board-approved retrospective study, CT studies, ALK status, and clinical-pathologic data in 172 patients with NSCLC from three institutions were analyzed. A screen of 24 CT image traits was performed in a training set of 59 patients, followed by random forest variable selection incorporating 24 CT traits plus six clinical-pathologic covariates to identify a radiogenomic predictor of ALK+ status. This predictor was then validated in an independent cohort (n = 113). Test-for-accuracy and subset analyses were performed. A similar analysis was performed to identify a biomarker associated with shorter progression-free survival (PFS) after therapy with the ALK inhibitor crizotinib. RESULTS ALK+ status was associated with central tumor location, absence of pleural tail, and large pleural effusion. An ALK+ radiogenomic CT status biomarker consisting of these three imaging traits with patient age of younger than 60 years showed strong discriminatory power for ALK+ status, with a sensitivity of 83.3% (15 of 18), a specificity of 77.9% (74 of 95), and an accuracy of 78.8% (89 of 113) in independent testing. The discriminatory power was particularly strong in patients with operable disease (stage IIIA or lower), with a sensitivity of 100.0% (five of five), a specificity of 88.1% (37 of 42), and an accuracy of 89.4% (42 of 47). Tumors with a disorganized vessel pattern had a shorter PFS with crizotinib therapy than tumors without this trait (11.4 vs 20.2 months, P = .041). CONCLUSION ALK+ NSCLC has distinct characteristics at CT imaging that, when combined with clinical covariates, discriminate ALK+ from non-ALK tumors and can potentially identify patients with a shorter durable response to crizotinib.

Pathogenesis of Varicose Veins

Despite the high prevalence of varicose veins and the recent surge in research on the condition, the precise mechanisms underlying their development remain uncertain. In the past decade, there has been a shift from initial theories based on purely mechanical factors to hypotheses pointing to complex molecular changes causing histologic alterations in the vessel wall and extracellular matrix. Despite progress in understanding the molecular aspects of venous insufficiency, therapies for symptomatic varicose veins are directed toward anatomic and physical interventions. The present report reviews current evidence identifying the underlying biochemical alterations in the pathogenesis of varicose veins.

Pelvic Congestion Syndrome: Etiology of Pain, Diagnosis, and Clinical Management

Pelvic congestion syndrome is associated with pelvic varicosities that result in chronic pelvic pain, especially in the setting of prolonged standing, coitus, menstruation, and pregnancy. Although the underlying pathophysiology of pelvic congestion syndrome is unclear, it probably results from a combination of dysfunctional venous valves, retrograde blood flow, venous hypertension, and dilatation. Asymptomatic women may also have pelvic varicosities, making pelvic congestion syndrome difficult to diagnose. This article explores the etiologies of pain, use of imaging techniques, and clinical management of pelvic congestion syndrome. Possible explanations for the spectrum of pain among women with pelvic varicosities are also discussed.

May-Thurner syndrome: diagnosis and management

For over fifty years, the pathogenesis of May-Thurner syndrome (MTS) has been associated with chronic left common iliac vein compression resulting in the formation of intraluminal, permanent obstructive lesions. However, despite this association, the mechanism by which compression produces these lesions is unknown. Diagnostic accuracy of MTS is critical since it often afflicts young patients requiring endovascular management. This review will focus on the historical, embryological and evolutionary description of MTS and examine its development, diagnosis, clinical management and potential diagnostic errors.

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

OBJECTIVE Ischemia-reperfusion (IR) injury is a significant problem in the management of patients with acute limb ischemia. Despite rapid restoration of blood flow after technically successful open and endovascular revascularization, complications secondary to IR injury continue to occur and limit clinical success. Our aim was to create a murine model of hind limb IR injury to examine the role of Toll-like receptor-4 (TLR4) and to determine whether inactive TLR4 led to a decrease in the detection of neutrophil extracellular traps (NETs), which are known to be highly thrombogenic and may mediate microvascular injury. METHODS A calibrated tension tourniquet was applied to unilateral hind limb of wild-type (WT) and TLR4 receptor mutant (TLR4m) mice for 1.5 hours to induce ischemia and then removed to initiate reperfusion. At the end of 48 hours of reperfusion, mice were euthanized and hind limb tissue and serum specimens were collected for analysis. Hematoxylin and eosin-stained sections of hind limb skeletal muscle tissue were examined for fiber injury. For immunohistochemistry, mouse monoclonal antihistone H2A/H2B/DNA complex antibody to detect NETs and rabbit polyclonal antimyeloperoxidase antibody were used to identify infiltrating cells containing myeloperoxidase. Muscle adenosine triphosphate levels, nuclear factor (NF)-κB activity, the α-subunit of inhibitor of NF-κB light polypeptide gene enhancer, poly (adenosine diphosphate-ribose) polymerase activity, and inducible nitric oxide synthase expression were measured. Systemic levels of keratinocyte-derived chemokine, monocyte chemotactic protein-1, and vascular endothelial growth factor in the serum samples were also examined. RESULTS IR injury in the hind limb of WT mice demonstrated significant levels of muscle fiber injury, decreased energy substrates, increased NF-κB activation, decreased levels of α-subunit of inhibitor of NF-κB light polypeptide gene enhancer, increased inducible nitric oxide synthase expression, and increased poly (adenosine diphosphate-ribose) polymerase activity levels compared with the TLR4m samples. Additionally, there was marked decrease in the level of neutrophil and monocyte infiltration in the TLR4m mice, which corresponded to similar levels of decreased NET detection in the interstitial space and in microvascular thrombi. In situ nuclease treatment of WT tissue sections significantly diminished the level of NET immunostaining, demonstrating the specificity of the antibody to detect NETs and suggesting a potential role for nuclease treatment in IR injury. CONCLUSIONS These results suggest a pivotal role for TLR4 in mediating hind limb IR injury and suggest that NETs may contribute to muscle fiber injury.

Iliac vein compression syndrome: Clinical, imaging and pathologic findings

May-Thurner syndrome (MTS) is the pathologic compression of the left common iliac vein by the right common iliac artery, resulting in left lower extremity pain, swelling, and deep venous thrombosis. Though this syndrome was first described in 1851, there are currently no standardized criteria to establish the diagnosis of MTS. Since MTS is treated by a wide array of specialties, including interventional radiology, vascular surgery, cardiology, and vascular medicine, the need for an established diagnostic criterion is imperative in order to reduce misdiagnosis and inappropriate treatment. Although MTS has historically been diagnosed by the presence of pathologic features, the use of dynamic imaging techniques has led to a more radiologic based diagnosis. Thus, imaging plays an integral part in screening patients for MTS, and the utility of a wide array of imaging modalities has been evaluated. Here, we summarize the historical aspects of the clinical features of this syndrome. We then provide a comprehensive assessment of the literature on the efficacy of imaging tools available to diagnose MTS. Lastly, we provide clinical pearls and recommendations to aid physicians in diagnosing the syndrome through the use of provocative measures.

May-Thurner syndrome: can it be diagnosed by a single MR venography study?

PURPOSE We aimed to evaluate the longitudinal stability of left common iliac vein (LCIV) compression by the right common iliac artery on magnetic resonance venography (MRV). MATERIALS AND METHODS This retrospective study included 214 patients diagnosed with May-Thurner syndrome by MRV. We identified a subset of patients who underwent contrast-enhanced cross-sectional imaging of the pelvis six months before or anytime after the MRV and did not undergo any interventional venous procedures between the two studies; 36 patients met these criteria. The degree of venous compression was calculated in both the index and comparison study. RESULTS On the index MRV, the mean compression of the LCIV was 62%. However, on the comparison study in the same patients, the mean compression was 39%. The mean change in degree of compression between the two studies was 23% (P < 0.0001), ranging from a 12% increase to 69% decrease in degree of compression on the comparison study. CONCLUSION The compressed LCIV on a single MRV study was not stable over time and thus may be insufficient to diagnose May-Thurner syndrome.

An injectable shear-thinning biomaterial for endovascular embolization

An engineered shear-thinning biomaterial is used as an embolic agent for vascular occlusion as treatment for bleeding. Stopping blood in its tracks Effective treatments for ruptured blood vessels must be rapidly deployed to promote hemostasis. Avery et al. formulated a gelatin and silicate nanoplatelet hydrogel material that occluded blood flow without requiring thrombus formation. When injected into arteries and veins in mice and pigs, the biomaterial occluded blood flow without evidence of fragmentation or displacement for up to 24 days. Occluded vessels showed evidence of connective tissue replacing the biomaterial in the vessel lumen. Shear-thinning biomaterials represent promising alternatives for stable endovascular embolization. Improved endovascular embolization of vascular conditions can generate better patient outcomes and minimize the need for repeat procedures. However, many embolic materials, such as metallic coils or liquid embolic agents, are associated with limitations and complications such as breakthrough bleeding, coil migration, coil compaction, recanalization, adhesion of the catheter to the embolic agent, or toxicity. Here, we engineered a shear-thinning biomaterial (STB), a nanocomposite hydrogel containing gelatin and silicate nanoplatelets, to function as an embolic agent for endovascular embolization procedures. STBs are injectable through clinical catheters and needles and have hemostatic activity comparable to metallic coils, the current gold standard. In addition, STBs withstand physiological pressures without fragmentation or displacement in elastomeric channels in vitro and in explant vessels ex vivo. In vitro experiments also indicated that STB embolization did not rely on intrinsic thrombosis as coils did for occlusion, suggesting that the biomaterial may be suitable for use in patients on anticoagulation therapy or those with coagulopathy. Using computed tomography imaging, the biomaterial was shown to fully occlude murine and porcine vasculature in vivo and remain at the site of injection without fragmentation or nontarget embolization. Given the advantages of rapid delivery, in vivo stability, and independent occlusion that does not rely on intrinsic thrombosis, STBs offer an alternative gel-based embolic agent with translational potential for endovascular embolization.