Vascular Configuration Research Articles

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

Unilateral Duplication of Renal Vessels: Exploring Anatomical, Clinical, and Surgical Insights

The classic description of renal vascularization typically refers to a renal artery and vein. Nevertheless, this vascular configuration exhibits numerous anatomical variations in terms of their number, origin, and course, primarily attributable to ontogenetic alterations. While performing standard abdominal dissections for medical students, we examined the kidneys and their vasculature observing variations in the morphological arrangements of the right renal artery and renal vein. This case report aims to shed light on these variations, thereby enhancing clinicians' awareness of the intricate blood supply to the kidney. Understanding the diverse patterns of renal artery variations holds significance for urologists, radiologists, and surgeons alike. Such insights can prove invaluable for practitioners engaged in invasive procedures and vascular surgeries. Keywords: renal artery, renal vein, vascular variation, anatomical variants, renal surgery

Model-guided navigation of magnetic soft guidewire for safe endovascular surgery

The emergent magnetic soft guidewires (MSGs) that can be remotely navigated by magnetic fields hold great promise in minimally invasive endovascular surgery. However, existing models of MSGs have been limited in practical applications, largely due to insufficient consideration of contacts within actual endovascular settings. In this work, we present a theoretical model incorporating the magneto-mechanical behavior of MSGs with these critical contacts, allowing for a detailed evaluation of their navigation capability in various vascular configurations. Specifically, we categorize blood vessels into two main types: curved vessels and bifurcated vessels and identify a critical contact angle between the MSG tip and the vessel wall, beyond which the vascular damage may occur. By applying the principles of hard-magnetic elastica to account for the large deflection of MSGs, we develop a numerical framework that employs polynomial approximations and an energy minimization strategy. Through parametric analysis of different vessel types, we propose a method for adjusting magnetic fields for the safe navigation of MSGs through them. Our theoretical predictions have been substantiated by finite element modeling and experimental validation. The results of this paper offer a solid foundation for establishing practical guidelines for remote MSG navigation with minimal risk of vascular damage.

Longitudinal changes in optic disc cupping from the baseline in chiasmal lesion optic neuropathy and glaucoma

We aimed to investigate the changes in cupping in chiasmal lesion optic neuropathy (chON) compared to baseline optic disc and glaucoma. We used a novel study design to enroll patients who had fundus photographs incidentally taken during routine health check-ups prior to the onset of optic neuropathy. In 31 eyes (21 patients) with chON and 33 eyes (30 patients) with glaucoma, we investigated the change in cup-to-disc (C/D) area from the baseline to overt cupping using flicker analysis. Compared to the baseline, 23 eyes (74.2%) had increased cup size and 3 (9.7%) had vascular configuration changes in the chONgroup; in contrast, all glaucoma eyes exhibited changes in cup size and vascular configuration. The increase in C/D area ratio was significantly smaller in chON (0.04 ± 0.04) compared to glaucoma (0.10 ± 0.04, P < 0.001); the minimum residual neuroretinal rim width showed a more pronounced difference (29.7 ± 8.2% vs 7.1 ± 3.9%, P < 0.001). The changes distributed predominantly towards the nasal direction in chON, contrasting the changes to the arcuate fibers in glaucoma. In conclusion, our results provide the first longitudinal evidence of true pathological cupping in chONcompared to photographically disease-free baseline. The marked difference in the residual minimum rim width reaffirms the importance of rim obliteration in the differential diagnosis between the two diseases.

Automatic enhancement of vascular configuration for self-healing concrete through reinforcement learning approach

Vascular self-healing concrete (SHC) has great potential to mitigate the environmental impact of the construction industry by increasing the durability of structures. Designing concrete with high initial mechanical properties by searching a specific arrangement of vascular structure is of great importance. Herein, an automatic optimization method is proposed to arrange vascular configuration for minimizing the adverse influence of vascular system through a reinforcement learning (RL) approach. A case study is carried out to optimize a concrete beam with 3 pores (representing a vascular network) positioned in the beam midspan within a design space of 40 possibilities. The optimization is performed by the interaction between RL agent and Abaqus simulation environment with the change of target properties as a reward signal. The results illustrates that the RL approach is able to automatically enhance the vascular arrangement of SHC given the fact that the 3-pore structures that have the maximum target mechanical property (i.e., peak load or fracture energy) are accessed for all of the independent runs. The RL optimization method is capable of identifying the structure with high fracture energy in the new optimization task for 4-pore concrete structure.

Non-destructive evaluation of ductile-porous versus brittle 3D printed vascular networks in self-healing concrete

Additive manufacturing (AM) can produce complex vascular network configurations, yet limited testing has been done to characterize the damage and healing behavior of concrete with embedded networks for self-healing. In this study, different AM methods and network wall materials were used to produce vascular networks for self-healing concrete prisms, where their load-response behavior, healing efficiency and microstructure were evaluated using non-destructive techniques: acoustic emission (AE), ultrasonic pulse velocity (UPV), digital image correlation (DIC), and X -ray computed tomography (CT). The types of healing agent release mechanisms that were studied include a ductile-porous network that supplies fluid from its pores and a brittle network that fractures under load to release fluid. DIC coupled with AE verified debonding of ductile-porous networks from the cementitious matrix, and was able to track damage progression as well as healing for all networks with load regains up to 56 % and stiffness regains up to 91 % using polyurethane.

Preliminary in-silico analysis of vascular graft implantation configuration and surface modification

Vascular grafts are used to reconstruct congenital cardiac anomalies, redirect flow, and offer vascular access. Donor tissue, synthetic, or more recently tissue-engineered vascular grafts each carry limitations spanning compatibility, availability, durability and cost. Synthetic and tissue-engineered grafts offer the advantage of design optimization using in-silico or in-vitro modeling techniques. We focus on an in-silico parametric study to evaluate implantation configuration alternatives and surface finishing impact of a novel silicon-lined vascular graft. The model consists of a synthetic 3D-generic model of a graft connecting the internal carotid artery to the jugular vein. The flow is assumed unsteady, incompressible, and blood is modeled as a non-Newtonian fluid. A comparison of detached eddy turbulence and laminar modeling to determine the required accuracy needed found mild differences mainly dictated by the roughness level. The conduit walls are modeled as non-compliant and fixed. The shunt configurations considered, are straight and curved with varied surface roughness. Following a grid convergence study, two shunt configurations are analyzed to better understand flow distribution, peak shear locations, stagnation regions and eddy formation. The curved shunt was found to have lower peak and mean wall-shear stress, while resulting in lower flow power system and decreased power loss across the graft. The curved smooth surface shunt shows lower peak and mean wall-shear stress and lower power loss when compared to the straight shunt.

Configuration-independent thermal invariants under flow reversal in thin vascular systems.

Modulating temperature fields is indispensable for advancing modern technologies: space probes, electronic packing, and implantable medical devices, to name a few. Bio-inspired thermal regulation achieved via fluid flow within a network of embedded vesicles is notably desirable for slender synthetic material systems. This far-reaching study-availing theory, numerics, and experiments-reveals a counter-intuitive yet fundamental property of vascular-based fluid-flow-engendered thermal regulation. For such thin systems, the mean surface temperature and the outlet temperature-consequently, the heat extracted by the flowing fluid (coolant)-are invariant under flow reversal (i.e. swapping the inlet and outlet). Despite markedly different temperature fields under flow reversal, our newfound invariance-a discovery-holds for anisotropic thermal conductivity, any inlet and ambient temperatures, transient and steady-state responses, irregular domains, and arbitrary internal vascular topologies, including those with branching. The reported configuration-independent result benefits thermal regulation designers. For instance, the flexibility in the coolant's inlet location eases coordination challenges between electronics and various delivery systems in microfluidic devices without compromising performance (e.g. soft implantable coolers for pain management). Last but not least, the invariance offers an innovative way to verify computer codes, especially when analytical solutions are unavailable for intricate domain and vascular configurations.

Macro- and micromorphology reveal four entities in the highly variable Oxalis polymorpha Mart. ex Zucc. (Oxalidaceae)

Leaf morphoanatomy can provide useful information for the taxonomy of morphologically similar species or the recognition of infraspecific taxa. Here, we evaluated the taxonomic utility of leaf morphological and anatomical characters for the recognition of distinct morphologies currently placed under Oxalis polymorpha Mart. ex Zucc., a highly polymorphic species of Oxalis from the Brazilian Atlantic Forest. We analyzed leaves of 13 specimens gathered from five populations throughout the species' geographic distribution. Leaf samples were analyzed under light and scanning electron microscopy. We observed differences in the leaf blade venation patterns, in the indumentum of petioles and leaf blades, in the pulvinar vascular tissue configuration, and in the midrib tissue organization. The variation in these characters allowed us to recognize four different morphotypes among these samples. These morphotypes are geographically disjunct and differ among each other in additional morphological features, such as leaf arrangement along the stem, leaflet shape, inflorescence position, petal color, and fruit shape. Oxalis polymorpha is a good candidate for investigating if phylogenetic relationships support recognition of each of its morphotypes at the species level.

A numerical study of tumor cell arrest in microvessels qualifying for mechanical entrapment

During hematogenous metastasis, the arrest of tumor cells in the microvasculature is a prerequisite for extravasation from the circulation to a distant host organ. To reveal such arrest behavior, we implement three-dimensional numerical simulations on the motion of a single tumor cell in microvessels at the cellular scale and mainly investigate the interactions among mechanical entrapment, adhesion, and cell stiffness, and their effects on the tumor cell arrest. Two types of vascular configurations qualifying for mechanical entrapment are considered, the constriction and bifurcation structures that are comparable in diameter with the tumor cell. The main results indicate that in the constriction tube, as the constriction radius is increased, the tendency that number of adhesion bonds increases with increasing shear modulus becomes more and more obvious. However, the adhesion behavior has little effect on the tumor cell arrest in the constriction region, regardless of the number of adhesion bonds. The mechanical entrapment plays a more important role than the cell stiffness in the tumor cell arrest in the constriction tube. In the bifurcated tube, the tumor cell is more likely to be arrested in the bifurcation region with a small bifurcation angle. Moreover, as the bifurcation angle or shear modulus is decreased, the effect of adhesion behavior on the tumor cell arrest becomes increasingly obvious. These results are helpful in understanding the biomechanism of tumor metastasis.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population

Background and Purpose: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. Methods: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. Results: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004–4.270) and CMB presence (OR = 1.542; 95% CI, 1.012–2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069–3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064–2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346–0.915). Conclusions: COW configuration was significantly related to various covert vascular brain injuries.

Research progress of the role of iris characteristics in angle closure

Glaucoma is a kind of optic nerve degenerative disease characterized by both depressed atrophy of optic nerve and visual field defect. In Asia, the number of patients with primary Angle closure glaucoma (PACG) is increasing year by year, posing serious impact on the life quality of patients. Angle closure is the pathogenic basis of PACG. Early identification of the risk factors for Angle closure and control on its progression are crucial to the prognosis of PACG. With the continuous in-depth study of the iris in recent years, it has been found that the changes in iris volume are also important dynamic risk factor for PACG. This paper summarizes the latest research results of both domestic and overseas, describes and summarizes the histology, biological characteristics, surface features, vascular configuration and genomics of the iris, and further analyzes the role of iris characteristics in angle closure in details, in order to provide a reference for the clinical diagnosis and research work.

The Uncancerous Helix-Benign Fibrous Histiocytoma

Benign fibrous histiocytoma occurs as an exceptional, painless, subcutaneous, mesenchymal, fibrohistiocytic neoplasm devoid of dermal incrimination. Additionally designated as deep dermatofibroma, deep seated benign fibrous histiocytoma commonly emerges within subcutaneous tissue, deep seated soft tissue or parenchymal organs. Generally, benign fibrous histiocytoma arises in adult males &gt; 25 years and appears between 6 years to 84 years with a median age of disease emergence at 40 years. A male predominance is observed. Commonly, benign fibrous histiocytoma emerges within lower or upper extremities, head and neck or trunk. Neoplasms confined to deep soft tissue of retroperitoneum, mediastinum or pelvis are infrequently discerned [1,2]. Deep seated benign fibrous histiocytoma emerges as a painless, gradually progressive, well circumscribed or encapsulated tumefaction [1,2]. Grossly, firm, yellow to tan, well circumscribed tumefaction encompassed with a pseudo-capsule is discerned. Pseudo-capsule may be absent where tumefaction extends to the cutis [1,2]. Characteristically, tumour magnitude is ~ 4 centimetres and varies from 0.5 centimetres to 25 centimetres. Cut surface exhibits variable foci of haemorrhage [1,2]. Upon microscopy, neoplasm exhibits a prominent storiform pattern configured of uniform, spindle-shaped cells imbued with eosinophilic cytoplasm with ill defined cellular perimeter and bland, elongated or plump nuclei with vesicular chromatin and delicate nucleoli. Tumour nuclei are devoid of nuclear atypia [1,2]. tumefaction is admixed with disseminated lymphocytes, plasma cells multinucleated giant cells, osteoclastic giant cells or foamy macrophages [1,2]. Frequently, prominent vascular articulations may configure a hemangiopericytoma-like pattern. Mitotic figures appear ≤5 mitosis per 10 high power fields [1,2]. Intervening stroma is myxoid or hyaline. Focal necrosis or tumour infiltration of lymphatic and vascular configurations is exceptional. Tumour perimeter is non-infiltrative and peripheral entrapment of adipose tissue is absent. Focal entrapment of collagen fibres may occur [1,2].

Optimization of diagnostics of retinopathy of prematurity stages based on the integration of clinical data using the Key to Diagnosis I software

Despite the improvement of algorithms of preterm infants’ management, methods for predicting, diagnosing and treating ROP remains a vital issue. Purpose: to improve the diagnostics of retinopathy of prematurity based on the assessment of vascular system configuration, using Key to Diagnosis I software. Material and methods. 279 patients with ROP were divided into 6 groups: group 1 included 152 patients (304 eyes) with stage I; group 2 — 45patients (90 eyes) with stage II; group 3 — 8patients (12 eyes) with stage III; group 4 — 7 patients (8 eyes) with stage IVA; group 5 — 7 patients (14 eyes) with posterior aggressive ROP; control group 6 — 60patients (120 eyes) diagnosed with immature retina who have no ROP signs. 28 eyes were analyzed using wide-field imaging, while 400 eyes were analyzed by separate images. The presence o f“mute” zones, macula localization, traction index of the macular zone (Tm), zone and span of pathological changes, fractal dimension (Df) and complexity of vascular system (СVS) were assessed on automatically created wide-field images, obtained by Ret-Cam Shuttle. Results. We revealed strong correlation between Df and stages (p = 0.85, p = 0.01); moderate negative correlation of Тm and stages (p = 0.62, p = 0.01), except for posterior aggressive ROP; strong positive correlation between CVS and stages ( p = 0.91, p = 0.001). Diagnostic modules of the software have been developed to create wide-field fundus imaging in infants, localize the macula as a marker for morphometry, and isolate the vascular system using deep convolutional neural networks. Conclusions. The developed algorithm for multivari­ate analysis of the retinal vascular system reduces the risks of subjective assessment of retinal changes.

A multi-scale/multi-physics model for the theoretical study of the vascular configuration of retinal capillary plexuses based on OCTA data.

The retinal tissue is highly metabolically active and is responsible for translating the visual stimuli into electrical signals to be delivered to the brain. A complex vascular structure ensures an adequate supply of blood and oxygen, which is essential for the function and survival of the retinal tissue. To date, a complete understanding of the configuration of the retinal vascular structures is still lacking. Optical coherence tomography angiography has made available a huge amount of imaging data regarding the main retinal capillary plexuses, namely the superficial capillary plexuses (SCP), intermediate capillary plexuses (ICP) and deep capillary plexuses (DCP). However, the interpretation of these data is still controversial. In particular, the question of whether the three capillary plexuses are connected in series or in parallel remains a matter of debate. In this work, we address this question by utilizing a multi-scale/multi-physics mathematical model to quantify the impact of the two hypothesized vascular configurations on retinal hemodynamics and oxygenation. The response to central retinal vein occlusion (CRVO) and intraocular pressure (IOP) elevation is also simulated depending on whether the capillary plexuses are connected in series or in parallel. The simulation results show the following: (i) in the in series configuration, the plexuses exhibit a differential response, with DCP and ICP experiencing larger pressure drops than SCP; and (ii) in the in parallel configuration, the blood flow redistributes uniformly in the three plexuses. The different vascular configurations show different responses also in terms of oxygen profiles: (i) in the in series configuration, the outer nuclear layer, outer plexiform layer and inner nuclear layer (INL) are those most affected by CRVO and IOP elevation; and (ii) in the in parallel configuration the INL and ganglion cell layer are those most affected. The in series results are consistent with studies on paracentral acute middle maculopathy, secondary to CRVO and with studies on IOP elevation, in which DCP and ICP and the retinal tissues surrounding them are those most affected by ischemia. These findings seem to suggest that the in series configuration better describes the physiology of the vascular retinal capillary network in health and disease.

Embolization Tactics of Spinal Epidural Arteriovenous Fistulas.

PurposeSpinal epidural arteriovenous fistulas (SEDAVFs) show an epidural venous sac often with venous congestive myelopathy (VCM) due to intradural reflux at a remote level to which a transarterial approach would be difficult. We present 12 cases of SEDAVF with VCM and describe 3 main tactics for effective transarterial embolization.Materials and MethodsAmong 152 patients with spinal vascular malformations diagnosed in our tertiary hospital between 1993 and 2019, 12 SEDAVF patients with VCM were included. Three different transarterial embolization tactics were applied according to the vascular configuration and microcatheter accessibility. We evaluated treatment results and clinical outcomes before and after treatment.ResultsTransarterial embolization with glue (20–30%) was performed in all patients. The embolization tactics applied in 12 patients were preferential flow (n=2), plug-and-push (n=6), and filling of the venous sac (n=4). Total occlusion of the SEDAVF, including intradural reflux, was achieved in 11 (91.7%) of 12 patients, and partial occlusion was achieved in 1 patient. No periprocedural complications were reported. Spinal cord edema was improved in all patients for an average of 18 months after treatment. Clinical functional outcome in terms of the pain, sensory, motor, and sphincter scale and modified Rankin scores improved during a mean 25-month follow-up (6.3 vs. 3.3, P=0.002; 3.6 vs. 2.3, P=0.002, respectively).ConclusionEndovascular treatment for 12 SEDAVF patients with VCM achieved a total occlusion rate of 91.7% without any periprocedural complication. The combined embolization tactics can block intradural reflux causing VCM, resulting in overall good clinical outcomes.

Impact of the Internal Carotid Artery Morphology on in silico Stent-Retriever Thrombectomy Outcome.

The aim of this work is to propose a methodology for identifying relationships between morphological features of the cerebral vasculature and the outcome of in silico simulations of thrombectomy, the mechanical treatment for acute ischemic stroke. Fourteen patient-specific cerebral vasculature segmentations were collected and used for geometric characterization of the intracranial arteries mostly affected by large vessel occlusions, i.e., internal carotid artery (ICA), middle cerebral artery (MCA) and anterior cerebral artery (ACA). First, a set of global parameters was created, including the geometrical information commonly provided in the clinical context, namely the total length, the average diameter and the tortuosity (length over head-tail distance) of the intracranial ICA. Then, a more exhaustive geometrical analysis was performed to collect a set of local parameters. A total of 27 parameters was measured from each patient-specific vascular configuration. Fourteen virtual thrombectomy simulations were performed with a blood clot with the same length and composition placed in the middle of the MCA. The model of TREVO ProVue stent-retriever was used for all the simulations. Results from simulations produced five unsuccessful outcomes, i.e., the clot was not removed from the vessels. The geometric parameters of the successful and unsuccessful simulations were compared to find relations between the vascular geometry and the outcome. None of the global parameters alone or combined proved able to discriminate between positive and negative outcome, while a combination of local parameters allowed to correctly identify the successful from the unsuccessful simulations. Although these results are limited by the number of patients considered, this study indicates a promising methodology to relate patient-specific geometry to virtual thrombectomy outcome, which might eventually guide decision making in the treatment of acute ischemic stroke.

Renal transplantation using vascular conduit reconstruction in deceased kidneys with multiple renal arteries and short renal veins

BackgroundTransplantation of kidneys with vascular anatomical variants remains a challenge. Due to its varying success in regard to graft function after transplantation, these organs have been frequently discarded assuming in advance an unaffordable rate of vascular complications. Patients and methodsWe performed three kidney transplants using organs from deceased donors harboring vascular variants (multiple arteries and short veins), including an unsplittable horseshoe kidney. Different grafts harvested from the same donor aorta, common iliac artery, and inferior vena cava, were used to reconstruct the initial vascular configuration by creating single arterial and venous conduits aimed to simplify the vascular anastomoses in the recipient. ResultsNo post-operative complications were recorded. Warm ischemia times remained comparable to single artery renal allografts. No delayed graft function was noted in any case, and every patient regained normal renal function after transplantation. ConclusionsVascular reconstruction using arterial and venous grafts harvested from the same deceased donor may result a helpful tool to simplify vascular anastomoses during transplantation surgery, thus avoiding their discard in advance, minimizing perioperative complications, and enabling normal graft function rates in the long-term follow-up. The successful outcome obtained by using this approach would help to expand the donor criteria for the inclusion of organs containing vascular anatomical variants.

Mathematical modeling of the impact of recirculation on exchange kinetics in tandem extracorporeal membrane oxygenation and therapeutic plasma exchange.

Vascular access connection configurations during tandem extracorporeal membrane oxygenation (ECMO) and therapeutic plasma exchange (TPE) may impact exchange kinetics. In these tandem procedures, typically the TPE inlet line is proximal to the TPE return line with respect to blood flow in the ECMO device, maximizing the opportunity for replacement fluid homogenization within the ECMO circuit. However, if TPE inlet and return line connections are switched, recirculation-a phenomenon in which replacement fluid leaving the TPE return line is prematurely drawn into the TPE inlet line prior to satisfactory homogenization within the ECMO circuit-will occur. Such recirculation could diminish TPE efficacy in patients on ECMO and mitigate therapeutic benefits. Using a mathematical model of recirculation in tandem ECMO and TPE, we demonstrate that the predicted impact of recirculation is negligible and vascular access connection positioning does not appear to be a point of clinical concern with regard to TPE kinetics.

Abstract 1477: LRG1 blockade normalizes tumor vasculature and improves efficacy of chemotherapy

Abstract In cancer blood vessels are dysfunctional, poorly perfused and leaky. Malfunctioning vessels contribute to the pro-oncogenic environment and limit the efficacy of current systemically administered drugs. Normalizing the tumor vasculature to improve vessel permeability, reduce hypoxia and vascular leakage and enhance drug delivery, has become an experimental objective in cancer research. This study was carried out to investigate the effect of blocking the secreted glycoprotein leucine-rich alpha-2-glycoprotein 1 (LRG1) on tumor vascular function, and evaluate the impact it has on the efficacy of the common standard of care chemotherapeutic drug cisplatin. Under normal conditions LRG1 is mainly expressed in the liver but also in other tissues such as bone marrow and immune cells. LRG1 has been described in multiple reports to be a serum prognostic biomarker in several cancers, for example lung, prostate, colorectal and breast. LRG1 promotes dysfunctional vessel growth by disrupting TGFβ signaling. We demonstrate that in Lrg1-/- mice and following treatment with a LRG1 function-blocking antibody (15C4) tumor growth was inhibited. In addition, we show using RNAscope that following subcutaneous grafting of the B16F0 and LL2 tumor cell lines in mice, Lrg1 is induced in tumor endothelial cells. Despite having no effect on total vessel area, the density was decreased upon LRG1 blockade, with the persisting larger vessels exhibiting improved vessel structure as evidenced by increased pericyte and basement membrane endothelial cell coverage. Better mural cell association with tumor vascular endothelial cells and basement membrane coverage are also indicators of vessel stabilization and maturation. Using a systemically delivered fluorescent lectin tracer to mark perfused vessels, we observed a significant increase in tumor perfusion in mice treated with 15C4. Lastly, vessel normalization, through LRG1 antibody blockade, significantly enhanced the efficacy of cisplatin chemotherapy as shown by a slower tumor growth rate and increased tumor cell death compared to monotherapy. These data further corroborate the hypothesis that inhibition of LRG1 improves the delivery, and hence efficacy, of a cytotoxic drug. In conclusion, deletion or inhibition of LRG1 results in an improved vascular configuration and function, and the efficacy of chemotherapy. LRG1 blockade may therefore represent a novel strategy to enhance vessel health and improve the efficacy of cancer therapeutics. Citation Format: Camilla Pilotti, Marie N O'Connor, David Kallenberg, Laura Dowsett, Jestin George, Stephen E. Moss, John Greenwood. LRG1 blockade normalizes tumor vasculature and improves efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1477.