Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy.

INTRODUCTION: Conventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI). MATERIALS AND METHODS: Mice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi-tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology. RESULTS AND DISCUSSIONS: All treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment.

Development of hemodynamically relevant acquired arterio-venous fistulae in patients with venous malformations.

BACKGROUND: Venous malformations tend to retain their slow-flow behavior, even in progressive disease or regression following therapy. OBJECTIVE: The aim of this study is to analyze the development of acquired hemodynamic relevant arterio-venous fistulae in patients with slow-flow malformations. METHODS: This study is a retrospective analysis based on a consecutive local registry at a tertiary care Interdisciplinary Center for Vascular Anomalies. Patients with venous malformations and development of secondary arterio-venous fistulae were included. Indications for therapy of the vascular malformation were based on patients' symptoms and complications. The following endpoints were of clinical interest and were assessed: origin of development of arteriovenous fistula, development of secondary comorbidities as a result of the vascular malformation. For analysis we focused on descriptive statistics. RESULTS: Out of 1213 consecutive patients with vascular malformations, in 6 patients perfusion changed from slow flow to arterio-venous fast-flow patterns. Four patients developed the fistula after local trauma in the area of the malformation, the other 2 patients developed the fistula due to progression of the disease and recurrent thrombophlebitis. These 2 patients had no trauma or interventions at the time of arterio-venous fistula development. CONCLUSIONS: Acquired arterio-venous fast-flow fistula in patients with slow flow vascular malformation is very rare and might be a result of local trauma or the progression of the disease with recurrent thrombophlebitis. Specific evidence-based treatment options for these patients do not exist.

Vascular malformations of the female and male genitalia: type and distribution patterns revealed by magnetic resonance imaging.

BACKGROUND: Vascular malformations of the genitalia often go undetected in clinical examination. These vascular malformations can cause a variety of clinical symptoms such as swelling, pain and bleeding. AIM: To characterize the distribution patterns of genital vascular malformations using magnetic resonance imaging (MRI) and to correlate these patterns with clinical findings in order to guide diagnostic decisions. METHODS: A retrospective analysis of MRIs of the pelvis and legs in 370 patients with vascular malformation was performed to determine the involvement of the internal and external genitalia. RESULTS: In 71 patients (19%), genital involvement could be identified by MRI. Of these, 11.3% (8 of 71) presented with internal involvement, 36.6% (26 of 71) with external involvement and 52.1% (37 of 71) with both internal and external involvement. Over half (57.1%) of the 49 patients with visible external genital signs detected during a clinical examination had additional internal genital involvement. CONCLUSIONS: Genital involvement is a common finding in patients with vascular malformation of the legs and/or pelvis. Based on our data, we recommend MRI of the legs and pelvic region in patients with externally visible signs of a vascular malformation of the external genitalia in order to exclude additional internal involvement.

Kidney Failure After Occlusion of Accessory Renal Arteries in Endovascular Abdominal Aneurysm Repair.

PURPOSE: To evaluate the incidence of acute renal failure and chronic kidney disease due to occlusion of accessory renal arteries during endovascular aneurysm repair of infrarenal abdominal aortic aneurysm. MATERIAL AND METHODS: We retrospectively reviewed the course of 181 patients (mean age, 71, SD ± 9  years) who underwent EVAR of infrarenal abdominal aortic aneurysm. The renal vessel anatomy was analyzed in all pre- and postoperative CT scans. Diameter and origin of accessory renal arteries were evaluated. Renal function was determined by pre- and postoperative serum creatinine and eGFR levels. Long-term follow-up (>3 months) of patients was available in 121 cases (66.9%). Acute kidney injury and chronic kidney failure were defined according to guidelines of "Kidney Disease: Improving Global Outcomes" (KDIGO). RESULTS: In 65 of 181 patients (33.9%), 82 accessory renal arteries were identified preoperatively. In 19 of 181 patients (10.5%), one or more accessory renal arteries were covered and subsequently occluded by the implanted stent-graft device. Neither acute kidney injury (10.3% vs 12.5%; p = .785) nor chronic kidney disease (10.7% vs 15.38%; p = .452) was detected significantly more often in patients with covered accessory renal artery. The only significant predictor of acute kidney injury was the preoperative serum creatinine level (1.12 mg/dl vs. 0.98 mg/dl; p = .03). Significant predictors for chronic kidney disease were preoperative serum creatinine, eGFR, and impaired renal function (p < .001). CONCLUSION: Coverage of accessory renal artery due to stent-graft does not lead either to temporary acute kidney injury after endovascular aneurysm repair or to chronic kidney disease. LEVEL OF EVIDENCE: Level II b.

Radiofrequency Ablation of the Marginal Venous System in Patients with Venous Malformations.

PURPOSE: To evaluate radiofrequency ablation (RFA) for closure of marginal veins in pediatric and adult patients with venous malformations. MATERIALS AND METHODS: Medical records, imaging and procedure details were retrospectively reviewed in patients who underwent RFA of the marginal vein in a 17-month period. Additional sclerotherapy (n = 19) and coil embolization of the marginal vein were performed (n = 2). RESULTS: A total of 23 marginal veins were treated in 20 patients. Mean age at treatment was 16 years ± 9.4 (1-37 years). Pre-procedural magnetic resonance imaging revealed thoracoabdominal marginal veins in 3 patients. A type I marginal vein (draining in the great saphenous vein below the popliteal vein) was identified in 1 and type IIa/IIb (draining in a median/lateral accessory saphenous vein) in 2/8 cases. Type III (draining into the profunda femoral vein) was detected in 8, and type IV (draining into gluteal veins) in 1. Mean diameter of the marginal veins was 13.2 mm ± 4 (7-20 mm). Patency was found in 1 during follow-up (22 months ± 9.8). Complete or partial occlusion was achieved in 94.5% of the veins. One patient showed signs of thrombophlebitis after the procedure, and another incomplete paresis of the peroneal nerve. CONCLUSION: RFA is effective as minimally invasive treatment of the marginal venous system. These veins should be treated early in life. Marginal veins with large diameter, residual tributaries and the intrafascial courses usually require adjunct coil embolization and sclerotherapy. LEVEL OF EVIDENCE: Case series, Level IV.

A multiphysics approach for modeling early atherosclerosis.

This work is devoted to the development of a mathematical model of the early stages of atherosclerosis incorporating processes of all time scales of the disease and to show their interactions. The cardiovascular mechanics is modeled by a fluid-structure interaction approach coupling a non-Newtonian fluid to a hyperelastic solid undergoing anisotropic growth and a change of its constitutive equation. Additionally, the transport of low-density lipoproteins and its penetration through the endothelium is considered by a coupled set of advection-diffusion-reaction equations. Thereby, the permeability of the endothelium is wall-shear stress modulated resulting in a locally varying accumulation of foam cells triggering a novel growth and remodeling formulation. The model is calibrated and applied to an murine-specific case study, and a qualitative validation of the computational results is performed. The model is utilized to further investigate the influence of the pulsatile blood flow and the compliance of the artery wall to the atherosclerotic process. The computational results imply that the pulsatile blood flow is crucial, whereas the compliance of the aorta has only a minor influence on atherosclerosis. Further, it is shown that the novel model is capable to produce a narrowing of the vessel lumen inducing an adaption of the endothelial permeability pattern.

Postinterventional tumor necrosis predicts recurrence-free long-term survival in liver transplant patients with advanced hepatocellular carcinoma.

BACKGROUND: Locoregional interventional bridging treatment (IBT) before liver transplantation (LT) is an accepted neoadjuvant approach in liver transplant patients with hepatocellular carcinoma (HCC). However, the effect of postinterventional tumor necrosis on posttransplantation outcome is known. METHODS: A total of 93 consecutive liver transplant patients with HCC were included in this prospective trial. Fifty-nine patients underwent pretransplantation IBT, by either transarterial chemoembolization (n = 51) or radiofrequency ablation (n = 8). The extent of tumor necrosis assessed at explant pathology (≥50% tumor necrosis rate = extended post-IBT tumor necrosis; <50% tumor necrosis rate = less extended tumor necrosis) and its impact on recurrence-free survival in the context of other prognostic relevant histopathologic variables were analyzed in uni- and multivariate analyses. RESULTS: Extended tumor necrosis was assessed in 44 patients among the IBT population, and tumor necrosis rate was <50% in 15 patients of the IBT and 34 patients of the non-IBT population, respectively. Five-year recurrence-free survival rates were 96% in patients with and 55% in patients without extended tumor necrosis rates (P < .001). Recurrence-free survival rates were similar between patients with HCC meeting the Milan criteria (85%) and those exceeding the Milan criteria but demonstrating extended post-IBT tumor necrosis on explant pathology (80%). On multivariate analysis, only microvascular invasion (odds ratio 6.4) and extended postinterventional tumor necrosis (odds ratio 9.2) were identified as independent histopathologic predictors of recurrence-free outcome (P < .05). CONCLUSIONS: Extended tumor necrosis should be the major objective of neoadjuvant IBT in liver transplant patients with HCC, because it significantly improves posttransplantation outcome. Thereby, even patients with HCC beyond the Milan criteria may achieve excellent survival rates.

Differences in patterns of peripheral arterial occlusive disease and eligibility for endovascular treatment.

BACKGROUND: To analyze differences in morphological changes in the vascular tree among patients presenting with intermittent claudication (IC) and critical limb ischemia (CLI). In addition, suitability for endovascular treatment was evaluated. PATIENTS AND METHODS: Our study included 690 lower extremities with IC or CLI in 500 consecutive patients who were assessed by magnetic resonance angiography (MRA) according to the TASC II classification and in terms of the below the knee run-off status. Multivariable logistic regressions models adjusted for cardiovascular risk factors were used to evaluate differences in arteriosclerotic lesion patterns and eligibility for endovascular treatment. RESULTS: Multivariable analysis showed that compared with IC extremities, CLI extremities have significantly more severe arteriosclerotic lesions at the aortoiliac (p < 0.001), femoropopliteal (p < 0.001), and crural levels (p < 0.001), with a greater risk of multilevel disease (odds ratio [OR], 1.71; 95 % confidence interval [CI] 1.10 - 2.66; p = 0.018). More than 80 % of extremities with IC and more than 50 % of extremities with CLI appeared to be eligible for endovascular treatment in an isolated evaluation of the aortoiliac and femoropopliteal axis. For combined evaluation of the aortoiliac and femoropopliteal axis, the proportion of endovascular suitability (TASC A+B lesions) decreased to 65 % (IC) and 41 % (CLI). For TASC A+B+C lesions, the proportions were 79 % (IC) and 41 % (CLI). CONCLUSIONS: Lower extremities with IC and CLI significantly differ in terms of arteriosclerotic lesion morphology and patterns of lesion localization. The majority of IC and CLI extremities appear to be eligible for endovascular treatment. Because of further improvement in endovascular equipment, even more patients will be eligible for treatment.

Inversion-recovery single-shot cardiac MRI for the assessment of myocardial infarction at 1.5 T with a dedicated cardiac coil.

OBJECTIVE: The aim of this study was to assess the diagnostic accuracy of imaging myocardial infarction with a two-dimensional (2D) single-shot inversion-recovery (IR)-gradient-echo (GE) sequence compared with a standard 2D segmented IR-GE sequence at 1.5 T using a dedicated cardiac coil. METHODS: 22 patients with myocardial infarction documented in the past 3-12 months were examined at 1.5 T using a 5 channel cardiac coil. Imaging of delayed enhancement was performed 15 min after administration of 0.2 mmol of gadopentetate dimeglumine per kilogram of body weight. Immediately after completion of the single-shot sequence, which allows for coverage of the entire ventricle during a single breath-hold with nine slices, the segmented IR sequence was started. Infarct volumes, infarct transmurality and contrast-to-noise ratios (CNRs) of infarcted and healthy myocardium were compared between both techniques. RESULTS: Despite a moderate, non-significant loss of CNR (CNR(single-shot IR)=31.2±4.1; CNR(segmented IR)=37.9±4.1; p=0.405), the 2D single-shot technique correctly determined infarct size when compared with the standard 2D segmented IR-GE sequence. Assessment of both infarct volume (r=0.95; p<0.0001) and transmurality (r=0.97; p<0.0001) is possible, with excellent correlation of both techniques. CONCLUSION: Single-shot delayed enhancement imaging during a single breath-hold is feasible at 1.5 T with the use of a dedicated cardiac coil. Despite a moderately lower CNR, the single-shot technique allows for fast and accurate determination of infarct size with high spatial resolution and has the potential to reduce electrocardiogram and breathing artefacts.

Significance of ankle brachial index and collaterals for prediction of critical limb ischemia in infrainguinal peripheral arterial occlusive disease.

PURPOSE: Chronic limb ischemia (CLI) is a clinical diagnosis, but should be approved by technical tests like the ankle-brachial index (ABI). Although the ABI is well established, less is known about the influence of collateralization on clinical stage. MATERIAL/METHODS: Magnetic resonance angiographies (MRA) of 129 lower extremities were searched for morphological changes and for the number of collateral vessels according to Sorlie. Ankle pressures were recorded as higher (APmax) and lower (APmin) systolic blood pressures of the two ankle arteries with consecutive calculation of ABImax and ABImin. RESULTS: In comparisons of ROC curves, APmax (AUC=0.749) did significantly better as a prognostic marker than APmin (AUC=0.642) (p=0.005) and ABImax (AUC=0.744) did significantly better than ABImin (AUC=0.650) (p=0.019). APmax showed a positive likelihood ratio (+LR) of 5.79 and a negative likelihood ratio (-LR) of 0.47 (cutoff ≤55 mmHg). For the number of collateral vessels a +LR 2.27 and a -LR of 0.09 and in patients with an APmax ≤55 mmHg a +LR of 5.50 and a -LR of 0.00 were calculated (cutoff ≤1 collateral vessel). CONCLUSION: Whereas APmax is more eligible for verification of CLI, collateral count is better in exclusion of CLI. Both seem to be independent factors for validating the clinical diagnosis of CLI.

WITHDRAWN: Rationale and Design of a Randomised Controlled Trial Comparing Stent-Protected Angioplasty with Bypass Surgery for Intermittent Claudication: The ABC Study.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Is serum pregnancy-associated plasma protein A really a potential marker of atherosclerotic carotid plaque stability?

OBJECTIVES: The search for markers predicting risk of plaque rupture in carotid atherosclerosis is still ongoing. Previous findings showed that pregnancy-associated plasma protein-A (PAPP-A) levels correlate with an adverse plaque morphology. However, the role of PAPP-A in plaque destabilisation is still uncertain. MATERIAL AND METHODS: Patients with carotid artery stenosis involved in the study were asymptomatic (n=29) and symptomatic (n=37). Carotid plaques were characterised by histology (n=33). Immunohistochemistry (n=17) was used to determine expression of PAPP-A and CD68 within the plaques. Serum levels of PAPP-A were measured by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Circulating PAPP-A levels were significantly higher in patients with unstable versus stable plaques (0.10+/-0.06 vs. 0.07+/-0.04 microg ml(-1), p=0.047) and interestingly, in asymptomatic versus symptomatic patients (0.11+/-0.05 vs. 0.069+/-0.09 microg ml(-1), p=0.025). These differences remained statistically significant after adjustment for age, gender and degree of stenosis (p=0.050). PAPP-A expression in plaques correlated significantly with CD68 positive macrophages, cap-thickness and its serological values (r=+0.291, p<0.001, r=-0.639, p<0.001 and r=0.618, p<0.008, respectively). Furthermore, PAPP-A serum values demonstrated a significant positive predictive value of 68.8% for unstable plaques. CONCLUSION: Our present data confirmed the close relationship between expression of PAPP-A and plaque instability and furthermore correlated significantly with cap thickness. However, the question whether PAPP-A is a useful predictive marker of plaque instability remains unresolved.

Association of circulating transforming growth factor beta, tumor necrosis factor alpha and basic fibroblast growth factor with restenosis after transluminal angioplasty.

OBJECTIVES: To assess prospectively the early time course of Transforming Growth Factor beta-1 (TGFbeta-1), basic Fibroblast Growth Factor (bFGF) and Tumor Necrosis Factor alpha (TNFalpha) as possible contributors to restenosis development after angioplasty. DESIGN: Prospective Study. METHODS: The levels of the soluble forms of these factors in the early response to Percutaneous Transluminal Angioplasty (PTA) in the arteries of the lower limb were prospectively assessed. 32 patients with peripheral arterial occlusive disease (PAOD), presenting with intermittent claudication (Fontaine stage IIb) were scheduled for angioplasty treatment. Serum levels of TGFbeta-1, TNFalpha and bFGF were assessed before intervention, 15 and 60 minutes after, 24 hours after as well as 2 and 4 weeks after intervention. We compared the distribution patterns between patients treated with balloon angioplasty and patients who required secondary stent implantation. Endpoint was the development of restenosis within 6 months after interventional treatment, defined as a lumen diameter reduction of more than 50% by ultrasound measurement compared to the result after PTA. RESULTS: The patients who later developed restenosis had significantly higher levels of TGFbeta-1 at 15 minutes, 24 hours and 2 weeks after PTA (p<0.05). TNFalpha and bFGF were only detected in a few patients and no significant change of serum levels was observed. CONCLUSION: The results demonstrate a possible role of TGFbeta-1 in the formation of restenosis after PTA.

Early endothelial and haematological response to cryoplasty compared with balloon angioplasty of the superficial femoral artery--a pilot study.

The purpose of the present study was to assess the course of adhesion molecules (intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), e-selectin, p-selectin and monocyte chemoatlractant protein 1 (MCP-1)), growth factors (transforming growth factor beta (TGFbeta) and basic fibroblast growth factor (bFGF)) and the cytokine tumour necrosis factor alpha (TNFalpha) after both angioplasty and cryoplasty. Recently cryoplasty has been suggested as a new method to oppose neointimal hyperplasia resulting in restenosis formation. While in vitro models have shown that the application of cryothermal energy to the endothelium during angioplasty leads to apoptosis induction and reduced proliferation rates, no human in vivo proof for an inhibition of neointimal hyperplasia exists. For restenosis initiation adhesion molecules, growth factors and cytokines play an important role. One possibility to investigate the endothelial response to angioplasty is the measurement of the soluble forms of adhesion molecules, growth factors and cytokines that are released into the circulation after denuding the vessel wall. In the present study we assessed the distribution pattern of the soluble forms of e-selectin, p-selectin, ICAM, VCAM, MCP-1, TGFbeta, bFGF and TNFalpha after angiography, angioplasty and cryoplasty of the femoropopliteal artery in the early course of 4 weeks in 29 patients with peripheral arterial occlusive disease. During the 4 weeks after intervention levels of e-selectin, ICAM, VCAM and MCP-1 increased after both angioplasty and cryoplasty. The course of the screened biomarkers was similar between angioplasty and cryoplasty. P-selectin and TGFbeta both decreased after cryoplasty, but not significantly. The present results show that the release of adhesion molecules, growth factors and cytokines is similar between balloon angioplasty and cryoplasty.