The Sonographic Stenosis Index: A New Specific Quantitative Measure of Transplant Hepatic Arterial Stenosis.

OBJECTIVES: This study evaluates the sensitivity and specificity of stenosis index (SI), which accounts for the entire spectral Doppler waveform, to detect significant transplant hepatic arterial stenosis. MATERIALS AND METHODS: In this institutional review board-approved, HIPAA compliant study, we retrospectively analyzed 69 patients who had catheter angiography for suspected transplant hepatic arterial stenosis (THAS) between January 2006 and December 2010; all patients had Doppler ultrasound within 30 days before angiography. Patients with angiographic stenosis requiring intervention were considered positive for THAS. Stenosis index was calculated from each patient's spectral Doppler ultrasound images by obtaining the ratio of the area under the high-frequency signal to low-frequency signal in the spectral Doppler. Resistive index (RI) and pulsatility index (PI) were also calculated. Receiver operator curve analysis was performed and the area under the curve (AUC) was compared among the three metrics. RESULTS: Forty-eight of 69 patients had THAS by angiography requiring intervention; 21patients had no angiographic evidence of THAS. SI was significantly different (P < .001) between patients with THAS (SI = 1.04 ± 0.20) and those without THAS (SI = 1.39 ± 0.30). Stenosis index had an AUC of 0.86 for detecting THAS, which was significantly higher than that from RI (AUC = 0.68, P = .038 for the comparison) and PI (AUC = 0.70, P = .029). For SI < 1.35, the sensitivity for THAS was 94% and specificity was 52%. For RI < 0.5, the sensitivity was 96% and the specificity was 29%. CONCLUSIONS: Stenosis index is more accurate than the resistive index and the pulsatility index for detecting transplant hepatic artery stenosis.

Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin.

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis and holds potential for lymphangiogenic therapy in diseases lacking adequate lymphatic drainage. However, the ability of VEGF-C to enhance sustainable, functional lymphatic growth in adult tissues remains unclear. To address this, we evaluated VEGF-C overexpression in adult lymphangiogenesis in regenerating skin. We used a model of mouse tail skin regeneration incorporating a suspension of either VEGF-C overexpressing tumor cells, which provide a continuous supplement of excess VEGF-C to the natural regenerating environment for more than 25 days, or otherwise identical control-transfected tumor cells. We found that excess VEGF-C did not enhance the rate of lymphatic endothelial cell (LEC) migration, the density of lymphatic vessels, or the rate of functionality -- even though lymphatic hyperplasia was present early on. Furthermore, the hyperplasia disappeared when VEGF-C levels diminished, which occurred after 25 days, rendering the lymphatics indistinguishable from those in control groups. In vitro, we showed that whereas cell-derived VEGF-C could induce chemoattraction of LECs across a membrane (which involves amoeboid-like transmigration), it did not increase LEC chemoinvasion within a 3-dimensional fibrin matrix (which requires proteolytic migration). These results suggest that whereas excess VEGF-C may enhance early LEC proliferation and cause lymphatic vessel hyperplasia, it does not augment the physiological rate of migration or functionality, and by itself cannot sustain any lasting effects on lymphatic size, density, or organization in regenerating adult skin.

Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype.

Most carcinomas spread to distant sites through lymphatic vessels. Several preclinical and clinical studies have shown a positive correlation between the incidence of lymph node metastasis and secretion of the lymphatic growth factor vascular endothelial growth factor-C (VEGF-C) by tumor cells, suggesting tumor lymphangiogenesis as an escape mechanism. However, recent evidence has shown VEGF receptor-3 (VEGFR-3) expression on tumor cells and autocrine signaling, which increase metastatic potential. Furthermore, there is growing evidence implicating lymphatic-homing chemokine receptors, particularly C-C chemokine receptor 7 (CCR7), in lymph node metastasis. We report here that expressions of VEGF-C and CCR7 by tumor cells act synergistically to promote their invasion toward lymphatics. First, VEGF-C acts to increase lymphatic secretion of CCL21, which in turn drives CCR7-dependent tumor chemoinvasion toward lymphatics. Second, VEGF-C acts in an autocrine fashion to increase tumor invasiveness by increasing the proteolytic activity and motility of tumor cells in a three-dimensional matrix. Both of these effects are VEGFR-3 dependent and evident only in three-dimensional environments. We further verified that VEGF-C induces lymphatic CCL21 up-regulation in vivo by direct injection of VEGF-C protein intradermally in the mouse. Taken together, these results bridge the prometastatic functions of CCR7 and VEGF-C in tumors and show that, beyond lymphangiogenesis, VEGF-C promotes tumor invasion toward lymphatics by both autocrine and CCR7-dependent paracrine signaling mechanisms, which may be a significant cause of lymph node metastasis.

Thermal osteonecrosis of the rib after radiofrequency ablation in the thorax.

A patient underwent radiofrequency (RF) ablation of a pleural-based pulmonary metastasis from treated hepatocellular carcinoma. Ten months after the procedure, computed tomography and positron emission tomography findings raised the concern of tumor recurrence with invasion of the chest wall, for which the patient underwent thoracotomy with resection. Pathologic evaluation demonstrated osteonecrosis of the rib but no malignancy. This case illustrates that thermal osteonecrosis may occur after RF ablation of a pleural-based lesion.