CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy.

Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1alpha at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.

Locoregional spread of cutaneous melanoma: sonography findings.

OBJECTIVE: This article reviews various aspects of locoregional spread of malignant cutaneous melanoma, as imaged with gray-scale sonography and Doppler techniques. The scenarios illustrated include disease staging (primary melanoma, satellite metastasis, in-transit metastasis, and lymphadenopathies), sentinel lymph node biopsy procedure, patient follow-up, recurrence detection, cutaneous metastasis, and sonographically guided intervention. CONCLUSION: High-resolution sonography allows recognition of small, clinically-occult melanomatous foci. It plays a major role in locoregional staging and follow-up of patients with cutaneous melanoma.

ADAPT with New Catalyst 5 Reperfusion Catheter for Distal M2 Ischemic Stroke: Preliminary Experience.

OBJECTIVE: We sought to assess preliminary technical and clinical outcomes of Catalyst 5 (CAT 5) as front-line aspiration treatment for M2-M3 occlusion in acute ischemic stroke. METHODS: Patients with symptomatic stroke and distal M2 or M3 occlusions were enrolled retrospectively. A direct aspiration first-pass technique was used as the first treatment option for absolute contraindication to intravenous fibrinolytic therapy. Time to recanalization, first attempt recanalization, and number of attempts were recorded. Successful recanalization was defined as a modified thrombolysis in cerebral infarction score ≥2b; incidence of procedure-related complications was recorded. National Institutes of Health Stroke Scale at discharge and modified Rankin Scale score at 90 days were evaluated by a dedicated neurologist. RESULTS: A total of 11 acute occlusions of distal M2-M3 segment were treated with a direct aspiration first-pass technique using CAT 5 (mean age 69.3 years). Tandem occlusion was present in 2 cases. Intracranial preocclusive mean vessel diameter was 1.9 mm. Overall modified thrombolysis in cerebral infarction score ≥2b was obtained in 72.7% of patients with mean time to recanalization of 36.4 minutes and a mean of 1.9 attempts. First-attempt recanalization with CAT 5 was obtained in 54% of patients with a mean time to recanalization of 29.2 minutes. A stent retriever with proximal aspiration was incorporated as a rescue device in 2 cases. Embolization of new territories was reported after CAT 5 aspiration in 1 patient. No intracranial hemorrhage was detected on follow-up computed tomography. The median National Institutes of Health Stroke Scale score at discharge was 3. At 90 days, a modified Rankin Scale score of 0-2 was achieved in 90.9% of patients. CONCLUSIONS: Preliminary experience using CAT 5 in distal occlusions demonstrates that it may be safe and effective in acute stroke treatment.

CEUS in abdominal trauma: multi-center study.

The objective of this study was to evaluate the concordance of US and contrast-enhanced US (CEUS) with CT in the assessment of solid organ injury following blunt trauma. Patients underwent complete US examination, including free fluid search and solid organ analysis. CEUS followed, using low-mechanical index techniques and SonoVue. CT was performed within 1 h. Among 156 enrolled patients, 91 had one or more abnormalities (n = 107) at CT: 26 renal, 38 liver, 43 spleen. Sensitivity, specificity, and accuracy for renal trauma at baseline US were 36%, 98%, and 88%, respectively, after CEUS values increased to 69%, 99%, and 94%. For liver baseline US values were 68%, 97%, and 90%; after CEUS were 84%, 99%, and 96%. For spleen, results were 77%, 96%, and 91% at baseline US and 93%, 99%, and 97% after CEUS. Per patient evaluation gave the following results in terms of sensitivity, specificity and accuracy: 79%, 82%, 80% at baseline US; 94%, 89%, and 92% following CEUS. CEUS is more sensitive than US in the detection of solid organ injury, potentially reducing the need for further imaging. False negatives from CEUS are due to minor injuries, without relevant consequences for patient management and prognosis.

Arterial Spin Labeling Magnetic Resonance Imaging to Diagnose Contrast-Induced Vasospasm After Intracranial Stent Embolization.

BACKGROUND: Contrast-induced encephalopathy (CIE) is a rare and misdiagnosed complication of intravascular injection of contrast, responsible for arterial vasospasm and neurologic effects. Conventional radiologic findings are not in themselves specific for cerebral vasospasm diagnosis. We present a case in which arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) was useful in early diagnosis of CIE. CASE DESCRIPTION: A 56-year-old woman was admitted for elective flow-diverter embolization of a recanalized left supra-ophthalmic internal carotid artery aneurysm; at 4 hours postprocedure, she acutely developed sensitive aphasia and right arm paresis. Although no-contrast computed tomography and MRI with fluid-attenuated inversion recovery and diffusion-weighted imaging sequences did not demonstrate acute ischemic/hemorrhagic cerebral foci or cortical edema, ASL showed decreased cerebral blood flow (CBF) in the insular-temporal-parietal anterior lobe, suspected for hypoperfusion due to vasospasm, which was not confirmed by subsequent emergent digital subtraction angiography. At 16 hours, because of worsening symptoms, patient underwent an additional MRI, which showed slight insular cortical edema on fluid-attenuated inversion recovery and corresponding slight restricted diffusion-weighted imaging with a severe reduction in CBF value; at this time, emergent digital subtraction angiography demonstrated distal arterial vasospasm of left middle cerebral artery, and vasospasm therapy was started. Within 48 hours of symptom onset, the patient gradually improved to a complete neurologic recovery, with normalization of CBF values in the concerning cerebral region. CONCLUSIONS: CIE should always be considered in patients with focal neurologic deficits after iodinate contrast exposure. ASL perfusion MRI with CBF maps could be a promising tool for prompt, early confirmation of underlying vasospasm, as cortical edema and distal vasospasm could not be detected on conventional radiologic imaging.

Real-time contrast-enhanced specific ultrasound in staging and follow-up of splenic lymphomas.

From January 2003 to April 2005 we studied 25 lymphoma patients (10 with HD, 4 with low-grade NHL, 6 with high-grade NHL and 5 with chronic lymphatic leukaemia; 14 men, 11 women, age range 28-79 years). After a baseline US study we rapidly injected 4.8 mL of the second-generation microbubble contrast agent SonoVue (Bracco, Italy). Contrast enhanced studies were carried out with the contrast-specific software named Contrast Tuned Imaging (Esaote, Italy) using a continuous, harmonic acquisition and a low acoustic pressure. The CS-US findings were correlated with results of standard tools, including CT, MRI, US follow up. CS-US revealed correctly 47 out of the 52 lesions identified by CT scan, in the absence of false positive findings (sensitivity = 90%; Specificity = 100%, in comparison to CT scan). Complete concordance in evaluating the lesion extension of the CS-US in respect to CT was 88%, while underestimate occurred in 9% and overestimate in 3% of cases. On the contrary, basic sonography defined correctly the dimensional alteration in 52% of the cases, underestimated in 35% and overestimated in 13%, thus showing significantly lower accuracy (chi-square = 30.0, p < 0.001). In our experience, CS-US was superior to conventional sonography even from a qualitative point of view.

Contrast-enhanced sonography of the spleen.

Sonography is frequently the first imaging modality employed to evaluate the spleen. Nevertheless, splenic abnormalities frequently determine subtle changes in echogenicity and may be overlooked. Additionally, splenic disorders have a nonspecific appearance, mostly appearing as hypoechoic defects. Difficulties in differential diagnosis are not uncommon, with splenic infarctions resembling, for example, focal lesions. Color Doppler is usually of limited additional value. Instead, the spleen is optimally suited for contrast-enhanced sonography, being superficial, small, and homogeneous, and showing intense and persistent contrast enhancement. Scarcely evident abnormalities become evident after contrast medium injection. Additional information can be obtained in many clinical scenarios, including blunt trauma, left flank pain, lymphoma, and incidental detection of splenic abnormalities.

Real-time harmonic contrast material-specific US of focal liver lesions.

Recent advances in contrast material-enhanced ultrasonography (US) mainly include (a) development of low-acoustic-pressure (low-mechanical-index) harmonic software, capable of obtaining real-time images without disrupting contrast material microbubbles, and (b) commercialization of new contrast media ("second-generation" contrast media), capable of producing intense echo signals in this low-mechanical-index setting. With use of low-mechanical-index continuous-mode contrast-enhanced US, the circulatory kinetic models of various focal liver lesions can be displayed dynamically. Hepatic lesions usually have typical perfusion characteristics and enhancement patterns through the various phases of parenchymal enhancement, which helps characterize lesions and, in most cases, allows definitive diagnosis, even among lesions that exhibit very similar baseline appearances. Because of the use of harmonic technologies at low emission frequencies, there is some loss of spatial resolution and overall image quality, typically resulting in a grainy appearance. In addition, lesion depth affects the detectability of vascularity to some degree in that poor signal arises from deep-seated lesions. Moreover, liver attenuation (eg, in patients with steatosis or chronic liver disease) further reduces the sensitivity of contrast-enhanced US. Nevertheless, with its unique capacity to provide images in real time, low-mechanical-index contrast-enhanced US is the dynamic imaging modality of choice in the differential diagnosis of focal liver lesions.

Cutaneous melanoma: role of ultrasound in the assessment of locoregional spread.

This article illustrates the various aspects of locoregional spread of cutaneous melanoma, as imaged with grayscale ultrasound (US) and Doppler techniques. High-resolution US allows recognition of small, clinically occult melanomatous foci within the skin and lymph nodes. Consequently, it plays a major role in locoregional staging and follow-up of patients with cutaneous melanoma. We discuss the possibilities and limitations of US in the initial staging (primary melanoma, satellite metastasis, in-transit metastasis, and lymphadenopathy), selection for sentinel lymph node biopsy procedure, patient follow-up, detection of recurrence, and US-guided intervention.

Transient hepatic echogenicity difference on contrast-enhanced ultrasonography: sonographic sign and pitfall.

OBJECTIVE: The purpose of this study was to report and analyze a new contrast-enhanced ultrasonographic (CEUS) imaging finding, the transient hepatic echogenicity difference due to perfusion changes, using computed tomography (CT) as a reference standard. METHODS: We retrospectively investigated the records of patients evaluated in a 2-year period, selecting those who had undergone both CT and CEUS within 15 days, who had CT evidence of a perfusion abnormality, and who had had a CEUS study that included the malperfused parenchymal area. RESULTS: There were 30 patients with 44 hepatic perfusion changes on CT scans (28 around liver focal lesions and 16 unrelated to focal lesions). Retrospectively, CEUS allowed recognition of 21 of 28 perifocal transient hepatic attenuation differences (THADs), 6 of 10 subsegmental THADs, 2 of 3 segmental THADs, and 1 of 3 lobar THADs. Only some of these abnormalities had been identified at the original CEUS examinations: 0 of 3 lobar THADs, 1 of 3 segmental THADs, 2 of 10 subsegmental THADs, and 16 of 28 perifocal THADs. CONCLUSIONS: Contrast-enhanced ultrasonography can show hepatic perfusion abnormalities similar to those well known from CT literature, although with a lower sensitivity. Knowledge of this transient hepatic echogenicity difference phenomenon may be relevant for avoiding incorrect image interpretation or incorrect tumor size measurement and for eventually identifying occult vascular disorders such as venous thrombosis or fistulas.

Post-treatment fistulas in patients with rectal cancer: MRI with rectal superparamagnetic contrast agent.

MRI is the standard modality in the pre- and post-treatment evaluation of patients with rectal cancer, particularly in those cases with locally advanced disease. We routinely employ a superparamagnetic iron oxide (SPIO) contrast enema to distend the rectal lumen and achieve maximal tumor-to-lumen contrast gradient. This practice also allowed the identification of a fistula in 24% of patients treated for rectal cancer. Contrast agent-related low intensity signal could be seen filling the tract and eventually opacifying surrounding organs (i.e., vagina) or collections (i.e., presacral abscess). Fistula formation after radiochemotherapy and surgery for rectal cancer is not uncommon. MRI with dark lumen contrast enema allows an effective demonstration of this complication in a high number of patients.

Combined ethanol injection therapy and radiofrequency ablation therapy in percutaneous treatment of hepatocellular carcinoma larger than 4 cm.

BACKGROUND: Optimal treatment of large-sized hepatocellular carcinoma (HCC) is still debated, because percutaneous ablation therapies alone do not always achieve complete necrosis. OBJECTIVE: To report our experience in the treatment of patients with HCC larger than 4 cm in diameter by combined percutaneous ethanol injection and radiofrequency thermal ablation. METHODS: In a 5-year period there were 40 consecutive patients meeting the inclusion criteria (24 men and 16 women; age range 41-72 years, mean 58 years). These subjects had a single HCC larger than 4 cm. Twelve subjects also had one or two additional nodules smaller than 4 cm (mean 1.2 nodules per patient). Patients were submitted to one to three sessions consisting of ethanol injection at two opposite tumor poles (mean 12 ml) and then of radiofrequency application through one or two electrodes placed at the tumor center (mean treatment duration 30 min). RESULTS: Complete necrosis was obtained in all cases with one to three sessions (mean 1.3 sessions per patient). All patients experienced pain and fever but one only subject had a major complication requiring treatment (abscess development and fistulization). Overall follow-up was 7-69 months. Two patients showed local recurrence and 9 developed new etherotopic HCC nodules. Seven subjects died during follow-up while 33 were free from recurrence 8-69 months after treatment. CONCLUSION: A combination of ethanol injection and radiofrequency ablation is effective in the treatment of large HCC.

Ruptured abdominal aortic aneurysm: categorization of sonographic findings and report of 3 new signs.

OBJECTIVE: The purpose of this study was to categorize the sonographic findings seen in patients with a ruptured abdominal aortic aneurysm (AAA) and to describe 3 previously undescribed sonographic findings. METHODS: From January 1997 to December 2003, we evaluated 388 consecutive patients with an AAA (transverse aortic diameter >30 mm). Among these patients, 29 had surgical or computed tomographic demonstration of aneurysm rupture. The remaining 359 were asymptomatic and had no evidence of AAA rupture at follow-up. RESULTS: Findings recognized among 29 positive cases included AAA deformation (n = 12), luminal thrombus inhomogeneity (n = 20), clear interruption of a luminal thrombus (n = 5), retroperitoneal hematoma (n = 22), and hemoperitoneum (n = 11). In addition, 3 previously unreported findings were noted: an intraluminal floating thrombus layer (n = 8), a parietal hypoechoic focus due to aneurysm wall interruption (n = 3), and a para-aortic hypoechoic area adjacent to the bleeding side (n = 4). Aside from AAA deformation and thrombus heterogeneity, no other signs were recognized among subjects with a nonruptured aneurysm. CONCLUSIONS: In the past, sonography has been used mainly to rapidly confirm aneurysm presence in the clinical setting of a patient with a suspected rupture. Instead, this retrospective series shows how this imaging technique can frequently identify several direct and indirect signs of aneurysm rupture itself. Moreover, 3 new indicators of AAA rupture have been observed.

Blunt hepatic trauma: evaluation with contrast-enhanced sonography: sonographic findings and clinical application.

OBJECTIVE: The purpose of this study was to report our initial experience in the assessment of liver trauma with real-time contrast-enhanced sonography (CES). METHODS: From January 2000 to December 2003, there were 431 hemodynamically stable patients evaluated with sonography for blunt abdominal trauma. Among these patients, 87 were selected to undergo second-level imaging, consisting of CES and computed tomographic (CT) evaluation. Indications for further assessment were baseline sonographic findings positive for liver injury, baseline sonographic findings positive for injury to other abdominal parenchyma, baseline sonographic findings positive for free fluid only, baseline sonographic findings indeterminate, and baseline sonographic findings negative with persistent clinical or laboratory suspicion. RESULTS: There were 23 hepatic lesions shown by CT in 21 patients. Peritoneal or retroperitoneal fluid was identified in 19 of 21 positive cases by all 3 imaging modalities. Liver injury was found in 15 patients on sonography and in 19 on CES. Contrast-enhanced sonography compared better than unenhanced sonography with the criterion standard for related injury conspicuity, injury size, completeness of injury extension, and involvement of the liver capsule. Both CES and CT showed intrahepatic contrast material pooling in 2 cases. All patients with false-negative sonographic or CES findings recovered uneventfully. CONCLUSIONS: Contrast-enhanced sonography is an effective tool in the evaluation of blunt hepatic trauma, being more sensitive than baseline sonography and correlating better than baseline sonography with CT findings. In institutions where sonography is regarded as the initial procedure to screen patients with trauma, this technique may increase its effectiveness. In addition, CES may be valuable in the follow-up of patients with conservatively treated liver trauma.

Contrast-enhanced sonography for diagnosis of ruptured abdominal aortic aneurysm.

OBJECTIVE: We describe the contrast-specific sonography features of ruptured abdominal aortic aneurysm, and we hypothesize that this technique would be useful for emergency imaging of patients with suspected aneurysm rupture. CONCLUSION: We used contrast-specific sonography to assess eight patients with ruptured abdominal aortic aneurysm. Five of these cases were correlated with CT findings. We found that contrast-enhanced sonography can reveal features specific for ruptured aortic aneurysm without causing a significant delay in surgery. This technique may be as effective as CT but may allow a more rapid and noninvasive diagnosis, especially when sonography can be performed bedside.

Real-time, contrast-enhanced sonography: a new tool for detecting active bleeding.

BACKGROUND: Active contrast medium extravasation is a known angiographic and computed tomographic sign of ongoing, potentially life-threatening hemorrhage. Sonography (US) is frequently the first imaging option for screening patients with abdominal emergencies. Because of the current possibilities of low-mechanical-index, real-time, contrast-specific systems, it is possible to detect contrast leakage by using US. The purpose of this article is report our pilot experience in the evaluation of active traumatic and nontraumatic bleeding with contrast-enhanced US. METHODS: In a 2-year period, we performed 153 consecutive emergent contrast-enhanced US studies. Traumatic emergencies accounted for 83 examinations and nontraumatic emergencies accounted for 70. We used the contrast-specific mode Contrast Tuned Imaging and the contrast medium SonoVue. A 2.4- to 4.8-mL contrast medium bolus was injected with continuous US acquisition, starting immediately after contrast injection and lasting 1 to 6 minutes. RESULTS: Contrast extravasation was found in 20 cases (13%). These included spleen injury (n = 8), liver injury (n = 3), kidney injury (n = 1), abdominal aortic aneurysm rupture (n = 5), splenic angiosarcoma rupture (n = 1), postsurgical bleeding after abdominal aortic aneurysm repair (n = 1), and postsplenectomy bleeding (n = 1). Active extravasation appeared as a round, hyperechoic pool or as a fountain-like, hyperechoic jet. CONCLUSION: Our retrospective clinical study shows for the first time how US can detect contrast medium extravasation, a significant indicator of active hemorrhage and of need for prompt surgical or interventional treatment.

Contrast-enhanced sonography of the spleen.

OBJECTIVE: Combined use of low-mechanical-index technologies and non-air-filled contrast media allows real-time sonographic assessment of the spleen. This pictorial essay focuses on several aspects of contrast-enhanced sonography of the spleen, including examination technique, clinical indications, normal findings obtained through all vascular phases, abnormal findings (splenomegaly, infarction, abscess, benign tumors, lymphoma, metastasis, injuries, and accessory spleen), limitations, and pitfalls. CONCLUSION: Real-time, contrast-enhanced sonography is a novel technique allowing depiction of a wide range of splenic abnormalities.