Cardiac Magnetic Resonance and Cardiac Implantable Electronic Devices: Are They Truly Still "Enemies"?

The application of cardiac magnetic resonance (CMR) imaging in clinical practice has grown due to technological advancements and expanded clinical indications, highlighting its superior capabilities when compared to echocardiography for the assessment of myocardial tissue. Similarly, the utilization of implantable cardiac electronic devices (CIEDs) has significantly increased in cardiac arrhythmia management, and the requirements of CMR examinations in patients with CIEDs has become more common. However, this type of exam often presents challenges due to safety concerns and image artifacts. Until a few years ago, the presence of CIED was considered an absolute contraindication to CMR. To address these challenges, various technical improvements in CIED technology, like the reduction of the ferromagnetic components, and in CMR examinations, such as the introduction of new sequences, have been developed. Moreover, a rigorous protocol involving multidisciplinary collaboration is recommended for safe CMR examinations in patients with CIEDs, emphasizing risk assessment, careful monitoring during CMR, and post-scan device evaluation. Alternative methods to CMR, such as computed tomography coronary angiography with tissue characterization techniques like dual-energy and photon-counting, offer alternative potential solutions, although their diagnostic accuracy and availability do limit their use. Despite technological advancements, close collaboration and specialized staff training remain crucial for obtaining safe diagnostic CMR images in patients with CIEDs, thus justifying the presence of specialized centers that are equipped to handle these type of exams.

A Novel Approach to Cardiac Magnetic Resonance Scar Characterization in Patients Affected by Cardiac Amyloidosis: A Pilot Study.

Background and Objectives: Cardiac magnetic resonance (CMR) imaging has become an essential instrument in the study of cardiomyopathies; it has recently been integrated into the diagnostic workflow for cardiac amyloidosis (CA) with remarkable results. An additional emerging role is the stratification of the arrhythmogenic risk by scar analysis and the possibility of merging these data with electro-anatomical maps. This is made possible by using a software (ADAS 3D, Galgo Medical, Barcelona, Spain) able to provide 3D heart models by detecting fibrosis along the whole thickness of the myocardial walls. Little is known regarding the applications of this software in the wide spectrum of cardiomyopathies and the potential benefits have yet to be discovered. In this study, we tried to apply the ADAS 3D in the context of CA. Materials and Methods: This study was a retrospectively analysis of consecutive CMR imaging of patients affected by CA that were treated in our center (Marche University Hospital). Wherever possible, the data were processed with the ADAS 3D software and analyzed for a correlation between the morphometric parameters and follow-up events. The outcome was a composite of all-cause mortality, unplanned cardiovascular hospitalizations, sustained ventricular arrhythmias (VAs), permanent reduction in left ventricular ejection fraction, and pacemaker implantation. The secondary outcomes were the need for a pacemaker implantation and sustained VAs. Results: A total of 14 patients were deemed eligible for the software analysis: 8 patients with wild type transthyretin CA, 5 with light chain CA, and 1 with transthyretin hereditary CA. The vast majority of imaging features was not related to the composite outcome, but atrial wall thickening displayed a significant association with both the primary (p = 0.003) and the secondary outcome of pacemaker implantation (p = 0.003). The software was able to differentiate between core zones and border zones of scars, with the latter being the most extensively represented in all patients. Interestingly, in a huge percentage of CMR images, the software identified the highest degree of core zone fibrosis among the epicardial layers and, in those patients, we found a higher incidence of the primary outcome, without reaching statistical significance (p = 0.18). Channels were found in the scar zones in a substantial percentage of patients without a clear correlation with follow-up events. Conclusions: CMR imaging plays a pivotal role in cardiovascular diagnostics. Our analysis shows the feasibility and applicability of such instrument for all types of CA. We could not only differentiate between different layers of scars, but we were also able to identify the presence of fibrosis channels among the different scar zones. None of the data derived from the ADAS 3D software seemed to be related to cardiac events in the follow-up, but this might be imputable to the restricted number of patients enrolled in the study.

Stress-rest dynamic-CT myocardial perfusion imaging in the management of myocardial bridging: A "one-stop shop" exam.

Myocardial bridging (MB) is a congenital anomaly characterized by the intramyocardial coronary course that can cause coronary compression during systole leading to myocardial ischemia, often with the concomitant presence of endothelial dysfunction.Improvements in computed tomography (CT) technology have increased the burden of MB detection during coronary-CT (cCT) but their anatomical and functional assessment is often challenging. A stress-rest myocardial perfusion imaging (MPI) by single-photon emission CT (SPECT) is usually required to decide the correct patient management. However, SPECT has long acquisition protocols, poor spatial resolution, and significant radiation doses for the patient. The recent advances in CT scan technology have allowed the evaluation of stress-rest MPI, representing a promising alternative to SPECT.In this paper, we report six cases of MBs assessed with cCT examination and further evaluated with a stress-rest dynamic-CT MPI and SPECT. A reversible perfusion defect in the left anterior descending (LAD) territory segments potentially due to MB was detected in two of six patients, and they were referred for heart team evaluation.In conclusion, cCT and stress-rest dynamic-CT MPI allowed to detect MBs, evaluate their functional significance, and decide the patients' management in a "one-stop shop" examination. Learning objective: Improvements in computed tomography (CT) technology have increased the burden of myocardial bridging (MB) detection during coronary-CT but their anatomical and functional assessment is often challenging.A stress-rest myocardial perfusion imaging (MPI) by single-photon emission CT (SPECT) is then usually required to decide the correct patient management.Recent advances in CT scan technology have allowed the evaluation of stress-rest MPI, that represent a promising alternative to SPECT.

Ultra-low radiation dose and contrast volume CT protocol and TAVI-CT score for TAVI planning and outcome.

OBJECTIVE: To investigate the feasibility of an ultra-low radiation dose and contrast volume protocol using third-generation dual-source (DS) CT for transcatheter aortic valve implantation (TAVI) planning with coronary artery disease (CAD) assessment, coronary artery calcium score (CACS) and aortic valve calcium score (AVCS) quantification and to evaluate their relationship with TAVI outcome. METHODS: In this retrospective study were selected 203 patients (131 males, 79.4 ± 5.4 years) underwent to TAVI and at 30- and 90-day follow-up. All patients had performed a third-generation 2 × 192-slices DSCT. The CT protocol included a non-contrast and a contrast high-pitch aortic acquisition for TAVI planning and CAD assessment. Semi-qualitative and quantitative image analysis were performed; the performance in CAD assessment was compared with ICA; the relationship between AVCS and CACS and paravalvular aortic regurgitation (PAR) and major cardiovascular events (MACEs) were evaluated. Mean radiation dose were calculated. Non-parametric tests were used. RESULTS: Semi-qualitative image analysis was good. Contrast enhancement >500 Hounsfield unit (HU) and contrast-to-noise ratio <20 were obtained in all segments. The diagnostic accuracy in CAD was 89.0%. AVCS was significantly higher in patients with 30-day severe PAR. AVCS and CACS were higher in patients with 90-day MACE complications, respectively, 1904.5 ± 621.3 HU (p < 0.0001) and 769.2 ± 365.5 HU (p < 0.0230). Mean radiation dose was 2.8 ± 0.3 mSv. CONCLUSION: A TAVI planning ultra-low radiation dose and contrast volume protocol using third-generation DSCT provides highly diagnostic images with CAD assessment, AVCS and CACS quantification and these latter were related with TAVI outcomes. ADVANCES IN KNOWLEDGE: The proposed protocol using third-generation 2 × 192-slices DSCT allows with an ultra-low radiation dose and contrast volume the TAVI planning and the coronary artery assessment.

Cardiac Masses and Pseudomasses: An Overview about Diagnostic Imaging and Clinical Background.

A cardiac lesion detected at ultrasonography might turn out to be a normal structure, a benign tumor or rarely a malignancy, and lesion characterization is very important to appropriately manage the lesion itself. The exact relationship of the mass with coronary arteries and the knowledge of possible concomitant coronary artery disease are necessary preoperative information. Moreover, the increasingly performed coronary CT angiography to evaluate non-invasively coronary artery disease leads to a rising number of incidental findings. Therefore, CT and MRI are frequently performed imaging modalities when echocardiography is deemed insufficient to evaluate a lesion. A brief comprehensive overview about diagnostic radiological imaging and the clinical background of cardiac masses and pseudomasses is reported.

The sub-millisievert era in CTCA: the technical basis of the new radiation dose approach.

Computed tomography coronary angiography (CTCA) has become a cornerstone in the diagnostic process of the heart disease. Although the cardiac imaging with interventional procedures is responsible for approximately 40% of the cumulative effective dose in medical imaging, a relevant radiation dose reduction over the last decade was obtained, with the beginning of the sub-mSv era in CTCA. The main technical basis to obtain a radiation dose reduction in CTCA is the use of a low tube voltage, the adoption of a prospective electrocardiogram-triggering spiral protocol and the application of the tube current modulation with the iterative reconstruction technique. Nevertheless, CTCA examinations are characterized by a wide range of radiation doses between different radiology departments. Moreover, the dose exposure in CTCA is extremely important because the benefit-risk calculus in comparison with other modalities also depends on it. Finally, because anatomical evaluation not adequately predicts the hemodynamic relevance of coronary stenosis, a low radiation dose in routine CTCA would allow the greatest use of the myocardial CT perfusion, fractional flow reserve-CT, dual-energy CT and artificial intelligence, to shift focus from morphological assessment to a comprehensive morphological and functional evaluation of the stenosis. Therefore, the aim of this work is to summarize the correct use of the technical basis in order that CTCA becomes an established examination for assessment of the coronary artery disease with low radiation dose.

Proposal of a low-dose, long-pitch, dual-source chest CT protocol on third-generation dual-source CT using a tin filter for spectral shaping at 100 kVp for CoronaVirus Disease 2019 (COVID-19) patients: a feasibility study.

AIM: To subjectively and objectively evaluate the feasibility and diagnostic reliability of a low-dose, long-pitch dual-source chest CT protocol on third-generation dual-source CT (DSCT) with spectral shaping at 100Sn kVp for COVID-19 patients. MATERIALS AND METHODS: Patients with COVID-19 and positive swab-test undergoing to a chest CT on third-generation DSCT were included. The imaging protocol included a dual-energy acquisition (HD-DECT, 90/150Sn kVp) and fast, low-dose, long-pitch CT, dual-source scan at 100Sn kVp (LDCT). Subjective (Likert Scales) and objective (signal-to-noise and contrast-to-noise ratios, SNR and CNR) analyses were performed; radiation dose and acquisition times were recorded. Nonparametric tests were used. RESULTS: The median radiation dose was lower for LDCT than HD-DECT (Effective dose, ED: 0.28 mSv vs. 3.28 mSv, p = 0.016). LDCT had median acquisition time of 0.62 s (vs 2.02 s, p = 0.016). SNR and CNR were significantly different in several thoracic structures between HD-DECT and LDCT, with exception of lung parenchyma. Qualitative analysis demonstrated significant reduction in motion artifacts (p = 0.031) with comparable diagnostic reliability between HD-DECT and LDCT. CONCLUSIONS: Ultra-low-dose, dual-source, fast CT protocol provides highly diagnostic images for COVID-19 with potential for reduction in dose and motion artifacts.

Third generation dual source CT with ultra-high pitch protocol for TAVI planning and coronary tree assessment: feasibility, image quality and diagnostic performance.

PURPOSE: To evaluate the feasibility, image quality (IQ) and diagnostic performance of third generation 192 × 2 dual source computer tomography (DSCT) with ultra-high pitch acquisition for trans-catheter aortic valve implantation (TAVI) planning and coronary tree assessment. METHOD: In this prospective study, 223 patients underwent to DSCT for TAVI. Coronary calcium scoring (CCS) was calculated. Attenuation values were measured at aortic levels, femoral and coronary arteries. IQ was evaluate with a 4-point scale. The CT performance, in the assessment of coronary stenosis ≥50 % and ≥70 %, was compared with invasive coronary angiography (ICA), served as reference standard. Aortic annulus (AoA) CT derived area and implanted prosthesis size were correlate with Spearman's test. RESULTS: Attenuation values >400HU were obtain in all segments. IQ median value was ≥ 3. In the assessment of stenosis ≥50 %, on a segment-based analysis, CT sensitivity, specificity, positive and negative predictive values and diagnostic accuracy were 97.6 %, 87.6 %, 64.2 %, 99.0 % and 89.6 %, on patient-based analysis were 97.8 %, 88.8 %, 68.8 %, 99.4 % and 90.6 %, respectively. In the assessment of stenosis ≥70 %, on segment-based analysis, were 88.5 %, 83.8 %, 54.7 %, 96.8 % and 84.8 %, and on patient-based analysis were 92.5 %, 85.8 %, 58.7 %, 98.1 % and 87.0 %, respectively. The CT performed better in the group with lower CCS. A direct correlation was found between AoA CT derived area and prosthesis size. CONCLUSION: DSCT, using a single prospective ECG-triggered ultra-high pitch acquisition, is feasible for TAVI planning and in the assessment of coronary stenosis. CT performed worse in patients with severe coronary calcifications.

In vivo radiation dosimetry and image quality of turbo-flash and retrospective dual-source CT coronary angiography.

PURPOSE: To compare measured radiation dose (MD), estimated radiation dose (ED) and image quality in coronary computed tomography between turbo-flash (TFP) and retrospective protocol (RP) and correlate MD with size-specific dose estimates (SSDE). MATERIALS AND METHODS: In this prospective study, we selected 68 patients (mean age, 59.2 ± 9.7 years) undergoing 192 × 2 dual-source CT (SOMATOM Force, Siemens) to rule out coronary artery disease. Thirty-one underwent TFP and 37 RP. To evaluate in vivo MD, thermoluminescent dosimeters were placed, superficially, at thyroid and heart level, left breast areola and left hemi-thorax. MD in each site, and ED parameters, such as volume CT dose index (CTDIvol), SSDE, dose length product (DLP), effective dose (E), were compared between two protocols with a t test. Image quality was compared between two protocols. Inter-observer agreement was evaluated with a kappa coefficient (k). In each protocol, MD was correlated with SSDE using a Pearson coefficient (r). RESULTS: Comparing TFP and RP, MD at thyroid (1.43 vs. 2.58 mGy; p = 0.0408), heart (3.58 vs. 28.72 mGy; p < 0.0001), left breast areola (3.00 vs. 24.21 mGy; p < 0.0001) and left hemi-thorax (2.68 vs. 24.03 mGy; p < 0.0001), CTDIvol, SSDE, DLP and E were significantly lower. Differences in image quality were not statistically significant. Inter-observer agreement was good (k = 0.796) in TFP and very good (k = 0.817) in RP. MD and SSDE excellently correlated with TFP (r = 0.9298, p < 0.0001) and RP (r = 0.9753, p < 0.0001). CONCLUSIONS: With TFP, MD, CTDIvol, SSDE, DLP and E were significantly lower, than with RP. Image quality was similar between two protocols. MD correlated excellently with SSDE in each protocol.

Third-generation dual-source dual-energy CT in pediatric congenital heart disease patients: state-of-the-art.

Cardiovascular computer tomography (CT) in pediatric congenital heart disease (CHD) patients is often challenging. This might be due to limited patient cooperation, the high heart rate, the complexity and variety of diseases and the need for radiation dose minimization. The recent developments in CT technology with the introduction of the third-generation dual-source (DS) dual-energy (DE) CT scanners well suited to respond to these challenges. DSCT is characterized by high-pitch, long anatomic coverage and a more flexible electrocardiogram-synchronized scan. DE provides additional clinical information about vascular structures, myocardial and lung perfusion and allows artifacts reduction. These advances have increased clinical indications and modified CT protocol for pediatric CHD patients. In our hospital, DSCT with DE technology has rapidly become an important imaging technique for both pre- and postoperative management of pediatric patients with CHDs. The aim of this article is to describe the state-of-the-art in DSCT protocol with DE technology in pediatric CHD patients, providing some case examples of our experience over an 18-month period.

Radiation dose and image quality with new protocol in lower extremity computed tomography angiography.

PURPOSE: To compare radiation dose and image quality of lower extremity computed tomography angiography (CTA) between cranio-caudal acquisition with single-source CT (SSCT) and flash caudo-cranial acquisition with dual-source CT (DSCT). MATERIALS AND METHODS: In this prospective study, 60 patients were randomly assigned to Group A (control) or Group B (experimental) to undergo lower extremity CTA for peripheral obliterative arterial disease. Group A received protocol 1 (P1) with SSCT cranio-caudal acquisition. Group B received protocol (P2) with DSCT flash caudo-cranial acquisition. Intravascular attenuation (IVA), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and image noise were compared. Two radiologists assessed the image quality. Computed tomography volume dose index (CTDIvol) and dose-length product (DLP) were also compared. RESULTS: IVA with P2 was higher than with P1 (586.8 ± 140.3 vs. 496.1 ± 129.3 HU, p = 0.011), as was SNR (33.0 ± 11.3 vs. 27.4 ± 12.3; p = 0.042), CNR (30.1 ± 13.3 vs. 24.2 ± 10.3; p = 0.029) and image quality score of small arteries below the knee (3.8 ± 0.2 vs. 3.1 ± 0.2; p = 0.001). Radiation dose was significantly lower in P2 than in P1 with CTDIvol reduction of 40.9% (1.3 ± 0.1 vs. 2.2 ± 0.3 mGy; p = 0.006) and DLP reduction of 42.8% (148.7 ± 21.9 vs 260.2 ± 59.1 mGy * cm; p = 0.018). CONCLUSION: Lower extremity CTA with DSCT flash caudo-cranial acquisition allows lower radiation dose with higher IVA, SNR, CNR and better image quality for small arteries below the knee than SSCT cranio-caudal acquisition.

MRI evaluation of peripheral vascular anomalies using time-resolved imaging of contrast kinetics (TRICKS) sequence.

INTRODUCTION: We describe the use of time-resolved imaging of contrast kinetics (TRICKS) sequence in the diagnosis of Peripheral Vascular Anomalies. In case of suspected vascular malformations time-resolved MR angiography might add important information for therapeutic decisions and follow-up. OBJECTIVE: The objective of our study was to assess the usefulness and diagnostic performance of time-resolved imaging of contrast kinetics sequence in the evaluation of peripheral vascular anomalies. SUBJECTS AND METHODS: Sixty-six patients (23 pediatric, 43 adult; mean age 26) affected by upper or lower limb vascular anomalies and studied using time-resolved imaging of contrast kinetics sequence were prospectively evaluated. All studies were performed on a 1.5-T whole-body MR system. Two independent readers tried to categorized the suspected vascular anomalies in pre-contrast and post-contrast MR sequences and assessed the overall TRICKS image quality. In 11 patients, the diagnostic performance comparability between TRICKS sequence and digital subtraction angiography was evaluated. RESULTS: On the basis of time-resolved imaging of contrast kinetics, 31 of the vascular anomalies were classified as high-flow vascular malformations, 29 as low-flow vascular lesions and 6 as hemangiomas. There was no significant difference in image quality evaluation and vascular anomaly classification between the two observers. The vascular anomalies characteristics provided by moderate, good or excellent quality TRICKS images were confirmed by digital subtraction angiography. CONCLUSION: Time-resolved imaging of contrast kinetics sequence let the radiologist to acquire useful temporal information to correctly evaluate vascular anomalies components, adding more data to those provided by conventional MR sequences, especially in case of arteriovenous malformation. Therefore, both in pediatric and adult population, TRICKS could be used as an additional initial diagnostic tool to rightly classify these lesions and evaluate if a treatment is needed and which.

Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation.

Ovarian cancer (OC) is the leading cause of death in gynecologic diseases in which there is evidence for a complex chemokine network. Chemokines are a family of proteins that play an important role in tumor progression influencing cell proliferation, angiogenic/angiostatic processes, cell migration and metastasis, and, finally, regulating the immune cells recruitment into the tumor mass. We previously demonstrated that astrocytes and glioblastoma cells express both the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1), and that SDF-1alpha treatment induced cell proliferation, supporting the hypothesis that chemokines may play an important role in tumor cells' growth in vitro. In the present study, we report that CXCR4 and SDF-1 are expressed in OC cell lines. We demonstrate that SDF-1alpha induces a dose-dependent proliferation in OC cells, by the specific interaction with CXCR4 and a biphasic activation of ERK1/2 and Akt kinases. Our results further indicate that CXCR4 activation induces EGF receptor (EGFR) phosphorylation that in turn was linked to the downstream intracellular kinases activation, ERK1/2 and Akt. In addition, we provide evidence for cytoplasmic tyrosine kinase (c-Src) involvement in the SDF-1/CXCR4-EGFR transactivation. These results suggest a possible important "cross-talk" between SDF-1/CXCR4 and EGFR intracellular pathways that may link signals of cell proliferation in ovarian cancer.

The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation.

Here we characterize the intracellular effectors of the antiproliferative activity of somatostatin in glioma cell lines and post-surgical specimens. The responsiveness to somatostatin correlated with the expression of the phosphotyrosine phosphatase DEP-1/PTPeta, identified in C6 and U87MG cells, in which somatostatin inhibited cell growth. The expression of a dominant negative mutant of DEP-1/PTPeta in C6 cells abolished somatostatin effects, confirming the involvement of this phosphotyrosine phosphatase in such effects. Somatostatin treatment increased the activity of DEP-1/PTPeta and inhibited ERK1/2 activation. Conversely, basic fibroblast growth factor-dependent MEK phosphorylation was not affected, suggesting a direct effect on ERK1/2. In vitro experiments showed that PTPeta was able to interact and dephosphorylate ERK1/2 activated by basic fibroblast growth factor. Furthermore, by transfecting PTPeta in the somatostatin-unresponsive, DEP-1/PTPeta-deficient U373MG cells, the somatostatin-dependent control of cell proliferation was recovered. Finally we evaluated the requirement for DEP-1/PTPeta in somatostatin inhibition of cell proliferation in post-surgical specimens derived from different grade human gliomas. Although all of the glioma analyzed expressed somatostatin receptor mRNA, DEP-1/PTPeta expression was limited to 8 of 22 of the tumors. Culturing seven gliomas, a correlation between the expression of DEP-1/PTPeta and the somatostatin antiproliferative effects was identified. In conclusion we propose that the expression and activation of DEP-1/PTPeta is required for somatostatin inhibition of glioma proliferation.

Expression of somatostatin receptor mRNA in human meningiomas and their implication in in vitro antiproliferative activity.

Somatostatin receptors (SSTRs) have been detected in many normal and malignant tissues. This wide expression has been used for diagnostic, prognostic and therapeutic purposes. Five SSTR subtypes (SSTR 1-5) have been identified whose activation is responsible for the signal transduction through many different intracellular pathways. In the present study the expression of SSTR mRNA was determined by reverse-transcriptase (RT)-PCR in 42 meningiomas. About 88% of the tumors analyzed (37/42) were positive for at least one of the five SSTR subtypes displaying a variable pattern of expression of the different SSTR subtypes. SSTRI and SSTR2 were the most frequently mRNA detected (69% and 79% of the sample analyzed, respectively). The other subtypes were found in the 43%, 33% and 33% of cases for SSTR3, SSTR4 and SSTR5, respectively. In 22, out of 42 patients (52%) three or more SSTRs were detected. The expression of the different SSTR subtypes did not correlate with the expression of bcl-2 (apoptosis-associated protein) and MIB-1 (a proliferation marker), assessed by immunohistochemistry in a series of 34 tumor samples, while a correlation between the expression of SSTR3 and p53 was observed (p = 0.08). To evaluate a possible role of SSTR in the control of human meningioma cell proliferation, seven primary cell cultures obtained from fresh meningioma surgical tissues, were analyzed for their proliferative behavior by MTT assay and for their response to SST by [3H]-thymidine incorporation. In four out of six tumors (in one case no SSTR were detected) the treatment with SST caused a significant inhibition of DNA synthesis induced by the tumor-promoter phorbol myristate acetate. The evidence of the expression of SSTRs, mainly of SSTR2, in this series of specimens we analyzed altogether with in vitro antiproliferative effects of SST may open interesting perspectives for the diagnosis and the therapy of meningiomas.

CXCR4 activation induces epidermal growth factor receptor transactivation in an ovarian cancer cell line.

Chemokines are a family of proteins that have pleiotropic biological effects. They are well known to regulate the recruitment and trafficking of leukocytes to sites of inflammation. Chemokines are grouped into four classes based on the positions of key cysteine residues: C, CC, CXC, and CX3C. Stromal cell-derived factor-1 (SDF-1), the ligand of the CXCR4 receptor, is a CXC chemokine and is a highly conserved gene. Ovarian cancer typically disseminates widely in the abdomen, a characteristic that limits curative therapy. The mechanisms that promote ovarian cancer proliferation are incompletely understood. We studied a human ovarian adenocarcinoma cell line (OC 314) and investigated the role of CXCR4 activation by SDF-1 in human ovarian cancer. We demonstrate that CXCR4 and SDF-1 mRNA are expressed in OC 314. We show that SDF-1alpha induces proliferation in ovarian cancer cells in a dose-dependent manner. Moreover, we demonstrate that the SDF-1-dependent proliferation correlates to the phosphorylation and activation of extracellular signal-regulated kinases (ERK)1/2, which in turn are correlated to epidermal growth factor (EGF) receptor transactivation. In fact, AG1478, a specific inhibitor of the EGF receptor kinase, blocked both SDF-1alpha-dependent proliferation and ERK1/2 activation.

Enhanced effectiveness of last generation antiblastic compounds vs. cisplatin on malignant pleural mesothelioma cell lines.

The purpose of this study was to examine the antiproliferative potentialities of a pool of new generation compounds (Paclitaxel, Docetaxel, Gemcitabine, Topotecan, SN-38) together with fenretinide, a synthetic derivative of retinoic acid, in comparison with the current first choice treatment cisplatin molecule, on a pool of human malignant pleural mesothelioma cell lines derived from either bioptic and pleural effusions samples. To evaluate the chemosensitivity features of malignant mesothelioma cells in vitro, we resorted to a rapid and reproducible colorimetric assay, a useful widely recognized tool for preclinical drug screening. In addition, by DNA content analysis and cellular morphologic assessment, we focused on the apoptosis as a potential mechanism of drug activity. The main results clearly indicate that, in all the models of malignant mesothelioma we handled in vitro, each tested antineoplastic agent is more powerful than cisplatin in inhibiting cell proliferation. Moreover, on experimental evidences basis, we can assume that the cytotoxic activity of tested compounds could be related, at least partially, to the drug-induced programmed cell death. This experimental study gives substance to the expected pharmacologic worth of the second generation antineoplastic drugs even if, in order to afford the most satisfactory biopharmacological approach, allowing to bypass the refractoriness to chemotherapy of this highly lethal tumour, further investigations at preclinical level are required.

Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt.

In this paper, we describe the role of chemokine receptor CXCR4 activation by its natural ligand, the chemokine stromal cell-derived factor (SDF-1) (CXCL12), in glioblastoma cell growth in vitro. We show that both CXC chemokine receptor 4 (CXCR4) and SDF-1 mRNA are expressed in several human glioblastoma multiforme tumor tissues and in two human glioblastoma cell lines, U87-MG and DBTRG-05MG. These cells are able to secrete SDF-1 under basal conditions, and the rate of secretion is highly increased after lipopolysaccharide or 1% fetal bovine serum treatment. Exogenous SDF-1alpha induces proliferation in a dose-dependent manner in both cell lines. Moreover, we observed that SDF-1alpha-dependent proliferation is correlated with phosphorylation and activation of both extracellular signal-regulated kinases 1/2 and Akt and that these kinases are independently involved in glioblastoma cell proliferation. The role of CXCR4 stimulation in glioblastoma cell growth is further demonstrated by the ability of human monoclonal CXCR4 antibody (clone 12G5) to inhibit the SDF-1alpha-induced proliferation as well as the proliferation induced by SDF-1-releasing treatments (lipopolysaccharide and 1% fetal bovine serum). These data support a role for SDF-1alpha in the regulation of glioblastoma growth in vitro, likely through an autocrine/paracrine mechanism.

Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation.

The study of chemokine role in the CNS indubitably represents an important step to understanding many aspects of brain pathology, physiology and development. Here we discuss our recent research on the expression of chemokines and chemokine receptors in brain tissues and in cultured CNS cells, with particular regard to the CXCL12/SDF-1-CXCR4 system. We showed their expression in both glial and neuronal cells in basal conditions and their modulation upon stimulation. We demonstrated that CXCL12/SDF-1 in vitro act as a growth factor for astrocytes by stimulating their proliferation, a phenomenon that could represent the basis of pathological conditions such as gliosis and malignant transformation. We investigated the signal transduction pathways, identifying in the sequential activation of G-protein-PI-3Kinase-ERK1/2 the main signaling cascade linked to the CXCL12/SDF-1-induced proliferation in astrocytes.

Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 in human brain tumors and their involvement in glial proliferation in vitro.

Chemokines are a family of proteins that chemoattract and activate cells by interacting with specific receptors on the surface of their targets. They are grouped into four classes based on the position of key cysteine residues: C, CC, CXC, and CX3C. Stromal cell-derived factor 1 (SDF1), the ligand of the CXCR4 receptor, is a CXC chemokine involved in chemotaxis and brain development that also acts as coreceptor for HIV-1 infection. It has been proposed that CXCR4 is overexpressed and required for proliferation in human brain tumor cells. We previously demonstrated that CXCR4 and SDF1 are expressed in culture of cortical type I rat astrocytes, cortical neurons, and cerebellar granule cells. In this study, we analyzed the expression of CXCR4 and SDF1 in four human brain tumor tissues, showing that CXCR4 is expressed in all tumors analyzed, whereas SDF1 is expressed only in two tumor tissues. We also investigated the possible functions of CXCR4 expressed in rat type I cortical astrocytes, demonstrating that SDF1alpha stimulates the proliferation of these cells in vitro. Moreover, we studied by western blot the intracellular pathway involved in cell proliferation, demonstrating that SDF1alpha induces the ERK1/2 phosphorylation that is reduced by the PD98059 compound, an MEK inhibitor.