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Salivary gland tumors are a heterogeneous group of neoplasms representing less than 10% of all head and neck tumors. Among salivary gland tumors, salivary duct carcinoma (SDC) is a rare, but highly aggressive malignant tumor resembling ductal breast carcinoma. Sublingual treatments are promising for SDC due to the induction of both local and systemic biological effects and to reduced systemic toxicity compared to other administration routes. In the present study, we first established that the sublingual administration of type I IFN (IFN-I) is safe and feasible, and exerts antitumor effects both as monotherapy and in combination with chemotherapy in transplantable tumor models, i.e., B16-OVA melanoma and EG.7-OVA lymphoma. Subsequently, we proved that sublingual IFN-I in combination with cyclophosphamide (CTX) induces a long-lasting reduction of tumor mass in NeuT transgenic mice that spontaneously develop SDC. Most importantly, tumor shrinkage in NeuT transgenic micewas accompanied by the emergence of tumor-specific cellular immune responses both in the blood and in the tumor tissue. Altogether, these results provide evidence that sublingual IFN holds promise in combination with chemotherapy for the treatment of cancer.

BACKGROUND: The use of thrombus aspiration during percutaneous coronary intervention (PCI) is recommended in patients with ST-elevation myocardial infarction (STEMI) undergoing mechanical revascularization. When thrombus aspiration is adopted, the standard technique includes, after mechanical thrombus extraction, angioplasty and/or stent implantation to eliminate residual stenosis. To date, no data are available concerning the use of thrombectomy alone without additional ballooning or stenting. METYHODS AND RESULTS: We report the angiographic and clinical outcome of a series of selected STEMI patients undergoing mechanical reperfusion by thrombus aspiration without additional ballooning or stenting. Four patients out of 316 consecutive STEMI patients were managed by thrombus aspiration alone (1.3). All patients had angiographic documentation of an occlusive large intracoronary thrombus in the infarct-related artery before intervention and complete restoration of coronary flow in the absence of critical coronary stenosis after thrombus aspiration. Three of these patients had a clinical contraindication to dual antiplatelet therapy, thus suggesting that to avoid stent implantation would be advisable. Angiographic reevaluation was performed before discharge in 3 patients confirming persistent patency of the infarct-related artery (in 1 case the residual stenosis was judged to require intravascular ultrasound evaluation and subsequent elective PCI with stent implantation). The thirty-day clinical course was uneventful in all patients. CONCLUSIONS: In selected patients with STEMI undergoing mechanical reperfusion, thrombus aspiration without additional ballooning or stenting may be successfully performed. Further studies are needed to assess the clinical relevance of this novel approach.

Gadolinium chelates have been recently proposed and preliminarily tested as contrast agents for diagnostic and interventional angiography in alternative to iodinated media. However, in most studies low-osmolarity agents were employed and digital subtraction was required for satisfactory images. In this article, we report for the first time in the literature two cases of successful percutaneous renal artery stenting in which gadobutrol, a high-osmolar (1 mmol/ml) gadolinium chelate, was employed as contrast agent because of chronic renal failure and substantial risk for iodinated contrast-associated nephrotoxicity. In both patients gadobutrol yielded high-quality images without digital subtraction and was well tolerated with no ensuing renal dysfunction.

Background. The main limitation of myocardial single photon emission computed tomography (SPECT) in detecting hibernating myocardium is the poor delivery of radiotracers in hypoperfused areas supplied by severely stenotic coronary arteries. Increasing local availability of radiotracers by intracoronary injection might represent an attractive solution. The hypothesis that the intracoronary administration of sestamibi could improve myocardial SPECT accuracy in detecting hibernating myocardium was addressed in this pilot study. Methods and Results. Seven patients with prior myocardial infarction and severe stenosis of the infarct-related artery underwent myocardial SPECT after intracoronary injection of technetium 99m sestamibi immediately before percutaneous transluminal coronary angioplasty (PTCA). Wall motion and perfusion were evaluated, before and 1 month after PTCA, by 2-dimensional echocardiography and rest-redistribution thallium 201 SPECT. A "low-flow area" was identified on the pre-PTCA Tl-201 SPECT image as the area with less than 50% of maximum radiotracer uptake. Changes in wall motion and perfusion in the low-flow area were compared with results of intracoronary sestamibi imaging. On a pixel-by-pixel analysis, intracoronary sestamibi predicted perfusion recovery within the low-flow area with a 91% sensitivity, a 78% specificity, and an 82% overall accuracy. Only in the 5 patients with an extent of sestamibi uptake greater than one third of the low-flow area was an improved regional and global left ventricular wall motion observed after PTCA (wall motion score index decreased from 1.95 ± 0.28 to 1.60 ± 0.34, P = .007; left ventricular ejection fraction increased from 42% ± 7% to 49% ± 7%, P = .001; asynergic segments in the low-flow area decreased from 3.6 ± 0.9 to 1.8 ± 1.5, P = .021). Conclusions. In patients with prior myocardial infarction and severe stenosis of the infarct-related artery, sestamibi uptake after intracoronary administration identified

Background - No information is available on the long-term results of radial artery (RA) grafts used as coronary artery bypass conduits. Methods and Results - In this report, we describe the long-term (105±9 months) angiographic results of a series of 90 consecutive patients in whom the RA was used as a coronary artery bypass conduit directly anastomosed to the ascending aorta. The long-term patency and perfect patency rates of the RA were 91.6% and 88%, respectively, versus 97.5% and 96.3% for internal thoracic artery grafts. The severity of stenosis of the target vessel clearly influenced long-term RA patency, whereas location of the target vessel and long-term use of calcium channel blockers did not influence angiographic results. Preserved endothelial function and absence of flow-limiting, fibrous, intimal hyperplasia were also documented. Conclusions - Ten years after surgery, RA grafts have excellent patency and perfect patency rates. Appropriate surgical technique and correct indication are the key factors for long-term RA patency.

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.

The reconstitution of a complex microenvironment on microfluidic chips is one of the cornerstones to demonstrate the improved flexibility of these devices with respect to macroscale in vitro approaches. In this work, we realised an on-chip model to investigate the interactions between cancer and immune system. To this end, we exploited mice deficient (Knock Out, KO) for interferon regulatory factor 8 (IRF-8), a transcription factor essential for the induction of competent immune responses, to investigate how IRF-8 gene expression contributes to regulate immune and melanoma cells crosstalk. In vivo, IRF-8 KO mice are highly permissive to B16 melanoma growth due to failure of immune cells to properly exert immunosurveillance. B16 cells and immune cells isolated from the spleen of wild type (WT) and IRF-8 KO mice were co-cultured for one week in a PDMS platform and monitored by fluorescence microscopy and time-lapse recordings. We observed that WT spleen cells migrated through microchannels connecting the culturing chambers towards B16 cells and tightly interacted with tumor cells, forming clusters of activation. In contrast, IRF-8 KO immune cells poorly interacted with melanoma cells. In parallel, B16 cells were more attracted towards microchannels, acquiring a more invasive behaviour in the presence of IRF-8 KO spleen cells, with respect to WT cells. Our results strongly confirm the in vivo observations and highlight the value of on-chip co-culture systems as a useful in vitro tool to elucidate the reciprocal interactions between cancer cells and host immune system, with relevant impact in the development of more effective anti-tumor therapeutic strategies.

BACKGROUND: To date, only two drug-eluting stents (DES) have been extensively tested in both randomized controlled clinical trials and large 'real world' registries: sirolimus-DES (Cypher stent, Cordis, Miami Lakes, Florida, USA) and paclitaxel-DES (Taxus stent, Boston Scientific, Natick, Massachusetts, USA). Recently, a new polymer-free tacrolimus-eluting Carbofilm-coated stent, the Janus stent (Sorin Biomedica, Saluggia, Italy), has entered the market but only few clinical data testing its safety and efficacy in selected patients are available. Thus, we performed a prospective registry of consecutive, unselected patients receiving this new DES. METHODS: A total of 118 patients scheduled for percutaneous coronary intervention (PCI) with DES were enrolled in two separate centers. End-points were: (i) immediate angiographic failure; (ii) major adverse coronary events (MACE) defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI) and target lesion revascularization (TLR); (iii) clinically driven TLR; (iv) and stent thrombosis at 6-month follow-up. RESULTS: A total of 192 Janus stents were successfully implanted during elective (36%) or urgent PCIs (64%), including patients with ST elevation MI (16%). Twenty-four percent of patients were diabetics and 27% underwent multivessel PCI. Target lesions were B2-C type in 54%, in-stent restenosis in 8%, and located in degenerated venous grafts in 9%. Angiographic failure was observed in five of the 147 (3.4%) lesions treated. Total MACE rate at 6-month follow-up was 22% and clinically-driven TLR was carried out in 14% of patients. Stent thrombosis occurred in 4% of cases. CONCLUSION: This registry of the new tacrolimus-eluting Carbofilm-coated Janus stent showed an incidence of MACE, TLR and stent thrombosis higher than that reported in previous similar studies on DES. Whether this risk is due to this specific device or to the unselected (i.e. high-risk) population warrants further research. © 200

Aim: Drug eluting stents (DES) have been shown to reduce restenosis compared with bare metal stents in bifurcated lesions. The aim of this study was to evaluate the long-term clinical outcomes of patients with bifurcated lesions treated by 3 different DES. Methods: Consecutive patients with symptomatic coronary artery disease on one bifurcated lesion with SB>2.25 mm (on visual estimation) undergoing at the Department of Cardiology of the Catholic University of Rome, Italy were screened. Patients treated with Sirolimus-eluting stent (Cypher Select; SES Group), Tacrolimus-eluting stent (Taxus-Libertè; TA Group) and Zotarolimus-eluting stent (Endeavor Driver; ZOT Group) were enrolled in the study. Clinical and angiographic characteristics of all patients were prospectively recorded. Major adverse clinical events (MACE), including death, acute myocardial infarction (MI) or target lesion revascularization (TVR) by either percutaneous coronary intervention (PCI) or coronary surgery were recorded during the follow-up. Incidence of definite or probable stent thrombosis was calculated according to the ARC criteria. Results: Two hundred and forty-one consecutive patients were enrolled (89 Group CY, 98 Group TA and 54 Group EN). Length of follow-up was 235+/-60 days. Baseline clinical and angiographic characteristic were similar across the groups. The adopted technique for stent implantation was provisional stenting (73.4%), T-stenting technique (7%), crush (7%) and V-stenting (2.6%). The rate of patients finally treated with two stents was similar among groups. The cumulative rate of MACE (9% SES, 12% TA, 11% ZOT: P=0.7) and of TVR (2% SES, 9% TA, 7% ZOT) was similar among groups. No definite stent thrombosis was observed during follow-up, while 1 probable stent thrombosis was observed in TA group. Conclusion: The clinical outcome of bifurcated lesions using DES and mainly a technique of single stent implantation is good. In the present observational study, clinical adver

OBJECTIVE: Transradial access for coronary angiography may offer some advantages in comparison with conventional transfemoral access in specific subgroups of patients. Therefore, the aim of this study was to compare the transradial and transfemoral approaches in patients with previous coronary artery bypass graft (CABG) surgery using the left internal mammary artery (IMA). METHODS: The time to left IMA cannulation, the time needed for left IMA evaluation, and total procedure time were compared in 60 patients previously submitted to CABG surgery using the left IMA. The homolateral radial access was attempted in 20 consecutive patients (TR group), whereas the transfemoral approach was undertaken in 40 patients (2: 1, TF group), matched for age, sex and number of grafts. RESULTS: In the TR group, the time to left IMA cannulation and the time needed for left IMA evaluation were 39% and 46%, respectively, lower than those in the TF group (P = 0.01 and P = 0.001, respectively), whereas total procedure time was similar. In the subgroup of patients with less than three saphenous vein grafts (n = 36), the time to left IMA cannulation, the time needed for left IMA evaluation as well as total procedure time were significantly reduced (P = 0.01, P = 0.001 and P = 0.004, respectively). The rate of ad-hoc coronary angioplasty procedures was unaffected by the access site (20% in the TR group and 27% in the TF group, P = 0.53). CONCLUSIONS: The present study shows that the homolateral transradial approach facilitates left IMA evaluation in patients with previous CABG surgery undergoing coronary angiography, in particular in patients with a lower number of coronary artery bypass conduits, in the absence of an excess of periprocedural complications. © 2008 Italian Federation of Cardiology.

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The "buddy" wire technique, i.e. the use of a second 0.014 inch guide wire placed alongside the one employed to advance balloons and stents inside the coronary artery during percutaneous coronary intervention (PCI), may help in a series of procedural challenges during PCI. Indeed, by improving both the stability of the guiding catheter and the support for balloon and stent, a buddy wire use is sometimes the simplest way to accomplish a successful procedure. In this paper, we discuss technical aspects of some specific circumstances frequently encountered during PCI, in which a buddy wire may be helpful. These include: 1) The reduction of balloon slippage during angioplasty for in-stent restenosis; 2) insufficient back-up of the guiding catheter; 3) stenting of lesions located in vessels with proximal tortuosities/angulations; 4) stenting of lesions distally located in the vessel; 5) facilitation in the positioning of distal protection devices; 6) stenting of a lesion distally located from a previously implanted stent or from a coronary segment with both calcification and sharp bend; 7) PCI on coronary arteries with anomalous origin. Because of its simplicity, low cost, and availability, the use of a buddy wire should be considered when dealing with the aforementioned conditions during PCI procedures. © 2005 HMP Communications.

Background - In patients who develop in-stent restenosis, successful revascularization can be difficult to achieve using percutaneous methods. This study was designed to verify the surgical results in this setting and to evaluate the potential beneficial role of arterial bypass conduits. Methods and Results - Sixty consecutive coronary artery bypass patients with previous in-stent restenosis and 60 control cases were randomly assigned to receive an arterial conduit (either right internal thoracic or radial artery; study group) or a great saphenous vein graft (control group) on the first obtuse marginal artery to complete the surgical revascularization procedure. At a mean follow-up of 52±11 months, patients were reassessed clinically and by angiography. Freedom from clinical and instrumental evidence of ischemia recurrence was found in 19 of 60 subjects in the study group versus 45 of 60 in the control series (P=0.01). The results of the arterial grafts were excellent in both the study and control groups (right internal thoracic artery patency rate, 19 of 20 for both, and radial artery patency rate, 20 of 20 versus 19 of 20; P=0.99). Saphenous vein grafts showed lower patency rate than arterial grafts in both series and had extremely high failure rate in the study group (patency rate, 10 of 20 in the study group versus 18 of 20 in the control group; P=0.001). Use of venous graft was an independent predictor of failure in the study group, whereas hypercholesterolemia was associated with graft failure in both series. Conclusions - Venous grafts have an high incidence of failure among cases who previously developed in-stent restenosis, whereas the use of arterial conduits can improve the angiographic and clinical results. Arterial grafts should probably be the first surgical choice in this patient population. © 2005 American Heart Association, Inc.

OBJECTIVES: The aim of this study was to evaluate the use of a new manual thrombus-aspirating device in unselected patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing urgent percutaneous coronary intervention (PCI). BACKGROUND: Failure to achieve myocardial reperfusion often occurs during PCI in patients with STEMI. The use of thrombus-aspirating devices might improve myocardial reperfusion by reducing distal embolization. METHODS: We prospectively randomized before coronary angiography 100 consecutive patients with STEMI to either standard PCI or PCI with manual thrombus-aspiration. Primary end points of the study were post-procedural rates of myocardial blush grade (MBG) <2 and ST-segment resolution (STR) <70%. Analyses were planned by intention to treat. RESULTS: Ninety-nine patients entered the analyses. The rates of post-procedural MBG <2 and STR <70% were, respectively, 68.0% and 44.9% in the thrombus-aspiration group compared with 58.0% and 36.7% in the standard PCI group: odds ratio (OR) 2.6 (95% confidence interval [CI] 1.2 to 5.9), p = 0.020, and 2.4 (95% CI 1.1 to 5.3), p = 0.034, respectively. Moreover, the rate of patients achieving both the angiographic and electrocardiographic (ECG) criteria of optimal reperfusion was significantly higher in the thrombus-aspiration group compared with standard PCI: 46.0% versus 24.5%, OR 2.6 (95% CI 1.1 to 6.2), p = 0.025. In multivariate analysis, randomization to thrombus-aspiration was a significant independent predictor of achievement of MBG <2 and STR <70% (p = 0.013). CONCLUSIONS: This prospective randomized study shows that manual thrombus-aspiration in unselected patients with STEMI undergoing primary or rescue PCI is clinically feasible and results in better angiographic and ECG myocardial reperfusion rates compared with those achieved by standard PCI. © 2005 by the American College of Cardiology Foundation.

We report a complex case of percutaneous intervention on a right coronary artery with calcific stenoses and a large coronary aneurysm with long longitudinal diameter, which was successfully performed using a polytetrafluoroethylene-covered self-expandable stent (Symbiot; Boston Scientific; Natick, MA). The use of this new device may enhance the anatomic indications for percutaneous interventions on coronary aneurysms.

Background: No data are available on the early vasoreactive profile of skeletonized internal thoracic artery grafts. Methods: Fifteen patients undergoing primary isolated coronary artery bypass grafting were randomly assigned to receive a skeletonized or pedicled internal thoracic artery graft. On the second postoperative day all patients were subjected to follow-up angiography and endovascular infusion of serotonin, acetylcholine, and isosorbide dinitrate. Results: Internal thoracic artery grafts were widely patent in all cases. Mean diameters of the internal thoracic artery were 1.95 ± 0.17 mm in the pedicled group and 2.26 ± 0.40 mm in the skeletonized group. After serotonin challenge, mean internal thoracic artery diameters were reduced to 1.44 ± 0.34 mm and 1.64 ± 0.14 mm, respectively; acetylcholine challenge lead to a moderate degree of vasoconstriction (1.55 ± 0.59 mm in the pedicled group and 1.84 ± 0.15 mm in the skeletonized group). No statistically significant difference was evident between the two groups at any step. Conclusion: Skeletonization does not affect the early vasoreactive profile of internal thoracic artery grafts used for surgical myocardial revascularization.

BACKGROUND: To better understand the mechanisms linking C reactive protein (CRP) to the risk of coronary thrombosis, we investigated the relation between inflammatory state and hemostatic response to coronary angioplasty in patients with either stable or unstable angina. METHODS: Plasma levels of von Willebrand factor (vWF) antigen, vWF collagen binding activity, vWF-cleaving-protease, CRP, and whole-blood platelet reactivity were measured before and 24 h after angioplasty in 18 patients with recent unstable angina and in 17 with stable angina. Each group was divided according to preprocedural CRP levels: >or=3 mg/l (in 9 unstable and 9 stable patients) or <3 mg/l (in 9 unstable and 8 stable patients). RESULTS: Baseline hemostatic parameters did not differ significantly among the four subgroups of patients. After angioplasty, virtually all patients with unstable angina and raised preprocedural CRP showed increased vWF antigen (P = 0.01), vWF collagen-binding (P = 0.001), CRP (P = 0.008), and platelet reactivity (P = 0.0007) compared to baseline, whereas no significant change of these variables was seen within the other three sets of patients. In the overall population, the changes in vWF antigen and vWF-collagen-binding induced by angioplasty correlated with those in CRP levels (r = 0.47, P = 0.004 and r = 0.44, P = 0.008). Baseline levels of vWF cleaving protease and modifications of this enzyme with angioplasty did not differ significantly among subgroups. CONCLUSIONS: Our data suggest that high preprocedural levels of CRP predict a significant vWF rise after angioplasty in patients with unstable angina. The rise in vWF is associated with that in CRP and with enhanced platelet reactivity. Such changes may contribute to the worse prognosis of unstable patients with raised indices of inflammation.

We report the case of a 60-year-old man with a history of recurrent transient ischemic attacks, effort syncope, cyanosis, erythrocytosis and a systolic murmur. Echocardiography and catheterization showed severe pulmonary stenosis and a patent foramen ovale with a right-to-left shunt. The patient was submitted to combined percutaneous pulmonary valvuloplasty and patient foramen ovale closure using the Amplatzer device.

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Previous studies indicate that percutaneous transluminal coronary angioplasty (PTCA) is associated with platelet activation. It is not well-established whether enhanced platelet aggregability after PTCA is prevented by the association of ticlopidine with aspirin. The aim of this study was to evaluate whole blood platelet aggregability before and after elective PTCA in patients with chronic stable angina receiving ticlopidine and aspirin. We studied 16 patients referred for elective PTCA, treated for ≥ 72 hours with oral aspirin and ticlopidine (group 1), and 10 patients referred for diagnostic coronary angiography, treated with oral aspirin alone (group 2). An intravenous bolus of heparin was administered at the start of PTCA. In both groups, platelet aggregability was assessed at baseline and 24 hours after the procedure, using the PFA 100® system. This method measures the time required for flowing whole blood to occlude a collagen and adenosine diphosphate (ADP)-coated ring, shorter times indicating greater aggregability. In both groups, platelet aggregability after the procedure was significantly increased compared with baseline: 104±30 seconds before versus 88±24 seconds at 24 hours in group 1 (p=0.03) and 84±16 seconds before versus 69± 14 seconds at 24hours in group 2 (p=0.004). Group 1 patients, compared with group 2, showed a trend toward reduced aggregability at baseline (p=0.06) and significantly lower aggregability 24 hours after the procedure (p=0.03). Ticlopidine and aspirin reduce whole-blood platelet aggregability compared with aspirin alone but fail to suppress the increased aggregability that occurs 24 hours after PTCA.

Background: The purpose of this study was to elucidate the midterm endothelium-dependent vasodilatory capacity of radial artery grafts anastomosed to the aorta, as well as their morphometric evolution with the time. Methods: Five years after surgery we evaluated the response of aorta-anastomosed radial artery grafts to the endovascular infusion of acetylcholine in 11 of the first 61 patients operated on at our institution, and we compared it to the response with that of internal thoracic artery grafts. Moreover, the first 20 patients who had a perfect radial artery graft on angiography at 1 year were restudied at 5 years and subjected to a comparative analysis of the diameters of the radial artery graft and the grafted coronary arteries. Results: At midterm angiography, dilation of the 2 types of grafts was similar in response to acetylcholine administration (radial artery, from 2.61 ± 0.39 to 2.90 ± 0.34 mm; internal thoracic artery, from 2.68 ± 0.21 to 2.93 ± 0.27 mm; P = .01 for both). The diameters of aorta-anastomosed radial artery grafts and grafted coronary arteries increased between both 1 and 5 years according to angiographic studies (radial artery grafts, from 2.08 ± 0.45 to 2.54 ± 0.53 mm; grafted coronary arteries, from 1.92 ± 0.47 to 2.18 ± 0.41 mm; P < .001 for both), but the increase was greater for the radial artery grafts (P < .001). Conclusions: Aorta-anastomosed radial artery grafts maintain an appreciable capacity for endothelium-dependent vasodilatation 5 years after implantation and undergo a progressive increase in luminal diameter with time. These observations contradict the presumed tendency for progressive fibrous intimal hyperplasia to develop in radial artery grafts.

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