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Background: We aimed to appraise the outcomes of diabetic patients with unprotected left main (ULM) disease treated with drug-eluting stents. Percutaneous coronary intervention with drug-eluting stent implantation is increasingly used for ULM disease. However, there are no data on the clinical results of drug-eluting stents for ULM disease in patients with diabetes., Methods: We collected baseline and outcome data from all patients undergoing percutaneous coronary intervention with drug-eluting stents for ULM disease at our institution since 2002. We identified three groups: insulin-requiring diabetes mellitus patients, noninsulin-requiring diabetes mellitus patients, and nondiabetes mellitus individuals. The primary end point was the rate of major adverse cardiac events, that is, cardiac death, myocardial infarction, or target vessel revascularization. We also appraised stent thrombosis according to the Academic Research Consortium., Results: A total of 185 patients were enrolled, 25/185 (14%) insulin-requiring diabetes mellitus patients, 30/185 (16%) noninsulin-requiring diabetes mellitus patients, and 130/185 (70%) nondiabetes mellitus individuals. In-hospital adverse events were overall uncommon and not significantly different across groups. After a median follow-up period of 23.1 months, major adverse cardiac events had occurred in similar rates across groups: 6/25 (24%) insulin-requiring patients with diabetes mellitus, 8/30 (27%) noninsulin-requiring patients with diabetes mellitus, and 31/128 (24%) nondiabetes mellitus individuals (P = 0.96). No case of definite or probable stent thrombosis was adjudicated. Intriguingly, possible stent thrombosis was nonsignificantly more common among insulin-requiring diabetes mellitus patients than among noninsulin-requiring diabetes mellitus patients or nondiabetes mellitus individuals [1/25 (4%) vs. 0/30 (0%) and 1/128 (0.8%), respectively, P = 0.30]., Conclusion: Drug-eluting stents provide favorable early and long-term results in both selected patients with diabetes and nondiabetic individuals undergoing percutaneous coronary intervention for ULM disease. Nonetheless, further randomized data are eagerly awaited to definitely confirm or disprove these findings.

Background: The major drawback of stent implantation in native human coronary vessels is the occurrence of restenosis. Drug-eluting stents significantly reduce restenosis after percutaneous coronary intervention (PCI), but may be associated with persistent local inflammation involved in the restenosis mechanisms. In this setting coating coronary devices with anti-inflammatory agents represents an intriguing alternative to stent-based local drug delivery. The aim of the present study was to test in a porcine model the safety and efficacy of a novel Genistein-eluting balloon preceding coronary stenting., Design: Female piglets underwent PCI in a randomized fashion with either a Genistein-eluting or a standard balloon angioplasty, followed in all vessels by bare-metal stent implantation. Pigs were sacrificed at different time points to appraise safety (i.e. endothelialization) and efficacy (i.e. anti-inflammatory and anti-proliferative effects): 1, 4, and 6-8 weeks following PCI., Results: Overall analysis was conducted on 14 piglets. Twenty-five bare-metal stents were implanted preceded by angioplasty with a conventional balloon in 13 vessels and by the Genistein-eluted balloon in 12. No untoward effects were reported in either group. Healing and endothelialization appeared universal within 4 weeks. The Genistein-eluted balloon group disclosed a significant reduction, at four weeks from implantation, of the peri-stent inflammatory cells count (mononucleocytes 39 +/- 32 Vs. 96 +/- 29 per square millimetre, P = 0.019). This effect did not clearly translate into a trend towards a reduced neointimal hyperplasia at 6-8 weeks (0.13 +/- 0.11 Vs. 0.14 +/- 0.09, P = 0.835)., Conclusion: This study provides the first in vivo demonstration of the anti-inflammatory effects of a Genistein-eluting balloon in PCI, warranting further research including the combination of a Genistein-eluting balloon with standard drug-eluting stent.

Background: The purpose of coronary revascularization in stable patients is anginal relief, yet there is no linear relationship between stenosis severity and clinical significance. A major factor in this complex lesion-myocardium interaction is collateral flow. We aimed to define which collateral flow cut-offs separate asymptomatic from symptomatic patients during coronary occlusion., Methods: Patients undergoing percutaneous transluminal coronary angioplasty for a single stenotic lesion were selected, collaterals were appraised angiographically, and fractional flow reserve was used during prolonged balloon occlusion to measure collateral flow index (FFRcoll). Changes in anginal symptoms, ST-T segment, and left ventricular wall motion were appraised before and during/shortly after balloon dilation. Receiver-operating-characteristic curves and area under the curve were computed to identify the most appropriate FFRcoll cut-offs., Results: Twenty consecutive patients were enrolled. At baseline, 10 patients had angiographic evidence of collaterals, whereas 10 had no angiographic evidence of collateral flow distal to the target lesion. FFRcoll had an excellent discriminatory performance for the presence of angiographic collaterals (area under the curve = 0.90, P = 0.003), a good discriminatory performance for the occurrence of angina (area under the curve = 0.80, P = 0.025), and a trend toward a good discriminatory performance for the occurrence of asynergy (area under the curve = 0.81, P = 0.06). On the basis of receiver-operating-characteristic curves, an FFRcoll cut-off greater than 0.26 could reliably distinguish patients with adequate collaterals (sensitivity = 0.90, specificity = 0.80), whereas a greater than 0.41 cut-off distinguished patients having angina or wall motion abnormalities from those remaining asymptomatic., Conclusion: This study shows that distal collateral pressure greater than 41% of proximal perfusion pressure protects from anginal symptoms or regional systolic dysfunction during coronary occlusion, whereas a greater than 26% cut-off is more appropriate to identify angiographically evident collaterals ensuring distal myocardial viability.

Aim: Percutaneous drug-eluting stent (DES) implantation is commonly used in patients with unprotected left main (ULM) disease. As this procedure has been performed routinely in Turin Center since 2002, this article aimed to summarize a five year-experience in DES implantation in the ULM., Methods: Baseline, procedural and in-hospital outcome data of all patients with ULM undergoing percutaneous coronary intervention (PCI) with DES between July 2002 and October 2006 at Turin Center have been collected. Patients were randomized into four groups: A (patients treated between July 2002 and December 2003), B (treated in 2004), C (treated in 2005) and D (treated in 2006). The baseline surgical risk features was to be compared with the European System for Cardiac Operative Risk Evaluation, disease location in the ULM, and in-hospital major adverse cerebro-cardiovascular events (MACCE), defined as death, myocardial infarction, repeat percutaneous revascularization, coronary artery bypass grafting, stroke, or stent thrombosis., Results: Out of a total of 4 432 coronary interventional procedures 198 patients treated with DES in the ULM were identified. There was a significant increase in the number of patients treated (P=0.00095), but no difference in EuroSCORE across groups (P=0.14). Conversely, there was a significant temporal trend in the incidence of bifurcational ULM being treated with DES (P=0.03). Intriguingly, despite this increase in adverse lesion characteristics, no significant increase was found in the rate of in-hospital MACCE (P=0.93)., Conclusion: In this single-center study, the number of patients being treated with DES for ULM disease has risen across the years, although keeping a similar surgical risk profile. Distal ULM involvement is no longer considered an absolute contraindication to PCI, as testified by the increasing frequency of such lesion among patients undergoing DES implantation at this Institution, with remarkably low rates of adverse events.

Objectives: In-stent restenosis occurs not infrequently after intracoronary implantation of bare-metal stents. Many techniques have been proposed for the treatment of in-stent restenosis, but drug-eluting stents seem to provide the best early and mid-term results. We aimed to appraise whether the effectiveness of drug-eluting stents for in-stent restenosis is maintained even in the long term., Methods: Participants in this prospective multicenter study were patients with in-stent restenosis treated with sirolimus-eluting stents. The primary endpoint was freedom from major adverse cardiovascular events (i.e. death, nonfatal myocardial infarction, target vessel revascularization, or stent thrombosis) in the long term (> or =24 months), with 6-month angiography planned for all patients., Results: A total of 271 consecutive patients were enrolled (332 sirolimus-eluting stents). Procedural success was obtained in all patients, with no case of in-hospital death, acute/subacute stent thrombosis, stroke, or urgent coronary bypass. Survival free from major cardiovascular events decreased progressively from 98.8% at 1 month, to 95.7, 83.7, 75.4, and 65.8% at 6, 12, 24, and 30 months, respectively. A similar attrition in freedom from repeat target vessel was found from 97.6% at 6 months to 76.7% at 30 months. A total of four possible and one definite stent thromboses (2.6%) were noted, all occurring several months after clopidogrel discontinuation and in patients on life-long aspirin., Conclusion: The present study supports the mid-term safety and effectiveness of sirolimus-eluting stents for the treatment of in-stent restenosis in comparison with the other available treatments. Whether the late catch-up phenomenon observed in repeat target revascularization and stent thrombosis is an incidental finding deserves further rigorous scrutiny.

Aims: Poor left ventricular function is considered a high risk condition for performing either percutaneous (PCI) or surgical revascularisation. The aim of this study was to evaluate immediate and long term results of PCI in patients with coronary artery disease (CAD) and severe left ventricular dysfunction (EF < 0.30)., Methods and Results: Seventy-eight consecutive patients with CAD and severe left ventricular dysfunction (EF < 30%) were selected. The majority of these patients (87%) had multivessel disease. Coronary angioplasty procedure was mainly motivated by angina associated with clinical manifestation of heart failure (54%). Total number of treated vessels was 181, and a total of 203 stents were implanted (2.6 stent/patient). Procedural success was achieved in 77 patients (97.8%). The total procedural and in-hospital adverse event rate was 7.8%. Mean follow-up period (FU) was 25+/-6 months. Event-free survival rate at the end of FU was 55%; repeat revascularisation was performed in 21 patients (27.6%). Female gender, diabetes, new acute myocardial infarction and number of treated vessels were independent predictors for death and combined mayor adverse cardiac events (MACE) during the follow-up., Conclusions: In symptomatic patients with CAD and severe left ventricular dysfunction, PCI can be performed with excellent procedural outcome and acceptable long-term morbidity and mortality.

Favorable early results of percutaneous drug-eluting stents in unprotected left main (LM) disease are available, but outcome data beyond 6 to 10 months are lacking. We evaluated the long-term results of sirolimus-eluting stents (SESs) in patients with LM disease. From November 2002 to December 2004, consecutive patients with LM disease, without contraindications to double antiplatelet therapy and undergoing SES implantation, were enrolled prospectively. The primary end point of the study was occurrence of major adverse cardiovascular events. In total 85 patients were treated with 118 SES and followed for 595 +/- 230 days. Event-free survival rates at 1 year and 2 years were 85.5% and 78.6%, respectively. Only 2 deaths occurred overall (2.4%), the first in-hospital in a very high-risk patient according to the European System for Cardiac Operative Risk Evaluation and the second in a patient with severe systolic dysfunction already at the index procedure). Myocardial infarction was adjudicated in 3 patients (3.6%), 2 occurring periprocedurally and 1 during follow-up for a de novo nontarget lesion. There were 7 (10.8%) target lesion revascularizations at 24 months, with all but 1 percutaneous and in a subject with bifurcation LM disease at baseline. At 9-month angiography, late loss was 0.15 +/- 0.81 mm and restenosis rate was 8.2%. An increased incidence of adverse events was noted in patients undergoing SES after dilation with extremely oversized balloons. No case of stent thrombosis was reported. In conclusion, this single-center experience suggests that percutaneous use of SESs to treat LM disease in unselected high-risk patients is safe and effective even 1 year after implantation.

Objective: One of the drug-eluting stents that have been introduced into clinical practice is the paclitaxel-eluting stent (PES). Several randomised, controlled clinical trials have already been conducted to evaluate the safety and efficacy of this stent, but data regarding clinical practice are still lacking. The aim of this study was to evaluate the safety and efficacy of PESs in a 'real-world' population., Methods: Two hundred and seventy-three patients with a high cardiovascular risk profile and complex coronary lesions were treated with PESs. Each patient was categorised using the following parameters: cardiovascular risk factors, clinical history, clinical presentation, angiographic pattern, and procedural characteristics. Primary endpoints were major adverse cardiac events (cardiovascular death, coronary artery bypass grafting, myocardial infarction, stroke, target vessel revascularisation, target lesion revascularisation, and remote revascularisation)., Results: A low rate of intraprocedural and periprocedural complications was observed. During the clinical follow-up period (mean 10.5 +/- 4.2 months), 78% of patients were event-free. Twenty-six patients (9.8%) underwent target vessel revascularisation, but only 11 of them (4.2%) had target lesion revascularisation. Seven patients (2.7%) had myocardial infarction, and cardiac death occurred in two patients (0.76%). Only one case (0.37%) of subacute stent thrombosis and one case of late stent thrombosis were observed., Conclusions: The present study demonstrates that the use of PESs is safe and effective also in patients with a high cardiovascular risk profile and complex coronary lesions.

Aim: In mitral stenosis (MS) patients with a poor symptom-echocardiography correlation, dobutamine stress echocardiography (DSE) still does not have a confirmed utility and predictive value. Our aim is to evaluate usefulness of DSE in assessing 2 and 5 years clinical outcomes., Methods: Forty-four consecutive patients with known MS were submitted, between April 1998 and July 1999, to basal and DSE. Patients were divided in 2 groups: group A if during DSE was reached a mean mitral gradient (MG) = or > 15 mmHg and/or a pulmonary arterial pressure (PAP) = or > 60 mmHg, and group B if MG and/or PAP were respectively lower than 15 and 60 mmHg. Endpoints considered were death, hospitalization for acute pulmonary edema, complications associated with mitral valve disease and mitral valve interventions (percutaneous or surgical). Mean follow-up was 73.6+/-16.6 months., Results: Mean age was 55.2+/-10.5 years; 83.7% were women; NYHA class was I-II-III respectively in 18.6%, 58.1% and 23.3% of the patients; mean mitral valve area was 1.39+/-0.26 cm2; mean MG 8.05+/-2.54 mmHg; PAP 39.3+/-7.9 mmHg. Twenty-five patients met criteria for group A and 18 for group B. The event-free interval (27.9+/-32.1 months in group A vs 53.5+/-25.8 months in group B; P=0.008) and the 2 years event-free survival (40% for group A vs 88.9% for group B; P=0.002) showed significantly different patterns between the 2 groups. The 5 years survival analysis did not reach significance., Conclusion: DSE seems to detect MS patients that will have rapid evolution of their valvular disease within 24 months.

Aim: This study compares the clinical and angiographic outcomes of sirolimus eluting stent (SES) and bare metal stent (BMS) implantation for unprotected left main coronary artery (ULMCA) stenosis., Methods and Results: We analysed 141 unselected patients with unprotected LMCA stenosis: 72 were treated with SES and 69 with BMS. SES patients were younger, with a higher ejection fraction, had more often hypertension, family history and were more often smokers. The procedural success rate was 94.2% in SES group and 87% in BMS group. In SES group there were 2 periprocedural myocardial infarction (3%). 1 intra-procedural death (1.4%) and 1 in-hospital death (1.4%) and respectively 2 (3%),4 (6%) and 3 (4%) in BMS group. No incidents of stent thrombosis, stroke and emergent CABG occurred during hospitalisation in either group. SES patients showed a lower late lumen loss (0.5+/-0.8 mm vs 1.1+/-1.0 mm; p<0.05) and a lower nine-month angiographic restenosis rate (13.6% vs 24.3%; p=NS). The MACE free survival rate at 2 years was 83% in the SES group vs 55% in the BMS group (p<0.001)., Conclusions: SES implantation for unprotected LMCA stenosis in "real world" population appears safe with a low restenosis and MACE rate at follow-up.

Background/aims: To evaluate feasibility, safety and pattern of bone marrow-derived cells (BMC) mobilization in patients with end stage liver cirrhosis following granulocyte-colony stimulating factor (G-CSF) administration., Methods: Eight patients with severe liver cirrhosis (Child-Pugh score B-C, spleen diameter less than 170 mm) were included. They were treated with G-CSF (5 microg/kg b.i.d for three consecutive days) to mobilize BMC, evaluated as circulating CD34+ve cells (flow cytometry) and myeloid CFU-GM progenitors (in vitro colony growth assay). Co-expression in CD34+ve cells markers of differentiation (Thy1, CD133, CXCR4, c1qRp) were investigated on CD34+ve cells by double direct immunofluorescence. Data from 40 healthy haematopoietic stem cell donors were used as controls., Results: Mobilization of CD34+ve cells occurred in all patients. It was paralleled by expansion of circulating CFU-GM progenitors. Circulating CD34+ve cells co-expressed epithelial and stem cell markers in both cirrhotics and volunteer stem cell donors. G-CSF was well tolerated, no adverse event occurred, a significant reversible increase of splenic longitudinal diameter was observed., Conclusions: (i) G-CSF mobilization of BMC co-expressing epithelial and stem markers occurred in all cirrhotic patients; (ii) splenomegaly up to 170 mm does not prevent safe BMC mobilization following G-CSF in patients with end stage liver disease; (iii) mobilized BMC may represent an easy immature cell source potentially useful for novel approaches for liver regeneration.

Human herpesvirus 8 (HHV-8) is causally associated with Kaposi's sarcoma (KS). KS is most frequently observed in HIV patients and in solid organ transplant recipients. The role of HHV-8 in allogeneic haematopoietic cell transplantation (HCT) remains to be determined. Here we describe a case in which KS concomitantly occurred with CMV reactivation after a non-myeloablative allogeneic HCT and presented with skin lesions, but not visceral involvement. Skin biopsy confirmed the diagnosis and ruled out graft versus host disease or disease recurrence. Molecular findings indicated viral reactivation of the recipient's primary infection. Tumour lesions completely receded when immunosuppression was tapered. Prevalence studies in donors and recipients are needed to determine the clinical impact of HHV-8 in HCT.

Aims: To verify feasibility and safety of bone marrow stem cells (BMC) mobilization in patients (pts) with acute myocardial infarction (AMI) and to monitor the clinical effects of BMC mobilization in terms of myocardial perfusion and function., Methods and Results: Eight male pts (median age: 50.5 years) treated with a primary PTCA were enrolled. The mobilization regimen consisted of G-CSF 5 microg/kg/12 h from day 0 to day +2 and GM-CSF 2.5 microg/kg/24 h. All pts underwent coronary angiography, intracoronary doppler flow study, echocardiography, and nuclear thallium scan before treatment and at 6 months. All pts showed increased values of WBC and circulating CD34+ following cytokine administration. No patient died. All patients completed a 6-months follow-up: target lesion revascularization rate was 12,5%, target vessel revascularization rate was 37.5%, angiographic mean ejection fraction increased from 49.8+/-11.9 to 55.4+/-8.7 (p=NS), mean coronary flow reserve from 1.63+/-0.42 to 2.5+/-0.4 (p=0.001), mean Thallium uptake raised from 55.56+/-16.42% to 67.56+/-13.66% (p=0.01), and normally perfused segments from 16% to 52% (p=0.01)., Conclusion: Cytokine-induced BMC mobilization is feasible in AMI pts. Improvements of myocardial perfusion can be expected after PTCA associated with G-CSF and GM-CSF induced mobilization. Further studies are required to define the role of BMC-mobilization and the most effective cytokine combination.

The presence of an anomalous origin and/or distribution of a coronary artery as the infarct-related vessel during primary angioplasty for acute myocardial infarction might represent a clinical and technical challenge. We report on a case of a patient with an acute anterior myocardial infarction who was referred to our hospital for primary angioplasty and whose culprit lesion was located on an aberrant left main coronary artery. The purpose of this case report was to review the incidence and angiographic evaluation of an anomalous coronary vessel and to discuss the technical approach to an anomalous left main intervention and its impact on clinical outcome.

Aim: In patients with mitral stenosis, symptoms do not always correlate with echocardiographic data. The aims of the study were to evaluate the role of cardiopulmonary exercise testing in the assessment of patients with mitral stenosis and to quantify nitric oxide production at rest and at the end of exercise., Methods: We evaluated 43 patients with moderate to severe mitral stenosis with a discrepancy between echocardiographic data and symptoms. Nitric oxide output was calculated by measuring nitric oxide concentration in the exhaled air at rest and at the end of exercise test., Results: Patients were divided in 2 groups: group 1 with a functional capacity <75% at cardiopulmonary exercise test (VO2max in % of the predicted one) and group 2 with functional capacity >75%. Transvalvular gradient and pulmonary artery pressure were significantly higher in group 1 than in group 2 (respectively 9.07 +/- 2.11 mmHg vs 6.01 +/- 1.08 mmHg, p<0.001 and 42.8 +/- 7.2 mmHg vs 33.1 +/- 4.7 mmHg, p<0.001). Patients of group 1 had a lower nitric oxide output at the end of exercise compared to group 2 (231.4 +/- 96.6 nl/min vs 326.3 +/- 74.0 ml/min, p=0.01) and to normal subjects (511.15 +/- 180.1 nl/min, p<0.001)., Conclusion: Cardiopulmonary exercise testing provides objective non invasive information in the evaluation of patients with discrepancy between symptoms and echocardiographic data. Different levels of nitric oxide output during exercise suggest the role of nitric oxide in regulating pulmonary vascular tone.

Several studies focused on the ability of bacterial lipopolysac-charides (LPS) in triggering platelet and/or leukocyte activation. The aim of this study was to investigate the molecular mechanisms involved in the aggregation of platelets and in their interaction with leukocytes in whole blood after stimulation with low doses of LPS. LPS did not directly induce platelet aggregation in whole blood, but they primed the aggregation of platelets induced by epinephrine, adenosine diphosphate and arachidonic acid. As shown by cytofluorimetry, platelets neither bind FITC-LPS, nor express the LPS-receptors CD14 and toll-like receptor 4 (TLR4). On the contrary, LPS primed monocytes and to a lesser extent polymorphonuclear neutrophils to adhere to platelets. Both platelet-leukocyte interaction and platelet aggregation in whole blood were inhibited by blockade of CD14 and TLR4. Moreover, the interaction between platelets and leukocytes was inhibited by P-selectin, and by blockade of PAF and reactive oxygen species, suggesting a role of P-selectin and of leukocyte-derived mediators. In conclusion, these results elucidate the mechanisms leading to platelet activation and interaction with leukocytes triggered by LPS. They suggest that the activation of platelets by LPS is mainly dependent on leukocytes and especially monocytes as a result of CD14 and TLR4 engagement. Moreover, we found that leukocyte-platelet interaction was triggered by the synthesis of PAF and the generation of oxygen radicals that induced upregulation of surface expression of P-selectin.

Non-myeloablative stem cell transplantation (NMT) has been increasingly used in compromised patients who would otherwise have been unable to undergo allotransplant. There is little understanding of the kinetics of immune reconstitution and its influence on infective complications following NMT. The aim of present study was to evaluate lymphocyte subset reconstitution over the first 12 months post-transplant in 15 adult patients receiving NMT with comparison to that of 30 patients grafted with a conventional hemopoietic stem cell transplantation (HSCT). NMT recipients were conditioned with fludarabine-based conditioning regimens. Peripheral blood stem cell (PBSC) was the source of stem cells in 13 NMT recipients and in 24 conventional HSCT recipients. Absolute numbers of helper (CD4+) T cells, naive (CD4+ CD45RA+) and memory (CD4+ CD45RO+) T cells as well as suppressor (CD8+) T cells, CD19+ B cells and NK cells were comparable in the two groups at all time points after transplantation. A median value of 200 CD4+ T cells/microl was achieved at 2 months post-transplant by the NMT and HSCT recipients. The CD4:CD8 ratio remained severely depressed throughout the study period. Almost all CD4+ lymphocytes expressed CD45RO antigen in the both groups of patients B lymphocytes showed low counts throughout the entire study period in both groups. Bacteremia and CMV antigenemia occurred respectively in 13 and 36% of the patients in the NMT group and in 15 and 39% of the patients in the HSCT group. Our preliminary data indicate that patients receiving a NMT have a lymphocyte reconstitution similar to that observed in patients who received a conventional HSCT. The incidence of bacteremia and CMV infection were not significantly different between the groups. Nevertheless, due to the small sample size, these results should be considered suggestive rather than definitive.

Coronary stent implantation is the predominant method of percutaneous coronary interventions (PCI). This is to be attributed to the ease of use beside the better short and long term clinical outcome as compared to balloon angioplasty. Nevertheless, improvements in operator skill and stent technology together with better use of adjunctive pharmacological therapy have contributed to the improvement in clinical outcome. However, the main limitation of coronary stenting is still represented by in-stent restenosis (ISR) with an estimated rate of 17-32%. Thus, compared to coronary bypass surgery, the major adverse cardiac events following stent implantation are still higher and mainly represented by the need for re-intervention. The advent of drug eluting stents (DES) has led the experts to predict that with DES there will be little or no difference between PCI and coronary bypass surgery in terms of long-term outcome leading to a further expansion of indications. The clinical trial programs of the 2 available DES for clinical use (sirolimus-eluting stent, SES - Cypher and paclitaxol-eluting stent - Taxus) have been able to demonstrate the safety and clinical efficacy of both. Nevertheless, off-label use in patients on high risk for restenosis confirmed these data. At least for SES as was demonstrated by 2 "real world" registries. Thus, the introduction of DES represents a remarkable evolution for new standards in coronary artery disease treatment and offers hope to those patients considered to be "high risk" such as diabetics, patients with ISR, diffuse disease in whom surgery was previously the only therapeutic option. This paper will discuss the main results of the clinical trial programs of the DES (mentioned above) available for clinical use in the present time and analyze technical and procedural aspects which could affect long term outcome.

BACKGROUND: Pulmonary hypertension (PH) is an important limiting factor of exercise tolerance in patients with mitral stenosis (MS). We wished to investigate the relationship between respiratory nitric oxide (NO), a potent vasodilator, and exercise tolerance in patients with moderate MS. In the same patients, we wondered whether acute change in pulmonary hemodynamics could affect respiratory NO. METHODS: Ten patients with moderate MS (valve area 1.4+/-0.2 cm(2)) were studied at rest, during incremental cycle ergometry exercise, and during dobutamine stress echocardiography (DSE). The concentration of NO in exhaled air (FE(NO)) and NO output (V'(NO)) were measured at baseline, at the end of exercise, and at the end of DSE. Eight healthy subjects served as normal controls for NO output during exercise. RESULTS: During exercise, FE(NO) decreased both in patients and in controls, while V'(NO) increased in both. At the end of exercise, both VO(2) max and V'(NO) were significantly higher in controls than in patients. The increase in V'(NO) during exercise was significantly correlated with VO(2) max, both in patients and in controls. During DSE, cardiac output (CO), pulmonary artery pressure (PAP), and mitral valve gradient increased. No changes in mean FE(NO), V'(NO), or ventilation were observed during DSE. There was a significant inverse correlation between FE(NO) and mitral valve gradient at the end of DSE. CONCLUSIONS: In patients with moderate MS, exercise performance is correlated with respiratory NO output. In the same patients, during DSE, the increase in CO, which is not accompanied by an increase in ventilation, is not associated with an increase in respiratory V'(NO).

Background and Objectives: Since optimal collection of peripheral blood progenitor cells (PBPC) remains crucial for high-dose therapy in patients with multiple myeloma (MM) in relapse phase or refractory to chemotherapy, we evaluated several variables that may influence mobilization., Design and Methods: Eighty-nine patients who underwent a standard mobilization procedure with cyclophosphamide (3 g/m2) and growth factors entered the study. A composite collection totalling at least 2x106 CD34+/kg was defined as a sufficient yield: 59 patients achieved an adequate collection. A reliable factor to predict adequate yields was prior therapy: an adequate collection was obtained in 92% of patients treated with conventional non-alkylating therapy (VAD-based regimens), in 56% treated with oral melphalan and in 23% who had received intravenous melphalan., Results: The three groups were similar for most clinical features. After adjustment for several potential confounders, the probability of an adequate PBPC collection remained higher in the group treated with non-alkylating agents, with an odds ratio (OR) of 6.14 (95% confidence interval, CI=1.34, 28.13) and lower in those treated with intravenous melphalan (OR=0.08; CI=0.01-0.61), when compared to the group treated with oral melphalan. Among the other prognostic factors (stage, percentage of bone marrow plasma cells, b2-microglobulin, labeling index, isotype, monoclonal component, Bence-Jones proteinuria) evaluated at diagnosis, there was no clear association with progenitor cell yield., Interpretation and Conclusions: In conclusion, patients who are potential candidates for high-dose therapy with PBPC support should not receive conventional alkylating therapy, even orally. Alternatively, progenitor cells should be collected early in the course of MM.

Objective: Autologous transplantation of bone marrow (BM) and peripheral blood progenitor cells (PBPC) is commonly used for treatment of multiple myeloma (MM). Although both stem cell sources harbor residual clonal cells, a quantitative evaluation of their level of tumor contamination (LTC) still needs to be performed through highly accurate and reproducible approaches. In this study, we used a validated real-time polymerase chain reaction (PCR) strategy to evaluate LTC of BM and PBPC samples obtained from MM patients., Materials and Methods: The patients underwent two different mobilization courses (defined as early or late course) following two cycles of cyclophosphamide 5 g/m(2). LTC was evaluated by measuring the number of clonal immunoglobulin heavy-chain rearrangements followed by normalization of samples using the GAPDH gene., Results: Overall, 26 PBPC and 12 BM samples were analyzed. Main results are as follows. 1) PBPC harvests are less contaminated than BM samples taken immediately after each mobilization course (median difference 2.68 logs; range 1.7 to 4.6) (p < 0.0001). 2) LTC of PBPC harvests has only minimal variation among different leukaphereses performed during the same mobilization course (median difference 0.45 logs; range 0.22 to 1.2). 3) No difference was observed among PBPC and BM samples obtained after the late mobilization course as compared to the early mobilization course (median reduction 0.21 logs; range -0.39 to 1.3) (p = 0.84). 4) In PBPC but not in BM samples, there is a clear overestimation of the percentage of plasma cells when flow cytometric evaluation of CD38(bright) cells is compared to real-time PCR results. This suggests that in PBPC, most CD38(bright) cells do not belong to the neoplastic clone., Conclusions: Real-time PCR using the IgH rearrangement proved an effective tool for monitoring LTC in stem cell harvests from MM patients. The smaller LTC of PBPC harvests supports the role of PBPC as stem cell rescue for MM patients compared to BM cells.

The purging efficacy of the Miltenyi sorting system was evaluated by qualitative and TaqMan quantitative polymerase chain reaction (PCR) in myeloma patients, using immunoglobulin genes. After small-scale selection, qualitative PCR showed that in 6 of 12 leukaphereses myeloma cells were no longer detectable. Envisaging a possible clinical application, the leukaphereses from three patients underwent large-scale selection. Qualitative PCR showed that myeloma cells were still detectable. Quantitative PCR, performed in two patients, showed a tumour depletion of 1 and 2 logs respectively. Although numbers are small, the promising results obtained with small-scale selection were not reproduced in large-scale experiments.

A clinical relationship between dose-intensity of melphalan and response rate has been demonstrated in multiple myeloma. Promising results have been reported after 200 mg/m(2) melphalan, especially in younger patients. It is uncertain whether 100 mg/m(2) melphalan (MEL100) can offer similar results in older patients. To address this issue, patients were treated with 2 or 3 MEL100 courses followed by stem cell support. Seventy-one patients (median age, 64 years) entered the protocol at diagnosis. Their clinical outcome was compared with that of 71 pair mates (median age, 64 years) selected from patients treated at diagnosis with oral melphalan and prednisone (MP) and matched for age and beta2-microglobulin. Complete remission was 47% after MEL100 and 5% after MP. Median event-free survival was 34 months in the MEL100 group and 17.7 months in the MP group (P <.001). Median overall survival was 56+ months for MEL100 and 48 months for MP (P <.01). In a multivariate analysis, beta2-microglobulin levels and MEL100 were independent risk factors associated with outcome: superior event-free and overall survival were observed in patients presenting low beta2-microglobulin levels at diagnosis and receiving MEL100 as induction regimen. In conclusion, MEL100 was superior to MP in terms of complete remission rate, event-free survival, and overall survival.

The possibility of reducing tumour cell contamination by cytotoxic drug courses prior to peripheral blood progenitor cell (PBPC) collection was evaluated in two consecutives groups of multiple myeloma (MM) patient candidates for autograft. All patients were at disease onset and received two VAD (vincristine, doxorubicin and dexamethasone) courses as initial debulking. In the first group (44 patients), mobilization and harvest were performed 'upfront', after a single cyclophosphamide (CY) administration of 4 g/m2; in the second group (17 patients), PBPC were collected at the end of a high-dose sequential chemotherapy programme, including: CY 5 g/m2, etoposide (VP16) 2 g/m2, a chemotherapy-free interval with three courses of high-dose dexamethasone, a final mobilizing CY at 7 g/m2. G-CSF was given following each high-dose cytotoxic drug. Cytofluorimetric analysis was performed to quantify progenitors (CD34+ cells) and plasma cells, identified by the high CD38 expression and/or CD38 and CD138 coexpression. Large amounts of PBPC were collected in either group (median harvested CD34+/kg: 15.8 x 10(6) and 13.4 x 10(6), respectively; P=0.9). Circulating plasma cells were significantly higher in patients mobilized 'upfront' compared to those who received the high-dose sequence (median peak values of CD38bright/microl: 39 and 10, respectively; P=0.02); a similar difference was observed in the amount of contaminating plasma cells in the harvest products (median CD38bright/kg: 7.4 x 10(6) and 1.3 x 10(6), respectively; P=0.02). The results demonstrate that an in vivo purging approach is feasible in myeloma patients through repeated high-dose chemotherapy courses; this may provide less-contaminated material suitable for further in vitro purging procedures.

Sequential administration of high-dose chemotherapy courses possibly allows extensive in vivo purging before circulating progenitor collection for autograft. To evaluate whether progenitor cell mobilization was negatively affected by repeated high-dose chemotherapy courses, we studied 23 lymphoma patients undergoing the HDS regimen. The scheme includes the sequential administration of cyclophosphamide (CY) given at 7 g/m2 and etoposide (VP16) given at 2 g/m2, each followed by G-CSF (filgrastim) at 5 micrograms/kg/day. Eleven patients received the standard HDS sequence, with a short interval between first and second myelotoxic courses of less than 45 days (median: 30 days); the remaining 12 patients received a modified HDS where the interval between first and second high-dose course was protracted over 2 months (median: 70 days); in this latter group, 2 to 4 conventional debulking courses were delivered prior to HDS. In patients receiving the standard HDS, progenitor mobilization following the first course was consistently high (median circulating CFU-GM/ml peak value: 29,022); however, significantly lower values were observed at the second course (median CFU-GM/ml peak value 3757, P = 0.002). Circulating BFU-E and CD34+ cell values paralleled those of CFU-GM. No significant difference was observed in progenitor mobilization following either course in patients receiving HDS with extended interval (median circulating CFU-GM/ml peak value: 14,363 vs 9208, at first and second course respectively, P = 0.27). Eleven patients had their progenitor cells harvested following the second delayed course and 2-4 leucaphereses allowed very satisfactory harvests in all of them (CFU-GM/kg ranging from 39-340 x 10(4)).(ABSTRACT TRUNCATED AT 250 WORDS)

Retinoic acid has been shown to induce growth inhibition in a variety of cell types including human myeloma cell lines. Bone marrow plasma cells from 31 multiple myeloma (MM) patients were cultured to investigate the activity of 13-cis-retinoic acid (cRA), all-trans-retinoic acid (tRA), interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), and dexamethasone (DEX), alone or in combination, on in vitro proliferation and immunoglobulin (Ig) secretion. Both cRA and tRA inhibited proliferation: the labelling index (LI) of treated cultures/controls, was 0.47 +/- 0.05 (mean +/- standard error mean, M +/- SEM) P < 0.0001, and 0.67 +/- 0.04 (M +/- SEM), P < 0.0001, respectively. The inhibitory effect of cRA was significantly superior to tRA (P = 0.0129) and IFN-alpha, similar to IFN-gamma and DEX. The combinations of cRA + IFN alpha, tRA + IFN-gamma, tRA + DEX did not show any synergistic effect on myeloma proliferation. In contrast, the combination cRA + DEX (0.29 +/- 0.04, M +/- SEM) markedly increased the effect of both cRA and DEX used as single agents. Ig synthesis was not significantly affected by CRA, tRA, IFN-gamma and the combination tRA + IFN-gamma. As expected, only IFN-alpha (P = 0.002) and DEX (P < 0.001) inhibited Ig production. The combinations cRA + IFN-alpha, cRA + DEX and tRA + DEX decreased Ig secretion to the same extent as IFN-alpha and DEX alone respectively. In conclusion, our data indicate that tRA and especially cRA strongly inhibited plasma cell proliferation but had no effect on Ig synthesis. The combination of cRA + DEX showed the highest degree of inhibitory activity of all cytokines, alone or in combination.

Peripheral blood (PB) T cells from 56 patients with B-cell chronic lymphocytic leukemia (B-CLL) were analyzed by two- and three-color immunofluorescence (IF) to determine the expansion of distinct T-cell subsets and their relationship with the clinical and biological features of the disease. We detected the expansion of an unusual T-cell subpopulation expressing lower CD4 or CD8 levels (CD4lo, CD8lo) than classic T cells (CD4hi, CD8hi). This subpopulation also expressed low levels of the CD3/TCR alpha/beta complex and was CD19-CD13-CD14-. A phenotypic analysis probing the activation level of CD4lo, CD8lo, CD4hi, and CD8hi cells showed that they comprised increased counts of HLA-DR+, CD11b+, CD45R0+, and CD45RA+ cells. Subset expansion ranged from 2.1- to 13.6-fold. Statistical analysis showed that the size of some of these subsets was correlated to intrinsic features of the tumor. First, CD4loHLA-DR+ cell counts were higher in patients with stage A than those with stages B and C disease. Second, CD8loHLA-DR+ cell counts were higher in patients in stable remission than in those at diagnosis. Third, CD4loHLA-DR+, CD4loCD45R0+, CD4loCD45RA+, and CD4hiCD11b+ cell counts were higher in patients whose tumor cells expressed high levels of surface immunoglobulin (sIg) than in those expressing low levels. The involvement of CD4lo and CD8lo cells in most of these correlations suggests that they may be tumor-reactive cells. Similar cells described in human and murine autoimmune disease have been shown to be autoreactive anergic cells, which may derive from nonclassic pathways of T-cell development.

Interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma) and dexamethasone (DEX) have shown anti-tumour effects in multiple myeloma (MM) cells. Bone marrow plasma cells from 39 MM patients were cultured to clarify the intensity and specific activity of each compound on bromo-deoxyuridine (BrdUrd) uptake and immunoglobulin (Ig) secretion. BrdUrd uptake was inhibited by recombinant human IFN-gamma (100 U/ml) and by DEX (10(-6) M). The stimulation index (StI), i.e. labelling index (LI) of treated samples/controls, was 0.49 +/- 0.09 (mean +/- standard error of the mean, M +/- SEM), P = 0.0003, and 0.52 +/- 0.07 (M +/- SEM), P < 0.0001, respectively. Ig secretion was reduced by IFN-alpha (100 U/ml) and DEX. The secretion index (SI), i.e. Ig quantitation of treated samples/controls, was 0.04 (M +/- SEM), P < 0.0001, and 0.52 +/- 0.04 (M +/- SEM), P < 0.0001, respectively. Finally, IFN-gamma inhibits BrdUrd uptake only and IFN-alpha secretion only. In 18 patients the simultaneous addition of IFN-alpha plus IFN-gamma mainly parallel the effect of IFN-gamma on BrdUrd uptake and IFN-alpha on secretion, but not result in any additive or synergistic effect, though both BrdUrd uptake and Ig secretion were decreased to about the same extent as with DEX. These data indicate that the combination of IFN-alpha plus IFN-gamma and DEX are the strongest inhibitors of both BrdUrd uptake and secretion. Since IFN-alpha and IFN-gamma appear to have a different mechanism of action, their combined use could be considered as a possible new treatment strategy.

The immunological phenotype of bone marrow myeloma cells and peripheral blood lymphocytes was evaluated in 38 untreated myeloma patients. A striking increase of monotypic cells expressing the same light chain as the M component was observed in bone marrow from 18/38 (47%) patients. A two-colour analysis clarified that the majority of myeloma cells co-expressed plasma cell and B lymphocyte markers (cyIg, CD38, CD56 and sIg), and were regarded as early-plasma cells (early-PC). In the remaining patients, myeloma cells expressed plasma cell markers only (late-PC). Phenotype corresponded to a distinct morphological pattern: early-PC showed a lympho-plasmocytoid feature with significantly lower diameters than late-PC (12.1 v 14.8 microns, P < 0.007). Moreover, the plasma cell labelling index was significantly increased in early-PC patients (1.2 v 0.5%, P < 0.04). In peripheral blood from patients with early-PC, monotypic cells co-expressing sIg and CD38, CD56, but not CD19, were also detected. These data suggest a recirculation of early-PC. Myeloma cells maintained their phenotypic pattern during the course of the disease. This observation suggests that the degree of maturation is an intrinsic characteristic of the myeloma cell population in individual patients. The evaluation of prognostic factors, such as beta 2-microglobulin, C-reactive protein and neopterin, showed a statistically significant increase in the early-PC patients, suggesting a poor outcome. In conclusion, myeloma cell phenotype allows identification of a myeloma variant with aggressive biological and clinical characteristics.

Cyclic neutropenia is a rare hematological disorder characterized by periodical severe granulocytopenia. A stem cell defect and/or immunological abnormalities are considered to play a role in this disease. Here we describe the case of an adult woman who was diagnosed as having both cyclic neutropenia and severe hypogammaglobulinemia. Her clinical history revealed that one or both abnormalities had been present since childhood. Normal in vitro growth of the patient's bone marrow CFU-GM was observed, while immunological analysis revealed the presence of a persistent excess of activated (HLA-DR+) CD8+ T lymphocytes in both bone marrow and peripheral blood. These T lymphocytes have been shown to be polyclonal by DNA analysis, and their role in determining the clinical picture of our patient remain uncertain since they could not be shown to produce inhibitors of in vitro CFU-GM growth. Intermittent low doses of human recombinant G-CSF were able to improve neutropenia and completely prevent infectious symptoms, thus confirming the efficacy of this cytokine in cyclic neutropenia patients.

Long-term bone marrow culture (LTBMC) was evaluated as a purging procedure in the murine plasmocytoma MOPC-315s system. MOPC-315s cells injected in Balb-c mice rapidly proliferate both in marrow and spleen, where macroscopic tumor colonies develop. A linear relationship between the number of injected cells and spleen colonies was observed, consistent with the presence of 1 clonogenic myeloma stem cell out of 1800 cells. In vitro, MOPC-315s cells are easily identifiable as rosette-forming cells (RFC+) with trinitrophenil acid (TNP) coated sheep red blood cells. When bone marrow (BM) cells containing 20-40% RFC+ were seeded in LTBMC, RFC+ rapidly decreased and were no longer detectable by day 14 of culture. Clonal Ig gene rearrangement was evident at time 0, but it was no more detectable later on. In addition, cells taken at days 14 and 21 of culture were no more tumorigenic when injected in vivo. The results suggest the efficacy of the LTBMC for the in vitro elimination of myeloma cells, including the neoplastic stem cells.

In this study we investigated serum neopterin levels in 73 multiple myeloma (MM) patients (63 determinations at diagnosis, 58 in remission, and 35 at relapse), in 56 monoclonal gammopathies of undetermined significance (MGUS), and in 70 normal controls. Median neopterin level was 5.3 nmol/l in normal controls, 6.8 nmol/l in MGUS, and 10.7 nmol/l in MM patients. In comparison to healthy subjects, significantly higher levels were observed in MM patients (p less than 0.0001). A statistical difference was observed between MGUS and MM patients at diagnosis (p less than 0.007). Compared to diagnosis, a further increase was noticed during relapse, suggesting a correlation between neopterin and disease activity. The prognostic significance of raised neopterin levels was confirmed by a survival analysis. Median survival for patients with high values was 20 months, whereas it was 63.9 months for those with low values (log-rank test p less than 0.003). Serum neopterin concentrations also correlated to beta 2 microglobulin levels and the percentage of CD38+ circulating lymphocytes, indicating a link between neopterin and other myeloma prognostic factors.

We report a case of T-cell hairy-cell leukemia with a dual rearrangement of Ig- and T-cell receptor genes. The cytochemical, transmission electron microscopy, and surface antigens data (CD3+, CD8+, CD11+, HLA-DR+, CD19-, CD20-) were consistent with a T-cell hairy-cell leukemia. Molecular analysis according to Southern revealed a dual rearrangement of immunoglobulin heavy-chain (JH) and T-cell receptor beta (TcR beta) chain genes. Our findings suggest that the coexistence of JH and TcR gene rearrangements, frequently detected in acute leukemia, may also be observed in hematologic malignancies derived from more differentiated cells.

The electrophoretic mobility of peripheral lymphocytes was studied in normal subjects and patients with myeloma and bronchial carcinoma. Distinct differences in anodic mobility were noted between the sub-populations in all three groups. Total lymphocyte migration was significantly slower in the two tumour groups.

Serum beta-2-microglobulin (beta 2M) has been suggested as the most powerful prognostic factor in multiple myeloma (MM). This paper investigates its ability to detect remission and relapse in individual patients. A correlation analysis was carried out between beta 2M and M component determinations, at diagnosis and monthly during follow-up in 21 consecutive MM patients with normal renal function. A statistically significant correlation was observed in 52.4% only. The lack of correlation in the remaining cases was due to low beta 2M production at diagnosis, or independent fluctuation of these 2 parameters. Serum beta 2M proved a much less reliable parameter for the detection of tumour variations than simpler M-component determination.

This case (a young man) presented a clinical picture of a hard periorbital edema, hepatosplenomegaly and a mild bilateral pulmonary fibrosis. The histopatological pattern of our case (as well as his sister affected with the same syndrome) was characterized by the presence of macrophages full of blue staining granules and bone marrow macrophagic infiltrations. In the pulmonary function tests the volumes and compliance test and diffusing capacity were normal. The enzymatic deficit of the macrophage leads to the increase storage of phosphoglicerides and phosphosphingolipids responsibles for the blue staining with Wright-Giemsa stain. Our case fit into the specific pathology of the macrophage cell in accordance with the more recent views of the autonomy of the MPS (Mononuclear Phagocytic System). The known relationship between macrophages and T and B lymphocites have prompted us to study the cellular and humoral immunological behaviour of our case. We have observed an increased IgM immunoglobulins and an increase of IgM surface membrane receptors. Our results will be illustrated and compared with the until known 70 publicated cases.