Incidence and very long- term outcomes of stent thrombosis after bare-metal or drug-eluting stent implantation: a retrospective analysis.

AIM: Stent thrombosis is a major safety issue after percutaneous coronary intervention (PCI) with stent implantation and it is associated with major early and mid-term complications. However, its long-term impact has been incompletely described. We thus aimed to appraise incidence, predictors and very long-term outlook of stent thrombosis after bare metal stent (BMS) or drug-eluting stent (DES) implantation. METHODS: We identified all patients undergoing PCI with BMS or DES at our center between July 2002 and June 2004. For the purpose of this study, we employed a composite definition of stent thrombosis including any Academic Research Consortium stent thromboses (definite, probable, or possible). We adjudicated the following clinical events: death, myocardial infarction (stent thrombosis related), repeated revascularization, and the composite of these events (i.e., major adverse cardiac events, MACE). RESULTS: A total of 1112 patients were included, 854 (76.8%) treated with BMS and 258 (23.2%) treated with DES. At a median follow-up of 61.2 (11.03) months the incidence of stent thrombosis was 20 (1.8%), with 14 (1.3%) definite, 4 (0.4%) probable, and 2 (0.1%) possible according to the American Research Consortium statement. Patients developing stent thrombosis were more likely to have more complex angiographic features at baseline (including angiographically evident thrombus, 4 [20%] vs. 73 [6.6%], P=0.02) and a saphenous vein graft as target vessel (2 [10%] vs. 28 [2.5%], P=0.04). Conversely, being treated with a BMS or a DES did not confer any significant decrease or increase in the risk of stent thrombosis, as 7 [35%] of those with stent thrombosis had received at least a DES vs. 251 [22.9%] of those without stent thrombosis, P=0.28). Early clinical outcomes (at 30 days) distinguishing those with stent thrombosis versus those without were as follows: death in four (20%) vs. 2 (0.2%, P<0.001), myocardial infarction in 1 (5%) vs. 7 (0.6%, P=0.02), revascularization in 5 (25%) vs. 43 (3.9%, P<0.001), and MACE in 8 (40%) vs. 53 (4.8%, P<0.001). After more than 60 months of clinical follow-up, outcomes were as follows: death in 7 (35%) vs. 147 (13.5%, P=0.057), myocardial infarction in 6 (30%) vs. 40 (3.6%, P<0.001), revascularization in 15 (75%) vs. 317 (29%, P<0.001), and MACE in 19 (95%) vs. 453 (41.5%, P<0.001). CONCLUSION: This long-term registry shows that stent thrombosis remains a major safety issue after PCI with stent implantation, with a significant prognostic impact. However, in the present work the risk of stent thrombosis was similar with either DES or BMS, suggesting thus that DES are not associated with any increase in long-term thrombotic risk in comparison to BMS.

Very long-term outcome of peripheral arterial disease in patients undergoing percutaneous coronary revascularization: a retrospective analysis.

AIM: Peripheral arterial disease (PAD) in patients undergoing percutaneous coronary intervention (PCI) with stent implantation is a well known risk factor leading to an increased rates of stroke, cardiovascular death and myocardial infarction. Anyway there are few data on very-long term outcome (more than 1 year follow up) of PAD after stent implantation. We thus aimed to evaluate the influence of PAD on very long-term outcome of our PCI-population. METHODS: We retrospectively identified all patients undergoing PCI with stent implantation at our center between July 2002 and June 2004, and thus eligible for at least 4 years of follow-up. For the purpose of this study, we considered a diagnosis of PAD based on clinical evaluation and/or angiographic documentation. We adjudicated the following clinical events: death, myocardial infarction, repeat revascularization, and their composite (i.e. major adverse cardiac events, MACE). RESULTS; A total of 1008 patients were included, 109 with PAD and 899 Without PAD. Those with had more often diabetes (35% vs. 25%, P=0.002), hypertension (83% vs. 68%, P=0.001) and unfavorable basal clinical condition at the start of this study: past-Percutaneous Coronary Intervention (PCI) (30% vs. 22%, P=0.005), past-Coronary Artery Bypass Graft (CABG) (24% vs. 14%, P=0.001), ejection fraction (EF) <35% (14% vs. 7%, P=0.02) and chronic renal failure (CRF) (15% vs. 6%, P=0.002). In addiction patient with PAD were more likely to have chronic total occlusion (CTO) (36% vs. 25%, p=0.02) and unprotected left main (16% vs. 8%,P=0.01). Clinical outcome at the time of follow-up (4,42 ± 1,66 years) was as follow: Revascularization (53% vs. 37%, P=0.002), Cardiac death (21% vs. 13%, P=0.04), MACE (69% vs. 49%, p<.001). Independent predictors of MACE according to our survival analysis were: PAD (HR 1.31; 95% CI 1.01-1.69), Age >75 (HR 1.23; 95% CI 1-1.51), Chronic heart failure (HR1.72; 95% CI 1.19-2.5), Unprotected left main (HR 1.48; 95% CI 1.12-1.96). CONCLUSION: This long-term registry shows that PAD remains an important clinical condition that negatively influences the outcome of patients undergoing PCI with stent implantation in a very long-term follow-up period.

Short and long term outcome of percutaneous coronary intervention with drug eluting stent and bare metal stent in patients with chronic kidney disease.

AIM: Coronary artery disease represents the most important cause of mortality and morbidity in chronic kidney disease (CKD). Despite continuous improvements in percutaneous coronary intervention (PCI), CKD is still associated with more adverse events after PCI. We performed a retrospective study to compare bare metal stents (BMS) versus drug eluting stents (DES) in CKD. METHODS: We included consecutively all patients undergoing PCI at our Centre from July 2002 to December 2005 with CKD, defined as creatinine clearance <60 mL/min. Patients who received only DES were compared to those who received only BMS. The primary end-point was the long-term rate of major adverse cardiac events (MACE, i.e. the composite of death, myocardial infarction and repeat revascularization). RESULTS: We included a total of 219 patients with CKD out of a total of 2354 patients, with 164 receiving BMS and 55 DES. After a mean follow up of 48 months, the MACE rate was significantly higher in BMS group (71% versus 38%, P<0.001). A similarly increased risk with BMS was found for death (45% versus 17%, P<0.001), whereas the rates for repeat coronary revascularization, myocardial infarction and stent thrombosis were not significantly different. Multivariable analysis showed that BMS vs.. DES implantation was not statistically significant associated with MACE, death, myocardial infarction, rePTCA or stent thrombosis. CONCLUSION: Compared with BMS, use of DES in patients with CKD is safe and effective in reducing adverse outcomes. However, differences found between groups in clinical end-point could be ascribed to selection bias and confounding factors.

Percutaneous drug-eluting stent implantation in diabetic patients: short and long term outcomes from an observational study.

AIM: The introduction of drug-eluting stents (DES) has markedly improved mid-term results of percutaneous coronary intervention (PCI) in diabetics. However, it is unclear whether the risk-benefit balance of DES in diabetics is maintained also at long-term and in insulin-requiring patients. We thus aimed to appraise long-term outcomes of diabetic patients treated with PCI with DES, stratifying according to insulin therapy. METHODS: We retrospectively collected baseline, procedural and outcome data from all patients undergoing PCI with DES from July 2002 to June 2004 at our center. We distinguished three groups: insulin-requiring diabetics, non-insulin-requiring diabetics and patients without diabetes. The primary end-point was the long-term rate of major adverse cardiac events (MACE, i.e. the composite of death, myocardial infarction, or target vessel revascularization). We also considered stent thrombosis according to the Academic Research Consortium Definition. RESULTS: We included a total of 1266 patients, with 3% of insulin-requiring diabetes, 22% with non-insulin-requiring diabetes, and 75% without diabetes. There were significant differences across groups in prevalence of male gender (respectively, 32.4%, 74.6% and 81%, P<0.001), and DES usage (54.1%, 34%, and 30.4%, P=0.007). Thirty-day MACE occurred with similar frequency in the three groups (8.1%, 7.3% and 6.3%, P=0.78), with death in 3%, 2%, and 1.4% (P=0.71) and myocardial infarction in 5.4%, 1.8% and 0.8% (P=0.02). After a median follow-up period of 58 months, MACE occurred in 59.5% of patients with insulin-requiring diabetes, in 50.6% of non-insulin-requiring diabetics and in 38.9% of non-diabetics (P<0.001). Death occurred in 24.3%, 17.5% and 8.5%, (P<0.001), myocardial infarction in 10.8%, 6.6%, and 5.1% (P=0.25), repeat revascularization in 46%, 31.6%, and 30% (P=0.11), and definite stent thrombosis in 0%, 1.1%, and 1.3% (P=0.78). CONCLUSION: Our study confirms the high risk profile of diabetic patients, especially when ischemic disease it is known. In this setting, diabetic and comorbidities fix the price not only in term of need of further revascularization, but mainly in survival decrease. It can be concluded that not only revascularization but also ­ and especially ­ comorbidities treatment plays a determinant role reducing follow-up events. Further research on additional pharmacologic treatments or hybrid revascularization strategies may mitigate the burden of morbidity and mortality.

Short and long-term outcomes of percutaneous revascularization in patients with prior coronary artery bypass graft.

AIM: Patients with prior coronary artery bypass grafting (CABG) represent a sizable portion of those undergoing percutaneous coronary intervention (PCI): in many instances, it is unclear whether performing PCI on the bypass graft or in the native coronary vessels can offer the best risk-benefit balance. METHODS: We included patients with prior CABG undergoing PCI at our center between July 2002 and June 2004 and we distinguished them in three groups. Those in whom PCI was performed on stenotic saphenous vein graft (SVG group), those in whom PCI was performed on native vessels despite the presence of potentially treatable SVG disease (optional native group), and those in whom PCI had to be performed mandatorily in the native vessels because of chronic SVG occlusions or disease in non-bypassed segments (mandatory native group). The primary end-point was long-term rate of major adverse clinical events (MACE, i.e. death, myocardial infarction, or target vessel revascularization). RESULTS: We identified 109 patients: 28 were in the SVG group, 25 in the optional native group, and 56 in the mandatory native group. Early major adverse cardiac events (MACE) occurred with similar frequency in the three groups (respectively, 9.1%, 0% and 5.7%, P=0.35). After more than three years of follow-up, MACE occurred in 39.3% vs. 28 and 39.4% (P=0.59), death occurred in 27.2 vs. 24.0% vs. 13.5% (P=0.30), and TVR in 27.3% vs. 8.0% vs. 28.8% (P=0.14). CONCLUSION: In selected patients, PCI of native coronary vessels despite the presence of apparently treatable SVG lesions can be envisioned.

Impact of multivessel coronary disease on long-term outcome after percutaneous recanalization of coronary chronic total occlusions.

AIM: Percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) is common even with concomitant multivessel disease. We aimed to investigate the impact of multivessel disease on long-term outcome after PCI for CTO. METHODS: We collected baseline, procedural and follow-up data on patients undergoing successful PCI with stenting for CTO. We divided our population into three groups: patients with 1 vessel disease (1VD), those with 2-vessel disease (2VD) and subjects with 3-vessel disease (3VD). The primary end-point was the occurrence of major adverse cardiac events (MACE), i.e. death, myocardial infarction or target vessel revascularization. RESULTS: A total of 111 patients were included: 24 (21%) in group 1VD, 28 (25%) in group 2VD, and 59 (53%) in group 3VD. Clinical follow-up was available in 109 (98%) of them after a median of 27 months (range 6-68), yielding MACE rates of 1 (4%) in group 1VD, 5 (18%) in group 2VD, and 17 (29%) in group 3VD, respectively (P=0.03). No statistically significant difference was found comparing the 3 groups for the individual rates of death, myocardial infarction or target vessel revascularization (all P>0.05). No case of definite or probable stent thrombosis was adjudicated, despite use of DES in 99 (89%) patients. CONCLUSION: Patients with diffuse coronary disease undergoing PCI for a CTO fare a significantly worse prognosis. Nonetheless, despite liberal use of DES, stent thrombosis is rare in this setting, without differences according to the initial severity of disease, thus supporting the long-term safety of DES, even if used in this "off-label" context.

Repeat adverse events long after percutaneous coronary revascularization in diabetics.

AIM: Diabetics with coronary artery disease face a high risk of adverse events following coronary revascularization. However, recurrence rates of after the first revascularization have never been appraised. The aim of this study was to evaluate recurrent events in diabetics undergoing percutaneous coronary intervention (PCI) in the current era. METHODS: Authors collected baseline and outcome data of consecutive type-2 diabetics treated with PCI (July 2002-December 2005) . End-points of interest were the long-term rates of major adverse cardiac events (MACE: cardiac death, myocardial infarction [MI], percutaneous target vessel revascularization [TVR-PCI], or coronary artery bypass grafting [CABG]), non-TVR PCI, and stent thrombosis. RESULTS: A total of 429 diabetics were included, 191 (44%) insulin-dependent, with drug-eluting stents implanted in 232 (54%). After a median of 38 months, events were as follows: MACE in 167 (38.9%) subjects, cardiac death in 38 (8.8%), MI in 42 (9.8%), TVR-PCI in 130 (30.3%), CABG in 11 (2.6%), non-TVR-PCI in 52 (12.1%), and definite stent thrombosis in 9 (2.1%). Among the 129 patients undergoing TVR-PCI as first event, as many as 28 (21.7%) underwent a second TVR-PCI, 7 (5.4%) underwent a third TVR-PCI, and a further 2 (1.5%) underwent a fourth TVR-PCI, whereas CABG was performed in 2 (1.5%) and non-TVR-PCI in 4 (3.1%). CONCLUSIONS: This work, originally reporting on the risk of recurrent repeat revascularization events among diabetics treated with PCI, showed that adverse events occur frequently in these patients, but can be managed in most cases safely and successfully by means of repeat PCI only.

Percutaneous aortic valve replacement in two cases at high surgical risk: procedural details and implications for patient selection.

The morbidity and mortality burden of heart valve disease is increasing in the developing world, especially among the elderly. Whereas surgery remains the standard of care in fit patients with degenerative aortic stenosis, percutaneous aortic valve replacement could become an effective alternative to surgery in selected higher risk patients. The authors report on two women with aortic stenosis, both at high surgical risk (an 81-year-old female with coronary artery and cerebro-vascular disease, and a 70-year-old female with end-stage cirrhosis), in whom percutaneous valve replacement was effectively performed by means of transfemoral access and retrograde CoreValve Re-valving System implantation. Two major post-procedural complications occurred, both effectively managed, in the second patient: a third degree atrio-ventricular block (requiring permanent pace-maker implantation) and bleeding from the right femoral artery access (requiring implantation of two covered stents and blood transfusion). Despite the increased baseline risk, both patients were discharged asymptomatic, the first twelve days and the other three weeks after admission. In the authors' experience percutaneous aortic valve replacement can be performed with reasonable safety in patient with severe aortic stenosis at high surgical risk.

Analysis of recurrent revascularization events following percutaneous coronary intervention of diabetic patients.

AIM: Greater incidence of recurrent events following percutaneous coronary intervention (PCI) has been described among patients with diabetes mellitus (DM). A clear actual picture of these events can hitherto be considered as lacking. Aim of this study was to describe frequency and peculiarity of recurrent cardiovascular events following PCI in a group of high risk DM patients and to compare the impact of repeat PCI and/or surgical revascularizations on the need of further coronary interventions in a long-term follow-up. METHODS: 254 consecutive DM patients undergoing PCI for known coronary artery disease (CAD) were followed by outpatient visits for 39+/-9 months. The registered endpoints were target vessel PCI (TVR PCI), target vessel surgical revascularizations (TVR CABG), non target vessel percutaneous revascularization interventions (NON TVR PCI), and no repeat revascularizations. RESULTS: 74 (35%) of the DM patients undergoing an index PCI required further revascularization and 10 (17%) patients needed more than one repeat TVR procedure. Second TVR revascularisation procedures occurred similarly following first PCI (15%) or surgical revascularisation (17%) driven by coronary lesions located in epicardial vessels treated during the index PCI. Patients undergoing TVR surgical revascularisation disclosed a higher probability of incurring in a second PCI driven by coronary lesions located in epicardial vessels not previously treated (P=0.003) compared to those approached by PCI. CONCLUSIONS: The present study reports on a seemingly superior coronary protection of PCI compared to surgical revascularization in preventing disease progression upon the native coronary arteries. These results need confirmation in larger population samples.

Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients.

Some evidences suggest that telomere restriction fragment length (TRF-L) is an effective indicator of histopathogenesis in B-cell tumors. As histopathogenesis is relevant for B-cell chronic lymphocytic leukemia (B-CLL) prognosis, TRF-L was assessed by Southern blot in 201 patients and compared to variable immunoglobulin heave chain gene mutational status (VH-MS) and to other known prognostic features. Overall survival (OS), time to first treatment (TTFT) and progression-free survival (PFS) were evaluated. Our results indicate the following: (1) TRF-L is heterogeneous among B-CLL patients (median 6014 bp, range 1465-16 762); (2) TRF-L correlates to VH-MS (r(2)=0.1994, P<0.0001) with VH-mutated patients showing long and VH-unmutated short telomeres; however, 41% of VH-unmutated and 5% of VH-mutated patients did not show this correlation and were thus defined as 'discordant'; (3) TRF-L effectively predicts outcome in terms of TTFT, PFS and OS; (4) VH-unmutated discordant patients have a better clinical outcome than VH-unmutated concordant patients (OS P<0.01, PFS P<0.05) and similar to that of VH-mutated patients (OS, PFS P=NS). Compared to VH-unmutated concordant patients, VH-unmutated discordant patients showed no peculiarity in their immunoglobulin rearrangement nor in their flow cytometry or fluorescence in situ hybridization profile. In conclusion, TRF-L can be helpful to refine prognostication of B-CLL patients, particularly those with a VH-unmutated immunoglobulin sequence.

Temporal trends in baseline characteristics and peri-procedural complications of percutaneous drug-eluting stent implantation for unprotected left main disease: a single high-volume center experience.

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.

Relevance of sample preparation for flow cytometry.

INTRODUCTION: Flow cytometry is a useful tool for diagnosis and minimal residual disease (MRD) study of hematological diseases. Standard sample preparation protocols are characterized by stain-lyse-wash (SLW). To prevent nonspecific bindings and achieve high sensitivity in MRD studies, lyse-wash-stain-wash (LWSW) is required. To our knowledge, no comparison between the two methods has been performed. METHODS: We compared mean fluorescence intensity (MFI), stain index, signal-to-noise ratio, and percentage of positive cells of 104 antibodies and of 13 selected antibodies tested in 10 samples simultaneously prepared with the two methods. RESULTS: MFI and percentages of positive cells obtained by the two methods did not show significant differences and showed a very high correlation. Stain index and signal-to-noise ratio presented higher values for kappa and lambda surface chains in LWSW samples and a trend of higher values for the other antibodies in SLW samples. CONCLUSIONS: We suggest to use LWSW method also at diagnosis to obtain more comparable antibody intensity expressions when samples from the same patient are processed for MRD evaluation after bulk lysis. Moreover, LWSW can prevent nonspecific bindings, shows no differences in the identification and quantitation of the populations of interest, and reduces acquisition of cell debris.

Extracellular vesicles as potential biomarkers of acute graft-vs-host disease.

Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk-by almost 60%-of developing GVHD, whereas CD31 and CD140-α (PECAM-1 and PDGFR-α) with a decreased risk-by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress.

Is dobutamine stress echocardiography predictive of middle and late term outcomes in mitral stenosis patients?

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.

Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis.

In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival 1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival 2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200 mg/m2 and ASCT (MEL200-ASCT) and 261 to CC+R. Median follow-up was 46 months. MEL200-ASCT significantly improved PFS1 (median: 42 vs 24 months, HR 0.53; P<0.001), PFS2 (4 years: 71 vs 54%, HR 0.53, P<0.001) and OS (4 years: 84 vs 70%, HR 0.51, P<0.001) compared with CC+R. The advantage was noticed in good and bad prognosis patients. Only 53% of patients relapsing from CC+R received ASCT at first relapse. Upfront ASCT significantly reduced the risk of death (HR 0.51; P=0.007) in comparison with salvage ASCT. In conclusion, these data confirm the role of upfront ASCT as the standard approach for all young myeloma patients.

Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.

The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.

Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20.

The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C-C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM.

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Detection of circulating tumor cells in multiple myeloma by a PCR-based method.

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal expansion of plasma cells producing monoclonal immunoglobulins. It has been regarded as a tumor typically involving only the bone marrow. The existence of circulating tumor cells has been suggested from phenotypic and genotypic studies. However, this issue is still controversial due to the limitations of the methods so far used. We describe a novel polymerase chain reaction (PCR) based method using clone-specific immunoglobulin heavy-chain gene sequences as tumor markers. From such sequences patient-specific oligonucleotide primers and probes were generated, and used to detect tumor cells. Seven MM patients were selected for this study, and tumor cells were found in all peripheral blood samples. The demonstration of circulating tumor cells suggests some caution when using peripheral blood for autograft procedures, even though its contamination is lower than bone marrow. In conclusion, we describe a specific and sensitive PCR-based method for detecting minimal disease which is of general applicability to all lymphoid malignancies transcribing rearranged immunoglobulin heavy-chain genes.

Clinical impact of immunophenotypic remission after allogeneic hematopoietic cell transplantation in multiple myeloma.

Immunophenotypic remission (IR) is a strong prognostic factor in myeloma patients. The combination of IR and conventional CR was retrospectively evaluated in 66 patients after allografting. IR was defined as the absence of monoclonal plasma cells in BM aspirates by multiparameter flow cytometry. Conditioning was non-myeloablative in 55 patients; reduced-intensity in 10 and myeloablative in 1 patient. The allograft was given upfront in 35/66 (53%) patients. After a median follow-up of 7.1 years, 24 patients achieved both CR and IR (CR/IR group), 21 achieved IR but not CR with persistence of a urine/serum M-component (no CR/IR group) and 21 did not achieve either CR or IR (no CR/no IR group). Median OS and EFS were 'not reached' and 59 months in the CR/IR group; 64 and 16 months in the no CR/IR; and 36 and 6 months in the no CR/no IR, respectively (P<0.001). Cumulative incidence of extramedullary disease was 4.4% in the CR/IR, 38.1% in the no CR/IR and 14.3% in the no CR/no IR groups, respectively, at 4 years (P<0.001). IR was a valid tool to monitor residual disease after allografting, and allowed definition of a cohort of patients at higher incidence of extramedullary relapse.