Remote ischaemic preconditioning in coronary artery bypass surgery: a meta-analysis

Aim Randomised trials exploring remote ischaemic preconditioning (RIPC) in patients undergoing coronary artery bypass graft (CABG) surgery have yielded conflicting data regarding potential cardiovascular and renal protection, and are individually flawed by small sample size. Methods Three investigators independently searched the MEDLINE, EMBASE and Cochrane databases to identify randomised trials testing RIPC in patients undergoing CABG. Results Nine studies with 704 patients were included. Standardised mean difference of troponin I and T release showed a significant decrease ( 120.36 (95% CI 120.62 to 120.09)). This difference held true after excluding the trials with cross-clamp fibrillation, the study with off-pump CABG and studies using a flurane as anaesthetic agent ( 120.41 (95% CI 120.69 to 120.12), 120.38 (95% CI 120.70 to 120.07) and 120.37 (95% CI 120.63 to 120.12), respectively). A similar trend was also obtained for patients with multivessel disease ( 120.41 (95% CI 120.73 to 120.08)). The trials evaluating postoperative creatinine reported a non-significant reduction (0.02 (95% CI 120.09 to 0.13)). Moreover, the length of in-hospital stay was not influenced by the kind of treatment (weighted mean difference 0.27 (95% CI 120.24 to 0.79)). Conclusion RIPC reduced the release of troponin in patients undergoing CABG. Larger randomised trials are needed to clarify the presence of a causal relationship between RIPC-induced troponin release and clinical adverse events

Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis

We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p = 0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments

Dual rearrangement of immunoglobulin and T-cell receptor gene in a case of T-cell hairy-cell leukemia

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

Circulating progenitors following high-dose sequential (HDS) chemotherapy with G-CSF: short intervals between drug courses severely impair progenitor mobilization

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

Qualitative and quantitative polymerase chain reaction detection of the residual myeloma cell contamination after positive selection of CD34+ cells with small- and large-scale Miltenyi cell sorting system

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

Multiple myeloma: reduced plasma cell contamination in peripheral blood progenitor cell collections performed after repeated high-dose chemotherapy courses

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

Discontinuation of Dual Antiplatelet Therapy Over 12 Months after Acute Coronary Syndromes Increases Risk for Adverse Events in Patients Treated with Percutaneous Coronary Intervention: Systematic Review and Meta-Analysis.

Introduction Duration of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) hospitalization remains to be defined, both for patients treated medically and for those undergoing percutaneous transluminal coronary angioplasty (PTCA). Methods PubMed, Cochrane, and Google Scholar were systematically searched for studies including patients presenting with ACS, and treated either with DAPT longer than or shorter than 12 months. Multivariable-adjusted risk estimates for death and recurrent ACS with stopping DAPT after 12 months (odds ratios [OR] 95% confidence intervals [CI]) were pooled after logarithmic transformation according to random-effect models with inverse-variance weighting. Results Five studies with 49,586 patients were included. Median age was 66 (64-67) years, with 67% (65-75) males. Myocardial infarction (MI) represented the admission diagnosis for 88% (60-100) of the patients, and 66% (50-74) were treated with stenting. After a follow-up of 2.1 years (1.5-2.7), 40% (35-46) still on DAPT after 12 months and the rates of death or recurrent ACS were 16.6 (14.5-17.0). Risk of adverse events for patients stopping DAPT after 1 year was significantly increased (OR = 1.19 [1.07-1.32]) for those receiving stents, but not for patients managed medically (OR = 1.13 [0.95-1.35]). The increased risk did not vary according to age, gender, myocardial infarction as admission diagnosis, and kind of stent. Conclusions Interruption of DAPT over 12 months after ACS increases the risk of adverse events for patients treated with PTCA, but not for those managed conservatively, independently from baseline features and admission diagnosis. This hypothesis-generating finding should be tested in randomized controlled trials

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

Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients

Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalanprednisone alone (n = 332), melphalan-prednisone- thalidomide (n = 332), melphalan-prednisone-bortezomib (n = 257), or melphalan-prednisone-bortezomib-thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS andOSwere 67% and 27% (hazard ratio = 0.16; P < .001), and 91% and 70% (hazard ratio = 0.15; P < .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.gov as #NCT00232934, #ISRCTN 90692740, and #NCT01063179. (Blood. 2011; 117(11): 3025-3031

Inaccuracy of available surgical risk scores to predict outcomes after transcatheter aortic valve replacement.

INTRODUCTION: Despite encouraging short-term and mid-term results, transcatheter aortic valve implantation (TAVI) interventions are still burdened from high rates of adverse events, stressing the need for accurate predictive risk instruments. We compared available surgical risk scores to describe unfavorable outcomes after TAVI. METHODS: The Age, Creatinine, and Ejection fraction (ACEF) score, the logistic Euroscore, and the Society of Thoracic Surgeons Mortality score (STS) were appraised for their independent power of prediction and for their accuracy (C-index) to predict 30-day and medium-term mortality, according to the Valve Academic Research Consortium. RESULTS: Nine hundred and sixty-two patients were included. All the scores demonstrated a moderate positive correlation. The closest correlation was observed between the STS score and Euroscore. After logistic regression analysis, STS score and Logistic Euroscore provided independent prediction for short-term all-cause mortality [P = 0.02, odds ratio (OR) 1.1; 95% confidence interval (CI) 1.06-1.31 and P = 0.027, OR 1.03; 95% CI 1.01-1.405]. For in-hospital complications, only STS score performed significantly (P = 0.005, OR 1.05; 95% CI 1.01-1.06). ACEF, Euroscore, and STS score showed low accuracy for 30-day all-cause mortality (area under the curve 0.6, 0.44-0.75; vs. 0.53, 0.42-0.61; vs. 0.62, 0.52-0.71, respectively), whereas STS score performed better for in-hospital complications (0.59, 0.55-0.64). Moreover, after Cox-multivariate adjustments, only ACEF score was near to significance to predict all-cause mortality at mid-term (OR 1.7; 0.8-2.9; P = 0.058), showing the highest accuracy (0.63, 0.55-0.71). CONCLUSION: In TAVI patients, ACEF score, STS score and Logistic Euroscore provided only a moderate correlation and a low accuracy both for 30-day and medium-term outcomes. Dedicated scores are needed to properly tailor time and kind of approach