Angeles Leon - Academia.edu (original) (raw)

Papers by Angeles Leon

British Journal of Haematology, 2003

The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloab... more The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloablative allogeneic transplant (NMT) was evaluated. Eventfree survival (EFS) at 24 months was 33%, being significantly higher for patients who developed chronic graft-versus-host disease (cGVHD) when compared with those who did not [51% vs 0% respectively, P ¼ 0AE02; hazard rate ¼ 3AE16 (95% confidence interval ¼ 1AE09-9AE15, P ¼ 0AE03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43% vs 0% respectively, P ¼ 0AE02). Overall survival (OS) at 24 months was 60% [72% vs 42% for patients who did and did not develop cGVHD respectively (P ¼ 0AE1); 63% vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P ¼ 0AE013)]. At a median follow-up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant-related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P ¼ 0AE04). The present study suggests that graft-versus-myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.

Bone Marrow Transplantation, 1997

Bone Marrow Transplantation, 1998

British Journal of Haematology, 2000

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT)... more High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m 2 melphalan (MEL200), 127 patients with 140 mg/m 2 melphalan plus total body irradiation (MEL140 1 TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m 2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P 0´003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26±68] compared with 43% (CI 31±54) for MEL140 1 TBI and 37% (CI: 18±56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 1 TBI groups respectively. These differences were non-significant (P 0´2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 1 TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P 0´01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.

British Journal of Haematology, 2000

We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treate... more We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, . 90% reduction in M-component) or PR2 (50±90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17±53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57±86, median not reached) compared with any other response group (univariate comparison P , 0´00000 to P 0´004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P 0´6; median survival 56, 44 and 42 months respectively, P 0´5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a threecategory classification: (i) CR1 (ii) CR2 1 PR1 1 PR2, and (iii) non-response (EFS P , 0´00000; OS P , 0´00000; both Cox models P , 0´00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.

Hematology Journal, 2000

Introduction: Renal function is one of the most important prognostic factors in multiple myeloma ... more Introduction: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insuciency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. Materials and methods: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were de®ned: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. Results and conclusion: Patients from groups BA and BB presented with a signi®cantly higher number of adverse prognostic factors, re¯ecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insuciency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was signi®cantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent in¯uence on TRM: poor performance status (ECOG 3), hemoglobin 59.5 g/dl and serum creatinine 55 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine 52 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically signi®cant dierence favoring group AA (P50.01). PFS did not dier signi®cantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high b 2 -microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insuciency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (45 mg/dl).

British Journal of Haematology, 2003

The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloab... more The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloablative allogeneic transplant (NMT) was evaluated. Eventfree survival (EFS) at 24 months was 33%, being significantly higher for patients who developed chronic graft-versus-host disease (cGVHD) when compared with those who did not [51% vs 0% respectively, P ¼ 0AE02; hazard rate ¼ 3AE16 (95% confidence interval ¼ 1AE09-9AE15, P ¼ 0AE03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43% vs 0% respectively, P ¼ 0AE02). Overall survival (OS) at 24 months was 60% [72% vs 42% for patients who did and did not develop cGVHD respectively (P ¼ 0AE1); 63% vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P ¼ 0AE013)]. At a median follow-up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant-related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P ¼ 0AE04). The present study suggests that graft-versus-myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.

Bone Marrow Transplantation, 1997

Bone Marrow Transplantation, 1998

British Journal of Haematology, 2000

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT)... more High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m 2 melphalan (MEL200), 127 patients with 140 mg/m 2 melphalan plus total body irradiation (MEL140 1 TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m 2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P 0´003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26±68] compared with 43% (CI 31±54) for MEL140 1 TBI and 37% (CI: 18±56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 1 TBI groups respectively. These differences were non-significant (P 0´2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 1 TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P 0´01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.

British Journal of Haematology, 2000

We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treate... more We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, . 90% reduction in M-component) or PR2 (50±90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17±53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57±86, median not reached) compared with any other response group (univariate comparison P , 0´00000 to P 0´004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P 0´6; median survival 56, 44 and 42 months respectively, P 0´5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a threecategory classification: (i) CR1 (ii) CR2 1 PR1 1 PR2, and (iii) non-response (EFS P , 0´00000; OS P , 0´00000; both Cox models P , 0´00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.

Hematology Journal, 2000

Introduction: Renal function is one of the most important prognostic factors in multiple myeloma ... more Introduction: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insuciency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. Materials and methods: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were de®ned: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. Results and conclusion: Patients from groups BA and BB presented with a signi®cantly higher number of adverse prognostic factors, re¯ecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insuciency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was signi®cantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent in¯uence on TRM: poor performance status (ECOG 3), hemoglobin 59.5 g/dl and serum creatinine 55 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine 52 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically signi®cant dierence favoring group AA (P50.01). PFS did not dier signi®cantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high b 2 -microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insuciency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (45 mg/dl).

Pace-pacing and Clinical Electrophysiology, 2002

BAKER, C.M., et al.: Addition of a Left Ventricular Lead to Conventional Pacing Systems in Patien... more BAKER, C.M., et al.: Addition of a Left Ventricular Lead to Conventional Pacing Systems in Patients with Congestive Heart Failure: Feasibility, Safety, and Early Results in 60 Consecutive Patients. Left bundle branch block worsens congestive heart failure (CHF) in patients with LV dysfunction. Asynchronous LV activation produced by RV apical pacing leads to paradoxical septal motion and inefficient ventricular contraction. Recent studies show improvement in LV function and patient symptoms with biventricular pacing in patients with CHF. The aim of this study was to determine the feasibility, safety, acute efficacy, and early effect on symptoms of the upgrade of a chronically implanted RV pacing system to a biventricular system. Sixty patients with NYHA Class III and IV underwent the upgrade procedure using commercially available leads and adapters. The procedure succeeded in 54 (90%) of 60 patients. Acute LV stimulation thresholds obtained from leads placed along the lateral LV wall via the coronary sinus compare favorably to those reported in current biventricular pacing trials. The complication rate was low (5/60, 8.3%): lead dislodgement (n = 1), pocket hematoma (n = 1), and wound infections (n = 3). During 18 months of follow-up (16.7%) of 60 patients died. Two patients that died failed the initial upgrade attempt. At 3-month follow-up, quality of life scores improved 31 ± 28 points (n = 29), P < 0.0001). NYHA Class improved from 3.4 ± 0.5 to 2.4 ± 0.7 (P = < 0.0001) and ejection fraction increased from 0.23 ± 0.8 to 0.29 ± 0.11 (P = 0.0003). Modification of RV pacing to a biventricular system using commercially available leads and adapters can be performed effectively and safely. The early results of this study suggest patients may benefit from this procedure with improved functional status and quality of life.

Pace-pacing and Clinical Electrophysiology, 2006

Background: Pacemakers and implanted cardioverter defibrillator (ICD) infection rates are rising.... more Background: Pacemakers and implanted cardioverter defibrillator (ICD) infection rates are rising. Renal insufficiency impairs immune function and is known to increase the risk of infection following implantation of orthopedic hardware. The purpose of the current study is to characterize the risk factors for pacemaker and ICD infection and to evaluate the role of renal insufficiency in this complication.Methods and Results: A large (n = 4,856) single center experience with pacemaker and ICD procedures was reviewed. Of these, 141 were extractions of infected devices and 76 of these patients had been implanted in the Emory system and had preimplant creatinine information available for analysis. These cases were compared to 76 control patients undergoing device implantation matched by date of implant who had no infective complications. Demographic and clinical data from both groups were compared using both univariate and multivariate analysis. The overall rate of infection was 1.5%. Patients with device infection were more likely to have congestive heart failure (CHF), be diabetic, have generator exchanges, and to take warfarin than controls. There was no difference in the prevalence of coronary disease, atrial fibrillation, steroid use, or malignancy between the two groups. Elevated creatinine (Cr ≥1.5 mg/dL) was much more frequent in patients with infection than in controls (38% vs 12%, odds ratio 4.6, P < 0.001). Moderate to severe renal disease (GFR ≤60 cc/min/1.73 m2) was the most potent risk factor for infection, with a prevalence of 42% in infected patients versus 13% in controls (odds ratio of 4.8).Conclusions: Renal insufficiency dramatically increases the risk of infection complicating pacemaker or ICD surgery. This association should be part of the risk-benefit consideration prior to device implantation. Additional study of more extensive perioperative antibiotic therapy in this subset of patients is warranted.

Background. Catheter ablation of accessory atrioventricular (AV) connections using radiofrequency... more Background. Catheter ablation of accessory atrioventricular (AV) connections using radiofrequency current has been demonstrated to be effective in the majority of patients with the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardia involving a concealed accessory AV connection. However, electrogram criteria have not been established to guide attempts at radiofrequency catheter ablation.

Pace-pacing and Clinical Electrophysiology, 1992

CALKINS, H. et al.: Effect of the Atrioventricular Relationship on Atrial Refractoriness in Human... more CALKINS, H. et al.: Effect of the Atrioventricular Relationship on Atrial Refractoriness in Humans. Atrial arrhythmias occur frequently in the setting of increased atrial size and pressure. This may result from contraction-excitation feedback. The objective of this study was to investigate the effect of alterations in atrial pressure, induced by varying the atrioventricular (AV) interval, on atrial refractoriness, and on the frequency of induction of atrial fibrillation. Twenty-seven patients without structural heart disease participated in the study. In each patient the atrial effective (ERP) and absolute refractory period (ARP) were measured during AV pacing at a cycle length of 400 msec and AV intervals of 0, 120, and 160 msec. The ERP was defined as the longest extrastimulus coupling interval that failed to capture with an extrastimulus current strength of twice the stimulation threshold. The ARP was defined in a similar manner with an extrastimulus current strength of 10 mA. The ERP and ARP were determined during continuous pacing using the incremental extrastimulus technique. A subset of patients had the pacing protocol performed during autonomic blockade. As the AV interval was increased from 0 to 160 msec, the peak right atrial pressure decreased from 16 ± 4 mmHg to 7 ± 3 mmHg and the mean right atrial pressure decreased from 7 ± 3 mmHg to 3 ± 22 mmHg (P < 0.001). The atrial ERP and ARP did not change with alterations in the AV interval. There was no difference in the frequency of induction of atrial fibrillation. Similar results were obtained during autonomic blockade. These findings suggests that the phenomenon of contraction-excitation feedback may not be of importance in the development of atrial arrhythmias in patients without structural heart disease.

Background-Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment... more Background-Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment for patients with moderate to severe systolic heart failure and ventricular dyssynchrony. The purpose of the present study was to determine whether improvements in left ventricular (LV) size and function were associated with CRT. Methods and Results-Doppler echocardiograms were obtained at baseline and at 3 and 6 months after therapy in 323 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Of these, 172 patients were randomized to CRT on and 151 patients to CRT off. Measurements were made of LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E-wave) and late (A-wave) diastolic filling, and the myocardial performance index. At 6 months, CRT was associated with reduced end-diastolic and end-systolic volumes (both PϽ0.001), reduced LV mass (PϽ0.01), increased ejection fraction (PϽ0.001), reduced MR (PϽ0.001), and improved myocardial performance index (PϽ0.001) compared with control. ␤-Blocker treatment status did not influence the effect of CRT. Improvements with CRT were greater in patients with a nonischemic versus ischemic cause of heart failure. Conclusions-CRT in patients with moderate-to-severe heart failure who were treated with optimal medical therapy is associated with reverse LV remodeling, improved systolic and diastolic function, and decreased MR. LV remodeling likely contributes to the symptomatic benefits of CRT and may herald improved longer-term survival. (Circulation. 2003;107:qqq-qqq.)

Background-Data from single-center studies suggest that echocardiographic parameters of mechanica... more Background-Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response. Methods and Results-Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction Յ35%, QRS Ն130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler-based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and Ն15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas left ventricular end-systolic volume decreased Ն15% in 56% of 286 patients with paired data. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was Յ0.62. There was large variability in the analysis of the dyssynchrony parameters. Conclusion-Given the modest sensitivity and specificity in this multicenter setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Efforts aimed at reducing variability arising from technical and interpretative factors may improve the predictive power of these echocardiographic parameters in a broad clinical setting. (J.M.). The online Data Supplement, which consists of an Appendix, can be found with this article at http://circ.ahajournals.org/cgi/content/full/ CIRCULATIONAHA.107.743120/DC1.

British Journal of Haematology, 2003

The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloab... more The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloablative allogeneic transplant (NMT) was evaluated. Eventfree survival (EFS) at 24 months was 33%, being significantly higher for patients who developed chronic graft-versus-host disease (cGVHD) when compared with those who did not [51% vs 0% respectively, P ¼ 0AE02; hazard rate ¼ 3AE16 (95% confidence interval ¼ 1AE09-9AE15, P ¼ 0AE03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43% vs 0% respectively, P ¼ 0AE02). Overall survival (OS) at 24 months was 60% [72% vs 42% for patients who did and did not develop cGVHD respectively (P ¼ 0AE1); 63% vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P ¼ 0AE013)]. At a median follow-up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant-related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P ¼ 0AE04). The present study suggests that graft-versus-myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.

Bone Marrow Transplantation, 1997

Bone Marrow Transplantation, 1998

British Journal of Haematology, 2000

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT)... more High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m 2 melphalan (MEL200), 127 patients with 140 mg/m 2 melphalan plus total body irradiation (MEL140 1 TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m 2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P 0´003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26±68] compared with 43% (CI 31±54) for MEL140 1 TBI and 37% (CI: 18±56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 1 TBI groups respectively. These differences were non-significant (P 0´2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 1 TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P 0´01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.

British Journal of Haematology, 2000

We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treate... more We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, . 90% reduction in M-component) or PR2 (50±90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17±53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57±86, median not reached) compared with any other response group (univariate comparison P , 0´00000 to P 0´004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P 0´6; median survival 56, 44 and 42 months respectively, P 0´5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a threecategory classification: (i) CR1 (ii) CR2 1 PR1 1 PR2, and (iii) non-response (EFS P , 0´00000; OS P , 0´00000; both Cox models P , 0´00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.

Hematology Journal, 2000

Introduction: Renal function is one of the most important prognostic factors in multiple myeloma ... more Introduction: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insuciency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. Materials and methods: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were de®ned: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. Results and conclusion: Patients from groups BA and BB presented with a signi®cantly higher number of adverse prognostic factors, re¯ecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insuciency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was signi®cantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent in¯uence on TRM: poor performance status (ECOG 3), hemoglobin 59.5 g/dl and serum creatinine 55 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine 52 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically signi®cant dierence favoring group AA (P50.01). PFS did not dier signi®cantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high b 2 -microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insuciency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (45 mg/dl).

British Journal of Haematology, 2003

The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloab... more The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloablative allogeneic transplant (NMT) was evaluated. Eventfree survival (EFS) at 24 months was 33%, being significantly higher for patients who developed chronic graft-versus-host disease (cGVHD) when compared with those who did not [51% vs 0% respectively, P ¼ 0AE02; hazard rate ¼ 3AE16 (95% confidence interval ¼ 1AE09-9AE15, P ¼ 0AE03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43% vs 0% respectively, P ¼ 0AE02). Overall survival (OS) at 24 months was 60% [72% vs 42% for patients who did and did not develop cGVHD respectively (P ¼ 0AE1); 63% vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P ¼ 0AE013)]. At a median follow-up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant-related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P ¼ 0AE04). The present study suggests that graft-versus-myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.

Bone Marrow Transplantation, 1997

Bone Marrow Transplantation, 1998

British Journal of Haematology, 2000

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT)... more High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m 2 melphalan (MEL200), 127 patients with 140 mg/m 2 melphalan plus total body irradiation (MEL140 1 TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m 2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P 0´003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26±68] compared with 43% (CI 31±54) for MEL140 1 TBI and 37% (CI: 18±56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 1 TBI groups respectively. These differences were non-significant (P 0´2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 1 TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P 0´01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.

British Journal of Haematology, 2000

We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treate... more We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, . 90% reduction in M-component) or PR2 (50±90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17±53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57±86, median not reached) compared with any other response group (univariate comparison P , 0´00000 to P 0´004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P 0´6; median survival 56, 44 and 42 months respectively, P 0´5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a threecategory classification: (i) CR1 (ii) CR2 1 PR1 1 PR2, and (iii) non-response (EFS P , 0´00000; OS P , 0´00000; both Cox models P , 0´00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.

Hematology Journal, 2000

Introduction: Renal function is one of the most important prognostic factors in multiple myeloma ... more Introduction: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insuciency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. Materials and methods: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were de®ned: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. Results and conclusion: Patients from groups BA and BB presented with a signi®cantly higher number of adverse prognostic factors, re¯ecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insuciency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was signi®cantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent in¯uence on TRM: poor performance status (ECOG 3), hemoglobin 59.5 g/dl and serum creatinine 55 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine 52 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically signi®cant dierence favoring group AA (P50.01). PFS did not dier signi®cantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high b 2 -microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insuciency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (45 mg/dl).

Pace-pacing and Clinical Electrophysiology, 2002

BAKER, C.M., et al.: Addition of a Left Ventricular Lead to Conventional Pacing Systems in Patien... more BAKER, C.M., et al.: Addition of a Left Ventricular Lead to Conventional Pacing Systems in Patients with Congestive Heart Failure: Feasibility, Safety, and Early Results in 60 Consecutive Patients. Left bundle branch block worsens congestive heart failure (CHF) in patients with LV dysfunction. Asynchronous LV activation produced by RV apical pacing leads to paradoxical septal motion and inefficient ventricular contraction. Recent studies show improvement in LV function and patient symptoms with biventricular pacing in patients with CHF. The aim of this study was to determine the feasibility, safety, acute efficacy, and early effect on symptoms of the upgrade of a chronically implanted RV pacing system to a biventricular system. Sixty patients with NYHA Class III and IV underwent the upgrade procedure using commercially available leads and adapters. The procedure succeeded in 54 (90%) of 60 patients. Acute LV stimulation thresholds obtained from leads placed along the lateral LV wall via the coronary sinus compare favorably to those reported in current biventricular pacing trials. The complication rate was low (5/60, 8.3%): lead dislodgement (n = 1), pocket hematoma (n = 1), and wound infections (n = 3). During 18 months of follow-up (16.7%) of 60 patients died. Two patients that died failed the initial upgrade attempt. At 3-month follow-up, quality of life scores improved 31 ± 28 points (n = 29), P < 0.0001). NYHA Class improved from 3.4 ± 0.5 to 2.4 ± 0.7 (P = < 0.0001) and ejection fraction increased from 0.23 ± 0.8 to 0.29 ± 0.11 (P = 0.0003). Modification of RV pacing to a biventricular system using commercially available leads and adapters can be performed effectively and safely. The early results of this study suggest patients may benefit from this procedure with improved functional status and quality of life.

Pace-pacing and Clinical Electrophysiology, 2006

Background: Pacemakers and implanted cardioverter defibrillator (ICD) infection rates are rising.... more Background: Pacemakers and implanted cardioverter defibrillator (ICD) infection rates are rising. Renal insufficiency impairs immune function and is known to increase the risk of infection following implantation of orthopedic hardware. The purpose of the current study is to characterize the risk factors for pacemaker and ICD infection and to evaluate the role of renal insufficiency in this complication.Methods and Results: A large (n = 4,856) single center experience with pacemaker and ICD procedures was reviewed. Of these, 141 were extractions of infected devices and 76 of these patients had been implanted in the Emory system and had preimplant creatinine information available for analysis. These cases were compared to 76 control patients undergoing device implantation matched by date of implant who had no infective complications. Demographic and clinical data from both groups were compared using both univariate and multivariate analysis. The overall rate of infection was 1.5%. Patients with device infection were more likely to have congestive heart failure (CHF), be diabetic, have generator exchanges, and to take warfarin than controls. There was no difference in the prevalence of coronary disease, atrial fibrillation, steroid use, or malignancy between the two groups. Elevated creatinine (Cr ≥1.5 mg/dL) was much more frequent in patients with infection than in controls (38% vs 12%, odds ratio 4.6, P < 0.001). Moderate to severe renal disease (GFR ≤60 cc/min/1.73 m2) was the most potent risk factor for infection, with a prevalence of 42% in infected patients versus 13% in controls (odds ratio of 4.8).Conclusions: Renal insufficiency dramatically increases the risk of infection complicating pacemaker or ICD surgery. This association should be part of the risk-benefit consideration prior to device implantation. Additional study of more extensive perioperative antibiotic therapy in this subset of patients is warranted.

Background. Catheter ablation of accessory atrioventricular (AV) connections using radiofrequency... more Background. Catheter ablation of accessory atrioventricular (AV) connections using radiofrequency current has been demonstrated to be effective in the majority of patients with the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardia involving a concealed accessory AV connection. However, electrogram criteria have not been established to guide attempts at radiofrequency catheter ablation.

Pace-pacing and Clinical Electrophysiology, 1992

CALKINS, H. et al.: Effect of the Atrioventricular Relationship on Atrial Refractoriness in Human... more CALKINS, H. et al.: Effect of the Atrioventricular Relationship on Atrial Refractoriness in Humans. Atrial arrhythmias occur frequently in the setting of increased atrial size and pressure. This may result from contraction-excitation feedback. The objective of this study was to investigate the effect of alterations in atrial pressure, induced by varying the atrioventricular (AV) interval, on atrial refractoriness, and on the frequency of induction of atrial fibrillation. Twenty-seven patients without structural heart disease participated in the study. In each patient the atrial effective (ERP) and absolute refractory period (ARP) were measured during AV pacing at a cycle length of 400 msec and AV intervals of 0, 120, and 160 msec. The ERP was defined as the longest extrastimulus coupling interval that failed to capture with an extrastimulus current strength of twice the stimulation threshold. The ARP was defined in a similar manner with an extrastimulus current strength of 10 mA. The ERP and ARP were determined during continuous pacing using the incremental extrastimulus technique. A subset of patients had the pacing protocol performed during autonomic blockade. As the AV interval was increased from 0 to 160 msec, the peak right atrial pressure decreased from 16 ± 4 mmHg to 7 ± 3 mmHg and the mean right atrial pressure decreased from 7 ± 3 mmHg to 3 ± 22 mmHg (P < 0.001). The atrial ERP and ARP did not change with alterations in the AV interval. There was no difference in the frequency of induction of atrial fibrillation. Similar results were obtained during autonomic blockade. These findings suggests that the phenomenon of contraction-excitation feedback may not be of importance in the development of atrial arrhythmias in patients without structural heart disease.

Background-Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment... more Background-Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment for patients with moderate to severe systolic heart failure and ventricular dyssynchrony. The purpose of the present study was to determine whether improvements in left ventricular (LV) size and function were associated with CRT. Methods and Results-Doppler echocardiograms were obtained at baseline and at 3 and 6 months after therapy in 323 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Of these, 172 patients were randomized to CRT on and 151 patients to CRT off. Measurements were made of LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E-wave) and late (A-wave) diastolic filling, and the myocardial performance index. At 6 months, CRT was associated with reduced end-diastolic and end-systolic volumes (both PϽ0.001), reduced LV mass (PϽ0.01), increased ejection fraction (PϽ0.001), reduced MR (PϽ0.001), and improved myocardial performance index (PϽ0.001) compared with control. ␤-Blocker treatment status did not influence the effect of CRT. Improvements with CRT were greater in patients with a nonischemic versus ischemic cause of heart failure. Conclusions-CRT in patients with moderate-to-severe heart failure who were treated with optimal medical therapy is associated with reverse LV remodeling, improved systolic and diastolic function, and decreased MR. LV remodeling likely contributes to the symptomatic benefits of CRT and may herald improved longer-term survival. (Circulation. 2003;107:qqq-qqq.)

Background-Data from single-center studies suggest that echocardiographic parameters of mechanica... more Background-Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response. Methods and Results-Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction Յ35%, QRS Ն130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler-based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and Ն15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas left ventricular end-systolic volume decreased Ն15% in 56% of 286 patients with paired data. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was Յ0.62. There was large variability in the analysis of the dyssynchrony parameters. Conclusion-Given the modest sensitivity and specificity in this multicenter setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Efforts aimed at reducing variability arising from technical and interpretative factors may improve the predictive power of these echocardiographic parameters in a broad clinical setting. (J.M.). The online Data Supplement, which consists of an Appendix, can be found with this article at http://circ.ahajournals.org/cgi/content/full/ CIRCULATIONAHA.107.743120/DC1.