Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. Cumulative meta-analysis of therapeutic trials for myocardial infarction. A randomized trial of high dose polyvalent intravenous immunoglobulin (HDIgG) vs. Cytomegalovirus (CMV) hyperimmune IgG in allogeneic hemopoietic stem cell transplants (HSCT). Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a randomised, multicentre trial. The quality of reporting of randomized controlled trials in solid organ transplantation. CONSORT adoption and quality of reporting of randomized controlled trials: a systematic analysis in two dermatology journals. Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following liver transplantation. Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients.
We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM).
                A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B).
                As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70).
                In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation. The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction.
                We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction.
                An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratios, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction.
                Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy. The role of high dose intravenous IgG (HDIgG) and of hyperimmune CMV IgG (CMV-IgG) in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT) is still unclear. The aim of this study was to compare prophylactic CMV-IgG with HDIgGin a randomized prospective trial in allogeneic HSCT recipients: primary end point of the study was the occurrence of post-transplant CMV antigenemia (CMVAg-emia). Secondary end-points were severity of acute and chronic graft-versus-host disease (GvHD), infections and transplant related mortality (TRM).
                Patients were randomized to receive 100 mg/kg/week of CMV-IgG (group A; n = 64) or 400 mg/kg/week of HDIgG (group B; n = 64) from day -7 to day +100. The two groups were comparable for age, diagnosis, disease status, and acute graft-versus host (aGvHD) prophylaxis.
                The actuarial risk at 1 year of CMV antigenemia was lower for CMV-IgG (61% vs. 71%) but not significantly (p = 0.37); CMVAg-emia occurred at the same interval from HSCT (47 vs. 48 days, p = 0.9), with a comparable number of CMVAg positive cells (3 vs. 3 p = 0.9). Eight patients died of interstitial pneumonia (IP) (4 in each group), two in group A of CMV-IP. Acute GvHD was scored as O-I, II and III-IV in 39 vs. 35, 23 vs. 22 and 2 vs. 7 patients respectively for the two groups (p = not significant). The actuarial risk of developing acute GvHD grade II-IV was lower for CMV-IgG (39% vs. 45%) but not significantly (p = 0.43). Chronic GvHD scored as absent in 7 vs. 10 patients, limited in 39 vs. 37 and extensive in 19 vs. 17 patients respectively (p = not significant). Numbered days with intravenous antibiotics, days in hospital, days of fever, number of local and disseminated infections, number of patients with fever of unknown origin were not significantly different. Actuarial 1 year TRM is 18% vs. 19%, respectively (p = 0.9).
                This study confirms that CMV antigenemia is comparable in recipients of hyperimmune CMV-IgG and of polyvalent HDIgG, although the former had a 32% lower cost. It also shows that the potential immunomodulating effect on acute GvHD and transplant mortality is similar with 100 or 400 mg of IgG/kg/week: this is relevant, in view of the high cost of prophylactic HDIgG. Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (</>/= 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v 10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P = .9), evolution to aGvHD grade III-IV 17% versus 20% (P = . 6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy. We report on 232 patients undergoing autologous haematopoietic stem cell transplantation (ASCT) entered into a multicentre, randomised trial comparing the efficacy and tolerability of meropenem (MPM) with that of piperacillin/tazobactam (P/T) as empirical antimicrobial first-line therapy for febrile neutropenia. In 27.6% of patients in the MPM group and 22.4% in the P/T group, therapy was initially supplemented with a glycopeptide for venous catheter infection or bacteraemia because of coagulase-negative staphylococci. Complete response rate after 72 h was 63.8% in the MPM group and 49.6% in the P/T group (P = 0.034). Overall complete response rate after treatment modification was 94.0% in the MPM group and 93.1% in the P/T group. Median time to defervescence was 2 d in the MPM group and 3 d in the P/T group. The most frequently isolated pathogens were Gram-positive cocci. Treatment was well tolerated in both groups. One patient (0.4%) died from infection. Empirical first-line therapy with MPM as well as with P/T is safe and effective in febrile episodes emerging after ASCT. Higher response rates to primary treatment can be achieved with MPM. Randomized controlled trials (RCTs) of interventions provide the highest level of evidence about efficacy but their value either alone or within a meta-analysis is dependent on its methodological quality. For this reason recent RCTs in organ transplantation were assessed for quality. RCTs published between 2004 and 2006 (n = 332) were assessed, after excluding duplicate and nonEnglish reports. Quality was evaluated using the Jadad score plus allocation concealment and intention to treat analysis. We noted journal type, journal author instructions, funding source, sample size and number and location of study centres. Around one-third of RCTs had a Jadad score of 3 or greater (indication of a methodologically good quality trial) and the other two parameters were satisfied in just over one third. Although the majority of trials were published in speciality journals the quality of those published in general journals was superior. Commercially sponsored trials were of better quality as were multicentre trials in contrast to single centre trials. Overall quality of reporting of RCTs in organ transplantation is poor and as RCTs provide the highest level of evidence in evaluations of interventions there needs to be a concerted effort within the transplant community to improve the standards of RCTs. CONSORT (Consolidated Standards for Reporting Trials) guidelines were constructed to ensure optimal reporting quality of randomized controlled trials (RCTs).
                To determine the effect of the adoption of CONSORT on the reporting quality of RCTs, we performed a systematic evaluation of RCTs published in two dermatology journals pre- and post-CONSORT adoption.
                The journals selected for the study were the Journal of the American Academy of Dermatology and the British Journal of Dermatology. We selected RCTs published in 1997 and 2006 using both Medline and hand searching. The following critical CONSORT criteria were recorded: sample size, type of disease studied, type of control, single-centre or multicentre study, type of funding, blinding, methods and type of randomization, definition of a primary endpoint, justification for sample size selection and power calculation, population for analysis, and adequacy of group comparison. A multivariable analysis was conducted to determine factors associated with optimal reporting quality.
                In total, 98 studies were included. Improvement in reporting quality was evident for the specification of the randomization method (20% in 1997 vs. 45% in 2006, P < 0.01) and for the justification of sample size (22% in 1997 vs. 43% in 2006, P = 0.027). The percentage of studies with optimal reporting quality increased from 11% in 1997 to 28% in 2006 (P = 0.03). Factors significantly associated with a good methodological quality were pharmaceutical industry funding and publication in 2006 vs. 1997.
                There is a need to improve the reporting quality of RCTs published in dermatology journals. With the development of sensitive tests to detect cytomegalovirus (CMV) viremia, preemptive approaches become a reasonable alternative to general CMV prophylaxis. We performed a randomized trial comparing pp65-antigenemia guided preemptive therapy using oral ganciclovir with symptom-triggered intravenous ganciclovir treatment.
                Eighty-eight of 372 liver transplant recipients developed antigenemia early after orthotopic liver transplantation. Twenty-eight symptomatic patients with antigenemia were excluded from randomization and treated with intravenous ganciclovir. Sixty pp65-antigen-positive asymptomatic patients were randomized to receive either oral ganciclovir 3x1 g/day for 14 days (group 1) or no preemptive treatment (group 2). Patients that developed CMV disease were treated with intravenous ganciclovir 2x5 mg/kg body weight for 14 days. The high-risk (Donor+/Recipient-) patients were equally distributed in the two study groups.
                Three of 30 (10%) patients on oral ganciclovir developed mild to moderate CMV disease compared with 6/30 (20%) patients in the control group. In the Donor+/Recipient- patients, the incidence of CMV disease was 1/6 and 3/7. All disease episodes resolved after intravenous treatment. The 1- and 3-year patient and organ survival was the same in the study groups and in the patients with or without CMV infection. No deaths related to CMV occurred.
                The positive predictive value of pp65-antigenemia for the development of CMV disease was very low, and, in 28/88 patients (32%), antigenemia did not precede symptoms. Therefore, pp65-antigenemia is of limited value in deciding on the timing and need for ganciclovir therapy after liver transplantation. Infection and rejection are two common complications after liver transplants. In a preliminary study, administration of granulocyte colony-stimulating factor (G-CSF) to liver transplant recipients was associated with a decrease in sepsis episodes, sepsis-related deaths, and rejection compared with a historical control group of patients. The purpose of this study was to evaluate further the efficacy of G-CSF in liver transplant patients in a randomized, placebo-controlled, double-blind, multicenter trial.
                Adult patients with a United Network Organ Sharing classification of 1 or 2 were randomized to receive a placebo, 100 microg/day of G-CSF or 300 microg/day of G-CSF. The study drug was started preoperatively and then continued after the transplant for a maximum of 21 days. Patients were evaluated for microbiologically-documented infection, biopsy-proven rejection, number of treatments for rejection, length of stay in the intensive care unit and hospital, graft survival, death, and adverse events.
                During the first 30 days after the transplant, the median peak white blood cell count was 16.5x10(9)/L, 34.6x10(9)L, and 54.8x10(9)/L for the placebo, low-dose G-CSF, and high-dose G-CSF patients, respectively. The incidence of infection was 30% in G-CSF patients (34 of 114 patients) and 34% in placebo patients (20 of 58 patients). Except for more nosocomial pneumonias in the G-CSF patients (7 in 114 patients vs. 0 in 58 patients, P=0.056), the types of infections and causative organisms were also similar in both treatment groups. Although the number of treatments for clinically suspected or proven rejection was similar in the G-CSF and placebo patients, biopsy-proven rejection occurred more often in G-CSF patients (34 of 114 patients or 30%) than placebo patients (11 of 58 patients or 19%) (P=0.093). There were no cases of graft loss caused by rejection. G-CSF had no effect on length of stay in the intensive-care unit or hospital. There were 22 G-CSF patients (18%) and 10 placebo patients (15%) who died within 120 days after the transplant. No serious adverse events were attributed to G-CSF.
                Despite producing substantial increases in the white blood cell count after the transplant, G-CSF had no beneficial effects on infection, rejection, or survival in this study. Biopsy-proven rejection and nosocomial pneumonias were more common in patients treated with G-CSF compared with those taking the placebo. No serious adverse events were attributed to G-CSF.
We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).