The Cochrane review of surgery for lumbar disc prolapse and degenerative lumbar spondylosis.

STUDY DESIGN: A Cochrane review of randomized controlled trials. OBJECTIVES: To collate the scientific evidence on surgical management for lumbar-disc prolapse and degenerative lumbar spondylosis. SUMMARY OF BACKGROUND DATA: Surgical investigations and interventions account for as much as one third of the health care costs for spinal disorders, but the scientific evidence for most procedures still is unclear. METHODS: A highly sensitive search strategy identified all published randomized controlled trials. Cochrane methodology was used for meta-analysis of the results. RESULTS: Twenty-six randomized controlled trials of surgery for lumbar disc prolapse and 14 trials of surgery for degenerative lumbar spondylosis were identified. Methodologic weaknesses were found in many of the trials. Only one trial directly compared discectomy and conservative management. Meta-analyses showed that surgical discectomy produces better clinical outcomes than chemonucleolysis, which is better than placebo. Three trials showed no difference in clinical outcomes between microdiscectomy and standard discectomy, but in three other studies, both produced better results than percutaneous discectomy. Three trials showed that inserting an interposition membrane after discectomy does not significantly reduce scar formation or alter clinical outcomes. Five heterogeneous trials on spinal stenosis and degenerative spondylolisthesis permit very limited conclusions. There were nine trials of instrumented versus noninstrumented fusion: Meta-analysis showed that instrumentation may facilitate fusion but does not improve clinical outcomes. CONCLUSIONS: There is now strong evidence on the relative effectiveness of surgical discectomy versus chemonucleolysis versus placebo. There is considerable evidence on the clinical effectiveness of discectomy for carefully selected patients with sciatica caused by lumbar disc prolapse that fails to resolve with conservative management. There is no scientific evidence on the effectiveness of any form of surgical decompression or fusion for degenerative lumbar spondylosis compared with natural history, placebo, or conservative management. The Cochrane reviews will be updated continuously as other trials become available.     

Reduction of Immunosuppression for Transplant-Associated Skin Cancer: Rationale and Evidence of Efficacy

BACKGROUND: Solid organ transplant recipients may develop numerous or life-threatening skin cancers. In addition to aggressive standard treatment of skin cancer, reduction of immunosuppression has been considered an adjuvant therapeutic strategy, albeit without direct proof of efficacy. OBJECTIVE: To review the rationale for and evidence supporting the efficacy of reduction of immunosuppression for severe skin cancer in transplant recipients. METHODS: Review of the literature regarding direct and indirect evidence on reduction of immunosuppression for transplant-associated skin cancer. RESULTS: Although there are no randomized controlled trials of reduction of immunosuppression as a therapeutic intervention for transplant patients with skin cancer, multiple lines of evidence suggest that this strategy may be an effective adjuvant therapy. A randomized trial has demonstrated a lower incidence of skin cancer in transplant recipients after reduction of immunosuppression, albeit in a cohort not previously affected by skin cancer. Case series of reduction or cessation of immunosuppression demonstrate a lower incidence of skin cancer or improved outcomes of preexisting skin cancer. Lower overall immunosuppression is associated with a lower incidence of skin cancer. Multiple cancers affecting the skin have been shown to regress with reduction of immunosuppression. CONCLUSIONS: Reduction of immunosuppression may be an effective adjuvant therapeutic strategy when confronting severe transplant-associated skin cancer. The risks of reduction of immunosuppression must be better defined, and randomized trials of this strategy are necessary.     

Laparoscopic and minimally invasive resection of malignant colorectal disease

Minimally invasive surgery for colorectal cancer is a burgeoning field of general surgery. Randomized controlled trials have assessed short-term patient-oriented and long-term oncologic outcomes for laparoscopic resection. These trials have demonstrated that the laparoscopic approach is equivalent to open surgery with a shorter hospital stay. Laparoscopic resection also may result in improved short-term patient-oriented outcomes and equivalent oncologic resections versus the open approach. Transanal excision of select rectal cancer using endoscopic microsurgery is promising and robotic-assisted laparoscopic surgery is an emerging modality. The efficacy of minimally invasive treatment for rectal cancer compared with conventional approaches will be clarified further in randomized controlled trials.     

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.     

Telemedically Supported Case Management of Living‐Donor Renal Transplant Recipients to Optimize Routine Evidence‐Based Aftercare: A Single‐Center Randomized Controlled Trial

Improving mid‐term and long‐term outcomes after solid organ transplantation is imperative, and requires both state‐of‐the‐art transplant surgery and optimization of routine, evidence‐based aftercare. This randomized, controlled trial assessed the effectiveness of standard aftercare versus telemedically supported case management, an innovative aftercare model, in 46 living‐donor renal transplant recipients during the first posttransplant year. The model includes three components: (i) chronic care case management initiated after discharge, (ii) case management initiated in emerging acute care situations, and (iii) a telemedically equipped team comprising a transplant nurse case manager and two senior transplant physicians (nephrologist, surgeon). Analyses revealed a reduction of unplanned inpatient acute care, with considerable cost reductions, in the intervention group. The prevalence of nonadherence over the 1‐year study period was 17.4% in the intervention group versus 56.5% in the standard aftercare group (p = 0.013). Only the intervention group achieved their pre‐agreed levels of adherence, disease‐specific quality of life, and return to employment. This comparative effectiveness study provides the basis for multicenter study testing of telemedically supported case management with the aim of optimizing posttransplant aftercare. The trial was registered with the German Clinical Trials Register ( www.DRKS.de ), DKRS00007634.     

Strategies of immunosuppression in cardiac transplantation

Immunosuppression for cardiac transplantation, as currently practiced, is based to a large extent on clinical trials that can best be characterized as single-institutional, uncontrolled, or historically controlled studies. While these non-randomized, retrospective studies clearly advanced the science and art of cardiac transplantation to the point that survival rates approaching 90% at 1 year are achievable, the specific immunosuppressive protocols used at any given institution are likely based more on the individual transplant surgeon's or physician's training and experience, than on a firm scientific basis. Thus, a significant lack of uniformity exists among transplant centers in virtually all phases of immunosuppression. More clinical and basic research efforts are needed to unify immunosuppressive strategies following cardiac transplantation. In the future, greater individualization of therapy is likely to occur and more prospectively randomized, multi-center trials are likely to be carried out, particularly in the area of early rejection prophylaxis.     

Lung transplantation. Bronchiolitis obliterans syndrome

BOS remains a difficult problem to control following lung transplantation, largely because of uncertainties regarding the underlying mechanisms that are responsible for it. Continued work on the pathogenesis of BOS is essential. The progressive nature and poor outlook when BOS stage 3 is reached indicates that current strategies should be focused on prevention and early intervention. There is a great need for randomized, controlled trials on intervention if the international transplant community is to make progress in this area.     

Versorgungsforschung

BACKGROUND: Besides basic, illness- and patient-oriented research, outcomes research is regarded as the fourth pillar of modern health care systems. Outcomes research investigates both the desirable and adverse effects of medical and surgical interventions under day-to-day conditions. METHOD: Because of rigorous entry criteria and selection of eligible subjects, the efficacy of a certain treatment derived from clinical experiments (i.e. classic randomized trials) may not necessarily be transferred to common patient populations or clinical settings. Apart from efficacy, a valuable (thus reimbursable) diagnostic or therapeutic procedure must prove its effectiveness in clinical practice as well. Demanding study designs are necessary to model effectiveness and to separate the observed intervention-related effects from bias and confounding. RESULTS: Registries and pragmatic randomized trials may represent the most appropriate modalities to establish outcomes research in trauma and orthopaedic surgery. Good examples for interventions still needing proof of effectiveness are kyphoplasty and vertebroplasty, navigated surgery, damage control, interlocking implants and bone growth factors. Revealing over- and undersupply, generating negative lists (i.e. interventions of questionable or almost nil effectiveness) and integrating patients as co-therapists requires networking between hospitals and private practitioners. CONCLUSION: Also, since outcomes research is a societal need, its development and funding must be ensured by all providers and payers of health care services.     

Suggested guidelines for reporting clinical results in transplantation trials

Randomized controlled trials are essential for decision making and improving patient care. Although the number of published clinical trials in the field of transplantation is constantly rising, recent publications addressed problems of proper reporting of study results. Far too often, not even the key data (patient and graft survival, rejection rates, transplant relevant characteristics of the population, and details on the immunosuppressive therapy) were given. Good reporting should include primary and secondary outcomes, graft and patient survival, acute rejection rates (biopsy proven acute rejections and all treated), and clear accounting of the participant number throughout the different stages of a study. Several recent attempts (Consolidated Standards of Reporting Trials guidelines, submission of the study protocol, registry database) failed to improve or improved only partly the reporting quality. To improve reporting quality of randomized controlled trials in the future, we propose to use a comprehensive checklist with modified criteria of the Consolidated Standards of Reporting Trials guidelines to better reflect the special needs in the field of transplantation.     

Effect of pretransplantation ursodeoxycholic acid therapy on the outcome of liver transplantation in patients with primary biliary cirrhosis.

As ursodeoxycholic acid (UDCA) delays the need for transplantation, this could result in patients with more comorbid disease, therefore more likely to have a worse outcome posttransplantation. The aim of this study is to compare posttransplantation outcome in patients who received UDCA versus placebo who subsequently required a liver transplant. Data on all trial patients referred for transplantation were retrospectively collected from three randomized controlled trials of UDCA in patients with primary biliary cirrhosis (PBC). An intent-to-treat analysis was conducted with patients assigned to their original treatment allocation. UDCA and placebo groups were compared at trial entry, transplant referral, just before transplantation, and 1 month and 1 year posttransplantation. From 1987 to 1996, 37 UDCA-treated and 53 placebo patients were referred for transplantation; their age, sex, and serum bilirubin levels were similar at study entry. Immediately before transplantation, these two groups were again similar with respect to age, bilirubin level, Mayo risk score, and serum creatinine level. Posttransplantation survival rates at 1 month were 93.9% in the UDCA group and 88.4% in the placebo group, and 1 year survival rates were 90.3% and 78.4%, respectively (not significant). Posttransplantation, the two groups had similar rates of infection (53.9% v 58%); however, rejection occurred significantly less often in the UDCA group; 42.9% versus 68. 8% in the placebo group (P =.04). The posttransplantation outcome of UDCA-treated patients with PBC is no different from those who were administered placebo. There is no evidence to suggest the beneficial effect of UDCA in delaying the need for transplantation is associated with a worse outcome once liver transplantation becomes necessary.     

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure

OBJECTIVE: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. SUMMARY BACKGROUND DATA: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. METHODS: A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. RESULTS: For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). CONCLUSIONS: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.     

Combination therapy with tacrolimus and mycophenolate mofetil: effects of early and late minimization of mycophenolate mofetil after renal transplant

The objectives of the study were: (i) to compare the efficacy and safety of minimizing mycophenolate mofetil (MMF) early (30 d) or late (90 d) after renal transplantation, when used in combination with tacrolimus; (ii) to retrospectively investigate factors associated with early, acute rejections and (iii) to investigate the pharmacokinetic interaction between tacrolimus and diltiazem. A prospective, randomized, multicenter, open-label study was conducted in 124 de novo kidney transplant recipients. Efficacy and safety outcomes were assessed for 180 d after transplantation and subjects were followed-up for a mean duration of 5.1 yr. The efficacy and safety outcomes were comparable whether the dose of MMF was minimized early or late. The incidence of early, acute rejection episodes was higher for recipients who were younger, received a graft from an unrelated donor or failed to achieve adequate tacrolimus concentrations (trough > 10 ng/mL) in the first seven d after transplant. Concomitant use of diltiazem had a tacrolimus-sparing effect in some subjects. Based on these results, we support the achievement of a high target tacrolimus concentration within the first week after renal transplant and suggest that early minimization of MMF can be achieved when used in combination with tacrolimus.     

Neural transplantation for the treatment of Parkinson's disease. Update and future

Cell transplantation to replace lost neurons is a recent approach to the treatment of progressive neurodegenerative diseases. Replacement of dopaminergic neurons in patients with Parkinson's disease (PD) was the first transplantation therapy to be tested in the clinical setting. In PD, cell replacement strategy has been based on the idea that neural graft-induced restoration of dopamine neurotransmission in the striatum could lead to substantial and long-lasting functional recovery. Since transplantation of embryonic dopaminergic cells was first reported in the early 1990s, several open-label clinical trials have confirmed the benefits of transplantation. But, the validity of these studies has been uncertain because of small patient numbers, variable inclusion criteria, and the absence of control groups. Two controlled trials have been recently designed and performed. Their designs incorporated a "sham-operated" versus a transplant group. The conclusions drawn by both teams are that fetal mesencephalic allograft can not, at present, be recommended as a treatment for severe PD. However, several lessons can be learnt and the efficacy can be improved employing more neurons and better targets, and/or neurotrophic factors.     

Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials

mTOR inhibitors have been associated with wound complications and lymphoceles. We systematically reviewed randomized controlled trials (RCTs) to compare these outcomes for solid organ transplant recipients. Relevant medical databases were searched to identify RCTs in solid organ transplantation comparing mTOR inhibitors with an alternative therapy reporting on wound complications and/or lymphoceles. Methodological quality of RCTs was assessed. Pooled analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Thirty-seven RCTs in kidney, heart, simultaneous pancreas-kidney and liver transplantation were included. Pooled analyses showed a higher incidence of wound complications (OR 1.77, CI 1.31-2.37) and lymphoceles (OR 2.07, CI 1.62-2.65) for kidney transplant recipients on mTOR inhibitors together with calcineurin inhibitors (CNIs). There was also a higher incidence of wound complications (OR 3.00, CI 1.61-5.59) and lymphoceles (OR 2.13, CI 1.57-2.90) for kidney transplant recipients on mTOR inhibitors together with antimetabolites. Heart transplant patients receiving mTOR inhibitors together with CNIs also reported more wound complications (OR 1.82, CI 1.15-2.87). We found a higher incidence of wound complications and lymphoceles after kidney transplantation and a higher incidence of wound complications after heart transplantation for immunosuppressive regimens that included mTOR inhibitors from the time of transplantation.     

Economic evaluation of bone stimulation modalities: A systematic review of the literature

Various bone stimulation modalities are commonly used in treatment of fresh fractures and nonunions; however, the effectiveness and efficiency of these modalities remain uncertain. A systematic review of trials evaluating the clinical and economical outcomes of ultrasounds, electrical stimulation, and extracorporeal sound waves on fracture healing was conducted. We searched four electronic databases for economic evaluations that assessed bone stimulation modalities using ultrasound therapy, electrical stimulation, or extracorporeal shock waves. In addition, we searched the references and related articles of eligible studies, and a content expert was contacted. Information on the clinical and economical outcomes of patients was independently extracted by reviewers. Fourteen studies met the inclusion criteria; therefore, very limited research was found on the cost associated with treatments and the corresponding outcomes. The data available focus primarily on the efficacy of newly introduced treatment methods for bone growth, but failed to incorporate the costs of implementing such treatments. One economic analysis was identified that assessed different treatment paths using ultrasound. A total cost savings of 24–40% per patient occurred when ultrasound was used for fresh fractures and nonunions (grade C recommendation). The results suggest that the ultrasound is a viable alternative for bone stimulation; however, the impacts of the other modalities are left unknown due to the lack of research available. Methodological limitations leave the overall economic and clinical impact of these modalities uncertain. Large, prospective, randomized controlled trials that include cost-effectiveness analyses are needed to further define the clinical effectiveness and financial burden associated with bone stimulation modalities.     

Clinical trials,immunosuppression and renal transplantation: new trends in design and analysis

Clinical trials provide a framework to search for more effective and less toxic immunosuppressive agents to control renal transplant rejection. Some methodological aspects are presented. Patient selection and the choice of study endpoints are discussed with emphasis on standardized definitions and classification of histopathology, and on qualification and quantification of chronic rejection. Choosing a Bayesian or a frequentist approach and the afferent hypotheses is discussed together with the interpretation of a P-value and a confidence interval. Strategies for limiting the number of patients, increasing power and feasibility are reviewed, including discussion of surrogate endpoints. New approaches to statistical analysis are then presented, including intention-to-treat versus per-protocol analysis, analysis of correlated data, dependent censoring, and meta-analysis applied to renal transplantation. Pharmacoeconomics are finally introduced as necessary for implementation of decision making regarding therapeutic strategies. Reporting research increases its standards, and the CONSORT (Consolidated Standards of Reporting Trials) and QOROM (Quality of Reporting of Meta-analyses) criteria are to be integrated in the process of clinical trial procedures. In conclusion, observational studies are presented as part of an evidence-based approach in the hierarchy of evidence, keeping in mind that high quality, randomized, controlled trials are still necessary to decrease uncertainty in the field of renal transplantation.     

Patient’s Preference and Randomization: New Paradigm of Evidence-based Clinical Research

The limitations associated with the traditional randomized controlled design as applied to clinical surgical research must be recognized. The aim of randomization is to ensure initial comparability between groups of eligible patients for whom treatments are compared, thus eliminating their individual influence on outcome. Randomized controlled trials in the surgical literature are sparse; patient preferences might be a major obstacle to their performance. External validity of results of clinical trials depends on the representativity of patients who participate in trials: Compliance to participate through informed consent may act as a selection bias. In surgical randomized trials where it is not often possible for patients to remain blinded to the treatment to which they have been allocated, patient preferences can influence the effectiveness of treatments. In this setting, we need to look at alternatives and the potential advantages of adopting more flexible and clinically relevant approaches to the design of surgical trials. We have to accept the weight of the patient’s individual decision in everyday practice. Hence, to negate the importance of these individual choices when evaluating surgical outcomes is unrealistic. An original design reported herein might become a new paradigm for surgical evaluation.     

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts

BACKGROUND: A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS: Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS: A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS: Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.     

Randomized trials of high-versus-low-dose steroids in renal transplantation. Does the evidence favor a consensus?

Published, randomized trials of high-versus-low-dose steroids in renal transplantation, individually and collectively, are too small (median trial size: 72 patients) to reach authoritative conclusions about mortality, graft failure, transplant failure, and the incidence of certain complications. The implications of this review for future therapeutic trials in renal transplantation are that randomization of 400 patients should be seen as minimum Phase III trial size, and that a research strategy is needed to encourage effective multicenter collaboration. One such strategy is described beginning with a single-center randomized Phase II trial to compare times to first rejection episode, thus rendering prior evidence on which the case for multicenter collaboration, effectively in an established trial, can be judged. Analysis by intention to treat and consistent reporting of the number of patients who experience certain classes of complication are two of four ground rules on which we assessed trials when combining evidence from similar studies. The other ground rules are randomization and common treatment theme. The statistical method of formally pooling results is outlined.