[Evidence-based medicine in surgical practice - locating clinical studies and systematic reviews by searching the Medline database]. / Evidenzbasierte Medizin in der chirurgischen Praxis - Die Literatursuche nach klinischen Studien und systematischen Übersichtsarbeiten in der Datenbank Medline.

BACKGROUND: Every day approximately 75 clinical trials and 11 systematic reviews are published in the health-care intervention and medical field. Due to this growing number of publications it is a challenge for every practicing clinician to keep track with the latest research. The implementation of new and effective diagnostic and therapeutic interventions into daily clinical routine may thus be delayed. Conversely, ineffective or even harmful interventions might still be in use. Decision-making in evidence-based medicine (EBM) requires consideration of the most recent high quality evidence. Randomised controlled trials (RCTs) are regarded as the "gold standard" to prove the efficacy of surgical interventions in patient-oriented research. Systematic reviews combine results from RCTs by summarising single RCTs which answer a particular clinical question. Some basic knowledge in systematic literature searching is required and helpful for detecting relevant publications. MATERIAL AND METHODS: This article shows various possibilities for locating clinical studies and systematic reviews in the database Medline on the basis of illustrative step-by-step instructions. RESULTS AND CONCLUSION. Depending on the aim and topic of the literature search, the time required for the task may vary. In routine practice, a systematic literature search is unrealistic in most cases. Clinicians in need of a quick update of current evidence on a certain clinical topic may make use of up-to-date systematic reviews. During a systematic literature search, different approaches and strategies might be necessary.

Randomized clinical trial of a modified Seldinger technique for open central venous cannulation for implantable access devices.

INTRODUCTION: Totally implantable access ports (TIAPs) are often used for patients who need permanent venous access. The primary success rate using direct open insertion is about 80 per cent, so rescue strategies are needed. This study compared the primary success rates of standard open insertion and a modified Seldinger technique. METHODS: This randomized trial recruited 164 patients scheduled for primary implantation of a TIAP and compared two interventions. The primary endpoint was the success rate of the implantation technique. RESULTS: The primary success rates were similar: 66 (80 per cent) of 82 patients who had standard open insertion versus 69 (84 per cent) of 82 patients undergoing the modified Seldinger method (P = 0.686). A logistic mixed regression analysis including treatment group, age, Karnofsky index, body mass index and surgeon's experience showed no advantage for the Seldinger method: odds ratio 1.30 (95 per cent confidence interval 0.62 to 2.70). TIAPs were eventually implanted successfully in 163 (99.4 per cent) of 164 patients. In 11 patients randomized to standard surgery, the Seldinger method was a successful rescue strategy. CONCLUSION: The primary success rate was similar for both open insertion methods. The modified Seldinger method is useful if standard open insertion fails. REGISTRATION NUMBER: ISRCTN 52368201 (http://www.controlled-trials.com).

[Clinical trials beyond the German Drug Law. Clinical trials in surgery]. / Klinische Studien ausserhalb des Arzneimittelgesetzes. Klinische Studien in der Chirurgie.

Proof of safety and effectiveness of surgical procedures follows the same scientific principles as for drugs. Control of bias and chance when evaluating new operations has to be considered and should generally be followed using randomized controlled trials (RCT). The expenditure for study design, execution and analysis can be substantial due to specific characteristics of surgical treatments. The largest challenges represent the maintenance of comparable treatment and assessment within and between the study groups of a RCT, such as, blinding of surgeons, learning curves, standardization of procedures, and monitoring interventions to ensure execution according to protocol. This evaluation is made even more difficult due to lack of broadly accepted definitions of surgically relevant endpoints in daily practice and research. Since 2004, new methods and procedures are being tested to demonstrate the feasibility of surgical RCTs through a grant program for surgical clinical trial centers in Germany. In six surgical trial centers, a number of surgical RCTs have been designed and conducted. The first results of high-quality surgical RCTs are described.

Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.

BACKGROUND: Post-operative ileus (POI) affects most patients undergoing abdominal surgery. AIM: To evaluate the effect of alvimopan, a peripherally acting mu-opioid receptor antagonist, on POI by negating the impact of opioids on gastrointestinal (GI) motility without affecting analgesia in patients outside North America. METHODS: Adult subjects undergoing open abdominal surgery (n = 911) randomly received oral alvimopan 6 or 12 mg, or placebo, 2 h before, and twice daily following surgery. Opioids were administered as intravenous patient-controlled analgesia (PCA) or bolus injection. Time to recovery of GI function was assessed principally using composite endpoints in subjects undergoing bowel resection (n = 738). RESULTS: A nonsignificant reduction in mean time to tolerate solid food and either first flatus or bowel movement (primary endpoint) was observed for both alvimopan 6 and 12 mg; 8.5 h (95% CI: 0.9, 16.0) and 4.8 h (95% CI: -3.2, 12.8), respectively. However, an exploratory post hoc analysis showed that alvimopan was more effective in the PCA (n = 317) group than in the non-PCA (n = 318) group. Alvimopan was well tolerated and did not reverse analgesia. CONCLUSION: Although the significant clinical effect of alvimopan on reducing POI observed in previous trials was not reproduced, this trial suggests potential benefit in bowel resection patients who received PCA.

Early results from a randomized clinical trial of colon J pouch versus transverse coloplasty pouch after low anterior resection for rectal cancer.

BACKGROUND: Patients with primary rectal cancer undergoing low anterior resection are often reconstructed using a pouch procedure. The aim of this trial was to compare colon J pouch (CJP) with transverse coloplasty pouch (TCP) reconstruction with regard to functional results, perioperative mortality and morbidity. As there is considerable uncertainty over the true anastomotic leak rate in patients with a TCP, the study analysed short-term outcome data. METHODS: Elective patients suitable for either procedure after sphincter-saving low anterior resection were eligible. Randomization took place during surgery. The primary endpoint was the rate of late evacuation problems after 2 years; secondary endpoints were anastomotic leak rate, perioperative morbidity and mortality. RESULTS: Between 21 October 2002 and 5 December 2005, 149 patients were randomized. All 76 patients randomized to TCP had the procedure compared with 68 of the 73 patients (93 percent) randomized to CJP. Both groups were comparable with regard to demographic and clinical characteristics. Surgical complications (CJP: 19 percent; TCP: 18 percent) and the overall anastomotic leak rate (8 percent) were equally distributed in both groups. CONCLUSION: This trial demonstrated a comparable early outcome for TCP and CJP. This contradicts previous reports suggesting a higher leak rate after TCP. REGISTRATION NUMBER: ISRCTN78983587 (http://www.controlled-trials.com).

Pancreaticoduodenectomy (classic Whipple) versus pylorus-preserving pancreaticoduodenectomy (pp Whipple) for surgical treatment of periampullary and pancreatic carcinoma.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death for men and the fifth for women. The standard treatment for resectable tumours is either a classic Whipple operation or a pylorus-preserving pancreaticoduodenectomy but it is still unclear which of the two procedures is more favourable in terms of survival, mortality, complications, perioperative factors and quality of life. OBJECTIVES: Several publications pointed out both advantages and disadvantages of both techniques and the current basis of evidence remains unclear. The objective of this systematic review is to compare the effectiveness of each technique. SEARCH STRATEGY: A search was conducted to identify all published and unpublished randomised controlled trials. Trials were identified by searching the following electronic databases - The Cochrane Library, MEDLINE, EMBASE and Current Contents. Reference lists from trials selected by electronic searching were hand-searched to identify further relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the classical Whipple (CW) with the pylorus-preserving pancreaticoduodenectomy (PPW) were considered eligible if patients with periampullary or pancreatic carcinoma were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data for included studies. A random-effects model was used for pooling data from the different trials. Binary outcomes were compared using odds ratios, continuous outcomes were pooled using weighted mean differences and hazard ratios were used to for the meta-analysis of survival data. The methodological quality of included studies was evaluated independently by two authors according to quality standards and by using a questionnaire that covers different aspects of quality. MAIN RESULTS: 1235 abstracts were retrieved and checked for eligibility and seven RCTs were finally included. The critical appraisal revealed vast heterogeneity with respect to methodological quality and outcome parameters. The comparison of overall in-hospital mortality (odds ratio 0.49; 95% CI 0.17 to 1.40; P=0.18), overall survival (hazard ratio 0.84; 95% CI 0.61 to 1.16; P=0.29) and morbidity showed no significant difference. However, operating time (weighted mean difference -68.26 min; 95% CI -105.70 to -30.83; P=0.0004) and intra-operative blood loss (weighted mean difference -0.76 ml; 95% CI -0.96 to -0.56; P<0.00001) were significantly reduced in the PPW group. AUTHORS' CONCLUSIONS: There is no evidence of relevant differences in mortality, morbidity and survival between the PPW and the CW. Given obvious clinical and methodological inter-study heterogeneity, future efforts have to be undertaken to perform high quality RCTs of complex surgical interventions on the basis of well defined outcome parameters.

Influence of two different resection techniques (conventional liver resection versus anterior approach) of liver metastases from colorectal cancer on hematogenous tumor cell dissemination - prospective randomized multicenter trial.

BACKGROUND: Surgical hepatic resection remains the treatment of choice for patients with liver metastases from colorectal cancer despite the use of alternative therapeutic strategies. Although this procedure provides long-term survival in a significant number of patients, 50-75% of the patients develop intra- and/or extrahepatic recurrence. One possible reason for tumor recurrence may be intraoperative hematogenous tumor cell dissemination due to mechanical manipulation of the tumor during hepatic resection. Surgical technique may have an influence on hematogenous tumor cell spread. We hypothesize that hematogenous tumor cell dissemination may be reduced by using the anterior approach technique compared to conventional liver resection. METHODS/DESIGN: This is a multi-centre prospective randomized controlled, superiority trial to compare two liver resection techniques of liver metastases from colorectal cancer. 150 patients will be included and randomized intraoperatively after surgical exploration just prior to resection. The primary objective is to compare the anterior approach with the conventional liver resection technique with regard to intraoperative haematogenous tumor cell dissemination. As secondary objectives we examine five year survival rates (OS and DFS), blood loss, duration of operation, requirement of blood transfusions, morbidity rate, prognostic relevance of tumor cell detection in blood and bone marrow and the comparison of tumor cell detection by different detection methods. CONCLUSION: This trial will answer the question whether there is an advantage for the anterior approach technique compared to the conventional resection group with regard to tumor cell dissemination. It will also add further information about prognostic differences, safety, advantages and disadvantages of each technique. TRIAL REGISTRATION: Current controlled trials - ISRCTN45066244.

[Multicentric randomised controlled trials in Germany: overview and interim analysis 1 year after inclusion of in the rubric "Clinical Trials"]. / Rekrutierende multizentrische chirurgische Studien in Deutschland : Zwischenbilanz ein Jahr nach Einführung der Rubrik.

BACKGROUND: For 1 year now, German surgical multicentric randomised controlled trials (MRCT) in Germany may be included under the heading "Clinical Trials" in our monthly updated trial list. MATERIAL AND METHODS: Quantitative and qualitative analysis of MRCT presented in the trial list was performed to give an overview and interim statement 1 year after implementation of the journal heading "Clinical Trials". RESULTS: In 1 year, the study list increased from four to eleven MRCT and the numbers of randomized patients from 396 to 1511. The MRCT show distinct differences regarding funding sources and reimbursement for participating centres per patient included. The study protocols of four of 11 MRCT were published in scientific journals. CONCLUSION: The new regular heading gives important details about ongoing surgical trials in Germany. The steady growth of trials and recruited patients demonstrates the practicability of randomized controlled trials in surgery.

[Systematic reviews and meta-analyses in surgery]. / Systematische Ubersichtsarbeiten und Metaanalysen in der Chirurgie.

The enormous number of medical publications available online and in print media makes it difficult for surgeons to keep abreast of new scientific developments. In addition to information overload and lack of time, studies of questionable quality and expertise when performing systematic literature searches jeopardize proper surgical decision making. The concept of systematic reviews (SR) and meta-analyses (MA) is based on a critically appraised synthesis of individual trials addressing comparable medical problems. This qualitative evaluation and quantitative aggregation of research findings offer valid decision making tools for the clinician, scientist, and health care authorities. Systematic reviews employ comprehensive methods to control for potential bias when synthesizing individual trials. Thus the clinical question and methodological aspects should be defined a priori in a protocol. In the following step the relevant literature must be identified through systematic searches in databases. After critical assessment of the methodological quality and heterogeneity of individual studies, the results can be presented qualitatively. They also can be quantitatively summarized in MA if appropriate. Compared to single trials, properly conducted SR and MA facilitate more precise estimation of the treatment effect of surgical interventions. Hence they represent an ideal basis for future research endeavors. In conclusion, SR and MA implemented in clinical guidelines, evidence-based consumer information, or health technology assessment, enable the necessary bridging between research and clinical practice.

[Multicenter surgical studies recruiting in Germany. A new regular heading in the German surgical journal "Der Chirurg"]. / Rekrutierende multizentrische chirurgische Studien in Deutschland. Eine neue Rubrik in der Zeitschrift "Der Chirurg".

BACKGROUND: Information about multicenter randomized controlled trials (mRCT) comparing surgical procedures that are open for patient recruitment is hardly available for potentially interested surgeons. On the other hand many mRCT fail because of poor recruitment of participating surgeons, not just of patients. MATERIAL AND METHOD: The available items in the International Clinical Trials Registry Platform (ICTRP) of the World Health Organisation were analyzed for their relevance to surgeons, and a basic data set was extracted by two surgeons in a consensus procedure. RESULTS: Of 20 items in the ICTRP, seven were identified as relevant to the surgeon in practice: study acronym with register number, principal investigator, patients, surgical procedures, status of the study (randomized patients and sample size), financing and case money, and contact information. DISCUSSION: In a new column introduced into the German surgical journal"Der Chirurg", a regularly updated list of recruiting mRCT will be printed. The trials must be registered internationally and provide basic information for interested surgeons. CONCLUSION: Through this new heading, improvements are expected in communication between surgeons performing trial studies, patient recruitment, and in planning, conducting, and analyzing mRCT.

[Randomized and nonrandomized controlled clinical trials in a German surgical journal]. / Randomisierte kontrollierte und kontrollierte klinische Studien in der Zeitschrift "Der Chirurg".

BACKGROUND: Comprehensive identification of relevant literature is mandatory for valid assessment of the effectiveness of surgical interventions. Thus, electronic database searches are often complemented by handsearching of relevant surgical journals. The aim of this study was to assess the quantity and quality of randomized controlled (RCTs) and controlled clinical trials (CCTs) in the German surgical journal Der Chirurg. METHODS: Quantitative and qualitative assessment was made after handsearching of studies published from 1948 to 2005 in Der Chirurg. Systematic database search (MEDLINE) was used for comparison of RCTs published in Der Chirurg and international surgical journals. RESULTS: Overall, 112 controlled clinical trials (90 RCTs, 22 CCTs) were identified by handsearching. The implementation of sample size calculation was reported in 12 of 90 (13%) RCTs. Forty-six (51%) did not specify the randomization process, and five (6%) incorporated the "intention to treat" principle in their analyses. After 2000, RCTs were published in declining frequency in Der Chirurg, whereas international surgical journals printed stable quantities of these studies. CONCLUSION: Improving the prerequisites of patient-centered clinical research in surgery, rigorous implementation of principles of the CONSORT statement, and modified publication strategies may improve the quality and quantity of reports on clinical studies in Germany.

[Project selection and protocol design in the Study Centre of the German Surgical Society]. / Projektauswahl und Protokollerstellung im Studienzentrum der Deutschen Gesellschaft für Chirurgie.

BACKGROUND: The Study Centre of the German Surgical Society (SDGC) designs, conducts, and analyses multicentre randomised controlled surgical trials. The aim of this paper is to present the decision-making process and responsibilities of the SDGC from submission of a study idea to full protocol development in order to achieve transparency in trial selection. METHODS: The process is divided into four steps. Study ideas can be submitted electronically by members of the German Surgical Society using a form via the homepage of the institution. Firstly, ideas are screened by staff members within 4 weeks for methodological and clinical relevance. Feasible and novel ideas are then converted to trial outlines in cooperation with the submitting surgeon. As a third step, the Steering Committee of the SDGC decides whether to accept the project using a list of defined criteria. Finally, the SDGC draws up a full protocol together with the submitting surgeon. All ideas and decisions are accessible via the SDGC homepage. CONCLUSIONS: The process described should help in the selection of relevant projects, acquisition of grants, and maintenance of transparency in trial selection and the protocol development process.

[Aim, content, evaluation and perspectives of surgical training in randomized trials at the Study Centre of the German Surgical Society]. / Chirurgischer Prüfarztkurs des Studienzentrums der Deutschen Gesellschaft für Chirurgie. Ziel, Inhalte, Evaluationsergebnisse und Ausblick.

BACKGROUND: Clinical research, especially the management of randomized controlled multicentre trials, is a challenge for surgical investigators. To provide the theoretical background and practical knowledge needed for surgical trials, it is necessary to revise standard training programmes, which focus on pharmacological research. The main differences concern regulatory aspects and content, especially in achieving and maintaining comparability, equal treatment, and outcome assessment using special randomisation techniques and standardised surgical procedures. METHODS: In November 2005, in cooperation with the Coordinating Centre for Clinical Trials in Heidelberg, the Study Centre of the German Surgical Society Study Group (SDGC) hosted a clinical investigation course for surgeons. During 3 days, 24 participants were systematically instructed by 16 lecturers on clinical trials (planning, treatment by protocol, data management, biometrics, ethics, and law), followed by participants' evaluation of the course. RESULTS: On a scale of 1 to 6 (excellent to insufficient, respectively) the mean grades for the course were 1.6 for content, 1.55 for clarity, and 1.55 for learning effect. Partial repetition, lack of work in small groups, and not enough materials to take home were the major criticisms. CONCLUSIONS: The evaluation emphasised the necessity and value of the course. Further courses with continued evaluation are necessary and can be based on the same underlying concept. However, the mere qualification of surgeons as clinical investigators without substantial additional improvements in structural problems and increased financial project support will not fundamentally improve clinical research in Germany.

[Operative standardization in randomized controlled surgical trials. Meeting of the INSECT trial]. / Operative Standardisierung bei randomisiert kontrollierten Studien in der Chirurgie. Studientreffen der INSECT-Studie.

BACKGROUND: INSECT is an internationally registered, three-armed, multicentre, intraoperatively randomised model trial of the Study Centre of the German Surgical Society. The interventions being compared are running suture technique with slowly absorbable monofilament suture material (PDS vs MonoPlus) and interrupted technique with a braided, rapidly absorbable suture material (Vicryl). The primary endpoint is the rate of incisional hernias 1 year postoperatively. MATERIAL AND METHODS: A total of 25 surgeons from 24 different institutions at all levels of care evaluated the theoretical and practical sessions of the surgical investigator meeting using 25 criteria, including course organisation, content, and speaker evaluation, and a categorical grading system from 1 (very good) to 6 (insufficient). RESULTS: Distribution of the 625 grades was: very good (1) n=367, good (2) n=207, satisfactory (3) n=39, adequate (4) n=2, and "No statement" n=10. The average score for the investigator meeting was 1.5. CONCLUSION: The participants felt they were successfully prepared theoretically and practically for trial interventions and conduct by attending the meeting. Clear explanation of the measures for treatment equivalence before and during trials is mandatory in randomised controlled surgical trials.

Oral administration of unsaturated fatty acids: effects on human peripheral blood T lymphocyte proliferation.

Oils enriched in certain polyunsaturated fatty acids suppress joint pain and swelling in rheumatoid arthritis (RA) patients. Because T lymphocyte activation is important to propagation of joint tissue injury in patients with RA, we examined the effects of fatty acids administered by mouth in vivo on proliferation of human lymphocytes activated through the T cell receptor complex. T cell proliferation was reduced after oral administration of 2.4 g gammalinolenic acid in capsules of borage seed oil. Oral administration of oils enriched in linoleic acid, the parent n-6 fatty acid, and alpha linolenic acid, the parent n-3 fatty acid, did not influence growth of stimulated cells. Fatty acid analyses indicated that suppression of lymphocyte proliferation after gammalinolenic acid administration was associated with increased plasma and peripheral blood mononuclear cell concentrations of gammalinolenic acid and dihomogammalinolenic acid.

Gene expression and serum thyroxine-binding globulin are regulated by adrenal status and corticosterone in the rat.

Supraphysiological doses of glucocorticoids reduce serum T4-binding globulin (TBG) concentrations when administered to human subjects. Studies were performed in rats to determine if glucocorticoid administration alters serum TBG in another species, if circulating concentrations of glucocorticoids tonically affect serum TBG concentrations, and if changes in TBG production are likely to be a cause of the glucocorticoid-induced changes in serum TBG concentrations that are observed in humans. The serum TBG-binding capacity was 14.9 +/- 2.3 nmol/liter in adrenalectomized male rats compared to 6.6 +/- 1.0 nmol/liter in intact male rats and 4.8 +/- 0.9 nmol/liter in adrenalectomized male rats that received corticosterone in a dose equal to or less than the replacement dose, as assessed by thymus weight (P < 0.01 for serum TBG in adrenalectomized vs. intact or adrenalectomized corticosterone-treated groups). Hepatic TBG mRNA content, as assessed by polymerase chain reaction amplification and expressed as a ratio of beta-actin mRNA content, was 0.10 +/- 0.03 density units in intact male rats, 0.59 +/- 0.17 density units in adrenalectomized male rats, and 0.05 +/- 0.02 density units in adrenalectomized corticosterone-treated male rats (P < 0.03 for adrenalectomized vs. intact or adrenalectomized corticosterone-treated rats). Adrenalectomy increased the serum TBG-binding capacity in female rats (intact female rats, 13.9 +/- 1.0 nmol/liter; adrenalectomized female rats, 39.0 +/- 6.4 nmol/liter; P < 0.01). These studies indicate that serum TBG is tonically down-regulated by adrenal glucocorticoids, because corticosterone decreases the TBG production rate, probably at the level of transcription. This effect is similar to that described for corticosterone-binding globulin, but differs from that for many proteins of the serine protease inhibitor family that are related to TBG.

Human peripheral blood T lymphocyte proliferation after activation of the T cell receptor: effects of unsaturated fatty acids.

Oils enriched in certain polyunsaturated fatty acids suppress joint pain and swelling in rheumatoid arthritis patients with active synovitis. Because T lymphocyte activation is important for propagation of joint tissue injury in patients with rheumatoid arthritis, we examined the effects of fatty acids added in vitro on proliferation of human T lymphocytes stimulated with monoclonal antibodies to CD3 and CD4. Unsaturated fatty acids reduced T cell proliferation in a dose dependent manner (dihomogammalinolenic acid > gammalinolenic acid > eicosapentaenoic acid > arachidonic acid). Removal of fatty acids from cultures before cell stimulation did not change the effects, but addition of fatty acids after cell stimulation failed to reduce T cell responses. The saturated palmitic acid did not influence T cell growth. These studies indicate that small changes in cellular fatty acids can have profound effects on early events in T cell signaling and on T cell function.