[Impact of clinical trials for surgery]. / Bedeutung klinischer Studien für die Chirurgie.

Clinical trials play a key role in patient care, academic education and research in surgery. Without valid studies the practice of evidence-based medicine is limited. Surgery is supported through funding by the German Ministry of Education and Research to establish an infrastructure for clinical trials. So far seven universities have worked together in a network since 2007 and successfully obtained funding for six large randomized trials from a program existing since 2004. Until now 2,249 patients have been randomized within 11 trials and 910 patients have been treated at local hospitals without academic responsibilities. An increase in the interest in clinical trials in daily practice has resulted through the certification of hospitals for special treatment that specifies that at least 5% of all patients are included in clinical trials.

[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.

Assessment of the ethical review process for non-pharmacological multicentre studies in Germany on the basis of a randomised surgical trial.

OBJECTIVE: To examine the current ethical review process (ERP) of ethics committees in a non-pharmacological trial from the perspective of a clinical investigator. DESIGN: Prospective collection of data at the Study Centre of the German Surgical Society on the duration, costs and administrative effort of the ERP of a randomised controlled multicentre surgical INSECT Trial (INterrupted or continuous Slowly absorbable sutures-Evaluation of abdominal Closure Techniques Trial, ISRCTN 24023541) between November 2003 and May 2005. SETTING: Germany. PARTICIPANTS: 18 ethics committees, including the ethics committee handling the primary approval, responsible overall for 32 clinical sites throughout Germany. 8 ethics committees were located at university medical schools (MSU) and 10 at medical chambers. Duration was measured as days between submission and receipt of final approval, costs in euros and administrative effort by calculation of the product of the total number of different types of documents and the mean number of copies required (primary approval acting as the reference standard). RESULTS: The duration of the ERP ranged from 1 to 176 (median 31) days. The median duration was 26 days at MSUs compared with 34 days at medical chambers. The total cost was euro2947. 1 of 8 ethics committees at universities (euro250) and 8 of 10 at medical chambers charged a median fee of euro162 (mean euro269.70). The administrative effort for primary approval was 30. Four ethics committees required a higher administrative effort for secondary approval (37, 39, 42 and 104). CONCLUSION: The ERP for non-pharmacological multicentre trials in Germany needs improvement. The administrative process has to be standardised: the application forms and the number and content of the documents required should be identical or at least similar. The fees charged vary considerably and are obviously too high for committees located at medical chambers. However, the duration of the ERP was, with some exceptions, excellent. A centralised ethics committee in Germany for multicentre trials such as the INSECT Trial can simplify the ERP for clinical investigators in and outside the country.

Phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma -- CapRI: study protocol [ISRCTN62866759].

UNLABELLED: After surgical intervention with curative intention in specialised centres the five-year survival of patients with carcinoma of the exocrine pancreas is only 15%. The ESPAC-1 trial showed an increased five-year survival of 21% achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation. DESIGN: The CapRI study is an open, controlled, prospective, randomised multi-centre phase III trial. Patients in study arm A will be treated as outpatients with 5-Fluorouracil; Cisplatin and 3 million units Interferon alpha-2b for 5 1/2 weeks combined with external beam radiation. After chemo-radiation the patients receive continuous 5-FU infusions for two more cycles. Patients in study arm B will be treated as outpatients with intravenous bolus injections of folinic acid, followed by intravenous bolus injections of 5-FU given on 5 consecutive days every 28 days for 6 cycles. A total of 110 patients with specimen-proven R0 or R1 resected pancreatic adenocarcinoma will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients' enrollment. DISCUSSION: The aim of this study is to evaluate the overall survival period attained by chemo-radiotherapy including interferon alpha 2b administration with adjuvant chemotherapy. The influence of interferon alpha on the effectiveness of the patients' chemoradiation regimen, the toxicity, the disease-free interval and the quality of life are analysed. Different factors are tested in terms of their potential role as predictive markers.

Quantitative contrast echocardiographic assessment of collateral derived myocardial perfusion during elective coronary angioplasty.

OBJECTIVE: To determine whether myocardial contrast echocardiography can be used to quantify collateral derived myocardial flow in humans. METHODS: In 25 patients undergoing coronary angioplasty, a collateral flow index (CFI) was determined using intracoronary wedge pressure distal to the stenosis to be dilated, with simultaneous mean aortic pressure measurements. During balloon occlusion, echo contrast was injected into both main coronary arteries simultaneously. Echocardiography of the collateral receiving myocardial area was performed. The time course of myocardial contrast enhancement in images acquired at end diastole was quantified by measuring pixel intensities (256 grey units) within a region of interest. Perfusion variables, such as background subtracted peak pixel intensity and contrast transit rate, were obtained from a fitted gamma variate curve. RESULTS: 16 patients had a left anterior descending coronary artery stenosis, four had a left circumflex coronary artery stenosis, and five had a right coronary artery stenosis. The mean (SD) CFI was 19 (12)% (range 0-47%). Mean contrast transit rate was 11 (8) seconds. In 17 patients, a significant collateral contrast effect was observed (defined as peak pixel intensity more than the mean + 2 SD of background). Peak pixel intensity was linearly related to CFI in patients with a significant contrast effect (p = 0.002, r = 0.69) as well as in all patients (p = 0.0003, r = 0.66). CONCLUSIONS: Collateral derived perfusion of myocardial areas at risk can be demonstrated using intracoronary echo contrast injections. The peak echo contrast effect is directly related to the magnitude of collateral flow.

Simultaneous intracoronary velocity- and pressure-derived assessment of adenosine-induced collateral hemodynamics in patients with one- to two-vessel coronary artery disease.

OBJECTIVES: The purpose of this investigation in patients with poorly and well developed coronary collaterals was to assess the influence of collateral and collateral adjacent vascular resistances and, in part, a stenotic lesion of the collateral supplying vessel on the hemodynamic collateral responses to adenosine. BACKGROUND: In humans, little is known about the functional behavior of the coronary collateral circulation. METHODS: In 50 patients with one- and two-vessel coronary artery disease (CAD) undergoing percutaneous transluminal coronary angioplasty (PTCA), collateral flow index (CFI, no unit) changes and vascular resistance index (R, cm/mm Hg) changes of the collateral (R(coll)) and the distal collateral receiving (R4) vessel in response to adenosine (140 microg/min/kg IV) were measured by intracoronary (i.c.) Doppler and pressure guidewires. The variables were determined at baseline and during adenosine in patients with poor (angiographic collateral degree before PTCA <2 of 0 to 3) and good coronary collaterals. RESULTS: Pressure-derived CFI (CFI(p)) decreased under adenosine in patients with poor collaterals, and it increased in the group with good collaterals. There were inverse correlations between the adenosine-induced change in CFI(p) and the change in R(coll) (r = 0.61, p = 0.0001). In the group with good, but not with poor collaterals, there was also a significant correlation between CFI(p) increase and the decrease in R4, between the severity of the contralateral stenosis and CFI(p) augmentation and among the left versus right coronary artery as ipsilateral vessel and CFI(p) change. CONCLUSIONS: Overall, patients with well, versus poorly developed coronary collaterals do better regarding the capacity to increase collateral flow in response to adenosine. In patients with good, but not poor, collaterals, an adenosine-induced collateral flow increase depends on the ipsilateral distal vascular resistance decrease, but is also directly influenced by the severity of a contralateral stenosis and probably by the size of the collateralized vascular bed.

Functional assessment of collaterals in the human coronary circulation.

The coronary collateral circulation is an alternative source of blood supply to a myocardial area jeopardized by the failure of the stenotic or occluded vessel to provide enough blood flow to this region. Until recently, only qualitative or semiqualitative methods have been available for the assessment of the coronary collateral circulation in humans, such as the patient's history of walk-through angina pectoris, the registration of intracoronary ECG signs for myocardial ischaemia or angina pectoris during coronary occlusion, or coronary angiographic classification (score 0-3) of collaterals. Studies of coronary wedge pressure measurements distal of a balloon-occluded coronary artery and the recent advent of ultrathin pressure and Doppler angioplasty guidewires have made it possible to obtain pressure or flow velocity data in remote vascular areas and, thus, to calculate functional variables for coronary collateral flow. Those coronary occlusive pressure- and flow velocity-derived parameters express collateral flow as a fraction of antegrade coronary flow during vessel patency of the collateral-receiving vessel. They are both interchangeable, and they have been validated in comparison to 'traditional' methods and against each other. The possibility of accurately measuring coronary collateral flow indices in humans undergoing coronary balloon angioplasty opens areas of investigation of the pathogenesis, pathophysiology and therapeutic promotion of the collateral circulation previously reserved for exclusively experimental studies. The purpose of this article is to review several clinically available methods for the functional characterization of the coronary collateral circulation.

[Efficacy of organ exchange rules in a 7 million population nation]. / Effizienz der Organaustauschregeln in einer 7 Mio Nation.

The suitability of organ exchange rules were analysed retrospectively in a country with a population of 7 million not connected to international organ sharing organisations following the opening of a national coordination centre 2 years previously. The results demonstrate that the sharing rules work frictionless and efficiently, and that compulsory registration of every organ donor (cadaveric and living) guarantees entire transparency of organ source and exchange, therefore preventing any illegal activity. An unacceptably high mortality rate for patients awaiting a highly urgent organ (specifically heart or liver) shows that connection to an international organ exchange organisation is desirable in this respect.