Randomized controlled multicenter trial on the effectiveness of the collagen hemostat Sangustop® compared with a carrier-bound fibrin sealant during liver resection (ESSCALIVER study, NCT00918619).

BACKGROUND: Despite improvements in liver surgery over the past decades, hemostasis during hepatic resections remains challenging. This multicenter randomized study compares the hemostatic effect of a collagen hemostat vs. a carrier-bound fibrin sealant after hepatic resection. METHODS: Patients scheduled for elective liver resection were randomized intraoperatively to receive either the collagen hemostat (COLL) or the carrier-bound fibrin sealant (CBFS) for secondary hemostasis. The primary endpoint was the proportion of patients with hemostasis after 3 min. Secondary parameters were the proportions of patients with hemostasis after 5 and 10 min, the total time to hemostasis, and the complication rates during a 3 months follow-up period. RESULTS: A total of 128 patients were included. In the COLL group, 53 out of 61 patients (86.9 %) achieved complete hemostasis within 3 min after application of the hemostat compared to 52 out of 65 patients (80.0 %) in the CBFS group. The 95 % confidence interval for this difference [-6.0 %, 19.8 %] does not include the lower noninferiority margin (-10 %). Thus, the COLL treatment can be regarded as noninferior to the comparator. The proportions of patients with hemostasis after 3, 5, and 10 min were not significantly different between the two study arms. Postoperative mortality and morbidity were similar in both treatment groups. CONCLUSION: The collagen hemostat is as effective as the carrier-bound fibrin sealant in obtaining secondary hemostasis during liver resection with a comparable complication rate.

A randomised, multi-centre, prospective, observer and patient blind study to evaluate a non-absorbable polypropylene mesh vs. a partly absorbable mesh in incisional hernia repair.

BACKGROUND: The implantation of a polymer mesh is considered as the standard treatment for incisional hernia. It leads to lower recurrence rates compared to suture techniques without mesh implantation; however, there are also some drawbacks to mesh repair. The operation is more complex and peri-operative infectious complications are increased. Yet it is not clear to what extent a mesh implantation influences quality of life or leads to chronic pain or discomfort. The influence of the material, textile structure and size of the mesh remain unclear. The aim of this study was to evaluate if a non-absorbable, large pore-sized, lightweight polypropylene (PP) mesh leads to a better health outcome compared to a partly absorbable mesh. METHODS/DESIGN: In this randomised, double-blinded study, 80 patients with incisional hernia after a median laparotomy received in sublay technique either a non-absorbable mesh (Optilene® Mesh Elastic) or a partly absorbable mesh (Ultrapro® Mesh). Primary endpoint was the physical health score from the SF-36 questionnaire 21 days post-operatively. Secondary variables were patients' daily activity score, pain score, wound assessment and post-surgical complications until 6 months post-operatively. RESULTS: SF-36, daily activity and pain scores were similar in both groups after 21 days and 6 months, respectively. No hernia recurrence was observed during the observation period. Post-operative complication rates also showed no difference between the groups. CONCLUSION: The implantation of a non-absorbable, large pore-sized, lightweight PP mesh for incisional hernia leads to similar patient-related outcome parameters, recurrence and complication rates as a partly absorbable mesh.

DISPACT trial: a randomized controlled trial to compare two different surgical techniques of DIStal PAnCreaTectomy - study rationale and design.

BACKGROUND: Surgery is of increasing importance in the treatment and outcome of diseases of the pancreas worldwide. The incidence of pancreatic cancer (7-11/ 100,000 per year) has risen over the last years and surgical resection remains the only option for definite cure. Twenty-five percent of all resections are left of the superior mesenteric vein (distal pancreatectomy) and the appropriate closure technique for the pancreatic remnant remains unclear. Pancreatic fistulas are the most common (0-40%) and relevant postoperative complication. The optimal surgical strategy for pancreatic resection needs to be identified from the large number of surgical procedures available today. PURPOSE: To evaluate the effectiveness of the two most common surgical techniques for distal pancreatectomy: stapler versus hand-sewn closure of the pancreatic remnant. METHODS: In order to account for the uncertainty and clinical heterogeneity in the management of the pancreatic remnant following distal pancreatectomy, a study protocol is developed on the basis of a retrospective survey of patients in a center of excellence for pancreatic surgery and a systematic review with meta-analysis. RESULTS: The DISPACT trial is a multicentered, randomized, controlled and patient-and observer-blinded trial using a two-group parallel group-sequential superiority design to compare the two techniques mentioned above. It will include approximately 336 randomized patients at up to 20 centers of excellence in pancreatic surgery, who are undergoing elective distal pancreatectomy for resectable benign, malign, and neuroendocrine tumors, chronic pancreatitis and pseudocysts of the pancreatic body and tail. The combination of the rate of postoperative pancreatic fistula and mortality will be evaluated as the primary endpoint. In addition, a set of general and surgical parameters will be analyzed. Pre-specified treatment manuals and continuous intra-operative (photo-documentation of surgical procedures and blinded evaluation thereafter) and on-site monitoring will assure that the treatment of the study patients conforms to protocol and will minimize clinical heterogeneity. Due to uncertainties about the effect sizes of the primary endpoint, an a priori planned interim analysis of the primary endpoint will be conducted after 224 evaluable patients are selected in order to reassess the initially planned sample size. LIMITATIONS: Since pre-existing evidence was limited our initial sample size calculation is based on uncertain assumptions and may need to be modified in a planned interim analysis. Moreover, since surgical experience remains a potential confounder in surgical trials, learning curve bias has to be taken into account when analyzing the results. Given the participating trial sites, standardization of peri-and postoperative treatment represents a major issue of trial conduct. CONCLUSIONS: A group-sequential study design accounts for the uncertainty of pre-existing evidence. Also, standardization of surgical and postoperative care and blinded outcome assessment as well as adjustment for varying surgical expertise will contribute to a high validity and generalizability of the results.

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.

[Current status of diagnostics and therapy of complicated intraabdominal infections]. / Aktueller Stand der Diagnostik und Therapie der Peritonitis.

Regardless of improved diagnostics and therapeutic options, complicated intraabdominal infections remain a challenge in medicine. The prognosis of secondary peritonitis depends upon diagnosis and therapy in time. Diagnostic gold-standard is the computed tomography enhanced by contrast medium. Antimicrobial and supportive therapy is initiated before surgery and should be continued throughout and after the operation. Surgery aims on clearing the focus with a one-step-procedure in order to reduce perioperative morbidity and mortality.

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.

[Septic shock due to vancomycin-resistant enterococci infection. Tigecycline monotherapy]. / Septischer Schock durch Vancomycin-resistente Enterokokken. Tigecyclin-Monotherapie.

Adequate antimicrobial therapy is of crucial importance for the survival of critically ill patients with severe nosocomial infections. Tigecycline is an important therapeutic option for the treatment of infections caused by multi-resistant Gram-positive and Gram-negative bacteria including vancomycin-resistant enterococci (VRE). A large randomised study (patients with APACHE-II-score >30 excluded/mean APACHE-II-score 6) demonstrated that tigecycline is not inferior to imipenem/cilastatin for treatment of complicated intra-abdominal infections. However, no case has been reported with microbiological eradication and clinical cure in a patient with septic shock due to peritonitis caused by VRE and treatment with tigecycline monotherapy. Clinical details of a patient suffering from postoperative peritonitis are presented. The patient developed severe septic shock after pancreatic surgery (multiple organ failure, APACHE-II-score 34). As the site of anastomotic leakage was very small and could not be exactly identified, irrigation-suction drains were placed followed by closed postoperative continuous lavage. The pathogen responsible was identified as a vancomycin-resistant Enterococcus faecium, therefore monotherapy with tigecycline was started which resulted in microbiological response and clinical cure. Tigecycline is a new therapeutic option for the treatment of intra-abdominal infections and from an economic point of view financially rewarding when used as monotherapy.

Postoperative bacterial/fungal infections: a challenging problem in critically ill patients after abdominal surgery.

Critically ill patients after extended surgical procedures are at high risk for postoperative infections. The overall incidence of sepsis increased constantly over the last decade, whereas sepsis-related mortality decreased, due to new intensive care options. After extended intra-abdominal surgery the abdomen is the predominant focus of sepsis, followed by respiratory tract infections. Unspecific clinical signs lead to the diagnosis of postoperative sepsis. Early focus identification by clinical, laboratory and radiologic examination is of major importance for a promising therapy, followed by immediately initiated procedures for source control and an adequate anti-infective drug therapy. For nosocomial sepsis, the use of antimicrobial regimens with extended spectra and potent activity against both Gram-negative and Gram-positive bacterial pathogens are warranted. Fungal infections play a great role for immunocompromized patients, e.g. after solid organ transplantation or under chronic corticoid therapy. An increasing incidence of multi-drug resistance in bacterial and fungal isolates has been observed in the last years. This is becoming a growing problem also for critically ill patients after abdominal surgery. Standardized treatment protocols including supportive and adjunctive therapy and the use of modern anti-infective agents may lead to a decrease in postoperative mortality due to sepsis.

Effect of Flt3 ligand gene transfer in experimental pancreatic cancer.

BACKGROUND: Fms-like tyrosine kinase 3 receptor (Flt3) is an important receptor expressed on the cell membrane of immature antigen-presenting cells. The binding of Flt3 to its ligand (FL) activates the proliferation of dendritic cells (DCs). This mechanism is currently being evaluated in the therapy of malignant tumors. The aim of the present study was to study the effect of FL gene transfer on the immune response and tumor growth in experimental pancreatic cancer. MATERIALS AND METHODS: The rat FL was sequenced and cloned from total mRNA extract of the spleen. Transfection efficiency of subcutaneously growing rat duct-like pancreatic cancer (DSL6A) with DOTAP-/cholesterol-based liposomes was tested using a pcDNA3.1-lacZ construct. Flt3 ligand production of in vitro transfected tumor cells and in vivo transfected tumors was measured by enzyme-linked immunosorbent assay. Tumor induction was achieved in Lewis rats by a subcutaneous inoculation of syngeneic pancreatic tumor cells (DSL6A). The animals were allocated into three groups: control, mock treatment, and treatment with FL plasmid. The plasmid was injected intratumorally three times per week for 2 weeks. The total observation time was 6 weeks. RESULTS: The tumor volume was significantly lower in the FL-transfected group during the first 3 weeks. The number of responders was significantly higher in the FL group compared with control and mock treatment. The number of CD80+ DCs in the spleen was significantly higher after FL gene transfer. The responders showed a significantly higher number of splenic natural killer (NK) cells. There were no differences of infiltrating lymphocytes, proliferation, and tumor blood vessels between the groups. CONCLUSION: Intratumoral gene transfer of FL in rats activated proliferation of DCs and NK cells, which causes a moderate reduction of tumor growth. This improvement of local tumor control during the first weeks could be explained by an improved antigen presentation.

Protocol design and current status of CLIVIT: a randomized controlled multicenter relevance trial comparing clips versus ligatures in thyroid surgery.

BACKGROUND: Annually, more than 90000 surgical procedures of the thyroid gland are performed in Germany. Strategies aimed at reducing the duration of the surgical procedure are relevant to patients and the health care system especially in the context of reducing costs. However, new techniques for quick and safe hemostasis have to be tested in clinically relevance randomized controlled trials before a general recommendation can be given. The current standard for occlusion of blood vessels in thyroid surgery is ligatures. Vascular clips may be a safe alternative but have not been investigated in a large RCT. METHODS/DESIGN: CLIVIT (Clips versus Ligatures in Thyroid Surgery) is an investigator initiated, multicenter, patient-blinded, two-group parallel relevance randomized controlled trial designed by the Study Center of the German Surgical Society. Patients scheduled for elective resection of at least two third of the gland for benign thyroid disease are eligible for participation. After surgical exploration patients are randomized intraoperatively into either the conventional ligature group, or into the clip group. The primary objective is to test for a relevant reduction in operating time (at least 15 min) when using the clip technique. Since April 2004, 121 of the totally required 420 patients were randomized in five centers. DISCUSSION: As in all trials the different forms of bias have to be considered, and as in this case, a surgical trial, the role of surgical expertise plays a key role, and will be documented and analyzed separately. This is the first randomized controlled multicenter relevance trial to compare different vessel occlusion techniques in thyroid surgery with adequate power and other detailed information about the design as well as framework. If significant, the results might be generalized and may change the current surgical practice.

Comparison of Venae Sectio vs. modified Seldinger Technique for totally implantable access ports; Portas-trial [ISRCTN:52368201].

BACKGROUND: The insertion of a Totally Implantable Access Port (TIAP) is a routinely employed technique in patients who need a safe and permanent venous access. The number of TIAP implantations is increasing constantly mainly due to advanced treatment options for malignant diseases. Therefore it is important to identify the implantation technique which has the optimal benefit/risk ratio for the patient. STUDY DESIGN: A single-centre, randomized, controlled superiority trial to compare two different TIAP implantation techniques. SAMPLE SIZE: 160 patients will be included and randomized intra-operatively. ELIGIBILITY CRITERIA: Age equal or older than 18 years, patients scheduled for primary elective implantation of a TIAP in local anaesthesia and a signed informed consent. Primary endpoint: Primary success rate of the randomized technique. INTERVENTION: Venae Sectio in combination with the Seldinger Technique (guide wire and a peel away sheath) will be used to place a TIAP. Reference treatment: Conventional Venae Sectio will be used with a direct insertion of the TIAP without guide wire or peel away sheath. Duration of study: Approximately 20 months. ORGANISATION/RESPONSIBILITY: The trial will be conducted in compliance with the protocol and in accordance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The trial will also be carried out in keeping with local and regulatory requirements. The Klinisches Studienzentrum Chirurgie (KSC)--Centre of Clinical Trials in Surgery at the Department of Surgery, University Hospital Heidelberg is responsible for planning and conduction of the trial. Documentation of patient's data will be accomplished via electronical Case Report Files (eCRF) with MACRO-Software by the KSC. Randomization, data management, monitoring and biometry are provided by the independent Koordinierungszentrum für Klinische Studien (KKS)--Coordination Centre for Clinical Trails at the University of Heidelberg.

[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.

[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.

[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.

[The role of 3-D imaging and computer-based postprocessing for surgery of the liver and pancreas]. / Bedeutung der 3-D-Bildgebung und computerbasierten Nachverarbeitung für die Chirurgie der Leber und des Pankreas.

Cross-sectional imaging based on navigation and virtual reality planning tools are well-established in the surgical routine in orthopedic surgery and neurosurgery. In various procedures, they have achieved a significant clinical relevance and efficacy and have enhanced the discipline's resection capabilities. In abdominal surgery, however, these tools have gained little attraction so far. Even with the advantage of fast and high resolution cross-sectional liver and pancreas imaging, it remains unclear whether 3D planning and interactive planning tools might increase precision and safety of liver and pancreas surgery. The inability to simply transfer the methodology from orthopedic or neurosurgery is mainly a result of intraoperative organ movements and shifting and corresponding technical difficulties in the on-line applicability of presurgical cross sectional imaging data. For the interactive planning of liver surgery, three systems partly exist in daily routine: HepaVision2 (MeVis GmbH, Bremen), LiverLive (Navidez Ltd, Slovenia) and OrgaNicer (German Cancer Research Center, Heidelberg). All these systems have realized a half- or full-automatic liver-segmentation procedure to visualize liver segments, vessel trees, resected volumes or critical residual organ volumes, either for preoperative planning or intraoperative visualization. Acquisition of data is mainly based on computed tomography. Three-dimensional navigation for intraoperative surgical guidance with ultrasound is part of the clinical testing. There are only few reports about the transfer of the visualization of the pancreas, probably caused by the difficulties with the segmentation routine due to inflammation or organ-exceeding tumor growth. With this paper, we like to evaluate and demonstrate the present status of software planning tools and pathways for future pre- and intraoperative resection planning in liver and pancreas surgery.

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.

Systematic review and meta-analysis of technique for closure of the pancreatic remnant after distal pancreatectomy.

BACKGROUND: Appropriate closure of the pancreatic remnant after distal pancreatectomy is still debated. A variety of procedures have been recommended to reduce the frequency of pancreatic fistula. This review quantitatively compares the available techniques. METHODS: Original articles and abstracts published up to the end of June 2004 were searched without language restriction in the Cochrane Controlled Trials Register, Medline and Embase. Three reviewers independently assessed each study's eligibility and quality, and extracted the data. A random effects model was performed using weighted odds ratios. RESULTS: Only ten of 262 articles could be included, two randomized clinical trials and eight observational studies. Reported postoperative morbidity varied from 13.3 to 64 per cent. The primary outcome measure, pancreatic fistula rate, occurred within the range 0-60.9 per cent. Meta-analysis of the six studies comparing stapler versus hand-sutured closure showed a non-significant combined odds ratio for occurrence of a pancreatic fistula of 0.66 (95 per cent confidence interval 0.35 to 1.26, P = 0.21) in favour of stapler closure. CONCLUSIONS: The quality and quantity of information extracted from the available trials are insufficient to enable any firm conclusion to be drawn on the optimal surgical technique of pancreatic stump closure; there is a trend in favour of the stapling technique.

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases.

Colorectal carcinomas (CRCs) with high microsatellite instability (MSI-H) share clinicopathological features distinctly different from their microsatellite stable (MSS) counterparts. Unlike MSS cancers, MSI-H CRCs occur predominantly in the right-sided colon and are often characterised by a strong lymphocyte infiltration. A poor differentiation pattern is found in most MSI-H CRCs, even though patients with MSI-H carcinomas seem to have a significantly longer survival after surgical resection. To clarify which factors contribute to the obvious paradoxon of a more favourable prognosis of MSI tumours, several clinical and histopathological features as well as the microsatellite status were evaluated in 120 colorectal cancer cases fulfilling clinical criteria (Bethesda) indicative for familial colorectal cancer. Microsatellite instability status and lymphocyte infiltration were related to tumour stage and patients' follow-up. Statistical analysis confirmed well-known relations, such as enhanced lymphocyte infiltration accompanied by Crohn's like reaction (CLR) in MSI-H cancers (CLR+ in 27 out of 47 MSI-H vs 14 out of 71 MSS CRCs, P<0.001). However, after stratification for depth of local invasion and penetration of the primary tumour, T3 tumours displaying MSI had a significantly lower rate of distant metastases (M1 in four out of 35 MSI-H vs 20 out of 41 MSS CRCs, P<0.001). A similar tendency was observed for CLR-positive CRCs (M1 in six out of 29 CLR+ vs 17 out of 45 CLR- CRCs, P=0.13). In a logistic regression model, the MSI-H phenotype and the presence of CLR were independent predictors of a low UICC stage (P=0.006 and 0.04, respectively). These data, together with the recent definition of highly immunogenic neo-antigens expressed in MSI-H tumour cells, suggest that MSI-H CRCs elicit a protective host response that may prevent metastasis formation.

[Surgical strategies for the prevention of gastrointestinal tumours]. / Chirurgische Ansätze zur Prävention bei gastrointestinalen Tumoren.

Over many decades the surgical treatment of gastrointestinal tumours was limited to cases of manifest malignancy and was performed with curative or palliative intent. Molecular diagnostics have now led to an optimised characterisation of different sporadic and hereditary tumour entities. Furthermore, a number of diseases which are an obligatory precancerosis or which carry a very high risk of cancer in their long courses have now been identified. Parallel to these developments, a dramatic reduction of morbidity has been achieved in major abdominal surgery due to more subtle and blood-sparing surgical techniques and mortality has been reduced to a minimum even in the most major procedures. This combination nowadays safely allows preventive or preventive extended surgical measures in cases where interventional therapy cannot be adequately employed.