Prospective multicenter registration study of colorectal cancer: significant variations in radicality and oncosurgical quality-Swiss Group for Clinical Cancer Research Protocol SAKK 40/00.

PURPOSE: This study aimed to investigate in a multicenter cohort study the radicality of colorectal cancer resections, to assess the oncosurgical quality of colorectal specimens, and to compare the performance between centers. METHODS: One German and nine Swiss hospitals agreed to prospectively register all patients with primary colorectal cancer resected between September 2001 and June 2005. The median number of eligible patients with one primary tumor included per center was 95 (range 12-204). RESULTS: The following variations of median values or percentages between centers were found: length of bowel specimen 20-39 cm (25.8 cm), maximum height of mesocolon 6.5-12.5 cm (9.0 cm), number of examined lymph nodes 9-24 (16), distance to nearer bowel resection margin in colon cancer 4.8-12 cm (7 cm), and in rectal cancer 2-3 cm (2.5 cm), central ligation of major artery 40-97 % (71 %), blood loss 200-500 ml (300 ml), need for perioperative blood transfusion 5-40 % (19 %), tumor opened during mobilization 0-11 % (5 %), T4-tumors not en-bloc resected 0-33 % (4 %), inadvertent perforation of mesocolon/mesorectum 0-8 % (4 %), no-touch isolation technique 36-86 % (67 %), abdominoperineal resection for rectal cancer 0-30 % (17 %), rectal cancer specimen with circumferential margin ≤1 mm 0-19 % (10 %), in-hospital mortality 0-6 % (2 %), anastomotic leak or intra-abdominal abscess 0-17 % (7 %), re-operation 0-17 % (8 %). CONCLUSION: In colorectal cancer, surgery considerable variations between different centers were found with regard to radicality and oncosurgical quality, suggesting a potential for targeted improvement of surgical technique.

Cilostazol improves hepatic blood perfusion, microcirculation, and liver regeneration after major hepatectomy in rats.

Major hepatectomy or small-for-size liver transplantation may result in postoperative liver failure. So far, no treatment is available to improve liver regeneration. Herein, we studied whether cilostazol, a selective phosphodiesterase III inhibitor, is capable of improving liver regeneration after major hepatectomy. Sprague-Dawley rats (n = 74) were treated with cilostazol (5 mg/kg daily) or a glucose solution and underwent either 70% liver resection or a sham operation. Before and after surgery, hepatic arterial and portal venous blood flow and hepatic microvascular perfusion were analyzed. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, western blotting, and bile excretion analysis. Cilostazol significantly increased hepatic blood flow and microcirculation before and after hepatectomy in comparison with sham-operated controls. This was associated with an elevation of hepatic vascular endothelial growth factor expression, an increase of hepatocellular proliferation, and an acceleration of liver regeneration. Furthermore, cilostazol protected the tissue of the remnant liver as indicated by an attenuation of hepatocellular disintegration. In conclusion, cilostazol increases hepatic blood perfusion, microcirculation, and liver regeneration after a major hepatectomy. Thus, cilostazol may represent a novel strategy to reduce the rate of liver failure after both extended hepatectomy and small-for-size liver transplantation.

Darbepoetin-α accelerates neovascularization and engraftment of extrahepatic colorectal metastases.

PURPOSE: Erythropoietin and its analogue darbepoetin (DPO)-α have been shown to improve liver function and regeneration after partial hepatectomy (Phx). However, previous experimental studies have also shown that DPO significantly enhances Phx-induced engraftment of colorectal liver metastases by increasing neovascularization and tumor cell proliferation. Therefore, the present study analyzed whether DPO affects engraftment and neovascularization of extrahepatic colorectal metastases after major hepatectomy. METHODS: Green fluorescent protein-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Animals received a single dose of DPO (10 µg/kg body weight) at the day of tumor cell implantation (day 0). Phosphate-buffered saline-treated animals served as controls. To study whether the effect of DPO is influenced by Phx, additional animals with and without DPO treatment underwent 70% Phx at day 0. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied repetitively over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry. RESULTS: In nonhepatectomized animals, DPO significantly accelerated tumor cell engraftment and slightly enhanced tumor neovascularization. Tumor cell migration and host tissue infiltration were not affected by DPO. In hepatectomized animals, DPO slightly enhanced tumor growth and significantly accelerated tumor neovascularization, but did not affect tumor cell migration and infiltration. CONCLUSION: The present study indicates that DPO accelerates extrahepatic engraftment of colorectal cancer cells, most probably by stimulating the process of neovascularization.

Is surgical quality more important than radicality? Long-term outcomes of stage I-III colon cancer (SAKK 40/00).

BACKGROUND: To prospectively determine the influence of variations of surgical radicality and surgical quality on long-term outcome in patients with stage I-III colon cancer. METHODS: From a prospective multicenter cohort study including 1040 patients undergoing surgery for colorectal cancer from 09/2001 to 06/2005 in nine Swiss and one German hospital, 423 patients with stage I-III colon cancer were selected and analyzed. Surgeons and pathologists filled in standardized forms prospectively assessing items of oncosurgical radicality and quality. Patients had standardized follow-up according to national guidelines. RESULTS: Follow-up was median 6.2 years (range 0.3-10.4) showing a 5-year disease-free survival/overall survival of 83 %/87 % in stage I (n = 85), 69 %/77 % in stage II (n = 187), and 53 %/61 % in stage III (n = 151) colon cancer. Despite remarkable variations of oncosurgical radicality and quality, the multivariate model revealed that mainly quality items correlated significantly with disease-free survival (surgical tumor lesion HR 2.12, p = 0.036, perioperative blood transfusion HR 1.67, p = 0.018, emergency resection HR 1.74, p = 0.035) and overall survival (early venous ligation HR 0.66, p = 0.023, surgical tumor lesion HR 2.28, p = 0.027, perioperative blood transfusion HR1.79, p = 0.010, emergency resection HR 1.88, p = 0.026), while radicality parameters (length of specimen, distance of the tumor to nearest bowel resection site, number of lymph nodes, height of resected mesocolon and of central vascular dissection) did not. CONCLUSION: Surgical quality seems to have a stronger impact on oncologic long-term outcome in stage I - III colon cancer than surgical radicality.

Reperfusion of liver graft during transplantation: techniques used in transplant centres within Eurotransplant and meta-analysis of the literature.

It remains unclear which liver graft reperfusion technique leads to the best outcome following transplantation. An online survey was sent to all transplant centres (n = 37) within Eurotransplant (ET) to collect information on their technique used for reperfusion of liver grafts. Furthermore, a systematic review of all literature was performed and a meta-analysis was conducted based on patients' mortality, number of retransplantations and incidence of biliary complications, depending on the technique used. Of the 28 evaluated centres, 11 (39%) reported performing simultaneous reperfusion (SIMR), 13 (46%) perform initial portal vein reperfusion (IPR), 1 (4%) performs an initial hepatic artery reperfusion (IAR) and 3 (11%) perform retrograde reperfusion (RETR). In 21 centres (75%), one reperfusion technique is used as a standard, but in only one centre is this decision based on available literature. Twenty centres (71%) said they would agree to participate in randomized controlled trials (RCT) if required. For meta-analysis, IAR vs. IPR, SIMR vs. IPR and RETR vs. IPR were compared. There was no difference between any of the techniques compared. There is no consensus on a preferable reperfusion technique. Available evidence does not help in the decision-making process. There is thus an urgent need for multicentric RCTs.

Hepatic arterial infusion but not systemic application of cetuximab in combination with oxaliplatin significantly reduces growth of CC531 colorectal rat liver metastases.

PURPOSE: Systemic chemotherapy still represents the gold standard in the treatment of irresectable colorectal liver metastases. Modern anticancer agents like the monoclonal antibody cetuximab have improved the outcome of patients in clinical studies. As hepatic arterial infusion (HAI) is capable to potentially increase the anticancer effect of cytostatics, we herein studied whether HAI of cetuximab (CE) as a single agent or in combination with oxaliplatin (OX) exerts increased anticancer effects compared to the systemic application (SYS) of the drugs. METHODS: WAG/Rij rats were randomized to eight groups and underwent 10 days after subcapsular hepatic tumor implantation either HAI or SYS of CE, OX, or the combination of both agents (CE + OX). Saline-treated animals served as controls. Tumor volume was measured at days 10 and 13 using three-dimensional ultrasound. On day 13, liver and tumor tissue was sampled for histological and immunohistochemical analysis. RESULTS: In controls, the tumor volume significantly increased from day 10 to 13. Application of OX alone via HAI or SYS did not inhibit tumor growth compared to controls. SYS of CE or CE + OX did also not reduce tumor growth. In contrast, HAI of CE and CE + OX significantly inhibited tumor growth. HAI of CE significantly reduced tumor vascularization as measured by the number of platelet endothelial cell adhesion molecule-1-positive cells and significantly increased the number of apoptotic tumor cells as measured by the cellular caspase-3 expression. CONCLUSION: HAI of CE and CE + OX reduces tumor growth of colorectal rat liver metastases involving the inhibition of angiogenesis and induction of tumor cell apoptosis.

Darbepoetin-α promotes neovascularization and cell proliferation in established colorectal liver metastases.

BACKGROUND: The erythropoietin-analogue darbepoetin-α (DPO) improves liver function and regeneration after hepatectomy (Phx), however, also enhances Phx-induced tumor cell engraftment and neovascularization. Because it is unknown whether DPO also enhances the growth of established tumors, we herein studied the effect of DPO on established colorectal liver metastases after Phx. METHODS: CT26.WT cells were implanted into the liver of BALB/c mice. Five days after tumor establishment, animals underwent 50% Phx and received 10 µg/kgBW DPO or saline. Non-Phx animals with DPO or saline-treatment served as controls. Seven days after Phx tumors were analyzed regarding blood vessel formation, leukocyte adhesion, cell proliferation, apoptotic cell death, and growth using intravital fluorescence microscopy, histology, and immunohistochemistry. RESULTS: The growth of established colorectal liver metastases was slightly stimulated after DPO-treatment in hepatectomized and non-hepatectomized animals. However, tumor vessel formation and tumor cell proliferation were significantly enhanced after DPO-treatment in hepatectomized and non-hepatectomized mice compared with controls. Apoptotic cell death and leukocyte-endothelial cell interaction were significantly reduced after DPO-treatment. CONCLUSION: Our study indicates that DPO-treatment promotes neovascularization and cell proliferation in established colorectal liver metastases of hepatectomized and non-hepatectomized mice. DPO-application in patients with colorectal liver metastases might promote tumor progression and should therefore be avoided.

Evidence for tumor cell spread during local hepatic ablation of colorectal liver metastases.

INTRODUCTION: The aim of the present study was to analyze the impact of cryosurgery (CRYO) on liver metastases compared to other thermoablative techniques. In a rat liver metastases model, evidence for tumor cell spread was analyzed comparing CRYO, radiofrequency ablation (RFA), and laser-induced thermotherapy (LITT). METHODS: In an experimental study, we compared cell spillage in the washout of isolated perfused rat livers undergoing thermal ablation. Within the same model, CC531-GFP rat liver tumors were treated with CRYO, RFA, or LITT and the number of vital tumor cells within the perfusate was measured. Matrix metalloproteinases (MMP-2, MMP-9) were analyzed after in vivo ablation of rat colorectal liver metastases in the third experimental model. RESULTS: Our data showed pronounced washout of cells after CRYO with a higher amount of intravascular cells and cell detritus compared to RFA and LITT. Only the effluent fluid of cryosurgery-treated livers revealed GFP-stained tumor cells. MMP-2 and MMP-9 expression was significantly higher after cryosurgery than after RFA and LITT. CONCLUSION: When using thermoablative techniques, intravascular metastatic cell spillage is highest in CRYO, and increased expression of matrix metalloproteinases may further facilitate tumor cell spread. Therefore, RFA and LITT may be preferable whenever surgical resection of liver tumors is impossible.

Normative values in anorectal manometry using microtip technology: a cohort study in 172 subjects.

PURPOSE: The aims of this study were to obtain normative values in resting/squeeze pressure and surface electromyography (s-EMG) in anorectal manometry using microtip technology and to determine the relationship between objective measurable values, gender and age in a cohort with no anorectal disorders. METHODS: One hundred seventy-two white central European subjects (106 males/66 females) were recruited prior to left colonic or upper rectal surgery and studied by anorectal rapid pull-through manometry with a microtip transducer system and endoanal s-EMG using a bipolar plug electrode. s-EMG patterns were determined as plateau, peak and decrease by a blinded co-investigator. Objective measurable sphincter pressures and s-EMG values were correlated with gender, age and s-EMG patterns. RESULTS: Squeeze pressure, voluntary pressure as well as s-EMG amplitude and its area under the curve were significantly lower in women compared to men (p < 0.001 each), whereas resting pressure showed no gender differences. s-EMG patterns were strongly influenced by gender. Male patients showed significantly more plateau pattern whereas peak pattern was significantly more often in women. In both genders, the peak pattern was associated with significant higher squeeze pressures. In all measurements, we found considerable inter-individual variations being higher in elder patients. There was no manometric parameter correlating with age. CONCLUSIONS: Gender is the strongest factor influencing objective measurable manometric data for healthy men and women. There are significant gender differences concerning squeeze patterns. All manometric values should be interpreted in the context of gender and of methodology used. Large prospective cohort studies matched for gender are necessary to clarify the effect of ageing on anal sphincter strength.

Estimate or calculate? How surgeons rate volumes and surfaces.

PURPOSE: Surgeons frequently describe the shape of intraoperative findings using visual judgement and their own sense of proportion or describing these findings in comparison to commonly used or metaphoric subjects. The aim of the study was to analyse the reliability of surgeon's estimations of dimensions. METHODS: The study was performed in two phases. First, physicians had to estimate the metric proportions of four well-known objects. Second, surgeons were asked intraoperatively to estimate the liver resection surface after partial hepatectomy. The exact surface of the resection plane was measured using computed tomography-guided planimetry of the resection specimen. Physician's estimations and the exact measurements of the well-known objects and the liver resection surface were compared. Systematic error was defined by the natural logarithm of estimated/real size. RESULTS: We found a large individual discrepancy in estimating the metric proportions of commonly used objects and a tendency to underestimate both commonly used objects and liver resection surface. Experienced liver surgeons were more accurate in estimating liver resection surface compared with younger staff members. CONCLUSIONS: We found a large bias in estimating the dimension of both commonly used objects and the surface area of liver parenchyma transection. Obviously, estimating errors are more influenced by the individual subject who estimates than by the object itself. In clinical routine, surgeons should rely more on simple measuring devices than on their own sense of proportion. Education in how to estimate more correctly human liver resection surfaces can be achieved by ex vivo studies using porcine livers.

How to ensure the survival of the surgeon-scientist? The Homburg Program.

BACKGROUND: Academic surgery requires competence in research, teaching, and patient care. Because of the increasing complexity of both surgical research and clinical surgery, and additional skills necessary for adequate patient care, including economics, management, and organization, it becomes more and more difficult to provide an attractive education for surgeon-scientists. This has resulted in a dramatic decline in the number of surgeon-scientists in the past and alarms us to systematically restructure our research training system. DISCUSSION: We herein introduce a program involving the clinical departments of surgery, trauma surgery, and cardiac-thoracic surgery as well as a surgical research institution. The program allows the clinical departments to sharpen their overall research profile and facilitates the establishment of competent working groups, guaranteeing long-term research activities on a high scientific level. The program involves both surgical residents and medical students, who will represent our future generation of academic surgeons, ensuring the survival of the surgeon-scientist.

Parenchyma-preserving hepatic resection for colorectal liver metastases.

BACKGROUND: Hepatic resection of colorectal liver metastases is the only curative treatment option. As clinical and experimental data indicate that the extent of liver resection correlates with growth of residual metastases, the present study analyzes the potential benefit of a parenchyma-preserving liver surgery approach. METHODS: Data from a prospectively maintained database of patients undergoing liver resection for colorectal metastases were reviewed. Evaluation of outcome was performed using the Kaplan-Meier method. Correlations were calculated between clinical-pathological variables. RESULTS: One hundred sixty-three patients underwent 198 liver resections for colorectal metastases: 26 major hepatectomies, 65 minor anatomical resections, 78 non-anatomical resections, as well as 29 combinations of minor anatomical and non-anatomical procedures. Overall 1-, 3-, and 5-year survival was 93%, 62%, and 40%, respectively. Patients with repeated liver resections had a 5-year survival of 27%. Interestingly, large dissection areas were associated with a significant reduction of the 5-year survival rate (33%). Five-year survival after major hepatectomy was not significantly reduced. CONCLUSION: For colorectal liver metastases, minor resections offer a prolonged survival compared to major hepatectomies. As patients with stage IV colorectal disease are candidates for repeat resections, preservation of hepatic parenchyma is of increasing importance in the setting of multi-modal and repeated therapy approaches.

Netrin-1 mediates early events in pancreatic adenocarcinoma progression, acting on tumor and endothelial cells.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. It is characterized by substantial tumor cell invasion and early-stage metastasis. We developed an in vivo model to analyze interactions between cancer and stromal cells during early stages of PDAC. METHODS: Human pancreatic adenocarcinoma cells were grafted onto the chick chorioallantoic membrane (CAM). Human and chicken GeneChips were used simultaneously to study gene regulation during PDAC cell invasion. Bioinformatic analysis was used to identify human orthologs and cell specificity of gene expression. The effects of netrin-1 encoded by NTN1 were investigated in adhesion, invasion, and apoptosis assays. The effects of NTN1 silencing with small interfering RNAs were investigated in PDAC cells in vivo. NTN1 expression was measured in human PDAC samples. RESULTS: PDAC cells rapidly invade the CAM stroma and remodel the CAM vasculature. Around 800 stromal genes were up-regulated by >2-fold; the angiogenesis regulators vascular endothelial growth factor D, thrombospondin 1, and CD151 were among the most highly regulated genes. Silencing of tumor cell NTN1, which is up-regulated 4-fold in the PDAC model, inhibited tumor cell invasion in vivo. Netrin-1 conferred apoptosis resistance to tumor and endothelial cells in vitro, induced their invasion, and provided an adhesive substrate for tumor cells. NTN1 and its gene product are strongly overexpressed in human PDAC samples. CONCLUSIONS: We developed a useful tool to study the invasive mechanisms of early-stage PDAC. Netrin-1 might be an important regulator of pancreatic tumor growth that functions in tumor and endothelial cells.

CXC receptor-4 mRNA silencing abrogates CXCL12-induced migration of colorectal cancer cells.

BACKGROUND: Interactions between CXCR4 and its ligand CXCL12 have been shown to be involved in cancer progression in colorectal cancer (CRC). We performed a comparative CXCL12/CXCR4 expression analysis and assessed the effect of external CXCL12 stimulation on migration of CRC cells without and with CXCR4 inhibition. METHODS: Expression of CXCL12/CXCR4 was assessed by quantitative real-time PCR, ELISA and immunohistochemistry in resection specimens of 50 CRC patients as well as in the corresponding normal tissues and in three human CRC cell lines with different metastatic potential (Caco-2, SW480 and HT-29). Migration assays were performed after stimulation with CXCL12 and CXCR4 was inhibited by siRNA and neutralizing antibodies. RESULTS: In CRC tissues CXCL12 was significantly down-regulated and CXCR4 was significantly up-regulated compared to the corresponding normal tissues. In cell lines CXCR4 was predominantly expressed in SW480 and less pronounced in HT-29 cells. CXCL12 was only detectable in Caco-2 cells. CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells. This effect was significantly abrogated by neutralizing anti-CXCR4 antibody as well as by CXCR4 siRNAs (P < 0.05). CONCLUSIONS: CXCR4 expression was up-regulated in CRC and CXCL12 stimulation increased migration in CXCR4 bearing cell lines. Migration was inhibited by both neutralizing CXCR4 antibodies and CXCR4 siRNAs. Thus, the expression and functionality of CXCR4 might be associated with the metastatic potential of CRC cells and CXCL12/CXCR4 interactions might therefore constitute a promising target for specific treatment interventions.

Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies.

Chemokines have been proposed to contribute to tumour growth and metastatic spread of several cancer entities. Here, we examined the relative levels of CXCL12/CXCR4 in resection specimens from patients with different malignant and non-malignant colorectal diseases as well as colorectal liver metastases (CRLM). CXCL12/CXCR4 mRNA and protein expression profiles were assessed by quantitative real-time PCR, Western blot analysis, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry in resection specimens from patients with ulcerative colitis (UC; n = 15), colorectal adenoma (CRA; n = 15), colorectal adenocarcinoma (CRC; n = 47) and CRLM (n = 16). Corresponding non-affected tissues served as control. In contrast to UC tissues, CXCL12 showed a distinct down-regulation in CRA, CRC and CRLM specimens, whereas the corresponding receptor CXCR4 demonstrated a significant up-regulation in CRC and CRLM related to corresponding non-affected tissues (p < 0.05, respectively). Our results strongly suggest an association between CXCL12/CXCR4 expression and the induction of CRA, CRC and the development of CRLM. Therefore, CXCR4 may be a potential target for specific therapeutic interventions.

Split-liver procedure and inflammatory response: improvement by pharmacological preconditioning.

BACKGROUND: Final outcome of split-liver (SL) transplantation is impaired due to an increased rate of vascular complications and primary non-function. Herein, we hypothesized that an in situ split-liver procedure induces an inflammatory response and a deterioration of graft quality. We further studied whether graft quality can be improved by pharmacologic preconditioning. MATERIAL AND METHODS: SL-procedure was performed in rats. One group (SL-HPP; n = 8) was pretreated according to a defined protocol [Homburg preconditioning protocol (HPP)], including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. A second SL group (SL-Con; n = 8) received NaCl. Untreated non-SL served as controls (Sham; n = 8). Cytokines release, leukocyte invasion, endothelial activation and liver morphology were studied directly after liver harvest and after 8 h cold storage. Lung tissue was studied to determine remote injury. RESULTS: The SL-procedure induced an increase of TNF-α concentration, intercellular-adhesion-molecule 1 (ICAM-1) expression, leukocytic-tissue infiltration and vacuolization. This was associated with an increased number of apoptotic hepatocytes. HPP reduced TNF-α release, ICAM-1 expression, the number of infiltrated leukocytes, as well as hepatocellular vacuolization and apoptosis. In lung tissue, the SL-procedure caused an increased IL-1 and IL-6 concentration and leukocyte infiltration. CONCLUSIONS: HPP was capable of abrogating cytokine-mediated leukocytic response. Pharmacologic preconditioning of liver donors prevents the SL procedure-mediated inflammatory response, resulting in an improved graft quality.

Popular belief meets surgical reality: impact of lunar phases, Friday the 13th and zodiac signs on emergency operations and intraoperative blood loss.

BACKGROUND: The influence of superstition, moon calendars, and popular belief on evidence-based medicine is stunning. More than 40% of medical staff is convinced that lunar phases can affect human behavior. The idea that Friday the 13th is associated with adverse events and bad luck is deep-rooted in the population of Western industrial countries. The aim of the present study was to test the hypothesis that these myths are transferable to real-life surgery. METHODS: We analyzed the extent to which moon phases, zodiac signs, and Friday the 13th influence blood loss, emergency frequency, and intestinal perforations by evaluating the operation records of all 27,914 consecutive patients of our institution undergoing general, visceral, or vascular surgery between August 2001 and August 2010. Dates of surgery were allocated to lunar phases and to zodiac signs, as well as to Friday the 13th. RESULTS: A total of 111 lunar cycles and 15 Fridays the 13th occurred within the 3,281-day observation period. Patients' characteristics did not differ in lunar phases, zodiac signs, or Fridays the 13th. Full moon phases, the presence of Friday the 13th, and zodiac signs influenced neither intraoperative blood loss nor emergency frequency. No statistical peaks regarding perforated aortic aneurysms and gastrointestinal perforations were found on full moon or Friday the 13th. CONCLUSIONS: Scientific analysis of our data does not support the belief that moon phases, zodiac signs, or Friday 13th influence surgical blood loss and emergency frequency. Our data indicate that such beliefs are myths far beyond reality.

Contribution of final-year medical students to operation room performance--economical and educational implications.

PURPOSE: The so-called "practical year" is the last part of medical students' education in Germany. Without being paid, final-year medical students have to work for 1 year under supervision in academic teaching hospitals. It is mandatory for every student to rotate to a surgical department for 4 months. The aim of the present study was to assess the working time contribution of final-year medical students on operation room performance at the surgical department of a university hospital. METHODS: Over an 8-year period, purely surgical times of 24,214 operations in 2,792 days were analyzed with special regard to final-year medical students' participation rate. Students' cumulative workload in the operating room was compared to that of surgical residents. RESULTS: Mean participation rate of final-year medical students was 47.8%, being higher in elective surgery than in emergency surgery (53.9% vs. 24.7%; p < 0.001). When students participated in operations, mean daily cumulative working time of student's cohort was 10.3 ± 0.12 h. Daily cumulative workload of medical students in the operating room strongly correlated with both medical doctors' cumulative workload (r (2) = 0.573) and daily workload of the team (r (2) = 0.740, p < 0.001 each). Final-year medical students assisted significantly more often in time-consuming operations. CONCLUSION: Final-year medical students contribute significantly to surgical operation room performance, similarly but less intensively than residents. Employment of students may counterbalance staff shortage in operating rooms. Therefore, it is likely that the German health care system relies on unpaid medical students to minimize the total cost of surgery. According to the extent of workload accomplished by final-year medical students, a remuneration of the "practical year" seems reasonable.

Multidrug donor preconditioning prevents cold liver preservation and reperfusion injury.

PURPOSE: Primary graft dysfunction still represents a major challenge in liver transplantation. We herein studied in an isolated rat liver perfusion model whether a multidrug donor preconditioning (MDDP) can not only reduce but also completely prevent cold ischemia-reperfusion injury. METHODS: MDDP included curcumin, simvastatin, N-acetylcysteine, erythropoietin, pentoxyphylline, melatonin, glycine, and methylprednisolone. Postischemic reperfusion was performed after 24 h cold storage in histidine-tryptophan-ketoglutarate solution with 37°C Krebs Henseleit bicarbonate buffer. RESULTS: Cold hepatic ischemia-reperfusion resulted in a massive K(+) release, protein loss, and aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase elevation. This was associated with increased malondialdehyde formation, enhanced tumor necrosis factor-alpha and interleukin-6 production, pronounced leukocytic tissue infiltration, and apoptotic cell death. CONCLUSIONS: MDDP abolished the inflammation response and was capable of completely preventing the manifestation of parenchymal injury. Thus, MDDP potentiates the protective effects reported after single-drug donor preconditioning and may therefore be an interesting approach to improve the outcome in clinical liver transplantation.

CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF-1.

Recent studies have shown that the chemokine stromal cell-derived factor (SDF)-1 and its receptor CXCR4 are involved in the metastatic process of colorectal cancer. The impact of SDF-1 on the stimulated metastatic growth during hepatectomy-associated liver regeneration is unknown. With the use of a heterotopic murine colon cancer model, we analyzed whether blockade of SDF-1 inhibits angiogenesis and extrahepatic growth of colorectal cancer after liver resection. Functional neutralization of SDF-1 by 1 mg/kg body weight anti-SDF-1 antibody only slightly delayed the initial tumor cell engraftment but also did not reduce the size of established extrahepatic tumors compared with controls. Tumor cell apoptosis was increased by anti-SDF-1 treatment only during the early 5-9-day period of tumor cell engraftment, but was found significantly decreased during the late phase of tumor growth. The initial delay of tumor cell engraftment was associated with an increase of tumor capillary density and microvascular permeability. This was associated with an increased vascular endothelial growth factor (VEGF) expression and an enhanced tumor cell invasion of the neighboring tissue. In contrast to the neutralization of SDF-1, blockade of the SDF-1 receptors CXCR4 and CXCR7 significantly reduced tumor capillary density and tumor growth. Thus, our study indicates that neutralization of SDF-1 after hepatectomy is not capable of inhibiting angiogenesis and growth of extrahepatic colorectal tumors, because it is counteracted by the compensatory actions through an alternative VEGF-dependent pathway.