Multicenter double-blinded randomized controlled trial of standard abdominal wound edge protection with surgical dressings versus coverage with a sterile circular polyethylene drape for prevention of surgical site infections: a CHIR-Net trial (BaFO; NCT01181206).

OBJECTIVE: To determine whether circular plastic wound edge protectors (CWEPs) significantly reduce the rate of surgical site infections (SSIs) in comparison to standard surgical towels in patients undergoing laparotomy. BACKGROUND: SSIs cause substantial morbidity, prolonged hospitalization, and costs and remain one of the most frequent surgical complications. CWEPs have been proposed as a measure to reduce the incidence of SSIs. METHODS: In this randomized controlled, multicenter, 2-arm, parallel-group design, patient- and observer-blinded trial patients undergoing open elective abdominal surgery were assigned to either intraoperative wound coverage with a CWEP or standard coverage with surgical towels. Primary endpoint was superiority of intervention over control in terms of the incidence of SSIs within a 30-day postoperative period. RESULTS: Between September 2010 and November 2012, 608 patients undergoing laparotomy were randomized at 16 centers across Germany. Three patients in the device group and 11 patients in the control group did not undergo laparotomy. Patients' and procedural characteristics were well balanced between the 2 groups. Forty-eight patients discontinued the study prematurely, mainly because of relaparotomy (control, n=9; intervention, n=9) and death (control, n=4; intervention, n=7). A total of 79 patients experienced SSIs within 30 days of surgery, 27 of 274 (9.9%) in the device group and 52 of 272 (19.1%) in the control group (odds ratio=0.462, 95% confidence interval: 0.281-0.762; P=0.002). Subgroup analyses indicate that the effect could be more pronounced in colorectal surgery, and in clean-contaminated/contaminated surgeries. CONCLUSIONS: Our trial shows that CWEPs are effective at reducing the incidence of SSIs in elective and clean or clean-contaminated open abdominal surgery.

Liver tissue concentrations of levofloxacin after single intravenous administration of 500 mg for antibiotic prophylaxis in liver surgery.

High concentrations of levofloxacin in soft tissues and body fluids, including gallbladder and bile, have been repeatedly reported, but no study on its penetration into human liver tissue after single-shot application has yet been published. Levofloxacin 500 mg was administered intravenously to 28 patients scheduled for liver resection. Blood samples were taken after the end of infusion and at the time of liver resection; concomitantly, a tissue specimen was also obtained. Serum concentrations (mean+/-standard deviation) 10 min after the end of infusion were 6.59+/-1.72 microg/mL and decreased only slightly throughout the operation. At the time of liver resection, levofloxacin concentrations in liver tissue were 18.14+/-5.44 microg/g with corresponding serum concentrations of 4.84+/-1.37 microg/mL. The tissue/serum ratio (3.72+/-0.73 at the time of resection) was nearly constant over the sampling period ranging from 0.4 h to 3.8 h after the end of infusion, indicating a fast distribution of levofloxacin into the liver tissue. The tissue concentrations showed a significant correlation with serum concentrations and an inverse correlation with the grade of steatosis but not cirrhosis. Infectious post-operative complications were not observed. Levofloxacin penetrates into liver tissue exceptionally well and fast and is therefore a good candidate for antibiotic prophylaxis before invasive hepatobiliary procedures such as liver surgery as well as for treatment of biliary tract infections caused by levofloxacin-susceptible microorganisms.

Differential response of arteries and veins to bipolar vessel sealing: evaluation of a novel reusable device.

BACKGROUND: A variety of energy-based techniques for arterial and venous vessel ligation have recently been introduced. Using a porcine model we studied the efficacy of the novel reusable BiClamp versus the standard disposable LigaSure bipolar vessel sealing device. We also compared whether arteries respond differently than veins upon sealing. MATERIALS AND METHODS: In five Swabian Hall pigs, splenectomy and nephrectomy were performed using two different bipolar vessel sealing devices. Measurements of the sealed arteries and veins (diameter 2-7 mm) included rate of seal failure, burst strength, and heat-associated vascular wall morphologic appearance. An additional three animals underwent splenectomy, salpingo-oophorectomy, and small bowel resection, and vessel seals were studied histologically after a seven-day survival period for vessel wall fusion, inflammation, and fibrous organization. RESULTS: Sealing was highly successful, with only one seal failure overall and thus no difference between the two instruments analyzed. The burst pressures of BiClamp-sealed arteries (842 +/- 117 mm Hg) did not differ from that of arteries sealed with LigaSure (856 +/- 102 mm Hg), but were significantly higher than the burst pressures of veins (155 +/- 26 and 216 +/- 71 mm Hg, respectively) (P < 0.05). Independent of the sealing device used, thermal spread was found increased in veins compared to arteries. Histologic analysis after seven days revealed appropriate healing of the vessel wall, including thrombus fibrosis, fibroblast proliferation, and collagen deposition. With both devices, however, the venous but not the arterial walls still presented with massive inflammatory cell infiltrates. CONCLUSION: Our study indicates that the BiClamp device is as appropriate as the LigaSure instrument to successfully ligate 2-7 mm arteries and veins, demonstrating supraphysiological bursting strengths and adequate lumenal fusion healing. However, veins are more prone to collateral tissue damage and inflammatory wall infiltration.

Use of spontaneous Epstein-Barr virus-lymphoblastoid cell lines genetically modified to express tumor antigen as cancer vaccines: mutated p21 ras oncogene in pancreatic carcinoma as a model.

Spontaneous Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (SP-LCLs) can be easily obtained from latently EBV-infected cancer patients and used as a source of antigen-presenting cells (APCs) for immunotherapy. Using point-mutated (codon 12) p21(ras) (muRas) as a model tumor antigen, we evaluated the practicability of using genetically modified SP-LCLs as cancer vaccines for patients with pancreatic cancer expressing mutated Ras (muRas). The repeated stimulation of peripheral blood mononuclear cells (PBMCs) from patients with muRas-LCLs elicited a strong, muRas-specific T cell response. A significant cytotoxic activity against EBV virus proteins or components of the expression vector was not observed. The T cells were able to recognize naturally presented muRas, as shown by their cytotoxicity against muRas (Gly-12 to Val-12 or Asp-12)-expressing tumor cells. The T cell response was mainly MHC class I restricted, and peptides containing amino acids 5 to 14 of muRas-Val-12 and muRas-Asp-12 were identified as immunogenic peptides for HLA-A2. In contrast to the situation in patients with putatively muRas-primed T cells, muRas-LCLs were not able to prime naive T lymphocytes from healthy controls. Vaccination of a pancreatic cancer patient with muRas-LCL induced muRas-specific T cells in PBMCs after 4 weeks. We conclude that genetically modified muRas-LCLs can efficiently present tumor antigens to the immune system and induce antigen-specific cytotoxic T cell responses in vitro and in vivo.

Expression pattern and regulation of heme oxygenase-1/heat shock protein 32 in human liver cells.

Heme oxygenase-1 (HO-1) is a stress response protein that is highly inducible under various conditions, such as oxidative or heat stress. The present study investigated expression pattern and regulation of HO-1 in human liver. Expression pattern of HO-1 immunoreactive protein was studied in liver biopsies by immunohistochemistry, revealing constitutive expression in Kupffer cells but not in hepatocytes. HO-1 was, however, inducible in hepatocytes and vascular tissue under pathological conditions, e.g. associated with fatty degeneration or liver malignancies. Regulation of HO-1 gene expression was further studied by Northern blot analysis in HepG2 cells and freshly isolated peripheral blood mononuclear cells as model systems of parenchymal and nonparenchymal liver cell populations, respectively. HO-1 mRNA was inducible in HepG2 cells and mononuclear cells by various agents inducing oxidative stress. However, HO-1 gene expression was not inducible by heat shock. Pyrrolidine dithiocarbamate, an inhibitor of nuclear factor kappaB-dependent gene expression, dose dependently decreased HO-1 mRNA transcripts in human mononuclear cells subjected to oxidative stress while slightly increasing HO-1 gene expression in HepG2 cells. In contrast, HO-1 induction upon oxidative stress was attenuated in HepG2 cells by cycloheximide and dexamethasone. Although activator protein-1 has been reported as the predominant redox-sensitive transcription factor inducing HO-1 expression in murine macrophages, nuclear factor kappaB seems to play a significant role in human mononuclear cells. Our data are consistent with a role for activator protein-1 in HO-1 induction in human HepG2 hepatoma cells. These data suggest a differential regulation of HO-1 gene expression in parenchymal and non-parenchymal human liver cells and may provide a topographic basis for the understanding of the role of the heme oxygenase/carbon monoxide pathway in human liver disease.

Aprotinin inhibits local platelet trapping and improves tissue destruction in hepatic cryosurgery.

BACKGROUND: During the last decade, cryosurgery became an interesting alternative in the treatment of nonresectable liver neoplasms. The freeze-thaw procedure, however, may be associated with life-threatening thrombocytopenia due to local platelet trapping, and success of neoplasm ablation may be compromised by inadequate parenchymal cell destruction. METHODS: Because aprotinin is capable of inhibiting the initiation of both coagulation and fibrinolysis, we studied-by whole body scintigraphy of Indium-111-labeled platelets and histomorphology in a porcine model of hepatic cryosurgery-whether this serine protease inhibitor is effective in attenuating platelet trapping and in improving tissue destruction. RESULTS: Fifteen minutes of cryotherapy (-168 degrees C at the tip of the cryoprobe) induced a 30 +/- 4 cm(3) cryolesion, which presented with massive platelet trapping (14.0 +/- 1.7% cryolesion activity/whole body activity) and incomplete parenchymal cell destruction (0.9 +/- 0.3; score of hepatocyte nuclear destruction within the margin of the cryolesion). Aprotinin treatment with 500,000 IU initial bolus injection and additional 500,000 IU infusion over 3 hours did not affect the size of the cryolesion (29 +/- 3 cm(3)) but reduced local platelet activity (1.9 +/- 1.9%; P<.001) and induced hepatocyte nuclear destruction (3.0 +/- 0.0; P<.001). CONCLUSIONS: Thus, our study indicates that aprotinin inhibits cryoablation-associated platelet trapping and improves tissue destruction. The serine protease inhibitor may represent a valuable adjunct in cryosurgery of hepatic neoplasms.

Boerhaave's syndrome: primary repair vs. esophageal resection--case reports and meta-analysis of the literature.

Boerhaave's syndrome is a life-threatening disease with a high mortality. With regard to the heterogeneity of treatment strategies, no comparative studies exist and recommendations remain controversial. Seventeen cases of Boerhaave's syndrome operated on between 1989 and 2000 at our hospital were reviewed retrospectively to compare the time period between perforation and diagnosis, and the morbidity and mortality among the different treatment options. In addition, we conducted a meta-analysis of the literature including all series containing five or more patients and compared the findings with our own data. Our patients with a perforation history of less than 12 hours showed significantly fewer signs of sepsis compared to patients with a history of more than 12 hours. In a comparison of patients with primary repair vs. patients treated with esophageal resection or an exclusion operation, no differences were found. In the literature, patients with a long period of perforation (more than 24 hours) were treated more often with an esophageal resection than patients with primary repair. In cases of Boerhaave's syndrome, primary suturing of the esophageal perforation should be reserved only for those patients presenting within 12 hours after perforation. In all other cases, depending on the extent of the tissue damage, a two-stage esophageal resection with cervical esophagostomy and gastrostomy is recommended as the safest treatment.

Biliary cystadenoma of the left intrahepatic duct (2007: 2b).

Biliary cystadenoma is a rare epithelial cystic neoplasm representing only 5% of intrahepatic cystic lesions of biliary origin. Commonly, the lesions are solitary cystic structures with multiple thin-walled septa predominantly arising from the right hepatic duct. Although the lesions are generally intrahepatic, extrahepatic tumors have been reported. Biliary cystadenomas range in diameter from 1.5 to 35 cm. The tumor usually affects middle-aged women. Clinical symptoms are related to the mass effect and comprise episodes of jaundice due to biliary obstruction and intermittent upper abdominal pain. Laboratory parameters are nonspecific. As the tumor is considered a premalignant lesion, complete surgical resection is the treatment of choice. We report a case of typical biliary cystadenoma of the left hepatic duct.

A multicentre controlled study of the InLine radiofrequency ablation device for liver transection.

BACKGROUND: Surgical resection is the most effective therapy for liver cancer. Intraoperative blood loss during liver resection remains a major concern due to association with higher postoperative complications. The InLine radiofrequency ablation device (ILRFA) has achieved promising results in liver surgery with minimal blood loss and no increase of postoperative complications. In this multicentre controlled study, 108 patients undergoing liver resection were investigated. PATIENTS AND METHODS: A total of 108 patients underwent liver resections in 4 medical centres; the prospective sequential cohort study consisted of 54 ILRFA and 54 ultrasonic surgical aspirator transections as the control group. RESULTS: The type of liver resection performed was very similar in both groups. The median number of RFA deployments was 3 (range 1-12) with a median coagulation time of 9 (range 3-36) min. Median blood loss was 165+/-20 ml (range 5-675) in the ILRFA and 654+/-83 ml (range 80-3600) in the control group (p<0.001). The median transection time was 27 (2-219) min in the ILRFA group and 35 (5-62) min in controls. CONCLUSIONS: Our study indicates that ILRFA device for liver transection is effective in reducing blood loss and is safe. Precoagulation before parenchymal transection appears to be a valid concept in liver surgery. The avoidance of vascular inflow occlusion during parenchymal transection could also be of value.

One-stage sigmoid colon resection for perforated sigmoid diverticulitis (Hinchey stages III and IV).

INTRODUCTION: Guidelines for the treatment of complicated sigmoid diverticulitis recommend Hartmann's procedure or anastomosis with protective colostomy for Hinchey stage III diverticulitis and Hartmann's procedure only for Hinchey stage IV diverticulitis. We evaluated the outcome of patients with perforated sigmoid diverticulitis Hinchey III/IV undergoing one-stage colon resection and primary anastomosis without protective colostomy. METHODS: After implementation of a protocol to treat Hinchey III/IV diverticulitis with primary anastomosis without protective ileocolostomy, the patients' data were recorded prospectively between August 2001 and August 2003 and analyzed retrospectively from a computer-related database. RESULTS: Of 41 patients, 34 (81%) underwent one-stage sigmoid resection and primary anastomosis, 3 of 41 patients (7%) underwent primary anatomosis with protective ileostomy, and 5 of 41 patients (12%) had a Hartmann's procedure. The mortality was 11% in patients undergoing primary anastomosis and 60% in patients with Hartmann's procedure. The relative risk of co-morbidity factors for lethal outcome after sigmoid resection was 6.94 for preceding operations, 3.75 for renal failure or renal transplantation, and 3.25 for immunosuppression. CONCLUSIONS: One-stage sigmoid resection and primary anastomosis can be performed safely in nearly 90% of all patients with perforated sigmoid diverticulitis (Hinchey III/IV) by surgeons of different training levels. Patients with immunosuppression, chronic renal failure, liver cirrhosis, or previous organ transplantation or complex cardiovascular reconstructive procedures have a significantly increased risk of dying after sigmoid resection for perforated diverticulitis.

Arteriolovenular shunting critically determines shutdown of microcirculation upon cryotherapy in tumor-bearing rat liver.

BACKGROUND: Tissue destruction by cryosurgery not only is mediated by direct cell damage, but also involves secondary mechanisms, such as ischemia due to shutdown of the microcirculation. Clinicians favor repetitive cryoapplication, although there is no proven evidence for a more effective tumor eradication. METHODS: The aims of this study were (1) to establish a rat liver tumor model that allows for intravital microscopic analysis of hepatic tumor microcirculation and (2) to elucidate critical determinants of shutdown of microvascular perfusion after single and repetitive cryotherapy. In WAG-Rji rats (n = 14), syngeneic colon carcinoma cells (CC531) were implanted into the left liver lobe. Hepatic and tumor microcirculation were studied by intravital microscopy. RESULTS: Two weeks after implantation, the tumors had developed a microvasculature with a capillary density markedly (P < .05) lower compared with the sinusoidal density of normal liver. However, at the tumor margin, venule diameters were significantly enlarged (P < .05), with high red blood cell velocities and arteriolovenular shunts. Both freeze procedures (temperature at the tumor margin: -32.4 degrees C +/- 1.6 degrees C and -36.4 degrees C +/- 2.0 degrees C) resulted in a complete shutdown of intratumoral and peritumoral capillary and hepatic sinusoidal perfusion. In contrast, some large venules showed maintenance of blood flow initially after freezing (15 minutes); however, this was abolished during the subsequent 2-hour observation period. CONCLUSIONS: Enlarged high-flow venules at the tumor margin, which participate in arteriolovenular shunting, critically determine the shutdown of the microcirculation upon cryotherapy. Repetitive freezing is not more effective than a single-freeze procedure to achieve complete tumor microcirculatory stasis.

Local platelet trapping as the cause of thrombocytopenia after hepatic cryotherapy.

Cryosurgery has been shown to be an effective approach to destruction of unresectable hepatic tumors. However, hepatic cryoablation may also be associated with local and systemic side effects, including thrombocytopenia and clotting dysfunction. Although thrombocytopenia is known to relate to the magnitude of hepatocellular injury, its etiology is still unknown. With the use of whole-body scintigraphy after injection of indium-111-labeled platelets we here demonstrated in six patients undergoing cryoablation of hepatic tumors that manifestation of systemic thrombocytopenia after cryosurgery is associated with excessive platelet trapping and destruction within the cryolesion. We therefore conclude that local platelet trapping represents a major cause of cryothermia-induced systemic thrombocytopenia.

Advanced hepatic tissue destruction in ablative cryosurgery: potentials of intermittent freezing and selective vascular inflow occlusion.

Recent studies indicate that cryosurgery represents a promising approach to treat non-resectable liver tumors. To improve parenchymal tissue destruction, a variety of modifications of the freeze-thaw procedure have been suggested, including repetitive freezing and portal-triad cross-clamping. The aim of the present study was to analyze whether intermittent freezing by application of a double freeze-thaw procedure or selective vascular inflow occlusion are more effective than a single freeze-thaw cycle to achieve complete hepatic tissue destruction. Using a porcine model, intrahepatic cryolesions were induced by freezing the hepatic tissue for a total of 15 min (n=6, SF). Additional animals (n=6) underwent a double freeze-thaw cycle of 7.5 min each (DF). A third group of animals (n=6) was treated by a single 15-min freeze-thaw cycle during selective vascular inflow occlusion (VO-SF). Seven days after freezing, DF did not change the volume of the cryolesion (25.4+/-1.7 cm(3)) compared to SF (29.9+/-3.7 cm(3)), however, resulted in enhanced destruction of hepatocyte nuclear morphology (DF-score: 2.4+/-0.2 versus SF-score: 1.1+/-0.3; p<0.05) and attenuated leukocyte infiltration within the margin of the cryolesion (DF-score: 1.5+/-0.2 versus SF-score: 2.8+/-0.1; p<0.05). VO-SF was also effective to significantly enhance destruction of hepatocyte nuclear morphology (2.8+/-0.1; p<0.05 versus SF), but, additionally, markedly increased the volume of the cryolesions (43.3+/-5.3 cm(3); p<0.05 versus SF and DF). Interestingly, VO-SF further increased the number of apoptotic cells, while leukocyte infiltration (2.3+/-0.3) was not affected compared to that after SF-treatment. Thus, our data indicate that both DF and VO-SF are effective to enhance parenchymal cell destruction within the margin of the cryolesion. VO-SF additionally increases the volume of the lesion and may therefore be most attractive for successful clinical application.

Expression of cancer testis antigens in pancreatic carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis.

In order to define antigens that might be suitable as vaccines for pancreatic carcinoma, we investigated the composite expression of 10 cancer testis (CT) antigens (SCP-1, NY-ESO-1, SSX-1, SSX-2, SSX-4, GAGE, MAGE-3, MAGE-4, CT-7 and CT-8) by Reverse Transcriptase-PCR (RT-PCR) in fresh biopsies of human pancreatic adenocarcinoma, chronic pancreatitis and pancreatic carcinoma cell lines. While all CT genes were frequently expressed in cell lines derived from pancreatic cancer, no expression of MAGE-3, SSX-1, SSX-2, NY-ESO-1 and CT-7 was detected in fresh tumor biopsies, and MAGE-4 (1/52), SSX-4 (1/39) and CT-8 (2/41) were only rarely expressed. In contrast, HOM-TES-14/SCP-1 was expressed in 48% (29/61) and GAGE in 21% (13/61) of cases, respectively. One CT gene was expressed by 59% (75% in male, 46% in female patients; p = 0.05) and 2 or more CT genes by 15% of the samples. SCP-1 protein expression correlated well with mRNA expression. While SCP-1 and GAGE were absent in normal pancreas, they were found in 2/8 (SCP-1) and 1/8 (GAGE) samples of chronic pancreatitis, respectively, supporting the concept of chronic pancreatitis as a premalignant condition. SCP-1 and GAGE represent promising candidates for vaccine development in pancreatic carcinoma. Whether SCP-1 and GAGE expression identify cases of chronic pancreatitis with a high risk of malignant transformation remains to be shown.