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Item does not contain fulltext BACKGROUND: Intra-abdominal infection may lead to adhesion and abscess formation. An adhesion barrier can reduce these complications but also aggravate intra-peritoneal infection, causing the opposite effects. The fear of infection propagation has limited clinical adhesion barrier use in a contaminated or infected abdomen. This study evaluated both adhesion and abscess reduction and infection propagation of a new ultrapure alginate-based anti-adhesive barrier gel in a rat peritonitis model. METHODS: In 64 male Wistar rats, bacterial peritonitis was induced via intra-abdominal injection of a mixture of sterile feces, 10(5) colony-forming units (CFU) of Escherichia coli, and 10(4) CFU of Bacteroides fragilis. Surgical debridement and peritoneal lavage were performed 1 h after inoculation. Animals were randomly allocated in equal numbers to a control group or an alginate gel group. Animals were sacrificed on day five post-operatively. Death and the presence and size of intra-abdominal abscesses were noted, and adhesions were scored. All outcomes were compared in the two groups. RESULTS: Seventeen rats (27%) died prematurely without any difference between the groups. Of the surviving rats in the alginate gel group, 88% developed abscesses vs. 100% of the control group. There was no significant difference in the abscess scores or incidence rates of adhesion formation between the groups. The adhesion scores were lower for the alginate gel group compared with control animals (p=0.04). CONCLUSION: Ultrapure alginate gel reduces adhesion severity but not abscesses. The gel seemed to be safe, not aggravating intra-peritoneal infection in this abdominal infection model.

Contains fulltext : 177936.pdf (Publisher’s version ) (Closed access) BACKGROUND: For any anti-adhesive barrier developed for abdominal surgery, the use under conditions in which anastomotic healing is compromised needs to be investigated. The current study evaluates the effect of a new ultrapure alginate gel on early healing of high-risk anastomoses in the ileum and compares this with the gold standard used in clinical practice. MATERIALS AND METHODS: In 75 adult male Wistar rats, a 5 mm ileal segment was resected and continuity was restored by construction of an inverted anastomosis. Rats were divided randomly into a control group and groups receiving either alginate gel or a sodium hyaluronate carboxymethylcellulose (HA/CMC) film around the anastomosis (n = 25 each). Carprofen, given in a daily dose of 1.25 mg/kg, was used to compromise anastomotic healing. At day three, animals were killed and scored for signs of anastomotic leakage and the presence of adhesions. RESULTS: The incidence of adhesion formation was 95% in the HA/CMC film group, which was significantly higher than in the controls (64%, p = 0.010) and the alginate gel group (52%, p = 0.004). The adhesion score was nearly 40% lower in the alginate gel group compared with the HA/CMC film group. The incidence of ileal leakage in the HA/CMC film group (92%) was significantly higher than in the controls (68%, p = 0.016). Leakage rate did not differ between the alginate gel and control groups. There was no significant difference between groups in either incision bursting pressure or incision breaking strength. CONCLUSION: Ultrapure alginate gel does not interfere with repair of ileal anastomoses constructed under conditions in which chances of anastomotic dehiscence are high. The alginate gel performs better than the HA/CMC film.

Background Ultrapure alginate gel is promising in terms of adhesion prevention. Because anti-adhesive barriers have been shown to disturb healing of bowel anastomoses, the effect of ultrapure alginate gel on the repair of colon anastomoses was studied. Materials and methods In 102 male Wistar rats, a 0.5-cm segment was resected from the descending colon and continuity was restored by an inverted single-layer end-to-end anastomosis. Animals were randomized into a control, an alginate gel, and a sodium hyaluronate carboxymethyl cellulose film group, each n = 34. Half of each group was sacrificed at day 3 and 7 postoperatively. Anastomotic strength was assessed by measuring both bursting pressure and breaking strength. Hydroxyproline content was measured and histologic analysis was performed. The incidence of adhesion and abscess formation was scored at sacrifice. Results No difference in either anastomotic-bursting pressure or breaking strength was found between experimental groups and the controls at any time point. Both the incidence of adhesion formation (35% versus 71%, P = 0.007) and the adhesion score (0.38 versus 0.79, P = 0.009) were significantly lower in the alginate gel group than in the controls. The abscess rate was higher (46% versus 18%, P = 0.030) in the hyaluronate carboxymethyl cellulose group than in the controls and unchanged in the alginate gel group. Conclusions While reducing adhesion formation, ultrapure alginate gel does not interfere with the development of colonic anastomotic strength during the crucial early healing period.

Contains fulltext : 171653.pdf (Publisher’s version ) (Open Access) BACKGROUND: Immunosuppressant agents are inevitable for solid organ recipients, but may have a negative effect on wound healing that is difficult to measure because of clinical use of a polydrug regime. The evidence on mycophenolate mofetil (MMF) is scarce and contradictory. This study aims to investigate the effect of MMF administration on wound healing. METHODS: Ninety-six male Wistar rats divided into 4 groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. Another group started the medication 3 days after the laparotomy and was analyzed after 7 days, half of this group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured using bursting pressure, breaking strength, and histology. Trough levels were measured. RESULTS: Significant differences in wound strength were seen in ileum tissue after 3 days, which surprisingly showed a stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength was higher in the low-dose and high-dose MMF group compared with the control group. A negative effect was measured in abdominal wall tissue for the highest-dose group, which disappeared when the medication was delayed for 3 days. Histology showed poorer bridging of the submucosal layer and more polymorphonuclear cell infiltration in the ileum specimens of the control group compared with the treatment groups. CONCLUSIONS: As a single agent in a preclinical wound healing model in the rat, MMF has no negative effect on healing of bowel anastomoses but might have a negative effect on the healing of abdominal wall.

Item does not contain fulltext PURPOSE: Protecting the anastomotic integrity using suture or staple line reinforcement remains an important goal for ongoing research. The present comprehensive study aims to establish the effects of fibrin glue on the early phase of anastomotic healing in the rat intestine. METHODS: One hundred and eight young adult male Wistar rats underwent resection and anastomosis of both the ileum and colon. In half, fibrin glue was applied around the anastomoses. Parameters for repair included wound strength, both bursting pressure and breaking strength at days 1, 3, and 5 after operation; hydroxyproline content; and histology, the latter also after 7 days. RESULTS: A transient colonic ileus was observed in the experimental group. Anastomotic breaking strength was always similar in both the control and fibrin glue groups. Anastomotic bursting pressures remained low at days 1 and 3, without any differences between the groups. In both groups, the bursting pressure increased sharply (p < 0.001) between days 3 and 5. At day 5, the bursting pressure in the fibrin glue group remained below than that in the controls, although only significantly (p = 0.0138) so in the ileum. At day 5, but not at day 7, the wounds in the fibrin glue group contained less collagen. Other aspects of microscopic wound architecture appeared to be the same. CONCLUSIONS: There is no justification for using fibrin glue on patent anastomoses constructed under low-risk conditions. Its potential benefit under conditions where chances for anastomotic leakage are enhanced needs further investigation. 01 augustus 2012

The use of mammalian target of rapamycin inhibitors coincides with an increased incidence of surgical complications. In previous experiments, serious negative effects of postoperative everolimus on anastomotic strength were found. This study aims to investigate if delayed drug administration can prevent loss of wound strength. Ten groups of Wistar rats each received daily oral doses of 1.0 or 2.0 mg/kg everolimus, starting the day of anastomotic construction in both ileum and colon, or 1, 2, 3, or 4 days later. The 11th group received saline. Seven days later, wound strength in anastomoses and in the abdominal wall and wound hydroxyproline levels were measured. Mean wound strength was significantly and dose-dependently reduced if everolimus was started on the day of operation. In ileum and colon, strength was not affected if drug administration was delayed until the third or second day, respectively. In abdominal fascia, this was the case only if everolimus was withheld until day 4. In general, changes in wound hydroxyproline content showed similarities to changes in wound strength. Thus, delaying administration of everolimus for 2-4 days after operation can prevent a serious loss of wound strength, both in the intestine and in the abdominal fascia.

Contains fulltext : 96613.pdf (Publisher’s version ) (Closed access) PURPOSE: Radiofrequency ablation (RFA) has shown to improve survival in patients not eligible for surgical resection of colorectal liver metastases. However, recurrences after RFA are a major problem. Adjuvant radioimmunotherapy (RIT) after surgical resection of liver metastases has shown to improve survival. The aim of the present study was to test the hypothesis that adjuvant RIT might be an effective way to prevent recurrent liver metastases after RFA in an experimental model. METHODS: Tumours in the liver were induced by intrahepatic injection of 300,000 CC531 cells in male Wag/Rij rats (n = 60). Ten days later, the intrahepatic tumours were treated with RFA. Adjuvant RIT ((177)Lu-labelled monoclonal antibody MG1 at 300 MBq/kg) was administered intravenously either at the day of RFA (day 10) or 7 days later. Control rats received no treatment. Primary endpoint was survival. RESULTS: Administration of (177)Lu-MG1 resulted in a transient decrease in body weight, compared to no adjuvant treatment. However, no other signs of clinical discomfort were registered. Log rank test showed that the survival curves of the groups treated with RIT, either at day 10 or day 17, did not differ significantly from the survival curve of the rats that did not receive adjuvant treatment (P = 0.902). CONCLUSION: This study shows that adjuvant RIT does not increase survival after RFA of colorectal liver metastases in rats.

Contains fulltext : 89798.pdf (Publisher’s version ) (Closed access) BACKGROUND: The study aimed to analyze if peritoneal cytokine levels can predict survival in an experimental model for peritonitis. Early identification of patients most at risk for adverse outcomes would facilitate the decision for aggressive therapy in order to maximally exploit their chance for survival. STUDY DESIGN: Peritonitis was induced by intraperitoneal injection of a feces/bacteria mixture in 175 rats. Surgical debridement was performed after 1 hour. Abdominal fluid samples were taken after 24 and 72 hours for the measurement of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. Surviving animals were sacrificed after 5 days and correlations between cytokine levels and survival were analyzed. RESULTS: Altogether, 60 animals died prematurely, 12 before the first sampling of cytokines. So, 48 nonsurvivors and 115 survivors were analyzed. Peritoneal cytokine levels were much higher (p < 0.0001) in nonsurvivors than in survivors. At 24 hours there were strong correlations between cytokine levels, especially between IL-6 and IL-10 (r = 0.93). Peritoneal cytokines at 24 hours also discriminated between animals dying within the next 24 hours and those dying later. A strongly (p < 0.0001) increased mortality was observed if IL-6, IL-10, or TNF-alpha levels exceeded 2, 1, or 0.2 ng/mL, respectively. Receiver operating characteristic curves were promising for all 3, but IL-10 showed the best characteristics, with an area under the curve of 0.94 and 67% sensitivity at 95% specificity, obtained at a cut-off value of 1.26 ng/mL. CONCLUSIONS: These data should generate renewed interest to examine the peritoneal cytokines as early markers for adverse outcomes in patients with secondary peritonitis. Possibly, combinations of peritoneal cytokines with other markers can lead to much needed, reliable early prediction of disease severity. 01 augustus 2010

Contains fulltext : 89457.pdf (Publisher’s version ) (Closed access) PURPOSE: Experimental studies indicate that perioperative hypoperfusion impairs anastomotic healing. In bowel surgery, the part of bowel that will be anastomosed is often pedicled, leaving the blood supply dependent on the marginal artery only. Little is known about the blood supply in such a segment, and whether anastomotic strength is affected when flow would be reduced. This study describes oxygenation and blood flow in pedicled bowel segments in the rat and investigates whether early anastomotic strength changes with variations in blood flow. METHODS: In rats, pedicled segments were created in ileum and colon by successive ligation of the feeding arteries. Oxygenation and blood flow were measured in the distal part of this segment by use of near-infrared spectroscopy with indocyanine green as an intravascular tracer. In a second experiment, a short pedicled colonic segment was created and, after flow measurements, an anastomosis was constructed. Wound strength and hydroxyproline content were analyzed 2 and 5 days after operation. RESULTS: After creation of a pedicled segment, the concentration of oxygenated hemoglobin decreased significantly. Blood flow also significantly decreased to even less than 10% of baseline. A very large variation was observed between animals, in particular, after ligation of the first arteries. The strength of colonic anastomoses was not significantly correlated with the blood flow in the pedicled segment before anastomotic construction. CONCLUSIONS: The creation of a pedicled bowel segment greatly reduces tissue oxygenation and blood flow to its distal part. Such impaired perioperative flow does not significantly affect early wound strength after anastomotic construction. 01 januari 2010

Contains fulltext : 81116.pdf (Publisher’s version ) (Closed access) Early administration of fibrinolytics after surgical treatment of peritonitis in the rat reduces abscess formation. The current study investigates the effect of various treatment protocols using intraperitoneal recombinant tissue plasminogen activator (rtPA). Peritonitis was induced in rats and surgical debridement was performed after 1 hour. Animals were treated with rtPA at different time points. Abdominal fluid samples were taken at 24, 72, and 120 hours for cytokine measurements and cell counts. After 5 days the abdomen was inspected for abscesses. Early administration of rtPA significantly reduced the number of rats with abscesses and the abscess load per rat. Delayed treatment significantly reduced abscess load but not the incidence of abscesses. No meaningful differences in the local inflammatory response were found. rtPA was most effective when applied early and continued for 72 hours, although mortality increased after prolonged treatment. rtPA consistently reduces intra-abdominal abscess formation, and a clinical study seems warranted.

Contains fulltext : 81121.pdf (Publisher’s version ) (Closed access) BACKGROUND: Intra-abdominal application of recombinant tissue-type plasminogen activator (rtPA) can decrease the rate of abscess formation in a rat peritonitis model. Before using rtPA clinically, its effects on healing of bowel anastomoses and laparotomy wounds should be investigated. METHODS: Peritonitis was induced in 148 male Wistar rats via intra-abdominal injection of a feces/bacteria mixture. Laparotomy, operative debridement and construction of a colo-colostomy after a limited colectomy or ileo-ileostomy after a limited ileal resection were performed after 1 hour. All animals received antibiotics (ceftriaxone plus metronidazole). In addition to untreated controls, other animals received rtPA in 1 of 3 dosing schemes, starting immediately after operation or 24 hour afterwards. Wound strength and hydroxyproline content of the wound were analyzed after 3 or 7 days. RESULTS: Mortality was 2% and manifestations of excessive bleeding were virtually absent. RtPA significantly decreased the rate of abscess formation. Neither bursting pressure nor breaking strength of the anastomoses was affected by any of the rtPA protocols. The same was true for wound strength in the abdominal fascia. Additionally, wound hydroxyproline content and architecture remained unchanged after rtPA administration. CONCLUSION: Intraperitoneal rtPA administration consistently and significantly decreased the rate of abscess formation, but did not affect wound healing. Clinical studies investigating its potential as an adjunct in the treatment of secondary peritonitis may be warranted.

Item does not contain fulltext BACKGROUND: Neoadjuvant radiochemotherapy (RCT) is thought to result in a favorable oncological outcome in esophageal cancer patients. Unfortunately, it also implies that adjacent healthy tissue is preoperatively exposed to the potential damaging influence of RCT. Here, the impact of preoperative RCT on matrix metalloproteinase (MMP) expression in healthy esophageal tissue aligned with the tumor at the time of surgery is examined. PATIENTS AND METHODS: 23 patients participating in a clinical trial were randomized to either the control (n = 12) or the neoadjuvant RCT group (n = 11). In the latter group, surgery was performed 5 weeks after the last course of RCT. Full-thickness biopsies were taken from healthy esophageal tissue at the proximal border of the resection specimen and more distally next to the tumor. MMP-2 and MMP-9 activity in the samples was assessed by quantitative gelatin zymography and immunohistochemistry. RESULTS: In the proximal segment, the activities of the MMP-9-dimer (135 kDa) and proMMP-9 (92 kDa) were significantly increased in the RCT group as compared with the control group: 28.5 versus 3.0 (p = 0.025) and 87.7 versus 13.0 (p = 0.015) arbitrary units for 135 kDa and 92 kDa, respectively. In the distal part, RCT resulted in a significant increase of proMMP-2 (72 kDa: 35.8 versus 17.8, p = 0.005) and proMMP-9 (81.2 versus 23.3, p = 0.03). CONCLUSION: In esophageal cancer patients, neoadjuvant RCT results in increased MMP expression in healthy esophageal tissue as measured at the time of surgery. Since increased levels of MMPs are associated with severe postoperative complications including anastomotic leakage this finding necessitates further clinical research. 6 p.

Background Intra-abdominal abscesses are sources of recurrent or ongoing abdominal sepsis. They are an important target for prevention and treatment during or after surgical treatment of peritonitis. Experimental data suggest that fibrinolytic therapy may be effective when antibiotics are not. Methods Peritonitis was induced via intra-abdominal injection of a faeces and bacteria mixture in male Wistar rats. Surgical debridement was performed after 1 h. Next to untreated controls, animals were treated with antibiotics (ceftriaxone plus metronidazole), recombinant tissue plasminogen activator (rtPA) or both. Abdominal fluid samples were taken at 24, 72 and 120 h for interleukin 6, interleukin 10 and tumour necrosis factor α measurements and cell counts. After 5 days the abdomen was inspected for the presence of abscesses. Results Antibiotics did not significantly affect abscess formation. However, giving rtPA significantly reduced the number of rats with abscesses and the abscess load per rat, both in the absence and presence of concomitant antibiotic therapy. No adverse side-effects were observed and no meaningful differences in the local inflammatory response were found. Conclusion In this rat model, rtPA consistently reduced abscess formation after surgical treatment of secondary peritonitis. It therefore represents a promising adjuvant to conventional therapy.

Contains fulltext : 70763.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cytoreductive surgery (CS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) results in limited survival benefit and high morbidity and mortality rates in patients with peritoneal carcinomatosis (PC). Radioimmunotherapy (RIT) after CS of experimental PC has been shown to increase survival and compare favorably to HIPEC. The effects of RIT and HIPEC on wound healing after CS need to be determined. METHODS: PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to CS and anastomotic construction only or followed by RIT or HIPEC. RIT consisted of 74 MBq (177)lutetium-labeled anti-CC531 antibody MG1. HIPEC was performed by a closed abdominal perfusion technique using mitomycin-C during 60 minutes. Anastomotic and abdominal wall strength measurements were performed 3 and 5 days after surgery. RESULTS: At day 5, bursting pressure in ileum and colon anastomoses in the CS + HIPEC group, but not in the CS + RIT group, was lower (P < .01) than in the CS group. In the CS group, the colonic bursting site was more often outside the true anastomotic area (8 of 12 animals) than in the CS + HIPEC (1 of 12) and CS + RIT (5 of 12) groups. Abdominal wall strength in the CS + HIPEC group was significantly (P < .01) lower, at both measuring points, than that in both the CS group and the CS + RIT group. There was no difference between the latter. CONCLUSION: As adjuvant to CS, HIPEC showed a decrease in anastomotic and abdominal wall wound strength in a model of PC of CRC, whereas RIT did not.

Contains fulltext : 71224.pdf (Publisher’s version ) (Closed access) BACKGROUND: Airway obstruction in acute asthma is the result of airway smooth muscle contraction, inflammation and mucus plugging. Case reports suggest that mucolytic therapy might be beneficial in acute asthma. The aim of this study was to determine the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase) in addition to standard treatment at the emergency department in children with an asthma exacerbation. METHODS: In a multicentre randomised double-blind controlled clinical trial, 121 children brought to the emergency room for a moderate to severe asthma exacerbation were randomly assigned to receive either a single dose of 5 mg nebulised rhDNase or placebo following the second dose of bronchodilators. An asthma score (scale 5-15) was assessed at baseline and at 1, 2, 6, 12 and 24 h. The primary outcome variable was the asthma score 1 h after the study medication. RESULTS: One hour after the study medication the asthma score in the rhDNase group showed an adjusted mean decrease from baseline of 1.0 (95% CI 0.5 to 1.6) points compared with 0.7 (95% CI 0.3 to 1.2) points in the placebo group (mean difference 0.4 (95% CI -0.2 to 1.0) points; p = 0.23). The asthma score over the study period of 24 h also did not differ significantly between the rhDNase and placebo group (mean difference 0.2 (95% CI -0.3 to 0.7) points, p = 0.40). The duration of oxygen supplementation and number of bronchodilator treatments in the first 24 h were similar in both groups. CONCLUSION: Adding a single dose of nebulised rhDNase to standard treatment in the emergency room has no beneficial effects in children with moderate to severe acute asthma.

Contains fulltext : 52894.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cytoreductive surgery (CS) followed by heated intraperitoneal chemotherapy (HIPEC) is considered the standard of care for the treatment of patients with peritoneal carcinomatosis (PC) of colorectal cancer (CRC). These surgical procedures result in a median survival of 2 years at the cost of considerable morbidity and mortality. In preclinical studies, radioimmunotherapy (RIT) improved survival after CS in a model of induced PC of colonic origin. In the present studies we aimed to compare the efficacy and toxicity of CS followed by adjuvant RIT in experimental PC to the standard of care, HIPEC. METHODS: PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in three groups of Wag/Rij rats. Treatment comprised CS only, CS + RIT or CS + HIPEC, immediately after surgery. RIT consisted of intraperitoneal administration of 74 MBq Lutetium-177 labeled MG1. HIPEC was performed by a closed abdomen perfusion technique using mitomycin C (16 mg/L during 60 minutes). The primary endpoint was survival. RESULTS: CS only or combined with RIT was well tolerated. Rats receiving CS + HIPEC were lethargic, suffered from diarrhea, and lost significantly more weight in the first postoperative week. Median survival of rats treated with CS + RIT was significantly longer than after CS alone (97 and 57 days, respectively, P < .004), whereas survival after CS + HIPEC or CS alone were not significantly different (76 and 57 days, respectively, P = .17). CONCLUSION: Survival after CS was significantly improved by RIT with Lutetium-177-MG1 in rats with PC of colorectal origin. Adjuvant HIPEC did not improve survival and was more toxic than adjuvant RIT.

Item does not contain fulltext BACKGROUND: Nonsteroidal anti-inflammatory drugs have been associated with anastomotic leakage. It was studied if diclofenac affects anastomoses differently depending on the location in the gut. METHODS: Ninety-five rats were randomized to 6 groups with an anastomosis in either ileum (IL), proximal colon (PC), or distal colon (DC). Groups IL+ (n = 10), PC+ (n = 30), and DC+ (n = 10) received diclofenac (3 mg/kg/day) from day 0 until sacrifice on day 3. Group PC- (n = 15) did not receive diclofenac. Groups PC1+ and PC2+ (n = 15 each) were given diclofenac from day 1 to 4 and from day 2 to 5. RESULTS: Leak rates were 10/10 in group IL+, 22/30 in PC+, 1/10 in DC+, and 1/15 in PC-. Delayed administration of diclofenac by 1 or 2 days (6/15, P = .05) resulted in reduced leakage rates. Mechanical strength results corresponded with leak rates. CONCLUSIONS: Diclofenac causes leakage of anastomoses in rat IL and PC, but not in the DC. This suggests a role for the ileal and proximal colonic content in diclofenac-induced leakage.

Contains fulltext : 152926.pdf (Publisher’s version ) (Closed access) A persistent clinical demand exists for a suitable arterial prosthesis. In this study, a vascular conduit mimicking the native 3-layered artery, and constructed from the extracellular matrix proteins type I collagen and elastin, was evaluated for its performance as a blood vessel equivalent. A tubular 3-layered graft (elastin-collagen-collagen) was prepared using highly purified type I collagen fibrils and elastin fibers, resembling the 3-layered native blood vessel architecture. The vascular graft was crosslinked and heparinised (37 +/- 4 mug heparin/mg graft), and evaluated as a vascular graft using a porcine bilateral iliac artery model. An intra-animal comparison with clinically-used heparinised ePTFE (Propaten(R)) was made. Analyses included biochemical characterization, duplex scanning, (immuno)histochemistry and scanning electron microscopy. The tubular graft was easy to handle with adequate suturability. Implantation resulted in pulsating grafts without leakage. One week after implantation, both ePTFE and the natural acellular graft had 100% patencies on duplex scanning. Grafts were partially endothelialised (Von Willebrand-positive endothelium with a laminin-positive basal membrane layer). After one month, layered thrombi were found in the natural (4/4) and ePTFE graft (1/4), resulting in occlusion which in case of the natural graft is likely due to the porosity of the inner elastin layer. In vivo application of a molecularly-defined tubular graft, based on nature's matrix proteins, for vascular surgery is feasible.

Contains fulltext : 52657.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of patients with peritoneal carcinomatosis (PC) of colorectal cancer (CRC) includes cytoreductive surgery (CS) in combination with (hyperthermic) intraperitoneal chemotherapy (HIPEC), resulting in a limited survival benefit with high morbidity and mortality rates. Radioimmunotherapy (RIT) as adjuvant therapy after CS of CRC has been shown to prolong survival in preclinical studies. However, the optimal setting of RIT remains to be determined. METHODS: PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to exploratory laparotomy (Sham), CS only or CS + RIT at different time points after surgery. RIT consisted of 55 MBq lutetium-177-labelled anti-CC531 antibody MG1 (183 mug). The primary endpoint was survival. RESULTS: Cytoreductive surgery with or without RIT was well tolerated. Median survival of animals in the Sham and CS group was 29 days and 39 days, respectively (P < 0.04). Compared to CS alone, median survival of rats after adjuvant RIT was 77 days (P < 0.0001), 52 days (P < 0.0001) and 45 days (P < 0.0001) when given directly, 4 and 14 days after surgery, respectively. CONCLUSION: The efficacy of adjuvant RIT after CS for the treatment of PC of colonic origin decreases when the administration of the radiolabelled MAbs is postponed. This study shows that adjuvant RIT should be given as early as possible after surgery.

Intra-abdominal abscesses are a potential source of recurrent or residual infection after surgical intervention for secondary peritonitis. The development of therapies requires a model which combines low mortality with the formation of persisting abscesses and which is also suitable to study the local inflammatory response. Male Wistar rats were injected intraperitoneally with a mixture of sterile rat faeces, increasing doses of E. coli (10(4)-10(8) cfu/ml) and a fixed dose of B. Fragilis (10(4) cfu/ml). After one h a laparotomy was performed and the peritoneal cavity was debrided. Blood samples were taken under anaesthesia after 6 and 24 h. Abdominal fluid samples were collected (by laparotomy) after 24 and 72 h. The rats were killed after 5 days and the abdomen was inspected for abscesses. Mortality was 90% in the two groups with the highest doses of E. coli and 30% in those with the two lowest doses. In the latter groups all surviving rats but one showed intraabdominal abscesses and bacteremia was encountered frequently, especially after 24 h in the 10(5) cfu E. coli group. The groups receiving 10(4)-10(6) cfu E. coli showed similar plasma IL-6 concentrations after 6 h which were lowered significantly after 24 h. No circulating TNF-alpha was found. Considerable concentrations of TNF-alpha, IL-6, IL-1beta, and IL-10, were found in the peritoneal fluid after 24 h but no differences were observed between the contro groups and those receiving 10(4)-10(6) cfu E. coli. At 72 h cytokine levels were reduced significantly and remained the highest in the animals dosed with 10(6) cfu E. coli. The present model is suitable to study the mechanisms involved in, and prevention of, intra-abdominal abscess formation after surgical treatment of generalized peritonitis.

Contains fulltext : 50770.pdf (Publisher’s version ) (Closed access) BACKGROUND: Under certain conditions, transient intestinal ischemia can reduce anastomotic strength. Preliminary findings suggest that prolonged reperfusion time, before anastomotic construction, results in reduced wound strength. The purpose of this study is to determine if wound strength indeed decreases with increasing duration of the interval between an ischemic period and construction of an anastomosis. METHODS: In male Wistar rats, ischemia was induced by crossclamping the superior mesenteric artery (SMA) for 40 minutes. In control groups, the SMA was exposed but not clamped. Resection and anastomosis in both ileum and colon were performed immediately after release of the clamp or after 90 minutes or 24 hours. Both the anastomotic bursting pressure and breaking strength were measured after 3 or 5 days, together with hydroxyproline levels. RESULTS: Neither bursting pressure nor breaking strength, either in ileum or in colon, changed significantly when the time between the end of ischemia and anastomotic construction increased. Similar values were obtained in all experimental and corresponding control groups. In the group in which anastomoses were constructed after 24-hour reperfusion, mechanical strength increased significantly from day 3 to day 5 and at the same rate as in the control group. No differences in anastomotic hydroxyproline levels were found between experimental and control groups analyzed at day 5. CONCLUSIONS: A prolonged interval between intestinal ischemia and anastomotic construction does not affect development of early wound strength. Therefore, delayed anastomosis after transient ischemia is not likely to increase the risk of anastomotic complications.

Contains fulltext : 48975.pdf (Publisher’s version ) (Closed access) BACKGROUND: Little is known about the impact of repeated laparotomies on intestinal anastomotic healing. While experimental data are completely lacking, the sparse data available from clinical studies report high anastomotic failure rates, suggesting a negative effect in this respect. Since the unequivocal determination of such an effect may have important consequences for choosing the optimal treatment strategy for patients suffering from intra-abdominal infection, an experimental study has been performed in an established rodent model. METHODS: Intestinal anastomoses were constructed in healthy Wistar rats (ileal and colonic anastomoses) or 24 h after peritonitis was induced by caecal ligation and puncture (colonic anastomosis only). Rats were then scheduled to undergo no, one (after 24 h) or two relaparotomies (after 24 and 48 h). Anastomotic strength was assessed 3 and 5 days after anastomotic construction. On the third post-operative day anastomotic hydroxyproline levels, matrix metalloproteinase activity and myeloperoxidase activity were measured. RESULTS: No negative impact of repeated laparotomies was measured on any of the parameters measured. Under non-infectious conditions even an improvement in breaking strength (+48%, p=0.017) but not bursting pressure was found after two relaparotomies, but only in the ileum on the third post-operative day. CONCLUSIONS: In this experimental setting, early anastomotic healing is not adversely affected by repeated laparotomies.

Contains fulltext : 59237.pdf (Publisher’s version ) (Closed access) OBJECTIVE: We sought to quantitate the course of specific cytokine mRNA expression in tissues that exhibit increasing histopathological changes in time in an animal model for the multiple organ dysfunction syndrome (MODS). SUMMARY BACKGROUND DATA: The development of treatment protocols for MODS requires elucidation of the mechanisms and mediators involved. To devise logical interventions, it is necessary to collect data on cytokine expression at tissue level during the development of MODS. METHODS: Ninety-four C57BL/6 mice were given an intraperitoneal injection of 40 microg of lipopolysaccharide (LPS), followed by zymosan at a dose of 0.8 mg/g body weight 6 days later (day 0). Six additional animals did not receive zymosan and acted as controls. At several time points after zymosan injection, 6 randomly assigned, zymosan-treated animals were killed, and their livers, lungs, spleens, and kidneys were collected. mRNA expression of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, macrophage migration inhibiting factor, IL-12, interferon-gamma, and IL-10 was measured using a real-time reverse transcription-polymerase chain reaction assay. RESULTS: The injection of zymosan induced an acute peritonitis, followed by an apparent recovery. From approximately day 6 onwards, animals started to display MODS-like symptoms. During the peritonitis phase, up-regulation of cytokine mRNA was limited. During the period of apparent recovery, cytokine mRNA expression strongly increased, mostly reaching its maximum at day 9 when deterioration of the clinical condition had already set in. The up-regulation of tumor necrosis factor-alpha mRNA was most pronounced, especially in the lungs and liver. CONCLUSIONS: Interventions should preferentially be targeted against multiple cytokines and, at least in this model, there may be a treatment window well after the initial challenge.

Background Clinical studies report conflicting results on the safety of primary intestinal anastomoses in the presence of peritonitis, and comprehensive experimental data are lacking. The present study investigated whether the strength of experimental colonic anastomoses is affected if surgery is performed in the presence of pre-existing bacterial peritonitis. Methods Colonic anastomoses were constructed in Wistar rats 24 h after caecal ligation and puncture or a sham procedure. Anastomotic strength was assessed by measuring breaking strength and bursting pressure during the first 5 days after operation. Anastomotic hydroxyproline levels were measured and matrix metalloproteinase (MMP) activity was analysed by quantitative gelatin zymography. Results Anastomotic strength was lowered in the presence of bacterial peritonitis but in a minor and transient way. The breaking strength was lower only immediately after construction of the anastomosis (− 15 per cent, P = 0·011) and the bursting pressure only on the third postoperative day (− 33 per cent, P = 0·038); no anastomotic dehiscence was observed. At 3 days after operation increased levels of MMP activity were observed but anastomotic hydroxyproline content was not affected by bacterial peritonitis. Conclusion The influence of bacterial peritonitis on the development of anastomotic strength is limited. This experimental finding lends support to recent clinical studies that have demonstrated the feasibility of constructing a primary anastomosis under these conditions.

Background and aims. The strength of intestinal anastomoses is relatively low in the first days after operation, possibly as a result of localized degradation of the supporting matrix by enzymes from the matrix metalloproteinase (MMP) family. This study examined whether BB-94, a broad spectrum inhibitor of MMP activity, could enhance anastomotic strength. Materials and methods. Male Wistar rats received anastomoses in both ileum and colon. From the day before operation onwards, animals were treated daily with BB-94 intraperitoneally at a dose of 30 mg/kg or with saline only. Rats were killed 1, 3, or 7 days after operation, and anastomotic bursting pressure and breaking strength were measured. On day 3 anastomotic hydroxyproline levels were measured, and MMP (gelatinase) activity was analyzed by gelatin zymography. Results. BB-94 strongly enhanced wound strength, but only on day 3, when it was at its lowest. Daily administration increased median colonic and ileal breaking strength by 27% and 108%, respectively; colonic and ileal bursting pressure were increased by 54% and 58%, respectively. MMP activities were significantly lowered in anastomotic extracts from the rats treated with BB-94. Conclusion. Administration of BB-94 enhances anastomotic strength. Specific inhibition of MMP activity should be investigated further as a means to preserve anastomotic integrity.

Item does not contain fulltext The authors examined the potential of the cyclooxygenase 2 (COX-2) inhibitor carprofen to reproducibly induce anastomotic leakage. In experiment 1, an anastomosis was constructed in both ileum and colon of 20 rats, and they were given carprofen (5 mg/kg subcutaneously every 24 hours) or buprenorphine (0.02 mg/kg subcutaneously every 12 hours). In another 20 rats an anastomosis was constructed in either ileum or colon, and all received carprofen (experiment 2). Animals were sacrificed after 3 days. In experiment 1, the ileal dehiscence rate was 60% in the carprofen group and 0% in the buprenorphine group (P = .0108). Colonic anastomoses in both groups remained patent. In experiment 2, the anastomotic leakage rate was 80% in ileum and 0% in colon. Thus, COX-2 inhibitors can severely interfere with intestinal healing, particularly in the ileum. Perioperative administration of carprofen yields a unique model for anastomotic leakage, which allows translational research on the effectiveness of perisuture line reinforcement.

Background Postoperative adhesion formation is a common consequence of abdominal surgery, and constitutes a major source of morbidity and mortality. This study evaluated an ultrapure alginate-based antiadhesive barrier gel. Methods Experiments were performed in a rat model with caecal abrasion and peritoneal side wall excision. The primary endpoint was the incidence of adhesions at 14 days after surgery. In experiment 1 (24 rats), animals treated with alginate gel were compared with controls that had no antiadhesive barrier. In experiment 2 (42 rats), alginate gel was compared with sodium hyaluronate carboxymethyl cellulose (HA/CMC) membrane and with no antiadhesive barrier. To check for any remote action of the gel, in experiment 3 (45 rats) application of alginate gel to the ipsilateral versus contralateral side of injury was compared with no antiadhesive barrier. Results In experiment 1, ultrapure alginate gel reduced the incidence of adhesions from eight of 12 in control animals to one in 12 (P = 0·009). Tissue healing assessed by histology was similar in both groups. In experiment 2, ultrapure alginate gel and HA/CMC membrane showed similar antiadhesive effectiveness, reducing the incidence of adhesions from ten of 14 rats in the control group to three of 14 (P = 0·021) and two of 14 (P = 0·006) respectively. In experiment 3, ultrapure alginate gel reduced the incidence of adhesions at the site of direct application (1 of 15) compared with controls (13 of 15; P = 0·001), but not if applied remotely (9 of 15; P = 0·214). Conclusion Ultrapure alginate gel decreased the incidence of postoperative adhesion formation in this rat model.

Contains fulltext : 155447.PDF (Publisher’s version ) (Open Access) BACKGROUND: Use of immunosuppressant drugs has been associated with complications in wound healing. The calcineurin inhibitor tacrolimus is thought to have a relatively low complication rate, but preclinical research has yielded contradictory data, prompting the current comprehensive study. METHODS: Three groups of 33 male Wistar rats received a daily subcutaneous dose of 0,5, 2 or 5 mg/kg tacrolimus. A control group received saline. On day 0 a resection of 1 cm ileum and 1 cm colon was performed, and end-to-end anastomoses were constructed. Ten rats of each group were killed on day 3 and day 5 and the remaining animals on day 7. Both anastomoses and the wound in the abdominal wall were analyzed. Wound strength was the primary outcome parameter. RESULTS: Mean strength of the abdominal wall increased significantly over time in all groups (p

Item does not contain fulltext BACKGROUND: Biologic grafts hold promise of a durable repair for ventral hernias with the potential for fewer complications than synthetic mesh. This systematic review was performed to evaluate the effectiveness and safety of biologic grafts for ventral hernia repair. METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched for studies on biologic grafts for the repair of ventral hernias. Outcomes are presented as weighted pooled proportions. RESULTS: Twenty-five retrospective studies were included. Recurrence depended on wound class, with an overall rate of 13.8% (95% confidence interval [CI], 7.6-21.3). The recurrence rate in contaminated/dirty repairs was 23.1% (95% CI, 11.3-37.6). Abdominal wall laxity occurred in 10.5% (95% CI, 3.7-20.3) of patients. The surgical morbidity rate was 46.3% (95% CI, 33.3-59.6). Infection occurred in 15.9% (95% CI, 9.8-23.2) of patients but only led to graft removal in 4.9% of cases. CONCLUSIONS: No randomized trials are available to properly evaluate biologic grafts for ventral hernia repair. The current evidence suggests that biologic grafts perform similarly to other surgical options. Biologic grafts are associated with a high salvage rate when faced with infection.

Background and purpose : Preoperative irradiation with direct postoperative chemotherapy could benefit patients undergoing surgery for colorectal cancer. This study was designed to examine, in an experimental model, if such treatment is feasible without detrimental effects on early anastomotic healing. Material and methods : A colonic segment was irradiated (25 Gy) in 3 groups ( n = 10 each) of male Wistar rats. After 5 days, a colonic resection was performed with anastomotic construction; only the distal limb consisted of irradiated bowel. Postoperatively, animals received daily intraperitoneal 5-fluorouracil (5-FU, group I/CH: 17.5 mg/kg; group I/CL: 12.5 mg/kg) or saline (group I). Three additional groups were treated similarly, but with sham-irradiation: CH, CL, and C, respectively. All rats were killed 7 days postoperatively. Parameters measured were: weight, serum albumin and protein, and anastomotic bursting pressure, breaking strength and hydroxyproline content. Results : Body weight was diminished significantly in rats receiving chemotherapy. Serum albumin and protein was significantly lower in irradiated groups. At sacrifice, 40% of I/CH rats had functional rectal stenosis. The average bursting pressure ( P = 0.0005) and the average breaking strength ( P = 0.012) were only reduced significantly in the CH group. The anastomotic hydroxyproline content was significantly higher in the I/CH and I/CL groups vs. the control group. Conclusion : High-dose direct postoperative 5-FU leads to reduced anastomotic strength. Although the combination of preoperative irradiation (25 Gy) and direct postoperative high-dose 5-FU does not reduce early anastomotic strength, some stenosis may occur. The combination of preoperative irradiation and low-dose 5-FU has no such effect.

Summary18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a known method to diagnose inflammatory processes and thus may be a promising imaging technique to detect anastomotic bowel leak. The aim of this study was to assess postoperative FDG uptake in colorectal anastomosis in patients without suspicion of active infection or anastomotic leakage. Patients, methods: Design of a prospective observational pilot study in order to assess normal FDG uptake in the patient anastomosis after colorectal surgery. Patients that underwent colorectal surgery with primary anastomosis received FDG-PET of the abdomen, 2–6 days postoperatively. Results: 35 patients met the inclusion criteria. Three patients were not scanned for various reasons. Of the remaining 32 patients, one demonstrated an increased uptake of FDG at the site of the anastomosis. In the other 31 patients FDG uptake was negligible (n = 17) or scored as physiological (n = 14). None of the scanned patients developed a clinical relevant anastomotic leakage within the first 30 days after surgery. Conclusion: The present study shows that FDG uptake in colorectal anastomosis remains low within the first six days after surgery in patients without anastomotic leakage. Therefore, FDG-PET might be useful to investigate further as a tool to detect anastomotic leakage in an the early postoperative phase.

Perioperative intraperitoneal chemotherapy is used as an adjunct to cytoreductive surgery (CS) for peritoneal carcinomatosis (PC) in order to prolong survival. Worldwide, hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and combinations of the two are used. It remains unclear which regimen is most beneficial. The rat colon carcinoma cell line CC-531 was injected into the peritoneal cavity of 80 WAG/Rij rats to induce PC. Animals were randomized into four treatment groups (n = 20): CS only, CS followed by HIPEC (mitomycin 35 mg/m2 at 41.5°C), CS followed by EPIC during 5 days (i.p. injection of mitomycin on day 1 and 5-fluorouracil on days 2–5), and CS followed by HIPEC plus EPIC. Primary outcome was survival. In rats treated with CS only, median survival was 53 days (95% confidence interval (CI) 49–57 days). In rats treated with CS followed by HIPEC, survival was significantly (P = 0.001) increased (median survival 94 days, 95% CI 51–137 days). In the group treated with EPIC after CS, 12 out of 20 rats were still alive at the end of the experiment (P

Contains fulltext : 96614.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The aim of this study was to test the hypothesis that adjuvant radioimmunotherapy (RIT) prevents recurrent liver metastases and/or results in improved survival after tumorectomy in an experimental model. BACKGROUND: Although partial hepatectomy can improve 5-year survival of patients with colorectal liver metastases up to 58%, recurrent tumor growth in the liver occurs frequently. Radioimmunotherapy using radiolabeled monoclonal antibodies directed against tumor-associated antigens is considered most suited for treating minimal residual disease and could therefore serve as an adjuvant after surgery. METHODS: Liver metastases were induced in male Wag/Rij rats by a mini-laparotomy with intrahepatic injection of 0.3 x 106 CC531 tumor cells. The biodistribution of the radiolabeled monoclonal antibody MG1, directed against a 80-kDa cell surface antigen on CC531 tumors, in this model was determined at 1, 3, and 7 days after intravenous administration. The therapeutic efficacy of 177Lu-MG1 was compared with that of a sham antibody (UPC10), labeled with the same activity dose of Lu-177, and saline only. Radioimmunotherapy was administered either at the day of the tumorectomy (day 14 after tumor cell inoculation) or 7 days later. Primary endpoint was survival. RESULTS: Radiolabeled MG1 preferentially accumulated in tumor lesions in the liver reaching a maximum 3 days postinjection (8.7 +/- 0.6% injected dose per gram). Both the administration of 177Lu-MG1 and 177Lu-UPC10 resulted in a transient decrease in body weight. No other signs of clinical discomfort were registered. The survival curves of the group that received 177Lu-UPC10 and the group that received saline only did not differ (P=0.886). Administration of RIT immediately after surgery improved survival compared to administration of the control antibody (hazard ratio [HR], 1.54; P = 0.051), which was even more pronounced when survival was adjusted for the weight of the resected tumor (HR, 1.71; P = 0.027). A therapeutic efficacy of delayed treatment seemed likely (HR, 2.34; P = 0.055). Survival after early administration did not differ from delayed administration (HR, 1.16; P = 0.763). CONCLUSION: This study provides proof of principle that RIT can be an effective adjuvant treatment modality after surgical treatment of colorectal liver metastases.

Item does not contain fulltext OBJECTIVE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C can improve survival if used as an adjunct to cytoreductive surgery (CS) for treatment of peritoneal carcinomatosis (PC). It remains unclear if both hyperthermia and chemotherapy are essential for the reported survival benefit. METHODS: Eighty WAG/Rij rats were inoculated intraperitoneally with the rat colon carcinoma cell line CC-531. Animals were randomly assigned to 1 of the 4 treatment groups (n = 20): CS only, CS followed by HIPEC (mitomycin 35 mg/m(2) at 41 degrees C), CS followed by intraperitoneal mitomycin perfusion at 37 degrees C, CS followed by intraperitoneal saline perfusion at 41 degrees C. Survival was the primary outcome with a maximum follow up of 126 days. RESULTS: Median survival was 62 days in rats treated with CS only and 57 days in rats treated with CS followed by hyperthermic saline perfusion. Rats receiving HIPEC had a median survival of 121 days (P = 0.022 when compared with CS only). In the group treated with chemotherapy at 37 degrees C, 13 of 20 animals were still alive at the end of the experiment so median survival was not reached. (CS vs. IPEC: P = 0.002, hazard ratio 0.36, 95% CI 0.19-0.69) Rats treated with hyperthermic saline perfusion did not have an increased survival as compared with CS only. CONCLUSIONS: The effectiveness of intraoperative intraperitoneal perfusion after CS is highly dependent on the presence of chemotherapeutic agents in the perfusate but not on hyperthermia. The need to include hyperthermia in the adjuvant intraoperative treatment after CS for PC should be further investigated.

Contains fulltext : 98303.pdf (Publisher’s version ) (Open Access) BACKGROUND: Biologic grafts are increasingly used instead of synthetic mesh for parastomal hernia repair due to concerns of synthetic mesh-related complications. This systematic review was designed to evaluate the use of these collagen-based scaffolds for the repair of parastomal hernias. METHODS: Studies were retrieved after searching the electronic databases MEDLINE, EMBASE and Cochrane CENTRAL. The search terms 'paracolostomy', 'paraileostomy', 'parastomal', 'colostomy', 'ileostomy', 'hernia', 'defect', 'closure', 'repair' and 'reconstruction' were used. Selection of studies and assessment of methodological quality were performed with a modified MINORS index. All reports on repair of parastomal hernias using a collagen-based biologic scaffold to reinforce or bridge the defect were included. Outcomes were recurrence rate, mortality and morbidity. RESULTS: Four retrospective studies with a combined enrolment of 57 patients were included. Recurrence occurred in 15.7% (95% confidence interval [CI] 7.8-25.9) of patients and wound-related complications in 26.2% (95% CI 14.7-39.5). No mortality or graft infections were reported. CONCLUSIONS: The use of reinforcing or bridging biologic grafts during parastomal hernia repair results in acceptable rates of recurrence and complications. However, given the similar rates of recurrence and complications achieved using synthetic mesh in this scenario, the evidence does not support use of biologic grafts.

Background Radioimmunotherapy (RIT) has been shown to reduce the incidence of local recurrence of colorectal cancer in an experimental model. The aim of the present study was to investigate the survival benefit of RIT compared with chemotherapy. Methods An anastomosis was constructed in male Wag/Rij rats after intraluminal injection of CC531 tumour cells. The therapeutic efficacy of 177Lu-labelled MG1 (single intravenous dose of 300 MBq/kg, n = 20) was compared with that of 5-fluorouracil-based chemotherapy (6 weekly cycles administered intraperitoneally, n = 20) and no treatment (n = 20). The primary endpoint was survival. Toxicity was monitored by bodyweight measurement. Results Both chemotherapy and RIT affected bodyweight, but the weight of animals in the RIT group remained significantly higher than in the chemotherapy group (median slope of bodyweight plot 0·48 versus 0·30 g/day; P < 0·001). Kaplan–Meier analysis showed that overall survival in the RIT and chemotherapy groups was significantly better than that in the control group (50 and 46 per cent versus 25 per cent respectively after 170 days; P = 0·024 and P = 0·029). Survival after treatment with RIT did not differ from that after chemotherapy (P = 0·911). Conclusion RIT is as effective as chemotherapy in experimental colorectal cancer.

Contains fulltext : 89759.pdf (Publisher’s version ) (Open Access) The introduction of mTOR-inhibitors in transplantation surgery has been associated with an increase in wound complications. We have previously reported a massive negative effect of everolimus on anastomotic strength in rat intestine at 7 days postoperatively. Because it is clinically important to know if this effect persists and occurs generally, repair in both intestine and abdominal wall has been investigated over a period of 4 weeks. Wistar rats received a daily dose of 1 or 2 mg/kg everolimus orally, from the operation day onwards. Controls received saline. In each rat a resection of ileum and colon was performed, and end-to-end anastomoses were constructed. On day 7, 14, and 28 the animals were killed and anastomoses and abdominal wall wounds were analyzed, wound strength being the primary parameter. Breaking strength of ileum, colon, and fascia was consistently and significantly reduced in the experimental groups at all time points. Anastomotic bursting pressures followed the same pattern. Loss of strength was accompanied by a decrease in hydroxyproline content after 7 days. Thus, the negative effect of everolimus on wound repair persists for at least 4 weeks after operation in this rodent model. This protracted effect may have clinical consequences and cause surgical morbidity.

ObjectiveDespite the efficacy of collagen in femoral artery pseudoaneurysm treatment, as reported in one patient study, its use has not yet gained wide acceptance in clinical practice. In this particular study, the collagen was not described in detail. To further investigate the potential of collagen preparations, we prepared and characterized highly purified injectable fibrillar type I collagen and evaluated its use for femoral artery pseudoaneurysm (PSA) treatment in vivo using a pig model.MethodsPurified fibrillar type I collagen was characterized using electron microscopy. The effect of three different sterilization procedures, ie, hydrogen peroxide gas plasma (H2O2), ethylene oxide gas (EtO), and gamma irradiation, was studied on both SDS-PAGE and platelet aggregation. Different collagen injectables were prepared (3%, 4%, and 5%) and tested using an injection force test applying a 21-gauge needle. To evaluate the network characteristics of the injectable collagen, the collagen was suspended in phosphate buffered saline (PBS) at 37°C and studied both macroscopically and electron microscopically. To determine whether the collagen induced hemostasis in vivo, a pig PSA model was used applying a 4% EtO sterilized collagen injectable, and evaluation by angiography and routine histology.ResultsElectron microscopy of the purified type I collagen revealed intact fibrils with a distinct striated pattern and a length

Background The combination of cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the treatment of choice for selected patients with peritoneal carcinomatosis (PC) of colorectal origin. However, it remains to be proven whether the addition of HIPEC to CS is essential for the reported survival benefit. Methods Sixty WAG/Rij rats were inoculated intraperitoneally with the rat colonic carcinoma cell line CC-531. Animals were randomized into three treatment groups: CS alone, CS followed by HIPEC (mitomycin 15 mg/m2) and CS followed by HIPEC (mitomycin 35 mg/m2). Survival was the primary outcome parameter. Results The median survival of rats treated with CS alone was 43 days. Rats receiving HIPEC 15 mg/m2 and HIPEC 35 mg/m2 both had a significantly longer median survival of 75 days (P = 0·003) and 97 days (P < 0·001) respectively. Rats receiving HIPEC showed a significantly lower tumour load at autopsy compared with rats treated with CS alone. Conclusion A combination of CS and HIPEC results in longer survival than CS alone in rats with PC of colorectal origin.

Blood transfusions are reported to impair the cell-mediated immune response. Because both T lymphocyte and macrophage function are important for wound repair, the authors investigated the effect of blood transfusions on anastomotic repair. Lewis rats underwent resection of both ileum and colon, followed by the construction of either an everted or an inverted end-to-end anastomosis. Immediately after operation, they received either 3 mL saline intravenously, or 3 mL heparinized blood from Lewis or Brown Norway donors. The animals were killed 3 or 7 days after operation, and anastomotic strength was assessed by measuring the bursting pressure. Anastomotic abscesses and generalized peritonitis were not found in the control group. Blood transfusions, particularly allogeneic, significantly increased the incidence of these septic complications. Three days after operation, anastomotic strength was significantly reduced in both Lewis and Brown Norway transfused groups. For instance, average bursting pressures (+/- standard deviation [SD]) of inverted ileal anastomoses were 79 +/- 13 mmHg in the control group and 46 +/- 14 and 21 +/- 12 mmHg in the Lewis and Brown Norway transfused groups, respectively. Seven days after operation, the rupture site was found significantly more often within the anastomotic line in the animals that had received blood transfusions. The authors conclude that blood transfusions impair the healing of experimental intestinal anastomoses and increase susceptibility to intra-abdominal sepsis.

Contains fulltext : 80885.pdf (Publisher’s version ) (Closed access) INTRODUCTION: During bowel surgery, perioperative blood loss and hypotension can lead to transient intestinal ischemia. Recent preclinical studies reveal that the strength of intestinal anastomoses can be compromised after reperfusion. So far, this phenomenon has not been investigated in the very first days of healing when wound strength is lowest. MATERIAL AND METHOD: Ischemia was induced in rats by clamping both the superior mesenteric artery and ileal branches for 30 min. Immediately after declamping, anastomoses were constructed in both terminal ileum and descending colon. The same was done in control groups after sham-ischemia. Anastomotic bursting pressure and breaking strength were measured immediately after operation (day 0) and after 1, 2, or 3 days. Anastomotic hydroxyproline content, gelatinase activity, and histology were analyzed. RESULTS AND DISCUSSION: In ileal anastomoses, at day 1, both the breaking strength and bursting pressure were significantly (p < 0.05) lower in the ischemic group, while at day 2, this was the case for the bursting pressure only. In the colon, the bursting pressure in the ischemic group was lower at day 1. Anastomotic hydroxyproline content remained unchanged. Increased presence of the various gelatinase activities was found in ileum only at day 0 and in colon at days 1 and 2. Histological mucosal damage was found in ischemia-reperfusion groups. CONCLUSION: Transient mesenteric ischemia can negatively affect anastomotic strength during the very first days of healing, even if the tissue used for anastomotic construction looks vital.

BackgroundRadioimmunotherapy (RIT) is suitable for the treatment of microscopic residual disease and might therefore have an adjuvant role after colonic cancer surgery.MethodsAn anastomosis was constructed in male Wag/Rij rats after intraluminal injection of 2 × 106 CC531 tumour cells. The biodistribution of 111In-labelled MG1 monoclonal antibody was assessed after intraperitoneal administration. The therapeutic efficacy of 177Lu-labelled MG1 (74 MBq per rat), administered on the day of surgery (D0, n = 13) or 5 days later (D5, n = 13), was compared with that of carrier only (n = 13). The primary endpoint was perianastomotic tumour growth 28 days after surgery.Results111In-labelled MG1 preferentially accumulated in perianastomotic CC531 tumours. RIT resulted in a transient reduction in bodyweight in both treatment groups compared with controls, but there were no other signs of clinical discomfort. No macroscopic or microscopic perianastomotic tumour growth was found in eight of 11 animals in the D0 group and 11 of 13 in the D5 group, whereas 11 of 13 controls had macroscopic tumour (P = 0·011 and P = 0·001 respectively).ConclusionThis study suggests that RIT may be an effective adjuvant treatment for preventing local recurrence after resection of colonic cancer.

Contains fulltext : 80074.pdf (Publisher’s version ) (Closed access) Liver metastases of colorectal carcinoma occur in about 50-60% of patients. To improve survival of these patients, there is an urgent need for new treatment strategies. For this purpose, the availability of a preclinical model to develop and test such treatments is mandatory. An ideal animal model for studying liver metastases of colorectal origin should mimic all aspects of the metastatic development in humans and be practical, predictable, and optimal in terms of ethical considerations. Thus far, no model has been developed which satisfies all these conditions. As a consequence, choosing an animal model for the study of liver metastases requires compromises and choices about the necessary characteristics that depend on the purpose of the intended experiments. This overview addresses the advantages and disadvantages of different animal models used for research on experimental liver metastases of colorectal origin. Based on data available in literature, we conclude that heterotopic injection of undifferentiated syngeneic tumor cells in immunocompetent rodents covers most of the desired characteristics. Both subcapsular as well as intraportal injection will yield suitable models and the eventual choice will depend on the aim of the study.

Contains fulltext : 69926.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVE: Cytoreductive surgery (CS) and heated intraperitoneal chemotherapy (HIPEC) are standard treatment for peritoneal carcinomatosis (PC) of colorectal cancer. Previously, we demonstrated that preclinical radioimmunotherapy (RIT) adjuvant to surgery in PC is a good alternative for HIPEC. Now we aimed to improve the effectiveness of RIT by combining it with whole-body hyperthermia (WBH) or fibrinolytic therapy. METHODS: Rats were inoculated intraperitoneally with colon carcinoma cells. Animals underwent CS, CS + WBH (40 degrees C, 3 hours), CS + RIT (74 MBq 177Lu-labeled MG1), or CS + WBH + RIT. In the second experiment, rats underwent CS, CS + RIT, CS + recombinant tissue plasminogen activator (rtPA, twice daily, 3 days), or CS + RIT + rtPA. RESULTS: Median survival after CS and CS + WBH was 34 and 37 days. Median survival after CS + RIT or CS + RIT + WBH was 63 and 86 days (p < 0.0003, p < 0.0006 compared to CS + WBH). Median survival after CS and CS + rtPA was 50 and 42 days (p = 0.1). Median survival was 106 days after CS + RIT and 103 days after CS + RIT + rtPA (p < 0.0001 compared to CS + rtPA). No difference was found between CS + RIT and CS + RIT + rtPA (p = 0.83). CONCLUSIONS: The application of WBH or rtPA in combination with adjuvant RIT after CS for the treatment of PC of colonic was feasible but did not significantly potentiate the efficacy of RIT.

Contains fulltext : 51827.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Transient intestinal ischemia can reduce anastomotic strength, which poses an increased risk of complications. The objective of this study is to establish if a prolonged interval between profound ischemia and construction of an anastomosis affects anastomotic strength. METHODS: Male Wistar rats were used: in experimental groups, profound mesenteric ischemia was induced by clamping both superior mesenteric artery and more distal arteries in the ileal mesentery. Resection and anastomosis in ileum and colon were performed immediately (IR0) or 24 h after releasing the clamps (IR24). In controls (C0 and C24), arteries were not clamped. After 5 days, anastomotic bursting pressure (BP), breaking strength (BS), and hydroxyproline were measured, and histological analysis was performed. RESULTS: Mortality and anastomotic dehiscence rates were significantly higher in IR0 compared to C0. In ileum, the BS was 34% lower (p

Contains fulltext : 52447.pdf (Publisher’s version ) (Closed access) PURPOSE: Experimental data suggest that transient preoperative ischemia and reperfusion may compromise anastomotic strength. However, data on this subject are equivocal, in particular as to the onset and duration of this effect. This study was designed to comprehensively characterize the effects of profound transient intestinal ischemia on anastomotic healing during the first postoperative week. METHODS: Ischemia was induced in rats by clamping both the superior mesenteric artery and ileal branches for 30 minutes. Immediately after declamping, anastomoses were constructed in both terminal ileum and descending colon. After three, five, or seven days, both bursting pressure and breaking strength were measured. Anastomotic collagen content, gelatinase activity, and histology were analyzed. RESULTS: Anastomotic leakage rate was 13 percent in ischemia-reperfusion group and 0 percent (P=0.02) in controls. The breaking strength in ileum remained significantly (P

Contains fulltext : 52659.pdf (Publisher’s version ) (Closed access) BACKGROUND: Optimal therapy of secondary peritonitis frequently results in the formation of residual abscesses, which bear a substantial mortality and morbidity. This study aims to prove that fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) can reduce abscess formation after surgical treatment of secondary peritonitis in a rat model, without causing unwanted side effects. MATERIALS AND METHODS: Male Wistar rats received an intra-abdominal injection with a suspension of sterile feces, 10(5) cfu Escherichia coli and 10(4) cfu Bacteroides fragilis. Surgical debridement was performed 1 h after inoculation. Animals were randomized into four groups (n = 14 each). Three groups received human rtPA at 1 h (rtPA1); 1 h and 6 h (rtPA2); and 1, 6, and 24 h (rtPA3), respectively. Each dose contained 1.25 mg rtPA. Controls received saline only. Animals were killed after 5 days. RESULTS: rtPA treatment reduced abscess formation in surviving animals, depending on number of doses given. Animals in group rtPA3 had no abscesses in contrast to 88% of the controls (mean 3.6 +/- 2.7 abscesses per rat; p < 0.05). In the rtPA1 and rtPA2 group, frequency of abscess formation was 58 and 33%, respectively. Mortality, course of body weight, and bacteremia were not affected by rtPA and neither were peritoneal cell counts and levels of TNF-alpha, IL-1beta, IL-6 and IL-10. No bleeding complications were observed. CONCLUSION: rtPA reduces intra-abdominal abscess formation after surgical treatment of generalized peritonitis without increasing mortality or affecting the local inflammatory response.

Background Selective cyclo-oxygenase 2 (COX-2) inhibitors are increasingly prescribed in the perioperative period. Recent recognition of a possible role for COX-2 in wound healing has raised concerns about the safety of their use in surgical practice. Therefore, the influence of celecoxib, a selective COX-2 inhibitor, on early anastomotic healing was investigated. Methods Celecoxib, in doses of 15, 50 or 200 mg per kg per day, was given daily from the day before operation onwards to male Wistar rats that received both ileal and colonic anastomoses. Anastomotic strength was assessed by measuring the breaking strength and bursting pressure on the third day after operation. A second group received a dose of 50 mg per kg per day and a colonic anastomosis only, and healing was assessed on the third and fifth day after surgery. Results Expression of COX-2 protein was upregulated in the anastomotic area. Administration of celecoxib, at all doses tested, resulted in a significantly higher ileal dehiscence rate than in control rats (P = 0·002). In contrast, colonic anastomoses healed normally within the same animals. The latter was confirmed in rats with colonic anastomoses only. Conclusion In this model, administration of the COX-2 inhibitor celecoxib affected ileal but not colonic anastomotic healing in the early postoperative period.

Contains fulltext : 50864.pdf (Publisher’s version ) (Closed access) AIMS: The degradation of the extracellular matrix is intrinsic to the invasion and progression of cancer. Matrix metalloproteinase (MMP)-2 and -9 and their natural inhibitors are involved in this process. The study aims to investigate if plasma MMP-2, -9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) can be useful markers in the diagnosis and prognosis of colorectal cancer (CRC) metastatic liver disease. METHODS: Fifty-seven patients undergoing liver metastasis operation were followed prospectively. ProMMP-2, -9 and TIMP-1 plasma levels were determined by zymography and ELISA, before and after the resection of liver metastases. Data were compared with those of healthy controls (n=51) and primary CRC patients (n=94). The diagnostic and prognostic potential was investigated with ROC-curves and Kaplan-Meier survival analysis. RESULTS: Plasma proMMP-2 levels were lower (P

Contains fulltext : 49970.pdf (Publisher’s version ) (Closed access) BACKGROUND: Although clinical data suggest its existence, little is known about the effect of rapamycin derivatives on wound repair. This study aims to delineate the influence of the mammalian target of rapamycin inhibitor everolimus on wound healing in the rat intestine. METHODS: Four groups of 26 male Wistar rats received everolimus in daily oral dosages of 0 (controls), 0.5 (group E-0.5), 1.0 (group E-1), and 3.0 (group E-3) mg/kg every 24 hours, respectively, starting four hours before the operation until killing. After resection of 1-cm segments of colon and ileum, intestinal anastomoses were constructed. The animals were killed at days three or seven after operation. Wound healing was assessed by mechanical (bursting pressure, breaking strength), biochemical (collagen content, gelatinase activity), and histologic parameters. RESULTS: No differences between groups were recorded for any of the parameters on day three. On day seven, a dose-dependent reduction in breaking strength (P