| 1. |
- Angenete, Eva, 1972, et al.
(författare)
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Matrix metalloproteinases in rectal mucosa, tumour and plasma: response after preoperative irradiation
- 2007
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Ingår i: International journal of colorectal disease. - 0179-1958. ; 22:6, s. 667-74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In rectal cancer treatment, preoperative radiotherapy has led to reduction of local recurrence, but it is associated with morbidity and increased risk for secondary tumours. Matrix metalloproteinases (MMPs) are associated with tumour progression through tissue remodeling. The aim of this study was to investigate tissue remodeling after preoperative radiotherapy and to explore possible correlations with clinical outcome. MATERIALS AND METHODS: Ninety-one patients scheduled for rectal cancer surgery were included; 49% received preoperative radiotherapy three-field treatment, 5 x 5 Gy. Blood samples and biopsies from tumour and adjacent mucosa were taken during surgery. Biopsies and plasma were assayed with ELISA for MMP-1, MMP-2 and MMP-9. Clinical outcome was reviewed focusing on infections, perineal healing, fistula formation, anastomotic dehiscence, small bowel obstruction, local recurrence and distant metastases. RESULTS: Compared to non-irradiated mucosa, MMP-2 (p < 0.0001), MMP-1 (p = 0.03) and MMP-9 (p = 0.04) were significantly higher in irradiated normal mucosa. Tumour tissue had higher levels of MMP-2 if irradiated (p < 0.0001). A correlation between MMP-2 levels and wound infection (p = 0.02) as well as fistula formation (p = 0.04) was found. MMP-1 in mucosa (p = 0.02) and tumour (p = 0.04) were higher in patients developing distant metastases. Plasma levels were not influenced by irradiation, but MMP-2 was higher in patients who were later developing distant metastases (p = 0.007). CONCLUSIONS: Extracellular matrix remodeling after radiotherapy seems to be correlated to postoperative morbidity; MMP-2 is associated with both wound infections and fistula formation. High levels of MMP-1 in tumour and mucosa as well as MMP-2 in plasma may be correlated to risk of developing distant metastases.
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| 2. |
- Angenete, Eva, 1972, et al.
(författare)
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Preoperative radiotherapy and extracellular matrix remodeling in rectal mucosa and tumour matrix metalloproteinases and plasminogen components.
- 2009
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Ingår i: Acta oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 48:8, s. 1144-1151
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Tidskriftsartikel (refereegranskat)abstract
- Background. Preoperative radiotherapy reduces recurrence but increases postoperative morbidity. The aim of this study was to explore the effect of radiotherapy in rectal mucosa and rectal tumour extracellular matrix (ECM) by studying enzymes and growth factors involved in ECM remodeling. Materials and methods. Twenty patients with short-term preoperative radiotherapy and 12 control patients without radiotherapy were studied. Biopsies from rectal mucosa and tumour were collected prior to radiotherapy and at surgery. Tissue MMP-1, -2, -9, TIMP-1, uPA, PAI-1, TGF-beta1 and calprotectin were determined by ELISA. Biopsies from irradiated and non-irradiated peritoneal areas were also analysed. Results. Radiotherapy increased the tissue levels of MMP-2 and PAI-1 in both the rectal mucosa and tumours while calprotectin and uPA showed an increase only in the mucosa after irradiation. The increase of calprotectin was due to an influx of inflammatory cells as revealed by immunohistochemistry. Prior to irradiation, the tumour tissues had increased levels of MMP-1, -2, -9, total TGF-beta1, uPA, PAI-1 and calprotectin compared to mucosa, while TIMP-1 and the active TGF-beta1 fraction showed no statistical difference. Conclusions. This study indicates a radiation-induced effect on selected ECM remodeling proteases. This reaction may be responsible for early and late morbidity. Interference of this response might reduce these consequences.
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| 3. |
- Angenete, Eva, 1972, et al.
(författare)
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Transforming growth factor beta-1 in rectal tumour, mucosa and plasma in relation to radiotherapy and clinical outcome in rectal cancer patients
- 2007
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Ingår i: Int J Colorectal Dis. - 0179-1958. ; 11, s. 1331-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rectal cancer patients are treated with surgery and sometimes radiotherapy. Transforming growth factor-beta1 (TGF-beta1) acts both as an inhibitor of tumour growth and as a promoter of tumour progression. The aim of this study was to determine the levels of TGF-beta1 in tumour tissue, adjacent mucosa and plasma in rectal cancer patients and relate these to the effect of radiotherapy and clinical outcome. MATERIALS AND METHODS: One hundred and ten patients scheduled for rectal cancer surgery were included, 49% received pre-operative radiotherapy three-field treatment 5 x 5 Gy. Blood samples and biopsies were taken during surgery and later assayed with enzyme-linked immunosorbent assay for total TGF-beta1 and active TGF-beta1. Patients were then followed for 3 years. RESULTS: Total and active TGF-beta1 was higher in tumour tissue compared with rectal mucosa (p < 0.0001). Active TGF-beta1 in tumour tissue and rectal mucosa was lower in the irradiated group (p = 0.007; p < 0.0001). Total TGF-beta1 was higher in patients with metastases at primary diagnosis (p = 0.005) compared to patients without. In patients who later developed metastases, the levels of active TGF-beta1 in plasma were lower (p = 0.004). Local recurrence was associated with lower levels of total TGF-beta1 in the rectal mucosa (p = 0.038). CONCLUSIONS: Higher levels of total TGF-beta1 in tumour tissue at surgery may be indicative of distant metastases, and low levels of active TGF-beta1 in plasma may indicate a risk of developing secondary metastases. Lower levels of total TGF-beta1 in rectal mucosa may influence risk of local recurrence. Measurement of TGF-beta1 in rectal cancer patients may be of clinical use in the future.
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| 4. |
- Angenete, Eva, 1972, et al.
(författare)
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uPA and PAI-1 in rectal cancer--relationship to radiotherapy and clinical outcome.
- 2009
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 153:1, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It is well known that the fibrinolytic system is of importance in inflammation, wound healing, and fibrosis development. However, it is also important in the process of tumor invasion and metastasis. We have investigated protein levels of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in rectal cancer and effects of radiotherapy, links to clinical outcome, and potential use as prognostic factors. MATERIALS AND METHODS: Ninety-one patients with rectal cancer were studied. Blood samples and biopsies were taken during surgery and assayed with enzyme-linked immunosorbent assay for uPA and PAI-1, and patients were followed prospectively (0-96 mo). RESULTS: Higher levels of uPA (P < 0.0001) and PAI-1 (P < 0.0001) were found in tumor compared with mucosa. Mucosa exposed to radiotherapy had higher levels of uPA (P < 0.0001) and of PAI-1 (P < 0.0001). Irradiated tumor tissue had higher levels of PAI-1 (P < 0.001). PAI-1 in tumor was correlated with T stage (P < 0.001) and N stage (P < 0.01). PAI-1 in plasma was higher in patients with synchronous distant metastases (P < 0.001). Cox regression was used to identify high levels of PAI-1 in tumor as an independent factor related to short disease-free survival (P < 0.01) and the ratio of uPA/PAI-1 to development of metastases (P < 0.01). CONCLUSIONS: There is a relationship between PAI-1 in plasma and rectal cancer metastases. PAI-1 in tumor tissue is correlated to histopathological data and to outcome of rectal cancer. If these findings can be confirmed in larger trials, there will be a possibility to use PAI-1 as a prognostic factor.
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| 5. |
- Bergström, Maria, 1964, et al.
(författare)
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Effect of acidosis on expression of mesothelial cell plasminogen activator inhibitor type-1.
- 2006
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Ingår i: Surgical endoscopy. - : Springer Science and Business Media LLC. - 1432-2218 .- 0930-2794. ; 20:9, s. 1448-52
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Abdominal mesothelial cells are exposed to carbon dioxide during laparoscopy. Previous data indicate that carbon dioxide increases release and expression of plasminogen activator inhibitor type-1 (PAI-1) and induces acidification. METHODS: To assess the impact resulting from a range of pH, human mesothelial cells were exposed to culturing media balanced to pH levels of 6.0 to 8.0 for 90 min. Samples from cell media were withdrawn at several time points. Concentrations of PAI-1 and PAI-1 activity were measured using enzyme-linked immunoassay techniques. To focus on the effect of clinically relevant pH, cells were subjected to pH 6.4 and 7.4. Samples were withdrawn for PAI-1 assessments and for PAI-1 mRNA analyses. RESULTS: During exposure to various levels of pH, PAI-1 secretion and activity were variable. However, 5 h after exposure, greater concentration and activity of PAI-1 were observed in acidified cultures. More PAI-1 mRNA was isolated after exposure of cells to a pH of 6.4, apparently indicating transcriptional regulation. CONCLUSIONS: Mesothelial cells seem to respond to acidification by an increased release and production of PAI-1 in vitro.
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| 6. |
- Bergström, Maria, 1964, et al.
(författare)
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Peritoneal and systemic pH during pneumoperitoneum with CO(2) and helium in a pig model.
- 2008
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Ingår i: Surgical Endoscopy. - : Springer Science and Business Media LLC. - 1432-2218 .- 0930-2794. ; 22:2, s. 359-364
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Local peritoneal effects of laparoscopic gases might be important in peritoneal biology during and after laparoscopic surgery. The most commonly used gas, CO(2), is known to be well tolerated, but also causes changes in acid-base balance. Helium is an alternative gas for laparoscopy. Although safe, it is not widely used. In this study a method for monitoring peritoneal pH during laparoscopy was evaluated and peritoneal pH during CO(2) and helium pneumoperitoneum was studied as well as its systemic reflection in arterial pH. METHODS: For these experiments 20 pigs were used, with ten exposed to pneumoperitoneum with CO(2), and ten to helium. Peritoneal and sub-peritoneal pH were continuously measured before and during gas insufflation, during a 30-minute period with a pneumoperitoneum and during a 30-minute recovery period. Arterial blood-gases were collected immediately before gas insufflation, at its completion, at 30 minutes of pneumoperitoneum and after the recovery period. RESULTS: Peritoneal pH before gas insufflation was in all animals 7.4. An immediate local drop in pH (6.6) occurred in the peritoneum with CO(2) insufflation. During pneumoperitoneum pH declined further, stabilising at 6.4, but was restored after the recovery period (7.3). With helium, tissue pH increased slightly (7.5) during insufflation, followed by a continuous decrease during pneumoperitoneum and recovery, reaching 7.2. Systemic pH decreased significantly with CO(2) insufflation, and increased slightly during helium insufflation. Systemic pH showed co-variation with intra-peritoneal pH at the the end of insufflation and after 30 minutes of pneumoperitoneum. CONCLUSIONS: Insufflation of CO(2) into the peritoneal cavity seemed to result in an immediate decrease in peritoneal pH, a response that might influence biological events. This peritoneal effect also seems to influence systemic acid-base balance, probably due to trans-peritoneal absorption.
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| 7. |
- Brokelman, Walter J A, et al.
(författare)
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Decreased peritoneal tissue plasminogen activator during prolonged laparoscopic surgery.
- 2009
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 151:1, s. 89-93
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Peritoneal fibrinolysis is crucial in the peritoneal healing processes and subsequent adhesion formation. During conventional surgery, the peritoneal fibrinolytic system is rapidly disturbed. Short-term laparoscopy does not seem to affect peritoneal fibrinolysis. The aim of the present study was to assess the effect of prolonged laparoscopic surgery on peritoneal fibrinolysis. METHODS: Twelve consecutive patients undergoing laparoscopic gastric bypass surgery for morbid obesity were included in the study. During the procedure, biopsies of the parietal peritoneum were taken at the start of the procedure and each 45 min afterward. Tissue samples were homogenized and tissue-type plasminogen activator (tPA) antigen, tPA activity, urokinase-type PA antigen, and plasminogen activating inhibitors type 1 antigen were measured using commercial assay techniques. RESULTS: Both tPA antigen and its activity progressively decreased during the procedure, reaching significant levels after 90 min of surgery. The levels of uPA antigen and plasminogen activating inhibitors antigen did not significantly change throughout the procedure. CONCLUSIONS: As for conventional surgery, prolonged laparoscopic surgery causes a decreased fibrinolytic activity in the peritoneum due to decreased tPA levels.
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| 8. |
- Brokelman, Walter J A, et al.
(författare)
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Peritoneal fibrinolytic response to various aspects of laparoscopic surgery: a randomized trial.
- 2006
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 0022-4804. ; 136:2, s. 309-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Peritoneal fibrinolysis is important in peritoneal wound healing processes and adhesion formation. The peritoneal fibrinolytic response to laparoscopy is merely unknown. In the present study we investigate the effect of short-term laparoscopy on the peritoneal fibrinolytic response and the influence of intra-abdominal pressure, light intensity and choice of dissection device on this response. METHODS: There were 50 patients scheduled for laparoscopic cholecystectomy randomized in five groups operated with various pressures, light intensities, and dissection devices. Peritoneal biopsies were taken at the beginning and the end of the procedure. Tissue concentrations of tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor type 1 (PAI-1), and the tPA-activity were measured using ELISA techniques. RESULTS: There were no differences in tPA antigen, tPA-activity, uPA antigen, or PAI-1 antigen concentrations in biopsies taken at the beginning compared to samples taken at the end of the operation. Different intra-abdominal pressures, light intensities and the choice dissection device did not affect any of the measured parameters. CONCLUSION: Short-term laparoscopy does not affect the peritoneal fibrinolytic activity. The used intra-abdominal pressure, light intensity and choice of dissection device do not affect peritoneal activity during short-term laparoscopy.
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| 9. |
- Brokelman, Walter J A, et al.
(författare)
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Peritoneal transforming growth factor beta-1 expression during laparoscopic surgery: a clinical trial.
- 2007
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Ingår i: Surgical endoscopy. - : Springer Science and Business Media LLC. - 1432-2218 .- 0930-2794. ; 21:9, s. 1537-41
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transforming growth factor-beta 1 (TGF-beta1) is a growth factor involved in various biologic processes, including peritoneal wound healing and dissemination of malignancies. Laparoscopic surgery is evolving rapidly, and indications are increasing. The peritoneal TGF-beta1 expression during laparoscopic surgery is unknown. METHODS: For this study, 50 patients scheduled for laparoscopic cholecystectomy were randomized into five groups, then surgically treated with various pressures, light intensities, and dissection devices. Peritoneal biopsies were taken at the beginning and end of surgery. Tissue concentrations of total and active TGF-beta1 were measured using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: There was no significant difference in either total or active TGF-beta1 concentration between peritoneal biopsies taken at the start of surgery and samples taken at the end of the procedure. Patients who underwent surgery with the ultrasonic scalpel had significant lower levels of both active (p < 0.005) and total (p < 0.01) TGF-beta1 at the end of surgery than patients treated with electrocautery. Patients who had surgery with a high light intensity had significantly lower levels of total TGF-beta1 levels (p < 0.005) with an unchanged active part than patients who had surgery with low light intensity. CONCLUSION: The choice of dissection device and the light intensity used in laparoscopic surgery affect peritoneal TGF-beta1 concentrations, indicating that peritoneal biology can be affected by laparoscopic surgery. Because TGF-beta1 is involved in various biologic processes in the peritoneal cavity, this observation may have important clinical consequences.
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| 10. |
- Brokelman, Walter, et al.
(författare)
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The peritoneal fibrinolytic response to conventional and laparoscopic colonic surgery.
- 2009
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Ingår i: Journal of laparoendoscopic & advanced surgical techniques. Part A. - : Mary Ann Liebert Inc. - 1092-6429 .- 1557-9034. ; 19:4, s. 489-93
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Laparoscopic surgery is considered to induce less peritoneal trauma than conventional surgery. The peritoneal plasmin system is important in the processes of peritoneal healing and adhesion formation. The present study assessed the peritoneal fibrinolytic response to laparoscopic and conventional colonic surgery. METHODS: Twenty-four patients scheduled for a right colonic resection were enrolled in the trial. Twelve underwent conventional surgery and 12 were operated laparoscopically. Biopsies of the parietal peritoneum were taken at standardized moments during the procedure. Tissue concentrations of tissue-type plasminogen activator (tPA) and its specific activity (tPA-activity), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) were measured, using commercial assays. RESULTS: After mobilization of the colon, peritoneal levels of tPA antigen and activity were significantly higher in the laparoscopic group (p < 0.005) due to a decrease in the conventional group (p < 0.05). At the end of the procedure, the concentrations of tPA antigen and activity significantly (p < 0.05) decreased in the laparoscopic group to levels comparable with the conventional group. Neither uPA antigen nor PAI-1 antigen changed throughout the procedures. CONCLUSIONS: Both conventional and laparoscopic surgery inflict a decrease in tPA antigen and its specific activity. Peritoneal hypofibrinolysis initiates more rapidly during conventional, compared to laparoscopic, surgery, but at the conclusion of the surgery, the effect was the same.
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