Intraperitoneal aerosolization of bupivacaine reduces postoperative pain in laparoscopic surgery: a randomized prospective controlled double-blinded clinical trial.

BACKGROUND: Laparoscopic strategies for managing intraabdominal pathologies offer significant benefits compared with conventional approaches. Of interest are reports of decreased postoperative pain, resulting in shorter hospitalization and earlier return to normal activity. However, many patients still require strong analgesia postoperatively. This study analyzed the use of intraoperatively delivered aerosolized intraperitoneal bupivacaine and its ability to reduce postoperative pain. METHODS: For this study, 80 patients undergoing laparoscopic cholecystectomy were recruited and divided randomly into four groups: control (n = 20), aerosolized bupivacaine (n = 20), aerosolized normal saline (n = 20), and local bupivacaine in the bladder bed (n = 20). All the patients had standard preoperative, intraoperative, and postoperative care. Pain scores were recorded by the nursing staff in recovery, then 6, 12, and 24 h postoperatively using a standard 0 to 10 pain scoring scale. In addition, opiate consumption and oral analgesia were recorded. RESULTS: Aerosolized bupivacaine significantly reduced postoperative pain in comparison with all other treatments (p < 0.05). Injection of bupivacaine into the gallbladder bed did not result in a significant difference from the control condition. CONCLUSION: Aerosolized intraperitoneal local anesthetic is an effective method for controlling postoperative pain. It significantly helped to reduce opiate use and contributed to rapid mobilization, leading to short hospitalization and possible reduction in treatment cost.

A surgically induced hypoxic environment causes changes in the metastatic behaviour of tumours in vitro.

The use of laparoscopic techniques for curative resections of malignant tumours has been under scrutiny. The potential benefits to the patient in the form of earlier recovery and less immune paresis are countered by the reports of increased tumour recurrence. The biological sequelae of the hypoxic laparoscopic environment on tumour cells is unknown. Components of the metastatic cascade were evaluated under in vitro laparoscopic conditions using a human colonic adenocarcinoma cell line (SW1222). Exposure to the laparoscopic gases carbon dioxide and helium for 4 h, comparable to the duration of a laparoscopic colorectal resection, had no effect on cell viability. A cellular hypoxic insult was demonstrated by the induction of hypoxia inducible factor 1alpha (HIF-1alpha). Exposure also resulted in significant reduction in homotypic adhesion as well as to a variety of extracellular matrix components. These effects were recoverable under re-oxygenation. The changes were reflected at the molecular level by significant down regulation of adhesion molecules known to be involved in tumour progression (E-cadherin, CD44 and beta1 sub-unit). Modulation of adherence has significant implications for laparoscopic oncological surgery, demonstrating that tumours become potentially more friable and easier to disseminate in surgeons who are less experienced or where instrumentation is sub-optimal.

Peritoneal nebulizer: a novel technique for delivering intraperitoneal therapeutics in laparoscopic surgery to prevent locoregional recurrence.

BACKGROUND: Peritoneal involvement is a significant issue in the treatment of gastrointestinal malignancies. Current statistics indicate that after surgical intervention, up to 20% of patients will present with locoregional metastasis. The ability to inhibit initial tumor adhesion to the mesothelial lining of the peritoneum may be considered critical in the inhibition of tumor development. This article describes, the use of a novel nebulizer system capable of delivering high-concentration, low-dose therapeutics to the peritoneal cavity. METHODS: For this study, 30 male WAG rats were inoculated with CC531 colorectal tumor cells. The rats were randomized into three groups: control group (n = 10), heparin-treated group (n = 10), and high-molecular-weight hyaluronan-treated group (n = 10). A peritoneal cancer index was used to determine tumor burden at 15 days. Analysis of variance (ANOVA) was used to compare multiple group means. RESULTS: Nebulization therapy was performed without any complication in the cohort. Heparin inhibited macroscopic intraperitoneal tumor growth completely (p = 0.0001) without affecting tumor cell viability. The introduction of hyaluronan attenuated both tumor size and distribution, was compared with the control group (p = 0.002). CONCLUSION: Nebulized heparin and hyaluronic acid using a novel nebulization technique attenuates peritoneal tumor growth after laparoscopic surgery. The technique itself is easy to use and safe.

Laparoscopic enhancement of tumour cell binding to the peritoneum is inhibited by anti-intercellular adhesion molecule-1 monoclonal antibody.

BACKGROUND: There still remain some concerns over the phenomenon of port-site metastases (PSM) after laparoscopic surgery. The aim of this study was to investigate the effect of the pneumoperitoneum on tumor-mesothelial cell interactions. METHODS: The adhesion of a colon carcinoma cell line to a mesothelial cell monolayer exposed to carbon dioxide, helium, or air was assessed using an in vitro adhesion assay. Changes in adherence were correlated with alterations in cell surface molecule expression by the mesothelial cells using flow cytometry after exposure to the different environments. RESULTS: Exposure of the mesothelial cells to an in vitro pneumoperitoneum significantly enhanced tumor cell binding to the mesothelial cell monolayer. No differences in cell viability were observed between the groups. This was associated with increased expression of mesothelial intercellular adhesion molecule-1 (ICAM-1) mediated by nuclear factor kappa-B. The enhanced adhesion was abolished by ICAM-1 inhibition. CONCLUSIONS: This study demonstrated that the laparoscopic environment increases the susceptibility of the mesothelium to tumor cell adherence, and this may be explained by changes in ICAM-1 expression.

Laparoscopic staging of pancreatic tumors induces increased invasive capacity in vitro.

INTRODUCTION: Laparoscopy and laparoscopic ultrasound have a well-defined role in staging patients with pancreatic malignancy. The effect of the hypoxic pneumoperitoneum induction on tumor biology is unknown. The authors investigated whether an in vitro pneumoperitoneum augments the invasive capacity of pancreatic tumors and elucidate a mechanism by which this may occur. METHODS: A pancreatic (PSN-1) adenocarcinoma cell line was exposed to an in vitro pneumoperitoneum (carbon dioxide (CO2) or helium) for a maximum of 2 h or left in normal growth conditions (control). Cells were nonenzymatically harvested and placed in invasion assays. These were performed over 72 h using Matrigel coated 8-mm Transwell filters and analyzed using MTS colorimetric assay. Gelatin zymography was employed to assess the level of matrix metalloproteases (MMP) 2 and 9 (gelatinase A and B) secretion. Expression of tissue inhibitor of metalloproteases 1 (TIMP-1) was assessed using ELISA (Biotrak). Inhibition of invasion assays was performed using a specific gelatinase inhibitor (MMPI; Calbiochem). RESULTS: The invasive capacity of pancreatic tumour cells is augmented versus control in both helium (p <0.05) and CO2 (p <0.001) groups. Concomitant significant upregulation of the gelatinase activity was demonstrated with both insufflants (p <0.05; 0.001, respectively). Enhanced invasion was attenuated by the addition of a specific gelatinase inhibitor (p <0.05). CONCLUSIONS: These results indicate the invasive capacity of pancreatic tumor cells is augmented by laparoscopic staging in vitro. This is in part mediated by increased gelatinase activity and may be attenuated by the addition of specific inhibitors.

Pneumoperitoneum augmented tumor invasiveness is abolished by matrix metalloproteinase blockade.

BACKGROUND: Certain surgical strategies, including Helium (He) and carbon dioxide (CO2) insufflation in laparoscopy, have been shown to induce a hypoxic environment. This may have a significant effect on the invasive capacity of tumor cells and may be a factor in the incidence of port-site metastases seen in patients following laparoscopic resection for malignancy. METHODS: A colon adenocarcinoma cell line (SW1222) was exposed to an in vitro pneumoperitoneum of CO2 or He at 3 mmHg or left in normal growth conditions (control). After a 4-hour exposure to an in vitro pneumoperitoneum, the ability of the cells to invade through 8.0-microm Transwell filters coated with Matrigel was analyzed by colorimetric MTS assay and by direct staining of the filters. The effect of the addition of a known blocker of matrix metalloproteinases (MMPs), 1,10-phenanthroline (1,10-P), was investigated. RESULTS: Cells exposed to an in vitro pneumoperitoneum demonstrate significantly increased invasive capacity compared to the control set, without loss of viability (He vs control, p <0.001; CO2 vs control, p <0.001). This augmented capacity is abolished by the addition of 1,10-P (p <0.01). CONCLUSION: Exposure of a colonic adenocarcinoma cell line to either a CO2 or He pneumoperitoneum causes an increase in tumor cell invasiveness, which is abolished by the presence of a known inhibitor of MMPs. This suggests that MMPs have an important role in the metastatic potential of tumors exposed to a hypoxic operative environment.

Laparoscopic environmental changes during surgery enhance the invasive potential of tumours.

OBJECTIVE: The use of laparoscopic techniques in resection of malignant tumours has been proposed to offer potential benefit to the patient in the form of earlier recovery and less immune paresis; however, reported tumour seeding, both peritoneal and at port site, has put this approach into question. The biological effects of the introduction of carbon dioxide or helium to form a pneumoperitoneum on tumour invasion and dissemination are unknown. METHODS: A human colonic adenocarcinoma cell line (SW1222) was exposed to in vitro laparoscopic environment of either carbon dioxide or helium for 4 h, mimicking the duration of a laparoscopic colorectal resection. Alteration in production of matrix metalloproteinase (MMP)-2, MMP-9 and urokinase-type plasminogen activator (uPA) due to exposure to a laparoscopic environment was determined by zymography and correlated to invasive capacity by a standard Matrigel-based invasion assay. Incorporation of specific gelatinase inhibitors or antibodies directed at the uPA receptor was utilized to determine the relative importance of proteases. RESULTS: Exposure to the laparoscopic environment significantly enhanced production of the proteases MMP-2, MMP-9 and uPA. A concomitant enhancement of invasive capacity was also observed, being blocked by specific protease inhibitors. Changes in both protease production and aggression were observable for at least 24 h following the removal of the operative environment, indicating the possible long-term effects of the initial insult. CONCLUSION: Exposure to the laparoscopic environment enhances the invasive capacity of colonic adenocarcinomas via a well-defined protease-determined pathway. It therefore appears likely that tumour cells released into the operative field can be made increasingly aggressive by a laparoscopic operative environment and can thus contribute to disease dissemination.

Perioperative diagnosis of cystosarcoma phyllodes of the breast may be enhanced by MIB-1 index.

BACKGROUND: The recurring theme in cystosarcoma phyllodes (CSP) is one of underdiagnosis by pathologists and undertreatment by surgeons. Major areas of investigation relating to the diagnosis of CSP center on accurate preoperative diagnosis, elucidating the relevance of histological classification with respect to outcome, and identifying novel markers to reliably differentiate CSP from fibroadenoma (FA). MATERIALS AND METHODS: Fifteen CSP and 7 cellular FA controls (where the preoperative diagnosis was unclear) were retrospectively investigated. Preoperative histological and radiological investigations were reviewed for efficacy. The ability of MIB-1 antibody to differentiate the two fibroepithelial lesions was investigated using immunohistochemical estimation of the MIB-1 index. RESULTS AND DISCUSSION: Preoperative core biopsy had a sensitivity of 75% but was carried out in only 23% of cases. Fine needle aspiration cytology and radiological assessment were not efficacious in preoperative diagnosis. Proliferative activity (MIB-1 indices) was significantly higher in CSP than in a selected population of FA where there was preoperative diagnostic uncertainty (P < 0.0001). Indices were also able to determine CSP subclassification. This suggests MIB-1 as a constructive adjunctive investigation when evaluating histological features to differentiate CSP from FA in difficult cases. CONCLUSIONS: The use of MIB-1 may increase the sensitivity of preoperative core biopsy diagnosis, offering more effective surgical planning and decreasing immediate reoperation rates.