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Importance: Tranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear., Objective: To determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection., Design, Setting, and Participants: Multicenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization., Interventions: Tranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia., Main Outcomes and Measures: The primary outcome was receipt of red blood cell transfusion within 7 days of surgery., Results: The primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P = .38; absolute difference, 2% [95% CI, -2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P = .75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P = .38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P = .03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P = .08)., Conclusions and Relevance: Among patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications., Trial Registration: ClinicalTrials.gov Identifier: NCT02261415.

Background: We have developed an algorithmic approach to laparoscopic cholecystectomy, including subtotal cholecystectomy, as a bailout strategy when the Critical View of Safety cannot be safely achieved due to significant inflammation and fibrosis of the hepatocystic triangle., Methods: This is a retrospective cohort study comparing postoperative outcomes in patients with severe cholecystitis who underwent laparoscopic cholecystectomy or laparoscopic subtotal cholecystectomy at St. Joseph's Health Centre from May 2016 to July 2021, as well as against a historical cohort. We further stratified laparoscopic subtotal cholecystectomy cases based on fenestrating or reconstituting subtype., Results: The cohort included a total of 105 patients who underwent laparoscopic cholecystectomy and 31 patients who underwent laparoscopic subtotal cholecystectomy. Bile leaks (25.8% vs 1.0%, relative risk 3.5, 95% confidence interval 3.5-208.4) were more common in the laparoscopic subtotal cholecystectomy group. Postoperative endoscopic retrograde cholangiopancreatography (22.6% vs 3.8%, relative risk 5.9, 95% confidence interval 1.9-18.9) and biliary stent insertion (19.4% vs 1.0%, relative risk 20.3, 95% confidence interval 2.5-162.5) were also more common in the laparoscopic subtotal cholecystectomy group. Bile leaks in laparoscopic subtotal cholecystectomy were only documented in the fenestration subtype, most of which were successfully managed with endoscopic retrograde cholangiopancreatography and biliary stenting. Compared to our previous study of laparoscopic cholecystectomy and subtotal cholecystectomy for severe cholecystitis between 2010 and 2016, there has been a decrease in postoperative laparoscopic cholecystectomy complications, subtotal cholecystectomy cases, and no bile duct injuries., Conclusion: Following our algorithmic approach to safe laparoscopic cholecystectomy has helped to prevent bile duct injury. Laparoscopic cholecystectomy remains the gold standard for the management of severe cholecystitis; however, in extreme cases, laparoscopic subtotal cholecystectomy is a safe bailout strategy with manageable morbidity., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Surgical site infection (SSI) is one of the most common sources of morbidity after pancreaticoduodenectomy. Surgical site infections are associated with readmissions, prolonged length of stay, delayed initiation of adjuvant chemotherapy and negative effects on quality of life. Incisional vacuum-assisted closure (iVAC) devices applied on closed incisions may reduce SSI rates. The objective of this retrospective review is to evaluate the impact of iVAC on SSI rate after pancreaticoduodenectomy., Methods: A cohort of patients undergoing pancreaticoduodenectomy at a single institution who had at least 1 risk factor for SSI and who received an iVAC were compared with a historical cohort of high-risk patients who received conventional dressings after pancreaticoduodenectomy. The primary outcome was incidence of SSI within 30 days, abstracted from chart review. Secondary outcomes were 30-day readmission, 90-day mortality, rate of postoperative pancreatic fistula and rate of delayed gastric emptying., Results: In total, 175 patients were included, of whom 61 received an iVAC. The incidence of SSI was 13% (8 of 61 patients) and 16% (18 of 114 patients) in the iVAC and conventional dressing groups, respectively (odds ratio 0.81, 95% confidence interval 0.33-1.98). Preoperative biliary drainage was the most frequent SSI risk factor. Binary logistic regression using SSI as the outcome demonstrated no significant association with iVAC use when adjusted for SSI risk factors. There were no differences in rates of postoperative pancreatic fistula, delayed gastric emptying or 90-day mortality., Conclusion: This report describes the outcomes of the integration of iVAC devices into routine clinical practice at a high-volume institution. Application of this device after pancreaticoduodenectomy for patients at elevated risk of SSI was not associated with a reduction in the rate of SSIs., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: Prospective audit and feedback (PAF) is an established practice in critical care settings but not in surgical populations. We pilot-tested a structured face-to-face PAF program for our acute-care surgery (ACS) service., Methods: This was a mixed-methods study. For the quantitative analysis, the structured PAF period was from August 1, 2017, to April 30, 2019. The ad hoc PAF period was from May 1, 2019, to January 31, 2021. Interrupted time-series segmented negative binomial regression analysis was used to evaluate change in antimicrobial usage measured in days of therapy per 1,000 patient days for all systemic and targeted antimicrobials. Secondary outcomes included C. difficile infections, length of stay and readmission within 30 days. Each secondary outcome was analyzed using a logistic regression or negative binomial regression model. For the qualitative analyses, all ACS surgeons and trainees from November 23, 2015, to April 30, 2019, were invited to participate in an email-based anonymous survey developed using implementation science principles. Responses were measured using counts., Results: In total, 776 ACS patients were included in the structured PAF period and 783 patients were included in the in ad hoc PAF period. No significant changes in level or trend for antimicrobial usage were detected for all and targeted antimicrobials. Similarly, no significant differences were detected for secondary outcomes. The survey response rate was 25% (n = 10). Moreover, 50% agreed that PAF provided them with skills to use antimicrobials more judiciously, and 80% agreed that PAF improved the quality of antimicrobial treatment for their patients., Conclusion: Structured PAF showed clinical outcomes similar to ad hoc PAF. Structured PAF was well received and was perceived as beneficial by surgical staff., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2023.)

Laparoscopic subtotal cholecystectomy (LSC) is a bailout strategy to prevent bile duct injury in difficult gallbladder cases. It is associated with acceptable morbidity that is readily managed with postoperative interventions. Here we share our techniques for LSC. We begin with landmarking, which includes the line of safety, a theoretical line the sulcus of Rouvière and the junction of the cystic and hilar plates. If the fundus can be grasped, then the gallbladder is dissected off the cystic plate using the top-around approach. The gallbladder is then amputated, creating a short cuff of proximal gallbladder. This cuff can be left patent (2A) or cinched close with an ENDOLOOP (Ethicon) if it is small, ideally less than 1 cm (1A). If the fundus cannot be grasped, then an inverted T incision is made on the anterior gallbladder wall. The longitudinal incision is extended toward the fundus, and the transverse incision is extended superiorly along the cystic plate edge. Two "bunny ears" are developed and ultimately resected to excise the anterior gallbladder wall at an oblique angle while leaving the posterior wall intact (2B). If the remaining cuff is small, then it can be sutured closed against the gallbladder back wall (1B). In the setting of extensive bowel adhesion to the anterior gallbladder, we perform a fundectomy, from which we extend two incisions along the cystic plate to open the gallbladder like a clamshell. Our paper describes and illustrates our St Joseph's Health Centre institutional LSC approach and subtype classification (1A, 1B, 2A, and 2B)., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Preoperative evaluation of resectable colorectal cancer liver metastases with positron emission tomography (PET) combined with computed tomography (PET-CT) is used extensively. The PETCAM trial evaluated the effect of PET-CT (intervention) vs no PET-CT (control) on surgical management. PET-CT resulted in 8% change in surgical management, therefore, we aimed to compare long-term outcomes (disease-free [DFS], overall survival [OS])., Methods: Trial recruitment (2005-2010) had prospective follow-up until 2013. Events from 2013 to 2017 were collected retrospectively. Survival was described by the Kaplan-Meier method and compared with log-rank test. Oncologic risk factors were calculated using Cox proportional hazard models., Results: Among 404 patients randomized, there were no differences in DFS (hazard ratio [HR] = 1.13; 95% confidence interval [CI], 0.89 to 1.43) or OS (HR, 1.02; 95% CI, 0.78-1.32) between groups. For all patients randomized, median DFS (PET-CT vs no PET-CT) was 16 months (95% CI, 13-18) and 15 months (95% CI, 11-22), P = .33. For patients who underwent liver resection (n = 368), DFS (17 vs 16 months, P = .51) and OS (58 months vs 52 months, P = .90) were similar between groups, respectively. Risk factors for DFS and OS were age, tumor size, node-positive disease, extrahepatic metastases and disease-free duration., Conclusion: Preoperative PET-CT changes surgical management in a small percentage of cases, without effect on recurrence rates or long-term survival., (© 2020 Wiley Periodicals, Inc.)

Background: Management of recurrence following liver resection for colorectal cancer metastases is a topic of debate. We determined risk factors for survival following recurrence after liver resection., Methods: Long-term follow-up of patients in the PETCAM trial who had recurrence following liver resection. Risk groups were created according to their survival risk. Differences in overall survival (OS) between groups were estimated. Disease-free survival (DFS), patterns of disease recurrence and management were determined. Cox proportional hazard models, Kaplan-Meier method, and the log-rank test were used., Results: Among 368 patients who underwent liver resection, 264 (72%) experienced disease recurrence (51% lung and 41% liver). Following liver resection, DFS: 17 months (95% CI, 14-19); OS: 57 months (95% CI, 46-70). In those who recurred, 120 (45%) received chemotherapy only, and 112 (42%) underwent second surgical resection. Among patients who experienced recurrence (n = 264), the high-risk group (more than one site of recurrence or disease-free duration < 5 months and node-positive disease) had median OS: 19 months (95% CI, 15-23) vs 36 months (95% CI, 30-48) for patients in the low-risk group (HR = 2.9, 95% CI, 2.2-3.9)., Conclusion: Recurrence following liver resection is common. Following recurrence after liver resection, patients should be carefully selected for surgical re-resection based on risk factors., (© 2019 Wiley Periodicals, Inc.)

Introduction: Selection criteria and benefits for resection of noncolorectal, nonneuroendocrine liver metastases (NCNNELM) remain debated. A prognostic score was developed by the Association Française de Chirurgie (AFC) for patient selection, but not validated. We performed a geographic external validation of this score., Methods: Patients with resected NCNNELM from six institutions (2000-2014) were assigned risk groups based on the AFC score. Discrimination was evaluated by visually inspecting separation of overall survival (OS) curves among risk categories. The slope of the continuous score on OS and hazard ratios for risk categories were examined., Results: Of 165 patients, 53 (32.1%) were low-risk, 85 (51.5%) intermediate-risk, and 27 (16.4%) high-risk. The OS curves did not separate among risk groups: 5-year OS were 60.1% (low), 57.1% (intermediate), and 55.6% (high). The parameter estimate (0.02) indicated lower discrimination than in the AFC cohort. Hazard ratios of 1.05 (0.63 to 1.70) for low vs intermediate, 0.87 (0.46 to 1.64) for low vs high, and 0.83 (0.46 to 1.49) for intermediate vs. high, demonstrated lack of discrimination in OS among risk groups., Conclusion: While long-term survival is achievable, discrimination of the AFC score is not maintained in a geographic external cohort of resected NCNNELM. It is not generalizable to this external population., (© 2018 Wiley Periodicals, Inc.)

Background: Bleeding and need for red blood cell transfusions (RBCT) remain a significant concern with hepatectomy. RBCT carry risk of transfusion-related immunomodulation that may impact post-operative recovery. This study soughs to assess the association between RBCT and post-hepatectomy morbidity., Methods: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry, we identified all adult patients undergoing elective hepatectomy over 2007-2012. Two exposure groups were created based on RBCT. Primary outcomes were 30-day major morbidity and mortality. Secondary outcomes included 30-day system-specific morbidity and length of stay (LOS). Relative risks (RR) with 95% confidence interval (95% CI) were computed using regression analyses. Sensitivity analyses were conducted to understand how missing data might have impacted the results., Results: A total of 12,180 patients were identified. Of those, 11,712 met inclusion criteria, 2,951 (25.2%) of whom received RBCT. Major morbidity occurred in 14.9% of patients and was strongly associated with RBCT (25.3% vs. 11.3%; P<0.001). Transfused patients had higher rates of 30-day mortality (5.6% vs. 1.0%; P<0.0001). After adjustment for baseline and clinical characteristics, RBCT was independently associated with increased major morbidity (RR 1.80; 95% CI: 1.61-1.99), mortality (RR 3.62; 95% CI: 2.68-4.89), and 1.29 times greater LOS (RR 1.29; 95% CI: 1.25-1.32). Results were robust to a number of sensitivity analyses for missing data., Conclusions: Perioperative RBCT for hepatectomy was independently associated with worse short-term outcomes and prolonged LOS. These findings further the rationale to focus on minimizing RBCT for hepatectomy, when they can be avoided., Competing Interests: Conflicts of Interest: This work has been presented as poster presentation at the 2015 Canadian Surgery Forum in Québec City, in September 2015.

Background: Patients with incurable malignancies can require surgical intervention. We prospectively evaluated patients treated with palliative surgery to qualitatively assess peri-operative outcomes., Methods: Eligible patients were assessed at a tertiary care cancer center. Demographic information and peri-operative morbidity and mortality were collected. Semi-structured qualitative interviews were obtained pre-operatively and post-operatively (1 month). Qualitative evaluation was performed using content analysis and an inductive approach., Results: Twenty-eight patients were approached and 20 consented to interview. Data saturation was achieved after 14 patients. Median patient age was 58% and 56% were female. Peri-operative morbidity and mortality were 44% and 22%, respectively. "No other option" was seen as a dominant pre-operative theme (14 of 18). Other pre-operative themes included a "poor understanding of prognosis and the role of surgery in overall treatment plan". Post-operative themes included a "perceived benefit from surgery" and "satisfaction with decision-making", notwithstanding significant complications. Improved understanding of prognosis and the role of surgery were described post-operatively., Conclusions: Despite limited options and a poor understanding of prognosis, many patients perceived benefit from palliative surgery. However, peri-operative mortality was substantial. A robust and thorough patient-centered discussion about individual goals for surgery should be undertaken by surgeon, patient and family prior to embarking on a palliative operation.

Background: More than half of the patients undergoing resection for colorectal cancer liver metastases develop recurrent hepatic disease. We report management and outcomes of patients undergoing repeat hepatectomy in routine practice., Methods: All cases of repeat hepatectomy for colorectal cancer liver metastases from 2002 to 2009 in the Canadian Province of Ontario were identified using the population-based Ontario Cancer Registry and linked treatment records., Results: Of 1,310 patients who underwent resection of CRLM, 78 (6.0%) underwent a repeat liver resection. Mean age was 56 years and the median time between resections was 19 months. Compared with the first resection, second resections were associated with fewer lesions (2.7 vs 1.5; P = .001) and fewer major resections (58% vs 31%; P = .024). The size of largest lesion, positive margin rate, length of hospital stay, and 90-day mortality were similar. Unadjusted 5-year overall survival from the time of second resection was 45% (95% confidence interval = 32% to 59%) and cancer-specific survival was 47% (95% confidence interval = 30% to 64%)., Conclusions: Repeat liver resections for metastatic CRC involve fewer lesions and less extensive surgery and a substantial proportion of patients achieve long-term survival., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Background: While the indications for surgery among patients with colorectal cancer liver metastases (CRCLM) are expanding, the role of surgery in patients with hepatic lymph node involvement remains controversial. We report management and outcomes in a population-based cohort of patients undergoing hepatectomy with concomitant hepatic lymphadenectomy for CRCLM., Methods: All cases of hepatectomy for CRCLM in the Canadian Province of Ontario from 2002 to 2009 were identified using the population-based Ontario Cancer Registry and linked electronic records of treatment. Pathology reports were used to identify concomitant lymphadenectomy with liver resection as well as extent of disease and surgical procedure., Results: Among 1310 patients who underwent resection for CRCLM, 103 (8%) underwent simultaneous regional lymphadenectomy. Seventy-one percent of cases with lymphadenectomy (70/103) had a major liver resection (≥3 segments). Of the 103 lymphadenectomy cases, 80 (78%) were hepatic pedicle, 16 (16%) were celiac and 7 (7%) were para-aortic. The mean number of nodes removed was 2.2 (range 1-15). Ninety-day mortality was 6%. Twenty-nine percent (30/103) of cases had positive nodes. Unadjusted overall survival at 5 years for positive vs negative nodes was 21% vs 42% (p = 0.003); cancer-specific survival was 10% vs 43% (p < 0.001). In adjusted analyses, hepatic node involvement was associated with inferior OS (HR 2.19, p = 0.010) and CSS (HR 3.07, p = 0.002)., Conclusions: Patients with resected CRC liver metastases with regional lymph node involvement have inferior survival compared to patients with negative nodes. Despite this poor prognostic factor, a small proportion of cases with involved nodes will achieve long-term survival., (Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Peri-operative red blood cell transfusions (RBCT) may induce transfusion-related immunomodulation and impact post-operative recovery. This study examined the association between RBCT and post-pancreatectomy morbidity., Methods: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry, patients undergoing an elective pancreatectomy (2007-2012) were identified. Patients with missing data on key variables were excluded. Primary outcomes were 30-day post-operative major morbidity, mortality, and length of stay (LOS). Unadjusted and adjusted relative risks (RR) with a 95% confidence interval (95%CI) were computed using modified Poisson, logistic, or negative binomial regression, to estimate the association between RBCT and outcomes., Results: The database included 21 132 patients who had a pancreatectomy during the study period. Seventeen thousand five hundred and twenty-three patients were included, and 4672 (26.7%) received RBCT. After adjustment for baseline and clinical characteristics, including comorbidities, malignant diagnosis, procedure and operative time, RBCT was independently associated with increased major morbidity (RR 1.49; 95% CI: 1.39-1.60), mortality (RR 2.19; 95%CI: 1.76-2.73) and LOS (RR 1.27; 95%CI 1.24-1.29)., Conclusion: Peri-operative RBCT for a pancreatectomy was independently associated with worse short-term outcomes and prolonged LOS. Future studies should focus on the impact of interventions to minimize the use of RBCT after an elective pancreatectomy., (© 2015 International Hepato-Pancreato-Biliary Association.)

Introduction: Portal pedicle clamping (PPC) may impact micro-metastases' growth. This study examined the association between PPC and survival after a hepatectomy for colorectal liver metastases (CRLM)., Methods: A matched cohort study was conducted on hepatectomies for CRLM at a single institution (2003-2012). Cohorts were selected based on PPC use, with 1:1 matching for age, time period and the Clinical Risk Score. Outcomes were overall and recurrence-free survival (OS and RFS). Cox regression was performed to assess the association between PPC and survival., Results: Of 481 hepatectomies, 26.9% used PPC. One hundred and ten pairs of patients were matched in the cohorts. There was no significant difference in OS [hazard ratio (HR) 1.18; 95% confidence interval (CI): 0.76-1.83], with a 5-year OS of 57.8% (95%CI: 52.4-63.2%) with PPC versus 62.3% (95%CI: 57.1-67.5%) without. Five-year RFS did not differ (HR 0.98; 95%CI: 0.71-1.35) with 29.7% (95%CI: 24.9-34.5%) with PPC versus 28.0% (95%CI: 23.2-32.8%) without. When adjusting for extent of resection, transfusion, operative time and surgeon, there was no difference in OS (HR 0.91; 95%CI: 0.52-1.60) or RFS (HR: 0.86; 95%CI: 0.57-1.30)., Conclusions: PPC was not associated with a significant difference in OS or RFS in a hepatectomy for CRLM. PPC remains a safe technique during hepatectomy., (© 2015 International Hepato-Pancreato-Biliary Association.)

Natural orifice translumenal endoscopic surgery (NOTES) is on the forefront of surgical technique, but existing research has produced mixed results regarding factors associated with interest in the procedure. Our objective was to ascertain patient opinions at a Canadian centre regarding scarless surgery. A survey comprising demographic data (gender, age, body mass index [BMI]), interest in NOTES, impact of increased risk, as well as importance of further research and shorter recovery time was administered to volunteer patients at outpatient general surgery clinics. Nonparametric tests were utilized to examine difference in response by age, sex, BMI, and preexisting scars. Of the 335 participants (57% female, mean age of 54.5 ± 15.9 years, mean BMI of 28.7 ± 6.9), the majority (83%) showed some interest, but this dropped to 38% when additional risk was factored in. Generally, women, those under 50 years of age and those of healthy weight, were more interested than male, older, and/or heavier patients. Most felt that research into NOTES and reduced length of inpatient stay were important (80% and 95%, respectively). Further investigation into objective NOTES outcomes are needed to provide patients adequate data to make an informed choice regarding surgical route.

The antinociceptive mechanism underlying protease-activated receptor-4 (PAR(4)) activation was studied in Fast Blue-labelled dorsal root ganglia (DRG) neurons from mouse colon which expressed transcript for PAR(4). Whole cell perforated patch clamp recordings were obtained from these neurons and the effects on neuronal excitability of PAR(4) activating peptides (AP) and reverse peptides (RP) were examined. A 3-min application of PAR(4)-AP (100 micromol L(-1)) markedly suppressed the number of action potential discharged at twice rheobase for up to 60 min. PAR(4)-RP had no effect. PAR(4) application suppresses the excitatory effects of PAR(2). These findings demonstrated that activation of PAR(4) on colonic DRG neurons suppresses their excitability, suggesting these receptors could provide important targets for modifying pain in colonic GI disorders such as IBS and IBD.

Caspase-independent cell death has drawn increasing attention. In the present study, we found that lipopolysaccharide (LPS) accelerated spontaneous death of human lung epithelial A549 cells in a serum- and cell density-dependent manner: while serum starvation has been demonstrated to induce apoptosis in the same cell line, LPS-induced cell death was only observed in the presence of serum; in addition, the cell death was not observed when the cells were seeded at 10- or 100-fold lower density. The apoptotic features were demonstrated by TUNEL assay, DNA laddering and Annexin V staining. However, treatment of cells with two commonly used pan-caspase inhibitors, zVAD.fmk or BOC-D.fmk, failed to block cell death. In contrast, two cathepsin B inhibitors, Ca074-Me or N-1845, reduced cell death significantly. A time-dependent activation of cathepsin B, but not caspase 3, was observed in both control and LPS-treated cells. Although LPS did not further activate cathepsin B or its release, it increased expression and translocation of apoptosis inducing factor from mitochondria to the nucleus, and increased release of cytochrome c from mitochondria. LPS-induced cell death was significantly attenuated by either N-acetyl-L-cysteine or pyrrolidine-dithiocarbamate, both free radical scavengers. Disruption of lipid raft formation with filipin or methyl-beta-cyclodextrin also reduced apoptosis significantly, suggesting that lipid raft-dependent signaling is essential. These data imply that confluent cells undergo spontaneous cell death mediated by cathepsin B; LPS may accelerate this caspase-independent cell death through release of mitochondrial contents and reactive oxygen species., (Copyright 2006 Wiley-Liss, Inc.)