Neutrophilic inflammation in gallbladder carcinoma correlates with patient survival: A case-control study.

Gallbladder carcinoma is an uncommon malignancy with an overall 5-year survival of less than 5%. Gallbladder carcinoma has been strongly linked with cholelithiasis and chronic inflammation. Case reports and series have described cholecystitis with acute (neutrophilic) inflammation in association with gallbladder carcinoma, although a clear relationship to patient outcome has not been established. Our series included 8 cases of gallbladder carcinoma with high tumor-associated neutrophils (>25 per high power field) that were associated with shorter patient survival (Cox regression coefficient 6.2, p = 0.004) than age- and stage-matched controls. High tumor-associated neutrophils were not associated with gallbladder rupture/perforation or increased bacterial load measured by 16S PCR. Neutrophilic inflammation with gallbladder carcinoma correlates to shorter survival, independent of patient age and stage of carcinoma. The findings suggest that the degree of neutrophilic inflammation may have prognostic significance in specimens from patients with gallbladder carcinoma after cholecystectomy. Further studies with larger case numbers are needed to confirm and generalize these findings.

A Retrospective Cohort Study on the Association between Red Cell Distribution Width and All-Cause Mortality of Patients with Cholecystitis at ICU Admission.

BACKGROUND: Elevated red cell distribution width (RDW) has been reported to be associated with mortality in some critically ill patient populations. The aim of this article is to investigate the relationship between RDW and in-hospital mortality and short- and long-term mortality of patients with cholecystitis. METHOD: We conducted a retrospective cohort study in which data from all 702 patients extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database were used. Receiver operating characteristic (ROC) curves were constructed to evaluate the prognostic predictive value of RDW for in-hospital mortality and short- (i.e., 30-day and 90-day) and long-term (i.e., 180-day, 1-year, 3-year, and 5-year) mortality. We converted RDW into a categorical variable according to quintiles as less than or equal to 13.9%, 14.0-14.8%, 14.9-15.8%, and 15.9-17.2% and more than 17.2%. The Kaplan-Meier (K-M) methods and log-rank tests were used to compare survival differences among different groups. The relationships between RDW levels and in-hospital mortality were evaluated by univariate and multivariate binary logistic regression models. Multivariable Cox regression models were built to investigate the association of RDW on the short-term and long-term mortality. RESULT: After adjusting for potential confounders, RDW was positively associated with in-hospital mortality (OR: 1.187, 95% CI [1.049, 1.343]) and short- (i.e., 30-day: HR: 1.183, 95% CI [1.080, 1.295], 90-day: HR: 1.175, 95% CI [1.089, 1.268]) and long-term (i.e., 1-year: HR:1.162, 95% CI [1.089, 1.240]) mortality in critically ill patients with cholecystitis. Similar results were also shown in the secondary outcomes of 180-day, 3-year, and 5-year mortality. RDW had a significant accurate prognostic effect on different endpoints and could improve the prognostic effect of scoring systems. CONCLUSION: High level of RDW is associated with an increased risk of in-hospital mortality and short- and long-term mortality in critically ill patients with cholecystitis. RDW can independently predict the prognosis of patients with cholecystitis.

Do surgical emergencies stay at home? Observations from the first United States Coronavirus epicenter.

BACKGROUND: During the coronavirus disease 2019 pandemic, New York instituted a statewide stay-at-home mandate to lower viral transmission. While public health guidelines advised continued provision of timely care for patients, disruption of safety-net health care and public fear have been proposed to be related to indirect deaths because of delays in presentation. We hypothesized that admissions for emergency general surgery (EGS) diagnoses would decrease during the pandemic and that mortality for these patients would increase. METHODS: A multicenter observational study comparing EGS admissions from January to May 2020 to 2018 and 2019 across 11 NYC hospitals in the largest public health care system in the United States was performed. Emergency general surgery diagnoses were defined using International Classification Diseases, Tenth Revision, codes and grouped into seven common diagnosis categories: appendicitis, cholecystitis, small/large bowel, peptic ulcer disease, groin hernia, ventral hernia, and necrotizing soft tissue infection. Baseline demographics were compared including age, race/ethnicity, and payor status. Outcomes included coronavirus disease (COVID) status and mortality. RESULTS: A total of 1,376 patients were admitted for EGS diagnoses from January to May 2020, a decrease compared with both 2018 (1,789) and 2019 (1,668) (p < 0.0001). This drop was most notable after the stay-at-home mandate (March 22, 2020; week 12). From March to May 2020, 3.3%, 19.2%, and 6.0% of EGS admissions were incidentally COVID positive, respectively. Mortality increased in March to May 2020 compared with 2019 (2.2% vs. 0.7%); this difference was statistically significant between April 2020 and April 2019 (4.1% vs. 0.9%, p = 0.045). CONCLUSION: Supporting our hypothesis, the coronavirus disease 2019 pandemic and subsequent stay-at-home mandate resulted in decreased EGS admissions between March and May 2020 compared with prior years. During this time, there was also a statistically significant increase in mortality, which peaked at the height of COVID infection rates in our population. LEVEL OF EVIDENCE: Epidemiological, level IV.

Obesity is not a risk factor for either mortality or complications after laparoscopic cholecystectomy for cholecystitis.

Obesity is a positive predictor of surgical morbidity. There are few reports of laparoscopic cholecystectomy (LC) outcomes in obese patients. This study aimed to clarify this relationship. This retrospective study included patients who underwent LC at Showa University Northern Yokohama Hospital between January 2017 and April 2020. A total of 563 cases were examined and divided into two groups: obese (n = 142) (BMI ≥ 25 kg/m2) and non-obese (n = 241) (BMI < 25 kg/m2). The non-obese group had more female patients (54%), whereas the obese group had more male patients (59.1%). The obese group was younger (56.6 years). Preoperative laboratory data of liver function were within the normal range. The obese group had a significantly higher white blood cell (WBC) count (6420/µL), although this was within normal range. Operative time was significantly longer in the obese group (p = 0.0001). However, blood loss and conversion rate were not significantly different among the groups, neither were surgical outcomes, including postoperative hospital stay and complications. Male sex and previous abdominal surgery were risk factors for conversion, and only advanced age (≥ 79 years) was an independent predictor of postoperative complications as observed in the multivariate analysis. Although the operation time was prolonged in obese patients, operative factors and outcomes were not. Therefore, LC could be safely performed in obese patients with similar efficacy as in non-obese patients.

Decreased survival of advanced colorectal cancer among patients with chronic cholecystitis: results from two clinical centers.

PURPOSE: Chronic cholecystitis is a common inflammatory disease of the gallbladder. It is related with various gastrointestinal tumors, although its pathogenesis is not clear. This study was designed to investigate the association between chronic cholecystitis and the survival of patients with advanced colorectal cancer (CRC). METHODS: We conducted a population-based large-scale retrospective case-control study involving 1094 patients with advanced CRC, 286 patients with cholecystitis, and 808 without. The patients were admitted in two hospitals in China. Data were obtained from a patient survey by professional interviewers in addition to medical records. The statistical significance was estimated by Kaplan-Mayer analysis and Cox proportional hazard regression. RESULTS: The chronic cholecystitis group had a shorter survival time than non- cholecystitis group (HR for Nanfang hospital patients 0.638, 95%CI 0.457-0.890, p=0.008; HR for Changzhou No.2 hospital patients 0.583, 95%CI 0.433-0.787, p<0.001). Surgery and chemotherapy could prolong the survival of patients CRC and reduce their mortality (surgery: HR for Nanfang hospital patients 1.638, 95%CI 1.087-2.469, p=0.018; HR for Changzhou No.2 hospital patients 2.137, 95%CI 1.399-3.265, p<0.001; chemotherapy: HR for Nanfang hospital patients 1.766, 95%CI 1.238-2.518, p=0.002; HR for Changzhou No.2 hospital patients 2.616, 95%CI 1.816-3.768. p<0.001). The higher the TNM staging, the shorter the survival time (TNM staging: HR for Nanfang hospital patients 3.912, 95%CI 3.201-4.781, p<0.001; HR for Changzhou No.2 hospital patients 3.907, 95%CI 3.05-5.005, p<0.001). CONCLUSION: Cholecystitis was strongly associated with a poor long-term prognosis for patients with CRC. The results suggest that special attention to gallbladder inflammation might be needed during the treatment of CRC.

Microbiology and risk factors for gram-positive Cocci bacteremia in biliary infections.

BACKGROUND: The rapid antibiotics treatment targeted to a specific pathogen can improve clinical outcomes of septicemia. We aimed to evaluate the clinical characteristics and outcomes of biliary septicemia caused by cholangitis or cholecystitis according to causative organisms. METHODS: We performed a retrospective cohort study in 151 patients diagnosed with cholangitis or cholecystitis with bacterial septicemia from January 2013 to December 2015. All patients showed clinical evidence of biliary tract infection and had blood isolates that demonstrated septicemia. RESULTS: Gram-negative, gram-positive, and both types of bacteria caused 84.1% (127/151), 13.2% (20/151), and 2.6% (4/151) episodes of septicemia, respectively. The most common infecting organisms were Escherichia coli among gram-negative bacteria and Enterococcus species (Enterococcus casseliflavus and Enterococcus faecalis) among gram-positive bacteria. There were no differences in mortality, re-admission rate, and need for emergency decompression procedures between the gram-positive and gram-negative septicemia groups. In univariate analysis, previous gastrectomy history was associated with gram-positive bacteremia. Multivariate analysis also showed that previous gastrectomy history was strongly associated with gram-positive septicemia (Odds ratio = 5.47, 95% CI: 1.19-25.23; P = 0.029). CONCLUSIONS: Previous gastrectomy history was related to biliary septicemia induced by gram-positive organisms. This information would aid the choice of empirical antibiotics.

[A retrospective analysis of clinical characteristics and mortality risks in elderly patients with acute cholecystitis and cholangitis].

Objective: To analyze the clinical characteristics and explore the risk predictors on mortality in elderly patients with acute cholecystitis and cholangitis. Methods: We conducted a retrospective analysis of elderly patients hospitalized in the Second Medical Center of General Liberation Army Hospital for acute cholecystitis and cholangitis during 2000 to 2018. Clinical data and risk predictors on mortality were assessed. The patients were stratified into three groups based on age:Ⅰ (65-74 years old),Ⅱ (75-84 years old), and Ⅲ (≥85 years old). Logistic regression analysis was used to identify the predictors of mortality. Results: A total of 574 patients were finally enrolled with the mean age 87.6 years including 191 in group Ⅰ, 167 in group Ⅱ, and 216 in group Ⅲ. The main cause of acute cholecystitis and cholangitis was gallstone (76.3%),and the main symptom was abdominal pain (62.9%),followed by chills(62.5%),fever(59.8%),jaundice (47.2%) and septic shock(26.3%). Cholecystitis was the most common diagnosis in groups Ⅰ and Ⅱ,whereas it was cholangitis in group Ⅲ. Percutaneous transhepatic biliary/gallbladder drainage (PTBD/PTGD) and endoscopic retrograde cholangiopancreatography (ERCP) were administrated more frequently in groups Ⅲ. A total of 35 patients (6.1%) died during follow-up. Senior in age (OR=11.1),the Charlson comorbidity index (OR=19.5),cancers (OR=9.6),blood stream infections (OR=7.4),severity of cholecystitis and cholangitis (OR=4.2) were risk factors associated with mortality. Conclusions: Even in the elderly patients with acute cholecystitis and cholangitis,comorbidity is one of the main factors affecting clinical outcomes. Due to the poor performance, this group of population presents more severe disease and undergoes conservative treatment strategies.

Comparison of 8- and 10-mm diameter fully covered self-expandable metal stents: A multicenter prospective study in patients with distal malignant biliary obstruction.

OBJECTIVES: The time to recurrent biliary obstruction (TRBO) of unresectable distal malignant biliary obstruction is generally thought to be longer when a self-expandable metal stent (SEMS) with a thicker inner diameter is used for drainage, but the dependence on the inner diameter using a fully covered SEMS (FCSEMS) is uncertain. The objective of this multicenter prospective study was to compare TRBO and adverse events, such as cholecystitis and pancreatitis, in treatment of patients with unresectable malignant biliary obstruction using 8- and 10-mm diameter FCSEMS. METHODS: Eighteen tertiary-care centers participated in the study. Patients were allocated to the 8- and 10-mm diameter groups. TRBO, non-inferiority of the 8-mm FCSEMS, overall survival time, frequency and type of adverse events, and non-recurrent biliary obstruction (RBO) rate at the time of death were compared between the two groups. RESULTS: Median TRBO did not differ significantly between the 8-mm (n = 102) and 10-mm (n = 100) groups (275 vs 293 days, P = 0.971). The hazard ratio of the 8- to 10-mm groups was 0.90 (80% confidence interval, 0.77-1.04; upper limit lower than the acceptable hazard ratio [1.33] of the null hypothesis). Based on these findings, the 8-mm diameter stent was determined to be non-inferior to the 10-mm diameter stent. Survival time, incidence of adverse events and non-RBO rate at the time of death did not differ significantly between the two groups. CONCLUSIONS: Time to RBO with an 8-mm diameter FCSEMS was non-inferior to that with a 10-mm diameter FCSEMS. This finding is important for development of future SEMS.

Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk patients (CHOCOLATE): multicentre randomised clinical trial.

OBJECTIVE: To assess whether laparoscopic cholecystectomy is superior to percutaneous catheter drainage in high risk patients with acute calculous cholecystitis. DESIGN: Multicentre, randomised controlled, superiority trial. SETTING: 11 hospitals in the Netherlands, February 2011 to January 2016. PARTICIPANTS: 142 high risk patients with acute calculous cholecystitis were randomly allocated to laparoscopic cholecystectomy (n=66) or to percutaneous catheter drainage (n=68). High risk was defined as an acute physiological assessment and chronic health evaluation II (APACHE II) score of 7 or more. MAIN OUTCOME MEASURES: The primary endpoints were death within one year and the occurrence of major complications, defined as infectious and cardiopulmonary complications within one month, need for reintervention (surgical, radiological, or endoscopic that had to be related to acute cholecystitis) within one year, or recurrent biliary disease within one year. RESULTS: The trial was concluded early after a planned interim analysis. The rate of death did not differ between the laparoscopic cholecystectomy and percutaneous catheter drainage group (3% v 9%, P=0.27), but major complications occurred in eight of 66 patients (12%) assigned to cholecystectomy and in 44 of 68 patients (65%) assigned to percutaneous drainage (risk ratio 0.19, 95% confidence interval 0.10 to 0.37; P<0.001). In the drainage group 45 patients (66%) required a reintervention compared with eight patients (12%) in the cholecystectomy group (P<0.001). Recurrent biliary disease occurred more often in the percutaneous drainage group (53% v 5%, P<0.001), and the median length of hospital stay was longer (9 days v 5 days, P<0.001). CONCLUSION: Laparoscopic cholecystectomy compared with percutaneous catheter drainage reduced the rate of major complications in high risk patients with acute cholecystitis. TRIAL REGISTRATION: Dutch Trial Register NTR2666.

[Perforated cholecystitis. Classification and atypical clinical forms]. / Perforativnyi kholetsistit. Klassifikatsiia i atipichnye klinicheskie formy.

AIM: To obtain new data for diagnosis and treatment of patients with perforated cholecystitis. MATERIAL AND METHODS: It was analyzed the variants of original classification of perforated cholecystitis by Fedorov S.P. - Neimeier O.W. (1934). Moreover, we have assessed treatment of 292 patients with gallbladder perforation (own material of Faculty Surgery Clinic). RESULTS: According to continuous 20-year follow-up perforated cholecystitis was observed in 2.9% of patients with various forms of gallbladder inflammation (n=292 out of 10 215). The frequency of atypical clinical forms of gallbladder perforation including multiple and combined perforation, perforation with acute intestinal obstruction and intraabdominal bleeding was 10% (n=29 of 292). Overall mortality in atypical clinical forms related to whole cohort with perforated cholecystitis was 2% (n=6 of 292). CONCLUSION: Atypical clinical forms of gallbladder perforation require specific treatment strategy due to the need for emergency surgical interventions. At the same time, the possibilities of video-assisted surgery are somewhat limited compared with other forms of gallbladder inflammation and can be used only in a third of patients.

Statewide assessment of surgical outcomes and the acute care surgery model.

BACKGROUND: The acute care surgery (ACS) model has been widely implemented with single institution studies demonstrating improved outcomes. Recent multicenter studies have raised questions about the economics and efficacy of ACS. This study compares traditional and ACS outcomes across an entire state. METHODS: A retrospective review of Virginia's Health Information administrative database was completed. Adults admitted with appendicitis or cholecystitis between 2008 and 2014 were included. Hospital administration was contacted to determine surgical model. To compare patient characteristics, t-test and chi-square analyses were used. Total charges and length of stay (LOS) differences between ACS and traditional were examined using generalized linear models, whereas logistic regression was used for the presence of complications and 30-day mortality. RESULTS: Overall, the ACS model showed an increased proportion of uninsured patients with a higher rate of comorbidities. In the appendicitis subgroup, (n = 22,011; ACS n = 1993), ACS patients had higher total charges ($30,060 versus $28,460, P = 0.013), longer LOS (3.31 versus 2.92 d, P < 0.001), and higher chance of complications (odds ratio [OR] = 1.2, P = 0.016) and mortality (OR = 2.4, P = 0.029). After adjustment for comorbidities and insurance, mortality was no longer significantly different. In the cholecystitis group (n = 6936; ACS n = 777), ACS patients had a longer LOS (4.55 versus 4.13 d; P = 0.009) without significant differences in mortality, complications, or cost. There were no significant differences after adjustment for patient characteristics. CONCLUSIONS: ACS patients in Virginia have a higher rate of medical comorbidities and uninsured status, with slightly worse outcomes than the traditional model for appendicitis. Further studies to determine which patients benefit the most from ACS are warranted.

The safety and prognostic factors for mortality in extremely elderly patients undergoing an emergency operation.

PURPOSE: As the number of elderly people has increased, the number of elderly patients who need emergency operations has also increased. Although there are many models to evaluate the risk of surgery in elderly patients, they all are associated with limitations. We herein evaluated the prognostic factors for surgical mortality in elderly patients more than 80 years old who needed emergency operations. METHODS: A total of 171 patients more than 80 years old underwent emergency operations from January 2001 to December 2012. Among them, 79 patients with acute cholecystitis, panperitonitis and intestinal obstruction with strangulation, which included mortality cases, were included. We retrospectively reviewed the medical records of the patients and analyzed the prognostic factors for surgical mortality. RESULTS: Forty-eight patients had a co-morbidity. Thirty-one patients initially had systemic inflammatory response syndrome. There were 27 surgical mortality cases. A univariate analysis revealed that panperitonitis, a positive blood culture and the level of albumin were significant prognostic factors predicting a worse prognosis. However, a multivariate analysis revealed that a serum albumin level more than 3.5 g/dL was the only significant prognostic factor (p = 0.037). CONCLUSION: Surgeons cannot fully evaluate the risk of emergency operation cases. However, our data indicate that if patients do not show hypoalbuminemia, the surgeon may be able to perform an emergency operation without a high risk of surgical mortality.

Gangrenous cholecystitis: Deceiving ultrasounds, significant delay in surgical consult, and increased postoperative morbidity!

BACKGROUND: Gangrenous cholecystitis (GC) is difficult to diagnose preoperatively in the patient with suspected acute cholecystitis. We sought to characterize preoperative risk factors and post-operative complications. METHODS: Pathology reports of all patients undergoing cholecystectomy for suspected acute cholecystitis from June 2010 to January 2014 and admitted through the emergency department were examined. Patients with GC were compared with those with acute/chronic cholecystitis (AC/CC). Data collected included demographics, preoperative signs and symptoms, radiologic studies, operative details, and clinical outcomes. RESULTS: Thirty-eight cases of GC were identified and compared with 171 cases of AC/CC. Compared with AC/CC, GC patients were more likely to be older (57 years vs. 41 years, p < 0.001), of male sex (63% vs. 31%, p < 0.001), hypertensive (47% vs. 22%, p = 0.002), hyperlipidemic (29% vs. 14%, p = 0.026), and diabetic (24% vs. 8%, p = 0.006). GC patients were more likely to have a fever (29% vs. 12%, p = 0.007) and less likely to have nausea/vomiting (61% vs. 80%, p = 0.019) or an impacted gallstone on ultrasound (US) (8% vs. 26%, p = 0.017). Otherwise, there was no significant difference in clinical or US findings. Among GC patients, US findings were absent (8%, n = 3) or minimal (42%, n = 16). Median time from emergency department registration to US (3.3 hours vs. 2.8 hours, p = 0.28) was similar, but US to operation was longer (41.2 hours vs. 18.4 hours, p < 0.001), conversion to open cholecystectomy was more common (37% vs. 10%, p < 0.001), and hospital stay was longer (median, 4 days vs. 2 days, p < 0.0001). Delay in surgical consultation occurred in 16% of GC patients compared with 1% of AC patients (p < 0.001). CONCLUSION: Demographic features may be predictive of GC. Absent or minimal US signs occur in 50%, and delay in surgical consultation is common. Postoperative morbidity is greater for patients with GC compared with those with AC/CC. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV.

Gangrenous cholecystitis: a contemporary review.

BACKGROUND: Despite the established superiority of laparoscopic cholecystectomy (LC) for acute cholecystitis, gangrenous cholecystitis (GC) is commonly treated with open cholecystectomy (OC). This study aimed to characterize outcomes of GC in the modern era and between LC or OC surgical approach. MATERIALS AND METHODS: Patients with a diagnosis of GC were identified using the 2005-2011 National Surgical Quality Improvement Project Participant User File. Baseline patient and operative characteristics and 30-d outcomes were established for all patients. Patients were stratified by surgical approach (LC or OC), and groups were propensity matched with a nearest-neighbor matching algorithm. Primary outcomes were 30-d mortality and any 30-d complication. A nonparsimonious multiple logistic regression model was used in the matched subset to adjust for patient comorbidities, demographics, and laboratory values. RESULTS: A total of 141,970 cholecystectomies were identified with 7017 having a diagnosis of GC. Overall 30-d mortality for the entire cohort was 0.8% (n = 239) and overall 30-d complication rate was 8.0% (n = 2485). For GC patients, the 30-d mortality was 1.2% (n = 84) and overall complication rate was 10.8% (n = 761). The multivariate logistic regression model demonstrated a significant decrease in overall (odds ratio = 0.46; P < 0.001) complication rates for LC patients but did not reveal a significant difference in 30-d mortality (odds ratio = 0.59; P = 0.12). CONCLUSIONS: GC is associated with increased morbidity and mortality compared with that of acute cholecystitis. A LC approach is a safe option for patients with GC and is associated with decreased 30-d morbidity. Although LC should be used when possible for GC to minimize postoperative complications, OC should not be avoided if necessary to ensure patient safety.

Expression of heat-shock protein gp96 in gallbladder cancer and its prognostic clinical significance.

PURPOSE: To detect the expression and prognostic clinical significance of heat-shock protein gp96 (HSP gp96) in gallbladder cancer. METHODS: Immunohistochemistry was used to detect and compare the rate of HSP gp96 expression in 107 samples of gallbladder cancer, 70 of gallbladder adenoma and 67 of chronic cholecystitis. The association of clinicopathological factors and patients' survival were calculated by univariate and multivariate (Cox proportional hazard regression method) analysis. RESULTS: The expression positive rate of HSP gp96 was 90.7% (97/107) in gallbladder cancer, 71.4% (50/70) in gallbladder adenoma and 47.76% (32/67) in chronic cholecystitis respectively. The positive rate of HSP gp96 in gallbladder cancer tissues was significantly higher than that in gallbladder adenoma and chronic cholecystitis tissues (P < 0.01). Multivariate and Cox regression analysis showed that positive of HSP gp96 (P = 0.026) expression was an independent poor prognostic predictor in gallbladder cancer. CONCLUSIONS: HSP gp96-positive expression is closely correlated with poor survival in gallbladder cancer.

Gangrenous cholecystitis: mortality and risk factors.

As a serious complication of cholelithiasis, gangrenous cholecystitis presents greater mortality than noncomplicated cholecystitis. The aim of this study was to specify the risk factors on mortality. 107 consecutive patients who underwent surgery due to gangrenous cholecystitis between January 1997 and October 2011 were investigated retrospectively. The study included 60 (56.1%) females and 47 (43.9%) males, with a mean age of 60.7 ± 16.4 (21-88) years. Cardiovascular diseases were the most frequently accompanying medical issues (24.3%). Thirty-six complications (33.6%) developed in 29 patients, and surgical site infection was proven as the most common. Longer delay time prior to hospital admission, low white blood cell count, presence of diabetes mellitus, higher blood levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin, pericholecystic fluid in abdominal ultrasonography, and conversion from laparoscopic surgery to open surgery were identified as risk factors affecting mortality (P < 0.001, P = 0.001, P = 0.044, P = 0.005, P = 0.049, P = 0.009, P = 0.022, P = 0.011, and P = 0.004, respectively). Longer delay time prior to hospital admission and low white blood cell count were determined as independent risk factors affecting mortality.

Aberrant activation of Sonic hedgehog signaling in chronic cholecystitis and gallbladder carcinoma.

Sonic hedgehog (Shh) signaling has been extensively studied and is implicated in various inflammatory diseases and malignant tumors. We summarized the clinicopathological features and performed immunohistochemistry assays to examine expression of Shh signaling proteins in 10 normal mucosa, 32 gallbladder carcinoma (GBC), and 95 chronic cholecystitis (CC) specimens. The CC specimens were classified into three groups according to degree of inflammation. Compared with normal mucosa, CC, and GBC specimens exhibited increased expression of Shh. The immunoreactive score of Shh in the GBC group was higher than that in the mild to moderate CC groups but lower than that in the severe CC group (P < .05). Expression of Patched (Ptch) and Gli1 gradually increased from non-malignant cholecystitis to malignant tumors. Compared with CC specimens, GBC specimens showed higher cytoplasmic and membranous expression for Ptch (P < .05). Gli1 staining showed cytoplasmic expression of Gli1 in both CC (60% for mild, 77% for moderate, and 84% for severe) and GBC specimens (97%). Nuclear expression of Gli1 was detected in 16% of severe CC specimens with moderate to poor atypical hyperplasia, and in 62.5% of GBC specimens. Shh expression strongly correlated with expression of Ptch and Gli1. Furthermore, patients with strongly positive Gli1 staining had significantly lower survival rates than those with weakly positive staining. Our data indicate that the Shh signaling pathway is aberrantly activated in CC and GBC, and altered Shh signaling may be involved in the course of development from CC to gallbladder carcinogenesis.

Immunohistochemical expression of vascular endothelial growth factor A in advanced gallbladder carcinoma.

Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. The molecular mechanisms involved in the pathogenesis of GBC remain poorly understood. The vascular endothelial growth factor A (VEGF-A) is a potent proangiogenic agent involved in the carcinogenesis of many human tumors and is an attractive target for cancer therapy. We characterized VEGF-A expression in advanced GBC and its relation to clinicopathologic features. VEGF-A expression was examined by immunohistochemistry in tissue microarrays containing 224 advanced gallbladder carcinomas and 39 chronic cholecystitis. The cases were classified as low or high expression to evaluate the association of VEGF-A expression level with clinicopathologic variables. The Kaplan-Meier method was used to estimate survival as a function of time, and survival differences were analyzed by the log-rank test. High expression of VEGF-A was observed in 81% (183/224) of tumors and 5.1% (2/39) of chronic cholecystitis (P<0.0001). The VEGF-A expression had a significant relationship with histologic grade and TNM stage (P<0.05). Moreover, 5-year survival analysis indicated that high expression of VEGF-A is associated with a poor prognosis in patients with advanced GBC (P=0.0116). Our results indicate that VEGF-A is highly expressed in GBC and correlates with poor prognosis, suggesting that VEGF-A expression could be used as a biomarker for predicting malignant behavior and for identifying a subset of patients who may benefit from anti-VEGF-A therapies.