Patients
In this study, we enrolled patients who underwent radical resection of GBC at the Japanese Red Cross Kumamoto Hospital between June 1986 and March 2022. Preoperative and postoperative clinical data were retrospectively collected. This study was conducted in accordance with the principles embodied in the Declaration of Helsinki (as revised in 2013) and was approved by the ethics board of the Japanese Red Cross Kumamoto Hospital (permission no. 515). The requirement for informed consent was waived owing to the retrospective nature of this study. We posted a summary of the trial on our website and asked eligible patients to inform us if they wished to be excluded from the study; none of the participants requested exclusion.
We excluded patients from the analysis if they were not able to undergo radical resection due to tumor infiltration and distant metastasis at surgery (22 and 8 patients, respectively). We also excluded 11 duplicate cases with advanced cancer of the gastrointestinal tract. Additionally, 109 cases with missing clinical information, which was required for data analysis in this study, were excluded. Finally, 218 patients were included in the analysis (Fig. 1).
GBC diagnosis was based on the pathology of resected specimens, and staging was classified according to the eighth edition of the Union for International Cancer Control (UICC) Staging Manual [10].
For cases of so-called “incidental GBC” in which the patients were operated on for benign gallbladder diseases (e.g., AC, cholelithiasis) and the coexistence of GBC was postoperatively confirmed, a comprehensive decision regarding whether or not additional surgery should be performed was made while taking the degree of cancer progression, presence of intraoperative BS, age, and performance status into account.
AC
Preoperative diagnosis of AC was based on physical symptoms (e.g., Murphy’s sign, pain in the right hypochondrium) and systemic inflammatory findings (e.g., fever, elevated white blood cell counts, inflammatory response on blood tests). In addition to these findings, ultrasound and computed tomography imaging studies were conducted to confirm the diagnosis of gallbladder enlargement, wall thickening, and edematous changes in the surrounding area.
The final diagnosis was based on intraoperative findings of gallbladder enlargement, edematous changes around the gallbladder, and abscesses due to wall perforation, as well as gallbladder wall congestion, edema, hemorrhage, and intramural abscess on histopathological examination. For cases in which AC was preoperatively diagnosed, surgical treatment was adopted as the first choice, and drainage procedures (e.g., percutaneous transhepatic gallbladder drainage) were not performed.
Surgical procedure
For preoperative GBC diagnosis, laparotomy was routinely performed. However, for preoperative diagnosis of gallstones, gallbladder polyps, or cholecystitis, laparoscopic surgery was also performed. Lymph node dissection (LND) was limited to sampling or dissection of pericholedochal lymph nodes at depths up to T1. D2 LND was routinely performed at T2 and above [11]. If surgery was performed for benign disease and GBC was detected postoperatively, D2 LND, resection of the liver bed, or extrahepatic bile duct resection was added to obtain negative resection margins. Alternatively, in some cases, additional port-site resection was performed if BS occurred during the initial surgery. Pre- and postoperative adjuvant chemotherapy was generally not administered.
Outcome
The primary endpoint of the study was overall survival (OS), and the secondary endpoint was recurrence-free survival (RFS), comparing AC patients with and without concomitant AC after adjusting for background factors. OS was defined as the time from the date of surgery to the last follow-up (in months). RFS was defined as the time from the date of surgery to the date of confirmed recurrence or last follow-up. The 5-year OS and RFS were calculated and used for evaluation.
Additionally, the incidence of recurrent GBC cases was compared according to the presence of AC and BS. Local recurrence was defined as disseminated recurrence in the abdominal cavity near the gallbladder resection site. Distant recurrence was defined as metastatic recurrence in the liver, lung, or distant lymph nodes.
PS analysis
We used PS matching (PSM) analysis to balance the significant variables of patient background and clinicopathological factors. PSs were calculated using logistic regression analysis, with the probability of AC as the dependent variable and age, sex, American Society of Anesthesiologists physical status (ASA-PS) score, tumor–node–metastasis classification and pathological stage according to the eighth edition of UICC Staging Manual, degree of LND, operative time, blood loss, and intraoperative BS as covariates. The goodness of fit of the logistic model used to estimate the PS was evaluated with a C statistic of 0.883 (95% confidence interval [CI], 0.833–0.934). On the logit of the PS for the presence of cholecystitis, one-to-one matching without replacement was performed using the nearest neighbor match with the caliper width set to 0.20 times the standard deviation (SD) of the logit of the PS. The balance of covariates between groups before and after one-to-one matching was assessed using the p-value and standardized difference.
In addition to one-to-one PSM, we compared the outcomes between the two groups using inverse probability weighting (IPW) analysis, stabilized IPW, and truncated (at the 99th percentile) IPW as sensitivity analyses.
Statistical analyses
Survival curves were estimated using the Kaplan–Meier method, and a comparison between two survival curves was conducted using the log-rank test under one-to-one PSM and adjusted IPW. The Cox proportional hazards model was used to calculate the hazard ratio (HR) for AC for each survival analysis.
Continuous variables were expressed as mean or median with SD or range. Categorical data were analyzed using either the chi-squared test or Fisher’s exact test, whereas continuous data were analyzed using Student’s t-test or Wilcoxon’s rank sum test for unpaired data.
All statistical analyses were performed using JMP® Pro 16.2.0 software (SAS Institute Inc., Cary, NC, USA) and R version 4.0.0 (The R Foundation for Statistical Computing, Vienna, Austria). All analyses were two-tailed, and p<0.05 was considered statistically significant.