• Humans
• Gallbladder Neoplasms/surgery
• Gallbladder Neoplasms/pathology
• Male
• Female
• Aged
• Middle Aged
• Lymph Node Excision
• Clinical Decision-Making
• Cholecystectomy
• Lymphatic Metastasis
• Treatment Outcome
• Retrospective Studies
• Algorithms
• Databases, Factual
• Aged, 80 and over
• Decision Support Techniques
• Adult
• Neoplasm Staging

• apparent diffusion coefficient
• gallbladder tumor
• magnetic resonance imaging
• malignancy
• prognostic prediction

• cholelithiasis in gallbladder carcinoma
• early-stage gallbladder carcinoma
• gallbladder carcinoma in jharkhand
• gallbladder histopathology
• incidental gallbladder carcinoma

• Endoscopic ultrasound
• Fine-needle aspiration
• Fine-needle biopsy
• Gallbladder masses
• Meta-analysis

• Humans
• Gallbladder/diagnostic imaging
• Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods
• Endosonography/adverse effects
• Sensitivity and Specificity

• Gallbladder carcinoma
• Pathologic sampling
• Survival
• pT1b

• Humans
• Gallbladder Neoplasms/pathology
• Cholecystectomy
• Carcinoma in Situ/pathology
• Carcinoma/pathology
• Neoplasm Staging
• Retrospective Studies

Introduction

Incidental discovery of gallbladder cancer (GBC) on postoperative histopathology or intra-operative suspicion is becoming increasingly frequent since laparoscopic cholecystectomy became the standard of care for gallstone disease. Incidental GBC (IGBC) portends a better survival than primarily detected GBC. Various factors affect the outcome of re-resection with the timing of re-intervention an important determinant of survival.

Methods

All patients of IGBC who underwent curative resection from January 2009 to December 2018 were considered for analysis. Details of demographic profile, index surgery, and operative findings on re-resection, histopathology and follow-up were retrieved from the prospectively maintained database. Patients were evaluated in three groups based on the interval between index cholecystectomy and re-resection: Early (<4 weeks), Intermediate (4-12 weeks) and Late (>12 weeks), using appropriate statistical tests.

Results

Ninety-one patients were admitted with IGBC during the study period of which 48 underwent re-resection with curative intent. The median age of presentation was 55 years (31-77 years). The median duration of follow-up was 40.6 months (Range: 1.2-130.6 months). Overall and disease-free survival among the above-mentioned three groups was the best in the early group (104 and 102 months) as compared to the intermediate (84 and 83 months) and late groups (75 and 73 months), though the difference failed to achieve statistical significance (p=0.588 and 0.581). On univariate analysis, factors associated with poor outcome were node metastasis, need for common bile duct (CBD) excision and high-grade tumor. However, on multivariate analysis, poor differentiation was the only independent factor affecting survival.

Conclusion

Early surgery, preferably within four weeks, possibly entails better survival in incidentally detected GBC. The grade of a tumor, however, is the most important determinant of survival in IGBC.

• Decision support techniques
• Models, statistical
• Neoplasms

Surgical resection is a treatment of choice for gallbladder cancer (GBC) patients but only 10% of patients have a resectable disease at presentation. Even after surgical resection, overall survival (OS) has been poor due to high rates of recurrence. Combination of surgery and systemic therapy can improve outcomes in this aggressive disease.

To summarize our single-center experience with multimodality management of resectable GBC patients.

Data of all patients undergoing surgery for suspected GBC from January 2012 to December 2018 was retrieved from a prospectively maintained electronic database. Information extracted included demographics, operative and perioperative details, histopathology, neoadjuvant/adjuvant therapy, follow-up, and recurrence. To know the factors associated with recurrence and OS, univariate and multivariate analysis was done using log rank test and cox proportional hazard analysis for categorical and continuous variables, respectively. Multivariate analysis was done using multiple regression analysis.

Of 274 patients with GBC taken up for surgical resection, 172 (62.7%) were female and the median age was 56 years. On exploration, 102 patients were found to have a metastatic or unresectable disease (distant metastasis in 66 and locally unresectable in 34). Of 172 patients who finally underwent surgery, 93 (54%) underwent wedge resection followed by anatomical segment IVb/V resection in 66 (38.4%) and modified extended right hepatectomy in 12 (7%) patients. The postoperative mortality at 90 d was 4.6%. During a median follow-up period of 20 mo, 71 (41.2%) patients developed recurrence. Estimated 1-, 3-, and 5-years OS rates were 86.5%, 56%, and 43.5%, respectively. Estimated 1- and 3-year disease free survival (DFS) rates were 75% and 49.2%, respectively. On multivariate analysis, inferior OS was seen with pT3/T4 tumor (P = 0.0001), perineural invasion (P = 0.0096), and R+ resection (P = 0.0125). However, only pT3/T4 tumors were associated with a poor DFS (P < 0.0001).

Multimodality treatment significantly improves the 5-year survival rate of patients with GBC up to 43%. R+ resection, higher T stage, and perineural invasion adversely affect the outcome and should be considered for systemic therapy in addition to surgery to optimize the outcomes. Multimodality treatment of GBC has potential to improve the survival of GBC patients.

• Gallbladder cancer
• Multimodality
• Surgical resection
• Adjuvant
• Chemotherapy
• Chemoradiotherapy

• Female
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/surgery
• Hepatectomy
• Humans
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Staging
• Retrospective Studies
• Survival Rate
• Tertiary Healthcare

• frozen section
• gallbladder cancer
• intraoperative assessment
• radical cholecystectomy

Gallbladder cancer is a rare, aggressive malignancy that has a poor overall prognosis. Effective treatment consists of early detection and surgical treatment. With the wide spread treatment of gallbladder disease with minimally invasive techniques, the rate of incidental gallbladder cancer has seen an equitable rise along with stage migration towards earlier disease. Although the treatment remains mostly surgical, newer modalities such as regional therapy as well as directed therapy based on molecular medicine has led to improved outcomes in patients with advanced disease. We aim to summarize the management of gallbladder cancer along with the newer developments in this formidable disease process.

• Gallbladder cancer
• Radical cholecystectomy
• Cholangiocarcinoma
• Epidemiology
• Gallbladder disease

Polyps are reported on 1–10% of routine transabdominal ultrasound studies of the gallbladder. Prior studies have reported poor sensitivity and specificity for this diagnostic modality at determining malignant potential of polyps. The aim of this study is to determine the incidence of gallbladder polyps documented on ultrasound at a community hospital, evaluate the congruency of ultrasound with final histopathology, and explore factors which may improve ultrasound accuracy at diagnosing true adenomatous polyps.

We conducted a 5-year retrospective cohort study of patients undergoing cholecystectomy at Danbury Hospital between 2014 and 2019, identifying those with a pre-operative ultrasound mention of a “polyp” or “mass.” We assessed the congruency of ultrasound findings with pathology reports.

Of the 2,549 cholecystectomies performed, 1,944 (76%) had pre-operative ultrasounds. Of those, 98 (5.0%) reported a polyp, measuring an average of 8.1 mm (SD 7.1 mm). Three (3.1%) specimens were identified as adenomas on final histopathology; the majority were benign pathologies including cholesterol polyp (18), cholesterolosis (20), adenomyoma (4), adenomyomatosis (7), and chronic or acute cholecystitis (44). Interestingly, only 1 of the 3 adenomas measured > 10 mm on ultrasound, the accepted indication for surgical resection.

The accuracy of transabdominal ultrasound in diagnosing true polyps is poor, with only 3% of polyps identified as adenomas based on pathology. Surgeons should use caution when making clinical decisions based on polyps identified on ultrasound, and more stringent diagnostic criteria are needed in order to decrease the false positive rate for diagnosis and screening.

• Adenocarcinoma
• Gallbladder polyps
• Ultrasound

Increasing evidence has suggested an association between the expression profiles of microRNAs (miRs) and gallbladder cancer (GBC). Recently, miR-182 has been demonstrated to exert tumor-promoting effects. However, the biological activity and molecular mechanisms of miR-182 in GBC remain unclear. The results of the present study demonstrated that miR-182 expression was significantly upregulated in GBC tissues and cell lines (GBC-SD and SGC-996). In addition, miR-182-knockdown attenuated epithelial-mesenchymal transition (EMT) in GBC cells, as indicated by decreased cell migratory and invasive abilities, decreased vimentin expression, and increased E-cadherin expression. The activities of β-catenin and its downstream factors, Cyclin D1 and c-Myc, were also demonstrated to decrease following miR-182-knockdown. Forkhead box N3 (FOXN3) was identified as the direct target of miR-182. Overexpression of FOXN3 ameliorated EMT and the β-catenin pathway. Taken together, the results of the present study suggested that miR-182 promotes EMT in GBC cells by targeting FOXN3, which suppresses the Wnt/β-catenin pathway.

• Forkhead box N3
• Wnt/β-catenin pathway
• epithelial-mesenchymal transition
• gallbladder carcinoma
• microRNA-182

• Incidental gallbladder carcinoma
• Laparoscopic surgery
• Oncologic extended resection

• Incidental gallbladder cancer management
• Neoadjuvant chemotherapy
• Operative strategy for reresection
• Prognostic factors
• Recurrence patterns

Gallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using population-based data from a low-incidence country. GBC patients diagnosed between 2005 and 2016 with GBC were identified from the Netherlands Cancer Registry. Patients were grouped according to time period (2005–2009/2010–2016) and disease stage. Trends in treatment and overall survival (OS) were analyzed. In total 1834 patients were included: 661 (36%) patients with resected, 278 (15%) with non-resected non-metastatic, and 895 (49%) with metastatic GBC. Use of radical versus simple cholecystectomy (12% vs. 26%, p < 0.001) in early (pT1b/T2) GBC increased. More patients with metastatic GBC received chemotherapy (11% vs. 29%, p < 0.001). OS improved from 4.8 months (2005–2009) to 6.1 months (2010–2016) (p = 0.012). Median OS increased over time (2005–2009 vs. 2010–2016) in resected (19.4 to 26.8 months, p = 0.038) and metastatic (2.3 vs. 3.4 months, p = 0.001) GBC but not in unresected, non-metastatic GBC. In early GBC, patients with radical cholecystectomy had a median OS of 76.7 compared to 18.4 months for simple cholecystectomy (p < 0.001). Palliative chemotherapy showed superior (p < 0.001) survival in metastatic (7.3 versus 2.1 months) and non-resected non-metastatic (7.7 versus 3.5 months) GBC. In conclusion, survival of GBC remains poor. Radical surgery and palliative chemotherapy appear to improve prognosis but remain under-utilized.

• chemotherapy
• cohort studies
• epidemiology
• gallbladder neoplasms
• surgery

Receptor-interacting serine/threonine-protein kinase 1 (RIP-1) is highly expressed in gallbladder cancer, and is very important in promoting tumor proliferation and invasion. The underlying mechanism in this promotion is the RIP-1-nuclear factor κ-B (NF-κB) and activator protein 1 (AP-1)-vascular endothelial growth factor-C (VEGF-C) signaling pathways. However, the precise mechanisms by which RIP-1 regulates VEGF-C expression are still unknown. The current study aims to clarify the detailed mechanisms by which RIP-1 upregulates VEGF-C expression. In the current study, the authors constructed various VEGF-C promoter deletions, VEGF-C promoter mutations and RIP-1 overexpression plasmids, and silenced RIP-1 with a small interfering RNA. Promoter analysis, an electrophoretic mobility shift assay, a chromatin immunoprecipitation assay was then performed, and an orthotopic transplantation model in nude mice was established by modified methods previously used. The authors also found that the core region for luciferase activity in the VEGF-C promoter was −332 to −190 nt, in which there are two overlapping AP-1 sites and an NF-κB site. RIP-1 was demonstrated to activate transcription factors NF-κB and AP-1 to combine with the core region and enhance VEGF-C promoter activity. In conclusion, the current study illustrated the mechanisms by which RIP-1 regulates VEGF-C expression, by activating NF-κB and AP-1 to combine with the −332 to −190 nt area of the VEGF-C promoter. By establishing an orthotopic mouse model of gallbladder cancer tumors, it was further elucidated that RIP-1 promotes gallbladder cancer metastasis. The findings provide evidence that targeting RIP-1 may prove to be useful in the treatment of gallbladder cancer.

• Endoscopic Retrograde Cholangio-Pancreatography
• Malignant hilar strictures
• Palliation
• Personalized medicine
• Self-expandable metal stents

• Aged
• Carcinoma/diagnosis
• Carcinoma/pathology
• Carcinoma/surgery
• Female
• Gallbladder Neoplasms/diagnosis
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/surgery
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Staging
• Retrospective Studies

• anastomosing hemangioma
• extended cholecystectomy
• gallbladder
• gallbladder carcinoma
• liver

• Gallbladder neoplasms
• Lymph node excision
• Lymphatic metastasis
• Lymphatic vessels
• Survival rate
• Tumor location

• CT
• Gallbladder cancer
• Lymph node metastases
• MRI
• Pre-operative staging

• Adenocarcinoma/mortality
• Adenocarcinoma/secondary
• Adenocarcinoma/therapy
• Aged
• Aged, 80 and over
• Cholecystectomy
• Databases, Factual
• Female
• Gallbladder Neoplasms/mortality
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/therapy
• Humans
• Lymph Node Excision
• Lymph Nodes/pathology
• Lymph Nodes/surgery
• Lymphatic Metastasis
• Male
• Middle Aged
• Predictive Value of Tests
• Propensity Score
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Treatment Outcome
• United States

• Gallbladder cancer
• immunologic markers
• overall survival
• prognostic factors
• serum markers

In December 2016, the Union for International Cancer Control (UICC) published the 8th edition of the Tumor-Node-Metastasis (TNM) classification of malignant tumors, including a number of vital changes in the definitions of the T2 category, the N category and the stages of gallbladder cancer (GBC). The clinical value of this newly updated classification in patients with surgically treated GBC has not been rigorously validated. The present study aimed to analyze the prognosis of patients with GBC in a high-volume surgical unit, and to validate the prognostic value of the new UICC TNM classification, particularly the main changes in the stages of GBC. Data from 307 patients who were surgically treated and histopathologically diagnosed with GBC between January 2011 and July 2016 in The West China Hospital (Chengdu, Sichuan, China) were retrospectively collected and analyzed. The new UICC criteria distributed 32, 60, 99 and 116 eligible patients in stages I, II, III and IV, respectively. The differences in overall survival time between each stage (I–IV) demonstrated statistical significance (P<0.05). As a result of the main change of this classification, the novel definitions of T2a and T2b effectively stratified the prognosis of patients with T2 GBC (P<0.001). Furthermore, patients with stage IIa tumors also obtained significantly improved overall survival time compared with patients with stage IIb tumors (P=0.04), whereas the comparison between patients with stage IIb and IIIa tumors did not present any notable difference (P=0.20). Additionally, the new N category stratified the survival of the patients effectively (P<0.001). Together with curative resection, this latest classification was indicated to be an independent predictor of survival via multivariate analysis (hazard ratio, 6.25; 95% confidence interval, 3.81–10.26; P<0.001). In conclusion, the newly updated UICC TNM classification could effectively reflect the clinical outcome of patients with surgically treated GBC. Furthermore, tumor location could predict the survival of surgically treated T2 GBC. The novel classification of the N category by the number of lymph nodes involved was also demonstrated to be valid.

• 8th edition
• Union for International Cancer Control Tumor-Node-Metastasis classification
• gallbladder cancer
• prognosis
• tumor location

• Cholecystectomy
• Gallbladder cancer
• Liver resection
• Recurrent gallbladder cancer
• Risk factors for gallbladder cancer

Biliary tract cancers (BTCs) are uncommon but fatal, with a low 5-year survival rate after surgical resection. This study was designed to investigate the prognostic factors for operable BTC.

Baseline demographics at diagnosis were retrospectively evaluated in 341 BTC patients undergoing radical surgery at The First Affiliated Hospital of Nanjing Medical University from January 2011 to December 2015. The association between prognostic factors and overall survival (OS) was determined by multivariate analysis using the Cox proportional hazards regression model.

Our study showed that 341 patients were included in the analysis, of which 166 (48.7%) were males and 175 (51.3%) were females. Older age, depth of tumor invasion, positive surgical margin, lower hemoglobin, and higher lactic dehydrogenase (LDH) were associated with significantly worse OS using multivariate analysis. In the entire cohort, the estimate of median OS in patients with LDH <271 U/L was 36.291 months (95% CI; 30.989–41.594 months), and 30.736 months (95% CI; 19.154–42.318 months) in patients with LDH ≥271 U/L (adjusted HR-1.505, 95% CI; 1.009–2.245, P = 0.045). Moreover, it was investigated whether serum LDH retained its significance as a prognostic marker in BTC subgroups separately. The results showed that LDH was prognostic in patients with distal bile duct (DBD) carcinoma undergoing radical surgery (HR-2.452, 95% CI; 1.167–5.152, P = 0.018). However, there were no statistical differences between LDH and OS in multivariate analysis in the other three individual subgroups except for DBD carcinoma. This may be due to the limited number of patients in the study, indicating that a greater number of patients may be required for statistical significance.

Older age, depth of tumor invasion, positive surgical margin status, lower hemoglobin levels, and elevated serum LDH level are associated with poor survival in operable BTC patients. Serum LDH level is a cost-effective prognostic biomarker in patients with operable BTC and especially DBD carcinoma.

• biliary tract cancer
• lactate dehydrogenase
• prognosis
• radical surgery
• tumor marker

• Gallbladder carcinoma
• Laparoscopic cholecystectomy
• Outcomes
• Reoperation
• Survival

Gallbladder carcinoma (GBC) sometimes presents with nonspecific signs, without forming a mass, mimicking benign gallbladder (GB) diseases. On the contrary, benign GB diseases may mimic GBC.

We retrospectively reviewed 107 cases over a period of 3 years (May 2012–April 2015), which included 41 review cases and 66 departmental cases. Carcinoembryonic antigen (CEA) immunomarker expression was done.

In 27 of the 41 review cases, the diagnoses were benign diseases of GB associated with mild-to-moderate dysplasia of mucosal glands; however, after review in our department, it was found that of these 27 cases, nine cases were actually well-differentiated adenocarcinoma of GB with diffuse CEA expression and were mis diagnosed as benign diseases of GB with dysplasia. In 32 out of 66 departmental cases, initial histopathological diagnoses were benign diseases of GB associated with dysplastic mucosal glands. After CEA staining, 11 out of these 32 cases turned out to be adenocarcinoma of the GB. Among the rest 34 (34/66) departmental primary GBC cases, no CEA expression was seen in six cases, focal expression was seen in 12 cases, and diffuse expression was seen in 16 cases. No diffuse CEA expression was seen in benign diseases of the GB with dysplasia.

GBC sometimes may not be diagnosed radiologically and grossly as it often presents without any mass and specific signs, which lead to under diagnosis. Some benign cases may mimic GBC and may complicate histological diagnosis. CEA expression may aid as an additional diagnostic aid in resolving diagnostic dilemmas.

• Carcinoembryonic antigen
• gallbladder carcinoma
• misdiagnosis

• Morbidity
• Mortality
• Survival

Conditional survival (CS) has been established as a clinically relevant prognostic factor for cancer survivors, and the CS in gallbladder (GB) cancer has not yet been fully evaluated. In this study, we evaluated the cancer-specific CS rate and cancer-specific survival (CSS) rate in patients with GB cancer at multiple time points and investigated prognostic factors which affect cancer-specific CS rate to provide more accurate survival information.

Between 2004 and 2013, a total of 9760 patients with GB cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) data. The 3-year cancer-specific CS rate was calculated using the covariate-adjusted survival function in the Cox model for each year since diagnosis, and the results were analyzed together with the adjusted CSS rates at the same time points. Cox proportional hazards regression was performed to ascertain the individual contribution of factors associated with CSS rate at diagnosis and cancer-specific CS rates at 1, 3, and 5 years after diagnosis.

The adjusted 5-year CSS rate was 26.1%. The adjusted 3-year cancer-specific CS rates at 1, 2, 3, 4, and 5 years after diagnosis were 55.5, 72.2, 81.5, 86.8, and 90.5%, respectively. At the time of diagnosis, age, race, histology, grade, T, N, and M categories, surgery, radiotherapy, insurance status, and marriage status were significant prognostic factors of CSS. Five years after diagnosis, however, T and M categories were significant prognostic factors for survivors (P = 0.007 and P = 0.009, respectively), whereas surgery and radiotherapy were not.

T and M categories were significant prognostic factors even 5 years after the initial diagnosis, whereas local treatments at the time of diagnosis were not, suggesting that patients with GB cancer at high risks might need further adjuvant therapy after primary treatments. The combined analysis of CSS and cancer-specific CS rates offered more accurate survival information for patients who have already survived a certain period of time after diagnosis.

• Conditional survival
• Gallbladder cancer
• SEER

• Adenosquamous carcinomas
• DDR2
• Gallbladder
• IFITM 1
• Immunohistochemistry
• Squamous cell carcinoma

To detect the expression of threonine and tyrosine kinase (TTK) in gallbladder cancer (GBC) specimens and analyze the associations between TTK expression and clinicopathological parameters and clinical prognosis.

A total of 68 patients with GBC who underwent surgical resection were enrolled in this study. The expression of TTK in GBC tissues was detected by immunohistochemistry. The assessment of TTK expression was conducted using the H-scoring system. H-score was calculated by the multiplication of the overall staining intensity with the percentage of positive cells. The expression of TTK in the cytoplasm and nucleus was scored separately to achieve respective H-score values. The correlations between TTK expression and clinicopathological parameters and clinical prognosis were analyzed using Chi-square test, Kaplan-Meier method and Cox regression.

In both the nucleus and cytoplasm, the expression of TTK in tumor tissues was significantly lower than that in normal tissues (P < 0.001 and P = 0.026, respectively). Using the median H-score as the cutoff value, it was discovered that, GBC patients with higher levels of TTK expression in the nucleus, but not the cytoplasm, had favorable overall survival (P < 0.001), and it was still statistically meaningful in Cox regression analysis. Further investigation indicated that there were close negative correlations between TTK expression and tumor differentiation (P = 0.041), CA 19-9 levels (P = 0.016), T stage (P < 0.001), nodal involvement (P < 0.001), distant metastasis (P = 0.024) and TNM stage (P < 0.001).

The expression of TTK in GBC is lower than that in normal tissues. Higher levels of TTK expression in GBC are concomitant with longer overall survival. TTK is a favorable prognostic biomarker for patients with GBC.

• Threonine and tyrosine kinase
• Biomarker
• Prognosis
• Gallbladder cancer

• Aged
• Biomarkers, Tumor/metabolism
• CA-19-9 Antigen/blood
• Cell Cycle Proteins/metabolism
• Cell Nucleus/metabolism
• Cytoplasm/metabolism
• Female
• Follow-Up Studies
• Gallbladder/cytology
• Gallbladder/pathology
• Gallbladder/surgery
• Gallbladder Neoplasms/blood
• Gallbladder Neoplasms/mortality
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/surgery
• Humans
• Kaplan-Meier Estimate
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasm Staging
• Prognosis
• Protein Serine-Threonine Kinases/metabolism
• Protein-Tyrosine Kinases/metabolism
• Retrospective Studies

• complications
• gallbladder cancer
• laparoscopic
• minimally invasive
• radical cholecystectomy
• survival

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents/therapeutic use
• Carcinoma/mortality
• Carcinoma/pathology
• Carcinoma/therapy
• Cholecystectomy
• Female
• Gallbladder Neoplasms/mortality
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/therapy
• Humans
• Lymph Nodes/pathology
• Male
• Middle Aged
• Neoadjuvant Therapy
• Retrospective Studies
• Survival Rate
• Treatment Outcome