Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Household cooking fuel and gallbladder cancer risk: a multi-centre case-control study in India.

PURPOSE: Gallbladder cancers (GBC), unique to certain geographical regions, are lethal digestive tract cancers, disproportionately affecting women, with limited information on risk factors. METHODS: We evaluated the association between household cooking fuel and GBC risk in a hospital-based case-control study conducted in the North-East and East Indian states of Assam and Bihar. We explored the potential mediation by diet, fire-vents, 'daily exposure duration' and parity (among women). We recruited biopsy-confirmed GBC (n = 214) men and women aged 30-69 years between 2019 and 2021, and controls frequency-matched by age, sex and region (n = 166). Information about cooking fuel, lifestyle, personal and family history, female reproductive factors, socio-demographics, and anthropometrics was collected. We tested associations using multivariable logistic regression analyses. RESULTS: All participants (73.4% women) were categorised based on predominant cooking fuel use. Group-1: LPG (Liquefied Petroleum Gas) users in the previous 20 years and above without concurrent biomass use (26.15%); Group-2: LPG users in the previous 20 years and above with concurrent secondary biomass use (15.9%); Group-3: Biomass users for ≥ 20 years (57.95%). Compared to group-1, accounting for confounders, GBC risk was higher in group-2 [OR: 2.02; 95% CI: 1.00-4.07] and group-3 [OR: 2.01; 95% CI: 1.08-3.73] (p-trend:0.020). These associations strengthened among women that attenuated with high daily consumption of fruits-vegetables but not with fire-vents, 'daily exposure duration' or parity. CONCLUSION: Biomass burning was associated with a high-risk for GBC and should be considered as a modifiable risk factor for GBC. Clean cooking fuel can potentially mitigate, and a healthy diet can partially reduce the risk among women.

Laparoscopic versus open surgery for gallbladder carcinoma: safety, feasibility, and oncological outcomes

Background Gallbladder carcinoma (GC) is a rare malignant tumor. Laparoscopic technology has revolutionized the reality of surgery. However, whether laparoscopic surgery is suitable for GC has not been clarified. We aimed to analyze the safety, feasibility, and oncological outcomes of laparoscopic surgery in GC. Methods The medical records of patients with GC treated at our hospital between January 2016 and December 2021 were retrospectively reviewed. Patients who underwent laparoscopic and open surgery were compared. Propensity score matched analysis was performed to balance the basic characteristics of the two groups. Kaplan–Meier curves were used to describe and compare the overall and disease-free survival rates between the groups. Results A total of 163 patients with GC were included. Cholelithiasis was detected in 64 (39.3%) patients. Seventy patients were matched after propensity score matching. The laparoscopic group was significantly better than the open group in terms of operation time (p < 0.001), blood loss (p = 0.002), drain time (p = 0.001), and hospital stay (p < 0.001). After a median follow-up time of 19 (12, 35) months, there was no significant difference in the cumulative overall (p = 0.650) and disease-free (p = 0.663) survival rates between the laparoscopic and open groups according to Kaplan–Meier curves. Conclusion Laparoscopic surgery can reduce the operation time and blood loss, and shorten drain time and hospital stay without increasing the incidence of complications. Patients undergoing laparoscopic and open surgery have a similar prognosis. Laparoscopic surgery is worth promoting in patients with GC (AU)

The risk and predictors of gallbladder cancer in patients with gallbladder polyps: A retrospective cohort study with an insight into confounding by indication.

BACKGROUND AND AIM: We aimed to determine the risk and predictors of gallbladder cancer in all individuals with gallbladder polyps (GP) including those who did not have cholecystectomy. METHODS: The STROCSS guideline was followed to conduct a retrospective cohort study. All individuals with GP between 2010 and 2019 were followed up to determine the risk and predictors of gallbladder cancer. The primary outcomes were gallbladder cancer and gallbladder dysplasia, and the secondary outcomes included polyp growth rate and polyp disappearance rate. Binary logistic regression analysis and receiver operating characteristic curve analysis were conducted to evaluate the outcomes. RESULTS: Analysis of 438 patients showed risk of gallbladder cancer was 0.7% in all polyps (0% in polyps < 10 mm; 5.9% in polyps ≥ 10 mm). The risk of gallbladder dysplasia or cancer was 1.1% in all polyps (0% in polyps < 10 mm; 10% in polyps ≥ 10 mm). The polyp size (P = 0.0001) was predictor of cancer; however, patient's age (P = 0.1085), number of polyps (P = 0.9983), symptomatic polyps (P = 0.3267), and change in size (P = 0.9012) were not. Size of 21 mm was cut-off for risk of cancer (area under the curve [AUC]: 0.995, P < 0.001) and 11.8 mm for risk of dysplasia or cancer (AUC: 0.986, P < 0.001). The mean polyp growth rate was 0.3 mm/year and polyp disappearance rate was 16%. CONCLUSIONS: The GP size remains the only predictor of malignant changes regardless of patient's age, patient's symptoms and number of polyps. The polyp growth rate is unremarkable, and a significant proportion disappears during follow-up. We changed our follow-up protocol with reduced number of scans and early discharge policy.

Acute cholecystitis in old adults: the impact of advanced age on the clinical characteristics of the disease and on the surgical outcomes of laparoscopic cholecystectomy.

BACKGROUND: Impact of advanced age on disease characteristics of acute cholecystitis (AC), and surgical outcomes after laparoscopic cholecystectomy (LC) has not been established. METHODS: This single-center retrospective study included patients who underwent LC for AC between April 2010 and December 2020. We analyzed the disease characteristics and surgical outcomes according to age: Group 1 (age < 60 years), Group 2 (60 ≤ age < 80 years), and Group 3 (age ≥ 80 years). Risk factors for complications were assessed using logistic regression analysis. RESULTS: Of the 1,876 patients (809 [43.1%] women), 723 were in Group 1, 867 in Group 2, and 286 in Group 3. With increasing age, the severity of AC and combined common bile duct stones increased. Group 3 demonstrated significantly worse surgical outcomes when compared to Group 1 and 2 for overall (4.0 vs. 9.1 vs. 18.9%, p < 0.001) and serious complications (1.2 vs. 4.2 vs. 8.0%, p < 0.001), length of hospital stay (2.78 vs. 3.72 vs. 5.87 days, p < 0.001), and open conversion (0.1 vs. 1.0 vs. 2.1%, p = 0.007). Incidental gallbladder cancer was also the most common in Group 3 (0.3 vs. 1.5 vs. 3.1%, p = 0.001). In the multivariate analysis, body mass index < 18.5, moderate/severe AC, and albumin < 2.5 g/dL were significant risk factors for serious complications in Group 3. CONCLUSION: Advanced age was associated with severe AC, worse surgical outcomes, and a higher rate of incidental gallbladder cancer following LC. Therefore, in patients over 80 years of age with AC, especially those with poor nutritional status and high severity grading, urgent surgery should be avoided, and surgery should be performed after sufficient supportive care to restore nutritional status before LC.

Laparoscopic versus open surgery for gallbladder carcinoma: safety, feasibility, and oncological outcomes.

BACKGROUND: Gallbladder carcinoma (GC) is a rare malignant tumor. Laparoscopic technology has revolutionized the reality of surgery. However, whether laparoscopic surgery is suitable for GC has not been clarified. We aimed to analyze the safety, feasibility, and oncological outcomes of laparoscopic surgery in GC. METHODS: The medical records of patients with GC treated at our hospital between January 2016 and December 2021 were retrospectively reviewed. Patients who underwent laparoscopic and open surgery were compared. Propensity score matched analysis was performed to balance the basic characteristics of the two groups. Kaplan-Meier curves were used to describe and compare the overall and disease-free survival rates between the groups. RESULTS: A total of 163 patients with GC were included. Cholelithiasis was detected in 64 (39.3%) patients. Seventy patients were matched after propensity score matching. The laparoscopic group was significantly better than the open group in terms of operation time (p < 0.001), blood loss (p = 0.002), drain time (p = 0.001), and hospital stay (p < 0.001). After a median follow-up time of 19 (12, 35) months, there was no significant difference in the cumulative overall (p = 0.650) and disease-free (p = 0.663) survival rates between the laparoscopic and open groups according to Kaplan-Meier curves. CONCLUSION: Laparoscopic surgery can reduce the operation time and blood loss, and shorten drain time and hospital stay without increasing the incidence of complications. Patients undergoing laparoscopic and open surgery have a similar prognosis. Laparoscopic surgery is worth promoting in patients with GC.

Arsenic causing gallbladder cancer disease in Bihar.

In recent times Gallbladder cancer (GBC) incidences increased many folds in India and are being reported from arsenic hotspots identified in Bihar. The study aims to establish association between arsenic exposure and gallbladder carcinogenesis. In the present study, n = 200 were control volunteers and n = 152 confirmed gallbladder cancer cases. The studied GBC patient's biological samples-gallbladder tissue, gallbladder stone, bile, blood and hair samples were collected for arsenic estimation. Moreover, n = 512 gallbladder cancer patients blood samples were also evaluated for the presence of arsenic to understand exposure level in the population. A significantly high arsenic concentration (p < 0.05) was detected in the blood samples with maximum concentration 389 µg/L in GBC cases in comparison to control. Similarly, in the gallbladder cancer patients, there was significantly high arsenic concentration observed in gallbladder tissue with highest concentration of 2166 µg/kg, in gallbladder stones 635 µg/kg, in bile samples 483 µg/L and in hair samples 6980 µg/kg respectively. Moreover, the n = 512 gallbladder cancer patient's blood samples study revealed very significant arsenic concentration in the population of Bihar with maximum arsenic concentration as 746 µg/L. The raised arsenic concentration in the gallbladder cancer patients' biological samples-gallbladder tissue, gallbladder stone, bile, blood, and hair samples was significantly very high in the arsenic exposed area. The study denotes that the gallbladder disease burden is very high in the arsenic exposed area of Bihar. The findings do provide a strong link between arsenic contamination and increased gallbladder carcinogenesis.

Threshold dose-response association between smoking pack-years and the risk of gallbladder cancer: A nationwide cohort study.

BACKGROUND AND AIMS: The association between smoking and gallbladder cancer (GBC) risk is unclear. We investigated the association between smoking (including pack-years) and GBC risk. We also examined the combined effects of smoking and diabetes or prediabetes on GBC risk. METHODS: This Korean nationwide cohort study included 9,520,629 adults without cancer who underwent national health screening in 2009 and were followed-up until 2018. Multivariable Cox proportional hazards models were used to determine risk estimates after adjusting for potential confounders. RESULTS: During 78.4 million person-years (mean 8.2 ± 0.9 years) of follow-up, we identified 6066 patients with newly diagnosed GBC. Current and former smokers were associated with increased GBC risk (hazard ratio [HR], 95% confidence interval [CI]: 1.117, 1.029-1.212 and 1.105, 1.016-1.202, respectively). Smoking of 20 to <30 and ≥30 pack-years was independently associated with increased GBC risk compared with never smoking (HR, 95% CI; 1.241, 1.100-1.400 and 1.231, 1.107-1.370, respectively). However, smoking of <10 and 10 to <20 pack-years was not. This threshold dose-response association between smoking pack-years and GBC risk was observed regardless of the glycaemic status (all P < 0.01). Furthermore, smoking of ≥20 pack-years and hyperglycaemia had a synergistic effect on the GBC risk (all P < 0.01). Smokers with ≥20 pack-years with diabetes had the highest risk of GBC compared to never smokers with normoglycaemia (HR, 1.658; 95% CI, 1.437-1.914). CONCLUSIONS: Smoking was associated with increased GBC risk with a threshold dose-response effect for smoking pack-years. The risk of GBC increases synergistically when smoking and hyperglycaemia coexist. More individualised cancer prevention education is required to reduce GBC risk.

Arsenic may be a carcinogenic determinant of a subset of gallbladder cancer: A pilot study.

Gallbladder cancer (GBC) is one of the deadliest malignancy and treatment options are deplorably limited. Better strategies of prevention are urgently needed but knowledge on risk factors remains scarce. Recent data suggested that arsenic (As) may be involved in GBC carcinogenesis but the question remains debated. To date, there are no data on As measurement in GBC samples. This pilot study aimed to measure As concentrations in tissue samples from patients with GBC compared to non-cancerous gallbladder (NCGB). Included patients underwent cholecystectomy at Hospital Clinico Universidad de Chile, Santiago in Chile, a country with high As exposure, between 2001 and 2020. Tissue samples were preserved in formalin-fixed, paraffin-embedded blocks. Selected samples were retrieved, processed and submitted to inductively coupled plasma mass spectrometry (ICP-MS) to determine As concentrations. A total of 77 patients were included, including 35 GBC and 42 NCGB. The two groups were comparable, except for age (68 vs. 49 years, p < 0.001). Measured in 11 GBC and 38 NCGB, total As was detected in 5 GBC (14%) compared to 0 NCGB samples (p < 0.001). GBC group also showed higher median values of As compared to NCGB (p < 0.001). This pilot study provided a proof-of-concept to measure As concentrations in gallbladder samples and showed higher level of As in GBC samples compared to NCGB, paving the way for future studies aiming to investigate the impact of As on GBC, which may contribute to the prevention of this deadly disease.

Occult pancreaticobiliary reflux is a pathogenic factor of some benign biliary diseases and gallbladder cancer.

BACKGROUND: Pancreaticobiliary maljunction (PBM) is a well-known high-risk factor for biliary malignant tumors because of constant pancreaticobiliary reflux (PBR). However, the impact of occult pancreaticobiliary reflux (OPR), which is characterized by high bile amylase levels in individuals with anatomically normal pancreaticobiliary junction, on biliary diseases remains unclear. The aim of this study was to assess the correlation between OPR and biliary diseases. METHODS: We enrolled 94 consecutive patients with normal pancreaticobiliary junction and primary biliary diseases confirmed by magnetic resonance cholangiopancreatography. We prospectively collected patients' bile samples and measured bile amylase levels. We investigated the incidence of OPR and the difference in bile amylase levels among these patients and assessed the correlation between high bile amylase levels (HBAL) and benign or malignant biliary diseases, as well as the OPR risk factors. RESULTS: The incidence of OPR was 36.6% in patients with benign biliary diseases, 26.7% in those with cholangiocarcinoma and 62.5% in those with gallbladder cancer. The median bile amylase level tended to be higher in patients with gallbladder cancer than in those with benign biliary diseases, but there was no significant difference (165.5 IU/L vs. 23.0 IU/L, P = 0.212). The prevalence of an HBAL with bile amylase levels of 1000-7500 IU/L was similar in patients with gallbladder cancer and benign biliary diseases. However, the incidence of HBAL with bile amylase levels greater than 7500 IU/L was significantly higher in patients with gallbladder cancer than in those with benign biliary diseases (37.5% vs. 4.2%, P = 0.012). Multivariate logistic regression analysis revealed that choledocholithiasis was an independent risk factor for OPR. CONCLUSIONS: OPR can occur in benign and malignant biliary diseases, and it may be a pathogenic factor for some benign biliary diseases and a high-risk factor for gallbladder cancer. There is a correlation between choledocholithiasis and OPR.

Personal comorbidities and their subsequent risks for liver, gallbladder and bile duct cancers.

Many environmental risk factors for hepatobiliary cancers are known but whether they are associated with specific cancer types is unclear. We present here a novel approach of assessing standardized incidence ratios (SIRs) of previously diagnosed comorbidities for hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cholangiocarcinoma (CCA) and ampullary cancer. The 13 comorbidities included alcohol and nonalcohol related liver disease, chronic obstructive pulmonary disease, gallstone disease, viral and other kinds of hepatitis, infection of bile ducts, hepatic and other autoimmune diseases, obesity and diabetes. Patients were identified from the Swedish Inpatient Register from 1987 to 2018, and their cancers were followed from 1997 onwards. SIRs for HCC were 80 to 100 in men and women diagnosed with hepatitis C virus and they were also >10 in patients diagnosed with hepatitis B virus, other kind of hepatitis, hepatic autoimmune disease and nonalcohol related liver disease. Many of these risks, as well as alcohol related liver disease, were either specific to HCC or were shared with intrahepatic CCA. For GBC, CCA and ampullary cancer infection of bile ducts was the main risk factor. Gallstone disease, nonhepatic autoimmune diseases and diabetes were associated with all hepatobiliary cancers. The limitations of the study include inability to cover some rare risk factors and limited follow-up time. Many of the considered comorbidities are characterized by chronic inflammation and/or overt immune disturbance in autoimmune diseases. The results suggest that local chronic inflammation and a related immune disturbance is the carcinogenic trigger for all these cancers.

Gallbladder polyps: correlation and agreement between ultrasonographic and histopathological findings in a population with high incidence of gallbladder cancer / Pólipos da vesícula biliar: correlação e concordância entre achados ultrassonográficos e histopatológicos em uma população com alta incidência de câncer de vesícula biliar

ABSTRACT BACKGROUND: Gallbladder polyps are becoming a common finding in ultrasound. The management has to consider the potential risk of malignant lesions. AIMS: The aim of this study was to analyze the ultrasound findings in patients undergoing cholecystectomy due to gallbladder polyps and compare them for histopathological findings (HPs). METHODS: Patients with an ultrasonographic diagnosis of gallbladder polyp and who underwent cholecystectomy from 2007 to 2020 were included in the study. RESULTS: A total of 447 patients were included, of whom 58% were women. The mean age was 45±12 years. The mean size of polyps in US was 7.9±3.6 mm. Notably, 9% of polyps were greater than 10 mm, and single polyps were significantly larger than the multiple ones (p=0.003). Histopathological findings confirmed the presence of polyps in 88.4%, with a mean size of 4.8±3.4 mm. In all, 16 cases were neoplastic polyps (4.1%), 4 of them being malignancies, and all were single and larger than 10 mm. We found a significant correlation between ultrasound and histopathological findings polyp size determination (r=0.44; p<0.001). The Bland-Altman analysis obtained an overestimation of the US size of 3.26 mm. The receiver operating characteristic (ROC) curve analysis between both measures obtained an area under the receiver operating characteristic curve (AUC) of 0.77 (95%CI 0.74-0.81). Ultrasound polyps size larger than 10 mm had an odds ratio (OR) of 8.147 (95%CI 2.56-23.40) for the presence of adenoma and malignancy, with a likelihood ratio of 2.78. CONCLUSIONS: There is a positive correlation and appropriate diagnostic accuracy between ultrasound size of gallbladder polyps compared to histopathological records, with a trend to overestimate the size by about 3 mm. Neoplastic polyps are uncommon, and it correlates with size. Polyps larger than 10 mm were associated with adenoma and malignancy.

RESUMO RACIONAL: Os pólipos da vesícula biliar estão se tornando um achado comum na ultrassonografia (US). O manejo deve levar em consideração o risco de lesões malignas. OBJETIVOS: Analisar os achados da ultrassonografia em pacientes submetidos à colecistectomia por pólipos vesicais e compará-los com os achados histopatológicos. MÉTODOS: Foram revisados os prontuários médicos dos pacientes com diagnóstico ultrassonográfico de pólipo vesicular e submetidos à colecistectomia no período de 2007 a 2020. RESULTADOS: Foram incluídos no estudo 447 pacientes. A média de idade foi 45±12anos, sendo 58% mulheres. O tamanho médio dos pólipos na US foide 7,9±3,6mm. Nove por cento foram maiores que 10 mm, e os pólipos únicos encontrados foram maiores do que os múltiplos (p=0,003). A HP confirmou a presença de pólipos em 88,4%, tamanho médio 4,8±3,4mm. Dezesseis eram pólipos neoplásicos (4,1%) e quatro deles malignos, únicos e maiores que 10 mm. Foi encontrado correlação significativa entre a determinação do tamanho do pólipo ao ultrassonografia e histopatológicos (r=0,44; p<0,001). A análise de Bland-Altman obteve uma superestimação do tamanho do pólipo ao US em 3,26 mm. A análise da curva da característica de operação do receptor entre as duas medidas obteve uma área sob a curva curva da característica de operação do receptor (AUC) de 0,77 (IC95% 0,74-0,81). Pólipos ao ultrassonografia maiores que 10 mm apresentaram razão de chance (OR) de 8,147 (IC95% 2,56-23,40) para presença de adenoma e malignidade, com razão de verossimilhança de 2,78. CONCLUSÕES: Há uma correlação positiva e acurácia diagnóstica apropriada entre o tamanho dos pólipos da vesícula biliar por ultrassonografia em comparação com os achados histopatológicos, com uma tendência de superestimar o tamanho em cerca de 3 mm. Pólipos maiores que 10 mm foram associados a adenoma e malignidade.

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider.

Compelling evidence derived from clinical and experimental research has demonstrated the crucial contribution of chronic inflammation in the development of neoplasms, including gallbladder cancer. In this regard, data derived from clinical and experimental studies have demonstrated that the receptor of advanced glycation end-products (RAGE)/AGEs axis plays an important role in the onset of a crucial and long-lasting inflammatory milieu, thus supporting tumor growth and development. AGEs are formed in biological systems or foods, and food-derived AGEs, also known as dietary AGEs are known to contribute to the systemic pool of AGEs. Once they bind to RAGE, the activation of multiple and crucial signaling pathways are triggered, thus favoring the secretion of several proinflammatory cytokines also involved in the promotion of gallbladder cancer invasion and migration. In the present review, we aimed to highlight the relevance of the association between high dietary AGEs intakes and high risk for gallbladder cancer, and emerging data supporting that dietary intervention to reduce gallbladder cancer risk is a very attractive approach that deserves much more research efforts.

Elevated serum triglyceride levels may be a key independent predicting factor for gallbladder cancer risk in gallbladder stone disease patients: a case-control study.

BACKGROUND: Gallbladder stone diseases (GSD) is a main risk factor of gallbladder cancer (GBC). This study aimed to reveal their bridge to metabolic syndrome. MATERIAL/METHOD: The clinical and experimental data of 2210 GBC patients, from 3524 Chinese patients, in our hospital from Jan. 2009 to Dec. 2020 were summarized. The metabolic syndrome indexes, influencing factors for both GBC and GSD, were analyzed by unconditional logistic regression in this case-control study. RESULT: There were significantly higher morbidity of GBC in the overall, GSD and non-GSD with hypertriglyceridemia patients versus non-hypertriglyceridemia ones (P < 0.001, all). In GSD patients, univariate regression showed a significantly positive correlation between serum triglyceride (TG), low density lipoprotein cholesterol (LDL-c), fasting insulin (FINS) levels, Homeostasis model assessment-insulin resistance (HOMA-IR), female being, body mass index, hypertriglyceridemia and hazard of GBC with GSD (P < 0.001, all), and a significantly negative correlation to systolic pressure (SBP), diastolic pressure (DBP), hypertension and high-density lipoprotein cholesterol (HDL-c), fasting blood glucose (FBG) (P < 0.05, all); multivariate regression showed that serum triglyceride was the most significantly positive factor associated to GBC (P < 0.001, all) among the hazard factors including serum TG, LDL-c levels, HOMA-IR. In non-GSD ones, multivariate regression showed that HOMA-IR was the most significantly positive factor associated to GBC among the hazard factors including serum TG, LDL-c levels, HOMA-IR, female being, while DM had a significantly inversion negative association (P < 0.001). CONCLUSION: We found initially that elevated serum TG levels could be the most remarkable independent predicting factor for GBC risk with GSD, while insulin resistance might act as the first one in non-GSD. More importantly, we advocated initially the sharp rise of serum TG levels as the potential of a candidate diagnostic or prognostic biomarker of GBC with GSD. TRIAL REGISTRATION: The study may be performed in accordance with the ethical standards provided by the responsible committee of our institution (First Affiliated Hospital of Xi'an Jiaotong University. XJTU1AF2020LSK-160) at which the work was carried out an in accordance with the Declaration of Helsinki. The ethics committee of our institution strictly comply with the requirements of ICH-GCP、GCP and relevant regulations to construct, operate and implement operating procedures.

A comparative study of gemcitabine and cisplatin versus oral capecitabine alone in metastatic gallbladder cancer.

Aims: There is no consensus for palliative chemotherapy regimen in metastatic gallbladder cancer. We did a retrospective study to compare the treatment outcome in patients of metastatic gallbladder cancer treated with either gemcitabine + cisplatin (regimen A) or oral capecitabine (regimen B) alone. Subjects and Methods: A total of 67 patients between January 2015 and September 15 treated with either regimen A or regimen B were retrospectively evaluated. Statistical analysis was done in June 2019. Kaplan-Meir and Log rank test were used to compare survival between two arms. Results: Out of 67 patients, 31/67 (46%) received regimen A, and 36/67 (54%) received regimen B. Male to female ratio was 1:3. About 42% patients in regimen A and 20% in regimen B required palliative stenting. Median number of chemotherapy cycles was 4 in both regimen A (range 1->6) and regimen B (range 1->6). Patients receiving 3 cycles and 6 cycles of chemotherapy in regimen A and regimen B was 68% and 31% versus 70% and 63%, respectively (P = 0.86). Response assessment as any response (complete response + partial response + disease was stable) after 3 cycles and 6 cycles was 71% and 57% (P = 0.20), 44% and 39% (P = 0.29), in regimen A and B, respectively. Median survival was 23 weeks (range 2-106 weeks) in regimen A and 15 weeks (range 4-83 weeks) in regimen B (P = 0.40). Conclusions: The present study shows gemcitabine and cisplatin has nonsignificant better survival compared to oral capecitabine. However, oral capecitabine is more convenient and easy to administer. Studies with larger sample size are needed to further establish the standard chemotherapy guidelines.

Associations between cigarette smoking and biliary tract cancer by anatomic subsite and sex: a prospective cohort study in Japan.

PURPOSE: Biliary tract cancer (BTC) has not been considered a tobacco-related cancer, largely because of inconclusive results from epidemiological studies. We herein evaluate the association between cigarette smoking and risk of death from BTC by anatomic subsite and sex using data from a large, prospective cohort study in Japan. METHODS: The present study included 97,030 Japanese individuals who were enrolled in 1988-1990 and followed until 31 December 2009. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the association of BTC with cigarette smoking, including smoking status, number of cigarettes smoked per day, and pack-years of smoking. RESULTS: During a mean follow-up of 16.2 years, we documented 484 deaths (187 from gallbladder cancers and 297 from cancers of other and unspecified biliary tract parts). After adjustment for sex, age, body mass index, alcohol consumption, and history of gallstones, current smokers had a higher risk of death due to BTC (RR = 1.35, 95% CI = 1.01-1.79) than never smokers. In the analyses by anatomic subsite, current smoking was associated with an increased risk of death from gallbladder cancer (RR = 1.89 95% CI = 1.19-3.02), whereas no evidence of an association was noted for cancers of other and unspecified biliary tract parts (RR = 1.10, 95% CI = 0.77-1.58). Moreover, mortality risk increased with an increasing number of cigarettes smoked per day and pack-years of smoking, particularly for gallbladder cancer in men. CONCLUSION: Cigarette smoking is associated with an increased risk of death from BTC, particularly gallbladder cancer, in Japanese men.

Long-term incidence and survival trends in cancer of the gallbladder and extrahepatic bile ducts in Denmark, Finland, Norway and Sweden with etiological implications related to Thorotrast.

Cancers of the gallbladder and extrahepatic bile ducts (called here "GBC" because gallbladder cancer is the main component) are rare in Europe, including the Nordic countries. Their incidence has varied for unknown reasons and we hypothesize that Thorotrast, a previously used carcinogenic radiographic contrast medium, has contributed to the incidence trends. We obtained incidence and survival data from the NORDCAN database, which includes cancer registry data from Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE), which are globally the oldest national cancer databases, starting from 1943 in DK, 1953 in FI and NO and 1960 in SE, and extending to 2016. The incidence trend for GBC showed a broad maximum around 1980 in men (close to 3/100 000) and women (4/100 000), except for NO, where this phenomenon was not seen. In 1955, FI and NO incidence rates were equal but FI rates peaked and later declined similar to DK and SE rates. By 2010, the incidence was similar in all Nordic countries, for both men and women, at close to 2.0/100 000. Birth cohort analysis showed strong effects for countries other than NO. Relative 1-year survival increased for men from 20% to about 50% and similarly for women although at a 5 percentage points lower level. Survival in NO was better than in other countries in the 1980s. Thorotrast, causing a high risk of GBC, was extensively used in the Nordic countries between 1930 and end of 1940s, with the exception of NO, where these was no documented use. These data suggest that Thorotrast influenced GBC epidemiology and probably worsened survival in certain periods.

Predictors of toxicity after neoadjuvant chemoradiotherapy for locally advanced gall bladder cancer.

Background: The present study evaluated the correlation of hepatobiliary toxicity and radiation dose received in patients undergoing neoadjuvant chemoradiotherapy (NACRT) for locally advanced unresectable gall bladder cancers (LAGBC). Methods: Twenty-six patients with LAGBC, treated with NACRT (55-57 Gy/25 fractions/5 weeks and weekly gemcitabine 300 mg/m2) within a phase II study, were included. Whenever feasible, surgery was performed after NACRT. Acute and late hepatobiliary toxicity was recorded. Treatment scans were retrieved to delineate central porto-hepatobiliary system (CPHBS), resected liver surface, segment IV B and V, and duodenum. The doses received by these structures were recorded and correlated with toxicity. Results: Of 26 patients, 20 (77%) had partial or complete response and 12 (46%) had R0 resection. At the median follow-up of 38 months, overall survival was 38%. Eight (30%) patients had post-treatment toxicity, of which most common was biliary toxicity (30%). A correlation was observed between the biliary leak and V45Gy CPHBS >50 cm3 (P = 0.070). Higher toxicity was observed in those with metallic stents (P = 0.072). Conclusion: The incidence of the biliary leak was 46%. CPHBS dose was found to correlate with biliary leaks. Restricting V45Gy CPHBS <50 cm3 and using plastic stent may facilitate a reduction in hepatobiliary toxicity in patients undergoing NACRT and surgery.

Pancreatobiliary Maljunction-associated Gallbladder Cancer Is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-induced Reflux-associated Physio-chemical Carcinogenesis.

OBJECTIVE: To determine the associations of pancreatobiliary maljunction (PBM) in the West. BACKGROUND: PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBc), attributed to reflux of pancreatic enzymes. Methods: Radiologic images of 840 patients in the US who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan. RESULTS: Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/ 171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; P = 0.01); were uncommonly associated with gallstones (14% vs 58%; P < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; P = 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; P = 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; P = 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.

Identification of cell cycle as the critical pathway modulated by exosome-derived microRNAs in gallbladder carcinoma.

Gallbladder cancer (GBC), the most common malignancy in the biliary tract, is highly lethal malignant due to seldomly specific symptoms in the early stage of GBC. This study aimed to identify exosome-derived miRNAs mediated competing endogenous RNAs (ceRNA) participant in GBC tumorigenesis. A total of 159 differentially expressed miRNAs (DEMs) was identified as exosome-derived miRNAs, contains 34 upregulated exo-DEMs and 125 downregulated exo-DEMs based on the expression profiles in GBC clinical samples downloaded from the Gene Expression Omnibus database with the R package. Among them, 2 up-regulated exo-DEMs, hsa-miR-125a-3p and hsa-miR-4647, and 5 down-regulated exo-DEMs, including hsa-miR-29c-5p, hsa-miR-145a-5p, hsa-miR-192-5p, hsa-miR-194-5p, and hsa-miR-338-3p, were associated with the survival of GBC patients. Results of the gene set enrichment analysis showed that the cell cycle-related pathways were activated in GBC tumor tissues, mainly including cell cycle, M phase, and cell cycle checkpoints. Furthermore, the dysregulated ceRNA network was constructed based on the lncRNA-miRNA-mRNA interactions using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0., consisting of 27 lncRNAs, 6 prognostic exo-DEMs, and 176 mRNAs. Together with prognostic exo-DEMs, the STEAP3-AS1/hsa-miR-192-5p/MAD2L1 axis was identified, suggesting lncRNA STEAP3-AS1, might as a sponge of exosome-derived hsa-miR-192-5p, modulates cell cycle progression via affecting MAD2L1 expression in GBC tumorigenesis. In addition, the biological functions of genes in the ceRNA network were also annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Our study promotes exploration of the molecular mechanisms associated with tumorigenesis and provide potential targets for GBC diagnosis and treatment.