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Background: In recent decades, laparoscopic liver resection (LLR) has been gradually adopted at high-volume centers, particularly for hepatocellular carcinoma and liver metastasis. However, LLR in patients with gallbladder cancer (GBC) is a controversial issue, and there are few studies of LLR for GBC. Our aim was to compare the outcomes of patients who underwent laparoscopic or open liver resection for GBC. Materials and Methods: All patients admitted with stage II or III GBC requiring liver resection, together with cholecystectomy and lymphadenectomy, were analyzed retrospectively. Patients with thickness of the resected liver specimen >2 cm in pathology reports were included. Results: A total of 56 patients with stage II or III GBC were included in this study; 23 (41.1%) underwent laparoscopic surgery and 33 (58.9%) underwent open surgery. Propensity score matching was performed using a 1:1 matching scheme. After matching, 12 patients were included in each group. The preoperative characteristics of both groups were similar, as were the operative times (laparoscopic versus open group: 237.5 minutes versus 272.5 minutes, respectively; P = .319) and blood loss (300 mL versus 275 mL, respectively; P = .307). The laparoscopic group had a significantly shorter postoperative hospital stay than the open surgery group (4.5 days versus 8 days, respectively; P = .012). There were no major complications in either group. There was no difference between the groups in the number of lymph nodes harvested at surgery (P = .910). There were no differences between the two groups in disease-free (P = .503) or overall (P = .719) survival. Conclusion: LLR extended to GBC provides outcomes similar to those of open surgery. With increasing experience, LLR can be a viable alternative to open surgery for GBC.

The risk of neoplasia in gallbladder polyps seems to be low, but the evidence from populations at high-risk of gallbladder cancer is limited. We aimed to estimate the risk and to identify the factors associated with neoplastic polyps in a high-risk Hispanic population.A retrospective cohort was recruited between January 2010 and December 2019 at a Chilean university center. Multivariate survival analyses were conducted. Fine-Gray models were fitted to account for competing risks. Covariate adjustment was conducted using propensity scores. The main outcome was the development of gallbladder adenomas or adenocarcinoma.Overall, 748 patients were included, 59.6% underwent cholecystectomy. The median follow-up of patients not subjected to cholecystectomy was 54.7 months (12-128.6 months). Seventeen patients (2.27%) developed the outcome. After adjustment by age, sex, intralesional blood flow, lithiasis and gallbladder wall thickening, only polyp size (≥10 mm, adjusted-HR: 15.01, 95%CI: 5.4-48.2) and number of polyps (≥3 polyps, adjusted-HR: 0.11, 95%CI: 0.01-0.55) were associated with neoplasia.In a Hispanic population at high-risk for gallbladder cancer, gallbladder polyps seem to have a low risk of neoplasia. Polyp size was the main risk factor, while having multiple polyps was associated with an underlying benign condition.

Background Metastases to the gallbladder (GBm) are rare and pose a unique diagnostic challenge because they can mimic a second primary tumor. This study aimed to gain insight into the clinicopathological and epidemiological characteristics of GBm. Methods A comprehensive literature review was performed (literature cohort) and compared with a nationwide cohort of GBm patients diagnosed between 1999 and 2015 in the Netherlands, collected via two linked registries (population cohort). Overall survival (OS) was estimated by Kaplan–Meier. Hazard ratios were determined by a Cox proportional hazard model. Results The literature cohort and population cohort consisted of 225 and 291 patients, respectively. In the literature cohort, melanoma was the most frequent origin (33.8%), while colorectal cancer was the most frequent origin in the population cohort (23.7%). Prognosis was poor with median OS ranging from 6.0 to 22.5 months in the literature and population cohorts, respectively. Age, timing of GBm (synchronous/metachronous) and primary tumor origin were independent prognostic factors for OS. Discussion Metastases to the gallbladder are rare and carry a poor prognosis. Differences between both cohorts can be attributable to the biased reporting of tumor types that are more easily recognized as GBm because of distinct histological features.

Background We have limited information about neuroendocrine carcinoma (NEC) of the gallbladder. The purpose of this paper is to compare clinical and pathological features between different age groups and prognostic factors for gallbladder NEC and how it differs from adenocarcinoma (ADC) of the gallbladder. Patients and methods This study included 28 gallbladder NEC patients and 137 ADC patients whose clinical characteristics and pathological findings were retrospectively collected. Propensity score matching and Cox regression analysis were used for the analysis of prognostic factors. Results We divided NEC patients into two groups based on the age more than or less than 60 years. Most of the NEC patients less than 60 years old complained of abdominal pain or discomfort (p = 0.038), and more younger patients accepted adjuvant therapy (p = 0.020) than older patients did. CD56 was positive in all patients more than 60 years old, which is significantly higher than that of younger patients (p = 0.039). The mean age was similar between NEC and ADC patients. After eliminating confounding factors between NEC and ADC patients, the overall survival rates were still lower in NEC patients. Univariate analysis extracted six possible risk factors. Multivariate analysis indicated that surgery type, tumor size, and existence of gallstones were independent prognostic factors. Conclusion The overall survival of gallbladder NEC is not associated with age. In this study, surgical method and tumor size were found to be independent risk factors for NECs. In addition, NEC patients have a worse prognosis than ADC patients with similar clinical and pathological features.

Background: Comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships in gallbladder cancer (GBC) is limited.Methods:We performed whole exome sequencing (WES) for 5 patients with primary tumor, metastatic lymph node (LNM) and corresponding normal tissue. Mutations, mutation signatures and copy number variations were analyzed with state-of-art bioinformatics methods. Phylogenetic tree was also generated to infer metastatic pattern. Results:Five driver mutations were detected in these patients. Among which, TP53 was the only shared mutation between primary tumor and LNM. Although tumor mutational burden was comparable between primary tumor and LNM, higher mutation burden was observed in LNM of one patient. Copy number variations (CNVs) burden was higher in LNM than their primary tumor. Phylogenetic analysis indicated both linear and parallel progression of metastasis exist in these patients. TP53 mutation and CNVs were homogenously between primary tumor and LNM.Conclusions:High consistence of genetic landscape were shown between primary tumor and LNM in GBC. However, heterogenicity still exist between primary tumor and LNM in particular patients in term of driver mutation, TMB and CNV burden. Phylogenetic analysis indicated both Linear and parallel progression of metastasis were exist among these patients.

Background Analysis of long-term clinical outcomes of patients with familial adenomatous polyposis is critical in reducing or preventing the incidence of extracolonic malignancies after initial surgery. The aim of the present study was to clarify the long-term outcomes, and establish a surveillance strategy for surgically treated familial adenomatous polyposis patients. Methods Between January 1967 and March 2020, retrospective data were collected from 37 patients with familial adenomatous polyposis treated or monitored in our department. Occurrence of metachronous cancers, including rectal cancers and extracolonic malignancies, and other diseases was analyzed. Results The median follow-up duration after the first surgery was 13.8 years. Initially, 16 patients underwent total proctocolectomy with ileal pouch-anal anastomosis, 18 underwent total colectomy with ileorectal anastomosis, and three underwent other procedures. A secondary proctectomy was performed for 9 of the 18 patients who underwent ileorectal anastomosis. Rectal cancer was diagnosed in 6 patients who underwent ileorectal anastomosis. In addition, 5 gastric cancer, 2 duodenal cancer, 1 gallbladder cancer, and 1 thyroid cancer cases were diagnosed. The age at which the extracolonic malignancies were diagnosed was >50 years. 4 patients died due to metachronous rectal cancer, gastric cancer, or gallbladder cancer. Conclusion Careful consideration should be paid before choosing ileorectal anastomosis as the treatment procedure for familial adenomatous polyposis patients because completion proctectomy was eventually necessary for half of the patients. Long-term surveillance, with more frequent gastric surveillance for patients over 50 years, is important for the prevention and treatment of extracolonic malignancies in familial adenomatous polyposis patients.

Objectives: Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. Kaplan–Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables. Results: Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3–4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p

PURPOSE For unresectable gallbladder cancer (GBC), gemcitabine and platinum is standard combination; however, outcome is poor. We conducted this study to find feasibility of modified flourouracil, oxaliplatin, and irinotecan in this group. MATERIALS AND METHODS We conducted a prospective, phase II single-arm pilot study. Inclusion criteria were histologically proven GBC and Eastern Cooperative Oncology Group 0-1. Primary end points were overall response rates and overall survival. The following treatment was given: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and irinotecan 150 mg/m2, all once on day 1, fluorouracil 2,400 mg/m2 continuous intra-venous infusion over 46 hours repeated every 2 weeks, and maximum 12 doses, with primary granulocyte colony-stimulating factor prophylaxis. RESULTS Between February 2019 and July 2020, 29 patients with unresectable GBC were enrolled. The median age was 52 years, and 18 were females. The Eastern Cooperative Oncology Group was 0 in 4. Five had bilirubin > normal, and 15 each had high serum alkaline phosphatase and carbohydrate antigen 19-9. Twenty-five patients had stage IV disease, and remaining unresectable locally advanced disease. A median of 8.5 cycles was given, and 11 completed treatment. Nine stopped chemotherapy because of progression, and one because of toxicity, and treatment is ongoing in three. Twenty-two required dose reduction. A treatment delay of 1-2 weeks was seen in 25 patients. Best response was complete response 1, partial response 13 (overall response rate 48.2%), and stable disease 9. Four patients with metastatic disease underwent R0 resection. As on cutoff date, nine are surviving (three without disease). Eighteen died of PD, and in two, cause was unknown. There was no toxic death. The median overall survival and progression-free survival were 309 and 252 days, respectively. Twenty-three patients experienced grade III or IV toxicity, and common were diarrhea (13), vomiting (12), and anemia (7). CONCLUSION First-line modified flourouracil, oxaliplatin, and irinotecan is feasible in unresectable GBC with encouraging responses. Toxicities are higher but manageable. Higher response rates make this an option to explore in borderline resectable cases.

Summary: Previous studies have explored the role of laparoscopic surgery (LS) in the surgical management of gallbladder carcinoma (GBC) and obtained satisfactory outcomes versus conventional open surgery. However, most of them either included a small number of patients or mainly focused on the early-staged lesions. Therefore, their results were less statistical powerful and a more comprehensive evaluation on the role of LS in GBC is warranted. A thorough database searching was performed in PubMed, EMBASE and Cochrane Library for comparative studies between the laparoscopic and open approach in the surgical management of GBC and 18 comparative studies were finally identified. RevMan 5.3 and Stata 13.0 software were used for statistical analyses. Pooled results revealed that patients in the laparoscopic group recovered faster with less intraoperative hemorrhage and less postoperative morbidity. Comparable operative time, overall recurrence rate, R0 resection rate, lymph node yield, intraoperative gallbladder violation rate and postoperative survival outcomes were also acquired. Regarding the debating issue of port-site recurrence, a significantly higher incidence of port-site recurrence was observed in laparoscopic group. However, having excluded studies on incidental gallbladder carcinoma, the subsequent pooled result showed no significant difference. Considering the inherent inconsistency of the surgical indication between laparoscopic and open surgeries and the deficiency of advanced lesions, we drew a conclusion that laparoscopic surgery seems to be only safe and feasible for early- or middle-staged lesions. Upcoming random controlled trials or comparative studies with equivalent surgical indication focused on advanced lesions are warranted for further evaluation.

The Gallbladder Reporting and Data System (GB-RADS) ultrasound (US) risk stratification is proposed to improve consistency in US interpretations, reporting, and assessment of risk of malignancy in gallbladder wall thickening in non-acute setting. It was developed based on a systematic review of the literature and the consensus of an international multidisciplinary committee comprising expert radiologists, gastroenterologists, gastrointestinal surgeons, surgical oncologists, medical oncologists, and pathologists using modified Delphi method. For risk stratification, the GB-RADS system recommends six categories (GB-RADS 0–5) of gallbladder wall thickening with gradually increasing risk of malignancy. GB-RADS is based on gallbladder wall features on US including symmetry and extent (focal vs. circumferential) of involvement, layered appearance, intramural features (including intramural cysts and echogenic foci), and interface with the liver. GB-RADS represents the first collaborative effort at risk stratifying the gallbladder wall thickening. This concept is in line with the other US-based risk stratification systems which have been shown to increase the accuracy of detection of malignant lesions and improve management. Graphical abstract: [Figure not available: see fulltext.].

To determine the association of malignancy potential of gallbladder polyps with tumor markers and cholesterol levels, and at which value the presence of malignancy should be suspected.Observational study.University of Health Sciences, Adana City training and research Hospital from December 2017 to November 2020.Ninety patients diagnosed with gallbladder polyp by abdominal ultrasonography, were included in the study. Patients were divided into subgroups of true pseudopolyp, cholesterol-non-cholesterolpolyp, malignant-non-malignant polyp. The groups were compared in terms of age, gender, polyp size, number of polyps, preoperative total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), triglyceride, Ca 19-9 (carbohydrate antigen 19-9), Ca 72-4 (carbohydrate antigen 72-4), Cea (carcinoembryonic antigen) levels.In the true polyp group, polyp size, Ca 19-9, Ca 72-4 and Cea median values were significantly higher (p=0.001, p=0.029, p=0.003, and p=0.007, respectively); whereas, triglyceride levels were significantly lower compared to the pseudopolyp group (p=0.002). Polyp size was significantly lower in cholesterol polyp group compared to non-cholesterol polyp group (p= 0.032), and LDL and triglyceride medians were significantly higher (p=0.031, and p0.001) in cholesterol group. Among the true polyps, polyp size, Ca 19-9, Ca 72-4 and Cea levels were significantly higher in adenocarcinoma group than non-malignant polyp groups (p0.05). Cut-off values were determined as11 mm AUC: 0.906 for size,24.1 U/mL. AUC: 1.00 for Ca 19-9,9.6 U/mL AUC: 1.00 for Ca 72-4, and40 ng/mL AUC: 0.984 for CEA, respectively.Polyps larger than 11mm with high levels of CEA, Ca 72-4, Ca 19-9, evaluated together, may act as a guide for the clinician in predicting malignancy. The availability of economical and accessible parameters may allow a new algorithm to be developed in the treatment and follow-up approach of gallbladder polyps. Key Words: Gallbladder polpys, Ca 19-9 antigen, Ca 72-4 antigen, Tumor marker, Gallbladder cancer.

Gallbladder cancer (GBC) is an uncommon but very aggressive malignancy with poor prognosis. Concerns for oncological inferiority related to the technical difficulties in performing laparoscopic portal lymphadenectomy discourage many surgeons to undertake this operation minimally invasively. With wide application of robotic technology to solve limitations of conventional laparoscopy, we describe our initial outcomes of robotic central hepatectomy and portal lymphadenectomy for gallbladder carcinoma in 15 consecutive patients. Data were presented as median (mean ± SD). Patients were 70 (73 ± 10.9) years old with BMI of 26 (26 ± 3.6) kg/m2. Tumor size was 3(4 ± 1.9) cm. Operative duration was 222 (237 ± 85.7) minutes and estimated blood loss was 200 (222 ± 135.4) mL. There were no intraoperative complications and complete resection (R0) was obtained in nearly all patients. Postoperative complications were seen in two patients (bile leak (n = 1) and respiratory failure (n = 1)). Length of stay was 3 (4 ± 4.0) days without 30-day mortality. Robotic approach is safe and effective for the treatment of GBC.

Background: Long non-coding RNAs (lncRNAs) has no protein-coding potential due to the lack of an apparent open reading frame. There is growing evidence that lncRNA DGCR5 has a vital regulatory role in human illnesses' pathological development, particularly in the digestive system's carcinogenesis and progression. Abnormal DGCR5 expression affects different cellular functions such as proliferation, aggression, and metastasis. This paper aims to probe into the pathophysiological functions and molecular mechanisms of DGCR5 in cancers of the digestive system. Methods: This review summarizes and analyzes the biological functions and mechanisms of lncRNA DGCR5 in digestive system cancers occurrence. Relevant studies were conducted and reviewed by searching PubMed for articles with lncRNA DGCR5 and digestive system cancer as keywords in recent years. Results: DCGR5, as a novel tumor-related lncRNA, is recently identified to be abnormally expressed in digestive system cancers, such as pancreatic ductal adenocarcinoma, pancreatic cancer, gastric cancer, gallbladder cancer, colorectal cancer, and hepatocellular carcinoma. The role played by DCGR5 is vital and varies in different digestive cancers. Taken together, aberrant expression of DCGR5 regulates the progression of digestive cancers by affecting cancer cell proliferation, aggression, metastasis, and drug resistance. Conclusion: LncRNA DGCR5 might be a viable marker or a promising therapeutic target in digestive system cancers.

Introduction: Gallbladder carcinoma is often difficult to distinguish from benign gallbladder diseases. While the diagnostic accuracy of endoscopic transpapillary gallbladder drainage (ETGD) has been reported, these results were obtained retrospectively. This prospective study aimed to evaluate the cytological diagnostic accuracy of ETGD in patients with gallbladder disease. Methods: This single-arm prospective clinical trial included a total of 35 patients scheduled to undergo ETGD between March 2017 and September 2019. A 5F pigtail nasobiliary drainage tube was inserted into the gallbladder, and bile was collected over 5 times; if ETGD failed, a drainage tube was placed into the bile duct. The endpoints were, first, the cytological diagnostic accuracy of ETGD and, second, technical success rates and adverse events. Results: Of the 35 patients, 19 were finally diagnosed with gallbladder cancer. The success rate of ETGD tube insertion was 85.7%, and the morphological pattern of the cystic duct with the angle down and located on the right side had a significantly lower success rate for ETGD than that of other cystic duct patterns (odds ratio, 13.5; 95% confidence interval, 1.7–143.7; p = 0.02). Cytological samples were collected 5 times on median. The sensitivity, specificity, and accuracy in all patients were 78.9%, 100%, and 88.6%, respectively, while those in 30 patients with successful ETGD were 87.5%, 100%, and 93.3%, respectively. Adverse events occurred in 3 patients: mild pancreatitis in 1 patient and obstructive jaundice in 2 patients; all complications were resolved with conservative therapy. Discussion/Conclusions: Cytology using an ETGD tube is useful in differentiating benign and malignant gallbladder diseases (Clinical Trial Registry No. UMIN000026929).

Background The genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS). Methods We retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status. Results The most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p Conclusions TP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.

Background Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy for GBC remains unknown. Methods RT-qPCR, MS-qPCR and ChIP-qPCR were used to evaluate the direct association between ELP5 transcription and DNA methylation in tumour and non-tumour tissues of GBC. EMSA, chromatin accessibility assays, and luciferase assays were utilized to analysis the DNA methylation in interfering PAX5-DNA interactions. The functional experiments in vitro and in vivo were performed to investigate the effects of DNA demethylating agent decitabine (DAC) on the transcription activation of elongator complex and the enhanced sensitivity of gemcitabine in GBC cells. Tissue microarray contains GBC tumour tissues was used to evaluate the association between the expression of ELP5, DNMT3A and PAX5. Results We demonstrated that transcriptional repression of ELP5 in GBC was highly correlated with hypermethylation of the promoter. Mechanistically, epigenetic analysis revealed that DNA methyltransferase DNMT3A-catalysed hypermethylation blocked transcription factor PAX5 activation of ELP5 by disrupting PAX5-DNA interaction, resulting in repressed ELP5 transcription. Pharmacologically, the DNA demethylating agent DAC eliminated the hypermethylated CpG dinucleotides in the ELP5 promoter and then facilitated PAX5 binding and reactivated ELP5 transcription, leading to the enhanced function of the elongator complex. To target this mechanism, we employed a sequential combination therapy of DAC and gemcitabine to sensitize GBC cells to gemcitabine-therapy through epigenetic activation of the elongator complex. Conclusions Our findings suggest that ELP5 expression in GBC is controlled by DNA methylation-sensitive induction of PAX5. The sequential combination therapy of DAC and gemcitabine could be an efficient therapeutic strategy to overcome chemotherapy resistance in GBC.

Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT).MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes.A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically.The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time.

Background Diagnostic laparoscopy is often a necessary, albeit invasive, procedure to help resolve undiagnosed peritoneal diseases. Previous retrospective studies reported that EUS-FNA is feasible on peritoneal and omental lesions, however, EUS-FNA provided a limited amount of tissue for immunohistochemistry stain (IHC). Aim This pilot study aims to prospectively determine the effectiveness of EUS-FNB regarding adequacy of tissue for IHC staining, diagnostic rate and the avoidance rate of diagnostic laparoscopy or percutaneous biopsy in patients with these lesions. Methods From March 2017 to June 2018, patients with peritoneal or omental lesions identified by CT or MRI at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand were prospectively enrolled in the study. All Patients underwent EUS-FNB. For those with negative pathological results of EUS-FNB, percutaneous biopsy or diagnostic laparoscopy was planned. Analysis uses percentages only due to small sample sizes. Results A total of 30 EUS-FNB passes were completed, with a median of 3 passes (range 2–3 passes) per case. For EUS-FNB, the sensitivity, specificity, PPV, NPV and accuracy of EUS-FNB from peritoneal lesions were 63.6%, 100%, 100%, 20% and 66.7% respectively. Adequate tissue for IHC stain was found in 25/30 passes (80%). The tissues from EUS results were found malignant in 7/12 patients (58.3%). IHC could be done in 10/12 patients (83.3%). Among the five patients with negative EUS results, two underwent either liver biopsy of mass or abdominal paracentesis, showing gallbladder cancer and adenocarcinoma. Two patients refused laparoscopy due to advanced pancreatic cancer and worsening ovarian cancer. The fifth patient had post-surgical inflammation only with spontaneous resolution. The avoidance rate of laparoscopic diagnosis was 58.3%. No major adverse event was observed. Conclusions EUS-FNB from peritoneal lesions provided sufficient core tissue for diagnosis and IHC. Diagnostic laparoscopy can often be avoided in patients with peritoneal lesions.

Introduction In the past, targeted therapies have not shown positive results as they have been used without adequate molecular selection of patients with biliary tract cancer (BTC). This has led to an expansion of research on characteristics and molecular selection to identify new effective strategies in this setting. Improved knowledge of the molecular biology of these neoplasms has highlighted their extraordinary heterogeneity and has made it possible to identify targetable gene alterations, including fibroblast growth factor receptor (FGFR) 2 gene fusions, and isocitrate dehydrogenase (IDH) mutations. The FDA recently approved ivosidenib and pemigatinib for the treatment of BTCs. Areas covered We review data in the literature regarding targeted therapies for the treatment of BTCs, as well as on the prospects deriving from the extraordinary molecular heterogeneity of these neoplasms. Expert opinion At present, it is essential to evaluate the expression of the genetic alterations expressed by these neoplasms to offer patients an increasingly personalized therapeutic approach. Studies are needed to better define the limits and potentials of targeted therapies and their role in the therapeutic algorithm to improve the poor prognosis of these patients.

This study aimed to investigate the impact of surgery on outcomes in patients with recurrent biliary tract cancer (BTC) and elucidate factors affecting survival after surgery for this disease.A single-center study was undertaken in 178 patients with recurrent BTC, of whom 24 underwent surgery for recurrence, 85 received chemotherapy, and 69 received best supportive care. Then, we carried out a multicenter study in 52 patients undergoing surgery for recurrent BTC (gallbladder cancer, 39%; distal cholangiocarcinoma, 27%; perihilar cholangiocarcinoma, 21%; intrahepatic cholangiocarcinoma, 13%).In the single-center study, 3-year survival after recurrence was 53% in patients who underwent surgery, 4% in those who received chemotherapy, and 0% in those who received best supportive care (p 0.001). Surgery was an independently prognostic factor (p 0.001). In the multicenter series, the respective 3-year and 5-year survival after surgery for recurrence was 50% and 29% in the 52 patients. Initial site of recurrence was the only independent prognostic factor (p = 0.019). Five-year survival after surgery for recurrence in patients with single distant, multifocal distant, and locoregional recurrence was 51%, 0%, and 0%, respectively (p = 0.002). Sites of single distant recurrence included the liver (n = 13, 54%), distant lymph nodes (all from gallbladder cancer, n = 7, 29%), lung (n = 2, 9%), peritoneum (n = 1, 4%), and abdominal wall (n = 1, 4%).Surgery may be an effective option for patients with less aggressive tumor biology characterized by single distant recurrence in recurrent BTC.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis‐associated gallbladder cancer lncRNA (lncRNA‐PAGBC), which we find to be an independent prognostic marker in GBC. Functional analysis indicates that lncRNA‐PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA‐PAGBC competitively binds to the tumour suppressive microRNAs miR‐133b and miR‐511. This competitive role of lncRNA‐PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA‐PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.

Aim of doing this review was to give a uniform consensus on prognostic impact of tumor location (hepatic vs peritoneal), liver resection and adjuvant chemotherapy in gall bladder cancer and, to compare them with previous well-studied factors of survival. We systematically review PubMed, Scopus and Cochrane for relevant articles with no date restrictions, language was restricted to English. Those articles were included that had provided Hazard ratio (HR) of survival for T2 gall bladder cancer. We identified nine retrospective studies published between 2014 and 2020 with 2345 patients. Meta-analysis showed that T2b (hepatic) cancers had higher odds of mortality (HR 3.16 [2.11, 4.74], I2 = 0%). Liver resection was associated with significantly higher odds of 5-year overall survival only in T2b (2.20 [1.33, 3.63], I2 = 67%), adjuvant chemotherapy was not associated with any significant decrease in mortality risk (0.98 [0.83–1.16]. I2 = 20%). Hepatic sided gall bladder tumors carry higher odds for mortality and recurrence. T2a tumors can be managed without hepatic resection. To risk stratify patients we also formulated a scoring system for mortality risk.

Objectives Evaluation of the association of PARP1 rs1136410 (A/G) polymorphism with gallbladder cancer susceptibility and its prognosis in the Indian population of eastern Uttar Pradesh and western Bihar. Methods PARP1 rs1136410 was genotyped by PCR-RFLP and its association with the prognosis of gallbladder cancer patients were analyzed using Kaplan-Meier plot and log-rank tests. Results Our results demonstrate that minor allele G is more frequent in gallbladder cancer patients than controls. The frequencies of minor allele G and GG genotype are significantly associated with increased risk of gallbladder cancer. Our data suggest that the minor allele G and homozygous genotype GG are significant predisposing factors for the early age of onset of gallbladder cancer. Similarly, women patients having AG and GG genotypes demonstrate an increased risk of gallbladder cancer. The risk group genotypes (AG + GG) are significantly more frequent in patients with thick gallbladder wall, with jaundice and with the presence of lymph node than in patients with normal gallbladder wall thickness, without jaundice and absence of lymph node involvement. Survival analysis data suggest that patients with risk group genotype (AG + GG) presenting jaundice have shorter overall survival. Conclusion Our study suggests that the minor allele G of PARP1 rs1136410 (A/G) is a predisposing factor for gallbladder carcinogenesis and is significantly associated with early onset of the disease. Interestingly, the minor allele G is significantly more frequent in the patients with jaundice, lymph node metastasis and gallbladder wall thickness.

Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions.

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer., The progression from biliary tract intraepithelial neoplasia (BilIN) to gallbladder carcinoma (GBC) remains unclear. Here the authors use genomics to analyze coexisting GBC lesions, low-grade and high-grade BilINs, revealing two distinct evolutionary paths for GBC development.

Background Krukenberg tumors are uncommon and are indicative of an ovarian metastatic carcinoma that originates from another site of primary malignancy. The majority of metastases to ovaries are derived from the stomach and colon. We present a rare case of a metastatic ovarian malignant tumor that originated from gallbladder adenocarcinoma. Case presentation A 45-year-old premenopausal Korean woman presented with abdominal distension. Bilateral multiseptated ovarian tumors and a wall-thickened gallbladder were found on abdominal computed tomography. The patient was diagnosed with metastatic ovarian carcinoma arising from gallbladder adenocarcinoma and was treated with adjuvant chemotherapy. Conclusions Metastases to the ovaries from other sites, including the gallbladder, are rare and usually resemble primary ovarian tumors. Therefore, potential metastatic ovarian tumors of newly diagnosed pelvic masses should be considered in differential diagnoses.

Background Although gallbladder cancer (GBCA) is characterized by a dismal prognosis, there is a proportion of patients who are cured. The aim of this study was to analyze the profile of these patients. Methods A database was queried for patients who underwent curative resection with a follow-up of at least 5 years. Patients were prospectively treated and registered by the same surgical team. A multivariate regression analysis was used to identify factors associated with long-term survival. Results From 1988 to 2013, 461 patients were evaluated and 112 who underwent resection were analyzed. Among the patients, five year survival was 57% while lymph node and liver compromise were the only independent factors associated with survival. On the other hand, the elapsed time between the cholecystectomy and the resection, the differentiation grade and the level of wall invasion did not have an independent effect on the prognosis. Conclusion Despite its poor prognosis, a subset of patients can be cured of GBCA. R0 resection of patients without lymph and liver infiltration are key to GBCA survival.

Background Cancer‐associated fibroblasts (CAFs) with different gene profiles from normal fibroblasts (NFs) have been implicated in tumor progression. Angiopoietin‐like protein 4 (ANGPTL4) has been shown to regulate tumor angiogenesis and metastasis, and predict poor prognosis. However, the ANGPTL4 expression in CAFs, especially in gallbladder CAFs (GCAFs) and its relationship with patient prognosis is unclear. Methods Affymetrix gene profile chip analysis in vitro was performed to detect the different gene expression profiles between GCAFs and NFs. RT‐qPCR, immunohistochemistry, and western blotting were performed to investigate the different expression levels of ANGPTL4 in GCAFs/NFs in vitro and in an in vivo nude mouse model of xenograft tumors. Finally, the ANGPTL4 expression was investigated in the stroma of different lesion tissues of the human gallbladder by immunohistochemistry, especially the expression in GCAFs in vivo by co‐immunofluorescence, and their prognostic significance in patients with gallbladder cancer (GBC) was assessed. Results ANGPTL4 was upregulated in both GCAFs in vitro and in the xenograft stroma of nude mice in vivo, and its expression was also significantly upregulated in human GBC stroma co‐localized with the interstitial markers fibroblast secreted protein‐1 and α‐smooth muscle actin. In addition, the elevated ANGPTL4 expression in GCAFs was correlated with tumor differentiation, liver metastasis, venous invasion and Nevin staging, and GBC patients with an elevated ANGPTL4 expression in GACFs were found to have a lower survival rate. Conclusions Increased ANGPTL4 expression in GCAFs correlates with poor patient prognosis, which indicates a potential therapeutic target for human GBCs., ANGPTL4 expression was upregulated in GCAF, which was significantly related to the degree of clinical GBC differentiation, liver metastasis, venous invasion, and Nevin staging, and GBC patients with elevated ANGPTL4 expression in GCAF had lower survival rate.

BACKGROUND AND AIMS Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P

Neuroendocrine neoplasms (NENs) of the gallbladder are very rare. As a result, the classification of pathologic specimens from gallbladder NENs, currently classified as gallbladder neuroendocrine tumors (GB-NETs) and carcinomas (GB-NECs), is inconsistent and makes nomenclature, classification, and management difficult. Our study aims to evaluate the epidemiological trend, tumor biology, and outcomes of GB-NET and GB-NEC over the last 5 decades. This is a retrospective analysis of the SEER database from 1973 to 2016. The epidemiological trend was analyzed using the age-adjusted Joinpoint regression analysis. Survival was assessed with Kaplan–Meier analysis and Cox regression was used to assess predictors of poor survival. A total of 482 patients with GB-NEN were identified. Mean age at diagnosis was 65.2 ± 14.3 years. Females outnumbered males (65.6% vs. 34.4%). The Joinpoint nationwide trend analysis showed a 7% increase per year from 1973 to 2016. The mean survival time after diagnosis of GB-NEN was 37.11 ± 55.3 months. The most common pattern of nodal distribution was N0 (50.2%) followed by N1 (30.9%) and N2 (19.2%). Advanced tumor spread (into the liver, regional, and distant metastasis) was seen in 60.3% of patients. Patients who underwent surgery had a significant survival advantage (111.0 ± 8.3 vs. 8.3 ± 1.2 months, p

Background Presence of jaundice in gallbladder carcinoma (GBC) is considered a sign of inoperability with no defined treatment pathways. Methods Retrospective analysis of all surgically treated GBC patients from January 2010 to December 2019 was performed for evaluating etiology of obstructive jaundice, resectability, postoperative morbidity, mortality, disease-free survival (DFS) and overall survival (OS). Results Out of 954 patients, 521 patients (54.61%) were locally advanced gallbladder carcinoma (LAGBC: Stage III and IV) and 113 patients (11.84%) had jaundice at presentation. Thirty-four (30%) patients had benign cause of obstructive jaundice. Median OS of the whole cohort (n=113) was 22 months (16.5-27.49 months) with resectability rate of 62% (70/113). Median OS of curative resection group (n=70) was 32 months and DFS was 25 months. Treatment completion was achieved in 30% (n= 21/70) patients with median OS of 46 months and median DFS of 27 months. Isolated bile duct infiltration subgroup fared the best with median OS of 74 months with a 5-year survival of 66.7%. Conclusion Surgical resection as a part of multimodality treatment improves survival in carefully selected locally advanced gallbladder cancer patients with jaundice. Early introduction of systemic therapy is the key in the management of this disease with aggressive tumor biology.

BACKGROUND AND AIMS Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-income and middle-income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. APPROACH AND RESULTS To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of formalin-fixed, paraffin-embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality-controlled data from 82 samples (gallstones n = 32, low-grade dysplasia n = 13, high-grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine-guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin-dependent kinase inhibitor 2A, MDM2 proto-oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb-B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. CONCLUSIONS Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.

Elevated systemic levels of soluble cluster of differentiation 14 (sCD14) have been associated with gallbladder cancer (GBC), but the association with sCD14 levels within the gallbladder has not been investigated. Here, we evaluated sCD14 in the bile of 41 GBC cases and 117 gallstone controls with data on 65 bile inflammation markers. We examined the relationship between bile sCD14 levels and GBC using logistic regression and stratified the analysis by stage. We included GBC-associated inflammatory biomarkers in the model to evaluate the influence of local inflammation. Bile sCD14 levels (third versus first tertile) were associated with GBC (adjusted odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.2–8.0). The association was equally strong for stage I/II (OR: 3.3, 95% CI: 0.9–15.6) and stage III/IV (OR: 3.2, 95% CI: 1.0–12.4) cancers. Including the GBC-associated inflammatory markers in the model removed the association between bile sCD14 and GBC (OR: 1.0, 95% CI: 0.3–3.5). The findings suggest that immune activation within the gallbladder may be related to GBC development, and the effect of sCD14 is influenced by inflammation. Similar associations across tumor stages suggest that elevated bile sCD14 levels may reflect changes early in GBC pathogenesis. Associations between GBC and sCD14 levels in both bile and plasma suggest sCD14 could be a potential biomarker for GBC.

Associations of obesity have been established for at least 11 cancer sites in observational studies, though some questions remain as to causality, strength of associations, and timing of associations throughout the life course. In recent years, Mendelian randomization (MR) has provided complementary information to traditional approaches, but the validity requires that the genetic instrumental variables be causally related to cancers only mediated by the exposure. We summarize and evaluate existing evidence from MR studies in comparison with conventional observational studies to provide insights into the complex relationship between obesity and multiple cancers. MR studies further establish the causality of adult obesity with esophageal adenocarcinoma and cancers of the colorectum, endometrium, ovary, kidney, and pancreas, as well as the inverse association of early life obesity with breast cancer. MR studies, which might account for lifelong adiposity, suggest that the associations in observational studies typically based on single measurement may underestimate the magnitude of the association. For lung cancer, MR studies find a positive association with obesity, supporting that the inverse association observed in some conventional observational studies likely reflects reverse causality (loss of lean body mass before diagnosis) and confounding by smoking. However, MR studies have not had sufficient power for gallbladder cancer, gastric cardia cancer, and multiple myeloma. In addition, more MR studies are needed to explore the effect of obesity at different timepoints on postmenopausal breast cancer and aggressive prostate cancer.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

Background The study aimed at establishing a nodal staging score (NSS) to quantify the likelihood that pathologic node-negative gallbladder cancer (GBC) patients are indeed free of lymph node (LN) metastasis. Methods Clinicopathological data of 1374 GBC patients with T1b-T2 stages were collected from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 1289) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 85). NSS was derived from the count of examined LNs (ELNs) and T stage by using a beta-binomial model, and represented the probability that a node-negative patient is correctly staged. The prognostic value of NSS in node-negative GBC was evaluated by survival analysis. Results The probability of missing a nodal disease in node-negative GBC patients with T1b-T2 stages (pT1bN0 and pT2N0) decreased as the number of ELNs increased. NSS increased as the number of ELNs increased. For pT1bN0 and pT2N0 patients, examination of 5 and 27 lymph nodes could ensure an NSS of 90.0%, respectively. Multivariate analysis revealed that NSS was an independent predictor for overall survival in pT1bN0 and pT2N0 GBC patients (DC, HR:0.53, 95%CI: 0.42–0.66, p Conclusion NSS could evaluate the adequacy of nodal staging and predict the prognosis in pT1bN0 and pT2N0 GBC patients, and hence was helpful to guide their treatment strategies.

Background & Aims Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival. Methods We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases. Results Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features. Conclusion These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Lay summary Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival.

SummaryBackground Combination therapy of gemcitabine with cisplatin (GC) is a standard first-line therapy for unresectable or recurrent biliary tract cancer (BTC). S-1 is often used as a second-line therapy in clinical practice, based on the results of some clinical studies investigating its efficacy and safety following gemcitabine monotherapy. However, few studies have reported on the clinical outcomes of S-1 following GC. The purpose of this study was to elucidate the efficacy and safety of S-1 following GC for unresectable and recurrent BTC. Methods We retrospectively collected the data of 116 patients (pts) who were treated with S-1 as a second-line therapy following GC for unresectable or recurrent BTC at Shizuoka Cancer Center (November 2009 to July 2019). Results Of these 116 pts., 84 were assessable. Patient characteristics were as follows: intrahepatic bile duct/extrahepatic bile duct/gallbladder cancer, 30/23/31 pts.; metastatic/recurrent/locally advanced, 57/17/10 pts. The median time to treatment failure and overall survival were 2.5 and 6.0 months, respectively. Among 65 pts. with measurable lesions, the overall response rate was 3.1% (2/65 pts) and the disease control rate was 24.6% (19/65 pts). The common grade 3/4 toxicities included anemia (12%), neutropenia (4%), infections (16%), fatigue (6%), and diarrhea (4%). Dose reduction or treatment schedule modification of S-1 was required in 29 pts. (34.5%), and 17 pts. (20%) terminated S-1 due to adverse events. Conclusions The efficacy and safety of S-1 following GC were almost the same as those of S-1 following GEM monotherapy for unresectable or recurrent BTC.

Background Biliary tract cancers (BTCs) are heterogeneous cancers that include cancers of the bile duct and gallbladder. Although they are relatively uncommon, most patients with BTC are diagnosed at advanced-stage disease with high mortality rates. Recently, systemic therapy options for patients with BTC have evolved. This paper reviews recent advancements in systemic therapy and the results of key clinical trials in BTC. Methods A literature search in PubMed and Google Scholar was performed using keywords related to BTC and systemic therapy. Studies that were presented in major international cancer research conferences were also included. Results The evidence shows that adjuvant capecitabine has been associated with a lower relapse rate in early-stage BTC. In unselected patients with advanced BTC, combination chemotherapy is a standard treatment option. However, with a better understanding of the molecular profile of BTC, there has been a shift toward targeted agents in BTC that have shown promising responses. The evolving data also support the evolving role of immunotherapy in patients with deficient DNA mismatch repair or PD-L1-positive BTC. Discussion Systemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.

We report a 48-year-old fit and healthy woman who was incidentally diagnosed to have adenocarcinoma of gallbladder after laparoscopic cholecystectomy. Subsequent imaging showed no evidence of regional or distant spread. She was scheduled for elective laparotomy and resection of gallbladder bed, but during laparotomy frozen section analysis of an incidentally discovered peritoneal deposit confirmed metastasis, so the procedure was abandoned. Thereafter, she received cisplatin and gemcitabine chemotherapy. However, surveillance computed tomography incidentally noted a urinary bladder mass which had not been present before. Transurethral resection of the bladder lesion revealed moderately differentiated adenocarcinoma of urinary bladder. The appearance and immunoprofile of the lesion confirmed metastasis from the primary gallbladder cancer, which has not been documented in the literature to the best of our knowledge. Her disease progressed and she is being challenged with gemcitabine and carboplatin as second-line palliative chemotherapy. She is still alive two years after the initial diagnosis.

Programmed death-1 (PD1) expression has not been reported in gallbladder adenocarcinoma. In this study we examined PD1 expression in gallbladder cancer to explore the correlation between PD1 expression and the clinicopathologic parameters. We found that 98% (46/47) cases expressed programmed death-ligand 1 (PD-L1) with 85% cases being PD-L1 3+. PD1+ tumor-infiltrating lymphocytes (TILs) were present in 78.7% cases (37/47). The tumor size was significantly smaller and the stromal CD3+ TILs were significantly higher in tumors with PD1+ TILs than those with PD1- TILs. In the tumors with size of3 cm, stromal CD3+ TILs115/HPF or stromal CD8+ TILs45/HPF were associated with much better survival than those with stromal CD3+ TILs ≤115/HPF or stromal CD8+ TILs ≤45/HPF. In tumors with the size of 3 cm or larger, PD1+ TILs or stromal CD8+ TILs45/HPF carried a significantly poorer survival than PD1- tumors or stromal CD8+ TILs=45/HPF. No correlation was identified between PD1 expression and lymphovascular invasion, distant metastasis, pathologic tumor stage or prognostic stage. Multivariate survival analysis showed that tumor TNM stage and age were independent prognostic factors in gallbladder adenocarcinomas. We conclude that gallbladder adenocarcinomas may have high PD-L1 expression and PD1+ TILs. Smaller tumor size and greater amount of stromal CD3+ T cells were found in tumors with PD1+ TILs. In small tumors (3 cm), high stromal CD3+ TILs or high stromal CD8+ TILs were associated with better survival. However, in large tumors (≥3 cm), PD1+ TILs or high stromal CD8+ TILs carried a poorer survival. Our study implied that immune-based therapy including PD1/PD-L1 checkpoint blockade might be useful in gallbladder adenocarcinomas.

Simultaneous positron emission tomography and MRI (PET/MRI) is an emerging technology that offers the benefits of MRI, including excellent soft tissue contrast, lack of ionizing radiation, and functional MRI techniques, with the physiologic information provided by PET. Although most PET/MRI systems are currently installed in tertiary care centers, PET/MRI technology is becoming increasingly widespread. The usefulness of PET/MRI varies by tumor type and organ system and has been shown to have utility in evaluation of primary and secondary hepatic neoplasms. Understanding the appropriate applications, techniques and relevant imaging findings is important for practicing radiologists considering or currently utilizing PET/MR for the evaluation of primary liver neoplasms, including hepatocellular carcinoma (HCC), as well as staging of biliary neoplasms including cholangiocarcinoma and gallbladder cancer, identification of liver metastases, and staging of neuroendocrine tumor.

Background The effect of postsurgical radiotherapy (PSRT) among T1-3 gallbladder cancer (GBC) patients with one to three lymph node metastases remains controversial. The aim of this study was to assess the impact of PSRT on gallbladder cancer-specific survival (GBCSS) in patients with stage IIIB. Methods The data of GBC patients were obtained from the American Surveillance, Epidemiology, and End Results (SEER) Data resources between 2004 and 2015. Then, a 1:1 propensity score matching (PSM) method was performed. GBCSS was compared among all patients. Subgroup analysis was conducted to identify patients who would benefit from PSRT. Results 726 AJCC (8th edition) stage IIIB GBC patients were included. PSRT failed to improve GBCSS (p = 0.168). Male sex, tumor size ≥ 4 cm and absence of chemotherapy were independent negative prognostic factors. No significant survival benefit from PSRT was found in any subgroup. Conclusions PSRT provides no survival benefit for IIIB GBC.

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.

Background: Selective or Routine histology of cholecystectomy specimens for benign gallbladder disease has always been a matter of debate because of the low prevalence and bad prognosis associated with gall bladder carcinoma. The objective of this study is to ascertain whether selective histology can be preferred over Routine histology without any harm. Methods: This systematic review is conducted according to PRISMA’s checklist; relevant articles were searched in the database until September 1 2020 in PubMed, Scopus, Science Direct, and Web of Science databases, manually, with search queries and without date restrictions. Studies included in this systematic review involved patients who underwent cholecystectomy for benign gallbladder disease and were diagnosed with gallbladder carcinoma incidentally either after selective or routine histology of the gallbladder. Results: A total of 24 routine or selective histology recommending studies were selected for the systematic review after following the inclusion and exclusion criteria. These studies comprised 77,213 numbers of patients and 486 numbers of Malignancies. These studies correlate the number of IGBC diagnosed histologically with the number of IGBC’s that were suspected by the surgeons intraoperative by macroscopy. Routine recommending studies show a significant number of IGBC diagnosed histologically as missed by surgeons whereas the selective recommending studies show most of the histologically diagnosed IGBC already suspected by the surgeons intraoperative. When comparing the macroscopic details of the IGBC’s between routine and selective studies, we found that there was significant overlap. Most of the findings missed by the surgeons as suspicious in routine studies were suspected by the surgeons involved in selective histology recommending studies. Thereby, favouring selective histology and emphasizing the need for careful intraoperative macroscopy for suspecting IGBC. Conclusion: Selective Histological examination of cholecystectomy specimens can be preferred if a careful intraoperative macroscopic examination is done and patient risk factors are taken into consideration.

Gallbladder cancer is a malignant tumor with high mortality. Early diagnosis is significance to improve the prognosis of patients. Gallbladder adenoma is recognized as a kind of precancerous disease, for the past few years, contrast-enhanced ultrasound was used in the diagnosis of biliary tumors. This case is about gallbladder papillary adenoma with carcinogenesis. There is rare literature on the contrast-enhanced ultrasound manifestations of this type of disease. We hope that this report can help improve the recognition of contrast-enhanced ultrasound features and improve the accuracy of early diagnosis of gallbladder cancer.