Prevalence of gallbladder cancer in cholecystectomized patients in Sulaymaniyah city.

Gallbladder cancers (GBC) are rare, and they are one of lethal neoplasms of biliary system. The diagnosis is either incidentally during histopathological examinations after cholecystectomy or due to complications of local or systemic spread of the malignancy. The incidence differs ethnically and geographically. The aim was to identify increase risk of cancer in the Kurdistan region by searching for the number of GBC cases among cholecystectomy patients in Sulaymaniyah governorate. This study is laboratory-based retrospective study, including data obtained from 8315 cholecystectomized patients in Sulaymaniyah governorate from 2017- 2021. The information within the questionnaire included: age, sex, clinical notes and histopathological findings; including GBC. The total of 8315 cases; were 2149 males (25.8%) and 6166 females (74.2%). The mean age was (44.67+/-15.18) years. Forty-five cases have been reported as adenocarcinoma of GB and one case of Carcinosarcoma. Among the patients, 875 cases (10.50%) had acute cholecystitis. A significant relationship was found between the findings and the age and gender of the patients. GBC is not common and is mainly diagnosed incidentally after routine post-operative histopathological examination, and mainly affects old ages.

Late port-site metastasis of unexpected gallbladder carcinoma after laparoscopic cholecystectomy: A case report.

INTRODUCTION: Incidental gallbladder carcinoma refers to a discovery of gallbladder cancer during or after cholecystectomy. Late port-site metastasis (PSM) following Laparoscopic cholecystectomy (LC) is rare with an incidence rate of 10.3%. PATIENT CONCERNS: We report a case of a 58-year-old man who presented with a painful abdominal wall mass for 6 weeks. He had a history of LC for symptomatic cholelithiasis, 8 years prior. DIAGNOSIS: Histopathological examination revealed a positive result for metastatic adenocarcinoma from the abdominal wall mass. Moreover, Positron emission tomography (PET) showed a small focus of intense fluorodeoxyglucose (FDG) uptake in the gallbladder bed, which was highly suspicious for malignancy. INTERVENTION: Decision was to proceed with surgery owing to uptake in the gallbladder bed with single-site metastasis to the previous port site. In addition, in the board meeting, an agreement was reached for performing distal pancreatectomy with splenectomy owing to uncertainty of malignancy based on what was discovered during the full metastatic workup. Diagnostic laparoscopy followed by midline laparotomy performed. Radical completion cholecystectomy with lymphadenectomy was done. Followed by complete resection of the anterior abdominal wall. Distal pancreatectomy and splenectomy were then performed. OUTCOME: Pathological diagnosis showed metastatic/invasive, moderately differentiated adenocarcinoma with positive margins on the posterior surface of excised port-site mass. The positive margins necessitated further chemoradiotherapy, followed by adjuvant chemotherapy until lung metastasis was identified. After this, the patient was scheduled for palliative chemotherapy. CONCLUSION: Presence of PSM is often associated with peritoneal metastasis. For this reason, it is advised to evaluate the patient for possible metastasis.

Contributions of endoscopic ultrasonography-guided tissue acquisition (EUS-TA) to the diagnostics of biliary stricture and gallbladder lesions.

Endoscopic ultrasonography (EUS) provides high spatial resolution and more detailed images than other diagnostic modalities. Furthermore, EUS-guided tissue acquisition (EUS-TA), such as EUS-guided fine needle aspiration or biopsy (EUS-FNA/FNB), is an indispensable tool in pancreaticobiliary disease diagnostics, supporting a conclusive pathological diagnosis. In this review, we evaluate the current status and the usefulness of EUS-TA for the diagnostics of the following biliary tract diseases: (A) biliary stricture diagnostics, (B) biliary tract cancer (BTC) itself, and (C) staging of advanced BTC. Previous reports have shown that EUS-FNA for biliary lesions is a safe procedure that is useful in differentiating biliary cancer from benign lesions and in the staging of BTC. On the other hand, the diagnostic performance of EUS-TA for bile duct lesions is reported to be similar to that of transpapillary biopsy. Overall, EUS-TA for biliary lesions may be a safe and effective method, but it should be performed with an understanding of the risk of serious adverse events such as bile leakage and peritoneal dissemination of cancer. It is recommended for distal biliary stricture lesions for which endoscopic retrograde cholangiopancreatography cannot confirm the diagnosis or gallbladder lesions if they do not require the needle to pass through the biliary lumen.

Insights for clinical management from the real-life data of the centralized West of Scotland biliary cancer clinic.

BACKGROUND: With the increasing of novel therapeutics for the treatment of Biliary Tract Cancers (BTC), and the need to assess their socio-economic impacts for national licence approvals, it is as important as ever to have real-life data in national populations. METHODS AND RESULTS: We performed an audit of the first 2 year-activity (Sep 2019-Sep 2021) of the centralized West-of-Scotland-BTC clinic. 122 patients accessed the service, including 68% with cholangiocarcinoma (CCA), 27% with gallbladder cancer (GBC), and 5% with ampulla of Vater carcinoma with biliary phenotype (AVC). Median age at diagnosis was 66 (28-84), with 30% of newly diagnosed patients being younger than 60 years-old. Thirty-five cases (29%) underwent surgery, followed by adjuvant-chemotherapy in 66%. 60% had recurrent disease (80% with distant relapse). Sixty-four patients (58%) started first-line Systemic-AntiCancer-Treatment (SACT). Of these, 37% received second line SACT, the majority of which had iCCA and GBC. Thirty-% of those who progressed received third line SACT. CONCLUSIONS: About 30% of BTC were eligible for curative surgery. Fifty-eight and twenty% of the overall cohort of advanced BTC patients received first and second line SACT. Our data suggest that reflex genomic profiling may not be cost-effective until molecularly driven strategies are limited to second line setting.

TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer.

Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics.

The aim of this investigation was to evaluate the differential expression of the sterol O-acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC-996, NOZ, and gallbladder cancer (GBC)-SD using Western blot and q-PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC-996 and GBC-SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer.

Prediction of neoplastic gallbladder polyps in patients with different age level based on preoperative ultrasound: a multi-center retrospective real-world study.

BACKGROUND: The prevalence of neoplastic polyps in gallbladder polyps (GPs) increases sharply with age and is associated with gallbladder carcinoma (GBC). This study aims to predict neoplastic polyps and provide appropriate treatment strategies based on preoperative ultrasound features in patients with different age level. METHODS: According to the age classification of WHO, 1523 patients with GPs who underwent cholecystectomy from January 2015 to December 2019 at 11 tertiary hospitals in China were divided into young adults group (n=622), middle-aged group (n=665) and elderly group (n=236). Linear scoring models were established based on independent risk variables screened by the Logistic regression model in different age groups. The area under ROC (AUC) to evaluate the predictive ability of linear scoring models, long- and short- diameter of GPs. RESULTS: Independent risk factors for neoplastic polyps included the number of polyps, polyp size (long diameter), and fundus in the young adults and elderly groups, while the number of polyps, polyp size (long diameter), and polyp size (short diameter) in the middle-aged groups. In different age groups, the AUCs of its linear scoring model were higher than the AUCs of the long- and short- diameter of GPs for differentiating neoplastic and non-neoplastic polyps (all P<0.05), and Hosmer-Lemeshow goodness of fit test showed that the prediction accuracy of the linear scoring models was higher than the long- and short- diameter of GPs (all P>0.05). CONCLUSION: The linear scoring models of the young adults, middle-aged and elderly groups can effectively distinguish neoplastic polyps from non-neoplastic polyps based on preoperative ultrasound features.

Pathologic significance of peribiliary capillary plexus in gallbladder neoplasm.

AIMS: Significance of peribiliary capillary plexus (PCP) in gallbladder neoplasms remains unclear. Aims are to characterize high-grade biliary intraepithelial neoplasm (BilIN), pyloric gland adenoma (PGA), and intracholecystic papillary neoplasm (ICPN), precursors of gallbladder carcinoma, and to differentiate invasive carcinoma from pseudo-invasive lesions in gallbladder walls, referring to PCP. MATERIALS AND METHODS: High-grade BilIN (38 cases), PGA (5 cases), and ICPN (25 cases) were examined using capillary immunostaining. Non-neoplastic gallbladders were used as controls. RESULTS: In non-neoplastic gallbladders, a single layer of regularly dotted capillaries (PCP) was located beneath lining epithelia and around non-neoplastic glands (NNGs), including Rokitansky-Aschoff sinus (RAS), presenting a two-layer of lining epithelia and PCP. Intra-luminal components of all cases of high-grade BilIN and PGA and one-third of ICPNs presented a two-layer pattern. In the remaining ICPNs, capillaries were irregular and sparse in intraluminal neoplastic components presenting irregular and complicated lesions. Neoplastic glands in gallbladder walls of high-grade BilIN and ICPN were classifiable into 2 types: glands that were underlain by densely dotted capillaries and those that were not, with the latter suggestive of invasive carcinoma, while the former suggestive of non-invasive neoplasms involving NNGs intraepithelially and/or showing an expanding growth into gallbladder wall (pseudo-invasion). CONCLUSION: A two-layer pattern of lining epithelia and underlining capillaries were preserved in all cases of high-grade BilIN and PGA and one-third of ICPN cases. Presence or absence of dotted capillaries around neoplastic glands may be able to be added as a new pathologic feature to differentiate invasive carcinomas from pseudo-invasion in gallbladder wall.

YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis.

Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells in vitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model in vivo. In vitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA.

SMARCA4-Deficient Poorly Differentiated Adenocarcinoma of the Gallbladder.

ABSTRACT: A 64-year-old woman presented with chest pain while eating and was referred to our hospital. Physical examination revealed abdominal distension, tenderness, and lower-extremity edema. Imaging revealed a large gallbladder tumor infiltrating the liver, with ascites and pleural effusion. A biopsy confirmed a poorly differentiated adenocarcinoma with SMARCA4 deficiency (cT3N2M1, cStage IV). Chemotherapy was ineffective and led to tumor progression. The patient died 9 months later. Recently, attention has been paid to SMARCA4 deficiency, which is a genetic mutation found in tumors. Here, we report on poorly differentiated adenocarcinomas of the gallbladder based on imaging findings, including FDG PET.

Decoding the role of long non-coding RNAs in gallbladder cancer pathogenesis: A review focus on signaling pathways interplay.

Gallbladder cancer (GBC) is one of the most aggressive types of biliary tree cancers and the commonest despite its rarity. It is infrequently diagnosed at an early stage, further contributing to its poor prognosis and low survival rate. The lethal nature of the disease has underlined a crucial need to discern the underlying mechanisms of GBC carcinogenesis which are still largely unknown. However, with the continual evolution in the research of cancer biology and molecular genetics, studies have found that non-coding RNAs (ncRNAs) play an active role in the molecular pathophysiology of GBC development. Dysregulated long non-coding RNAs (lncRNAs) and their interaction with intracellular signaling pathways contribute to malignancy and disease development. LncRNAs, a subclass of ncRNAs with over 200 nucleotides, regulate gene expression at transcriptional, translational, and post-translational levels and especially as epigenetic modulators. Thus, their expression abnormalities have been linked to malignancy and therapeutic resistance. lnsRNAs have also been found in GBC patients' serum and tumor tissue biopsies, highlighting their potential as novel biomarkers and for targeted therapy. This review will examine the growing involvement of lncRNAs in GBC pathophysiology, including related signaling pathways and their wider clinical use.

[Can laparoscopic surgery be the preferred strategy for gallbladder cancer?]

Gallbladder cancer, notoriously known for its high malignancy, predominantly requires radical surgery as the treatment of choice. Although laparoscopic techniques have become increasingly prevalent in abdominal surgeries in recent years, the progress of laparoscopic techniques in gallbladder cancer is relatively slow. Due to the anatomical complexity, technical difficulty, and biological features of gallbladder cancer that is prone to metastasis and dissemination, traditional open surgery is still the main surgical approach. This study aims to reappraisal the current state of laparoscopic surgery for gallbladder cancer by appraising clinical practice and research evidence. Laparoscopic surgery for various stages of gallbladder cancer, including early, advanced, incidental, and unresectable gallbladder cancer were discussed. The promise and limitations of laparoscopic techniques are systematically explored.

[Progress and controversy in minimally invasive approach to radical cholecystectomy for gallbladder cancer].

Surgical treatment is one of the most important forms of treatment in patients with gallbladder cancer. With the development of minimally invasive technology, the feasibility, safety and efficacy of minimally invasive approaches such as laparoscopic or robotic-assisted radical cholecystectomy for gallbladder cancer have received continuous attention.For patients with an early T-stage (Tis or T1a), laparoscopic simple cholecystectomy is safe and economical, with a good prognosis for postoperative patients, and it has been widely accepted and performed. Radical resection of advanced gallbladder cancer requires resection of the gallbladder, its liver bed, and other neighboring invaded organs, as well as clearance of regional lymph nodes, which requires experienced gallbladder cancer treatment teams to strictly grasp the indications, select appropriate patients, and formulate a good surgical strategy to ensure the therapeutic effect. Meanwhile, robot-assisted radical resection for gallbladder cancer has been performed in a few centers and shows good clinical potential, but more high-quality studies are needed to further evaluate its value in gallbladder cancer treatment.

Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality.

Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal-organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.

Risk prediction and analysis of gallbladder polyps with deep neural network.

The aim of this study is to analyze the risk factors associated with the development of adenomatous and malignant polyps in the gallbladder. Adenomatous polyps of the gallbladder are considered precancerous and have a high likelihood of progressing into malignancy. Preoperatively, distinguishing between benign gallbladder polyps, adenomatous polyps, and malignant polyps is challenging. Therefore, the objective is to develop a neural network model that utilizes these risk factors to accurately predict the nature of polyps. This predictive model can be employed to differentiate the nature of polyps before surgery, enhancing diagnostic accuracy. A retrospective study was done on patients who had cholecystectomy surgeries at the Department of Hepatobiliary Surgery of the Second People's Hospital of Shenzhen between January 2017 and December 2022. The patients' clinical characteristics, lab results, and ultrasonographic indices were examined. Using risk variables for the growth of adenomatous and malignant polyps in the gallbladder, a neural network model for predicting the kind of polyps will be created. A normalized confusion matrix, PR, and ROC curve were used to evaluate the performance of the model. In this comprehensive study, we meticulously analyzed a total of 287 cases of benign gallbladder polyps, 15 cases of adenomatous polyps, and 27 cases of malignant polyps. The data analysis revealed several significant findings. Specifically, hepatitis B core antibody (95% CI -0.237 to 0.061, p < 0.001), number of polyps (95% CI -0.214 to -0.052, p = 0.001), polyp size (95% CI 0.038 to 0.051, p < 0.001), wall thickness (95% CI 0.042 to 0.081, p < 0.001), and gallbladder size (95% CI 0.185 to 0.367, p < 0.001) emerged as independent predictors for gallbladder adenomatous polyps and malignant polyps. Based on these significant findings, we developed a predictive classification model for gallbladder polyps, represented as follows, Predictive classification model for GBPs = -0.149 * core antibody - 0.033 * number of polyps + 0.045 * polyp size + 0.061 * wall thickness + 0.276 * gallbladder size - 4.313. To assess the predictive efficiency of the model, we employed precision-recall (PR) and receiver operating characteristic (ROC) curves. The area under the curve (AUC) for the prediction model was 0.945 and 0.930, respectively, indicating excellent predictive capability. We determined that a polyp size of 10 mm served as the optimal cutoff value for diagnosing gallbladder adenoma, with a sensitivity of 81.5% and specificity of 60.0%. For the diagnosis of gallbladder cancer, the sensitivity and specificity were 81.5% and 92.5%, respectively. These findings highlight the potential of our predictive model and provide valuable insights into accurate diagnosis and risk assessment for gallbladder polyps. We identified several risk factors associated with the development of adenomatous and malignant polyps in the gallbladder, including hepatitis B core antibodies, polyp number, polyp size, wall thickness, and gallbladder size. To address the need for accurate prediction, we introduced a novel neural network learning algorithm. This algorithm utilizes the aforementioned risk factors to predict the nature of gallbladder polyps. By accurately identifying the nature of these polyps, our model can assist patients in making informed decisions regarding their treatment and management strategies. This innovative approach aims to improve patient outcomes and enhance the overall effectiveness of care.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Neuroendocrine neoplasms of the gallbladder: A single institute analysis of outcomes and prognostic factors.

INTRODUCTION: Neuroendocrine neoplasms (NENs) are classified as neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine and nonneuroendocrine neoplasms (MiNENs) according to World Health Organization classification. We present our experience of NENs of the gallbladder (GB) from a high-volume cancer hospital. MATERIALS AND METHODS: The present study is a retrospective analysis of all patients with GB NENs who presented between January 2015 and June 2023. The patient details and treatment received with follow-up were noted. The primary endpoint was overall survival (OS). RESULTS: A total of 147 patients were included in the study. The median age was 52 (27-81) years. There was a female predominance (70.7%). NEC was the most common subtype (84.4%) followed by MiNEN (12.9%) and NET (2.7%). The most common stage at presentation was metastatic (70.7%) followed by locally advanced (21.8%), and early disease (7.5%). The median follow-up was 9.92 (1.77-76.06) months. Median OS was 6.14 (3.93-8.35) months. Median OS in patients who received multimodality treatment was 20.20 (17.99-22.41) months versus 4.00 (2.91-5.10) months in those who did not receive it. CONCLUSION: GB NENs are rare, but aggressive tumors with NEC being the most common type. Multimodality treatment yields favorable outcomes. However, the development of better systemic therapy is needed to help improve survival further.