Early Diagnosis Of Gallbladder Cancer Research Articles

Early Diagnosis of Gall Bladder Cancer: An Appeal

A team of gastroenterologists, oncologists, pathologists, radiologists, and surgeons from a university teaching hospital in western India make an appeal, through the Journal, to the statutory bodies and the scientific societies related to surgery, oncology, gastroenterology, radiology, and pathology for considering measures, which, if implemented, can help in early diagnosis of gallbladder cancer, the most common nongender organ cancer in women in some parts of India.

Comparison between early gall bladder cancer and advanced gall bladder cancer in terms of clinicopathologic factors: large volume tertiary center experience

Background: Early diagnosis of gallbladder cancer (GBC) which enables to surgical resection is key for improve prognosis. Aim of this study was to investigate clinical features of early GBC patients compare to advanced ones.Methods: We retrospectively reviewed medical records of all pathologically confirmed primary GBC patients between in single tertiary referral center.Results: 250 patients (57.3%) were early GBC (stage I and II) and 186 (42.7%) were advanced GBC (stage III and IV). Less patients with early GBC had symptom at initial diagnosis (69.2% versus 90.8%, p<0.001). Large number of patients with early GBC were diagnosed GBC incidentally after surgical resection which initially suspected benign gallbladder polyp or symptomatic gallbladder stones (71/250, 28.4% versus 7/186, 3.8%) (p<0.001). Patients who initially diagnosed gallbladder stone or cholecystitis tended to more advanced than gallbladder polyp.Conclusions: There were no definitive symptoms which can detect early GBCs. Large number of early GBCs were diagnosed incidentally and many of these initially diagnosed with or accompany with benign cholecystic disease. Careful examination should be performed before diagnosis and after treatment, even in patient with vague symptom or benign cholecystic disease without elevated tumor markers.

Epigenome-Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer.

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. 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. 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.

Risk factors for the onset of gallbladder cancer: a review

Gallbladder cancer (GBC) is the most common malignancy of the biliary system in clinic, which has the characteristics of insidious onset and high degree of malignancy. Most patients have progressed to an advanced stage when they are diagnosed. Early identification of risk factors of the onset of gallbladder cancer and active intervention are the key to improve the rate of early diagnosis and prognosis of gallbladder cancer. At present, the risk factors related to the onset of gallbladder cancer include gallstone, gallbladder polyps, primary sclerosing cholangitis, etc. In this review, we discuss the relevant latest research on the risk factors of the onset of gallbladder cancer in order to provide clinical evidence for the prevention and early diagnosis of gallbladder cancer. The intervention, follow-up, and monitoring of risk factors should be strengthened, and the possibility of malignancy of the gallbladder should be accurately assessed in combination with factors such as age and sex. In the case of possible malignancy, prophylactic cholecystectomy should be actively performed.

C24-Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5-Phosphate 4-Kinase Type-2 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation.

The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated. In the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) of de novo ceramide biosynthesis and length-specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24-Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24-Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C24 -Ceramide promoted GBC cell proliferation and migration in vitro and in vivo. Mechanistically, C24-Ceramide directly bound to phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6-Ceramide, an analogue of natural ceramide, competed with C24-Ceramide for PIP4K2C binding, thereby abrogating C24-Ceramide-mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6-Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells in vitro and in vivo, which was dependent on PIP4K2C. Our findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24-Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6-Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24-Ceramide.

Evaluation of platelet distribution width as novel biomarker in gall bladder cancer.

INTRODUCTION:Gall bladder cancer (GBC) tends to present in advanced stages, therefore, early diagnosis of GBC is necessary. There is no ideal single tumor marker available presently for the diagnosis and prognosis of GBC. Platelet distribution width (PDW) is an early marker for activated platelets and has been used in a variety of tumors to assess prognosis. This study was designed to evaluate the utility of PDW in identifying GBC patients and its association with tumor markers, staging and resectability of GBC.MATERIALS AND METHODS:This cross sectional study was done on 100 patients of GBC and 100 age- and sex- matched healthy controls. PDW was evaluated and compared between GBC and healthy controls. Receiver-operating characteristics was plotted to determine optimal cut-off for identifying GBC patients and to determine sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PDW. Correlation between serum tumor markers (carbohydrate antigen 19-9, carcinoembryonic antigen, and carbohydrate antigen 125) and PDW were evaluated. Association of PDW with hyperbilirubinemia, staging and resectability of GBC was also studied.RESULTS:A significantly higher PDW with a median of 18.1 was observed in GBC as compared to healthy controls with median value of 13. PDW was found to have a very high sensitivity (90%), specificity (95%), PPV (94%) and NPV (90%) in identifying GBC at cut-off of 16 with area under the curve (AUC) of 0.97. An increase of PDW was observed with increasing stage and unresectable GBC. However, it was not statistically significant. Significant positive correlation was observed between PDW and all three serum tumor markers and good positive correlation with r = 0.61 was observed with CA 19-9.CONCLUSION:PDW was associated with GBC and may be considered as a cost- effective marker in adjunct to other investigations for the diagnosis of GBC.

An In silico method to study structure, function, and regulatory role alteration mediated by single-nucleotide polymorphisms in gallbladder cancer

Introduction: Gallbladder cancer (GBC) is a fatal malignancy of gallbladder and bile ductswhich shows delayed symptoms and sometimes can be asymptomatic, being fatal. Reported globally, for a very low survival rate, it suffers from the lack of early diagnostic and prognostic markers. Single nucleotide polymorphisms (SNPs) have been reported to be associated in different cancers. Methods: In this study using in silico methods, we report for the first time a combination of SNPs from the coding and noncoding region leading to alteration in GBC. Different pipelines were designed for the study of SNPs. Regulatory role alteration of Synonymous and non-coding SNPs were studied using RegulomeDB, DeepSEA analysis and funcPred. Structural alteration and energy parameters for non-synonymous SNPs were studied by Swiss-PDB, Chimera and Gromacs. Protein stability analysis was done using MutPred, mCSM and I-mutant. Results: As a result, three potential variants from the coding region rs1042838, rs11887534, and rs700519 associated with progesterone receptor, ATP binding cassette subfamily G member 8 (ABCG8), and cytochrome P450 19A1, respectively, were predicted to be potentially damaging SNPs in GBC leading to structure and function alteration. Three noncoding SNPs (rs2978974, rs4633 and rs2830) and 1 missense SNP(rs523349) were shown to be associated with damaging effect in GBC, and one of these SNPs (rs2978974) showed significant chromatin feature alteration. Conclusion: Our study strongly shows that SNPs both in the coding and noncoding region may be exploited as a combination of potential biomarkers in early diagnosis of GBC due to structure function alteration by nonsynonymous SNPs and regulatory role alteration by noncoding SNPs.

Individualized nomogram improves diagnostic accuracy of stage I-II gallbladder cancer in chronic cholecystitis patients with gallbladder wall thickening

Early diagnosis of gallbladder cancer (GBC) can remarkably improve the prognosis of patients. This study aimed to develop a nomogram for individualized diagnosis of stage I-II GBC in chronic cholecystitis patients with gallbladder wall thickening. The nomogram was developed using logistic regression analyses based on a retrospective cohort consisting of 89 consecutive patients with stage I-II GBC and 1240 patients with gallbladder wall thickening treated at one biliary surgery center in Shanghai between January 2009 and December 2011. The accuracy of the nomogram was validated by discrimination, calibration and a prospective cohort treated at another center between January 2012 and December 2014 (n=928). Factors included in the nomogram were advanced age, hazardous alcohol consumption, long-standing diagnosed gallstones, atrophic gallbladder, gallbladder wall calcification, intraluminal polypoid lesion, higher wall thickness ratio and mucosal line disruption. The nomogram had concordance indices of 0.889 and 0.856 for the two cohorts, respectively. Internal and external calibration curves fitted well. The area under the receiver-operating characteristic curves of the nomogram was higher than that of multidetector row computed tomography in diagnosis of stage I-II GBC (P<0.001). The proposed nomogram improves individualized diagnosis of stage I-II GBC in chronic cholecystitis patients with gallbladder wall thickening, especially for those the imaging features alone do not allow to confirm the diagnosis.

PTU-084 Incidental gallbladder cancer after laparoscopic cholecystectomy: treatment and surveillance policies in the UK: result of a survey

IntroductionIncreasingly diagnosis of early gallbladder cancer (GBC) is incidentally made after laparoscopic cholecystectomy (LC). T stage correlates with nodal metastases and potential for residual disease. Although there is no controversy...

Proteomic-based analysis for identification of potential serum biomarkers in gallbladder cancer

Gallbladder cancer is the most common malignant tumor of the biliary tract. Early diagnosis of gallbladder cancer is difficult because of the latent onset and lack of good biomarkers. To identify new biomarkers that improve the early diagnosis and/or serve as possible therapeutic targets in gallbladder cancer is essential. In the present study, serum proteins were separated by two-dimensional gel electrophoresis (2-DE) in 3 patients with gallbladder cancer and 3 healthy volunteers. The differentially expressed spots were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Western blotting and immunohistochemistry were performed to verify the expression of certain candidate proteins. Protein expression and clinical correlation was evaluated. We found that 64 protein spots were significantly changed in gallbladder cancer. Twenty-four proteins including S100A10, haptoglobin, cystatin-B, profilin-1 and superoxide dismutase were successfully identified. Among these proteins, S100A10 and haptoglobin were validated using Western blotting. Immunohistochemically, the expression of S100A10 and haptoglobin proteins was found to be higher in gallbladder cancer tissues compared to that in gallbladder adenoma, liver cholangiocarcinoma and cholecystitis tissue. Patients with high expression of S100A10 and haptoglobin were linked to late stage disease and poor clinical prognosis. Our data suggest that combined comparative proteomic analysis by 2-DE and MALDI-TOF-MS is an effective method for identifying differentially expressed proteins in serum samples. These proteomic approaches could be used for identifying new serum biomarkers in gallbladder cancer. S100A10, haptoglobin and other identified proteins may be potential molecular targets for early gallbladder cancer diagnostics and therapeutic applications.

Screening for the differentially expressed proteins in human gallbladder cancer by two-dimensional gel electrophoresis and mass spectrometry and functional exploration of AnnexinA3

Objective To find potential molecular targets for gallbladder cancer diagnostics by analyzing and comparing the proteomes expressed in human gallbladder carcinoma and benign gallbladder tissues, and investigate whether annexinA3 down-regulation by miRNA leads to inhibition of proliferation and arrest of cell cycle in human gallbladder cancer cell line SGC-996. Methods The proteins expressed in these tissues were analyzed by the two-dimensional gel electrophoresis. Proteins expressed differently of a 2-fold change were cut and analyzed by MALDI-TOF/TOF mass spectrometry. After miRNA expression plasmid targeting to annexinA3 gene was constructed and transfected into cancer cells, the methyl thiazolyl tetrazolium ( MTT) assay was performed for measuring cell proliferation and flow cytometic analysis for cell cycle. Results Protein extracts of individual sample in each type of tissues were separated on two-dimensional gels. There were 46 differentially expressed proteins in the tissues of gallbladder cancer. Seventeen proteins were successfully identified by MS, in which 9 proteins were overexpressed in tumors and the rest 8 proteins were underexpressed, including Annexi-nA3, TTR protein, etc. After interfering annexinA3 in gallbladder cancer SGC-996 cell line, the cell proliferation was suppressed. Flow cytometry revealed that after interfering annexinA3 in gallbladder cancer SGC-996 cell line, the cells in G1 phase were increased, while those in S phase were declined as compared with control group (P<0.05). Conclusion Significant discrepancies in protein expression exist between gallbladder cancer tissues and benign gallbladder tissues. Some of the differentially expressed proteins found by the proteomic approach may be potential molecular targets for early diagnosis of gallbladder cancer. miRNA interfering to annexi-nA3 effectively reverses some of the malignant biological characters of gallbladder cancer cells. Key words: Carcinoma of gallbladder; Proteomic; Tumor markers; AnnexinA3; RNA interference

Long‐term follow up of gallbladder polyps

The management of gallbladder polyps (GBP) is directly linked to the early diagnosis of gallbladder cancer (GBC). This study aimed to evaluate the malignant risk of GBP. In total, 1558 patients diagnosed with GBP were followed. Neoplastic polyps were defined as GBC and its premalignant lesions. The risk for malignancy was estimated with the cumulative detection rate of neoplastic polyps. Thirty-three cases (2.1%) were diagnosed with neoplastic polyps. The cumulative detection rates of neoplastic polyps were 1.7% at 1 year, 2.8% at 5 years, and 4% at 8 years after diagnosis. The size of GBP and the presence of gallstones were risk factors for neoplastic polyps. Polyps > or = 10 mm had a 24.2 times greater risk of malignancy than polyps < 10 mm. However, 15 of 33 neoplastic polyps (45.5%) were < 10 mm at the time of diagnosis of GBP. During follow up in 36 (3.5%) of 1027 cases, an increase in size was detected; of these, nine (25%) had neoplastic polyps. Even small polyps have a risk of malignancy, and careful long-term follow up of GBP will help detect and treat early GBC.

Diagnosis of biliary tract and ampullary carcinomas

Diagnostic methods for biliary tract carcinoma and the efficacy of these methods are discussed. Neither definite methods for early diagnosis nor specific markers are available in this disease. When this disease is suspected on the basis of clinical symptoms and risk factors, hemato-biochemical examination and abdominal ultrasonography are performed and, where appropriate, enhanced computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP) is carried out. Diagnoses of extrahepatic bile duct cancer and ampullary carcinoma are often made based on the presence of obstructive jaundice. Although rare, abdominal pain and pyrexia, as well as abnormal findings of the hepatobiliary system detected by hemato-biochemical examination, serve as a clue to making a diagnosis of these diseases. On the other hand, the early diagnosis of gallbladder cancer is scarcely possible on the basis of clinical symptoms, so when this cancer is found with the onset of abdominal pain and jaundice, it is already advanced at the time of detection, thus making a cure difficult. When gallbladder cancer is suspected, enhanced CT is carried out. Multidetector computed tomography (MDCT), in particular — one of the methods of enhanced CT — is useful for decision of surgical criteria, because MDCT shows findings such as localization and extension of the tumor, and the presence or absence of remote metastasis. Procedures such as magnetic resonance imaging, endoscopic ultrasonography, bile duct biopsy, and cholangioscopy should be carried out taking into account indications for these procedures in individual patients. However, direct biliary tract imaging is necessary for making a precise diagnosis of the horizontal extension of bile duct cancer.

A CASE OF PEDUNCULATED POLYPOID CANCER ASSOCIATED WITH FLAT‐TYPE CANCER OF THE GALLBLADDER

Pedunculated polypoid cancer of the gallbladder ordinarily shows cancer spread within the polyp consisting mainly of adenoma. We experienced a case of pedunculated mucosal cancer associated with flat‐type cancer of the gallbladder without an adenomatous component, the details of which are reported herein. The lesion was first detected by transabdominal ultrasonography (US) as a polypoid lesion of the gallbladder, 5 mm in size. Distinct growth of the lesion was revealed at follow‐up US after a year. Endoscopic ultrasonography showed not only a pedunculated polypoid lesion, 9 mm in size, with a solid internal echo pattern and a nodular surface, but also slight thickening of the surrounding gallbladder wall. Cholecystectomy was performed with a preoperative diagnosis of early gallbladder cancer, and a pedunculated polypoid lesion, 8 × 8 × 3 mm in size with a thin stalk and a nodular contour, surrounded by a widely spreading flat lesion with a coarse‐granular surface, was confirmed. Microscopically, the stalk was 700 µm in size, and both the pedunculated polypoid lesion and flat lesion consisted of well‐differentiated tubular adenocarcinoma limited to the mucosa, without an adenomatous component.

早期胆嚢癌の術前, 術中診断

早期胆嚢癌の術前, 術中診断

A Study for Diagnosis of Early Gallbladder Cancer in Ultrasonographic Mass Survey

A Study for Diagnosis of Early Gallbladder Cancer in Ultrasonographic Mass Survey

A CASE OF CARCINOMA IN ADENOMA OF GALLBLADDER

The diagnosis of early gallbladder cancer is difficult. In addition to the diagnostic difficulty, surgical managements of it are still in controversy.We can have no any established management.A 60-year-old man was admitted to our hospital because of a hematological abnormality detected by medical examination. He had no abdominal abnormality.Hematological examination revealed no abnormal parameters including tumor makers except slightly increased levels of GOT and cholinesterase on admission. A 14×10 mm polyp was found at the neck of the gallbladder by abdominal ultrasonography and drip infusion cholangiography.In consideration of a possible complication of cancer, the gallbladder was excised. Pathological diagnosis established the lesion to be an early gallbladder cancer (carcinoma in adenoma) of depth m. Secondary look lymphadenectomy was not performed postoperatively.The post-operative condition was satisfactory and the patient was discharged 12 days after operation. Oral administration of 600 mg/day of 5 FU is continued and the patient is followed on ambulant basis.Our experience of early gallbladder cancer was presented, and the diagnostic methods, surgical treatment and especially secondary surgical intervention (resection of liver base and lymphadenectomy) following cholecystectomy were discussed with a review of the literature.