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Background: Gallbladder malignancies, especially gallbladder cancer, are aggressive lesions with a poor prognosis, and correct differentiation from benign lesions is crucial for improved outcomes. Recently, diffusion-weighted imaging (DWI) has demonstrated potential for this aim to evaluate suspicious lesions detected by initial imaging (e.g., ultrasound).The protocol of this review was pre-registered at (https://osf.io/ury4k) PubMed, Web of Science, Embase, and Cochrane Library were searched. The performance of both qualitative (i.e., visual) and quantitative (i.e., apparent diffusion coefficient (ADC)) DWIs was assessed for visualized suspicious lesions detected on preliminary imaging. The added value of combining DWI with conventional magnetic resonance imaging (MRI) for this purpose was also evaluated.After the screening, 27 studies were included. Qualitative analysis showed an area under curve (AUC) of 0.93 (95% confidence interval (CI) = 0.90 to 0.95), while AUC of quantitative analysis was 0.91 (95% CI = 0.89 to 0.94). Adding DWI to conventional MRI protocol added significant values of + 11.27% (95% CI = 0.78% to 21.76%) to sensitivity and + 9.64% (95% CI = 3.90% to 15.39%) to specificity for suspicious lesions on preliminary imaging.DWI offers an accurate, noninvasive method for differentiating benign gallbladder lesions from malignant ones after preliminary imaging. While adding the DWI protocol to conventional MRI imaging does not require technical resources, it significantly improves performance.Material and methods: Gallbladder malignancies, especially gallbladder cancer, are aggressive lesions with a poor prognosis, and correct differentiation from benign lesions is crucial for improved outcomes. Recently, diffusion-weighted imaging (DWI) has demonstrated potential for this aim to evaluate suspicious lesions detected by initial imaging (e.g., ultrasound).The protocol of this review was pre-registered at (https://osf.io/ury4k) PubMed, Web of Science, Embase, and Cochrane Library were searched. The performance of both qualitative (i.e., visual) and quantitative (i.e., apparent diffusion coefficient (ADC)) DWIs was assessed for visualized suspicious lesions detected on preliminary imaging. The added value of combining DWI with conventional magnetic resonance imaging (MRI) for this purpose was also evaluated.After the screening, 27 studies were included. Qualitative analysis showed an area under curve (AUC) of 0.93 (95% confidence interval (CI) = 0.90 to 0.95), while AUC of quantitative analysis was 0.91 (95% CI = 0.89 to 0.94). Adding DWI to conventional MRI protocol added significant values of + 11.27% (95% CI = 0.78% to 21.76%) to sensitivity and + 9.64% (95% CI = 3.90% to 15.39%) to specificity for suspicious lesions on preliminary imaging.DWI offers an accurate, noninvasive method for differentiating benign gallbladder lesions from malignant ones after preliminary imaging. While adding the DWI protocol to conventional MRI imaging does not require technical resources, it significantly improves performance.Results: Gallbladder malignancies, especially gallbladder cancer, are aggressive lesions with a poor prognosis, and correct differentiation from benign lesions is crucial for improved outcomes. Recently, diffusion-weighted imaging (DWI) has demonstrated potential for this aim to evaluate suspicious lesions detected by initial imaging (e.g., ultrasound).The protocol of this review was pre-registered at (https://osf.io/ury4k) PubMed, Web of Science, Embase, and Cochrane Library were searched. The performance of both qualitative (i.e., visual) and quantitative (i.e., apparent diffusion coefficient (ADC)) DWIs was assessed for visualized suspicious lesions detected on preliminary imaging. The added value of combining DWI with conventional magnetic resonance imaging (MRI) for this purpose was also evaluated.After the screening, 27 studies were included. Qualitative analysis showed an area under curve (AUC) of 0.93 (95% confidence interval (CI) = 0.90 to 0.95), while AUC of quantitative analysis was 0.91 (95% CI = 0.89 to 0.94). Adding DWI to conventional MRI protocol added significant values of + 11.27% (95% CI = 0.78% to 21.76%) to sensitivity and + 9.64% (95% CI = 3.90% to 15.39%) to specificity for suspicious lesions on preliminary imaging.DWI offers an accurate, noninvasive method for differentiating benign gallbladder lesions from malignant ones after preliminary imaging. While adding the DWI protocol to conventional MRI imaging does not require technical resources, it significantly improves performance.Conclusion: Gallbladder malignancies, especially gallbladder cancer, are aggressive lesions with a poor prognosis, and correct differentiation from benign lesions is crucial for improved outcomes. Recently, diffusion-weighted imaging (DWI) has demonstrated potential for this aim to evaluate suspicious lesions detected by initial imaging (e.g., ultrasound).The protocol of this review was pre-registered at (https://osf.io/ury4k) PubMed, Web of Science, Embase, and Cochrane Library were searched. The performance of both qualitative (i.e., visual) and quantitative (i.e., apparent diffusion coefficient (ADC)) DWIs was assessed for visualized suspicious lesions detected on preliminary imaging. The added value of combining DWI with conventional magnetic resonance imaging (MRI) for this purpose was also evaluated.After the screening, 27 studies were included. Qualitative analysis showed an area under curve (AUC) of 0.93 (95% confidence interval (CI) = 0.90 to 0.95), while AUC of quantitative analysis was 0.91 (95% CI = 0.89 to 0.94). Adding DWI to conventional MRI protocol added significant values of + 11.27% (95% CI = 0.78% to 21.76%) to sensitivity and + 9.64% (95% CI = 3.90% to 15.39%) to specificity for suspicious lesions on preliminary imaging.DWI offers an accurate, noninvasive method for differentiating benign gallbladder lesions from malignant ones after preliminary imaging. While adding the DWI protocol to conventional MRI imaging does not require technical resources, it significantly improves performance. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC) represents a wide geographical diversity as well as heterogeneity in clinical and genomic landscape. There seems to be little progress in the development of diagnostic biomarkers, targeted therapies or individualized approaches to GBC management. In this study, we investigated the whole transcriptome profile of GBC patients using RNA sequencing and identified key genes and pathways associated with gallbladder cancer using bioinformatics. Methodology: A total of 10 cases of GBC were collected and sequenced. The raw reads of the gallbladder sample was compared with the gallbladder normal control (SRA Database ID: ERX288537: HPA RNA-seq normal tissues gallbladder). Using Gene ontology analysis the differentially expressed genes were categorized into the biological pathway, cellular component, and molecular function. Pathway enrichment analyses, protein-protein interaction, transcription factor and miRNA interaction that regulate the expression of hub genes were conducted using bioinformatics tool. Results: A total of 954 differentially expressed mRNA transcripts were identified, including overexpression of REG4, TMEM238, S100A2, LYPD2, and KRT17, as well as underexpressed genes like CCKAR, IGSF10, CHRM2, CRISP3, and FGF19. Enrichment analysis showed the metabolic pathways to be the top five cancer pathways in gallbladder carcinogenesis besides PI3k-Akt signalling pathway, cAMP signalling pathway, miRNAs in cancer, and cell adhesion profile of GBC. Conclusions: CCKAR, CDKN2A and LRRK2 were found to be most involved genes in its progression and development through different regulatory pathways. Further, most of the genes were significantly involved in PI3k-Akt, Wnt and hedgehog signaling pathways which have a key role in gallbladder cancer development. [ABSTRACT FROM AUTHOR]

Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM AC ( P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) involves interplay of sex steroids, including estrogen and progesterone. Since CYP17 is a key enzyme involved in estrogen and testosterone hormone biosynthesis as well as in xenobiotic metabolism, it may be a potential candidate gene in the carcinogenesis of the gallbladder. Hence, the present study aimed to investigate the association of CYP17 (rs2486758, and rs743572) polymorphisms with GBC susceptibility. The present study included a total of 414 histologically confirmed GBC and 230 healthy controls. The CYP17 (rs2486758 and rs743572) polymorphisms were genotyped by TaqMan-Allele discrimination assays. Statistical analysis was performed by using SPSS ver. 16. Overall, both the CYP17 SNPs did not indicate any association with GBC risk at genotype, haplotype, or at the genotypic interaction levels. However, in the case-only analysis, CYP rs743572 showed association with increased risk of GBC in tobacco users at hetero genotype and dominant models, as compared to non-user GBC patients. The TC-AG genotypic combination was also associated with increased GBC susceptibility in tobacco users. CYP17 rs743572 is associated with increased risk of GBC in tobacco users in the North Indian population. However, the study requires confirmation in other populations. [ABSTRACT FROM AUTHOR]

Purpose: Gallbladder cancer (GBC), the most common gastrointestinal and biliary tract malignancy, often coincides with gallstone disease (GSD). The genetic variants of adrenergic receptor (ADR) have been previously reported to be associated with hypomotility disorder of cardiovascular system and GSD. Since GSD may function as GBC precursor, the present study aimed to investigate the association of common functional genetic variants of ADRA2A C-1291G, ADRβ3 T190C or Trp64Arg, and ADRβ1 C1165G or Arg389Gly with GBC and GSD susceptibility. Methods: The present study included a total of 400 histologically confirmed GBC, 230 GSD, and 268 healthy controls. The ADRA2A C-1291G, ADRβ3 T190C, and ADRβ1 C1165G polymorphisms were determined by PCR-RFLP. Statistical analysis was performed by using SPSS version 16. Results: ADRβ3 T190C polymorphism was significantly associated with increased risk of GBC (CT: Pcorr = 0.015, OR 2.87; CC: Pcorr = 0.038, OR 10.33; C allele: Pcorr = 0.014, OR 2.7; CT + CC: Pcorr = 0.017, OR 3.05). These associations existed even after gallstone and gender stratification. Similarly, ADRβ3 T190C polymorphism was also associated with GSD risk, though limited only to female GSD patients. In contrary, ADRA2A C-1291G conferred a marginally increased risk only in GSD patients. ADRβ1 C1165G polymorphism was not associated with GBC and GSD susceptibility when compared to controls. Conclusion: ADRβ3 T190C polymorphism is significantly associated with GBC and GSD susceptibility. The ADRβ3 T190C may be involved in the pathophysiology of GBC by both gallstone-dependent pathway and by some other independent mechanisms. [ABSTRACT FROM AUTHOR]

CD44 is an important marker for cancer stem cells. Germline variants in CD44 gene have been associated with susceptibility to breast and nasopharyngeal carcinomas but no study in gallbladder cancer (GBC) has been done yet. The present study included 405 GBC patients and 200 healthy controls from North India. Tagger SNPs for CD44 were selected from the GIH population data. Genotyping was carried out by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSS. Bonferroni correction was applied in subgroup analysis. Logistic regression analysis showed no individual association of CD44 polymorphisms with GBC risk. However, [CCAT] haplotype was associated with overall reduced risk of GBC [ P = 0.04, odds ratios (OR) = 0.47]. Gender stratification revealed that [CCAT] and [TAGT] haplotypes were significantly associated with decreased risk in female GBC patients [ P = 0.022, OR = 0.38; P = 0.011, OR = 0.17, respectively]. The CAAT haplotype was marginally associated with low GBC risk in patients with co-existing gallstones [ P = 0.026, OR = 0.53]. The cancer risk was not further modified with tobacco usage or age of onset. In silico analysis showed change in transcriptional regulation of selected SNPs. This study reports an important role of CD44 haplotypes with reduced risk of GBC. [ABSTRACT FROM AUTHOR]

Aim: Carcinoma of gallbladder (GBC) is a relatively rare but highly fatal disease. The DNA (cytosine-5-)-methyltransferase 3 beta ( DNMT3B) −579 G>T promoter polymorphism (rs1569686) influences gene function and has been associated with various malignancies. Present population-based case-control study was undertaken to examine the potential association of DNMT3B −579 G>T variation with GBC in North Indian population. Methods: Genotypes and allelic frequencies of the DNMT3B −579 G>T polymorphism were determined for 212 GBC patients and 219 controls using PCR-RFLP. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of DNMT3B polymorphism with GBC. Analysis of potential transcription factor binding sites was also identified in the region harboring the polymorphism. Results: The DNMT3B −579 G>T polymorphism was found to be non-significantly associated with an overall increased risk of GBC (OR = 1.10 and 1.56 for T/G and G/G genotypes, respectively, P = 0.227). The increased risk was predominant in both male and female cohorts and also non-significantly in GBC patients with gallstone status (OR = 1.44; P = 0.280, OR = 1.06; P = 0.804 and OR = 1.45; P = 0.143, respectively). Conclusion: DNMT3B −579 G>T polymorphism may alter susceptibility to GBC although it may not play a major role in the pathoetiology of this disease in North Indian population. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, non-coding RNA molecules that function as negative regulators of gene expression. Common genetic variants (single nucleotide polymorphisms, SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences. Present case–control study evaluated the potential association of three SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs with gallbladder cancer (GBC) risk in 230 GBC cases and 230 controls in a North Indian population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of individual SNPs and their interactions with GBC. A non-significant increased risk was observed between carriers of variant genotypes of rs2910164, rs11614913 and rs3746444 (ORs=1.3, 1.3 and 1.1, respectively). This increased risk was more profound in GBC patients with gallstones (ORs=1.4, 1.6 and 1.1, respectively). To further evaluate the cumulative effects of the variant allele, we did a combined unfavorable genotype analysis, which showed a borderline statistical significance. In comparison with the low-risk group (0–2 variant alleles), the high-risk group (>2 variant alleles) had a 1.7-fold (95% CI=1.0–2.8) increased risk for GBC (Ptrend=0.056). These findings suggest, for the first time, that common miRNA variants may not contribute to GBC susceptibility in North Indian population. [ABSTRACT FROM AUTHOR]