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Gallbladder Cancer

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Latest Research Publications
Gastrointestinal System Cancers

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Utsumi M, Aoki H, Kunitomo T, et al.
Evaluation of surgical treatment for incidental gallbladder carcinoma diagnosed during or after laparoscopic cholecystectomy: single center results.
BMC Res Notes. 2017; 10(1):56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Laparoscopic cholecystectomy (LC) is the accepted standard management for benign gallbladder disease. LC rarely results in a diagnosis of incidental gallbladder carcinoma (IGBC). The aim of our study was to report our experience with IGBC diagnosed during or following LC.
METHODS: Between January 2008 and January 2015, 352 patients underwent LC at Iwakuni Clinical Center. Among these patients, 8 (2.3%) were diagnosed with IGBC. We evaluated their characteristics, surgical related variables, histopathological findings and surgical outcomes.
RESULTS: Patient median age was 71 (range 49-88) years, and 3 out of 8 were female. All patients with IGBC were Japanese. The grade of cancer was as follows: pT1a (3 cases), pT2 (4 cases) and pT3 (1 case). Two patients with pT2 disease underwent radical surgery. The median follow-up time of these patients was 24 (range 11-80) months. All patients are still alive and two of three patients who refused radical surgery have developed recurrence (liver metastases and recurrence in the peritoneum).
CONCLUSIONS: Although the number of cases was small, the results of this study further support the suggestion that gallbladder carcinoma may be curable if diagnosed as IGBC at an early stage. If the cancer has reached an advanced stage, radical surgery should be performed.

Khandelwal A, Malhotra A, Jain M, et al.
The emerging role of long non-coding RNA in gallbladder cancer pathogenesis.
Biochimie. 2017; 132:152-160 [PubMed] Related Publications
Gallbladder cancer (GBC) is the most common and aggressive form of biliary tract carcinoma with an alarmingly low 5-year survival rate. Despite its high mortality rate, the underlying mechanisms of GBC pathogenesis are not completely understood. Recently, from a growing volume of literature, long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and appear to play vital roles in many human cancers. To date, a number of lncRNAs have been implicated in GBC, but their potential roles in GBC have not been systematically examined. Thus, in this review, we critically discuss the emerging roles of lncRNAs in GBC, and the pathways involved. Specifically, we note that some lncRNAs show greater expression in T1 and T2 tumor stages compared to T3 and T4 tumor stages and that their dysregulation leads to alterations in cell cycle progression and can cause an increase in GBC cell proliferation or apoptosis. In addition, some lncRNAs control the epithelial-mesenchymal transition process, while others take part in the regulation of ERK/MAPK and Ras cancer-associated signaling pathways. We also present their potential utility in diagnosis, prognosis, and/or treatment of GBC. The overall goal of this review is to stimulate interest in the role of lncRNAs in GBC, which may open new avenues in the determination of GBC pathogenesis and may lead to the development of new preventive and therapeutic strategies for GBC.

Dhakre VW, Nagral S, Jayesh Nanavati A
Castleman's disease in carcinoma gall bladder.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Castleman's disease (CD) also known as angiofollicular lymph node hyperplasia represents a group of uncommon non-clonal lymphoproliferation. We herein report a case of CD associated with carcinoma of the gall bladder. To the best of our knowledge, it is the first of its kind and has not been reported in the past. The hypothesis regarding the aetiopathogenesis of CD is that it is associated with interleukin-6 surges. This may be explained by the overproduction of IL-6 by tumour cells or IL-6 production due to a long-standing/smouldering localised inflammatory response. An important question raised by this observation is whether the finding of CD has any effect on the outcome of this patient of carcinoma of the gall bladder. Further research is required in this matter.

Kumar R, Srinivasan R, Gupta N, et al.
Spectrum of gallbladder malignancies on fine-needle aspiration cytology: 5 years retrospective single institutional study with emphasis on uncommon variants.
Diagn Cytopathol. 2017; 45(1):36-42 [PubMed] Related Publications
BACKGROUND: Ultrasound-guided fine-needle aspiration cytology (FNAC) is the standard modality for diagnosis of gallbladder malignant neoplasms. Adenocarcinoma is the most common malignancy; however, other types may also be encountered. The aim of this study was to perform a retrospective analysis of gallbladder malignancies diagnosed on FNAC in the last 5 years to document the cytomorphological spectrum and the variations thereof.
METHODS: The records of the Department of Cytology, PGIMER were searched from July 2010 to June 2015 and all cases of gallbladder malignancies were analyzed in detail for cytomorphological characteristics. Giemsa and Hematoxylin-Eosin stained slides were evaluated with immunocytochemistry on cell blocks wherever available.
RESULTS: A total of 791 gallbladder FNAC performed in cases of radiologically suspected gallbladder malignancies were evaluated. Gallbladder carcinoma (GBC) was more common in females with a male to female ratio of 1:2.3. Median age was 53.4 years (range 24-85 years); 81 cases (10.2%) were nondiagnostic and 31 (3.9%) were suspicious of malignancy. A total of 645 FNACs were positive for malignancy, out of which there were 619 (96%) adenocarcinoma and 26 cases with unusual malignancies. These included adenosquamous carcinoma (8, 1.2%), squamous cell carcinoma (7, 1.1%), small cell neuroendocrine carcinoma (9, 1.3%), and one case each of undifferentiated carcinoma and Non Hodgkin lymphoma respectively. The unusual malignancies were confirmed on cell block immunocytochemistry.
CONCLUSION: Adenocarcinoma is most common type of gallbladder malignancy; however, other unusual types of carcinomas occur and in such cases, FNAC supplemented by cell block immunocytochemistry is required for an accurate diagnosis. Diagn. Cytopathol. 2017;45:36-42. © 2016 Wiley Periodicals, Inc.

Hu HJ, Zhou RX, Tan YQ, et al.
Coexisting cancers: a mixture of neuroendocrine carcinoma and adenocarcinoma in the gallbladder: A case report.
Medicine (Baltimore). 2016; 95(44):e5281 [PubMed] Related Publications
BACKGROUND: Neuroendocrine carcinoma is rare with a proportion of less than 2% in gallbladder malignancies, cases of gallbladder neuroendocrine cell carcinoma coexisting with adenocarcinoma are exceptionally rare, and the prognosis is dismal.
METHODS: Herein, we presented an unusual case of poorly differentiated gallbladder neuroendocrine cell carcinoma coexisting with poorly differentiated adenocarcinoma who survived 20 months after the multimodal treatment (MT) of extended surgery and postoperative chemotherapy.
RESULTS: Our result indicated that for advanced gallbladder neuroendocrine cell carcinoma coexisting with adenocarcinoma, MT including extended surgical approach combined with postoperative chemotherapy may contribute to a relatively good survival outcome.
CONCLUSION: MT may contribute to a relatively good survival outcome for advanced gallbladder neuroendocrine cell carcinoma coexisting with gallbladder adenocarcinoma.

Di Carlo I, Toro A
Gallbladder cancer: results achieved and future challenges.
Future Oncol. 2017; 13(3):209-211 [PubMed] Related Publications
26th World Congress of International Association of Surgeons Gastroenterologists and Oncologists, Seoul, South Korea, 8-10 September 2016 This year, the 26th World Congress of the International Association of Surgeons, Gastroenterologists, and Oncologists (IASGO) was hosted by Seoul in South Korea. The congress was extremely well organized, and the quality of the submissions and the relevance of the speakers were excellent. This report highlights the newest and most interesting results regarding the treatment of gallbladder tumors from the conference.

Arcega R, Wu JX, Magaki S, et al.
A hitherto undescribed benign mesenchymal polyp of the gallbladder: edematous angiomyolipoma-like polyp.
Acta Gastroenterol Belg. 2016 Jul-Sep; 79(3):245-250 [PubMed] Related Publications
We report a case of two peculiar gallbladder polyps in a sixty-four year old male who presented with symptomatic cholelithiasis. Cholecystectomy was performed, which revealed two polyps measuring 0.6 cm and 1.9 cm, located in the body of the gallbladder. Microscopic examination of the polyps showed composite mesenchymal lesions with vascular proliferation of small-to-medium sized arterioles, myoid stroma, and lipomatous periphery. The myoid component was characterized by wisps of bland smooth muscle fibers loosely separated by proteinaceous and focally myxoid matrix. The surface of the polyps was lined by a single layer of bland epithelial cells. The unique histomorphologic features differentiate the lesions from other known mesenchymal polyps of the gallbladder. We propose the name "edematous angiomyolipoma-like polyp" for these rare lesions given their histomorphologic similarity to angiomyolipoma. (Acta gastroenterol. belg., 2016, 79, 371-374).

Ma F, Wang SH, Cai Q, et al.
Overexpression of LncRNA AFAP1-AS1 predicts poor prognosis and promotes cells proliferation and invasion in gallbladder cancer.
Biomed Pharmacother. 2016; 84:1249-1255 [PubMed] Related Publications
BACKGROUND: Long non-coding RNA actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been elucidated to be associated with some kinds of human cancers. However, whether lncRNA AFAP1-AS1 implicates in tumor development of gallbladder cancer (GBC) remains largely unknown. This study aims to elucidate the tumorigenic role and regulatory function of lncRNA AFAP1-AS1 in gallbladder cancer.
METHODS: We analyzed lncRNA AFAP1-AS1 expression by quantitative real time PCR (qRT-PCR) in 40 gallbladder cancer tissue and adjacent normal tissues, survival plots were generated by Kaplan-Meier analysis and the log-rank test. The expression levels of transcription factor Twist1 and epithelial-to mesenchymal transition (EMT) makers (E-cadherin and Vimentin) were detected by quantitative real time PCR and western blotting analysis after knockdown of lncRNA AFAP1-AS1.
RESULTS: The expression levels of lncRNA AFAP1-AS1 were significantly elevated in GBC tissues and GBC cell lines. In addition, the expression level of lncRNA AFAP1-AS1 was significantly associated with tumor sizes and the higher expression of lncRNA AFAP1-AS1 was correlated with poor prognosis in GBC patients. Knockdown of LncRNA AFAP1-AS1 suppressed cell growth and invasion in NOZ and GBC-SD cells. Furthermore, we found that knockdown of LncRNA AFAP1-AS1 in GBC cells inhibited EMT by down-regulating the transcription factor Twist1 and Vimentin and up-regulated the E-cadherin.
CONCLUSIONS: Our results suggested lncRNA AFAP1-AS1 was correlated with poor prognosis in GBC patients and lncRNA AFAP1-AS1 might be novel therapeutic target in gallbladder cancer.

Kazmi HR, Chandra A, Kumar S, et al.
A let-7 microRNA binding site polymorphism in the KRAS 3'UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population.
J Cancer Res Clin Oncol. 2016; 142(12):2577-2583 [PubMed] Related Publications
PURPOSE: Gallbladder cancer is a lethal malignancy of hepato-biliary system with high incidence in North India, especially along gangetic plain. The let-7 microRNAs play a key role in regulating KRAS expression and a polymorphism in 3' untranslated region (rs61764370, T/G) of KRAS leads to its higher expression. This polymorphism is known to be associated with increased risk and prognosis of various cancers but its association with gallbladder cancer has not been evaluated. To address this research question, we evaluated whether rs61764370 variant is associated with gallbladder cancer susceptibility and clinical outcomes.
METHODS: In present case-control study, we enrolled 541 patients with gallbladder malignancy and 307 controls. Genomic DNA was obtained from peripheral blood and genotyping was performed using Taqman allelic discrimination assay.
RESULTS: Heterozygous (TG) individuals are at a significant higher risk for GBC as compared with wild genotype (TT) (p = 0.007, odds ratio = 2.56, 95 % CI 1.27-5.18). At allelic level, allele G has significant higher risk for GBC as compared with T allele (p = 0.008, odds ratio = 2.5, 95 % CI 1.25-5.01). Survival analysis reveals decrease in overall survival for heterozygous genotype (p < 0.0001, hazard ratio = 3.42, 95 % CI 1.21-4.20). Also, significant decrease in overall survival was observed for patient carrying allele G (p < 0.0001, HR = 2.89, 95 % CI 1.21-4.20) as compared with allele C.
CONCLUSIONS: We conclude that KRAS rs61764370 polymorphism is significantly associated with risk and prognosis of gallbladder malignancy in this endemic belt.

Singh A, Mishra PK, Saluja SS, et al.
Prognostic Significance of HER-2 and p53 Expression in Gallbladder Carcinoma in North Indian Patients.
Oncology. 2016; 91(6):354-360 [PubMed] Related Publications
BACKGROUND/OBJECTIVE: Proto-oncogenes (HER-2) and tumor suppressor genes (p53) are commonly deregulated in gallbladder cancer (GBC). Available literature discloses skewed data from endemic Asian countries, especially north India. This study evaluates the prognostic significance of HER-2 and p53 in GBC patients from two major hospitals.
METHODS: Sixty resectable tumor and control specimens were prospectively collected from December 2012 to January 2016. Immunohistochemical staining was done using monoclonal antibodies to semiquantitatively evaluate HER-2 and p53 protein expression. The criterion for HER-2 positivity was set at >30% tumor cells showing complete, membranous staining while p53 positivity was established at <50% tumor cells showing complete nuclear staining. Clinicopathological correlations were drawn with major clinical outcomes.
RESULTS: It was observed that 36.67% (22/60) tumor cases and 5% (3/60) control cases showed strong HER-2 overexpression significantly correlating with sex, T-stage, nodal spread and distant metastasis (p < 0.05), while 33.3% (20/60) positivity was observed for p53 in tumor cases and 1.7% (1/60) in control cases. Multivariate analysis showed HER-2 (p = 0.04; hazard ratio: 2.36; 95% confidence interval: 1.04-5.33) and p53 (p = 0.03; hazard ratio: 5.63; 95% confidence interval: 1.21-26.26) expression to be independent prognostic factors.
CONCLUSION: Our study thus suggests the plausible role of HER-2 and p53 expression in worse prognosis of GBC in a north Indian population.

Wang SH, Zhang MD, Wu XC, et al.
Overexpression of LncRNA-ROR predicts a poor outcome in gallbladder cancer patients and promotes the tumor cells proliferation, migration, and invasion.
Tumour Biol. 2016; 37(9):12867-12875 [PubMed] Related Publications
LncRNA-ROR has been reported to be involved in many kinds of human cancers. However, whether LncRNA-ROR is involved in gallbladder cancer progression remains largely unknown. The objective of this study is to investigate the role of LncRNA-ROR in gallbladder cancer. We found that LncRNA-ROR expression level was upregulated in gallbladder cancer tissues (P < 0.05) and was significantly associated with tumor sizes (P < 0.05) and lymph node metastasis (P < 0.05). High expression of LncRNA-ROR was significantly associated with poor prognosis in gallbladder cancer patients (P < 0.05). Moreover, knockdown of LncRNA-ROR inhibited cell proliferation, migration, and invasion. The epithelial-mesenchymal transition (EMT) phenotype induced by TGF-β1 was reversed after LncRNA-ROR knocking down in SGC-996 and Noz cells. LncRNA-ROR plays an important role in the development of gallbladder cancer and mediates the EMT in gallbladder cancer. LncRNA-ROR might act as a marker of prognosis and therapeutic target for gallbladder cancer.

Kanaya N, Aoki H, Yamasaki R, et al.
Granulocyte Colony-Stimulating Factor-Producing Gallbladder Cancer.
Acta Med Okayama. 2016; 70(5):393-396 [PubMed] Related Publications
We report a case of a granulocyte colony-stimulating factor (G-CSF)-producing gallbladder tumor associated with fever in a middle-aged female. Preoperative blood analysis showed leukocytosis with elevated levels of C-reactive protein and G-CSF. We resected the liver at S4a+S5, with regional lymph node dissection and partial resection of the duodenum. Histology revealed undifferentiated carcinoma with spindle and giant cells and papillary adenocarcinoma. Immunohistochemistry revealed Stage IIIB G-CSF-producing gallbladder cancer. Postoperatively, leukocyte and serum G-CSF levels decreased to within normal limits. Adjuvant gemcitabine chemotherapy was administered for 16 months, and she has been recurrence-free for 48 months.

Pujani M, Makker I, Makker A, et al.
Expression of Human Epidermal Growth Factor Receptor (Her 2/neu) and Proliferative Marker Ki-67: Association with Clinicopathological Parameters in Gallbladder Carcinoma.
Asian Pac J Cancer Prev. 2016; 17(8):3903-9 [PubMed] Related Publications
PURPOSE: To evaluate the expression of Her2/neu and Ki-67 in benign and malignant gallbladder lesions, and to establish correlations with clinico-pathologic parameters.
MATERIALS AND METHODS: A retrospective analysis was conducted on formalin fixed paraffin embedded (FFPE) benign (n=25) and malignant gallbladder (n=25) tissue samples. Hematoxylin and eosin stained slides of each case were reviewed for: type of malignancy (whether adenocarcinoma, squamous cell carcinoma, or any other type); grade (well, moderate, and poor); depth of invasion; and pre-neoplastic changes in adjacent mucosal epithelium like metaplasia and dysplasia. Immunohistochemistry for Her 2 neu and Ki-67 was performed and data analysis was conducted using SPSS 17 software. Chi-square test was used to compare categorical/dichotomous variables. A P value of ≤0.05 was considered significant.
RESULTS: The difference of Her 2 neu expression and Ki67 index between benign and malignant groups was found to be statistically significant. Her2/neu positivity did not have any significant correlation with various clinicopathological parameters other than liver involvement. Five cases of gallbladder cancer showed both Her2/neu and Ki67 positivity. Ten cases were Ki67 positive but Her2/neu negative while one case was Her2/neu positive but Ki67 negative.
CONCLUSIONS: The present study demonstrated overexpression of Her2/neu and Ki67 in gallbladder cancer. A trend of decreasing Her2/neu expression with increasing grade of tumor was observed. Furthermore, greater Ki67 positivity was found in cases with lymph node metastasis and distant metastasis. Future studies with a larger number of patients will be required to precisely define the correlation of Her2/neu expression and Ki67 positivity with clinicopathological parameters. The results however are encouraging and suggest evaluation of Her2/neu as a candidate for targeted therapy.

Abe T, Amano H, Hanada K, et al.
Preoperative Systemic Inflammation and Complications Affect Long-term Gallbladder Carcinoma Outcomes Following Surgery with Curative Intent.
Anticancer Res. 2016; 36(9):4887-94 [PubMed] Related Publications
BACKGROUND/AIM: Gallbladder carcinoma (GBCA) has extremely poor outcomes. We aimed to investigate clinicopathological prognostic variables, including the modified Glasgow prognostic score (mGPS), for patients with resected GBCA.
PATIENTS AND METHODS: This retrospective study included 54 patients with GBCA resected between 1996 and 2014. Univariate and multivariate analyses were performed to identify prognostic factors associated with overall and recurrence-free survival.
RESULTS: Curative resection (R0) was achieved in 43 patients (79.6%). The median patient age was 74 years (range=25-99 years), and the majority (n=33, 61.1%) were women. Incidental GBCA was detected in 18 patients (33.3%). The overall and recurrence-free survival rates were 63.3% and 55.8% at 3 years and 58.4% and 51.3% at 5 years, respectively. In multivariate analysis, postoperative intra-abdominal complications (p=0.015), non-curative resection (p=0.008), worse histological type (p=0.003), and elevated mGPS (p=0.002) were independent predictors of worse overall survival. Surgical complications (p=0.015), non-curative resection (p=0.005), worse histological type (p=0.002), and elevated mGPS (p=0.022) were also independent predictors of worse recurrence-free survival.
CONCLUSION: Curative resection was important for long-term survival for GBCA. A high preoperative mGPS and occurrence of surgical complications were independent prognostic indicators of poor survival in GBCA.

Sharma P, Bhunia S, Poojary SS, et al.
Global methylation profiling to identify epigenetic signature of gallbladder cancer and gallstone disease.
Tumour Biol. 2016; 37(11):14687-14699 [PubMed] Related Publications
Promoter methylation in various tumor suppressor genes is reported to influence gallbladder carcinogenesis. Here, we aimed to identify methylation status in gallbladder cancer (GBC) by performing a comprehensive genome-wide DNA methylation profiling. The methylation status of 485,577 CpG sites were investigated using Illumina's Infinium Human Methylation 450 BeadChip array in 24 tissues (eight each of tumor, adjacent non-tumor, and gallstone). About 33,443 differentially methylated sites (DMRs) were obtained in the whole human genome, of which 24,188 (72 %) were hypermethylated and 9255 (28 %) were hypomethylated. The data also revealed that majority of the DMRs are localized on the proximal promoter region [Transcription start sites (TSS200, TSS1500) and 5' untranslated region (5'UTR)] and first exon. Exclusion of first exon detected a total of 10,123 (79 %) hypermethylated and 2703 (21 %) hypomethylated sites. Comparative analysis of the later with our differential proteomics data resulted in identification of 7 hypermethylated or down-regulated (e.g., FBN1, LPP, and SOD3) and 61 hypomethylated or up-regulated markers (e.g., HBE1, SNRPF, TPD52) for GBC. These genes could be further validated on the basis of their methylation/expression status in order to identify their utility to be used as biomarker/s for early diagnosis and management of GBC.

Ueda K, Kinoshita A, Akasu T, et al.
A case of adenosquamous cell carcinoma of the gallbladder with markedly elevated PTHrP and G-CSF levels.
Nihon Shokakibyo Gakkai Zasshi. 2016; 113(9):1564-71 [PubMed] Related Publications
A 76-year-old woman was referred to our hospital with anorexia. Computed tomography revealed a tumor lesion measuring 110mm in the liver at S4/5 with calcification and swelling of a paraaortic lymph node. The gallbladder was not visualized. Histological examination of a biopsy specimen from the liver tumor revealed squamous cell and undifferentiated carcinomas, and several tumor markers were elevated. Therefore, we diagnosed the patient with gallbladder adenosquamous cell carcinoma T3N2M0 stage III. Because the serum parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels were significantly elevated, we suspected that PTHrP and G-CSF production occurred because of adenosquamous cell carcinoma in the gallbladder. We initiated chemotherapy with S-1.

Xu SY, Guo H, Shen Y, et al.
Multiple schwannomas synchronously occurring in the porta hepatis, liver, and gallbladder: first case report.
Medicine (Baltimore). 2016; 95(33):e4378 [PubMed] Related Publications
BACKGROUND: Schwannomas are mesenchymal neoplasms that arise from Schwann cells with low malignant potential. Schwannomas originating from the porta hepatis or intra-abdominal organs are extremely rare. To our knowledge, multiple schwannomas synchronously occurring in the porta hepatis, liver, and gallbladder have not been reported so far and we first report one in the present case.
CASE SUMMARY: A 31-year-old female was referred to our hospital because of repeated abdomen discomfort, slight abdominal distension, and occasional abdominal pain for seven years. Ultrasound and computed tomography and magnetic resonance cholangiopancreatography found multiple intrahepatic and extrahepatic cystic lesions with the dilation of intrahepatic and extrahepatic bile ducts. By exploratory laparotomy, multiple tumors were found in the porta hepatis, liver, and gallbladder, the biggest one was 11 × 6 cm in size. We completely resected these tumors combined with the left lateral liver lobe, gallbladder, and the invaded left and right hepatic arteries, and then severed vessels were reconstructed. Microscopically, the tumor cells were spindle shaped and palisading arrangement. Atypical cells or signs of malignancy were not found. Immunohistochemical investigation showed the protein S-100 was positive, while SMA, CD34, and CD117 negative. Finally, these tumors were diagnosed as schwannomas in the porta hepatis, liver, and gallbladder. The patient is followed-up for 70 months and has been doing well without any complications.
CONCLUSION: We report the first patient with multiple schwannomas synchronously occurring in the porta hepatis, liver, and gallbladder. Accurate preoperative diagnosis of these tumors is difficult. Due to closely adhering to the surrounding important tissues, complete removal is challenging.

Ikoma T, Kapoor VK, Behari A, et al.
Lack of an Apparent Association between Mycotoxin Concentrations in Red Chili Peppers and Incidence of Gallbladder Cancer in India : an Ecological Study.
Asian Pac J Cancer Prev. 2016; 17(7):3499-503 [PubMed] Related Publications
Our recent studies conducted in South America have shown that mycotoxin contamination of red chili peppers (RCPs) may be associated with an increased risk of gallbladder cancer (GBC). Whether this relationship exists in India, a country with a high incidence of GBC and high consumption of RCPs, is unclear. We therefore measured concentrations of aflatoxins (AFs) and ochratoxin A (OTA) in RCPs from areas of low, medium, and high incidence of GBC in India, and compared these concentrations with GBC incidence in each area. Twentyone RCP samples were collected from nine cities (eight from a lowincidence area, five from a mediumincidence area, and eight from a highincidence area). Concentrations of AFs and OTA were measured using highperformance liquid chromatography. No significant differences in mean concentrations of AFs and OTA were found in the three areas. AFB1 levels in the lowincidence area (10.81 ?g/kg) and highincidence area (12.00 ?g/kg) were more than 2.2 and 2.4 times higher compared with the maximum permitted level of AFB1 in spices (5.0 ?g/kg) set by the Commission of the European Communities, or that (4.4 ?g/kg) obtained in our previous study in Chile. Our results show that the mean concentrations of mycotoxins in RCPs are similar among the three areas in India with different incidences of GBC. Further studies with human subjects are needed to evaluate any association between AFB1 and GBC.

Tamrakar D, Paudel I, Adhikary S, et al.
Risk Factors for Gallbladder Cancer in Nepal a Case Control Study.
Asian Pac J Cancer Prev. 2016; 17(7):3447-53 [PubMed] Related Publications
BACKGROUND: Gall bladder cancer (GBC) is highly fatal disease with poor prognosis, with a 5 year survival rate of <10%. It is relatively rare cancer worldwide; however it is the sixth cancer and second most common gastrointestinal tract cancer in Nepalese women. The study focused on associations of certain demographic, lifestyle, dietary, and reproductive factors with gall bladder cancer.
MATERIALS AND METHODS: We conducted a hospitalbased matched case control study on newly diagnosed cases of primary GBC at BP Koirala Institute of Health Sciences and BP Koirala Memorial Cancer Hospital. Controls were healthy nonGBC relatives of cancer patients, matched for age, sex and marital status (in case of females) with cases at a ratio of 1:2. Data were collected between April 2012April 2013 by semi structured interview from both cases and controls. Analyses were carried out with SPSS. Conditional logistic regression was used to find odds ratios and 95% confidence intervals for bivariate and multivariate analysis.
RESULTS: A total of 50 cases and 100 controls were enrolled in this study. On bivariate analysis, factors found to be significantly associated with gallbladder cancer were illiteracy (OR= 3.29, CI= 1.0610.2), history of gallstone disease (OR=27.6, CI=6.57, 115.6), current smoker (OR=2.42, CI=1.005 5.86), early menarche <13 years (OR=2.64, CI=1.096.44), high parity more than 3 (OR=3.12, CI=1.25,7.72), and use of mustard oil (OR=3.63, CI=1.40, 9.40). A significant protective effect was seen with high consumption of fruits at least once a week (OR=0.101, CI=0.030.35). On multivariate analysis, history of gallstone disease, early menarche, current smoker and high consumption of fruits persisted as significant factors.
CONCLUSIONS: History of gallstone disease, cigarette smoking and early menarche were associated with increased risk of gallbladder cancer while high consumption of fruits was found to have a protective effect.

Nanashima A, Izumino H, Sumida Y, et al.
Relationship Between Urinary 8-hydroxydeoxyguanine (8-OHdG) Levels and Clinicopathological Findings in Hepatobiliary Malignancies.
Anticancer Res. 2016; 36(8):3899-903 [PubMed] Related Publications
BACKGROUND/AIM: Oxidative stress is defined as an imbalance between the pro-oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases.
MATERIALS AND METHODS: Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients.
RESULTS: Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057).
CONCLUSION: The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker.

Elmasry M, Lindop D, Dunne DF, et al.
The risk of malignancy in ultrasound detected gallbladder polyps: A systematic review.
Int J Surg. 2016; 33 Pt A:28-35 [PubMed] Related Publications
INTRODUCTION: Gallbladder polyps (GBPs) are a common incidental finding on ultrasound (US) examination. The malignant potential of GBPs is debated, and there is limited guidance on surveillance. This systematic review sought to assess the natural history of ultrasonographically diagnosed GBPs and their malignant potential.
METHODS: The keywords: "Gallbladder" AND ("polyp" OR "polypoid lesion") were used to conduct a search in four reference libraries to identify studies which examined the natural history of GBPs diagnosed by US. Twelve studies were eligible for inclusion in this review.
RESULTS: Of the 5482 GBPs reported, malignant GBPs had an incidence of just 0.57%. True GBPs had an incidence of 0.60%. Sixty four patients of adenomatous and malignant polyps were reported. Only in one patient was a malignant GBP reported to be <6mm. Risk factors associated with increased risk of malignancy were GBP >6mm, single GBPs, symptomatic GBPs, age >60 years, Indian ethnicity, gallstones and cholecystitis.
CONCLUSION: With the reported incidence of GBP malignancy at just 0.57%, a management approach based on risk assessment, clear surveillance planning, and multi disciplinary team (MDT) discussion should be adopted. The utilization of endoscopic ultrasound(EUS) should be Only considered on the grounds of its greater sensitivity and specificity when compared to US scans.

Babatunde TO, Ogunbiyi JO
Pattern of biliary tract carcinoma at the University College Hospital, Ibadan.
Afr J Med Med Sci. 2015; 44(4):329-34 [PubMed] Related Publications
BACKGROUND: Biliary tract carcinomas are uncommon but highly fatal malignancies. Most patients in our environment are diagnosed late and are not candidates for curative resection.
OBJECTIVE: To determine the pattern and risk factors of biliary tract carcinoma in Ibadan.
METHODOLOGY: This was a retrospective study of histologically confirmed cases of biliary tract carcinoma diagnosed at the University College Hospital, Ibadan between January 1971 and December 20 10. Data was obtained from the records of the Ibadan Cancer Registry, surgical day books and post-mortem records of the Department of Pathology. Histological classification based on the 2010 'WHO classification for tumours of the intrahepatic bile duct, gallbladder and extrahepatic bile duct' was done.
RESULTS: There were 37 cases of biliary tract carcinoma accounting for 0.18% of cancers seen during the period of study. These comprised of 26 (70.3%) females and 11 (29.7%) males. 20 females and 4 males had gallbladder carcinoma, while 6 females and 7 males had cholangiocarcinoma (P = 0.02). The age range was from 37 years to 75 years (mean = 52.5 ± 9.7 years). The peak occurrences of gallbladder carcinoma and cholangiocarcinoma were in the fifth and sixth decades of life respectively. The identified risk factors included female gender (83%), gallstones (33%), and dysplasia (42%).
CONCLUSION: The findings in this study agree with what has been described in the English literature in respect of gender distribution, histological types and some associated risk factors as well as in the fact of its being rare.

Stergios K, Damaskos C, Frountzas M, et al.
Can gallbladder polyps predict colorectal adenoma or even neoplasia? A systematic review.
Int J Surg. 2016; 33 Pt A:23-7 [PubMed] Related Publications
OBJECTIVE: The purpose of the present systematic review is to identify whether an association between gallbladder polyps and colorectal adenoma or neoplasia exists.
DATA SOURCES: We conducted a systematic review searching the Medline (1966-2016), Scopus (2004-2016), ClinicalTrials.gov (2008-2016) and Cochrane Central Register of Controlled Trials CENTRAL (1999-2016) databases together with reference lists from included studies.
STUDY ELIGIBILITY CRITERIA: All prospective and retrospective observational cohort studies were included.
RESULTS: Four studies were finally included which included 17,437 patients. The association between gallbladder polyps and colorectal adenoma or even neoplasia is not unanimously supported. However, a possible association is clearly depicted. According to one study it seems that this correlation seems to become significant only when the gallbladder polyps exceed the size of 5 mm. However, the impact of size of gallbladder polyps was not investigated in the remaining studies.
CONCLUSION: According to the results of our systematic review there is some evidence to support the hypothesis that gallbladder polyps might adequately predict future risk of colorectal neoplasia. At present, however, current knowledge is very limited and the available data scarce. In this context further studies are necessary to be carried out, before the presence of gallbladder polyps on ultrasound can be recommended as an indication to perform a screening colonoscopy on the same patient.

Wang Q, Yang ZL, Zou Q, et al.
SHP2 and UGP2 are Biomarkers for Progression and Poor Prognosis of Gallbladder Cancer.
Cancer Invest. 2016; 34(6):255-64 [PubMed] Related Publications
Biomarkers for the diagnosis, prognosis, and targeting therapy of gallbladder cancers are not clinically available. This study demonstrated that the percentage of cases with positive SHP2 and UGP2 expression significantly correlated with the percentage of cases with positive vimentin, β-catenin, MMP2, MMP9, and Ki-67 expression, large tumor size, high TNM stage, lymph node metastasis, and survival in patients with adenocarcinomas and squamous cell/adenosquamous carcinomas. Positive SHP2 and UGP2 expression are independent poor-prognostic factors in both types of tumors. Our study suggested that positive SHP2 and UGP2 expression correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer.

Tekcham DS, Tiwari PK
Epigenetic regulation in gallbladder cancer: Promoter methylation profiling as emergent novel biomarkers.
Asia Pac J Clin Oncol. 2016; 12(4):332-348 [PubMed] Related Publications
DNA methylation, once considered to rule the sex determination in Mary Lyon's hypothesis, has now reached the epicenter of human diseases, from monogenic (e.g. Prader Willi syndrome, Angelman syndromes and Beckwith-Wiedemann syndrome) to polygenic diseases, like cancer. Technological developments from gold standard to high throughput technologies have made tremendous advancement to define the epigenetic mechanism of cancer. Gallbladder cancer (GBC) is a fatal health issue affecting mostly the middle-aged women, whose survival rate is very low due to late symptomatic diagnosis. DNA methylation has become one of the key molecular mechanisms in the tumorigenesis of gallbladder. Various molecules have been reported to be epigenetically altered in GBC. In this review, we have discussed the classes of epigenetics, an overview of DNA methylation, technological approaches for its study, profile of methylated genes, their likely roles in GBC, future prospects of biomarker development and other discovery approaches, including therapeutics.

Sheikh MR, Osman H, Cheek S, et al.
T2 Gallbladder Cancer-Aggressive Therapy Is Warranted.
Am Surg. 2016; 82(6):518-21 [PubMed] Related Publications
Treatment of gall bladder cancer (GBC) has traditionally been viewed with pessimism and lymph node positivity has been associated with worse prognosis. The aim of this study is to analyze the role of radical cholecystectomy in T2 tumors. All patients who underwent surgery for GBC between September 2005 and June 2014 were identified retrospectively. Data collected included clinical presentation, operative findings, and histopathological data. Twenty-five patients had incidental GBC diagnosis after cholecystectomy. Ten patients were T2 on initial cholecystectomy pathology and all underwent radical resection. Two patients were N1 on initial cholecystectomy pathology. Four were upstaged to N1 and two patients were upstaged to T3 after further surgery. Overall, 60 per cent patients with T2 disease had node positivity and 60 per cent were upstaged by further surgery. Eleven patients were diagnosed on imaging. Four of these patients were unresectable and six were either stage T3 or higher or node positive. Sixty per cent of T2 GBC was node positive and 60 per cent were upstaged with radical cholecystectomy. This finding supports the call for radical resection in patients with incidental diagnosis of T2 tumor on cholecystectomy. This study also emphasizes the role of radical surgery in accurate T staging.

Evangelista L, Burei M, Basso U
A Solitary Metastasis for a Malignant Schwannoma in the Gallbladder Detected by 18F-FDG PET/CT.
Clin Nucl Med. 2016; 41(8):666-7 [PubMed] Related Publications
A 63-year-old woman with a history of malignant schwannoma in the left shoulder (pT1aNxMx) was treated with surgical resection in 2012. During follow-up, patient developed a metastasis in the right lung treated by further surgical intervention. For a suspicion on persistent disease in the lung, patient was sent to FDG PET/CT examination, which showed a focal uptake in the gallbladder. The patient underwent cholecystectomy, and a solitary metastasis from schwannoma was diagnosed by pathology. This case highlights that, in patients with a malignant schwannoma, a careful differential diagnosis should be made in case of a significant FDG uptake in the gallbladder.

Okada K, Kawai M, Ueno M, et al.
Depth of Hepatic Infiltration and Lymph Node Swelling as Factors for Considering Surgery for T2-4 Gallbladder Carcinoma Patients.
Anticancer Res. 2016; 36(6):3075-80 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to clarify if the degree of hepatic infiltration and lymph node swelling of gallbladder carcinoma (GBC) should be held as deciding factors for T2-4 GBC patients to undergo surgery.
PATIENTS AND METHODS: Fifty consecutive patients with T2-4 GBC who underwent surgery were reviewed retrospectively. We investigated the preoperative information and imaging factors as predictors of survival.
RESULTS: The estimated overall survival in all patients was lower in patients with hepatic infiltration ≥5 mm (n=12) than in those with <5 mm (n=38) (p=0.003). Multivariate analyses demonstrated that liver infiltration ≥5 mm (OR=2.251; 95%CI=0.906-5.596, p=0.081) and lymph node swelling (OR=2.462; 95%CI=1.034-5.859, p=0.042) were risk factors of poor survival.
CONCLUSION: Our results suggested that ≥5 mm liver infiltration and lymph node swelling may serve as deciding factors for surgery consideration in GBC patients.

Jang JY, Heo JS, Han Y, et al.
Impact of Type of Surgery on Survival Outcome in Patients With Early Gallbladder Cancer in the Era of Minimally Invasive Surgery: Oncologic Safety of Laparoscopic Surgery.
Medicine (Baltimore). 2016; 95(22):e3675 [PubMed] Free Access to Full Article Related Publications
Laparoscopic surgery has been widely accepted as a feasible and safe treatment modality in many cancers of the gastrointestinal tract. However, most guidelines on gallbladder cancer (GBC) regard laparoscopic surgery as a contraindication, even for early GBC. This study aims to evaluate and compare recent surgical outcomes of laparoscopic and open surgery for T1(a,b) GBC and to determine the optimal surgical strategy for T1 GBC.The study enrolled 197 patients with histopathologically proven T1 GBC and no history of other cancers who underwent surgery from 2000 to 2014 at 3 major tertiary referral hospitals with specialized biliary-pancreas pathologists and optimal pathologic handling protocols. Median follow-up was 56 months. The effects of depth of invasion and type of surgery on disease-specific survival and recurrence patterns were investigated.Of the 197 patients, 116 (58.9%) underwent simple cholecystectomy, including 31 (15.7%) who underwent open cholecystectomy and 85 (43.1%) laparoscopic cholecystectomy. The remaining 81 (41.1%) patients underwent extended cholecystectomy. Five-year disease-specific survival rates were similar in patients who underwent simple and extended cholecystectomy (96.7% vs 100%, P = 0.483), as well as being similar in patients in the simple cholecystectomy group who underwent open and laparoscopic cholecystectomy (100% vs 97.6%, P = 0.543). Type of surgery had no effect on recurrence patterns.Laparoscopic cholecystectomy for T1 gallbladder cancer can provide similar survival outcomes compared to open surgery. Considering less blood loss and shorter hospital stay with better cosmetic outcome, laparoscopic cholecystectomy can be justified as a standard treatment for T1b as well as T1a gallbladder cancer when done by well-experienced surgeons based on exact pathologic diagnosis.

Bridgewater JA, Goodman KA, Kalyan A, Mulcahy MF
Biliary Tract Cancer: Epidemiology, Radiotherapy, and Molecular Profiling.
Am Soc Clin Oncol Educ Book. 2016; 35:e194-203 [PubMed] Related Publications
Biliary tract cancer, or cholangiocarcinoma, arises from the biliary epithelium of the small ducts in the periphery of the liver (intrahepatic) and the main ducts of the hilum (extrahepatic), extending into the gallbladder. The incidence and epidemiology of biliary tract cancer are fluid and complex. It is shown that intrahepatic cholangiocarcinoma is on the rise in the Western world, and gallbladder cancer is on the decline. Radiation therapy has emerged as an important component of adjuvant therapy for resected disease and definitive therapy for locally advanced disease. The emerging sophisticated techniques of imaging tumors and conformal dose delivery are expanding the indications for radiotherapy in the management of bile duct tumors. As we understand more about the molecular pathways driving biliary tract cancers, targeted therapies are at the forefront of new therapeutic combinations. Understanding the gene expression profile and mutational burden in biliary tract cancer allows us to better discern the pathogenesis and identify promising new developmental therapeutic targets.

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