Expression Profile of KRAS and p16 in Periampullary Cancer.

Activating point mutations in codons 12, 13, and 61 of the KRAS gene and loss of p16 expression, a tumor suppressor gene, are common genetic alterations in periampullary cancer (PAC). The present study explores expression profile of KRAS and p16 genes in PAC and its prognostic relevance. A total of 50 patients with PAC who underwent potentially curative pancreaticoduodenectomy were included in the study. Formalin-fixed, paraffin-embedded tissue samples were analyzed for point mutations in codons 12 and 13 of KRAS and codon 9 of p16 using polymerase chain reaction. KRAS mutation in codon 12/13 was found in 32 (64%) and loss of p16 expression in 36 (72%) cases. KRAS mutation was significantly associated with higher grade, higher pathological tumor (pT) stage, lymphovascular invasion (LVI), perineural invasion (PNI), and pathological lymph nodes (pN) involvement on univariate analysis. On multivariate analysis, significant association of KRAS remained with higher grade (p = 0.031), pT stage (p = 0.09), and LVI (p = 0.028). On univariate analysis, loss of p16 expression was significantly associated with higher grade, pN involvement, LVI, PNI, and pT stage whereas on multivariate analysis, statistical significant association of p16 was found with higher grade of tumor only (p = 0.04). Patients with KRAS mutation had significantly (p = 0.018) worse disease-free survival (DFS) whereas no significant association was found in overall survival (OS). Loss of p16 expression had no association with either DFS or OS. The presence of p16 and KRAS alterations in patients with PAC suggests aggressive tumor biology. KRAS mutations confer a significantly poor DFS in PAC.

Epigenetic Silencing of p16INK4a gene in Sporadic Breast Cancer.

Epigenetic alterations of tumor suppressor genes (TSG) involved in the onset and progression of Breast Cancer (BC) may serve as biomarkers for early detection and prediction of disease prognosis. We have herein tried to determine the methylation status of TSG, p16INK4a, in our 50 BC patients and their association with clinicopathological parameters. The methylation status of the p16INK4a gene in fresh tissue samples from 50 patients with BC was assessed by methylation-specific polymerase chain reaction (MS-PCR). The mean age of BC patients was 49.30 ± 9.75 years. Of 50 BC samples tested, 21 (42%) had methylated p16INK4a gene. p16INK4a gene hypermethylation was significantly associated with age ≤ 50 years, premenopausal status and advanced BC stage. Multivariate analysis revealed a strong association between advanced BC stage (Stage III and Stage IV) and p16INK4a hypermethylation (P = 0.008, RR = 5.996, 95% CI = 1.581-22.739). p16INK4a methylation was significantly associated with Triple Negative BC (TNBC) (P = 0.045, OR = 4.181, 95% CI = 1.030-16.981). These findings indicate that p16INK4a hypermethylation frequently occurs in BC. Hypermethylation of p16INK4a in young, premenopausal, TNBC and with advance stage in BC patients suggests its association with aggressive BC.

Dendritic cell therapy in advanced gastric cancer: a promising new hope?

Advanced gastric cancer carries a very poor prognosis when the tumor becomes unresectable. Even with the best currently available chemotherapy regimens the survival rate remains dismal. A recent breakthrough in the treatment paradigm has been the approval of trastuzumab, a monoclonal antibody, in HER2-positive metastatic gastric cancer. A large number of trials are underway using dendritic cells (DCs) in a number of human malignancies and do show a ray of hope in management of these patients. This review attempts to summarize tumor immunology and the current data regarding use of DCs in gastric cancer therapy.

Genetic aberrations in gallbladder cancer.

Gallbladder carcinoma (GBC) is the most common type of biliary tract carcinoma and the third commonest digestive tract malignancy in our region. Studies available in literature do not clearly define the molecular genetic mechanisms involved in the pathogenesis of GBC. Most of these studies are limited to protein expression analysis by immunohistochemistry and western blotting, and only a few have been done on mRNA (messenger RNA) and mutation analysis. This review aims to critically analyze all the available evidence on genetic aberrations in gallbladder carcinoma.

Helicobacter pylori and pathogenesis of gallbladder cancer.

BACKGROUND AND AIM: Gallbladder cancer (GBC) is a rare but leading cause of cancer-related deaths worldwide. The incidence of GBC is increasing at an alarming rate in the Varanasi region, and its etiology remains obscure. METHODS: A total of 108 patients, 54 with GBC and 54 with gallstone diseases (GSD), were examined for Helicobacter pylori (H. pylori) in gallbladder specimens by rapid urease test, biochemical test, histology, culture, serology, polymerase chain reaction (PCR), and partial DNA sequencing. PCR was done using heat shock protein-60 (Hsp60) gene-nested primers. RESULT: Forty (74%) patients with GBC had gallstones. Upon culture, H. pylori colonies were identified in 24 (44%) GBC and 18 (33%) GSD specimens. H. pylori was detected in 20 (37%) GBC and 15 (28%) GSD samples upon histology. Serology was positive in 17 (32%) GBC and 15 (28%) GSD patients. The DNA isolated from GBC and GSD specimens was amplified by PCR with Hsp60-nested primers in 18 (33%) patients with GBC and 15 (28%) with GSD (P > 0.05). These sequences had 98% similarity with the presubmitted Hsp60 sequences of H. pylori in the National Centre for Biotechnology Information's GenBank. CONCLUSION: The results revealed that H. pylori was present in a large population, including both GBC and GSD patients, which indicates its endemic presence in the Varanasi region. Thus, it appears H. pylori might not have a significant role in the etiopathogenesis of GBC in our region.

Salmonella typhi and gallbladder cancer: report from an endemic region.

BACKGROUND: Evidence exists of a link between chronic infection by Salmonella typhi (S. typhi) and the development of gallbladder cancer (GBC), but several studies from endemic regions contradict its role in the etiopathogenesis of GBC. This study used various tools to assess the prevalence of S. typhi in patients with GBC and gallstone disease (GSD) in this region with a high incidence of GBC. METHODS: S. typhi was detected in tissue and bile by PCR and culture and in serum by the Widal test and indirect hemagglutination assay (IHA). PCR with two pairs of S. typhi specific primers (flagellin gene H1d and SOP E gene) could detect 0.6 ng of S. typhi DNA. Fifty-four patients with GBC (cases) were matched with 54 patients with GSD (controls). RESULTS: Of the 54 cases, 24 (44.44%) were positive on the Widal test and 12 (22.22%) on IHA, compared to 13 (24.07%) and 5 (9.26%) respectively in the controls. Eighteen (33.33%) cases showed a positive result on PCR (tissue) and 2 on PCR (bile) vs. none in the controls. Bile culture revealed no Salmonella colonies in either cases or controls. Only 3 cases were positive for Salmonella on tissue culture compared to none in the controls. The sensitivity of PCR (tissue) relative to the Widal test, IHA, culture (bile and tissue) and PCR (bile) was 100% vs. 66.67%, 11.11%, and 11.11%, and the specificity was 83.33% vs. 100%, 100%, and 100%, respectively. CONCLUSIONS: S. typhi is significantly associated with GBC compared to GSD (33% vs. 0%). PCR appears to be the most specific diagnostic tool, the gold standard for S. typhi in tissue samples.

Helicobacter bilis in human gallbladder cancer: results of a case-control study and a meta-analysis.

INTRODUCTION: Gallbladder cancer is an uncommon neoplasm of uncertain etiology and poor survival. Recently, interest has been generated in bacterial infections and cancers. Helicobacter is one such bacterium found to be associated with gastric MALToma, gastric adenocarcinoma and hepatobiliary neoplasms. PATIENTS AND METHODS: Fifty four gallbladder cancer and 55 controls with cholelithiasis were studied. Helicobacter bilis was identified using 16S rRNA PCR. Relative risk and odds ratio with 95% CI were estimated. A detailed search of literature was carried out and selected relevant articles were extracted. A meta analysis was carried out using a random effect model. RESULTS: Helicobacter bilis was identified in 32/54 patients and 32/55 controls, The relative risk of gallbladder cancer in H. bilis positive cases was 1.05 (95% CI 0.49 to 2.24). Of the 10 identified case control studies on Helicobacter in the hepatobiliary tract 3 each were on gallbladder cancer and H. bilis. In meta analysis a pooled odds ratio of 4.13 (95% CI 2.68-6.36) favoring Helicobacter was observed. Pooled analysis of published studies on gallbladder cancer showed an odds ratio of 1.24 (95% CI 0.63-2.44). CONCLUSIONS: The present study failed to demonstrate any increase in risk of gallbladder cancer in presence of Helicobacter bilis. It may be hypothesized that increased risk observed in earlier studies may be indirectly due to increase in the risk of gallstones, although lack of any study specifically looking at this aspect and absence of normal controls in the present study makes this assumption superfluous.

Is there a role for cholecystectomy in gallbladder carcinoma discovered to be unresectable for cure at laparotomy?

BACKGROUND: Palliative operative resection in patients with locally advanced cancer of the gallbladder (GBC) found not to be amenable to radical resection for cure at exploration has received little attention. This article evaluates the benefits, if any, of cholecystectomy with biliary drainage in such patients. METHODS: Available records of locally advanced but nonmetastatic GBC patients treated in the Department of Surgical Oncology, B.H.U., Varanasi, India, during the last 8 years were retrospectively reviewed. Of these, 30 patients (group I) with GBC (T(3-4),N(0-1),M(0)) treated with cholecystectomy +/- biliary bypass were selected and compared with equal number of controls matched for age (+/-5 years), sex, histopathology, stage, residence, and postoperative chemotherapy who underwent biopsy +/- biliary bypass only (group II) followed by chemotherapy during the same period. Survival rates were calculated by using Kaplan-Meier curves. Follow-up ranged from 1-15 months. RESULTS: The median survival was 7 and 2 months for groups I and II (P < 0.0001), respectively. The 30-day postoperative mortality and morbidity was 3% vs. 12% and 13% vs. 16% in groups I and II, respectively. CONCLUSIONS: Results suggest that a better median survival can be achieved after cholecystectomy in locally advanced unresectable GBC compared with only bypass and biopsy procedures. These findings may justify a palliative cholecystectomy in selected patients with locally advanced GBC.