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.

Mediating Role of Affective Experiences in the Relationship between Perceived Social Support and Life Satisfaction among Breast Cancer Patients.

AIM: The role of social support network in managing psychological symptoms in cancer patients is widely acknowledged. The purpose of this study was to investigate the potential mediating role of Affective experiences in the relationship between perceived social support (PSS) and life satisfaction (LS) among breast cancer patients in India. METHODS: A total of 100 breast cancer patients from S. S. Hospital, Banaras Hindu University participated in the study. They were tested using the PGI Social Support questionnaire, Satisfaction with Life Scale and Scale of Positive and Negative Experiences. RESULTS: Co-relational results indicated that PSS was positively associated with positive affect and LS, while inversely related to negative affect. Affect was also associated with LS. Results showed that the mediation of affective experiences in the relationship between PSS and LS was significant (P <.01 level). CONCLUSION: Both PSS played a big role in LS among breast cancer patients. Besides focusing on improvement of the social support network, the psychologists and counsellors should adopt an integrated approach for evidence-based intervention strategies to enhance their ability to effectively balance their positive and negative emotions to promote LS among cancer patients.

In Silico Profiling of the Potentiality of Curcumin and Conventional Drugs for CagA Oncoprotein Inactivation.

The oncoprotein cytotoxic associated gene A (CagA) of Helicobacter pylori plays a pivotal role in the development of gastric cancer, so it has been an important target for anti-H. pylori drugs. Conventional drugs are currently being implemented against H. pylori. The inhibitory role of plant metabolites like curcumin against H. pylori is still a major scientific challenge. Curcumin may represent a novel promising drug against H. pylori infection without producing side effects. In the present study, a comparative analysis between curcumin and conventional drugs (clarithromycin, amoxicillin, pantoprazole, and metronidazole) was carried out using databases to investigate the potential of curcumin against H. pylori targeting the CagA oncoprotein. Curcumin was filtered using Lipinski's rule of five and the druglikeness property for evaluation of pharmacological properties. Subsequently, molecular docking was employed to determine the binding affinities of curcumin and conventional drugs to the CagA oncoprotein. According to the results obtained from FireDock, the binding energy of curcumin was higher than those of amoxicillin, pantoprazole, and metronidazole, except for clarithromycin, which had the highest binding energy. Accordingly, curcumin may become a promising lead compound against CagA+ H. pylori infection.

HER2 Expression in Gastric and Gastroesophageal Cancer: Report from a Tertiary Care Hospital in North India.

Despite improvements in chemotherapy, survival of metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma remains poor. Trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2), has shown promise in improving survival of these patients by a recent large phase III trial. HER2 status in gastric and GEJ cancers, although reported from across the world, is yet unknown in India due to lack of published literature from the country. HER2 status in 70 samples of gastric and GEJ adenocarcinomas (Siewert type III) was evaluated by immunohistochemistry (IHC) in this study using the gastric cancer scoring system. It was also correlated with clinic-pathologic factors. Samples with IHC score 2+ and 3+ were taken as HER2 positive. HER2 overexpression was found in 15 (21.4 %) samples, was significantly (p = 0.006) more common in intestinal type (45 %), but it did not correlate with age, gender, stage, or grade of tumor and did not affect the 2-year disease-free survival. HER2 overexpression is found only in a minority of patients with gastric and GEJ cancers in the Indian population. A large cohort of patients with a longer follow-up will be required to assess for any significant statistical association of HER2 expression with prognosis of these patients.

Gallbladder carcinoma: high rate of mitochondrial D-loop mutations.

The molecular mechanisms leading to gallbladder carcinoma (GBC) are poorly understood. Different molecular disorders, including nuclear and mitochondrial genomic alteration, are associated with different cancers. The frequency of mitochondrial genome mutation has remained completely unexplored. In GBC, this is the first report of a mutation analysis in the mitochondrial genome, especially in the D-loop region. For a comprehensive D-loop view in GBC in humans, we sequenced the mitochondrial genome of 35 GBC patients and matched germ-line DNA. A wide range of point mutations and polymorphisms was observed. These variations in the D-loop sequence of human GBC represent good evidence of the mitochondrial role in GB carcinogenesis and may be used as a marker for GBC.

Association of Helicobacter pylori infection with inflammatory cytokine expression in patients with gallbladder cancer.

AIM: Gallbladder cancer (GBC) may be associated with Helicobacter pylori. The present study was designed to analyze the association of cytokine expression with H. pylori in patients with GBC. METHODS: GBC tissue sample and 5 mL blood were collected from each of 54 GBC patients. H. pylori was identified in tissue samples using biochemical tests, histology, culture, nested polymerase chain reaction (PCR), and partial genome sequencing. Tissue samples were categorized as H. pylori-positive (case) and H. pylori-negative groups (control) on the basis of nested PCR of tissue sample. Cytokines interleukin 1-ß (IL-1ß), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-5 (IL-5) were assayed in blood samples using ELISA. RESULTS: Presence of H. pylori was confirmed in 18 (33 %) of 54 GBC tissue samples. Levels of IL-1ß (p = 0.001) and TNF-α (p = 0.01) were significantly elevated in H. pylori-positive GBC compared to the control group. IFN-γ and IL-5 levels did not significantly differ between the two groups. CONCLUSIONS: H. pylori DNA was detected in the gallbladder of a third of GBC patients and was associated with higher circulating levels of some cytokines.

Epigenetic changes in carcinogenesis of gallbladder.

Gallbladder cancer (GBC) is a lethal and a common malignancy affecting mostly females. There are restricted high incidence pockets across the world and in northern India highest incidence of GBC is reported from the Gangetic belt. The etiology of this disease remains largely unknown though several risk factors have been stated. The genetic aberrations in GBC involving mutations in tumor suppressor genes and oncogenes have been reported in literature. However, there is scarcity of data regarding epigenetic changes that may also be involved in gallbladder carcinogenesis. This review attempts to summarize our current understanding of the epigenetic changes in GBC.

Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer.

Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers.

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.

Expression profile of cholecystokinin type-A receptor in gallbladder cancer and gallstone disease.

BACKGROUND: Regulatory peptide receptors have attracted the interest of oncologists as a new promising approach for cancer pathology, imaging and therapy. Although cholecystokinin (CCK) is a potent modulator of gallbladder contractility and plays a potential role in pancreatic carcinogenesis through CCK type-A receptor (CCKAR), its role in gallbladder cancer (GBC) is still unknown and immunohistochemical detection of CCKAR in the gallbladder has not yet been reported. This novel case-control study aimed to investigate the expression profile of CCKAR in GBC and gallstone disease (GSD). METHODS: This study included 162 samples of gallbladder: 94 from GBC and 68 from GSD. Expression of CCKAR was analyzed by immunohistochemistry and immunoblotting. The results were statistically correlated with disease history including age, sex, presence of gallstone, stage and differentiation. RESULTS: CCKAR was positive in 30/68 (44.1%) of GSD and 72/94 (76.6%) of GBC samples. Fifty-one of the 72 (70.8%) CCKAR-positive GBC samples showed over-expression. Interestingly, consistent results also appeared in the immunoblotting study. CONCLUSIONS: CCKAR expression was significantly increased in GBC compared to GSD. Moreover, CCKAR expression was associated with the degree of tumor differentiation, i.e., less expression in poorly-differentiated tumors. Thus, it has future prognostic and therapeutic implications in the management of GBC.

Obesity augmented breast cancer risk: a potential risk factor for Indian women.

BACKGROUND: Obesity is caused by disturbances of energy balance, which is homeostasized by the physiological processes. The study aims to determine the possible impact of rising prevalence of obesity and its effect in the development of breast carcinoma (BC) in Indian population. METHODS: This study is carried out on patients (N = 358) who were diagnosed with BC and breast diseases (BD) by calculating their BMI admitted during the period of 2005 to 2009. NIH criteria were used to categorize the patients. Pathological factors of BC patient were then compared among groups. RESULT: These results were indicative of significant positive association between BC risks with peri/post menopausal status, residence, diet nature, and tobacco uses. Metastases were identified more commonly with increasing weight. It was found to be independently associated with obesity I (OR = 3.103, 95% CI = 1.633-5.895) and obesity II (OR = 6.803, 95% CI = 2.415-19.162). Disease stage and cancer related mortality were significantly associated with increased BMI. CONCLUSION: The higher prevalence of severe obesity among Indian population was associated with BC. The only alteration apart from early diagnosis is opting for a more natural lifestyle that will affect energy equilibrium and prove to be a viable option for prevention in carcinoma of breast for better survival.

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.

p53: its alteration and gallbladder cancer.

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract. Despite the recent advancements in the understanding of cancer biology the disease still remains a therapeutic challenge with poor survival, and with early surgical resection as the only powerful treatment. Understanding the molecular events in gallbladder carcinogenesis may provide a novel targeted therapeutic approach. Of these, alterations in the tumour suppressor gene, p53, are commonly observed in most human cancers. However, its impact on the pathogenesis of GBC remains obscure. This study attempts to outline the p53 structure, function and its alterations, with special attention to GBC.

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 species and pathogenesis of gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is a rare disease but a leading cause of cancer-related death worldwide. A number of etiological factors have been implicated in the causation of GBC and pathogenic infection by bacteria is one of these. DATA SOURCES: A PubMed search on "helicobacter", "gallbladder cancer", and "biliary tract malignancies" was done on the topic, and the relevant data were collected, reviewed, and analyzed. RESULTS: Helicobacter is an epsilon proteobacterium that infects the mucosal lining of the human gastrobiliary system. Infection with helicobacter is an important risk factor for the development of cancer and the bacterium has been categorized as a group-I carcinogen by the International Agency for Research on Cancer (IARC). These microbes enter the human body by means of contaminated food and water. Thereby they invade the tissues and produce chemical carcinogens that lead to DNA damage and subsequently a series of gene mutations transform normal cells into cancer cells. In this review, we focus our attention on the role of helicobacter in the causation of biliary tract malignancies. CONCLUSIONS: The review attempts to summarize the current available data on the role of helicobacter in the causation of GBC. There are accountable data available to suggest the role of helicobacter species in the causation of GBC although larger studies are urgently required for confirmation.

Options of restorative pancreaticoenteric anastomosis following pancreaticoduodenectomy: a review.

Pancreatic fistula (PF), haemorrhage and delayed gastric emptying are some of the common causes of morbidity and PF is the single most important cause of mortality following pancreaticoduodenectomy (PD). Authors, who claim to have reduced leak rates, recommend modifications of the standard technique of pancreaticojejunostomy (PJ) that are often complex and difficult to standardize for wider applications. Most individual studies, multicenter retrospective analysis and certain prospective studies report a lower leak rate with pancreaticogastrostomy (PG) when compared with PJ. However, the only three randomized controlled clinical trials (RCTs) to date have failed to demonstrate the superiority of either technique. Here we discuss the various aspects of pancreaticoenteric anastomosis following pylorus preserving pancreaticoduodenectomy (PPD) and the standard pancreaticoduodenectomy (PD).

Gallbladder carcinoid masquerading as gallbladder carcinoma.

BACKGROUND: Carcinoid of the gallbladder is rare. Since it often presents as a gallbladder mass it may be confused with gallbladder carcinoma. METHODS: A 35-year-old lady presented with pain in the right upper abdomen, and was radiologically found to have a gallbladder mass. A provisional diagnosis of gallbladder carcinoma was made. Laparotomy revealed a 20 x 20 cm, exophytic, friable growth arising from the fundus of the gallbladder. It was excised with segment IVb and V of the liver and regional lymphadenectomy. RESULT: Histopathological examination revealed it was a neuroendocrine carcinoma, atypical carcinoid of the gallbladder. CONCLUSION: Gallbladder carcinoid has a poor outcome, requires aggressive treatment, and should be considered as one of the rare but possible gallbladder lesions.