Molecular aspects of BRAF and HER2 in prognosis of periampullary carcinoma.

BACKGROUND: Biological behaviour of Periampullary cancers (PACS) differs from pancreatic head cancer, and analysis of molecular alteration is needed. BRAF and HER2 are keys members of the RAS/RAF and EGFR pathway, playing roles in prognostic markers and therapeutic targets. METHODS: A study on 89 PACS patients, undergoing Whipple Pancreaticoduodenectomy, PCR-RFLP, and qPCR methods used for SNP and mRNA expression studies. Clinicopathological and survival data collected. Molecular changes were correlated with Clinicopathological parameters. Survival outcomes were assessed by Kaplan Meir Log rank test. RESULTS: The study revealed that homozygous mutant BRAF V600E was significantly higher in PAC compared to a healthy control (p = 0.0012). Whereas the genotype frequency of HER2 I1655V was similar among PAC and healthy control. The A > G change in HER2 was associated with tumor arising from duodenum (p = 0.004) and showed poor survival outcome (p = 0.001). Upregulation of BRAF and HER2 was found in 43 % of patients with synergistic effect, the median overall survival (OS) being 50.5 ± 13 months. The increased expression of HER2 was higher in early stage (p = 0.04) PAC. The gene expression did not impact the OS, whereas female gender, G3 tumors, T3-T4 depth of tumour, advanced stage, LN metastasis, LVI and PNI were poor predictors of OS. CONCLUSIONS: BRAF V600E SNP was associated with disease susceptibility, and had increased mRNA expression while HER2 I1655V SNP was associated with poor survival outcome in PAC. The increased expression of BRAF and HER2 in early tumors and their co-expression in PAC exhibit cross talk between RAS/RAF and EGFR pathway in PAC.

Harnessing nature's potential: Alpinia galanga methanolic extract mediated green synthesis of silver nanoparticle, characterization and evaluation of anti-neoplastic activity.

With the advent of nanotechnology, the treatment of cancer is changing from a conventional to a nanoparticle-based approach. Thus, developing nanoparticles to treat cancer is an area of immense importance. We prepared silver nanoparticles (AgNPs) from methanolic extract of Alpinia galanga rhizome and characterized them by UV-Vis spectrophotometry, Fourier transform Infrared (FTIR) spectroscopy, Zetasizer, and Transmission electron Microscopy (TEM). UV-Vis spectrophotometry absorption spectrum showed surface plasmon between 400 and 480 nm. FTIR spectrum analysis implies that various phytochemicals/secondary metabolites are involved in the reduction, caping, and stabilization of AgNPs. The Zetasier result suggests that the particles formed are small in size with a low polydispersity index (PDI), suggesting a narrow range of particle distribution. The TEM image suggests that the particles formed are mostly of spherical morphology with nearly 20-25 nm. Further, the selected area electron diffraction (SAED) image showed five electron diffraction rings, suggesting the polycrystalline nature of the particles. The nanoparticles showed high anticancer efficacy against cervical cancer (SiHa) cell lines. The nanostructures showed dose-dependent inhibition with 40% killing observed at 6.25 µg/mL dose. The study showed an eco-friendly and cost-effective approach to the synthesis of AgNPs and provided insight into the development of antioxidant and anticancer agents.

Clinical significance of SPOP and APC gene alterations in colorectal cancer in Indian population.

Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression. Mutations in Adenomatous Polyposis Coli (APC) gene is reported in most sporadic and hereditary colorectal cancer (CRC). Identifying the cellular changes involved in carcinogenesis when APC is mutated is an important issue that needs attention. The tumor suppressive function of SPOP and APC has long been a major focus in the research field of colorectal cancer. However, the clinical significance of SPOP and APC gene alteration in CRC has not been established to date. Mutational analysis was performed by single-strand conformational polymorphism followed by Sanger sequencing, methylation status by methylation-specific PCR, and protein expression by immunohistochemistry on 142 tumor tissues along with their adjacent non-cancerous specimens. The overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier Curve. Mutation rates of APC and SPOP gene were 2.8% and 11.9% while that of promoter hypermethylation were 37% and 47%, respectively. The grade of differentiation and Lymph node metastasis were significantly correlated with APC methylation pattern (p ≤ 0.05). The down regulation of APC was more often seen in colonic cancer compared to rectal cancer (p = 0.07) and more commonly in T3-4 depth of invasion (p = 0.07) and in patients without lymphovascular and perineural invasion (p = 0.007, p = 0.08 respectively). The median overall survival and recurrence free survival (RFS) was 67 & 36 months while 3-yr and 5-yr OS and RFS were 61.1% & 56.4% and 49.2% & 44.8%, respectively. APC promoter methylation had a better overall survival (p = 0.035) while loss of SPOP expression had a worse survival (p = 0.09). Our findings reveal high percentage of SPOP gene mutations in CRC. A significant link is found between promoter hyper methylation and protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.

Molecular aspects of ABCB1 and ABCG2 in Gallbladder cancer and its clinical relevance.

The function of ABC transporters in the body is manifold; such as maintenance of homeostasis, effect on multi-drug resistance and their role in tumor initiation & progression. Evidence pointing towards the direct or indirect role of ABC transporter genes in particular; ABCB1 and ABCG2 in cancer genesis is increasing. However, their role in gallbladder cancer is unexplored. Therefore, we investigated the methylation status and expression pattern of ABCB1 and ABCG2in gallbladder carcinogenesis. The methylation and expression study of ABCB1/MDR1 and ABCG2/BCRP was performed in tumour and normal fresh tissue samples collected from 61 histopathologically diagnosed gallbladder cancer patients. The methylation status was analysed by Methylation-Specific PCR and expression was determined by Real-Time PCR and Immunohistochemistry. Hypomethylation of ABCB1 and ABCG2 was found in 44 (72.13%) and 48 (78.6%) cases, respectively. ABCB1 hypomethylation pattern showed association with female patients (p = 0.040) and GradeII tumors (p = 0.036) while, ABCG2 hypomethylation was more frequent in early tumors (T1-T2). The mRNA expression ofABCB1 and ABCG2 was up-regulated in 33 (54.10%) and 41 (67.21%) patients with fold change of 4.7 and 5.5, respectively. The mRNA expression of both genes showed association with Grade II tumours and the increased fold change of ABCG2 was higher in (T1-T2) depth of invasion (p = 0.02) and Stage I-II disease (p = 0.08). The protein expression on IHC was strongly positive for ABCB1/MDR1and ABCG2/BCRP in 32 (52.46%) and 45 (73.77%) patients, respectively. The protein expression in ABCG2 showed association with patients age > 50 years (p = 0.04) and GradeII differentiation (p = 0.07). Interestingly, the hypomethylation of both the genes showed significant correlation with increased expression. ABCB1/MDR1 and ABCG2/BCRP hypomethylation and overexpression could have a potential role in gallbladder cancer tumorigenesis especially in early stages. The epigenetic change might be a plausible factor for altered gene expression of ABCB1 and ABCG2 in gallbladder cancer.

Ligand decorated biodegradable nanomedicine in the treatment of cancer.

Cancer is one of the major global health problems, responsible for the second-highest number of deaths. The genetic and epigenetic changes in the oncogenes or tumor suppressor genes alter the regulatory pathways leading to its onset and progression. Conventional methods are used in appropriate combinations for the treatment. Surgery effectively treats localized tumors; however, it fails to treat metastatic tumors, leading to a spread in other organs, causing a high recurrence rate and death. Among the different strategies, the nanocarriers-based approach is highly sought for, but its nonspecific delivery can cause a profound side effect on healthy cells. Targeted nanomedicine has the advantage of targeting cancer cells specifically by interacting with the receptors overexpressed on their surface, overcoming its non-specificity to target healthy cells. Nanocarriers prepared from biodegradable and biocompatible materials are decorated with different ligands by encapsulating therapeutic or diagnostic agents or both to target cancer cells overexpressing the receptors. Scientists are now utilizing a theranostic approach to simultaneously evaluate nanocarrier bio-distribution and its effect on the treatment regime. Herein, we have summarized the recent 5-year efforts in the development of the ligands decorated biodegradable nanocarriers, as a targeted nanomedicine approach, which has been highly promising in the treatment of cancer.

Management of Obscurely Dilated Common Bile Duct with Normal Liver Function Tests: A Pragmatic Approach.

OBJECTIVE: Dilated common bile duct (CBD) (8-15 mm) with normal liver function tests is seen not infrequently, while management of such patients is ambiguous. We propose a treatment algorithm for this cohort of patients after observing them over a period of 8 years. METHODS: Seventy-eight such patients were managed from 2009 to 2017 and categorized as: Group A-dilated CBD with post-cholecystectomy status (n = 15); B-dilated CBD with cholelithiasis (n = 34); C-dilated CBD without cholelithiasis (n = 16); D-dilated CBD with no cause identified and underwent CBD excision (n = 13). Causes for CBD dilatation were evaluated. The outcome of patients in Group B + C without any cause (n = 33) was compared with Group D. RESULT: Median age, CBD diameter, bilirubin and alkaline phosphatase were 51 years (13-79), 10 mm (8-20), 0.6 mg/dl (0.2-2.5) and 126 IU (60-214), respectively. Group-A patients who did not manifest any cause of CBD dilatation were managed conservatively. The aetiology was identified in 17/50 patients in Group B & C [acute pancreatitis (n = 6), passed CBD calculi (n = 3), perivaterian diverticulum (n = 3), viral aetiology (n = 4) and tumour (n-1)]. In Group-C, 7 patients with no obvious cause underwent endoscopic sphincterotomy, pancreatoduodenectomy (n = 1), and the rest were managed conservatively (n = 8). There was no significant difference in the complication between Group B + C (without any cause) and Group D (3/33 vs. 1/13; p = 0.58) at a median follow-up of 72 months (30-90). CONCLUSION: Dilated CBD with normal LFT's without apparent cause is mostly benign and of no consequence. Excision of the CBD is not required for most of these patients.

Elevated expression of RUNX3 co-expressing with EZH2 in esophageal cancer patients from India.

BACKGROUND: Runt related transcription factor3 (RUNX3) is considered as a tumor suppressor gene (TSG) that functions through the TGF-ß dependent apoptosis. Promoter methylation of the CpG islands of RUNX3 and overexpression of enhancer of zeste homolog 2 (EZH2) has been suggested to downregulate RUNX3 in cancer. METHODS: Here, we studied the expression of RUNX3 and EZH2 in 58 esophageal tumors along with paired adjacent normal tissue. mRNA levels, protein expressions and cellular localizations of EZH2 and RUNX3 were analyzed using real-time PCR and immunohistochemistry, respectively. DNA methylation was further assessed by the methylation specific-PCR. RESULTS: Compared to normal tissue, a significant increase in expression of RUNX3 mRNA in 31/57 patient's tumor tissue (p < 0.04) was observed. The expression of EZH2 was found to be upregulated compared to normal, and a significant positive correlation between EZH2 and RUNX3 expression was observed (p = 0.002). 22 of the 27 unmethylated cases at the promoter region of the RUNX3 had elevated RUNX3 protein expression (p < 0.001). CONCLUSION: The data presented in this study provide new insights into the biology of RUNX3 and highlights the need to revisit our current understanding of the role of RUNX3 in cancer.

Raised CA19-9 and CEA have prognostic relevance in gallbladder carcinoma.

BACKGROUND: Role of tumor markers in gall bladder carcinoma (GBC) is not well established. We evaluated the prognostic value of carbohydrate antigen 19-9 (CA19-9) and carcinoma embryonic antigen (CEA) in patients with GBC. METHODS: Of the 225 patients of GBC enrolled,176 patients were included in the study (excluded 49 patients with jaundice). Patients were divided into 3 groups; resectable n = 92, unresectable n = 17, metastatic n = 67. The clinico-pathological characteristics, tumor markers and survival data were analysed. The cutoff values of CA19-9 & CEA for predicting metastases were computed using receiver operating characteristic curve. Kaplan Meir survival and Cox regression analysis were done for factors predicting survival and recurrence. RESULTS: The median value of Ca19-9 was significantly higher in metastatic group [resectable: 21.3, unresectable: 53.9 and metastatic: 79; p < 0.001] but not for CEA [3.5, 7.8 and 5 ng/ml (p = 0.20)]. A cutoff value of 72 IU/ml for CA19-9, 5 ng/ml for CEA had a sensitivity and specificity of 52 and 80%, 51 and 72% respectively for detection of metastatic disease. Median, 3-year & 5-year survival were significantly lower in patients with CEA > 4 (p = 0.041), Ca19.9 > 37 (p = 0.019), T3/T4 (p = 0.001), node positive (p = 0.001) and presence of perineural invasion (p = 0.001). However, on multivariate analysis, only Ca19.9 > 37 predicted recurrence (p = 0.002, HR 5.8). CONCLUSIONS: Raised CA19.9 and CEA predict metastatic disease in patients with GBC without jaundice with a high specificity and may help in prognostication of the patient. CA19-9 was better than CEA in prediction of tumor burden and in predicting recurrence.

ERCP-related perforation: an analysis of operative outcomes in a large series over 12 years.

BACKGROUND: Perforation is a rare but serious adverse event of endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to determine the predictors of morbidity and mortality after surgical management of ERCP-related perforation (EP). METHODS: The records of patients with EP requiring surgical intervention at a tertiary referral center in a 12-year period (2004-2016) were retrospectively analyzed for demography, indications for ERCP, risk factors, timing and type of surgical repair, post-operative course, hospital stay, and outcome. Multiple logistic regression was used to identify the parameters predicting survival. RESULTS: Of 25,300 ERCPs, 380 (1.5%) had EP. Non-operative management was successful in 330 (86.8%) patients. 50 (13.2%) patients were operated for EP. Out of 50, the perforation was detected during ERCP (intra-procedure) in 32 patients (64%). In 30 patients (60%), the surgery was performed within 24 h of ERCP. Twenty patients underwent delayed surgery (after 24 h of ERCP) following the failure of initial non-operative management. The delayed surgery after an unsuccessful medical treatment had a detrimental effect on morbidity, mortality and hospital stay. Post-operative duodenal leak was the only independent predictor of 90-day mortality (p = 0.02, OR = 9.1, 95% CI 1.52-54.64). Addition of T-tube duodenostomy (TTD) to the primary repair for either type I or type II perforations increased post-operative duodenal leak (type I, p = 0.048 and type II; p = 0.001) and mortality (type I, p = 0.009 and type II, p = 0.045). CONCLUSION: Although EP is a rare event, it has a serious impact on morbidity and mortality. Delaying of surgery following failed non-operative management worsens the prognosis. Addition of TTD to the repair is not helpful in these patients.

Endoscopic cystogastrostomy versus surgical cystogastrostomy in the management of acute pancreatic pseudocysts.

Background: Studies comparing surgical versus endoscopic drainage of pseudocyst customarily include patients with both acute and chronic pseudocysts and the endoscopic modalities used for drainage are protean. We compared the outcomes following endoscopic cystogastrostomy (ECG) and surgical cystogastrostomy (SCG) in patients with acute pseudocyst. Methods: Seventy-three patients with acute pseudocyst requiring drainage from 2011 to 2014 were analysed (18 patients excluded: transpapillary drainage n = 15; cystojejunostomy n = 3). The remaining 55 patients were divided into two groups, ECG n = 35 and SCG n = 20, and their outcomes (technical success, successful drainage, complication rate and hospital stay) were compared. Results: The technical success (31/35 [89%] vs. 20/20 [100%] P = 0.28), complication rate (10/35 [28.6%] vs. 2/20 [10%]; P = 0.17) and median hospital stay (6.5 days [range 2-12] vs. 5 days [range 3-12]; P = 0.22) were comparable in both the groups, except successful drainage which was higher in surgical group (27/35 [78%] vs. 20/20 [100%] P = 0.04). The conversion rate to surgical procedure was 17%. The location of cyst towards tail of pancreas and presence of necrosis were the main causes of technical failure and failure of successful endoscopic drainage, respectively. Conclusion: Surgical drainage albeit remains the gold standard for management of pseudocyst drainage; endoscopic drainage should be considered a first-line treatment in patients with acute pseudocyst considering the reasonably good success rate.

Early recurrence after laparoscopic radical cholecystectomy in a patient with gallbladder cancer.

Laparoscopic radical cholecystectomy for gallbladder cancer (GBC) has been performed at various oncology centres reporting its technical feasibility. Considering GBC an aggressive malignancy, laparoscopic radical cholecystectomy should be dealt with caution. We recently encountered a case of carcinoma gallbladder who underwent laparoscopic radical cholecystectomy elsewhere and presented with early recurrence. The patient's records were evaluated and he underwent re-resection. Hereby, we discuss the factors that could lead to early recurrence after laparoscopic radical cholecystectomy and measures that can be taken to prevent it.

Utilization of Gastric Conduit in the Management of Combined Corrosive Esophageal and Stomach Stricture.

BACKGROUND: Corrosive stricture of esophagus may be associated with variable involvement of stomach. We analyzed the outcome of gastric conduit used in the management of corrosive esophageal stricture with concomitant antro-pyloric stricture. STUDY DESIGN: Among 101 esophageal replacements performed, 53 patients had combined esophagus and stomach strictures. Colon was used as a conduit in 43 patients, while stomach was used in ten patients. Indications, perioperative complications and early/late outcomes of patients with gastric pull-up were reviewed and compared with those undergone colon pull-up. RESULTS: The indications of using gastric conduit were impromptu in four patients [colonic conduit ischemia (n = 2) and an oversight of antro-pyloric stricture after forming the gastric conduit (n = 2)]. Six patients had preconceived gastric conduit (distal antro-pyloric stricture with distended stomach). The median age was 29 years (range 16-50), and median BMI was 15.4 kg/m2 (range 14.5-20.1). The stomach was drained using loop gastrojejunostomy (n = 7) or Roux-en-Y gastrojejunostomy (n = 3). One patient died due to sepsis secondary to anastomotic leak. Median hospital stay was 9 days (range 7-22). At median follow-up of 25 months (range 14-80), the remaining nine patients are able to have solid diet and have gained weight. The level of esophageal stricture was low (p = 0.01), and duration of surgery (p = 0.02) and median hospital stay (p = 0.04) were significantly less in patients with gastric conduit plus drainage as compared to patients undergone colonic pull-up. CONCLUSION: Gastric conduit in a subject with distal antro-pyloric stricture can be used safely along with gastrojejunostomy in selected patients of corrosive esophageal stricture.

Decreased expression of MGMT in correlation with aberrant DNA methylation in esophageal cancer patients from North India.

O-6-methylguanine-DNA methyltransferase, DNA repair gene, has been found to be involved with the pathogenesis of the esophageal cancer. DNA hypermethylation and other factors have been suggested to downregulate O-6-methylguanine-DNA methyltransferase. In this communication, the methylation status of O-6-methylguanine-DNA methyltransferase gene and the corresponding O-6-methylguanine-DNA methyltransferase protein expression in esophageal cancer from North India has been studied. In all, 80 samples of tumor tissue along with adjacent normal tissue as controls were analyzed for messenger RNA level of O-6-methylguanine-DNA methyltransferase gene, protein expression, and subcellular localization. The messenger RNA expression was studied using real-time quantitative polymerase chain reaction, protein expression, and its subcellular localization by Western blotting and immunohistochemistry. DNA methylation was assessed through methylation-specific polymerase chain reaction. Clinicopathological parameters were recorded and correlated with the O-6-methylguanine-DNA methyltransferase expression. O-6-methylguanine-DNA methyltransferase messenger RNA expression was found to be downregulated in 65% cases (52/80). The expression of O-6-methylguanine-DNA methyltransferase at the protein level was also found to be absent in 65% (52/80) cases. In all, 52 cases had low or no expression of the protein, whereas out of those 28 remaining cases, 11.25% (09/80) cases had high O-6-methylguanine-DNA methyltransferase protein expression. The absence of O-6-methylguanine-DNA methyltransferase protein coincided with the methylated cases in 84% (38/45), whereas in 07 cases, out of the 45 methylated, O-6-methylguanine-DNA methyltransferase protein was present. The aggressive esophageal cancer patients having methylated O-6-methylguanine-DNA methyltransferase had more than 50% cases with no/mild expression of the O-6-methylguanine-DNA methyltransferase protein ( p > 0.001). Loss of O-6-methylguanine-DNA methyltransferase protein was very frequent in the incidence of esophageal cancer from North Indian patients, and methylation of the promoter region of O-6-methylguanine-DNA methyltransferase was significantly associated in its downregulation.

Association of mitochondrial copy number variation and T16189C polymorphism with colorectal cancer in North Indian population.

Globally, colorectal cancer is the third most common type of cancer. Genetic instability leading to cancer development is one of the major causes for development of cancer. Alterations in mitochondrial genome, that is, mutations, single-nucleotide polymorphisms, and copy number variations are known to contribute in cancer development. The aim of our study was to investigate association of mitochondrial T16189C polymorphism and copy number variation with colorectal cancer in North Indian population. DNA isolated from peripheral blood of 126 colorectal cancer patients and 114 healthy North Indian subjects was analyzed for T16189C polymorphism and half of them for mitochondrial copy number variation. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism, and copy number variation was estimated using real-time polymerase chain reaction, numbers of mitochondrial copies and found to be significantly higher in colorectal cancer patients than healthy controls (88 (58-154), p = 0.001). In the regression analysis, increased mitochondrial copy number variation was associated with risk of colorectal cancer (odds ratio = 2.885, 95% confidence interval = 1.3-6.358). However, T16189C polymorphism was found to be significantly associated with the risk of rectal cancer (odds ratio = 5.213, p = 0.001) and non-significantly with colon cancer (odds ratio = 0.867, p = 0.791). Also, false-positive report probability analysis was done to validate the significant findings. Our results here indicate that mitochondrial copy number variation may be playing an important role in the development of colorectal cancer, and detection of mitochondrial copy number variation can be used as a biomarker for predicting the risk of colorectal cancer in North Indian subjects.

Step-Down Approach for Pharyngoesophageal Corrosive Stricture: Outcome and Analysis.

BACKGROUND: Pharyngoesophageal stricture (PES) is an Achilles' heel in the management of corrosive injury. Advances in endoscopic techniques were utilized in its management. We classified the stricture as per its dilatability and then planned their treatment. METHODS: PES was sub-categorized based on endoscopic dilatation and availability of cervical oesophagus: group-1 stricture with available cervical oesophagus; group-2 stricture with some part of upper oesophagus made available after endoscopic dilatation and anastomosis in cervico-pharyngeal area; group-3 stricture not amenable for dilatation, anastomosis done at the pharynx. Endoscopic dilatation was performed using through-the-scope pyloric balloon. Number and duration of dilatation sessions before surgery, incidence of tracheostomy, time and incidence for re-stricture and present status of swallowing were evaluated. RESULTS: Of 226 patients managed, 46 underwent oesophageal replacement for PES. Group 1, 2 and 3 had 12, 14 and 20 patients, respectively. An average 3 (2-4) preoperative balloon dilatation sessions were performed over 6-8 weeks. Tracheostomy was required in 1, 0, 8 patients (p = 0.010), and median hospital stay was 10, 9 and 13 days (p = 0.09) in group 1, 2, 3, respectively. Re-stricture developed in 4/12, 4/14, 9/20 patients with average sessions of dilatation required in post-operative period was 4, 3.5 and 8 in group 1, 2, 3, respectively. >90% of patients are taking normal diet in each group. CONCLUSION: We attempted to avoid the high anastomosis by dilating the PES and step down the level of anastomosis in two-third patients. We thereby avoided tracheostomy, aspiration and swallowing problems related to high strictures.

Prognostic Significance of HER-2 and p53 Expression in Gallbladder Carcinoma in North Indian Patients.

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.

Allelic loss at PTEN locus leads to progression of colorectal carcinoma among North Indian patients.

We evaluated the loss of heterozygosity (LOH) at 10q23.3 locus of microsatellite markers; D10S198, D10S192, and D10S541 of PTEN gene in 223 North Indian colorectal cancer (CRC) specimens. DNA was isolated and microsatellite-specific markers polymerase chain reaction was performed. Out of total 223 cases 102 showed LOH for at least one of the locus. In addition, thereto a significant association was found with the clinicopathologic features like grade of differentiation, clinical stage, invasion, lymph node invasion, and the clinical outcome (p < 0.05). These data argue that the given markers to check the possible LOH of PTEN gene at locus 10q23.3 could be considered as one of the diagnostic markers in CRC.

Chronic pancreatitis with benign biliary obstruction: management issues.

BACKGROUND: Benign biliary obstruction (BBO) is an important complication in patients with advanced chronic pancreatitis (CP). Its presentation varies from an incidental finding to overt jaundice. Thus it presents certain management issues. The present study was therefore performed to analyze the clinical presentation and management of biliary obstruction in patients with CP. METHODS: Retrospective analysis was performed from a prospectively collected database of 155 CP patients managed at our institute from October 2003 to June 2012. RESULTS: Among 43 (28 %) CP patients with biliary obstruction, 3 patients had evidence of malignancy on follow-up examination and were excluded from the final analysis. The various presentations include chronic nonprogressive elevation of serum alkaline phosphatase (SAP) (n = 15), a progressive increase in SAP with episodes of jaundice (n = 17), and persistent jaundice (n = 8). Of 15 patients with chronic nonprogressive elevation of SAP, 5 were managed conservatively, and the remaining 10 underwent only a pancreatic drainage procedure. During a median follow-up of 41 months (range 11-90 months), none of the 15 patients developed complications related to biliary obstruction. All patients with progressive increase in SAP levels and persistent jaundice underwent the biliary drainage procedure [choledochojejunostomy (CDJ, n = 20) and choledochoduodenostomy (CDD, n = 3)]. During a median follow-up of 30 months (range 10-89 months), two patients died of unrelated causes and two patients had an asymptomatic elevation of SAP. CONCLUSIONS: BBO is common in patients with CP; however, biliary drainage is not indicated for chronic nonprogressive elevation of SAP. In patients with a progressive increase in SAP or persistent jaundice, both CDJ and CDD provide effective biliary drainage.

An update on the cell-free DNA-derived methylome as a non-invasive biomarker for coronary artery disease.

Cardiovascular diseases are the foremost contributor to global mortality, presenting a complex etiology and an expanding array of risk factors. Coronary artery disease characterized by atherosclerotic plaque build-up in the coronary arteries, imposes significant mortality and financial burdens, especially in low- and middle-income nations. The pathogenesis of coronary artery disease involves a multifaceted interplay of genetic, environmental, and epigenetic factors. Epigenetic regulation contributes to the dynamic control of gene expression without altering the underlying DNA sequence. The mounting evidence that highlights the pivotal role of epigenetic regulation in coronary artery disease development and progression, offering potential avenues for the development of novel diagnostic biomarkers and therapeutic targets. Abnormal DNA methylation patterns are linked to the modulation of gene expression involved in crucial processes like lipid metabolism, inflammation, and vascular function in the context of coronary artery disease. Cell-free DNA has become invaluable in tumor biology as a liquid biopsy, while its applications in coronary artery disease are limited, but intriguing. Atherosclerotic plaque rupture causes myocardial infarction, by depriving heart muscles of oxygen, releasing cell-free DNA from dead cardiac cells, and providing a minimally invasive source to explore tissue-specific epigenetic alterations. We discussed the methodologies for studying the global methylome and hydroxy-methylome landscape, their advantages, and limitations. It explores methylome alterations in coronary artery disease, considering risk factors and their relevance in coronary artery disease genesis. The review also details the implications of MI-derived cell-free DNA for developing minimally invasive biomarkers and associated challenges.

Role of adjuvant therapy in resected periampullary adenocarcinoma: A propensity matched case-control study.

Backgrounds/Aims: The published data had contradictory information on the role of adjuvant therapy on resected periampullary carcinomas (PACA). The study was performed to evaluate the survival benefit of adjuvant treatment. Methods: This was a propensity score matched case-control study from a prospectively maintained database from 2004-2019. The study included patients with nonpancreatic PACA who underwent curative resection. The patients (cases) who received adjuvant chemotherapy were compared with patients (controls) who were observed alone after surgery. Results: Of 510 patients with PACA, 230 patients (cases = 107, controls = 123) formed the unmatched study cohort. After propensity score matching, 140 patients (cases = 70, controls = 70) formed the matched study cohort. The median overall survival (OS) was similar in cases than controls in the unmatched population but doubled non-significantly in cases after matching (unmatched population, 54 months vs. 54 months, p-value = 0.624; matched population, 71 months vs. 36 months, p-value = 0.087). However, the median recurrence-free survival (RFS) was non significantly higher in the control group (unmatched population, 59 months vs. 38 months, p-value = 0.195; matched population, 53 months vs. 40 months, p-value = 0.797). In cox regression analysis, age < 60 years, advanced T stage, and presence of perineural invasion were independent factors for worse RFS, while tumor recurrence was an independent factor for poor OS. Conclusions: Patients with nonpancreatic PACA may have an OS benefit from adjuvant chemotherapy, and this needs to be validated with large prospective randomized studies.