CCND1 Amplification in Pancreatic Ductal and Ampullary Adenocarcinoma and Its Impact on Patients' Survival: a Single-Center Observational Study.

Studies conducted worldwide in the last few decades have demonstrated that various high- and low-frequency inherited and somatic mutations play important roles in the pathogenesis of periampullary carcinoma. Owing to relatively inaccessible location and lack of specific early diagnostic signs, majority of periampullary tumors are difficult to manage. Limited chemotherapeutic options that are available are highly toxic and not very efficacious. CyclinD1, if found to be amplified in these malignancies, might become an important gene to be targeted for monoclonal antibody therapy. An analytical retrospective-prospective study was done on 35 patients of operable periampullary carcinoma, in Medical College, Kolkata from January 2019 to July 2020. After isolating DNA from tumor and corresponding normal tissue by Qiagen DNEasy kit, CyclinD1 amplification was assessed by RT-PCR using Taqman DNA copy number in the laboratory of Indian Statistical Institute. Survival analysis was done by Kaplan-Meier estimator and all statistical calculations performed through SPSS software. Six (17%) out of 35 patients were found to have > twofold amplifications of CyclinD1 gene. However, no positive correlation was found between CyclinD1 amplification and overall survival of the patients (p value 0.21). Positive correlation was not found in our study between CCND1 amplification and periampullary malignancy. However, a single large study conducted in Japan by Yamazaki showed reduced survival and higher metastasis in CyclinD1 positive periampullary carcinoma. So there is reasonable scope in future for large-scale population-based studies to establish similar association in our subcontinent as well.

DNA methylome in pancreatic cancer identified novel promoter hyper-methylation in NPY and FAIM2 genes associated with poor prognosis in Indian patient cohort.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a 5-year survival rate of only 8.5%. In this study we investigated altered DNA methylation associated with PDAC severity and prognosis. METHODS: Methylome data, generated using 450 K bead array, was compared between paired PDAC and normal samples in the TCGA cohort (n = 9) and our Indian cohort (n = 7). The total Indian Cohort (n = 75) was split into cohort 1 (n = 7), cohort 2 (n = 22), cohort 3 (n = 26) and cohort 4 (n = 20).Validation of differential methylation (6 selected CpG loci) and associated gene expression for differentially methylated genes (10 selected gDMs) were carried out in separate validation cohorts, using MSP, RT-PCR and IHC correlations between methylation and gene expression were observed in TCGA, GTEx cohorts and in validation cohorts. Kaplan-Meier survival analysis was done to study differential prognosis, during 2-5 years of follow-up. RESULTS: We identified 156 DMPs, mapped to 91 genes (gDMs), in PDAC; 68 (43.5%) DMPs were found to be differentially methylated both in TCGA cohort and our cohort, with significant concordance at hypo- and hyper-methylated loci. Enrichments of "regulation of ion transport", "Interferon alpha/beta signalling", "morphogenesis and development" and "transcriptional dysregulation" pathways were observed among 91 gDMs. Hyper-methylation of NPY and FAIM2 genes with down-regulated expression in PDAC, were significantly associated with poor prognosis in the Indian patient cohort. CONCLUSIONS: Ethnic variations among populations may determine the altered epigenetic landscape in the PDAC patients of the Indian cohort. Our study identified novel differentially methylated genes (mainly NPY and FAIM2) and also validated the previously identified differentially methylated CpG sites associated with PDAC cancer patient's survival. Comparative analysis of our data with TCGA and CPTAC cohorts showed that both NPY and FAIM2 hyper-methylation and down-regulations can be novel epigenetically regulated genes in the Indian patient population, statistically significantly associated with poor survival and advanced tumour stages.

A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5-2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now. METHODS: Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the p.A138V mutant of TP53. Key polymorphisms at TP53 and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured. RESULTS: Among the total 114 detected somatic mutations, TP53 was the most frequently mutated (41%) gene, followed by KRAS, SMAD4, CTNNB1, and ERBB3. We identified a novel hotspot TP53 mutation (p.A138V, in 17% of all patients). Low frequency of KRAS mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted p.A138V to have oncogenic characteristics. Patients with p.A138V mutation showed poorer overall survival (p = 0.01). So, our finding highlights elevated prevalence of the p53p.A138V somatic mutation in PDAC and pancreatobiliary PAC patients. CONCLUSION: Detection of p.A138V somatic variant in TP53 might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of KRAS hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.

Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions.

BACKGROUND: Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered an epigenetic disease. DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor. In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma (PDAC), the epigenetic changes play a significant role. DATA SOURCES: Relevant studies for this review were derived via an extensive literature search in PubMed via using various keywords such as pancreatic ductal adenocarcinoma, precancerous lesions, methylation profile, epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest. The literature search was intensively done considering a time frame of 20 years (1998-2018). RESULT: In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions (pancreatic intra-epithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm and chronic pancreatitis) and PDAC along with the potential biomarkers. We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC. A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC (ppENK, APC, p14/5/16/17, hMLH1 and MGMT) are also documented. We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy. Epigenetic inactivation occurs by hypermethylation of CpG islands in the promoter regions of tumor suppressor genes. We listed all hyper- and hypomethylation of CpG islands of several genes in PDAC including its precancerous lesions. CONCLUSIONS: The concept of the review would help to understand their biological effects, and to determine whether they may be successfully combined with other epigenetic drugs. However, we need to continue our research to develop more specific DNA-demethylating agents, which are the targets for hypermethylated CpG methylation sites.

Genetic Alterations of Periampullary and Pancreatic Ductal Adenocarcinoma: An Overview.

Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies of all solid cancers. Precancerous lesions for PDAC include PanIN, IPMNs and MCNs. PDAC has a poor prognosis with a 5-year survival of approximately 6%. Whereas Periampulary AdenoCarcinoma (PAC) having four anatomic subtypes, pancreatic, Common Bile Duct (CBD), ampullary and duodenum shows relative better prognosis. The highest incidence of PDAC has been reported with black with respect to white population. Similarly, incidence rate of PAC also differs with different ethnic populations. Several lifestyle, environmental and occupational exposures including long-term diabetes, obesity, and smoking, have been linked to PDAC, however, for PAC the causal risk factors were poorly described. It is now clear that PDAC and PAC are a multi-stage process resulting from the accumulation of genomic alterations in the somatic DNA of normal cells as well as inherited mutations. Approximately 10% of PDAC have a familial inheritance. Germline mutations in CDKN2A, BRCA2, STK11, PALB2, PRSS1, etc., as well as certain syndromes have been well associated with predisposition to PDAC. KRAS, CDKN2A, TP53 and SMAD4 are the 4 "mountains" (high-frequency driver genes) which have been known to earliest somatic alterations for PDAC while relatively less frequent in PAC. Our understanding of the molecular carcinogenesis has improved in the last few years due to extensive research on PDAC which was not well explored in case of PAC. The genetic alterations that have been identified in PDAC and different subgroups of PAC are important implications for the development of genetic screening test, early diagnosis, and prognostic genetic markers. The present review will provide a brief overview of the incidence and prevalence of PDAC and PAC, mainly, increased risk in India, the several kinds of risk factors associated with the diseases as well as required genetic alterations for disease initiation and progression.

Transient Diabetes Insipidus Following Thermal Burn; A Case Report and Literature Review.

Diabetes insipidus is a disease charaterised by increased urine production and thrist. Neurogenic diabetes insipidus following head trauma,autoimmune disease and infection is quite common but diabetes insipidus following thermal burn injury is a rare complication.We should know about this complication as its management need a comprehensive approach for satisfactory outcome. Thermal burn can cause different complications in early post burn period like electrolyte imbalance, dehydration, acute renal failure, but diabetes insipidus is a very rare and unusual complication that may come across in thermal burn. We should be aware about this condition to prevent and treat mortality and morbidity in burn patients. We have reported a case of transient diabetes insipidus in a patient of thermal burn in early post burn period. Patient was treated accordingly, leading to complete recovery.

Plexiform angiomyxoid myofibroblastic tumour of the duodenum: a rare entity.

Plexiform angiomyxoid myofibroblastic tumour (PAMT) has recently emerged as a new entity among gastrointestinal mesenchymal tumours. All of the 27 cases reported until now originated from the stomach. We report the first case of a duodenal PAMT arising from the first part of the duodenum in a 19-year-old woman presenting with upper abdominal pain and an abdominal lump.

Appendiceal knotting causing small bowel strangulation.

Small bowel obstruction is a common cause of an emergency admission in the surgical wards. Acute appendicitis presenting with small bowel obstruction due to appendiceal knotting is a very rare and unsuspected condition in an emergency scenario. We report a case of acute small bowel obstruction in a 26-year-old male who, on exploration was found to have small bowel strangulation due to appendiceal knotting. Though rare, the possibilities of such a diagnosis should be kept in mind in patients with small bowel obstruction with no known identifiable etiology.

Spontaneous retroperitoneal haemorrhage in a young adult.

We report a rare case of a primary adrenal cortical malignancy presenting with spontaneous retroperitoneal haemorrhage in a young adult. To the best of our knowledge, this is the thirteenth such case to be reported in the English literature.

An unusual presentation of foreign body in the common carotid artery.

Penetrating trauma to neck resulting in arteriovenous (AV) fistula and aneurysms involving the carotid system are uncommon injuries with life-threatening consequences. We report here a case of a young factory worker who developed a traumatic AV fistula with false aneurysm, with however, no other complications. He was successfully operated when he presented to us two months after the injury and is doing well in follow-up.

Gastric tuberculosis - a diagnostic dilemma.

Gastric tuberculosis is an extremely rare entity particularly when it is not associated with pulmonary tuberculosis or an immunodeficient state. Here one patient required surgery for gastric outlet obstruction and was subsequently put on antituberculous drugs. The patient responded well to treatment and is currently doing well in follow-up. This disease though rare should be considered in the differential diagnosis of gastric malignancy and severe peptic ulcer disease.

A study of 500 cancer patients to know any relation between malignancy and socio-economic status.

It was a common belief that cancer is more prevalent among the lower socio-economic group. It was also generally accepted that mortality was higher in this group due to various reasons. In this hospital based study, an attempt had been made to find out any association between cancer incidence and socio-economic factors like age, sex, education, occupation, and income. The relative distribution of cancers in different parts of the body was also analysed. Collected data for cancers of the breast, lung, cervix and gall bladder were also analysed separately. It was found that there was a significant association between the occurrence of cancer and the middle income group earning Rs 12000-60000 annually. On the other side people having higher education and higher income were less likely to suffer from cancer and presented at an earlier stage.

Single stage primary anastomosis without colonic lavage for left-sided colonic obstruction due to acute sigmoid volvulus: a prospective study of one hundred and ninety-seven cases.

BACKGROUND: The purpose of this study was to examine the feasibility of single-stage resection and anastomosis for acute left-sided colonic obstruction due to acute sigmoid volvulus without intraoperative lavage. Mechanical bowel preparation has been shown to be unnecessary for elective colorectal surgery. Colonic decompression without intraoperative lavage may simplify operations in acute left-sided colorectal obstruction. METHODS: Emergency resection of acute sigmoid volvulus was performed. This was followed by primary anastomosis without on-table lavage after closed bowel decompression. RESULTS: A total of 197 patients underwent bowel decompression, resection and primary colonic anastomosis. Two patients developed anastomosis leak, requiring re-laparotomy, Hartmann's procedure and delayed closure. Two deaths occurred postoperatively; these were unrelated to the nature of the surgery. The mean hospital stay was 9.8 days. CONCLUSION: Primary colonic anastomosis can be safely done for obstructed left colon due to acute sigmoid volvulus without intraoperative colonic lavage.

Acute appendicectomy for appendicular mass: a study of 87 patients.

OBJECTIVE: To study the feasibility of acute appendicectomy in patients with an appendicular mass. SETTING: Department of Surgery, Bankura Sammalani Medical College (BSMCH), Bankura, West Bengal, India. PATIENTS: From January 1998 to May 2001. 87 patients were diagnosed and operated for appendix mass within 24 h of admission. None of the patients had any associated complications. INTERVENTION: A McBurney's incision with Rutherford-Morrison extension was made in most patients. RESULTS: 48 patients presented with a classical appendix mass. 25 patients (28.7%) had classical features of appendix abscess, and in 14 (16.1%) a loculated collection of pus (10 to 50 ml) was found. Operative time ranged from 45 to 90 min (mean 65). Pathologic evidence of appendicitis was present in all patients. 71 patients were discharged on the seventh postoperative day. 15 patients developed minor wound infection. One patient developed band obstruction, which subsided spontaneously on conservative treatment. Rest of the patients are doing well. CONCLUSION: Low morbidity, reduced hospital stay, low cost and patient compliance favour operative management of appendicular mass by experienced surgeons thus obviating the old practice of conservative treatment followed by interval appendicectomy.