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The prognostic and predictive value of serum CA19.9 in pancreatic cancer.

Abstract

Published July 2012

BACKGROUND:

Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.

METHODS:

We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.

RESULTS:

By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P=0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels>90 U/ml did not benefit from adjuvant chemotherapy (P=0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P=0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P=0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.

CONCLUSIONS:

Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.

Collaborators:

Biankin A, Merrett N, Cosman P, Das A, Pavey D, Asghari R, Ismail K, Samra J, Gill A, Pavlakis N, Toon C, Guminski A, Lam V, McLeod D,Pleass H, James V, Sandroussi C, Crawford M, Joseph D, Kench J, Cooper C.

PMID: 22241899 [PubMed – indexed for MEDLINE] PMCID: PMC3387824

RON is not a prognostic marker for resectable pancreatic cancer.

Abstract

Published September 2012

BACKGROUND:

The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown.

METHODS:

RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed.

RESULTS:

RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study.

CONCLUSIONS:

Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/22958871

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Abstract

Published October 2012

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/23103869

Transcriptionally active human papillomavirus is strongly associated with Barrett’s dysplasia and esophageal adenocarcinoma.

Abstract

Published April 2013

OBJECTIVES:

The role of human papillomavirus (HPV) in Barrett’s esophagus (BE) remains unclear. The few studies that have previously investigated HPV and esophageal adenocarcinoma (EAC) or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types. We therefore prospectively determined the prevalence of biologically active HPV in esophageal epithelium of patients representing the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence.

METHODS:

HPV DNA was estimated by nested PCR and viral transcriptional activity detected by E6/7 oncogene mRNA expression and p16INK4A immunohistochemistry in fresh frozen and paraffin-embedded esophageal biopsies of patients with BE, Barrett’s dysplasia (BD), and EAC, as well as controls. Biopsies were obtained from the transformation zone (squamocolumnar junction (SCJ)) and the lesion, or corresponding site in controls, i.e., 2 cm above the gastroesophageal junction (GEJ).

RESULTS:

Of the 261 patients, 81 were positive for HPV DNA. In controls and BE, the virus was mostly detected at the transformation zone. Compared with controls (18.0%), HPV positivity was significantly more common in BD (68.6%, incidence rate ratio (IRR) 2.94, 95% confidence interval (CI) 1.78-4.85, P<0.001) and EAC (66.7%, IRR 2.87, 95% CI 1.69-4.86, P<0.001), but not in BE (22.1%, IRR 1.06, 95% CI 0.60-1.85, P=0.85). Of the patients, 92.6% were high-risk (HR) HPV, i.e., types 16 and 18. Again, p16INK4A positivity was greatest in BD and EAC and much less in BE patients (44.1%, IRR 17.0 (95% CI 4.86-59.6, P<0.001), 44.4%, 17.0 (95% CI 4.87-59.4, P<0.001), and 10.6%, 3.93 (95% CI 1.01-15.3, P=0.048) respectively). In 66 HPV DNA-positive patients tested for E6/E7 mRNA, none of the control (n=16) or BE (n=13) individuals were positive, whereas 9/22 BD and 9/15 EAC patients demonstrated oncogene expression (P<0.001). When HPV DNA, p16INK4A, and E6/E7 mRNA were all positive, there was a very strong association with disease severity (SCJ: odds ratio (OR) 104, 95% CI 20.3-529, P<0.001; lesion: OR 62.2, 95% CI 12.4-311, P<0.001) than when all were negative.

CONCLUSIONS:

Transcriptionally active HR-HPV was strongly associated with BD and EAC, but was largely biologically irrelevant in BE and controls, suggesting a potential role in esophageal carcinogenesis. These data provide robust justification for further detailed longitudinal, interventional, and molecular studies.

Authors:

Rajendra S, Wang B, Snow ET, Sharma P, Pavey D, Merrett N, Ball MJ, Brain T, Fernando R, Robertson IK.

 

PMID: 23588239 [PubMed – indexed for MEDLINE]

 

Persistence of Human Papillomavirus, Overexpression of p53, and Outcomes of Patients After Endoscopic Ablation of Barrett’s Esophagus.

Abstract

We investigated the role of high-risk human papillomavirus (hr-HPV) in patients with Barrett’s dysplasia and adenocarcinoma (EAC). Clearance vs persistence of HPV (DNA, E6 or E7 mRNA, and p16INK4A protein) and overexpression or mutation of p53 were determined for 40 patients who underwent endotherapy for Barrett’s dysplasia or EAC. After ablation, dysplasia or neoplasia was eradicated in 34 subjects (24 squamous, 10 intestinal metaplasia). Six patients had detectable lesions after treatment; 2 were positive for transcriptionally active hr-HPV, and 4 had overexpression of p53. Before endotherapy, 15 patients had biologically active hr-HPV, 13 cleared the infection with treatment, and dysplasia or EAC was eliminated from 12 patients. One patient who cleared HPV after ablation acquired a p53 mutation, and their cancer progressed. Of 13 patients with overexpression of p53 before treatment, 10 cleared the p53 abnormality after ablation with eradication of dysplasia or neoplasia, whereas 3 of 13 had persistent p53 mutation-associated dysplasia after endotherapy (P = .004). Immunohistochemical and sequence analyses of p53 produced concordant results for 36 of 40 samples (90%). Detection of dysplasia or neoplasia after treatment was associated with HPV persistence or continued p53 overexpression.

Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Barrett’s Esophagus; Carcinogenesis; Genetic; Immunohistochemistry; Tumor Suppressor

Comment in

Authors:

Rajendra S, Wang B, Pavey D, Sharma P, Yang T, Lee CS, Gupta N, Ball MJ, Gill RS, Wu X.

 

Clin Gastroenterol Hepatol. 2015 Jul;13(7):1364-1368.e5. doi: 10.1016/j.cgh.2014.11.017. Epub 2014 Nov 21.

 

PMID: 25460562

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/25460562

 

Australian clinical practice guidelines for the diagnosis and management of Barrett’s esophagus and early esophageal adenocarcinoma.

Abstract

Barrett’s esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.

© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Authors:

Whiteman DC, Appleyard M, Bahin FF, Bobryshev YV, Bourke MJ, Brown I, Chung A, Clouston A, Dickins E, Emery J, Eslick GD, Gordon LG, Grimpen F, Hebbard G, Holliday L, Hourigan LF, Kendall BJ, Lee EY, Levert-Mignon A, Lord RV, Lord SJ, Maule D, Moss A, Norton I, Olver I, Pavey D, Raftopoulos S, Rajendra S, Schoeman M, Singh R, Sitas F, Smithers BM, Taylor AC, Thomas ML, Thomson I, To H, von Dincklage J, Vuletich C, Watson DI, Yusoff IF.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/25612140

Genomic analyses identify molecular subtypes of Pancreatic Cancer.

Abstract

Published February 2016

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

 

Published: https://www.ncbi.nlm.nih.gov/pubmed/26909576

Pancreatic Cancer Awareness Month – November

Go purple for November 16Early Detection Saves lives

On World Pancreatic Cancer Day, people around the world will unite to Demand Better in the fight against the world’s toughest cancer, starting with earlier diagnosis. Join us as we work together on this special day to make a world of difference.

 

 

 

 

 

 

 

 

 

 

 

Know the Symptoms and Risks

Currently, there is no screening test or early detection method for pancreatic cancer. Some are in development – another sign of the progress happening in the field that needs greater attention and funding support. 

Early diagnosis is vital, so listen to your body and don’t ignore the signs. If you have symptoms, speak to your healthcare provider as soon as you can. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Further details on how you can create awareness can be found here www.worldpancreaticcancerday.org 

 

Colorectal Cancer Awareness Month

National Colorectal Cancer Awareness Month, held in March each year, offers healthcare providers who care for patients with diseases of the colon and rectum a valuable opportunity to educate their community about these diseases and promote awareness of the importance of colorectal cancer screening, prevention, and treatment. These efforts may also provide a window into the profession and encourage others to consider careers in the field of colon and rectal surgery.

Colorectal Cancer Awareness Month

Colorectal Cancer Awareness Month

Concentrated radio waves provide new approach to treating precancerous esophagus condition

The use of concentrated radio waves appears to be a safe and effective way to “burn” away abnormal cell growth in the esophagus that can be a precursor of cancer.

Published: 2007

The new procedure is being tested in patients with Barrett’s esophagus, a condition associated with the continued reflux of stomach acids into the lower esophagus that can damage its lining over time. While this condition is relatively common, a small percentage of patients will go on to develop abnormal cell growth known as dysplasia, a condition that can lead to esophageal cancer.

Gastroenterologists at Duke University Medical Center found that delivering concentrated radio waves through a catheter inserted down the esophagus can effectively treat the dysplasia with fewer side effects than current treatment methods. After the treatment, known as radiofrequency ablation, the treated cells die, slough off and are replaced within four to six weeks by new, healthier cells.

In a review of the first 12 patients treated with radiofrequency ablation at Duke, gastroenterologist Darren Pavey, M.B.B.S., found that three months after treatment, 89 percent of patients had more normal-looking esophageal tissue when viewed with an endoscope inserted down the esophagus. When samples of the new cells were analyzed in the laboratory, half of the patients were shown to have healthier tissues.

Pavey presented the results of the analysis on Tuesday, May 22, at the annual Digestive Disease Week conference in Washington, D.C. His analysis was supported by Duke’s Division of Gastroenterology.

“In the procedure, which takes about 20 to 30 minutes, we insert a catheter down the esophagus and superficially burn the layer of cells that are abnormal,” Pavey said. “The procedure is performed on patients as an outpatient procedure under conscious sedation, much as during a colonoscopy. The patients find that they have little or no discomfort following the procedure.”

Pavey said that if radiofrequency ablation is proven effective in larger trials now under way, physicians will be able to offer a technique that has fewer side effects and is better tolerated by patients.

There are currently two main treatments for Barrett’s esophagus with high grade dysplasia. The surgical approach involves removing the affected portion of esophagus. It is a major operation that has up to a 6 percent mortality rate and also can leave patients with reflux and swallowing problems, Pavey said.

A second approach, in use for the past 10 years, is known as photodynamic therapy. It involves a photosensitizing agent that is preferentially taken up by abnormal cells. Physicians then shine a laser light into the esophagus, and the light kills the target cells. However, patients must avoid direct sunlight for several weeks, and up to 30 percent of patients experience scarring of the esophagus severe enough to affect swallowing.

“So far, radiofrequency ablation seems to be less invasive than surgery and better tolerated than photodynamic therapy,” Pavey said. “This approach has the potential to dramatically alter the way we treat patients with Barrett’s esophagus.”

While the incidence of Barrett’s esophagus is difficult to determine, studies at autopsy indicate that the condition occurs in one in every 60 to 80 people in the United States, mostly in Caucasians. It also occurs four times more frequently in men than women. About 10 percent of patients with long-term gastrointestinal reflux, or heartburn, will go on to develop Barrett’s esophagus.

“In our study, we also found that radiofrequency ablation appears to be effective for those patients who have had an incomplete response following treatment with photodynamic therapy,” Pavey said

 

Published: http://www.news-medical.net/news/2007/05/24/25565.aspx