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

Posted 22nd December 2017

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

 

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

Posted 22nd December 2017

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

Genomic analyses identify molecular subtypes of Pancreatic Cancer.

Posted 17th December 2017

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

Concentrated radio waves provide new approach to treating precancerous esophagus condition

Posted 24th February 2016

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

Whole genomes redefine the mutational landscape of pancreatic cancer.

Posted 14th March 2018

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Collaborators:

Biankin AV, Johns AL, Mawson A, Chang DK, Scarlett CJ, Brancato MA, Rowe SJ, Simpson SH, Martyn-Smith M, Thomas MT, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead RS, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Tao J, DiPietro R, Watson C, Steinmann A, Ching Lee H, Wong R, Pinho AV, Giry-Laterriere M, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M,Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Bailey P, Quinn M,Nagaraj S, Kazakoff S, Waddell N, Krisnan K, Quek K, Wood D, Fadlullah MZ, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Asghari R,Merrett ND, Pavey D, Das A, Cosman PH, Ismail K, O’Connnor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL,Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V,Tang H, Barbour AP, Clouston AD, Martin P, O’Rourke TJ, Chiang A, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C,Nikfarjam M, Mountain A, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Hodgin M, Scarpa A,Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Biankin AV, Grimmond SM, Chang DK, Musgrove EA, Jones MD, Nourse C,Jamieson NB, Graham JS, Biankin AV, Chang DK, Jamieson NB, Graham JS, Oien K, Hair J.

 

PMID: 25719666 [PubMed – indexed for MEDLINE] PMCID:PMC4523082

 

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

Posted 14th March 2018

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2′-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

Comment in
Collaborators:

Biankin AV, Johns AL, Mawson A, Chang DK, Brancato MA, Rowe SJ, Simpson SL, Martyn-Smith M, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead R, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink J, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Blankin AV, Asghari R, Merrett ND, Chang DK, Pavey DA, Das A, Cosman PH, Ismail K, O’Connor C, Lam VW, McLeod D, Pleass HC, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford L, Texler M, Forrest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Feeney K, Zeps N, Beilin M, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O’Rourke TJ, Chiang A, Fawcet JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Scarlett CJ, Kaplan W, Scarpa A.

PMID: 22699621 [PUBMED – INDEXED FOR MEDLINE] PMCID: PMC3376394

Retrospective analysis of the utility of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in pancreatic masses, using a 22-gauge or 25-gauge needle system: a multicenter experience.

Posted 14th March 2018

Abstract

BACKGROUND AND STUDY AIMS:

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is now performed routinely in many advanced endoscopy centers and has enhanced the ability to diagnose pancreatic masses. However, there is uncertainty about which needle size is optimal for EUS-FNA of pancreatic masses. We aimed to evaluate the performance of the 22-gauge and 25-gauge needles in obtaining cytologic diagnosis of pancreatic masses.

METHODS:

All cases that were referred for EUS-FNA for pancreatic masses between February 2001 and June 2007 were reviewed, and patients who underwent EUS-FNA using the 22-gauge and 25-gauge needle system were identified. In patients who underwent surgery, operative histopathological findings were compared with the cytopathological findings from EUS-FNA.

RESULTS:

A total of 842 patients with pancreatic masses detected on computed tomography (CT) and/or magnetic resonance imaging (MRI) and confirmed by EUS underwent EUS-FNA with the 22-gauge needle (n = 540) or the 25-gauge needle (n = 302). Results of EUS-FNA cytology findings were compared with the gold standard of surgical histopathological findings or long-term clinical follow-up. The sensitivity, specificity, PPV, and NPV of FNA were respectively 84%, 100%, 100%, and 73% [corrected] for the 22-gauge needle compared with 92%, 97%, 98%, and 87%, [corrected] respectively for the 25-gauge needle. No complications were noted in the 25-gauge needle group, compared with pancreatitis in 2% of the 22-gauge needle group.

CONCLUSIONS:

This retrospective comparative study shows that EUS-FNA with a 25-gauge needle system is a safe and reliable method for tissue sampling in pancreatic masses. The system is more sensitive and has a slightly [corrected] higher NPV than the standard 22-gauge needle. Our study suggests that perhaps the smaller caliber FNA needle causes less trauma during EUS-FNA and hence less complications. Further studies including randomized trials are needed.

Authors:

Yusuf TE, Ho S, Pavey DA, Michael H, Gress FG.

Endoscopy. 2009 May;41(5):445-8. doi: 10.1055/s-0029-1214643. Epub 2009 May 5. Erratum in: Endoscopy. 2009 Jun;41(6):509.

PMID: 19418399 [PubMed – indexed for MEDLINE]

 

Endoscopic therapy for upper-GI vascular ectasias

Posted 10th November 2015

Abstract

BACKGROUND:

Upper-GI vascular ectasias, including angiodysplasia and gastric antral vascular ectasia may present with either acute or chronic bleeding. Endoscopic thermal modalities have been used to control acute bleeding and reduce transfusion requirements.

METHODS:

Endoscopic experience was reviewed for a 6-year period during which 32 patients requiring blood transfusions for upper-GI angiodysplasia or gastric antral vascular ectasia were evaluated. Patients seen during the first 5 years were treated with either Nd:YAG laser photocoagulation or multipolar electrocoagulation. During the most recent 12 months, all patients were treated by argon plasma coagulation. Response to therapy was assessed by change in mean Hb and transfusion requirements.

RESULTS:

Overall, 16 patients were treated by laser photoablation alone; 9, argon plasma coagulation with or without laser; and 7, multipolar electrocoagulation with or without laser. Mean follow-up for all patients was 19 months. After therapy, mean Hb concentration rose from 76 to 114 g/L for patients with gastric antral vascular ectasia and from 85 to 118 g/L for those with angiodysplasia. Endoscopic therapy abolished or reduced transfusion requirements in 93% of patients with gastric antral vascular ectasia and 76% with angiodysplasia. Patients with gastric antral vascular ectasia required a mean of 6 treatment sessions, while those with angiodysplasia required one to two sessions.

CONCLUSIONS:

Endoscopic thermal ablation effectively controls acute bleeding and reduces transfusion requirements in most patients with upper-GI vascular ectasias. Patients with gastric antral vascular ectasia require significantly more treatment sessions to achieve this effect.

Authors:

Pavey DA, Craig PI.

PMID: 14745397 [PubMed – indexed for MEDLINE]

Whole genomes redefine the mutational landscape of pancreatic cancer.

Posted 10th November 2015

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

PMID: 25719666 [PubMed – indexed for MEDLINE] PMCID: PMC4523082

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