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Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection


IMPORTANCE High-risk human papillomavirus (HPV) has been associated with Barrett dysplasia and esophageal adenocarcinoma. Nevertheless, the prognostic significance of esophageal tumor HPV status is unknown.


This case-control study compares disease-free and overall survival among patients with Barrett high-grade dysplasia or esophageal adenocarcinoma with vs without underlying human papillomavirus (HPV) infection demonstrated on biopsy.


To determine the association between HPV infection and related biomarkers in highgrade dysplasia or esophageal adenocarcinoma and survival.


Retrospective case-control study. The hypothesiswas that HPV-associated esophageal tumors would show a favorable prognosis (as in viral-positive head and neck cancers). Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction, in situ hybridization for E6 and E7 messenger RNA (mRNA), and immunohistochemistry for the proteins p16INK4A and p53. Sequencing of TP53 was also undertaken. The study took place at secondary and tertiary referral centers, with 151 patients assessed for eligibility and 9 excluded. The study period was from December 1, 2002, to November 28, 2017.


Disease-free survival (DFS) and overall survival (OS).
RESULTS Among 142 patients with high-grade dysplasia or esophageal adenocarcinoma (126 [88.7%] male; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. Patients who were HPV positive mostly had high p16INK4A expression, low p53 expression, and wild-type TP53. There were more Tis, T1, and T2 tumors in HPV-positive patients compared with HPV-negative patients (75.7%vs 54.3%; difference, 21.4%; 95%CI, 4.6%-38.2%;
P = .02). Mean DFS was superior in the HPV-positive group (40.3 vs 24.1 months; difference, 16.2 months; 95%CI, 5.7-26.8; P = .003) as was OS (43.7 vs 29.8 months; difference, 13.9 months; 95% CI, 3.6-24.3; P = .009). Recurrence or progression was reduced in the HPV-positive cohort (24.3%vs 58.1%; difference, −33.8%; 95%CI, −50.5%to −17.0%; P < .001) as was distant metastasis (8.1%vs 27.6%; difference, −19.5%; 95%CI, −31.8%to −7.2%; P = .02) and death from esophageal adenocarcinoma (13.5%vs 36.2%; difference, −22.7%; 95%CI, −37.0% to −8.3%; P = .01). Positive results for HPV and transcriptionally active virus were both associated with a superior DFS (hazard ratio [HR], 0.33; 95%CI, 0.16-0.67; P = .002 and HR, 0.44; 95%CI, 0.22-0.88; P = .02, respectively [log-rank test]). Positivity for E6 and E7 mRNA, high p16INK4A expression, and low p53 expression were not associated with improved DFS. On multivariate analysis, superior DFS was demonstrated for HPV (HR, 0.39; 95%CI, 0.18-0.85; P = .02), biologically active virus (HR, 0.36; 95%CI, 0.15-0.86; P = .02), E6 and E7 mRNA (HR, 0.36; 95%CI, 0.14-0.96; P = .04), and high p16 expression (HR, 0.49; 95%CI, 0.27-0.89; P = .02).



Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are positive for HPV are distinct biological entities with a favorable prognosis compared with viral-negative esophageal tumors. Confirmation of these findings in larger cohorts with more advanced disease could present an opportunity for treatment deescalation in the hope of reducing toxic effects without deleteriously affecting survival.

Key Points


What is the prognostic significance of esophageal tumor humanpapillomavirus (HPV) status?


In this case-control study involving 142 patients with Barrett highgrade dysplasia and esophageal adenocarcinoma, HPV positivity was associated with a significantly improved disease-free survival compared with viral negativity. Recurrence and progression were reduced in the HPV-positive cohort as were distant metastasis and death from esophageal adenocarcinoma.


Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are HPV positive have a favorable prognosis compared with viral-negative esophageal tumors and may benefit from treatment de-escalation.


Shanmugarajah Rajendra, MSc,MD, FRACP;Wei Xuan, PhD; Neil Merrett, FRACS; Preeti Sharma, BSc; Prateek Sharma, MD; Darren Pavey, FRACP; Tao Yang, PhD, FRCPA;Leonardo D. Santos, FRCPA; Omar Sharaiha, FRACP; Girish Pande, PhD, FRACS; Peter Cosman, PhD, FRACS; XiaojuanWu, MBBS, MSc; BinWang, MBBS, MMed, PhD


Full article details can be found here:  JAMA Network Open. 2018;1(4):e181054. doi:10.1001/jamanetworkopen.2018.1054

Bowel cancer: Are you at risk?

A/Prof Paveyrecently had the pleasure of being interviewed by the Fairfax group on the Risk Factors for Bowel Cancer. See below for full article details.

Australia has one of the highest bowel cancer rates in the world, with 15,253 people diagnosed with bowel cancer in 2014.

After lung cancer, bowel or colorectal cancer (cancer of the large intestine or rectum) is our second biggest cancer-related killer, responsible for 4,346 deaths in 2015.

“Australia has a growing overweight and obese population. Along with insufficient physical activity, dietary factors and high tobacco and alcohol consumption rates, these factors contribute to the high rate of bowel cancer,” said Sydney-based Gastroenterologist A/Prof Pavey. Non-modifiable risk factors, including genetic predisposition also play a role, he said.


Diet and Lifestyle

“The first thing I tell my patients is to stop smoking and to reduce alcohol consumption,” A/Prof Pavey said.

“For men that means no more than two standard drinks a day, and for women no more than one.” 100 millilitres of wine equates to a standard drink (10 grams of alcohol), but an average restaurant serve is 150 millilitres.

Although not entirely clear what makes red meat carcinogenic (cancer-promoting), the link between its consumption and bowel cancer incidence is evident, A/Prof Pavey said.

“People should eat no more than 100 grams of lean red meat per day”; that’s a palm-sized steak the thickness of a deck of cards, and ideally not barbecued.

“We should be avoiding charred meat, and processed meats like salami and sausages.”

A diet rich in fibre from fruit, vegetables and whole grains however is likely to reduce bowel cancer risk, A/Prof Pavey said.

“Fibre promotes a regular bowel habit. The theory is this allows for less contact between foods and potential carcinogens with the bowel lining.”

Non-Modifiable Risk Factors

“Bowel cancer incidence goes up significantly from age 50,” A/Prof Pavey said. “That’s the stage when the screening program kicks in and becomes so important.”

The National Bowel Cancer Screening Program distributes kits to detect blood in the stool to 50 to 74-year-olds every two years.

“Patients are at higher risk of developing bowel cancer if there is a family history of bowel cancer or bowel polyps (pre-cancerous lumps). They should be screened earlier and more frequently, as should those with an inflammatory bowel disease history, such as Crohn’s disease or ulcerative colitis.”



“If a polyp or growth in the bowel that may be an early cancer is found, we can remove it at the time of colonoscopy, following a positive faecal occult blood test (where traces of blood are found in the stool). That may be all that is required,” A/Prof Pavey said.

“In more advanced cases where the cancer has grown too deep into the bowel wall, patients might require surgery, and chemotherapy or radiotherapy.”


Early detection is key

There are two actions every individual should take, says A/Prof Pavey said.

“One, be aware of those modifiable (lifestyle) risk factors, and two, participate in screening from age 50, because often there are no symptoms.

“Patients should discuss with their doctor any bleeding from the bowel, changes in bowel habit, unexplained weight loss or severe abdominal pain.

“Fewer than 39 per cent of eligible Australians over age 50 complete the National Bowel Cancer screening kit. This means we are potentially missing the early detection of some treatable cancers. Unfortunately, NSW has one of the lowest participation rates at only 36 per cent.

“If we can detect bowel cancer early, 90 per cent of patients will have a good outcome.”


Original article published online: 3 July 2018  – St George & Sutherland Shire Leader

Image from Bowel Cancer Australia


Bowel Cancer Awareness Month | June 1 -30

Bowel cancer claims the lives of over 80 Australians every week. IF FOUND early,  Bowel cancer is one of the most treatable types of cancer.

What is bowel cancer?

Bowel cancer, also known as colorectal cancer, can affect any part of the large bowel (colon) or rectum; it may also be referred to as colon cancer or rectal cancer, depending on where the cancer is located. 


Common Symptoms include:

  • A recent, persistent change in bowel habit
  • A change in shape or appearance of bowel movements
  • Blood in the stool or rectal bleeding
  • Frequent gas pain, cramps
  • A feeling that the bowel has not emptied completely after a bowel movement
  • Unexplained anaemia
  • Abdominal pain or swelling

Not everyone experiences symptoms, particularly in the early stages of bowel cancer.  The above symptoms may be suggestive of bowel cancer, but they can also be due to other medical conditions, some foods or medicines.


Don’t delay in talking to your GP is you are experiencing any of the described symptoms for two weeks or more, because when diagnosed early 90 percent of cases can be successfully treated.

Blood in the stool or rectal bleeding should never be ignored.


However old you are, you should never be told by your GP that you are too young to have bowel cancer.

While bowel cancer is more common in people aged 55 and over, it increasingly affects people of all ages.

Ask your GP to be referred FOR further investigations including direct to procedure.


Early detection of bowel cancer saves lives.

Images and content from:  Bowel Cancer Australia

Colorectal Cancer Awareness Month

March is Colorectal Cancer Awareness Month. Campaigns are focused on the importance of prevention and treatment in the fight against colorectal cancer.

According to the Australian Government’s Institute of Health and Welfare, Colorectal Cancer was the 3rd most common cancers diagnosed in 2017.

It is estimated that 16,682 new cases of colorectal cancer will be diagnosed in Australia in 2017 (9,127 males and 7,555 females).

Colonoscopy is the recommended screening test to help detect and prevent colorectal cancer.

For any concerns speak with your local GP or specialist to find out more details.










































Statistics from: Australian Institute of Health & Welfare

Images from: American College of Gastroenterology

Help Us Beat Bowel Cancer












Click here to listen to an audio recording of A/Prof Darren Pavey on Bowel Cancer Awareness.


Bowel cancer is Australia’s second biggest cancer killer, after lung cancer.

It affects men and women, young and old.

Bowel cancer often develops without warning signs and the importance of early detection is extremely important in saving lives.

Over 15,200 Australians are diagnosed with bowel cancer each year, 2,186 of whom are under age 55.

1 in 13 Australians will be diagnosed with bowel cancer in their lifetime.

Our goal is to have a lasting impact where no one dies of bowel cancer and all those diagnosed receive the support they need.

If detected early, 90% of cases can be successfully treated so . . . don’t wait until it’s too late!


*Statistics and image is from Bowel Cancer Australia website. 






Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis.


Published February 2007


Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a minimally invasive alternative technique for mediastinal staging of non-small cell lung cancer. A metaanalysis was performed to estimate the diagnostic accuracy of EUS-FNA for staging mediastinal lymph nodes (N2/N3 disease) in patients with lung cancer.


Relevant studies were identified using Medline (1966 to November 2005), CINAHL, and citation indexing. Included studies used histology or adequate clinical follow-up (> 6 months) as the “gold standard,” and provided sufficient data for calculating sensitivity and specificity. Summary receiver operating characteristic curves metaanalysis was performed to estimate the pooled sensitivity and specificity.


In 18 eligible studies, EUS-FNA identified 83% of patients (95% confidence interval [CI], 78 to 87%) with positive mediastinal lymph nodes (pooled sensitivity) and 97% of patients (95% CI, 96 to 98%) with negative mediastinal lymph nodes (pooled specificity). In eight studies that were limited to patients who had abnormal mediastinal lymph nodes seen on CT scans, the sensitivity was 90% (95% CI, 84 to 94%) and the specificity was 97% (95% CI, 95 to 98%). In patients without abnormal mediastinal lymph nodes seen on CT scans (four studies), the pooled sensitivity was 58% (95% CI, 39 to 75%). Minor complications were reported in 10 cases (0.8%). There were no major complications.


EUS-FNA is a safe modality for the invasive staging of lung cancer that is highly sensitive when used to confirm metastasis to mediastinal lymph nodes seen on CT scans. In addition, among lung cancer patients with normal mediastinal adenopathy seen on CT scans, despite lower sensitivity, it has the potential to prevent unnecessary surgery in a large proportion of cases missed by CT scanning.


Micames CG, McCrory DC, Pavey DA, Jowell PS, Gress FG.

PMID: 17296659 [PubMed – indexed for MEDLINE]


Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer.


Published November 2017

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.


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Active human papillomavirus involvement in Barrett’s dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.


Published November 2017

We have previously demonstrated that transcriptionally active high-risk HPV (hr-HPV) is strongly incriminated in Barrett’s dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett’s metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway, which are targets for the viral oncoproteins, E6/E7, respectively. Prospectively, BM (n = 81)/BD (n = 72)/OAC (n = 65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A , cyclin D1 , p53 and RNA in-situ hybridization for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n = 42), 18 (n = 13), 6 (n = 1)]. Viral load was low. Transcriptionally active HPV (DNA+ /RNA+ ) was only found in the dysplastic and adenocarcinoma group (n = 21). The majority of HPV DNA+ /RNA+ BD/OAC were characterized by p 16highINK4A (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA /RNA (n = 94) and HPV DNA+ /RNA cohorts (n = 22)]. p53low had the strongest association with DNA+ /RNA+ oesophageal lesions (OR = 23.5, 95% CI = 2.94-187.8, p = 0.0029). Seventeen HPV DNA+ /RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow /p53low provided the best balance of strength of association (OR = 8.0, 95% CI = 2.6-25.0, p = 0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+ /RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.


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Circumferential ablation of Barrett’s esophagus that contains high-grade dysplasia: a U.S. Multicenter Registry.


Published July 2008


The management strategies for Barrett’s esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy.


To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD.


Multicenter U.S. registry.


Sixteen academic and community centers; treatment period from September 2004 to March 2007.


Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation.


Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment.


Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM).


A total of 142 patients (median age 66 years, interquartile range [IQR] 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%.


A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up.


Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.

Focal or diffuse “fullness” of the pancreas on CT. Usually benign, but EUS plus/minus FNA is warranted to identify malignancy.


Published January 2009


The role of EUS to evaluate subtle radiographic abnormalities of the pancreas is not well defined.


To assess the yield of EUS+/-FNA for focal or diffuse pancreatic enlargement/fullness seen on abdominal CT scan in the absence of discrete mass lesions.


Retrospective database review.


Tertiary referral center.


Six hundred and 91 pancreatic EUS exams were reviewed. Sixty-nine met inclusion criteria of having been performed for focal enlargement or fullness of the pancreas. Known chronic pancreatitis, pancreatic calcifications, acute pancreatitis, discrete mass on imaging, pancreatic duct dilation (greater than 4 mm) and obstructive jaundice were excluded.


Rate of malignancy found by EUS+/-FNA.


FNA was performed in 19/69 (27.5%) with 4 new diagnoses of pancreatic adenocarcinoma, one metastatic renal cell carcinoma, one metastatic colon cancer, one chronic pancreatitis and 12 benign results. Eight patients had discrete mass lesions on EUS; two were cystic. All malignant diagnoses had a discrete solid mass on EUS.


Pancreatic enlargement/fullness is often a benign finding related to anatomic variation, but was related to malignancy in 8.7% of our patients (6/69). EUS should be strongly considered as the next step in the evaluation of patients with focal enlargement of the pancreas when clinical suspicion of malignancy exists.


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