Darren Pavey

Circumferential ablation of Barrett's esophagus that contains high-grade dysplasia: a U.S. multicenter registry

BACKGROUND The management strategies for Barretts esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy. OBJECTIVE To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD. DESIGN Multicenter U.S. registry. SETTING Sixteen academic and community centers; treatment period from September 2004 to March 2007. PATIENTS 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. INTERVENTION Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment. OUTCOMES 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). RESULTS 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%. LIMITATIONS 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. CONCLUSIONS 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.

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

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.

Endoscopic therapy for upper-GI vascular ectasias

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.

Transcriptionally Active Human Papillomavirus Is Strongly Associated With Barrett's Dysplasia and Esophageal Adenocarcinoma

OBJECTIVES:The role of human papillomavirus (HPV) in Barretts 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 Barretts 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, Barretts 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.

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

Barretts 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.

Persistence of human papillomavirus, overexpression of p53 and outcomes of patients after endoscopic ablation of Barrett's esophagus

We investigated the role of high-risk human papillomavirus (hr-HPV) in patients with Barretts 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 Barretts 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.

Viral load and Integration status of High-Risk Human Papillomaviruses in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

Viral Load and Integration Status of High-Risk Human Papillomaviruses in the Barretts Metaplasia–dysplasia–adenocarcinoma Sequence

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

We have previously demonstrated that transcriptionally active high‐risk HPV (hr‐HPV) is strongly incriminated in Barretts dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barretts 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.

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

Key Points Question What is the prognostic significance of esophageal tumor human papillomavirus (HPV) status? Findings In this case-control study involving 142 patients with Barrett high-grade 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. Meaning 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.