Hooi Ee

More than just counting eosinophils: proximal oesophageal involvement and subepithelial sclerosis are major diagnostic criteria for eosinophilic oesophagitis

Background According to American Gastroenterological Association Institute criteria, the diagnosis of eosinophilic oesophagitis (EOE) requires clinicopathological correlation. In the appropriate clinical context, a high eosinophil count (HEC, defined as ≥15/HPF) is considered pathological evidence of EOE. However, HEC may not always be identified in biopsies given its patchy distribution, and there may be histological overlap between EOE and gastro-oesophageal reflux disease (GORD) in the distal oesophagus. Aims To evaluate the utility of subepithelial sclerosis and HEC in proximal oesophageal biopsies as additional diagnostic criteria. Methods Cases between 2004 and 2008 with paired proximal and distal oesophageal biopsies and the mention of eosinophils in the reports were retrieved from PathWest Queen Elizabeth II Medical Centre archives. Biopsies were reviewed and assessed for eosinophilic count and presence of subepithelial stroma and sclerosis. A final diagnosis was made after review of both biopsy and clinical details. Results There were 23 cases of EOE and 20 cases of GORD in an adult cohort. In comparison to GORD, cases of EOE had significantly higher eosinophil counts in proximal (39.4 vs 0.6 eosinophils/HPF) and distal biopsies (35.6 vs 1.9), with HEC in proximal biopsies a feature exclusive to EOE (83% vs 0%). Subepithelial sclerosis was identified in at least one biopsy in 74% of EOE and in only a single case of GORD. Conclusions HEC in proximal oesophageal biopsies and subepithelial sclerosis should be considered major diagnostic findings in EOE.

Colonoscopic surveillance after surgery for colorectal cancer

Background:  Intensive colonoscopic surveillance after resection of colorectal cancer (CRC) has been shown not to improve outcome. The National Health and Medical Research Council of Australia (NHMRC) has recently published guidelines recommending appropriate surveillance intervals after CRC resection. The aims of the present study were to assess current and past patterns of postoperative CRC surveillance and to determine the yield of neoplasia from such surveillance.

Population-based screening for Lynch syndrome in Western Australia

We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994–2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the states single familial cancer registry. Prior to the introduction of routine laboratory‐based screening, an average of 2–3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population‐based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state‐ or region‐wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for follow‐up and germline testing.

Outcomes of endoscopic resection of large colorectal neoplasms: An Australian experience

Background and Aims:  Endoscopic resection of large colorectal neoplasms is increasingly being used as an alternative to surgery. However data on failure rates, safety and long‐term outcomes remain limited. The aim of the study was to report short‐ and long‐term outcomes from endoscopic resection of large colorectal neoplasms from a single centre and use a model to predict mortality had surgery been performed.

P-glycoprotein expression in Helicobacter pylori-positive patients: The influence of MDR1 C3435T polymorphism

OBJECTIVE:  The aim of this study was to determine whether the presence of Helicobacter pylori (H. pylori) infection and multidrug resistance protein 1 (MDR1) C3435T polymorphism had an influence on P‐glycoprotein (P‐gp) expression in the upper gastrointestinal tract.

Gastric intraepithelial neoplasia in a Western population

Background and study aims Descriptions of the natural history and endoscopic appearances of gastric dysplasia/intraepithelial neoplasia (IEN) that originate mainly from Europe. Currently, there are no Australian data available. We aimed to document endoscopic appearances and progression rates of gastric IEN and to determine the significance of indefinite for IEN. Patients and methods This is a retrospective study, in which cases diagnosed with gastric IEN were identified between 2000 and 2009. Endoscopic appearances, progression rates to more advanced IEN or cancer, and long-term outcomes were recorded. Results A total of 160 cases with IEN (26.9% high grade, 57.5% low grade, 15.6% indefinite) were identified. The mean age was 67.8 years and 53.8% were men. Endoscopic lesions were polypoid in 29.4% and nonpolypoid in 70.6%. The most common location was the antrum (58.7%). Forty patients had an intervention and 76 underwent endoscopic follow-up only. Twenty-two cancers were diagnosed; three who had an intervention were diagnosed within 12 months, one with low-grade intraepithelial neoplasia developing a cancer after 9.9 years, and 13 undergoing surveillance only, were diagnosed with cancer within 12 months of index endoscopy. Five cases had cancer after a mean of 2.6 years. Forty-seven cases initially labelled as indefinite; following rereview 25 remained unchanged, 11 reclassified as negative for IEN, 10 as low grade, and one as high grade. Three of these cases developed cancer over the study period. Conclusion We concluded that (a) majority of gastric IEN are associated with endoscopic lesions, (b) high rate of early cancer diagnosis was observed (c) rates of progression to cancer were lower than reported rates, and (d) indefinite for IEN is not innocuous requiring an expert pathologists review.

Survey of consent practices for inpatient colonoscopy and endoscopic retrograde cholangiopancreatography at a tertiary referral center

Background:  The purpose of the present paper was to determine informed consent practices for inpatient, open‐access colonoscopy and endoscopic retrograde cholangiopancreatography (ERCP) at a tertiary referral center.

Helicobacter pylori overcomes natural immunity in repeated infections

Repeated experimental reinfection of two subjects indicates that Helicobacter pylori infection does not promote an immune response protective against future reinfection. Our results highlight the importance of preventing reinfection after eradication, through public health initiatives, and possibly treatment of family members. They indicate difficulties for vaccine development, especially therapeutic vaccines.

Increasing Incidence of Colorectal Cancer in Adolescents and Young Adults Aged 15–39 Years in Western Australia 1982–2007: Examination of Colonoscopy History

Aims To examine trends in colorectal cancer (CRC) incidence and colonoscopy history in adolescents and young adults (AYAs) aged 15–39 years in Western Australia (WA) from 1982 to 2007. Design Descriptive cohort study using population-based linked hospital and cancer registry data. Method Five-year age-standardized and age-specific incidence rates of CRC were calculated for all AYAs and by sex. Temporal trends in CRC incidence were investigated using Joinpoint regression analysis. The annual percentage change (APC) in CRC incidence was calculated to identify significant time trends. Colonoscopy history relative to incident CRC diagnosis was examined and age and tumor grade at diagnosis compared for AYAs with and without pre-diagnosis colonoscopy. CRC-related mortality within 5 and 10 years of incident diagnosis were compared for AYAs with and without pre-diagnosis colonoscopy using mortality rate ratios (MRRs) derived from negative binomial regression. Results Age-standardized CRC incidence among AYAs significantly increased in WA between 1982 and 2007, APC = 3.0 (95% CI 0.7–5.5). Pre-diagnosis colonoscopy was uncommon among AYAs (6.0%, 33/483) and 71% of AYAs were diagnosed after index (first ever) colonoscopy. AYAs with pre-diagnosis colonoscopy were older at CRC diagnosis (mean 36.7 ± 0.7 years) compared to those with no prior colonoscopy (32.6 ± 0.2 years), p < 0.001. At CRC diagnosis, a significantly greater proportion of AYAs with pre-diagnosis colonoscopy had well-differentiated tumors (21.2%) compared to those without (5.6%), p = 0.001. CRC-related mortality was significantly lower for AYAs with pre-diagnosis colonoscopy compared to those without, for both 5-year [MRR = 0.44 (95% CI 0.27–0.75), p = 0.045] and 10-year morality [MRR = 0.43 (95% CI 0.24–0.83), p = 0.043]. Conclusion CRC incidence among AYAs in WA has significantly increased over the 25-year study period. Pre-diagnosis colonoscopy is associated with lower tumor grade at CRC diagnosis as well as significant reduction in both 5- and 10-year CRC-related mortality rates. These findings warrant further research into the balance in benefits and harms of targeted screening for AYA at highest risk.

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Background Nexvax2® is a novel, peptide-based, epitope-specific immunotherapy intended to be administered by regular injections at dose levels that increase the threshold for clinical reactivity to natural exposure to gluten and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients administered fixed intradermal doses of Nexvax2 become unresponsive to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but gastrointestinal symptoms and cytokine release mimicking gluten exposure, that accompany the first dose, limit the maximum tolerated dose to 150 μg. Our aim was to test whether stepwise dose escalation attenuated the first dose effect of Nexvax2 in celiac disease patients. Methods We conducted a randomized, double-blind, placebo-controlled trial at four community sites in Australia (3) and New Zealand (1) in HLA-DQ2·5 genotype positive adults with celiac disease who were on a gluten-free diet. Participants were assigned to cohort 1 if they were HLA-DQ2·5 homozygotes; other participants were assigned to cohort 2, or to cohort 3 subsequent to completion of cohort 2. Manual central randomization without blocking was used to assign treatment for each cohort. Initially, Nexvax2-treated participants in cohorts 1 and 2 received an intradermal dose of 30 μg (consisting of 10 μg of each constituent peptide), followed by 60 μg, 90 μg, 150 μg, and then eight doses of 300 μg over six weeks, but this was amended to include doses of 3 μg and 9 μg and extended over a total of seven weeks. Nexvax2-treated participants in cohort 3 received doses of 3 μg, 9 μg, 30 μg, 60 μg, 90 μg, 150 μg, 300 μg, 450 μg, 600 μg, 750 μg, and then eight of 900 μg over nine weeks. The dose interval was 3 or 4 days. Participants, care providers, data managers, sponsor personnel, and study site personnel were blinded to treatment assignment. The primary outcome was the number of adverse events and percentage of participants with adverse events during the treatment period. This completed trial is registered with ClinicalTrials.gov, number NCT02528799. Findings From the 73 participants who we screened from 19 August 2015 to 31 October 2016, 24 did not meet eligibility criteria, and 36 were ultimately randomized and received study drug. For cohort 1, seven participants received Nexvax2 (two with the starting dose of 30 μg and then five at 3 μg) and three received placebo. For cohort 2, 10 participants received Nexvax2 (four with starting dose of 30 μg and then six at 3 μg) and four received placebo. For cohort 3, 10 participants received Nexvax2 and two received placebo. All 36 participants were included in safety and immune analyses, and 33 participants completed treatment and follow-up; in cohort 3, 11 participants were assessed and included in pharmacokinetics and duodenal histology analyses. Whereas the maximum dose of Nexvax2 had previously been limited by adverse events and cytokine release, no such effect was observed when dosing escalated from 3 μg up to 300 μg in HLA-DQ2·5 homozygotes or to 900 μg in HLA-DQ2.5 non-homozygotes. Adverse events with Nexvax2 treatment were less common in cohorts 1 and 2 with the starting dose of 3 μg (72 for 11 participants) than with the starting dose of 30 μg (91 for six participants). Adverse events during the treatment period in placebo-treated participants (46 for nine participants) were similar to those in Nexvax2-treated participants when the starting dose was 3 μg in cohort 1 (16 for five participants), cohort 2 (56 for six participants), and cohort 3 (44 for 10 participants). Two participants in cohort 2 and one in cohort 3 who received Nexvax2 starting at 3 μg did not report any adverse event, while the other 33 participants experienced at least one adverse event. One participant, who was in cohort 1, withdrew from the study due to adverse events, which included abdominal pain graded moderate or severe and associated with nausea after receiving the starting dose of 30 μg and one 60 μg dose. The most common treatment-emergent adverse events in the Nexvax2 participants were headache (52%), diarrhoea (48%), nausea (37%), abdominal pain (26%), and abdominal discomfort (19%). Administration of Nexvax2 at dose levels from 150 μg to 900 μg preceded by dose escalation was not associated with elevations in plasma cytokines at 4 h. Nexvax2 treatment was associated with trends towards improved duodenal histology. Plasma concentrations of Nexvax2 peptides were dose-dependent. Interpretation We show that antigenic peptides recognized by CD4-positive T cells in an autoimmune disease can be safely administered to patients at high maintenance dose levels without immune activation if preceded by gradual dose escalation. These findings facilitate efficacy studies that test high-dose epitope-specific immunotherapy in celiac disease.