Endoscopic features of low-grade dysplastic Barrett's.

Background and study aims Barrett's esophagus (BE) with low-grade dysplasia (LGD) is considered usually endoscopically invisible and the endoscopic features are not well described. This study aimed to: 1) evaluate the frequency of visible BE-LGD; 2) compare rates of BE-LGD detection in the community versus a Barrett's referral unit (BRU); and 3) evaluate the endoscopic features of BE-LGD. Patients and methods This was a retrospective analysis of a prospectively observed cohort of 497 patients referred to a BRU with dysplastic BE between 2008 and 2022. BE-LGD was defined as confirmation of LGD by expert gastrointestinal pathologist(s). Endoscopy reports, images and histology reports were reviewed to evaluate the frequency of endoscopically identifiable BE-LGD and their endoscopic features. Results A total of 135 patients (27.2%) had confirmed BE-LGD, of whom 15 (11.1%) had visible LGD identified in the community. After BRU assessment, visible LGD was detected in 68 patients (50.4%). Three phenotypes were observed: (A) Non-visible LGD; (B) Elevated (Paris 0-IIa) lesions; and (C) Flat (Paris 0-IIb) lesions with abnormal mucosal and/or vascular patterns with clear demarcation from regular flat BE. The majority (64.7%) of visible LGD was flat lesions with abnormal mucosal and vascular patterns. Endoscopic detection of BE-LGD increased over time (38.7% (2009-2012) vs. 54.3% (2018-2022)). Conclusions In this cohort, 50.4% of true BE-LGD was endoscopically visible, with increased recognition endoscopically over time and a higher rate of visible LGD detected at a BRU when compared with the community. BRU assessment of BE-LGD remains crucial; however, improving endoscopy surveillance quality in the community is equally important.

Location and appearance of dysplastic Barrett's esophagus recurrence after endoscopic eradication therapy: no additional yield from random biopsy sampling neosquamous mucosa.

BACKGROUND AND AIMS: Surveillance after complete remission of intestinal metaplasia (CRIM) is essential. Current recommendations are to sample visible lesions first, followed by random 4-quadrant biopsy sampling of the original Barrett's esophagus (BE) length. To inform post-CRIM surveillance protocols, we aimed to identify the anatomic location, appearance, and histology of BE recurrences. METHODS: We performed an analysis of 216 patients who achieved CRIM after endoscopic eradication therapy for dysplastic BE at a Barrett's Referral Unit between 2008 and 2021. The anatomic location, recurrence histology, and endoscopic appearance of dysplastic recurrences were evaluated. RESULTS: After a median of 5.5 years (interquartile range, 2.9-7.2) of follow-up after CRIM, 57 patients (26.4%) developed nondysplastic BE (NDBE) recurrence and 18 patients (8.3%) developed dysplastic recurrence. From 8158 routine surveillance biopsy samplings of normal-appearing tubular esophageal neosquamous epithelium, the yield for recurrent NDBE or dysplasia was 0%. One hundred percent of dysplastic tubular esophageal recurrences were visible and in BE islands, whereas 77.8% of gastroesophageal junction dysplastic recurrences were nonvisible. Four distinct endoscopic features suspicious for recurrent advanced dysplasia or neoplasia were identified: buried or subsquamous BE, irregular mucosal pattern, loss of vascular pattern, and nodularity or depression. CONCLUSIONS: The yield of routine surveillance biopsy sampling of normal-appearing tubular esophageal neosquamous epithelium was zero. BE islands with indistinct mucosal or loss of vascular pattern, nodularity or depression, and/or signs of buried BE should raise clinician suspicion for advanced dysplasia or neoplasia recurrence. We suggest a new surveillance biopsy sampling protocol with a focus on meticulous inspection, followed by targeted biopsy sampling of visible lesions and random 4-quadrant biopsy sampling of the gastroesophageal junction.

Direct percutaneous endoscopic gastrostomy for nutritional support in patients with aerodigestive tract cancers.

BACKGROUND: Conventional pull-through percutaneous endoscopic gastrostomy (PEG) risks infection and tumour implantation in head and neck cancers. Endoscopically inserted direct gastrostomy has lower rates of complications but is underutilised. AIMS: To describe the endoscopic steps for direct gastrostomy insertion and review our single-centre experience to assess the technical feasibility and safety. METHODS: Patients who underwent endoscopic direct gastrostomy insertion between December 2016 and June 2021 were included. A 24Fr introducer kit for gastrostomy feeding tube (Avanos Healthcare, Australia) was used. Patient and tumour characteristics, procedural data and 30-day outcomes were recorded. RESULTS: Thirty patients underwent direct PEG insertion (mean age 64 years and 24 male). All were planned for or currently undergoing radiotherapy. Twenty-six (87%) of 30 cases were performed under conscious sedation over a median procedure time of 21 min (interquartile range 11 min). No tumour seeding was seen, and one case of PEG-site infection was observed. CONCLUSIONS: Direct PEG is safe and effective and should be considered for patients with aerodigestive tract cancer in need of nutritional support.

Clinical application and diagnostic accuracy of artificial intelligence in colonoscopy for inflammatory bowel disease: systematic review.

Background and aims Artificial intelligence (AI) technology is being evaluated for its potential to improve colonoscopic assessment of inflammatory bowel disease (IBD), particularly with computer-aided image classifiers. This review evaluates the clinical application and diagnostic test accuracy (DTA) of AI algorithms in colonoscopy for IBD. Methods A systematic review was performed on studies evaluating AI in colonoscopy of adult patients with IBD. MEDLINE, Embase, Emcare, PsycINFO, CINAHL, Cochrane Library and Clinicaltrials.gov databases were searched on 28 th April 2021 for English language articles published between January 1, 2000 and April 28, 2021. Risk of bias and applicability were assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Diagnostic accuracy was presented as median (interquartile range). Results Of 1029 records screened, nine studies with 7813 patients were included for review. AI was used to predict endoscopic and histologic disease activity in ulcerative colitis, and differentiation of Crohn's disease from Behcet's disease and intestinal tuberculosis. DTA of AI algorithms ranged between 52-91 %. The sensitivity and specificity for AI algorithms predicting endoscopic severity of disease were 78 % (range 72-83, interquartile range 5.5) and 91 % (range 86-96, interquartile range 5), respectively. Conclusions AI has been primarily used to assess disease activity in ulcerative colitis. The diagnostic performance is promising and suggests potential for other clinical application of AI in IBD colonoscopy such as dysplasia detection. However, current evidence is limited by retrospective data and models trained on still images only. Future prospective multicenter studies with full-motion videos are needed to replicate the real-world clinical setting.

Quality of upper GI endoscopy: a prospective cohort study on impact of endoscopist education.

BACKGROUND AND AIMS: Guidelines on quality of upper GI (UGI) endoscopy have been proposed by the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE). However, these guidelines have not been evaluated in clinical practice. We aimed to measure the impact of endoscopist education on the quality of gastroscopy based on these guidelines and the association between compliance with guidelines and the detection of clinically significant premalignant pathology such as Barrett's esophagus (BE), esophageal squamous dysplasia, gastric intestinal metaplasia (GIM), and Helicobacter pylori. METHODS: Endoscopists participated in a 1-hour education session on recommended performance measures and endoscopic detection of premalignant pathologies. A controlled before and after study was performed, measuring compliance with guidelines and rates of detection of pathology in control and intervention groups. RESULTS: Over 2 years, 2719 procedures were performed: 1412 in the control group and 1307 in the intervention group. The proportion of procedures complying with guidelines was higher in the intervention group. The use of biopsy sampling protocols (eg, management of precancerous conditions of the stomach, 52% vs 91%; P = .007) and standardized terminology (eg, Forrest classification, 24% vs 68%; P < .001) was significantly higher. Detection of H pylori was higher in the intervention group (5.5% vs 9.8%, P = .003). Minimum inspection time of 7 minutes was associated with detection of BE (7.4% vs 2.0%, P < .001). CONCLUSIONS: A simple endoscopist education session enhanced the quality of UGI endoscopy by improving compliance with BSG and ESGE recommendations and increasing the detection of clinically significant pathology. A minimum inspection time of 7 minutes was associated with increased diagnostic yield and may be a feasible quality indicator for clinical practice.

Evaluation of Endoscopic Practices and Outcomes in Follow-up of Gastric Ulcers.

GOAL: The aim of this study was to evaluate current practice in gastric ulcer follow-up to establish diagnostic yield and predictors of malignancy. BACKGROUND: Repeat gastroscopy is routinely performed to confirm gastric ulcer healing and exclude malignancy. However, the incidence of malignancy at follow-up endoscopy is low, without consensus regarding case selection and timing. STUDY: New gastric ulcers diagnosed on gastroscopy at 2 institutions in Australia were identified through keyword search of endoscopy reports over a 5-year period (2013 to 2017). Data collected included patient demographics, clinical presentation, and endoscopic and histologic findings from initial and subsequent gastroscopies. RESULTS: Of 795 patients, repeat gastroscopy was performed in 440 (55%). Malignancy was diagnosed in 52 (7%) with 83% identified at initial gastroscopy. Eight cancers were identified at repeat gastroscopy with malignancy yield of 2% (8/440). Three were diagnosed in patients with benign initial ulcer histology (3/286, 1%). One cancer was diagnosed during follow-up in a patient with benign histology but no repeat gastroscopy (1/286, 0.3%). Predictors of benign ulcers were absence of endoscopic suspicion [odds ratio (OR) 0.1 (0.03-0.13), P≤0.005], complete healing on repeat gastroscopy [OR 0.5 (0.34-0.70), P=0.036] and benign initial histology [OR 0.12 (0.43-0.90), P≤0.005]. CONCLUSIONS: Seven percent of new gastric ulcers were malignant with most identified with biopsy on initial gastroscopy. Malignancy yield from follow-up gastroscopy was 2%. Diagnostic yield of endoscopic follow-up may be low in ulcers with benign appearance and adequate histology. However, current practice of repeat gastroscopy is warranted in the absence of patient-based and lesion-based predictors of malignancy.

Not all low grade dysplasia in Barrett's oesophagus is the same: using specific histological criteria in predicting progression to neoplasia.

Barrett's oesophagus with low grade dysplasia (LGD) is a risk factor for progression to high grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC); however, only a subgroup of LGD will progress. We used a combination of specific histological criteria to identify patients with LGD who are more likely to progress to HGD or OAC. LGD slides from 38 patients within the progressor group (PG) and 17 patients from the non-progressor group (NPG) were obtained and reviewed by two expert GI pathologists, to be stratified by the same four specific histological variables identified by Ten Kate et al.: loss of surface maturation, mucin depletion, nuclear enlargement, and increase of mitosis. After review of LGD slides by two expert GI pathologists, 27 suitable patients were identified. Of these 27 patients there was a higher proportion of patients from the PG with all four specific criteria reported, compared to the NPG: 14 (78%) vs 3 (33%) p=0.0394. Patients with all four specific criteria were more likely to progress compared to those who had one or less specific criteria reported (OR 7, 95% CI 1.1848-41.3585, p=0.032). A combination of ≥2 or ≥3 specific histological criteria was not prognostic. Patients with a combination of all four specific histological criteria (loss of surface maturation, mucin depletion, nuclear enlargement, and increase of mitosis) were associated with greater progression from LGD to HGD or OAC in Barrett's oesophagus.

Barrett's esophagus with low-grade dysplasia: high rate of upstaging at Barrett's esophagus referral units suggests progression rates may be overestimated.

BACKGROUND AND AIMS: The reported progression rate from low-grade dysplasia (LGD) in Barrett's esophagus (BE) to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) ranges from .4% to 13.4% per year. We hypothesize that some reported progression rates may be overestimated because of prevalent HGD or EAC that was not identified during endoscopic assessments performed in the community. Our aim is to determine the proportion of prevalent HGD or EAC detected by BE referral units (BERUs) in patients referred from the community with a recent diagnosis of LGD. METHODS: All patients referred from the community to 6 BERUs with a diagnosis of BE with LGD were identified. Patients with an assessment endoscopy performed at BERUs more than 6 months from their referral endoscopy in the community were excluded. Visible lesions and histology outcomes were compared between the community referral endoscopy and the assessment endoscopy performed at BERUs. RESULTS: The median time between BERU assessment and referral endoscopy was 79 days (interquartile range, 54-114). Of the 75 patients referred from the community with LGD, BERU assessment identified HGD or EAC in 20 patients (27%). BERU assessment identified more visible lesions than referral endoscopy performed in the community (39 [52%] vs 9 [12%], respectively; P = .029). CONCLUSIONS: BERU assessment endoscopy identified more visible lesions than community referral endoscopy and identified HGD or EAC in 27% of patients referred from the community with a recent diagnosis of LGD. Reported progression rates from LGD to HGD or EAC may be overestimated.

Quantifying early gastric cancer in Australia: What is the opportunity for gastric endoscopic submucosal dissection?

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is the recommended treatment for early gastric cancer (EGC). However, there are challenges in attaining expertise in ESD in countries where the incidence of gastric cancer and proportion diagnosed at an early stage of disease are relatively low. This study aims to establish the proportion of gastric cancer meeting histological criteria for EGC, which may be suitable for ESD, in a Western population. METHODS: Gastric cancers reported to the Victorian Cancer Registry between January 2011 and December 2016 were analyzed. EGC was defined as tumor confined to mucosa (T1a) or submucosa (T1b). Histology reports were analyzed using Japanese and European guidelines to identify potential ESD candidates. Criteria for extended ESD were based on grade of differentiation, tumor depth, lymphovascular and perineural invasion, and ulceration. RESULTS: Twenty percent of 1217 gastric cancers was EGC (237 cases), with detailed histopathology reports suitable for evaluating ESD criteria recorded in 182 cases. Standard and extended ESD criteria were met in 46% (84/182) and 75% (132/182), respectively. Actual treatment of the 237 EGC was endoscopic in 14% (n = 33) and surgery in 86% (n = 204). Endoscopically treated EGCs were more likely to be stage T1a and located in the proximal stomach. CONCLUSIONS: EGCs represented 20% of reported gastric adenocarcinomas with the majority fulfilling criteria for ESD. ESD should be considered in the management algorithm and discussed at tumor board meetings involving interventional endoscopists. To increase utilization of ESD, systems need to be implemented to improve training, accreditation, and access to ESD.

A qualitative exploration of enablers for hepatitis B clinical management among ethnic Chinese in Australia.

An estimated 18% of people living with chronic hepatitis B (CHB) in Australia were born in China. While guideline-based care, including regular clinical monitoring and timely treatment, prevent CHB-related cirrhosis, cancer and deaths, over three-quarters of people with CHB do not receive guideline-based care in Australia. This qualitative study aimed to identify enablers to engagement in CHB clinical management among ethnic Chinese people attending specialist care. Participants self-identified as of Chinese ethnicity and who attended specialist care for CHB clinical management were interviewed in Melbourne in 2019 (n = 30). Semi-structured interviews covered experiences of diagnosis and engagement in clinical management services, and advice for people living with CHB. Interviews were recorded with consent; data were transcribed verbatim and thematically analysed. Receiving clear information about the availability of treatment and/or the necessity of long-term clinical management were the main enablers for participants to engage in CHB clinical management. Additional enablers identified to maintain regular clinical monitoring included understanding CHB increases risks of cirrhosis and liver cancer, using viral load indicators to visualize disease status in patient-doctor communication; expectations from family, peer group and medical professionals; use of a patient recall system; availability of interpreters or multilingual doctors; and largely subsidized healthcare services. In conclusion, to support people attending clinical management for CHB, a holistic response from community, healthcare providers and the public health sector is required. There are needs for public health programmes directed to communicate (i) CHB-related complications; (ii) availability of effective and cheap treatment; and that (iii) long-term engagement with clinical management and its benefits.

Endoscopic features of buried Barrett's mucosa.

BACKGROUND AND AIMS: Buried Barrett's mucosa is defined as intestinal metaplasia that is "buried" under the normal-appearing squamous epithelium. This can occur in Barrett's esophagus with or without previous endoscopic therapy. Dysplasia and neoplasia within buried Barrett's mucosa have also been reported. However, endoscopic features of buried Barrett's mucosa have not been described. At our tertiary referral center for Barrett's esophagus, several endoscopic features have been observed in patients who were found to have buried Barrett's mucosa on histology. These features are squamous epithelium which is (1) darker pink on white-light and darker brown on narrow-band imaging and/or (2) has a slightly raised or nodular appearance. It was also observed that either of these 2 features is frequently seen adjacent to a Barrett's mucosa island. This study aimed to (1) evaluate the diagnostic accuracy of these endoscopic features, and (2) evaluate the frequency of endoscopically identifiable buried Barrett's mucosa in patients with dysplastic Barrett's esophagus, before and after endoscopic eradication therapy. METHODS: This was a retrospective analysis of a prospectively observed cohort of all cases of dysplastic Barrett's esophagus referred to St Vincent's Hospital, Melbourne. Endoscopy documentation software and histopathology reports of esophageal biopsy and EMR specimens between March 2013 and March 2019 were searched for terms "buried" or "subsquamous" Barrett's mucosa. Endoscopic reports, images, and histopathology reports of suspected buried Barrett's mucosa were then reviewed to apply the endoscopic features and correlate with the histologic diagnosis. RESULTS: In a cohort of 506 patients with dysplastic Barrett's esophagus, 33 (7%) patients (73% male, median age at referral 70.5 years) had buried Barrett's mucosa on histology. Twenty-seven (82%) patients had previous treatment for dysplastic Barrett's esophagus; radiofrequency in 2 (6%), EMR in 4 (12%), and both modalities in 21 (64%). Six (18%) had no previous treatment. Histologically confirmed buried Barrett's mucosa was suspected at endoscopy in 26 patients (79%). Endoscopic features were (1) darker pink or darker brown mucosa underneath squamous epithelium (24%), (2) raised areas underneath squamous mucosa (27%), and both features present concurrently (27%). These features were associated with adjacent islands of Barrett's esophagus in 48%. Forty-four cases of buried Barrett's mucosa were suspected endoscopically, and these were sampled by biopsy (50%) and EMR (50%). Buried Barrett's mucosa was confirmed in 26 cases, with a positive predictive value of endoscopic suspicion of 59%. Eighteen cases of endoscopically suspected buried Barrett's mucosa had no buried Barrett's mucosa on histology; inflammation or reflux was identified in 12 (67%) patients. Dysplasia was identified within buried Barrett's mucosa in 12 (36%) patients; 5 intramucosal adenocarcinoma, 1 high-grade dysplasia, and 6 low-grade dysplasia. Endoscopic features of buried Barrett's mucosa were observed in 11 of 12 cases harboring dysplasia or neoplasia, compared with 15 of 21 cases of buried Barrett's mucosa without dysplasia. CONCLUSIONS: In this retrospective analysis of prospectively observed patients with dysplastic Barrett's esophagus, buried Barrett's mucosa was identified in 7%, including treatment-naive patients. The proposed endoscopic features of buried Barrett's mucosa were seen in 79% of patients with histology confirmed disease. These endoscopic features may predict the presence of buried Barrett's mucosa, which may contain dysplasia or neoplasia. An overlap between the endoscopic features of inflammation, reflux, and buried Barrett's mucosa was observed. Future prospective studies are required to develop and validate endoscopic criteria for identifying buried Barrett's mucosa.

Factors that predict a poor response to radiofrequency ablation for Barrett's oesophagus with dysplasia.

BACKGROUND: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's oesophagus (BO). This study aimed to determine the factors that affect response to RFA for BO with dysplasia in a tertiary metropolitan referral centre. METHODS: All patients with dysplastic BO treated with regular proton pump inhibitor twice a day and RFA from November 2008 to July 2019 were identified. These patients were sorted into good responders (GR) (defined as eradication of dysplasia and intestinal metaplasia within three or less treatment sessions) and poor responders (PR) (defined as patients requiring four or more treatment sessions). The following features were compared between the groups: age, gender, presence of hiatus hernia, hiatus hernia size, circumferential and maximal length of BO, grade of dysplasia on histology at referral and presence of endoscopically visible reflux oesophagitis. RESULTS: A total of 152 patients received RFA for dysplastic BO, of whom 125 (82%) patients were classified as GR and 27 (18%) patients were classified as PR. PR had a longer circumferential length of BO compared to GR (mean length of 8.3 versus 3.3 cm, P < 0.0001). PR also had a longer maximal length of BO compared to GR (mean length of 8.7 versus 4.8 cm, P < 0.0001). More patients had reflux oesophagitis identified on gastroscopy in the PR group compared to GR group (12 (44%) versus 20 (16%), P = 0.001). CONCLUSION: Factors such as circumferential and maximal length of BO and presence of reflux oesophagitis on gastroscopy are associated with poorer response to RFA.

Diffuse endoscopically visible, predominantly low grade dysplasia in Barrett's esophagus (with video).

Background Low grade dysplasia (LGD) in Barrett's esophagus (BE) has generally been considered as undetectable endoscopically. Aim To describe a phenotype which consists of diffuse, endoscopically visible, predominantly low grade dysplasia in Barrett's esophagus (DEVLB), with often subtle but visible endoscopic changes seen with high definition white light (HDWL) and narrow-band imaging (NBI). Method A systematic search of a prospectively collected database for patients satisfying predefined criteria for DEVLB and a review of endoscopic and histological features of biopsies and endoscopic mucosal resection (EMR) specimens. Results Out of a total of 419 patients referred to our expert center for assessment of dysplastic Barrett's esophagus during the period January 2009 to March 2018, there were 7 patients (1.7 %) who satisfied the criteria defined for DEVLB, identified on their initial assessment endoscopy. All patients were treated by EMR of visible abnormal mucosa during their assessment endoscopy at our tertiary referral center. There was a total of 47 EMR specimens obtained, with a median of 6 (IQR 5-9) EMR resection pieces per patient, of which 36 (77 %) contained LGD, 8 (17 %) high grade dysplasia (HGD), 2 (4 %) non-dysplastic Barrett's esophagus (NDBE), and 1 (2 %) contained early esophageal adenocarcinoma (EAC). Conclusion DEVLB is a distinct phenotype seen in a small but significant proportion of individuals with dysplastic Barrett's esophagus. Patients with DEVLB have widespread LGD, with many having areas of focal HGD or early cancer within this area. We believe these patients are best treated with extensive EMR of the visibly abnormal area.

"B in IT" - a community-based model for the management of hepatitis B patients in primary care clinics using a novel web-based clinical tool.

BACKGROUND: The current model of care for the treatment of chronic hepatitis B (CHB) in Australia is through specialist Hepatology or Infectious Diseases clinics, and limited accredited primary care practices. Capacity is limited, and less than 5% of Australians living with CHB currently access therapy. Increasing treatment uptake is an urgent area of clinical need. Nucleos(t)ide analogue therapy is safe and effective treatment for CHB that is suitable for community prescribing. We have evaluated the success of a community-based model for the management of CHB in primary care clinics using a novel web-based clinical tool. METHODS: Using guidelines set out by the Gastroenterological Society of Australia, we developed an interactive online clinical management tool for the shared care of patients with CHB in primary care clinics, with remote oversight from tertiary hospital-based hepatologists and a project officer. We call this model of care the "B in IT" program. Suitable patients were referred from the specialist liver clinic back to primary care for ongoing management. Compliance with recommended appointments, pathology tests and ultrasounds of patients enrolled in "B in IT" was assessed and compared to that of the same patients prior to community discharge, as well as a matched control group of CHB outpatients continuing to attend a specialist clinic. RESULTS: Thirty patients with CHB were enrolled in the "B in IT" program. Compliance with attending scheduled appointments within 1 month of the suggested date was 87% across all 115 visits scheduled. Compliance with completing recommended pathology within 1 month of the suggested date was 94% and compliance with completing recommended liver ultrasounds for cancer screening within 1 month of the suggested date was 89%. The compliance rates for visit attendance and ultrasound completion were significantly higher than the control patient group (p < 0.0001) and the "B in IT" patients prior to community discharge (p = 0.002 and p = 0.039, respectively). CONCLUSIONS: The "B in IT" program's novel web-based clinical tool supports primary care physicians to treat and monitor patients with CHB. This program promotes community-based care and increases system capacity for the clinical care of people living with CHB.

Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study.

OBJECTIVES: To determine the factors associated with survival of patients with hepatocellular carcinoma (HCC) and the effect of HCC surveillance on survival. DESIGN, SETTING AND PARTICIPANTS: Prospective population-based cohort study of patients newly diagnosed with HCC in seven tertiary hospitals in Melbourne, 1 July 2012 - 30 June 2013. MAIN OUTCOME MEASURES: Overall survival (maximum follow-up, 24 months); factors associated with HCC surveillance participation and survival. RESULTS: 272 people were diagnosed with incident HCC during the study period; the most common risk factors were hepatitis C virus infection (41%), alcohol-related liver disease (39%), and hepatitis B virus infection (22%). Only 40% of patients participated in HCC surveillance at the time of diagnosis; participation was significantly higher among patients with smaller median tumour size (participants, 2.8 cm; non-participants, 6.0 cm; P < 0.001) and earlier Barcelona Clinic Liver Cancer (BCLC) stage disease (A/B, 59%; C/D, 25%; P < 0.001). Participation was higher among patients with compensated cirrhosis or hepatitis C infections; it was lower among those with alcohol-related liver disease or decompensated liver disease. Median overall survival time was 20.8 months; mean survival time was 18.1 months (95% CI, 16.6-19.6 months). Participation in HCC surveillance was associated with significantly lower mortality (adjusted hazard ratio [aHR], 0.60; 95% CI, 0.38-0.93; P = 0.021), as were curative therapies (aHR, 0.33; 95% CI, 0.19-0.58). Conversely, higher Child-Pugh class, alpha-fetoprotein levels over 400 kU/L, and later BCLC disease stages were each associated with higher mortality. CONCLUSIONS: Survival for patients with HCC is poor, but may be improved by surveillance, associated with the identification of earlier stage tumours, enabling curative therapies to be initiated.

Sustained virological response halts fibrosis progression: A long-term follow-up study of people with chronic hepatitis C infection.

BACKGROUND/AIMS: Long-term follow-up studies validating the clinical benefit of sustained virological response (SVR) in people with chronic hepatitis C (CHC) infection are lacking. Our aim was to identify rates and predictors of liver fibrosis progression in a large, well characterized cohort of CHC patients in whom paired liver fibrosis assessments were performed more than 10 years apart. METHODS: CHC patients who had undergone a baseline liver biopsy pre-2004 and a follow up liver fibrosis assessment more than 10 years later (biopsy or liver stiffness measurement (LSM) using transient elastography [FibroScan]) were identified. Subjects who had undergone a baseline liver biopsy but had no follow up fibrosis assessment were recalled for LSM. Fibrosis was categorised as mild-moderate (METAVIR F0-2 / LSM result of ≤ 9.5 kPa) or advanced (METAVIR F3-4/ LSM >9.5 kPa). The primary objective was to assess the association between SVR and the rate of liver fibrosis progression over at least 10 years, defined as an increase from mild-moderate fibrosis at baseline liver biopsy (METAVIR F0-2) to advanced fibrosis at follow-up liver fibrosis assessment. RESULTS: 131 subjects were included in this analysis: 69% male, 82% Caucasian, 60% G1 HCV, 25% G3 HCV. The median age at F/U fibrosis staging was 57 (IQR 54-62) years with median estimated duration of infection 33-years (IQR 29-38). At F/U, liver fibrosis assessment was performed by LSM in 86% and liver biopsy in 14%. The median period between fibrosis assessments was 14-years (IQR 12-17). 109 (83%) participants had received interferon-based antiviral therapy. 40% attained SVR. At F/U, there was a significant increase in the proportion of subjects with advanced liver fibrosis: 27% at baseline vs. 46% at F/U (p = 0.002). The prevalence of advanced fibrosis did not change among subjects who attained SVR, 30% at B/L vs 25% at F/U (p = 0.343). However, advanced fibrosis became more common at F/U among subjects with persistent viremia: 10% at B/L vs 31% at F/U (p = 0.0001). SVR was independently associated with protection from liver fibrosis progression after adjustment for other variables including baseline ALT (p = 0.011), duration of HCV infection and mode of acquisition. CONCLUSION: HCV eradication is associated with lower rates of liver fibrosis progression. The data support early treatment to prevent long-term liver complications of HCV infection.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

Efficacy and safety of tenofovir in chronic hepatitis B: Australian real world experience.

AIM: To evaluate the long-term treatment outcomes of tenofovir therapy in patients in a real world Australian tertiary care setting. METHODS: We performed a retrospective analysis of treatment outcomes among treatment-naïve and treatment-experienced patients receiving a minimum 3 mo tenofovir therapy through St Vincent's Hospital Melbourne, Australia. We included patients receiving tenofovir [tenofovir disoproxil fumarate (TDF)] monotherapy, as well as patients treated with TDF in combination with a second antiviral agent. Patients were excluded if they demonstrated human immune-deficiency virus/hepatitis C virus/hepatitis delta virus coinfection or were less than 18 years of age. We considered virological and biochemical response, as well as safety outcomes. Virological response was determined by measurement of hepatitis B virus (HBV) DNA using sensitive assays; biochemical response was determined via serum liver function tests; histological response was determined from liver biopsy and fibroscan; safety analysis focused on glomerular renal function and bone mineral density. The primary efficacy endpoint was complete virological suppression over time, defined by HBV DNA < 20 IU/mL. Secondary efficacy endpoints included rates of biochemical response, and HB e antigen (HBeAg)/HB surface antigen loss and seroconversion over time. RESULTS: Ninety-two patients were identified who fulfilled the enrolment criteria. Median follow-up was 26 mo (range 3-114). Mean age was 46 (24-78) years, 64 (70%) were male and 77 (84%) were of Asian origin. 55 (60%) patients were treatment-naïve and 62 patients (67%) were HBeAg-negative. Complete virological suppression was achieved by 45/65 (71%) patients at 12 mo, 37/46 (80%) at 24 mo and 25/28 (89%) at 36 mo. Partial virological response (HBV DNA 20-2000 IU/mL) was achieved by 89/92 (96.7%) of patients. Multivariate analysis showed a significant relationship between virological suppression at end of follow-up and baseline HBV DNA level (OR = 0.897, 95%CI: 0.833-0.967, P = 0.0046) and HBeAg positive status (OR = 0.373, 95%CI: 0.183-0.762, P = 0.0069). There was no difference in response comparing treatment-naïve and treatment-experienced patients. Three episodes of virological breakthrough occurred in the setting of non-compliance. Tenofovir therapy was well tolerated. CONCLUSION: Tenofovir is an efficacious, safe and well-tolerated treatment in an Australian real-world tertiary care setting. Our data are similar to the reported experience from registration trials.

Five-year efficacy and safety of tenofovir-based salvage therapy for patients with chronic hepatitis B who previously failed LAM/ADV therapy.

BACKGROUND: Multidrug-resistant HBV continues to be an important clinical problem. The TDF-109 study demonstrated that TDF±LAM is an effective salvage therapy through 96 weeks for LAM-resistant patients who previously failed ADV add-on or switch therapy. We evaluated the 5-year efficacy and safety outcomes in patients receiving long-term TDF±LAM in the TDF-109 study. METHODS: A total of 59 patients completed the first phase of the TDF-109 study and 54/59 were rolled over into a long-term prospective open-label study of TDF±LAM 300 mg daily. RESULTS: Results are reported at the end of year 5 of treatment. At year 5, 75% (45/59) had achieved viral suppression by intent-to-treat analysis. Per-protocol assessment revealed 83% (45/54) were HBV DNA undetectable. Nine patients remained HBV DNA detectable, however 8/9 had very low HBV DNA levels (<264IU/mL) and did not meet virological criteria for virological breakthrough (VBT). One patient experienced VBT, but this was in the setting of documented non-compliance. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Four patients discontinued TDF, one patient was lost to follow-up and one died from hepatocellular carcinoma. CONCLUSIONS: Long-term TDF treatment appears to be safe and effective in patients with prior failure of LAM and a suboptimal response to ADV therapy. These findings confirm that TDF has a high genetic barrier to resistance is active against multidrug-resistant HBV, and should be the preferred oral anti-HBV agent in CHB patients who fail treatment with LAM and ADV.

Recurrent intestinal metaplasia at the gastroesophageal junction following endoscopic eradication of dysplastic Barrett's esophagus may not be benign.

BACKGROUND AND STUDY AIMS: Radiofrequency ablation (RFA) combined with endoscopic mucosal resection (EMR) is effective for eradicating dysplastic Barrett's esophagus. The durability of response is reported to be variable. We aimed to determine the effectiveness and durability of RFA with or without EMR for patients with dysplastic Barrett's esophagus. PATIENTS AND METHODS: Patients with dysplastic Barrett's esophagus referred to two academic hospitals were assessed with high definition white-light endoscopy, narrow-band imaging, and Seattle protocol biopsies. EMR was performed in visible lesions. RFA was performed at 3-month intervals until complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM) was achieved. RESULTS: In total, 137 patients received RFA (78 with EMR); 75 with over 12 months follow-up since commencing RFA. Pretreatment histology was intramucosal cancer (IMC) 21 %, high grade dysplasia (HGD) 54 %, low grade dysplasia (LGD) 25 %. CR-D rates were 88 %, 92 %, and 100 % at 1, 2, and 3 years; CR-IM rates were 69 %, 74 %, and 81 %. Kaplan-Meier analysis showed increasing probability of achieving CR-D/CR-IM over time. Of 26 patients maintaining CR-IM for > 12 months, five relapsed with intestinal metaplasia (19 %), and three with dysplasia (12 %). Recurrences occurred in patients with prior HGD/IMC, predominantly at the gastroesophageal junction (GEJ). None relapsed with cancer. Adverse events occurred in 4 % of RFA and 6.5 % of EMR procedures. CONCLUSIONS: RFA combined with EMR is effective in achieving CR-D/CR-IM in the majority of patients with dysplastic Barrett's esophagus, with an incremental response over time. While durable in the majority, recurrent intestinal metaplasia and dysplasia, frequently occurring at the GEJ, suggest long-term surveillance is warranted in high risk groups.