Impact of the COVID-19 pandemic on patients with hepatocellular carcinoma in the West of Scotland: a cohort study.

OBJECTIVE: The COVID-19 pandemic had an undoubted impact on the provision of elective and emergency cancer care, including the diagnosis and management of patients with hepatocellular carcinoma (HCC). Our aim was to determine the effects of the COVID-19 pandemic on patients with HCC in the West of Scotland. DESIGN: This was a retrospective audit of a prospectively collated database of patients presented to the West of Scotland Multidisciplinary Team (MDT) between April and October 2020 (during the pandemic), comparing baseline demographics, characteristics of disease at presentation, diagnostic workup, treatment and outcomes with patients from April to October 2019 (pre pandemic). RESULTS: There was a 36.5% reduction in new cases referred to the MDT during the pandemic. Patients presented at a significantly later Barcelona Cancer Liver Clinic stage (24% stage D during the pandemic, 9.5% pre pandemic, p<0.001) and with a significantly higher Child-Pugh Score (46% Child-Pugh B/C during the pandemic vs 27% pre pandemic, p<0.001). We observed a reduction in overall survival (OS) among all patients with a median OS during the pandemic of 6 months versus 17 months pre pandemic (p=0.048). CONCLUSION: The impact of the COVID-19 pandemic is likely to have contributed to a reduction in the presentation of new cases and survival among patients with HCC in the West of Scotland. The reason for this is likely multifactorial, but disruption of standard care is likely to have played a significant role. Resources should be provided to address the backlog and ensure there are robust investigation and management pathways going forward.

Liver, visceral and subcutaneous fat in men and women of South Asian and white European descent: a systematic review and meta-analysis of new and published data.

AIMS/HYPOTHESIS: South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. METHODS: We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ). RESULTS: We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women. CONCLUSIONS/INTERPRETATION: South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians. FUNDING: There was no primary direct funding for undertaking the systematic review and meta-analysis.

Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study.

INTRODUCTION: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival. METHODS: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that. RESULTS: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, p < 0.001). CONCLUSIONS: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival; however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias.

Abdominal Compression by Waist Belt Aggravates Gastroesophageal Reflux, Primarily by Impairing Esophageal Clearance.

BACKGROUND & AIMS: Central obesity promotes gastroesophageal reflux, which may be related to increased intra-abdominal pressure. We investigated the effect of increasing abdominal pressure by waist belt on reflux in patients with reflux disease. METHODS: We performed a prospective study of patients with esophagitis (n = 8) or Barrett's esophagus (n = 6); median age was 56 years and median body mass index was 26.8. Proton pump inhibitors were stopped at least 7 days before the study and H2 receptor antagonists were stopped for at least 24 hours before. The severity of upper GI symptoms was assessed and measurements of height, weight, and waist and hip circumference taken. Combined high-resolution pH measurement and manometry were performed in fasted state for 20 minutes and for 90 minutes following a standardized meal. The squamocolumnar junction was marked by endoscopically placed radiopaque clips. The procedures were performed with and without a waist belt (a weight-lifter belt applied tightly and inflated to a constant cuff pressure of 50 mmHg). We compared variables between groups using the Wilcoxon Signed Rank test and tested for correlations using Spearman Rho bivariate analysis. RESULTS: Without the belt, intragastric pressure correlated with waist circumference (r = 0.682; P = .008), with the range in pressure between smallest and largest waist circumference being 15 mmHg. The belt increased intragastric pressure by a median of 6.9 mmHg during fasting (P = .002) and by 9.0 mmHg after the meal (P = .001). Gastroesophageal acid reflux at each of the pH sensors extending 5.5 cm proximal to the peak lower esophageal sphincter pressure point was increased by approximately 8-fold by the belt (all P < .05). Following the meal, the mean number of reflux events with the belt was 4, vs 2 without (P = .008). Transient lower esophageal sphincter relaxations were not increased by the belt, but those associated with reflux were increased (2 vs 3.5; P = .04). The most marked effect of the belt was impaired esophageal clearance of refluxed acid (median values of 23.0 seconds without belt vs 81.1 seconds with belt) (P = .008). The pattern of impaired clearance was that of rapid re-reflux after peristaltic clearance. CONCLUSIONS: In a prospective study of patients with esophagitis or Barrett's esophagus, we found belt compression increased acid reflux following a meal. The intragastric pressure rise inducing this effect is well within the range associated with differing waist circumference and likely to be relevant to the association between obesity and reflux disease.

The gastric acid pocket is attenuated in H. pylori infected subjects.

OBJECTIVE: Gastric acid secretory capacity in different anatomical regions, including the postprandial acid pocket, was assessed in Helicobacter pylori positive and negative volunteers in a Western population. DESIGN: We studied 31 H. pylori positive and 28 H. pylori negative volunteers, matched for age, gender and body mass index. Jumbo biopsies were taken at 11 predetermined locations from the gastro-oesophageal junction and stomach. Combined high-resolution pH metry (12 sensors) and manometry (36 sensors) was performed for 20 min fasted and 90 min postprandially. The squamocolumnar junction was marked with radio-opaque clips and visualised radiologically. Biopsies were scored for inflammation and density of parietal, chief and G cells immunohistochemically. RESULTS: Under fasting conditions, the H. pylori positives had less intragastric acidity compared with negatives at all sensors >1.1 cm distal to the peak lower oesophageal sphincter (LES) pressure (p<0.01). Postprandially, intragastric acidity was less in H. pylori positives at sensors 2.2, 3.3 and 4.4 cm distal to the peak LES pressure (p<0.05), but there were no significant differences in more distal sensors. The postprandial acid pocket was thus attenuated in H. pylori positives. The H. pylori positives had a lower density of parietal and chief cells compared with H. pylori negatives in 10 of the 11 gastric locations (p<0.05). 17/31 of the H. pylori positives were CagA-seropositive and showed a more marked reduction in intragastric acidity and increased mucosal inflammation. CONCLUSIONS: In population volunteers, H. pylori positives have reduced intragastric acidity which most markedly affects the postprandial acid pocket.

Hiatus hernia in healthy volunteers is associated with intrasphincteric reflux and cardiac mucosal lengthening without traditional reflux.

BACKGROUND AND AIMS: Hiatus hernia (HH) is a key mediator of gastro-oesophageal reflux disease but little is known about its significance in the general population. We studied the structure and function of the gastro-oesophageal junction in healthy volunteers with and without HH. METHODS: We compared 15 volunteers with HH, detected by endoscopy or MRI scan, but without gastro-oesophageal reflux disease with 15 controls matched for age, gender and body weight. Jumbo biopsies were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed upright and supine, before and after a meal. The SCJ was marked with an endoscopically placed clip and visualised fluoroscopically. RESULTS: Cardiac mucosa was longer in volunteers with HH (3.5 vs 2.5 mm, p=0.01). There was no excessive acid reflux 5 cm above the upper border of the lower oesophageal sphincter (LOS) in either group but those with HH had short segment reflux 11 mm above the pH transition point after the meal when supine (pH<4 for 5.5% vs 0.3% of time, p=0.01). The SCJ and pH transition point were proximally displaced within the gastro-oesophageal junction in those with HH versus controls (p<0.05). The pH transition point was proximal to the peak LOS pressure point in HH subjects but distal to it in controls after the meal (p<0.05). When supine, the postprandial pH transition point crossed the SCJ in those with HH (p=0.03). CONCLUSIONS: Healthy volunteers with HH have increased intrasphincteric reflux and lengthening of cardiac mucosa in the absence of traditional transsphincteric reflux.

In healthy volunteers, immunohistochemistry supports squamous to columnar metaplasia as mechanism of expansion of cardia, aggravated by central obesity.

INTRODUCTION: Recently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine whether it may be due to columnar metaplasia of the distal oesophagus. METHODS: We used the squamocolumnar junction (SCJ), antral and body biopsies from the 52 Helicobacter pylori-negative healthy volunteers who had participated in our earlier physiological study and did not have hiatus hernia, transsphincteric acid reflux, Barrett's oesophagus or intestinal metaplasia (IM) at cardia. The densities of inflammatory cells and reactive atypia were scored at squamous, cardiac and oxyntocardiac mucosa of SCJ, antrum and body. Slides were stained for caudal type homeobox 2 (CDX-2), villin, trefoil factor family 3 (TFF-3) and liver-intestine (LI)-cadherin, mucin MUC1, Muc-2 and Muc-5ac. In addition, biopsies from 15 Barrett's patients with/without IM were stained and scored as comparison. Immunohistological characteristics were correlated with parameters of obesity and high-resolution pH metry recording. RESULTS: Cardiac mucosa had a similar intensity of inflammatory infiltrate to non-IM Barrett's and greater than any of the other upper GI mucosae. The immunostaining pattern of cardiac mucosa most closely resembled non-IM Barrett's showing only slightly weaker CDX-2 immunostaining. In distal oesophageal squamous mucosa, expression of markers of columnar differentiation (TFF-3 and LI-cadherin) was apparent and these correlated with central obesity (correlation coefficient (CC)=0.604, p=0.001 and CC=0.462, p=0.002, respectively). In addition, expression of TFF-3 in distal oesophageal squamous mucosa correlated with proximal extension of gastric acidity within the region of the lower oesophageal sphincter (CC=-0.538, p=0.001). CONCLUSIONS: These findings are consistent with expansion of cardia in healthy volunteers occurring by squamo columnar metaplasia of distal oesophagus and aggravated by central obesity. This metaplastic origin of expanded cardia may be relevant to the substantial proportion of cardia adenocarcinomas unattributable to H. pylori or transsphincteric acid reflux.

Central obesity in asymptomatic volunteers is associated with increased intrasphincteric acid reflux and lengthening of the cardiac mucosa.

BACKGROUND & AIMS: In the West, a substantial proportion of subjects with adenocarcinoma of the gastric cardia and gastroesophageal junction have no history of reflux. We studied the gastroesophageal junction in asymptomatic volunteers with normal and large waist circumferences (WCs) to determine if central obesity is associated with abnormalities that might predispose individuals to adenocarcinoma. METHODS: We performed a study of 24 healthy, Helicobacter pylori-negative volunteers with a small WC and 27 with a large WC. Abdominal fat was quantified by magnetic resonance imaging. Jumbo biopsy specimens were taken across the squamocolumnar junction (SCJ). High-resolution pH-metry (12 sensors) and manometry (36 sensors) were performed in upright and supine subjects before and after a meal; the SCJ was visualized fluoroscopically. RESULTS: The cardiac mucosa was significantly longer in the large WC group (2.5 vs 1.75 mm; P = .008); its length correlated with intra-abdominal (R = 0.35; P = .045) and total abdominal (R = 0.37; P = .034) fat. The SCJ was closer to the upper border of the lower esophageal sphincter (LES) in subjects with a large WC (2.77 vs 3.54 cm; P = .02). There was no evidence of excessive reflux 5 cm above the LES in either group. Gastric acidity extended more proximally within the LES in the large WC group, compared with the upper border (2.65 vs 4.1 cm; P = .027) and peak LES pressure (0.1 cm proximal vs 2.1 cm distal; P = .007). The large WC group had shortening of the LES, attributable to loss of the distal component (total LES length, 3 vs 4.5 cm; P = .043). CONCLUSIONS: Central obesity is associated with intrasphincteric extension of gastric acid and cardiac mucosal lengthening. The latter might arise through metaplasia of the most distal esophageal squamous epithelium and this process might predispose individuals to adenocarcinoma.

Effect of nitrite delivered in saliva on postprandial gastro-esophageal function.

OBJECTIVE: Acid reflux produces troublesome symptoms (heartburn) and complications including esophagitis, Barrett's esophagus, and adenocarcinoma. Reflux occurs due to excessive and inappropriate relaxation of the lower esophageal sphincter. An important mediator of this is nitric oxide, high concentrations of which are generated within the lumen when swallowed saliva meets gastric acid. Saliva contains nitrite, derived from the enterosalivary recirculation of dietary nitrate, which is reduced to nitric oxide by gastric acid. The aim of this study was to investigate whether salivary nitrite contributes to dysfunction of the lower esophageal sphincter. MATERIALS AND METHODS: In 20 volunteers, studies of gastro-esophageal function were performed on four separate days, following consumption of a standardized meal, with saliva nitrite concentrations modified differently each day by intra-oral nitrite infusion. RESULTS: The infusions produced an appropriate range in saliva nitrite concentrations, from below to well above the physiological range. The standardized meal induced expected physiological changes in gastro-esophageal function confirming the recordings were sensitive and robust. Esophageal acid exposure (primary outcome) was similar on each study day. Secondary outcomes, including number and duration of reflux events, rate of transient lower esophageal sphincter relaxations, lower esophageal sphincter pressure and rate of gastric emptying were also unaffected by variations in saliva nitrite concentration. CONCLUSIONS: Nitrite in swallowed saliva does not modify gastro-esophageal junction function or predispose to gastro-esophageal reflux. The wide range in saliva nitrite concentrations, the sensitivity of the physiological recordings and the number of subjects studied make it very unlikely that an effect has been missed.

Ectopic pancreatic-type malignancy presenting in a Meckel's diverticulum: a case report and review of the literature.

BACKGROUND: Neoplasms arising from Meckel's diverticulae reported in the literature are mainly carcinoid tumours, gastrointestinal stromal tumours, and gastric or intestinal adenocarcinomas. CASE PRESENTATION: We describe a 50-year-old man who presented with rectal bleeding and anaemia, later found to be caused by a pancreatic adenocarcinoma arising from ectopic pancreatic tissue in a Meckel's diverticulum. The tumour was unfortunately highly aggressive, and the patient passed away within 5 months of symptom onset. CONCLUSION: We believe this is the first case of pancreatic adenocarcinoma in a Meckel's diverticulum to be reported in the literature. The diagnosis of Meckel's should be considered in patients with acute gastrointestinal complaints; when found incidentally at laparotomy, it should be carefully examined for any gross abnormality and resection should be considered.