A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.

EUS-guided choledochoduodenostomy with electrocautery-enhanced lumen-apposing metal stents in patients with malignant distal biliary obstruction: multicenter collaboration from the United Kingdom and Ireland.

BACKGROUND AND AIMS: EUS-guided choledochoduodenostomy (EUS-CDD) with an electrocautery-enhanced lumen-apposing metal stent (EC-LAMS) has emerged as a viable method of establishing biliary drainage in patients with malignant distal biliary obstruction (MDBO). Our aim was to assess the efficacy, safety, and outcomes in patients with MDBO who underwent EUS-CDD with an EC-LAMS. METHODS: A retrospective review of consecutive patients with MDBO who underwent EUS-CDD with EC-LAMSs at 8 tertiary institutions across the United Kingdom and Ireland between September 2016 and November 2020 was undertaken. RESULTS: One hundred twenty patients (55% men) with a median age of 73 years (interquartile range, 17; range, 43-94) were included. The median follow-up period in 117 patients was 70 days (interquartile range, 169; range, 3-869), and 23 patients (19.2%) were alive at the end of the follow-up. Three patients were lost to follow-up. Technical success was achieved in 109 patients (90.8%). Clinical success (reduction of serum bilirubin to ≤50% of original value within 14 days) was achieved in 94.8% of patients (92/97). The adverse event rate was 17.5% (n = 21). Biliary reintervention after initial technical success was required in 9 patients (8.3%). CONCLUSIONS: EUS-CDD with EC-LAMSs at tertiary institutions within a regional hepatopancreatobiliary network for treatment of MDBO was effective in those where ERCP was not possible or was unsuccessful. When technical failures or adverse events occur, most patients can be managed with conservative or endoscopic therapy.

Gastrointestinal conditions related to tooth wear.

Gastro-oesophageal reflux disease (GORD) is a relatively common condition that occurs in adults and less commonly in children. It develops when the reflux of stomach contents into the oesophagus causes troublesome symptoms and/or complications. Signs and symptoms include heartburn, retrosternal discomfort, epigastric pain and hoarseness, dental erosion, chronic cough, burning mouth syndrome, halitosis and laryngitis. A proportion of patients will, however, have silent reflux. Strongly associated risk factors include family history, age, hiatus hernia, obesity and neurological conditions, such as cerebral palsy. There are different treatment options which may be considered for GORD, consisting of conservative, medical and surgical therapy. Dentists should be aware of the symptoms of GORD and dental signs of intrinsic erosion indicative of possible GORD so that they can question patients about this and, if appropriate, initiate a referral to a general medical practitioner.

Pancreaticobiliary Malignancies in the Emergency Room: Management of Acute Complications and Oncological Emergencies.

BACKGROUND: Management of pancreaticobiliary (PB) malignancies remains a clinical challenge. In this review, we focus on the management of oncological emergencies in PB malignancies and the potential complication of associated therapeutic interventions. METHODS: Biobliographic review of current evidence on the management of oncological emergencies, their potential complications, as well as synthesis of recommendations was performed. The pathogenesis, frequency, related symptoms as well as appropriate investigations are presented. RESULTS: The oncologic emergencies in PB patients were summarised in six categories: (1) hematological (including febrile neutropaenia, thrombocytopenia, coagulopathies), (2) gastrointestinal (gastric outlet and biliary obstruction, gastrointestinal bleeding), (3) thromboembolic events, (4) ascites, (5) metabolic disorders and (6) neurologic complications. The pathogenesis, frequency, related symptoms as well as appropriate investigations are also presented. CONCLUSION: Patients with PB malignancies are at increased risk of a wide variation of medical emergencies. Clinical knowledge, early recognition and collaboration with the relevant specialties are critical to manage these complications effectively, tailoring overall management around the actual prognosis and individuals' expectations.

Pancreatic Enzyme Replacement Therapy for Patients Diagnosed With Pancreaticobiliary Cancer: Validation of an Algorithm for Dose Escalation and Management.

OBJECTIVE: An algorithm was designed aiming to provide consistency of pancreatic enzyme replacement therapy (PERT) dosing/titration across healthcare professionals in pancreaticobiliary cancers (PBCs). This prospective observational study aimed to validate this algorithm. METHODS: Consecutive patients with inoperable or postoperative PBC with pancreatic exocrine insufficiency (PEI) symptoms, not taking PERT, or taking below the algorithm "starting dose," were eligible. A dietitian or clinical nurse specialist reviewed patients for up to 3 weeks, titrating PERT as per the algorithm. Feasibility of algorithm deliverability was assessed by the percentage of patients with successful completion (primary objective). RESULTS: Twenty-five patients were eligible (N = 25): at baseline, 22 took PERT (100% on suboptimal doses, 54.5% taking incorrectly) and 3 initiated PERT because of PEI symptoms. Algorithm completion (20 of 25, 80%) confirming deliverability by dietitians (11 of 12, 92%) and clinical nurse specialists (9 of 13, 69%). Symptom resolution occurred in 8 of 19 (42%), 3 of 7 (43%), and 1 of 3 (33%) patients at first, second, and third reviews, respectively; advice compliance was between 63% and 86%. CONCLUSIONS: This algorithm provides a structured method to titrate PERT. At diagnosis, all patients with PBC should be assessed for PEI and adequate PERT initiated. Regular reviews are required for timely symptom resolution and adequate escalation, facilitating differential diagnosis if refractory symptoms exist.

National survey to determine current practices, training and attitudes towards advanced polypectomy in the UK.

OBJECTIVE: Developments in advanced polypectomy technique provide an alternative to surgery in the management of large and complex colorectal polyps. These endoscopic techniques require expertise and can potentially incur high complication rates. This survey evaluates current UK practice, attitudes and training in advanced polypectomy. DESIGN: Anonymous online questionnaire. SETTING: Colonoscopists within the UK were asked about their approach to large polyps (>2 cm). RESULTS: Among the 268 respondents (64% of whom were BCSP accredited), 86% were confident in removing lesions >2 cm by endoscopic mucosal resection (EMR). Of these, 27% were classed as low volume operators (<10 lesions resected/annum) and 14% as high volume operators (>50/annum). By comparison, only 3% currently performed endoscopic submucosal dissection (ESD). Referring one or more benign polyps for surgery a year was common among responders of all levels (11-68%). Training deficiencies were common: only 21% of responders had received a period of training dedicated to advanced polypectomy; 58% of responders would welcome a national training scheme and a majority supported the implementation of advanced polypectomy accreditation with national guidelines. However, while 41% wanted nominated regional EMR experts, only 18% would welcome an integrated national referral network for large/complex polyps. CONCLUSIONS: EMR is practised widely while ESD service provision is very limited. Most experienced colonoscopists are confident to perform piecemeal EMR, even if their training is suboptimal and annual numbers low. Practices and attitudes were variable, even among self-defined level 4 operators. Improving training and implementation of accreditation were welcomed, but there was little appetite for mandated referral to subspecialist 'experts' and national networks.

Helicobacter pylori, HIV and Gastric Hypochlorhydria in the Malawian Population.

BACKGROUND: HIV and Helicobacter pylori are common chronic infections in sub-Saharan Africa. Both conditions can predispose to gastric hypochlorhydria that may be a risk factor for enteric infections and reduced drug absorption. We have investigated to what extent HIV and H. pylori infections are associated with hypochlorhydria in a Malawian cohort of patients undergoing endoscopy. METHODS: 104 sequential symptomatic adults referred for gastroscopy at Queen Elizabeth Central Hospital, Blantyre, Malawi, had blood taken for rapid HIV testing and fasting serum gastrin analysis. Gastric fluid was aspirated for pH testing, and gastric biopsies were taken. RESULTS: After 9/104 HIV-infected patients who were already established on anti-retroviral therapy were excluded, 17/95 (25.0%) were seropositive for untreated HIV, and 68/95 (71.6%) patients were H. pylori positive by histology. Hypochlorhydria (fasting gastric pH>4.0) was present in 55.8% (53/95) of patients. H. pylori infection was significantly associated with hypochlorhydria (OR 2.91, [1.02-7.75], p=0.046). While single infection with HIV was not significantly independently associated with hypochlorhydria. H. pylori and HIV co-infection was more strongly associated with hypochlorhydria (OR 6.25, [1.33-29.43], p=0.020) than either infection alone, suggesting an additive effect of co-infection. HIV infection was associated with higher serum gastrin levels (91.3 pM vs. 53.1 pM, p=0.040), while H. pylori infection was not (63.1 pM vs. 55.1 pM, p=0.610). Irrespective of H. pylori and HIV status, most patients (>90%) exhibited pangastritis. Only three patients had histological evidence of gastric atrophy, of which only one was HIV-infected. CONCLUSION: H. pylori infection was associated with fasting hypochlorhydria, while HIV was not independently associated. HIV and H. pylori co-infection, however, was more strongly associated with hypochlorhydria than H. pylori infection alone. The mechanism of this apparent additive effect between HIV and H. pylori remains unclear, but appears to be related to chronic pangastritis rather than gastric atrophy, and associated with hypergastrinaemia in HIV-infected individuals.

Colonic stenting: a practical update.

Colonic stenting is part of the UK service provision guidelines for colorectal cancer. However, there are issues about availability and expertise within the UK, and controversies remain regarding various clinical and technical aspects of the technique. Based on the current evidence, this article will provide a practical update on the indications, the clinical and technical considerations and the remaining unanswered questions regarding colonic stenting.

A multicentre study to determine the incidence, demographics, aetiology and outcomes of 6-day emergency readmission following day-case endoscopy.

BACKGROUND: Emergency readmission after elective procedures is a quality indicator of healthcare delivery, but data for endoscopy are limited. OBJECTIVES: Using hospital episode statistics (HES) registration systems and a multicentre audit to describe outcomes of emergency readmission following elective endoscopy. METHODS: Emergency readmissions (April 2008-2009) within 6 days of an elective day-case upper-GI endoscopy (UE) and lower GI endoscopy (LE) were subjected to a multicentre retrospective audit (north-west of England) following the identification of cases from routinely coded hospital administrative data from HES. RESULTS: Of 29 868 day cases, there were 235 readmissions, of which 147 (63%) were endoscopy related. The overall endoscopy readmission rate was 0.5% and the highest for therapeutic UE (1.74%; P=0.0001). The rates for therapeutic LE, diagnostic UE and LE were 0.6, 0.5 and 0.4%, respectively. The incidence of readmission was 0.2% because of cardiorespiratory event, 0.14% for symptoms and 0.08, 0.03, 0.02 and 0.016%, respectively, for bleeding, perforation, obstruction and nonrespiratory sepsis. Management was simple observation in 84.4%, intravenous antibiotics in 7.5%, surgery in 4.8% and repeat endoscopy in 2.7%. Although 24.5% were short-stay discharges, the mean hospital stay was 8.2 days. All-cause 30-day mortality was low at 0.06%, but was considerably higher in readmitted patients at 6.8% (P=0.0001). CONCLUSION: Novel insights into readmission rates can be gained following endoscopy using a combination of commercial analytical tools to examine HES data to identify eligible readmitted cases; multicentred patient-level audit readmission rates varied predictably across procedure types with cardiorespiratory events, the major cause. The risk of mortality in readmitted patients was significant.