Searching for low phospholipid associated cholelithiasis among patients with post-cholecystectomy biliary pain.

INTRODUCTION: Low phospholipid associated cholelithiasis (LPAC) is associated with variants of the adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) gene and is characterized by reduced phosphatidylcholine secretion into bile, impairing the formation of micelles and thus exposing bile ducts to toxic bile acids and increasing cholesterol saturation. LPAC is present in 1% of patients with gallstones and post-cholecystectomy pain is common in this group. LPAC is an under-appreciated cause of post-cholecystectomy pain. The aim of this study is to assess a cohort of patients with post-cholecystectomy pain to identify those with clinical features suggesting that further investigations for LPAC would be beneficial. METHODS: A retrospective chart review was performed of the first 2 years of post-operative follow-up for all patients under 40 years of age undergoing cholecystectomy for symptomatic gallstones at a tertiary centre between January 2016 and December 2017. RESULTS: 258 patients under the age of 40 underwent a cholecystectomy. 50 patients (19.4%) reported abdominal pain post-cholecystectomy. Five patients (1.9%) fulfilled the criteria for suspected LPAC. Family history of gallstones was documented in 33 of 258 (12.8%) of cases. Obstetric history was obtained in 69 of 197 (35%) female patients. None of the five patients identified above who satisfied the criteria of LPAC had the diagnosis of LPAC considered by their treating clinicians. CONCLUSION: LPAC is an under-recognized cause of post-cholecystectomy pain. Treatment can avoid long-term symptoms and complications. Clinicians should take a family history and obstetric history to alert them to the diagnosis of LPAC.

Effectiveness and safety of cold snare polypectomy and cold endoscopic mucosal resection for nonpedunculated colorectal polyps of 10-19 mm: a multicenter observational cohort study.

BACKGROUND : Cold snare polypectomy (CSP) is the standard of care for the resection of small (< 10 mm) colonic polyps. Limited data exist for its efficacy for medium-sized (10-19 mm) nonpedunculated polyps, especially conventional adenomas. This study evaluated the effectiveness and safety of CSP/cold endoscopic mucosal resection (C-EMR) for medium-sized nonpedunculated colonic polyps. METHODS : A prospective multicenter observational study was conducted of all morphologically suitable nonpedunculated colonic polyps of 10-19 mm removed by CSP/C-EMR between May 2018 and June 2021. Once resection was complete, multiple biopsies were taken of the margins circumferentially and centrally. The primary outcome was the incomplete resection rate (IRR), based on residual polyp in these biopsy specimens. Secondary outcomes were recurrence rate at first surveillance colonoscopy and rates of adverse events (AEs). RESULTS : CSP/C-EMR was performed for 350 polyps (median size 15 mm; 266 [76.0 %] Paris 0-IIa classification) in 295 patients. Submucosal injection was used for 87.1 % (n = 305) of polyps. Histology showed 68.6 % adenomas, 26.0 % sessile serrated lesions (SSLs) without dysplasia, 4.0 % SSL with dysplasia, and 1.4 % hyperplastic polyps. The IRRs based on margin or central biopsies being positive were 1.7 % (n = 6) and 0.3 % (n = 1), respectively. The polyp recurrence rate was 1.7 % (n = 4) at first surveillance colonoscopy - completed for 65.4 % (n = 229) of polyps at a median interval of 9.7 months. AEs occurred in 3.4 % (n = 10) of patients: four with post-polypectomy pain; three self-limiting post-polypectomy bleeds; two post-polypectomy-syndrome-like presentations; and one intraprocedural bleed treated with clips. There were no perforations. CONCLUSION : CSP/C-EMR for morphologically suitable nonpedunculated colonic polyps of 10-19 mm is effective and safe, including for conventional adenomas. Rates of incomplete resection and recurrence were low, with few AEs. Studies directly comparing this method with hot snare resection are required.

Targeted liver ultrasound performed by an expert is the pivotal imaging examination for low phospholipid-associated cholelithiasis.

OBJECTIVES: Low phospholipid-associatedcholelithiasis (LPAC) is a clinical syndrome that can be associated with variants in the adenosinetriphosphate-binding cassette subfamily B, member 4 (ABCB4) transporter gene, in a proportion of patients. The diagnosis of LPAC is defined by clinical as well as imaging criteria of intrahepatic hyperechoic foci or microlithiasis and biliary sludge on ultrasound. The aim of the study was to assess the role of imaging in investigating patients presenting with clinical features suggesting a diagnosis of LPAC. METHODS: Imaging findings in 51 patients with clinical LPAC were retrospectively reviewed. Most patients had been referred with difficult-to-manage biliary pain postcholecystectomy and some with intrahepatic dilated ducts and stones. The diagnosis of LPAC was made on clinical features. RESULTS: The patients were young with symptom onset at median age 24 years and were mainly female (75%). Ultrasound was performed by an expert in 48/51 and magnetic resonance cholangiopancreatography (MRCP) in 47/51 patients. Targeted liver ultrasound found small hyperechoic foci with comet tail artifacts or posterior acoustic shadowing typical of LPAC in 30/48 (63%) of examinations. However, ultrasound examinations performed before referral for investigation did not report these findings. Intrahepatic duct dilatation was seen in 26/51 (51%) of cases. MRCP did not reliably detect microlithiasis. CONCLUSIONS: Targeted liver ultrasound performed by an expert aware of the possible diagnosis is the pivotal investigation for patients with clinical features suggesting LPAC. The findings in ultrasound performed before referral suggest LPAC is under-recognized and under-diagnosed.

Erratum: Cold snare polypectomy of colorectal polyps ≤ 10 mm on clopidogrel: Australian and New Zealand randomized controlled trial.

[This corrects the article DOI: 10.1055/a-1813-1019.].

Low-cost and clinically applicable copy number profiling using repeat DNA.

BACKGROUND: Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell's genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. RESULTS: We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman's rank correlation coefficient, rs=0.94) between conliga's inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (rs=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (rs=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga's hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. CONCLUSIONS: We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.

Prodromal Signs and Symptoms of Chronic Pancreatitis: A Systematic Review.

GOAL: We aimed to extract the percent of signs and symptoms at the time of diagnosis from published studies and to pool these using meta-analytic techniques. BACKGROUND: Delayed or misdiagnosis of chronic pancreatitis may occur because the signs and symptoms are nonspecific and varied. STUDY: We performed a systematic review of studies reporting the signs and symptoms of chronic pancreatitis at diagnosis. The percentage of patients with each sign and symptom was extracted and random-effects meta-analyses used to calculate pooled percentages. RESULTS: In total, 22 observational studies were included. Across 14 studies, 55% of chronic pancreatitis patients were classified as having alcoholic etiology. Abdominal pain was the most common symptom (76%), and weight loss was reported in 22% of patients. Jaundice occurred in 11% of patients and steatorrhoea in 3%. Half of the patients had a history of acute pancreatitis, and 28% had diabetes mellitus at diagnosis. Heterogeneity between the studies was high for all signs and symptoms. CONCLUSIONS: This research has identified some common features of patients with chronic pancreatitis, but the high heterogeneity makes it difficult to draw solid conclusions. Carefully designed studies to examine the signs and symptoms leading up to a diagnosis of chronic pancreatitis, and common combinations, are required. These would enable the development of a tool to aid in the early identification of chronic pancreatitis in the primary care setting, with potential for improved short-term and long-term outcomes for patients.

Drainage of pancreatic fluid collections using a lumen-apposing metal stent with an electrocautery-enhanced delivery system.

BACKGROUND AND AIM: Our aim was to evaluate the efficacy and safety of a lumen-apposing metal stent with an electrocautery-enhanced delivery system (EDS-LAMS) for endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) in regular clinical practice. METHODS: A retrospective and subsequent prospective analysis was undertaken of all patients who underwent EUS-guided drainage of their PFCs using the EDS-LAMS at 17 tertiary therapeutic endoscopy centers. RESULTS: Two hundred eight cases of EDS-LAMS deployment were attempted in 202 patients (mean age 52.9 years) at time of evaluation. Ninety-seven patients had pancreatic pseudocysts (PPs), 75 walled-off pancreatic necrosis (WOPN), 10 acute peripancreatic fluid collections (APFCs), 6 acute necrotic collections (ANCs), and 14 postoperative collections (POCs). Procedural technical success was achieved in 202/208 cases (97.1%). Maldeployment occurred in 7/208 cases (3.4%). Clinical success was achieved in 142/160 (88.8%) patients (PP 90%, WOPN 85.2%, APFC 100%, ANC 75%, POC 100%). Delayed adverse events included stent migration in 15/202 (7.4%), stent occlusion and infection in 16/202 (7.9%), major bleeding in 4/202 (2%), and buried EDS-LAMS in 2/202 (1%). PFC recurrence occurred in 13/142 (9.2%) patients; 9/202 (4.5%) required surgical or radiological intervention for PFC management after EDS-LAMS insertion. CONCLUSIONS: This large international multicenter study evaluating the EDS-LAMS for drainage of PFCs in routine clinical practice suggests that the EDS-LAMS are safe and effective for drainage of all types of PFCs; however, further endoscopic therapy is often required for WOPN. Major bleeding was a rare complication in our cohort.

Test performance and predictors of accuracy of endoscopic ultrasound-guided fine-needle aspiration for diagnosing biliary strictures or masses.

Background and study aims Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has emerged as an important method for obtaining a preoperative tissue diagnosis for suspected cholangiocarcinoma. However, doubts remain about test sensitivity. This study assessed the value and limitations of EUS-FNA in clinical practice. Patients and methods Patients undergoing EUS-FNA for biliary strictures/masses at a UK tertiary referral center from 2005 to 2014 were prospectively enrolled. Data on EUS-FNA findings, histology, and endoscopy and patient outcomes were collected to evaluate test performance and identify factors predictive of an inaccurate diagnostic result. Results Ninety-seven patients underwent a total of 112 EUS-FNA procedures. Overall test sensitivity for an initial EUS-FNA for suspected cholangiocarcinoma was 75 % (95 % CI 64 %-84 %), with specificity 100 % (95 % CI 85 %-100 %) and negative predictive value 0.62 (95 % CI 0.47-0.75). Hilar lesions, the presence of a biliary stent, and a diagnosis of PSC were significantly independently associated with an inaccurate result. For the most difficult cases, repeat sampling and use of the Papanicolaou cytopathology grading scale led to an increase in test sensitivity from 17 % to 100 % ( P  = 0.015) with no loss of specificity. Conclusions EUS-FNA was found to be a useful method for obtaining a preoperative tissue diagnosis for patients with suspected cholangiocarcinoma. This study identified markers that can reduce test accuracy and measures that can improve test performance of EUS-FNA.

A prospective trial of CONfocal endomicroscopy in CYSTic lesions of the pancreas: CONCYST-01.

Background and study aims Pancreatic cystic lesions (PCL) are common. While some harbor malignant potential, accurate preoperative diagnosis remains challenging. Needle-based confocal laser endomicroscopy (nCLE) via a 19G FNA needle enables real-time imaging of the cyst wall. This study evaluated the safety and utility of nCLE in patients with an indeterminate PCL undergoing EUS-FNA. Patients and methods The CONCYST study prospectively recruited patients with indeterminate PCL attending three hepatopancreaticobiliary (HPB) referral centers in the UK, with indeterminate PCL, who required EUS-FNA between July 2014 and October 2016. Following the procedure, all patients were followed up in telephone clinic for at least 12 months. Ethical approval for the study was granted by the National Research Ethics Service (14/LO/0040). Results Sixty-seven patient were recruited, 11 excluded and 56 included in the final analysis: 35 male, 21 female; median age 68 (range 28 - 80). Recognizable confocal images were obtained in 48 of 56 cases. Median nCLE scanning time was 5 minutes and did not exceed 10 minutes in any case. EUS-nCLE findings correlated with final diagnosis (based on imaging, cytology and multidisciplinary team review) in 43/56 (77 %) of cases, compared with 37/56 (66 %) for cytology alone ( P  = 0.12). One patient experienced mild pruritus following the procedure and another developed an infected pseudocyst, which resolved with antibiotics. Conclusions EUS-nCLE under conscious sedation in the day case setting is safe and provides additional information to standard EUS-FNA for diagnosing indeterminate PCL.

Risk factors for intraprocedural and clinically significant delayed bleeding after wide-field endoscopic mucosal resection of large colonic lesions.

BACKGROUND & AIMS: Wide-field endoscopic mucosal resection (WF-EMR) of large sessile colonic polyps is a safe and cost-effective outpatient treatment. Bleeding is the main complication. Few studies have examined risk factors for bleeding during the procedure (intraprocedural bleeding [IPB]) or after it (clinically significant post-endoscopic bleeding [CSPEB]). We investigated factors associated with IPB and CSPEB in a large prospective study. METHODS: We analyzed data from WF-EMRs of sessile colorectal polyps ≥ 20 mm in size (mean size, 35.5 mm), which were performed on 1172 patients (mean age, 67.8 years) from June 2008-March 2013 at 7 tertiary hospitals as part of the Australian Colonic Endoscopic Resection Study. Data were collected on characteristics of patients and lesions, along with outcomes of procedures and clinical and histologic analyses. Independent predictors of IPB and CSPEB were identified by multiple logistic regression analysis. RESULTS: Of the patients studied, 133 (11.3%) had IPB. Independent predictors included increasing lesion size (odds ratio, 1.24/10 mm; P < .001), Paris endoscopic classification of 0-IIa + Is (odds ratio, 2.12; P = .004), tubulovillous or villous histology (odds ratio, 1.84; P = .007), and study institutions that performed the procedure on fewer than 75 patients (odds ratio, 3.78; P < .001). All IPB was successfully controlled endoscopically. IPB prolonged procedures and was associated with early recurrence (relative risk, 1.68; P = .011). Seventy-three patients (6.2%) had CSPEB. On multivariable analysis, CSPEB was associated with proximal colon location (odds ratio, 3.72; P < .001), use of an electrosurgical current not controlled by a microprocessor (odds ratio, 2.03; P = .038), and IPB (odds ratio, 2.16; P = .016). Lesion size and comorbidities did not predict CSPEB. CONCLUSIONS: In a prospective study of patients undergoing WF-EMR of large sessile colonic polyps, IPB is associated with larger lesions, lesion histology, and Paris endoscopic classification of type 0-IIa + Is. IPB prolongs the duration of the procedure, is a marker for recurrence, and is associated with CSPEB. CSPEB occurs most frequently in the proximal colon and less when current is controlled by a microprocessor.

A correlation of the endoscopic characteristics of colonic laterally spreading tumours with genetic alterations.

OBJECTIVES: Laterally spreading tumours (LSTs) are a heterogeneous group of adenomas that are emerging as important precursors of colorectal cancer and in which the risk for cancer is related to their endoscopically definable morphology. It is currently unclear whether different molecular alterations determine their morphologies. We aimed to assess this relationship in LSTs using strict morphological classifications. METHODS: We characterized 135 sessile adenomatous lesions (≥ 20 mm) according to histopathology and the Paris classification. We investigated key molecular changes commonly found in colorectal neoplasms, namely mutation of KRAS, BRAF, APC and CTNNB1 and microsatellite instability, and determined their relationship with morphology. RESULTS: The Paris classification revealed a heterogeneous cohort comprising Is/IIa+Is (41.5%), IIa/IIb (53.3%) and IIc/IIa+IIc (5.2%) lesions. Histopathological analysis showed that 19 (14.1%) of these were sessile serrated adenomas. Here, we defined a group of 58 lesions that showed either Paris IIa or IIb morphology with no serrated histopathology. These 'classical LSTs' showed the following molecular characteristics: microsatellite instability 0/56 (0%), APC mutation 29/30 (96.7%), CTNNB1 mutation 2/55 (3.6%), KRAS mutation 24/55 (43.6%) and BRAF mutation 2/55 (3.6%). Separation of lesions according to surface morphology showed that KRAS mutations occurred much more frequently in granular (56.4%, 22/39) than in nongranular LSTs (12.5%, 1/16, P=0.004). CONCLUSION: The microsatellite instable pathway is not important in the development of LSTs, which are instead likely to develop along a divergent chromosomal instability pathway. We demonstrate the biological significance of endoscopic findings by showing that the morphological characteristics of LSTs are underpinned by distinctive molecular profiles.

A blinded comparison of the safety and efficacy of hot biopsy forceps electrocauterization and conventional snare polypectomy for diminutive colonic polypectomy in a porcine model.

BACKGROUND: Although linked with perforation, serositis, delayed bleeding, and incomplete resection, hot biopsy forceps electrocauterization (HBF) is still widely used for diminutive colonic polypectomy. OBJECTIVE: To evaluate the safety and efficacy of HBF in comparison with conventional snare polypectomy (CSP). DESIGN: Randomized, blinded, controlled trial. SETTING: Academic endoscopy unit. SUBJECTS: Ten swine. INTERVENTION: Eighty-two paired polypectomies (41 HBF, 41 CSP) of small, minimally elevated, artificial lesions. Standardized technique using coagulating current at 25 W. HBF: the tissue was avulsed after 1 to 2 seconds of current caused blanching of the artificial pedicle. CSP: the polyp was removed by snare diathermy. MAIN OUTCOME MEASUREMENTS: Histopathology of resected specimens and polypectomy sites in colectomy specimens at necropsy (lateral mucosal and depth of ulceration, necrosis and inflammation). RESULTS: Some (21%) of the HBF specimens were ablated and uninterpretable. All CSP specimens yielded interpretable specimens. Mucosal necrosis adjacent to HBF resection sites varied widely, between 1.5 and 9 mm (mean 5.7 mm, standard deviation ± 2). There was visible mucosa under the HBF ulcer in 14% of cases. The depth of necrosis in the colon wall was significantly different between the two techniques, with partial muscularis propria (MP) necrosis in 14 of 41 lesions (34%) with HBF, compared with 1 of 41 (2%) of CSP (P < .001), and full-thickness MP necrosis in 9 of 41 lesions (22%) with HBF, compared with 1 of 41 (2%) of CSP (P = .014). There was full-thickness MP inflammation in 13 of 41 lesions (32%) with HBF compared with 5 of 41 (12%) of CSP (P = .06). Transmural subserosal inflammation was seen in 13 of 41 lesions (32%) with HBF compared with 4 of 41 (10%) of CSP (P = .027). There was no relationship between visible lateral mucosal injury and depth of injury (rs = -0.07). LIMITATIONS: Animal study. CONCLUSION: Despite use of the standardized HBF technique, there is a wide range of lateral mucosal and deep thermal injury as well as residual target mucosa. HBF also results in a significantly greater depth of tissue injury, with a high proportion of transmural necrosis. Ensuring minimal blanching of the mucosa during the procedure does not protect from deep injury. In comparison to conventional snare polypectomy, HBF is imprecise, potentially ineffective, and hazardous.

Beyond the snare: technically accessible large en bloc colonic resection in the West: an animal study.

BACKGROUND: Endoscopic submucosal dissection (ESD) and circumferential submucosal incision endoscopic mucosal resection (CSI-EMR) are techniques for en bloc excision of large sessile colonic lesions. Our aims were to compare the efficacy, safety and learning curve of colonic hybrid knife (HK) ESD versus CSI-EMR for en bloc excision of 50 mm diameter hemi-circumferential artificial lesions in a porcine model. PATIENTS AND METHODS: Two separate 50 mm diameter areas of normal recto-sigmoid mucosa were marked out in each of ten pigs. One was excised with HK-ESD using succinylated gelatin (SG) submucosal injection. The other was isolated with CSI with the Insulated Tip Knife 2 followed by SG submucosal injection then EMR with a large snare. Euthanasia and colectomy was performed at 72 h followed by blinded histopathology assessment. RESULTS: En bloc excision rates were: HK-ESD 100% versus CSI-EMR 20% (P = 0.008). The mean number of resections per lesion was HK-ESD 1 versus CSI-EMR 3 (P = 0.001). The mean dimensions of the largest specimen per technique were HK-ESD 63 × 54 mm versus CSI-EMR 49 × 41 mm (P = 0.005). Procedure duration mean was HK-ESD 54 min versus CSI-EMR 22 min (P < 0.001). When procedure duration was adjusted for the size of the resected en bloc specimen, a statistically significant and accelerated learning effect was noted for HK-ESD (r = -0.83, P = 0.003). There were no perforations and no significant bleeding. CONCLUSIONS: HK-ESD with SG submucosal injection is superior to CSI-EMR for en bloc excision of 50 mm diameter lesions in a porcine model. The technique is rapidly learnt. This novel approach may lower the barrier to colonic ESD for Western endoscopists.

A randomized, double-blind trial of succinylated gelatin submucosal injection for endoscopic resection of large sessile polyps of the colon.

OBJECTIVES: Succinylated gelatin (SG) is an inexpensive, safe, colloidal solution. It was superior to normal saline (NS) in a porcine colon endoscopic resection (ER) model. Our aim was to compare the efficacy, efficiency, and safety of ER with SG vs. NS. METHODS: A randomized double-blind trial of submucosal injection with SG vs. NS was conducted for patients undergoing colonoscopy and ER for sessile lesions ≥20 mm in size at an Australian academic hospital endoscopy unit. The primary end point was the "Sydney Resection Quotient" (SRQ), defined as "lesion size in mm divided by the number of pieces to resect." This allows a comparison of technical outcomes for lesions of various sizes. A large lesion removed in fewer pieces gives a greater value. RESULTS: Eighty patients (45 men, mean age 69) with lesions sized 20-100 mm were randomized. A total of 41 SG subjects were well matched to 39 NS subjects, with median (interquartile range) lesion size 40 mm (25-45) vs. 35 mm (30-50), respectively (P=0.382). Complete single-session lesion excision was 90% in both groups. There were no adverse events attributable to SG. The SRQ (median (interquartile range)) was SG 10.0 (7.5-20.0) vs. NS 5.9 (4.4-11.7), P=0.004. Other end points (median (interquartile range)) included fewer resections per lesion in the SG group: 3.0 (1.0-6.0) vs. NS 5.5 (3.0-10.0), P=0.028; fewer injections per lesion with SG: 2.0 (1.0-3.0) vs. NS 3.0 (2.0-11.0), P=0.002; lower injection volume: 14.5 ml (8.5-23.0) vs. NS 20.0 ml (16.0-46.0), P=0.009; and shorter procedure duration with SG: 12.0 min (8.0-28.0) vs. NS 24.5 min (15.0-36.0), P=0.006. CONCLUSIONS: SG significantly improves SRQ by almost halving the number of resections for piecemeal ER. SG also safely halves procedure duration.