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The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data. Genome complexity is a distinguishing feature of advanced cancers in contrast to precancerous conditions. Here, by analysing chromosomal copy-number evolution in early cancers and precancerous lesions of the oesophagus, the authors reveal signatures of ongoing chromosomal instability and its role in promoting tumour progression. [ABSTRACT FROM AUTHOR]

Background: Endoscopic ultrasound (EUS)-guided transmural or endoscopic retrograde cholangiography (ERC)-based transpapillary drainage may provide alternative treatment strategies for high-risk surgical candidates with symptomatic gallbladder (GB) disease. The primary aim of this study was to perform a systematic review and meta-analysis to investigate the efficacy and safety of endoscopic GB drainage for patients with symptomatic GB disease.Methods: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed in accordance with PRISMA and MOOSE guidelines. Pooled proportions were calculated for measured outcomes including technical success, clinical success, adverse event rate, recurrence rate, and rate of reintervention. Subgroup analyses were performed for transmural versus transpapillary, transmural lumen apposing stent (LAMS), and comparison to percutaneous transhepatic drainage. Heterogeneity was assessed with I2 statistics. Publication bias was ascertained by funnel plot and Egger regression testing.Results: Thirty-six studies (n = 1538) were included. Overall, endoscopic GB drainage achieved a technical and clinical success of 87.33% [(95% CI 84.42-89.77); I2 = 39.55] and 84.16% [(95% CI 80.30-87.38); I2 = 52.61], with an adverse event rate of 11.00% [(95% CI 9.25-13.03); I2 = 7.08]. On subgroup analyses, EUS-guided transmural compared to ERC-assisted transpapillary drainage resulted in higher technical and clinical success rates [OR 3.91 (95% CI 1.52-10.09); P = 0.005 and OR 4.59 (95% CI 1.84-11.46); P = 0.001] and lower recurrence rate [OR 0.17 (95% CI 0.06-0.52); P = 0.002]. Among EUS-guided LAMS studies, technical success was 94.65% [(95% CI 91.54-96.67); I2 = 0.00], clinical success was 92.06% [(95% CI 88.65-94.51); I2 = 0.00], and adverse event rate was 11.71% [(95% CI 8.92-15.23); I2 = 0.00]. Compared to percutaneous drainage, EUS-guided drainage possessed a similar efficacy and safety with significantly lower rate of reintervention [OR 0.05 (95% CI 0.02-0.13); P < 0.001].Discussion: Endoscopic GB drainage is a safe and effective treatment for high-risk surgical candidates with symptomatic GB disease. EUS-guided transmural drainage is superior to transpapillary drainage and associated with a lower rate of reintervention compared to percutaneous transhepatic drainage. [ABSTRACT FROM AUTHOR]