Patient and operative factors influence delayed discharge following bariatric surgery in an enhanced recovery setting.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) programs have been widely adopted in bariatric surgery. However, not all patients are successfully managed in the ERAS setting and there is currently little way of predicting the patients who will deviate from the program. Early identification of these patients could allow for more tailored protocols to be implemented preoperatively to address the issues, thereby improving patient outcomes. OBJECTIVES: The aim of this study was to elucidate the factors which preclude discharge by comparing patients who were successfully discharged by the end of the first postoperative day (POD 0/1) to those who stayed longer, including revisional surgery in this analysis. SETTING: A tertiary, high-volume Bariatric Centre, United Kingdom. METHODS: A retrospective analysis was performed of all patients undergoing bariatric surgery in a single centre in 1 year. Multivariate analyses compared patient and operative variables between patients who were discharged on POD 0/1 and those who stayed longer. RESULTS: A total of 288 bariatric operations were performed: 78% of operations performed were laparoscopic Roux-en-Y gastric bypass; 22% laparoscopic sleeve gastrectomy. Of these cases, 13% were revisional operations. Four patients returned to theatre on the index admission. 81% of patients were discharged by POD 0/1. A re-presentation within 30 days was seen in 6% of patients. There was no significant difference in length of stay for the type of operation performed (P = .86). Patients who had a revisional procedure were not more likely to stay longer. Length of stay was also independent of age, BMI, and comorbidities. Caucasian patients were more likely to be discharged on POD 0/1 than those of other ethnicities (90% versus 78%; P = .02). Operations performed by trainee surgeons, under consultant supervision, were significantly more likely to be discharged on POD 0/1 (P = .03). However, a logistic regression analysis was unable to predict patients who had a prolonged stay. CONCLUSIONS: Patient length of stay is independent of BMI, operation, and comorbidities and these factors do not need special consideration in ERAS pathways. Patients undergoing revisional procedures can be managed in the same way as those having primary procedures, with a routine POD 0/1 discharge. However, the impact of individual patient factors, and their interaction, is complex and cannot predict overstay.

Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma.

A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked with TP53 mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.

Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus.

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

Molecular phenotyping reveals the identity of Barrett's esophagus and its malignant transition.

The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett's esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett's esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett's esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.

Identification of Subtypes of Barrett's Esophagus and Esophageal Adenocarcinoma Based on DNA Methylation Profiles and Integration of Transcriptome and Genome Data.

BACKGROUND & AIMS: Esophageal adenocarcinomas (EACs) are heterogeneous and often preceded by Barrett's esophagus (BE). Many genomic changes have been associated with development of BE and EAC, but little is known about epigenetic alterations. We performed epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity. METHODS: In a retrospective cohort study, we collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Oesophageal Cancer Classification and Molecular Stratification consortium in the United Kingdom. We analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering. Data from whole-genome sequencing and transcriptome studies were then incorporated; we performed integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions. Levels of different immune cell types were computed using single-sample gene set enrichment methods. We derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs. RESULTS: BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes. Subtype 1 was characterized by DNA hypermethylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways. Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and lack methylation at specific binding sites for transcription factors; 83% of samples of this subtype were BE and 17% were EAC. The third subtype did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor type was associated with the shortest time of patient survival. The fourth subtype was characterized by DNA hypomethylation associated with structure rearrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors). Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs. CONCLUSIONS: In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, we identified 4 subtypes that were associated with patient outcomes and potential responses to therapy.

Application of a multi-gene next-generation sequencing panel to a non-invasive oesophageal cell-sampling device to diagnose dysplastic Barrett's oesophagus.

The early detection and endoscopic treatment of patients with the dysplastic stage of Barrett's oesophagus is a key to preventing progression to oesophageal adenocarcinoma. However, endoscopic surveillance protocols are hampered by the invasiveness of repeat endoscopy, sampling bias, and a subjective histopathological diagnosis of dysplasia. In this case-control study, we investigated the use of a non-invasive, pan-oesophageal cell-sampling device, the Cytosponge™, coupled with a cancer hot-spot panel to identify patients with dysplastic Barrett's oesophagus. Formalin-fixed, paraffin-embedded (FFPE) Cytosponge™ samples from 31 patients with non-dysplastic and 28 with dysplastic Barrett's oesophagus with good available clinical annotation were selected for inclusion. Samples were microdissected and amplicon sequencing performed using a panel covering >2800 COSMIC hot-spot mutations in 50 oncogenes and tumour suppressor genes. Strict mutation criteria were determined and duplicates were run to confirm any mutations with an allele frequency <12%. When compared with endoscopy and biopsy as the gold standard the panel achieved a 71.4% sensitivity (95% CI 51.3-86.8) and 90.3% (95% CI 74.3-98.0) specificity for diagnosing dysplasia. TP53 had the highest rate of mutation in 14/28 dysplastic samples (50%). CDKN2A was mutated in 6/28 (21.4%), ERBB2 in 3/28 (10.7%), and 5 other genes at lower frequency. The only gene from this panel found to be mutated in the non-dysplastic cases was CDKN2A in 3/31 cases (9.7%) in keeping with its known loss early in the natural history of the disease. Hence, it is possible to apply a multi-gene cancer hot-spot panel and next-generation sequencing to microdissected, FFPE samples collected by the Cytosponge™, in order to distinguish non-dysplastic from dysplastic Barrett's oesophagus. Further work is required to maximize the panel sensitivity.

The role of rapid thromboelastography in trauma.

Evaluation of: Hampton DA, Lee TH, Diggs BJ, McCully SP, Schreiber MA. A predictive model of early mortality in trauma patients. Am. J. Surg. 207(5), 642-647 (2014). In their prospective multi-centred observational study, Hampton et al. tested the ability of rapid thromboelastography (r-TEG) to predict mortality in trauma patients. A total of 795 patients were assessed. The authors analysed both patient demographic and physiological measures. Validation of variables that significantly related to mortality was subsequently undertaken. Ly30 (a measurement of the degree of clot lysis over 30 min) was observed to be a predictor of 24-h mortality in trauma (odds ratio 3.7 p = 0.03). This was incorporated with haemoglobin level, international normalized ratio, Glasgow Coma Score and the presence of penetrating injury to form their five-variable mortality prediction model. Hampton et al. conclude that the correlation between r-TEG measurements and trauma mortality makes it a useful tool in mortality prediction. The report highlights the importance of using this point-of-care coagulation assessment machine in mortality prediction for trauma patients.

A cadaveric study of the anatomical variation of the origins of the celiac trunk and the superior mesenteric artery: a role in median arcuate ligament syndrome?

Gray's Anatomy states, "the celiac trunk is the first anterior branch of the abdominal aorta and arises just below the aortic hiatus. The superior mesenteric artery originates from the aorta c1.0 cm below the celiac trunk." (Standring, 2008a, Gray's Anatomy. 40th Ed. London: Churchill Livingstone Elsevier, p. 1073-1074). During dissection classes with medical students we found this not to be the case. We have re-evaluated the anatomy of the origins of the celiac trunk (CT) and superior mesenteric artery (SMA) and the relationship of the CT to the median arcuate ligament (MAL) in 99 cadavers. We have found the external distance between the CT and SMA to range from 0 to 20 mm (mean 3.4 mm, SD 5.17 mm), with the two in direct apposition in 57.6% (n = 99) of cases: a higher figure than previously documented. However, the internal distance between the CT and SMA ranged from 10 to 30 mm (mean 18.9 mm, SD 4.09 mm). There was no distance measurable between the MAL and the CT in 88 cadavers (92.6%, n = 95) and, of these, 32 (33.7%) showed evidence of compression or kinking of the CT. We suspect that the MAL is responsible for the approximation of the CT to the SMA in these cadavers, and that the high incidence of kinking of the CT (33.7% of cases) may have implications with regard to its role in MAL syndrome.