Abstract Background Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative ...stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for use in clinical practice. Patients and methods Preoperative patient and disease-related variables were identified from a prospective cholecystectomy database (CholeS) of 8820 patients, divided into main and validation sets. Preoperative predictors of conversion were identified by multivariable binary logistic regression. A risk score was developed and validated using a forward stepwise approach. Results Some 297 procedures (3.4%) were converted. The risk score was derived from six significant predictors: age (p = 0.005), sex (p < 0.001), indication for surgery (p < 0.001), ASA (p < 0.001), thick-walled gallbladder (p = 0.040) and CBD diameter (p = 0.004). Testing the score on the validation set yielded an AUROC = 0.766 (p < 0.001), and a score >6 identified patients at high risk of conversion (7.1% vs. 1.2%). Conclusion This validated risk score allows preoperative identification of patients at six-fold increased risk of conversion to open cholecystectomy.
Bariatric surgery can influence the presentation, diagnosis, and management of gastrointestinal cancers. Esophagogastric (EG) malignancies in patients who have had a prior bariatric procedure have ...not been fully characterized.
To characterize EG malignancies after bariatric procedures.
University Hospital, United Kingdom.
We performed a retrospective, multicenter observational study of patients with EG malignancies after bariatric surgery to characterize this condition.
This study includes 170 patients from 75 centers in 25 countries who underwent bariatric procedures between 1985 and 2020. At the time of the bariatric procedure, the mean age was 50.2 ± 10 years, and the mean weight 128.8 ± 28.9 kg. Women composed 57.3% (n = 98) of the population. Most (n = 64) patients underwent a Roux-en-Y gastric bypass (RYGB) followed by adjustable gastric band (AGB; n = 46) and sleeve gastrectomy (SG; n = 43). Time to cancer diagnosis after bariatric surgery was 9.5 ± 7.4 years, and mean weight at diagnosis was 87.4 ± 21.9 kg. The time lag was 5.9 ± 4.1 years after SG compared to 9.4 ± 7.1 years after RYGB and 10.5 ± 5.7 years after AGB. One third of patients presented with metastatic disease. The majority of tumors were adenocarcinoma (82.9%). Approximately 1 in 5 patients underwent palliative treatment from the outset. Time from diagnosis to mortality was under 1 year for most patients who died over the intervening period.
The Oesophago-Gastric Malignancies After Obesity/Bariatric Surgery study presents the largest series to date of patients developing EG malignancies after bariatric surgery and attempts to characterize this condition.
New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell ...line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33. Transposase-accessible chromatin sequencing (ATAC-seq) was performed in MFD-1, OE33, and non-neoplastic HET1A cells. Functional studies were performed. MFD-1 had a high SNP genotype concordance with matched germline/tumour. Parental tumour and MFD-1 carried four somatically acquired mutations in three recurrent mutated genes in OAC: TP53, ABCB1 and SEMA5A, not present in FLO-1 or OE33. MFD-1 displayed high expression of epithelial and glandular markers and a unique fingerprint of open chromatin. MFD-1 was tumorigenic in SCID mouse and proliferative and invasive in 3D cultures. The clinical utility of whole genome sequencing projects will be delivered using accurate model systems to develop molecular-phenotype therapeutics. We have described the first such system to arise from the oesophageal International Cancer Genome Consortium project.
Abstract
Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE ...transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.
Graphical Abstract
Graphical Abstract
Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole ...transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.
Angiosarcoma: A rare cause of splenomegaly Balamurugan, Thiagarajah; R. Preston, Shaun; N. Bagwan, Izhar
Hematology & Medical Oncology,
2017, Volume:
2, Issue:
5
Journal Article
The bombesin-like peptides gastrin releasing peptide (GRP) and neuromedin B are found in the submucosal and myenteric plexuses of the human gastrointestinal tract. These peptides are potent mitogens ...to Swiss 3T3 fibroblasts and are important autocrine growth factors in human small cell lung cancer cells. We have recently described the presence of receptors for the bombesin-like peptide, GRP, on the human gastric cancer cell line St42. In this study, we examined fresh resected gastric cancer and uninvolved mucosa from 23 patients for the presence of binding sites to the bombesin-like peptides. Thirteen of 23 gastric cancers expressed high affinity binding sites for bombesin (mean Kd = 3.42 nM; mean Bmax = 40.5 pmol/mg protein), of which 12 were subsequently characterized and found to be of the GRP-preferring subtype. One of 23 mucosal samples specifically bound bombesin and was the only sample from a patient with Ménétrier's disease, a disorder of mucosal growth known to be premalignant. The early gastric cancer from this patient also possessed high affinity binding sites for GRP. This is the first description of binding sites to bombesin-like peptides on human gastric cancer and Ménétrier's mucosa. The role of bombesin/GRP antagonists in the treatment of gastric cancer warrants investigation.
Bombesin-like peptides and cancer Preston, Shaun R.; Miller, Glenn V.; Primrose, John N.
Critical reviews in oncology/hematology,
07/1996, Volume:
23, Issue:
3
Journal Article
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