Oesophageal cancer Gatenby, Piers A.C; Preston, Shaun R
Surgery (Oxford),
11/2014, Volume:
32, Issue:
11
Journal Article
Peer reviewed
Abstract Oesophageal cancer is one of the most challenging of all tumours to manage. The two main histological types are squamous cell carcinoma and adenocarcinoma. The incidence of adenocarcinoma is ...increasing secondary to a number of factors including the ageing population, eradication of Helicobacter pylori and increasing gastro-oesophageal reflux disease/Barrett's oesophagus. The most common presentation is dysphagia and at diagnosis (usually by upper gastrointestinal endoscopy) two-thirds of patients are unsuitable for radical treatment due to the early metastatic dissemination of the tumour or poor patient physiological status. Mucosal disease may be treated by endoscopic resection; however, once disease has penetrated the submucosal layer there is a significant chance of lymphatic dissemination and so endoluminal therapy will likely prove inadequate and more radical therapy should be utilized. Tumours with lymph node involvement or invasion of the muscularis propria should be considered for multimodal therapy wherever possible – perioperative chemotherapy (UK) or neoadjuvant chemoradiotherapy (outside UK) and resection, or radical/definitive chemoradiotherapy. Surgery alone or radical radiotherapy are also options for those unfit for multimodal therapy. For patients treated with radical intent the 5-year survival now approaches 50% in some series. Surgery is associated with significant morbidity and a prolonged recovery period to regain preoperative status.
Lichen planus of the oesophagus is rare with a predilection for middle-aged to elderly women. There is a potential risk of malignant transformation to squamous cell carcinoma. Squamous cell carcinoma ...of the oesophagus still accounts for 30-40% of oesophageal cancer cases in the west and is almost exclusively the disease still encountered in the rest of the world. An increased awareness of oesophageal lichen planus is suggested in patients with cutaneous, oral or vulval disease. Endoscopic investigation of patients with lichen planus, possibly initially limited to those with oesophageal symptoms, and consideration of surveillance in patients with proven oesophageal lichen planus, will aid understanding of natural history of lesions and may help detect early stage tumours. Squamous cell carcinoma still accounts for 30-40% of oesophageal cancer cases in the west and is almost exclusively the disease still encountered elsewhere. Lichen planus of the oesophagus is potentially a premalignant condition for squamous cell carcinoma that could be surveilled in order to detect early-stage tumours with a consequent greater chance of cure. Oesophageal lichen planus is, however, rare, frequently asymptomatic and although the majority of cases occur in conjunction with lichen planus in other sites, the oesophageal features may be subtle and easily missed by endoscopic assessment. Furthermore, the histological changes are difficult to interpret and there may be significant underreporting. As a consequence, the true prevalence of these lesions is hard to determine. The difficulties in detection may mean that we are underestimating the frequency of oesophageal lichen planus. Endoscopic detection may be aided by the use of magnification indigo carmine chromoendoscopy and this warrants further evaluation. The risk of malignant transformation is currently unknown but may parallel that of oral lesions at approximately 1-3%. An increased awareness of the condition can only help to identify more cases and increase our understanding of this interesting condition.
Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) ...analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.
Complete (R0) resection and extent of lymphadenectomy are important prognostic factors for survival in patients undergoing surgery for esophageal carcinoma. We describe the first case of combined ...open and thoracoscopic esophagectomy with extended lymphadenectomy including abdominal, cervical, right, and left mediastinal (four-field, four-phase) nodal clearance in a 37-year-old woman with squamous cell carcinoma of the esophagus. This report provides a tailored strategy to achieve a high level of tumor clearance and complete resection. The approach described challenges the limitations of standard radical nodal clearance and may encourage surgeons to consider more extensive resections.
Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular ...biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.
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.
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.
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.
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.
A literature review was made on the role of totally extraperitoneal (TEP) hernia repairs for groin pain in athletes. Electronic databases were searched for literature published from January 1993 to ...November 2011. There were 10 articles incorporating 196 patients included in this review. Thirty percent of patients were reported to have direct inguinal hernias, 22% had indirect inguinal hernias, and 41% had dilated internal rings. Of note, 30% of cases had no macroscopic abnormality. Four studies reported on an early follow-up ranging between 3 and 6 weeks. Only minimal or mild symptoms were reported. Up to 33% of patients had impaired ability to perform at peak levels. Up to 53% of patients had persistence of symptoms at the early follow-up. Total follow-up time ranged from 3 to 80 months, and most patients were active (90%-100%). At long-term follow-up, 3% to 10% were unable to play, and 5% were reported as being unable to train. Two studies from the same center reported on TEP surgery for osteitis pubis, and most patients returned to sporting activity after 4 to 8 weeks. TEP repair is a good operative intervention in athletes with chronic groin pain not relieved by conservative measures. Athletes recover quickly and return to sport early.
Background
Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20–30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is ...difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches.
Methods
Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model.
Results
A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal–external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent).
Conclusion
The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.
Antecedentes
la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20‐30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático.
Métodos
Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo.
Resultados
En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna‐externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%).
Conclusión
El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.
Early recurrence after surgery for adenocarcinoma of the oesophagus is common. A risk prediction model was derived using modern machine learning methods that accurately predicts risk of early recurrence using postoperative pathology.
Machine learning may help
Background
Perioperative complications can affect outcomes after gastrectomy for cancer, with high mortality and morbidity rates ranging between 10 and 40%. The absence of a standardized system for ...recording complications generates wide variation in evaluating their impacts on outcomes and hinders proposals of quality-improvement projects. The aim of this study was to provide a list of defined gastrectomy complications approved through international consensus.
Methods
The Gastrectomy Complications Consensus Group consists of 34 European gastric cancer experts who are members of the International Gastric Cancer Association. A group meeting established the work plan for study implementation through Delphi surveys. A consensus was reached regarding a set of standardized methods to define gastrectomy complications.
Results
A standardized list of 27 defined complications (grouped into 3 intraoperative, 14 postoperative general, and 10 postoperative surgical complications) was created to provide a simple but accurate template for recording individual gastrectomy complications. A consensus was reached for both the list of complications that should be considered major adverse events after gastrectomy for cancer and their specific definitions. The study group also agreed that an assessment of each surgical case should be completed at patient discharge and 90 days postoperatively using a Complication Recording Sheet.
Conclusion
The list of defined complications (soon to be validated in an international multicenter study) and the ongoing development of an electronic datasheet app to record them provide the basic infrastructure to reach the ultimate goals of standardized international data collection, establishment of benchmark results, and fostering of quality-improvement projects.
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