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Background The complexity of the upper gastrointestinal (UGI) multidisciplinary team (MDT) is continually growing, leading to rising clinician workload, time pressures, and demands. This increases heterogeneity or ‘noise’ within decision-making for patients with oesophageal cancer (OC) and may lead to inconsistent treatment decisions. In recent decades, the application of artificial intelligence (AI) and more specifically the branch of machine learning (ML) has led to a paradigm shift in the perceived utility of statistical modelling within healthcare. Within oesophageal cancer (OC) care, ML techniques have already been applied with early success to the analyses of histological samples and radiology imaging; however, it has not yet been applied to the MDT itself where such models are likely to benefit from incorporating information-rich, diverse datasets to increase predictive model accuracy. Methods This review discusses the current role the MDT plays in modern UGI cancer care as well as the utilisation of ML techniques to date using histological and radiological data to predict treatment response, prognostication, nodal disease evaluation, and even resectability within OC. Results The review finds that an emerging body of evidence is growing in support of ML tools within multiple domains relevant to decision-making within OC including automated histological analysis and radiomics. However, to date, no specific application has been directed to the MDT itself which routinely assimilates this information. Conclusions The authors feel the UGI MDT offers an information-rich, diverse array of data from which ML offers the potential to standardise, automate, and produce more consistent, data-driven MDT decisions.

Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing neoplastic condition which is poorly understood, with a 5-year progression-free survival rate as low as 48%. PMP is most commonly caused by appendiceal mucinous neoplasms (AMN), and understanding their genetic biology and pathogenicity may allow for the development of better novel systemic treatments to target key deleterious mutations and the implicated pathways. The primary aim of this systematic review was to identify the genetic profile of histologically confirmed human PMP or AMN samples. The secondary aim was to identify whether genetic marks could be used to predict patient survival. Ovid EMBASE, Ovid MEDLINE, PubMed, and Web of Science were searched to identify studies investigating the genetic profile of histologically-confirmed human PMP or AMN samples. We review findings of 46 studies totalling 2181 tumour samples. The most frequently identified somatic gene mutations in patients with PMP included KRAS (38–100%), GNAS (17–100%), and TP53 (5–23%); however, there were conflicting results of their effect on survival. Three studies identified molecular subtypes based on gene expression profiles classifying patients into oncogene-enriched, immune-enriched, and mixed molecular subtypes with prognostic value. This review summarises the current literature surrounding genetic aberrations in PMP and AMNs and their potential utility for targeted therapy. Given the recent advances in clinical trials to directly target KRAS and GNAS mutations in other cancers, we propose a rationale to explore these mutations in future pre-clinical studies in PMP with a view for a future clinical trial.

Background Oesophagectomy is associated with significant morbidity and mortality. A simple score to define a patient's risk of developing major complications would be beneficial. Methods Patients who underwent upper gastrointestinal resections with an oesophageal anastomosis between 2005 and 2010 were reviewed and formed the development dataset with resections performed in 2011 forming a prospective validation dataset. The association between post-operative C-reactive protein (CRP), white cell count (WCC) and albumin levels with anastomotic leak (AL) or major complication including death using the Clavien–Dindo (CD) classification were analysed by receiver operating characteristic curves. After multivariate analysis, from the development dataset, these factors were combined to create a novel score which was subsequently tested on the validation dataset. Results Two hundred fifty-eight patients were assessed to develop the score. Sixty-three patients (25%) developed a major complication, and there were seven (2.7%) in-patient deaths. Twenty-six (10%) patients were diagnosed with AL at median post-operative day 7 (range: 5–15). CRP ( p = 0.002), WCC ( p < 0.0001) and albumin ( p = 0.001) were predictors of AL. Combining these markers improved prediction of AL (NUn score > 10: sensitivity 95%, specificity 49%, diagnostic accuracy 0.801 (95% confidence interval: 0.692–0.909, p < 0.0001)). The validation dataset confirmed these findings (NUn score > 10: sensitivity 100%, specificity 57%, diagnostic accuracy 0.879 (95% CI 0.763–0.994, p = 0.014)) and a major complication or death (NUn > 10: sensitivity 89%, specificity 63%, diagnostic accuracy 0.856 (95% CI 0.709–1, p = 0.001)). Conclusions Blood-borne markers of the systemic inflammatory response are predictors of AL and major complications after oesophageal resection. When combined they may categorise a patient's risk of developing a serious complication with higher sensitivity and specificity.

Background Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours. Results We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS. Conclusions The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients.

Immunohistochemistry reveals prominent IgG4-positive plasma cells within the inflammatory cell infiltrate. 1 The precise number of IgG4-positive plasma cells required per high power microscope field (or per unit area) in order to provide significant support to a diagnosis of IgG4-related disease is currently the subject of debate, with figures between >10 and >50 such cells per high power microscope field suggested by different groups. 2 It has become more recently apparent that the ratio of IgG4-positive plasma cells to the total number of IgG-positive plasma cells may be at least as important as the number of IgG4-positive plasma cells alone. Recurrence can occur on cessation of steroid therapy and sometimes alternative immunosuppressants are required, for example, azathioprine. 1 Liver Portal inflammation, large bile duct obstruction, portal sclerosis, lobular hepatitis, canalicular cholestasis Gallbladder Chronic cholecystitis Lymph nodes Follicular hyperplasia Lung Interstitial pneumonia Colon Chronic colitis Gastric Chronic gastritis Retroperitoneum Retroperitoneal fibrosis Kidney Tubulointerstitial nephritis Bile duct Periductular inflammation and fibrosis Salivary gland Chronic sclerosing sialadenitis Ampulla Active chronic duodenitis Hypothalamus Lymphocytic hypophysitis Prostate Chronic inflammation, obliterative phlebitis, glandular atrophy Mediastinum Mediastinal fibrosis Thyroid Thyroiditis, hypothyroidism Orbit Pseudotumour 3 Meninges Chronic meningitis 4 IgG4-related disease has recently been described as a cause of non-neoplastic polyp formation in the stomach and colon. 5 Two previous studies, from Japan and Taiwan, have identified an increased prevalence of gastric ulceration in patients with autoimmune pancreatitis and this appears to be independent of Helicobacter pylori infection status. 6 7 In one of these studies, gastric biopsy material was obtained from some of the patients and this revealed prominence of IgG4-positive plasma cells within the gastric mucosa. 6 However, there is only one previous report, from Japan, of a patient presenting with refractory gastric ulcer that on resection was found to be associated with prominent IgG4-positive plasma cells. 8 Our case is the first report of a patient presenting in this way outside of Asia.

ObjectiveTo understand the CD8+ tumour infiltrating lymphocyte (TIL) compartment of oesophageal adenocarcinoma (OAC) with regards to markers of lymphocyte exhaustion, tissue residency and to identify possible reasons behind differential responses to therapy.DesignTumour samples from 44 patients undergoing curative resection for OAC were assessed by flow cytometry for presence of antigen-experienced TILs and markers of activation and exhaustion. Populations of PD-1 and CD39 positive OAC TILs were sorted, and bulk RNA sequencing undertaken using a modified SmartSeq2 protocol. Flow cytometric assessment of functionality was completed.ResultsA higher proportion of antigen experienced CD8+ OAC TILs was associated with improved survival following surgery; while, high double positivity (DP) for PD-1 and CD39 among these TILs also correlated significantly with outcome. These DP TILs possess a minority population which is positive for the markers of exhaustion TIM3 and LAG3. Transcriptomic assessment of the PD-1 and CD39 DP TILs demonstrated enrichment for a tissue resident memory T lymphocyte (TRM) phenotype associated with improved survival in other cancers, reinforced by positivity for the canonical TRM marker CD103 by flow cytometry. This population demonstrated maintained functional capacity both in their transcriptomic profile, and on flow cytometric assessment, as well as preserved proliferative capacity.ConclusionResected OAC are variably infiltrated by PD-1 and CD39 DP TILs, an abundance of which among lymphocytes is associated with improved survival. This DP population has an increased, but still modest, frequency of TIM3 and LAG3 positivity compared to DN, and is in keeping with a functionally competent TRM phenotype.

Oesophageal adenocarcinoma (OAC) is increasing in incidence and has a poor prognosis. Tumour derived fibroblasts (TDFs) differ functionally from normal fibroblasts (NDFs), and play a pivotal role in cancer. Many of the differences persist through subculture. We measured the DNA methylation profiles of 10 TDFs from OAC with 12 NDF from normal oesophageal mucosa using Infinium HumanMethylation450 Beadchips and found they differed in multidimensional scaling analysis. We identified 4,856 differentially methylated CpGs (DMCs, adjusted p < 0.01 and absolute difference in average β-value > 0.15), of which 3,243 (66.8%) were hypomethylated in TDFs compared to NDFs. Hypermethylated DMCs were enriched at transcription start sites (TSSs) and in CpG islands, and depleted in transcriptional enhancers. Gene ontology analysis of genes with DMCs at TSSs revealed an enrichment of genes involved in development, morphogenesis, migration, adhesion, regulation of processes and response to stimuli. Alpha-smooth muscle actin ( α -SMA) is a marker of activated fibroblasts and a poor prognostic indicator in OAC. Hypomethylated DMCs were observed at the TSS of transcript variant 2 of α-SMA, which correlated with an increase in α- SMA protein expression. These data suggest that DNA methylation may contribute to the maintenance of the TDF phenotype.

The aim of this study was to interrogate whether blood-borne inflammatory and nutritional markers predict long-term survival and response to neoadjuvant chemotherapy in radically treated oesophagogastric cancer patients. This retrospective study included 246 patients who underwent oesophageal resection for high-grade dysplasia or carcinoma between 2005 and 2010. The predictive value of routine preoperative immunonutritional blood tests was assessed for their association with survival and response to chemotherapy. On multivariate analysis, higher neutrophil–lymphocyte ratio (NLR) ( p  < 0.0001), N stage ( p  < 0.0001) and perineural invasion ( p  < 0.0001) were associated with poor overall survival. Regarding disease-free survival, multivariate analysis showed reduced serum albumin ( p  = 0.034), N stage ( p  < 0.0001), M stage ( p  = 0.037), vascular invasion ( p  < 0.0001) and presence of R1 resection ( p  = 0.003) to correlate with earlier recurrence. In those who received neoadjuvant chemotherapy, analysis of prechemotherapy characteristics showed only serum albumin ( p  = 0.037) to predict pathological response to chemotherapy. Preoperative immunonutritional markers, NLR and albumin, were independent prognostic markers for overall survival and disease-free survival, respectively, after oesophageal cancer resection. Prospective studies evaluating the role of immunonutritional modulation to improve response to chemotherapy and long-term outcome are required.

Background Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy. Materials and Methods Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients ( n  = 128) undergoing curative treatment. Results Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs ( p  = 0.003), completeness of resection ( p  < 0.0001) and lower pathological N stage ( p  < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment ( p  = 0.015), completeness of resection ( p  = 0.001), increased CD8+ TILs ( p  < 0.0001) and reduced pathological N stage ( p  < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ ( p  = 0.017) and CD8+ TILs ( p  = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively. Discussion Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.

BackgroundCancers of the oesophagus and stomach are a major cause of morbidity and mortality. Research is crucial to improving outcomes. However, to maximise value and impact, areas of focus should be prioritised in partnership with patients.ObjectiveWe undertook a comprehensive analysis of UK and Ireland patient and healthcare professional (HCP) priorities for research into oesophagogastric cancers across the domains of prevention, diagnosis and staging, treatment, palliative care and survivorship.DesignA scoping exercise sourced research questions from patients and HCPs. These were consolidated and then confirmed by systematic review to represent a true research uncertainty. Research questions were scored on potential impact by an interdisciplinary group of HCPs and prioritised using a weighting derived from a patient survey.ResultsThere were 835 (395 HCP, 440 patient) respondents to the scoping (n=455) and prioritisation (n=380) surveys. Across these, 4295 suggested research uncertainties were consolidated to 92 uncertainties that were prioritised. HCP respondents represented 25 professional groups from community and hospital settings. Patient weighting changed 22.2–46.3% of priority rankings established by HCPs. All domains were represented by the 20 highest priority questions, 5 of which focused on personalising and optimally combining treatment modalities. Two other key themes related to optimising nutrition and improving quality of life during and after treatment, including in patients not cured of their cancer.ConclusionThis work highlights the impact of patient input on HCP-ranked research priorities and provides a robust list of priorities to guide funders, policymakers and researchers to support and undertake impactful research.