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IntroductionHPN use in those with malignant bowel obstruction or palliative cancer is relatively commonplace. The 2009 ESPEN guidelines advise consideration if tumour related prognosis is 2–3 months, where TPN is expected to improve or stabilise performance status and/or quality of life. To review our practice we undertook a retrospective audit of all palliative HPN discharges over 4 years.MethodRetrospective audit of all palliative HPN discharges between October 2012 and November 2016 from UHCW. Data collected included: diagnosis, demographics, nutritional and biochemical parameters, estimated prognosis, complications, and outcome. Outcomes were collected up to 31st January 2017.Results17 patients were identified; age 36–79 (mean 57); 59% female. Diagnosis included: malignant GI tract obstruction (n=12; 70%); malignant enterocutaneous fistulae (n=2; 12%); and malabsorption/autonomic dysfunction (n=3; 18%).Estimated prognosis was documented in 11/17 (65%):>3 months in 4 (36%); 3–6 months in 2 (18%);>6 months in 3 (27%), and >12 months in 2 (18%). 9/17 (53%) received chemotherapy alongside TPN.Weight at start of PN was 46.4–94.5 kg (mean 63.7); BMI 16.3–34.6 (mean 21.8); weight loss 0%–32% (mean 12.5%) prior to referral.7/17 (42%) patients were alive at analysis. Of these, 3/17 (18%) had discontinued HPN due to resolution of intestinal failure, and 4/17 (24%) continuned HPN. Duration of HPN was 6.5–21 months (mean 13.4) in those with resolution, and 13.3–18 months (mean 15) in those continuing HPN. The remaining 10 patients (59%) had died; duration of HPN in this group was 0.3–29.1 months (mean 6.5). 12/17 patients (71%) survived longer than their estimated prognosis.Mean weight change on HPN was +8% (-12 to +39%). Starting grip strength was measured in 15/17 (8–33.9 kg; mean 18.7), and repeated in 11/17. It had improved in 91%; mean 4.7 kg (35.7%).13 patients (77%) had anthropometric measurements at start of PN, and repeated in 9/17 (53%). Follow-up MUAC ranged from 5% decrease to 4% increase (average 0.2% decrease); 89% patients had a reduction in TSF (range −8.5% to +3.2%; mean 3.7% reduction); however MAMC had remained stable or increased in 7/9 patients measured (range −14.6% to +24.4%; mean +4.2%).ConclusionOur results shows successful improvement in nutritional parameters and survival in patients managed on HPN with a palliative cancer diagnosis. Average survival on HPN was 9.7 months (294 days) with 71% surviving longer than their estimated prognosis. Grip strength improved in 91%. Although TSF thickness reduced and MUAC remained static despite TPN in the majority, MAMC increased highlighting that HPN resulted in gain of lean muscle mass despite their palliative cancer diagnosis.Disclosure of InterestNone Declared

The situation of the Malaysian consumer is presented, but at the same time a number of issues likely to be of significance in many other developing countries are raised. The absence of appropriate protection laws, the lack of enforcement of existing laws, and the failure to provide suitable redress mechanisms for the resolution of consumer grievances is highlighted. In each case, examples are presented of objectionable practices and inadequacies of present laws and institutional arrangements. Suggestions are given as to some reasons why the consumer movements in the developing countries have failed to achieve a greater degree of success. An important reason for this is that the consumer associations have failed to express the consumers' cause in terms of the priorities of the developing countries.

The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5) compared with 25·5 months (22·7–27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68–0·98], p=0·032). 608 grade 3–4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3–4 adverse events in 196 of 366 patients in the gemcitabine group. The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. Cancer Research UK.

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. Genomic analysis of 551 esophageal adenocarcinomas identifies new driver mutations and biomarkers associated with poor prognosis. More than 50% of esophageal adenocarcinomas contain sensitizing events for CDK4/CDK6 inhibitors, thus providing an evidence base for targeted therapeutics.

Rebecca Fitzgerald and colleagues report the whole-genome sequences of 129 esophageal adenocarcinomas, showing frequent copy number alterations and prevalent mutations in receptor tyrosine kinases concomitant with mitogenic activation. They further characterize mutation signatures and find three distinct molecular subtypes with potential for application to clinical diagnosis and treatment. 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.

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2 , MYC , MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma. Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.