Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.
Background Common symptoms of oesophageal cancer are dysphagia, pain, and bleeding. These symptoms can be relieved with palliative radiotherapy. The aim of this study was to analyse the outcome of two different palliative radiotherapy schedules. Methods We conducted a retrospective cohort study on palliative radiotherapy for oesophageal cancer given at Karolinska University Hospital. Patients included were treated with either short-course (20 Gy in 4 Gy fractions daily, 5 consecutive workdays) or long-course (30–39 Gy in 3 Gy fractions, 10–13 consecutive workdays) palliative external beam radiotherapy between January 2009 and December 2013. The primary endpoint was dysphagia relief and secondary endpoints were adverse events, re-interventions, and overall survival. Cox regression analyses were used to estimate the effect of treatment schedule on survival. Results A total of 128 patients received external beam radiotherapy under the study period, of these 75 (58.6%) received short-course radiotherapy and 53 (41.4%) long-course radiotherapy. Sixteen (30.8%) patients experienced dysphagia relief after short-course radiotherapy and 9 (22.0%) patients after long-course radiotherapy (p = 0.341). Acute toxicity was less frequent after short-course radiotherapy than after long-course radiotherapy, particularly oesophagitis (35.4% vs. 56.0%, p = 0.027) and nausea/emesis (18.5% vs. 36.0% p = 0.034). Re-interventions tended to be more common after short-course radiotherapy (32.0%) than after long-course radiotherapy (18.9%) (p = 0.098). There was no difference in overall survival between the two groups. Conclusions Short- and long-course palliative radiotherapy for oesophageal cancer were equally effective to relieve dysphagia and no difference was seen in overall survival. Acute toxicity was, however, more frequent and more severe after long-course radiotherapy. Our results suggest that short-course radiotherapy is better tolerated with equal palliative effects as long-course radiotherapy.
BackgroundThe globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC.MethodsThis is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT04460352.
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