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Background: The survival benefit of primary tumor surgery for metastatic esophageal cancer (mEC) patients has been observed, but methods for discriminating which individual patients would benefit from surgery have been poorly defined. Herein, a predictive model was developed to test the hypothesis that only certain metastatic patients would gain a survival benefit from primary tumor surgery.Methods: Clinical data for patients with mEC were extracted from the Surveillance, Epidemiology and End Results (SEER) database [2004][2005][2006][2007][2008][2009][2010][2011][2012][2013][2014][2015][2016] and then divided into surgery and no-surgery groups according to whether surgery was performed on the primary tumor. Propensity-score-matching (PSM) was performed to balance the confounding factors. We hypothesized that the patients who had undergone surgery and lived longer than the median cancer-specific-survival (CSS) of the no-surgery group could benefit from surgery.We constructed a nomogram to predict surgery benefit potential based on multivariable logistic-regression analysis using preoperative factors. The predictive performance of the nomogram was evaluated by the area under the receiver operating characteristic (AUC) and calibration curves. The clinical application value of the nomogram was estimated with decision curve analysis (DCA). Results: A total of 5,250 eligible patients with mEC were identified, and 9.4% [492] received primary tumor surgery. After PSM, CSS for the surgery group was significantly longer [median: 19 vs. 9 months; hazard ratio (HR) 0.52, P<0.001] compared with the no-surgery group. Among the surgery group, 69.3%[327] survived >9 months (surgery-beneficial group). The prediction nomogram showed good discrimination both in training and validation sets (AUC: 0.72 and 0.70, respectively), and the calibration curves indicated a good consistency. DCA demonstrated that the nomogram was clinically useful. According to this nomogram, surgery patients were classified into two groups: no-benefit-candidate and benefit-candidate. The benefitcandidate group was associated with longer survival than the no-benefit-candidate group (median CSS: 19 vs. 6.5 months, P<0.001). Additionally, there was no difference in survival between the no-benefit-candidate and no-surgery groups (median CSS: 6.5 vs. 9 months, P=0.070). Conclusions: A predictive model was created for the selection of candidates for surgical treatment among mEC patients. This predictive model might be used to select patients who may benefit from primary tumor surgery.

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Background The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. Method Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. Results All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. Conclusions Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.