Circumferential resection margin rates in esophageal cancer resection- oncological equivalency and comparable clinical outcomes between open versus minimally invasive techniques: A retrospective cohort study.

BACKGROUND: Radical surgery for esophageal cancer requires macroscopic and microscopic clearance of all malignant tissue. A critical element of the procedure is achieving a negative circumferential margin (CRM) to minimize local recurrence. The utility of minimally invasive surgery poses challenges in replicating techniques developed in open surgery, particularly for hiatal dissection in esophago-gastrectomy. In this study, the technical approach and clinical and oncological outcomes for open and laparoscopic esophago-gastrectomy are described with particular reference to CRM involvement. MATERIALS AND METHODS: This cohort study included all patients undergoing either open or laparoscopic esophago-gastrectomy between January 2004 to June 2022 in a single tertiary center. A standard surgical technique for hiatal dissection of the esophago-gastric junction developed in open surgery was adapted for a laparoscopic approach. Clinical parameters, length of stay (LOS), post-operative complications and mortality data were collected and analyzed by a Mann-Whitney U or Fisher's exact method. RESULTS: Overall 447 patients underwent an esophago-gastrectomy in the study with 219 open and 228 laparoscopic procedures. The CRM involvement was 18.8% in open surgery and 13.6% in laparoscopic surgery. The 90-day-mortality for open surgery was 4.1% compared with 2.2% for laparoscopic procedures. Median Intensive care unit (ITU), inpatient LOS and 30-day readmission rates were shorter for laparoscopic compared with open esophago-gastrectomy (ITU: 5 versus 8 days, P=0.0004; LOS: 14 versus 20 days, P=0.022; 30-day re-admission 7.46% versus 10.50%). Post-operative complication rates were comparable across both cohorts. The rates of starting adjuvant chemotherapy were 51.8% after open and 74.4% in laparoscopic esophago-gastrectomy. CONCLUSION: This study presents a standardized surgical approach to hiatal dissection for esophageal cancer. We present equivalence between open and laparoscopic esophago-gastrectomy in clinical, oncological and survival outcomes with similar rates of CRM involvement. We also observe a significantly shorter hospital length of stay with the minimally invasive approach.

Stroma AReactive Invasion Front Areas (SARIFA) improves prognostic risk stratification of perioperative chemotherapy treated oesophagogastric cancer patients from the MAGIC and the ST03 trial.

BACKGROUND: Tumour-associated fat cells without desmoplastic stroma reaction at the invasion front (Stroma AReactive Invasion Front Areas (SARIFA)) is a prognostic biomarker in gastric and colon cancer. The clinical utility of the SARIFA status in oesophagogastric cancer patients treated with perioperative chemotherapy is currently unknown. METHODS: The SARIFA status was determined in tissue sections from patients recruited into the MAGIC (n = 292) or ST03 (n = 693) trials treated with surgery alone (S, MAGIC) or perioperative chemotherapy (MAGIC, ST03). The relationship between SARIFA status, clinicopathological factors, overall survival (OS) and treatment was analysed. RESULTS: The SARIFA status was positive in 42% MAGIC trial S patients, 28% MAGIC and 48% ST03 patients after pre-operative chemotherapy. SARIFA status was related to OS in MAGIC trial S patients and was an independent prognostic biomarker in ST03 trial patients (HR 1.974, 95% CI 1.555-2.507, p < 0.001). ST03 patients with lymph node metastasis (ypN + ) and SARIFA-positive tumours had poorer OS than patients with ypN+ and SARIFA-negative tumours (plogrank < 0.001). CONCLUSIONS: The SARIFA status has clinical utility as prognostic biomarker in oesophagogastric cancer patients irrespective of treatment modality. Whilst underlying biological mechanisms warrant further investigation, the SARIFA status might be used to identify new drug targets, potentially enabling repurposing of existing drugs targeting lipid metabolism.

Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

PURPOSE: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Prognostic Significance of Negative Lymph Node Long Axis in Esophageal Cancer: Results From the Randomized Controlled UK MRC OE02 Trial.

OBJECTIVE: To analyze the relationship between negative lymph node (LNneg) size as a possible surrogate marker of the host antitumor immune response and overall survival (OS) in esophageal cancer (EC) patients. BACKGROUND: Lymph node (LN) status is a well-established prognostic factor in EC patients. An increased number of LNnegs is related to better survival in EC. Follicular hyperplasia in LNneg is associated with better survival in cancer-bearing mice and might explain increased LN size. METHODS: The long axis of 304 LNnegs was measured in hematoxylin-eosin stained sections from resection specimens of 367 OE02 trial patients (188 treated with surgery alone (S), 179 with neoadjuvant chemotherapy plus surgery (C+S)) as a surrogate of LN size. The relationship between LNneg size, LNneg microarchitecture, clinicopathological variables, and OS was analyzed. RESULTS: Large LNneg size was related to lower pN category ( P = 0.01) and lower frequency of lymphatic invasion ( P = 0.02) in S patients only. Irrespective of treatment, (y)pN0 patients with large LNneg had the best OS. (y)pN1 patients had the poorest OS irrespective of LNneg size ( P < 0.001). Large LNneg contained less lymphocytes ( P = 0.02) and had a higher germinal centers/lymphocyte ratio ( P = 0.05). CONCLUSIONS: This is the first study to investigate LNneg size in EC patients randomized to neoadjuvant chemotherapy followed by surgery or surgery alone. Our pilot study suggests that LNneg size is a surrogate marker of the host antitumor immune response and a potentially clinically useful new prognostic biomarker for (y)pN0 EC patients. Future studies need to confirm our results and explore underlying biological mechanisms.

The Cancer Hub Approach for Upper Gastrointestinal Surgery During COVID-19 Pandemic: Outcomes from a UK Cancer Centre.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused unprecedented disruption to global healthcare delivery. In England, the majority of elective surgery was postponed or cancelled to increase intensive care capacity. Our unit instituted the 'RM Partners Cancer Hub' at the Royal Marsden Hospital in London, to deliver ongoing cancer surgery in a 'COVID-lite' setting. This article describes the operational set-up and outcomes for upper gastrointestinal (UGI) cancer resections performed during this period. METHODS: From April 2020 to April 2021, the Royal Marsden Hospital formed the RM Partners Cancer Hub. This approach was designed to coordinate resources and provide as much oncological treatment as feasible for patients across the RM Partners West London Cancer Alliance. A UGI surgical case prioritisation strategy, along with strict infection control pathways and pre-operative screening protocols, was adopted. RESULTS: A total of 231 patients underwent surgery for confirmed or suspected UGI cancer during the RM Partners Cancer Hub, with 213 completed resections and combined 90-day mortality rate of 3.5%. Good short-term survival outcomes were demonstrated with 2-year disease free survival (DFS) and overall survival (OS) for oesophageal (70.8% and 72.9%), gastric (66.7% and 83.3%) and pancreatic cancer resections (68.0% and 88.0%). One patient who developed perioperative COVID-19 during the RM Partners Cancer Hub operation made a full recovery with no lasting clinical sequelae. CONCLUSION: Our experience demonstrates that the RM Partners Cancer Hub approach is a safe strategy for continuing upper gastrointestinal (GI) resectional surgery during future periods of healthcare service disruption.

Identifying the limitations of cardiopulmonary exercise testing prior to esophagectomy using a pooled analysis of patient-level data.

Preoperative cardiopulmonary exercise testing (CPET) provides an objective assessment of aerobic fitness in patients undergoing surgery. While peak oxygen uptake during exercise (VO2peak) and anaerobic threshold have demonstrated a moderate correlation with the development of complications following esophagectomy, no clinically useful threshold values have been defined. By pooling patient level data from existing studies, we aimed to define optimal thresholds for preoperative CPET parameters to predict patients at high risk of postoperative complications. Studies reporting on the relationship between preoperative CPET variables and post-esophagectomy complications were determined from a comprehensive literature search. Patient-level data were obtained from six contributing centers for pooled-analyses. Outcomes of interest included cardiopulmonary and non-cardiopulmonary complications, unplanned intensive care unit readmission, and 90-day and 12-month all-cause mortality. Receiver operating characteristic curves and logistic regression models estimated the predictive value of CPET parameters for each individual outcome of interest. This analysis comprised of 621 patients who underwent CPET prior to esophagectomy during the period from January 2004 to March 2017. For both anaerobic threshold and VO2peak, none of the receiver operating characteristic curves achieved an area under the curve value > 0.66 for the outcomes of interest. The discriminatory ability of CPET for determining high-risk patients was found to be poor in patients undergoing an esophagectomy. CPET may only carry an adjunct role to clinical decision-making.

Effect of perioperative FLOT versus ECF/ECX on short-term outcomes after surgery for resectable oesophagogastric adenocarcinoma: propensity score-matched study.

BACKGROUND: Perioperative FLOT (fluorouracil plus leucovorin, oxaliplatin, and docetaxel) chemotherapy is a recent regimen used to treat resectable oesophagogastric (OG) adenocarcinoma, associated with improved overall survival versus earlier chemotherapy strategies. This study compared short-term perioperative morbidity in a large tertiary centre series of FLOT to a matched cohort receiving ECX/ECF (epirubicin, cisplatin, capecitabine (X) or 5-fluorouracil (F)). METHODS: Consecutive patients completing four perioperative cycles of FLOT and proceeding to surgery with resectable OG adenocarcinoma were included. This was matched to patients from a historic ECX/ECF cohort from the same institution. A propensity score was calculated, and a secondary analysis using a propensity-matched group performed. RESULTS: Cohorts were matched by tumour location and operations performed. In total there were 129 (64.5 per cent) oesophageal and 71 (35.5 per cent) gastric resections (FLOT 57 oesophageal, 43 gastric; ECF/ECX 64 oesophageal, 36 gastric). The median length of stay after surgery was 12 days in the FLOT group versus 15 in ECF/ECX (P = 0.035). There were no significant differences in overall perioperative complications and, specifically, no difference in OG anastomotic leaks, analysed by site (gastric (FLOT 0/79 (0 per cent) versus ECX 2/79 (2.5 per cent); P = 0.123), oesophageal (FLOT 4/121 (3.3 per cent) versus ECX 5/121 (4.1 per cent); P = 0.868) or type of surgery (open FLOT 1/121 (0.8 per cent) versus ECX 3/121 (2.5 per cent); P = 0.368; minimally invasive (FLOT 3/121 (2.5 per cent) versus ECX 2/121 (1.7 per cent); P = 0.555)). There was no statistical difference in leak-related return to theatre, 30-day (FLOT 0 (0 per cent) versus ECX 3/100 (3.0 per cent); P = 0.081), or 90-day (FLOT 0 (0 per cent) versus ECX 2/100 (2.0 per cent); P = 0.155) mortality. CONCLUSION: In terms of surgical complications, FLOT and ECX/ECF were equally safe in patients undergoing resection for OG adenocarcinoma.

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma - A comparison of the FLOT and 'MAGIC' regimens.

BACKGROUND: Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. METHODS: Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas' Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. RESULTS: Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50-0.94) and disease-free survival (HR = 0.75, 95% CI 0.58-0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. CONCLUSIONS: Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study.

BACKGROUND: Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning-based classifiers to detect microsatellite instability and EBV status from routine histology slides. METHODS: In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0·5. FINDINGS: Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0·597 (95% CI 0·522-0·737) to 0·836 (0·795-0·880) and EBV status in five of eight cohorts, with AUROCs ranging from 0·819 (0·752-0·841) to 0·897 (0·513-0·966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0·723 (95% CI 0·676-0·794) to 0·863 (0·747-0·969) for detection of microsatellite instability and from 0·672 (0·403-0·989) to 0·859 (0·823-0·919) for detection of EBV status. INTERPRETATION: Classifiers became increasingly robust when trained on pooled cohorts. After prospective validation, this deep learning-based tissue classification system could be used as an inexpensive predictive biomarker for immunotherapy in gastric cancer. FUNDING: German Cancer Aid and German Federal Ministry of Health.

The role of surgery after prolonged primary chemotherapy for advanced oesophageal adenocarcinoma.

BACKGROUND: Most patients presenting with oesophageal cancer do so with advanced disease not suitable for surgery. However, there are examples of encouraging survival following surgery in highly selected patients who respond well to chemotherapy. METHODS: This was a retrospective cohort study of patients who presented with advanced but nonvisceral metastatic oesophageal cancer. Consecutive patients on a prolonged primary chemotherapy pathway who underwent surgical resection following a favourable response to chemotherapy were included. Survival and recurrence rates were analysed using Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: A total of 57 patients included in the cohort operated between 2007 and 2015, the overall median survival was 44 months and the 5-year survival was 42%. Prechemotherapy cN0/cN1 (HR: 0.27, 95% CI: 0.12-0.62) conferred an independent survival advantage compared to cN2 and cN3 disease. Poor differentiation (HR: 2.46, 95% CI: 1.11-5.42), R1 resection (HR: 2.43, 95% CI: 1.14-5.19) and advanced nodal status (HR: 3.28, 95% CI: 1.44-7.47) predicted worse survival on univariable analysis. Poor differentiation (HR: 3.93, 95% CI: 1.62-9.56) was independently associated with poor survival when adjusted for other variables. CONCLUSION: Patients who present with advanced inoperable oesophageal cancer who have a favourable response to chemotherapy represent a limited group of patients who may benefit from surgery.

Consensus recommendations for the standardized histopathological evaluation and reporting after radical oesophago-gastrectomy (HERO consensus).

BACKGROUND: Variation in the approach, radicality, and quality of gastroesophageal surgery impacts patient outcomes. Pathological outcomes such as lymph node yield are routinely used as surrogate markers of surgical quality, but are subject to significant variations in histopathological evaluation and reporting. A multi-society consensus group was convened to develop evidence-based recommendations for the standardized assessment of gastroesophageal cancer specimens. METHODS: A consensus group comprised of surgeons, pathologists, and oncologists was convened on behalf of the Association of Upper Gastrointestinal Surgery of Great Britain & Ireland. Literature was reviewed for 17 key questions. Draft recommendations were voted upon via an anonymous Delphi process. Consensus was considered achieved where >70% of participants were in agreement. RESULTS: Consensus was achieved on 18 statements for all 17 questions. Twelve strong recommendations regarding preparation and assessment of lymph nodes, margins, and reporting methods were made. Importantly, there was 100% agreement that the all specimens should be reported using the Royal College of Pathologists Guidelines as the minimum acceptable dataset. In addition, two weak recommendations regarding method and duration of specimen fixation were made. Four topics lacked sufficient evidence and no recommendation was made. CONCLUSIONS: These consensus recommendations provide explicit guidance for gastroesophageal cancer specimen preparation and assessment, to provide maximum benefit for patient care and standardize reporting to allow benchmarking and improvement of surgical quality.

Adjuvant therapy following neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma in patients with clear resection margins.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. METHODS: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. RESULTS: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06; p .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11; p .1.081). CONCLUSIONS: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.

Histological intratumoral heterogeneity in pretreatment esophageal cancer biopsies predicts survival benefit from neoadjuvant chemotherapy: results from the UK MRC OE02 trial.

Despite the use of multimodal treatment, survival of esophageal cancer (EC) patients remains poor. One proposed explanation for the relatively poor response to cytotoxic chemotherapy is intratumor heterogeneity. The aim was to establish a statistical model to objectively measure intratumor heterogeneity of the proportion of tumor (IHPoT) and to use this newly developed method to measure IHPoT in the pretreatment biopsies from from EC patients recruited to the OE02 trial. A statistical mixed effect model (MEM) was established for estimating IHPoT based on variation in hematoxylin/eosin (HE) stained pretreatment biopsy pieces from the same individual in 218 OE02 trial patients (103 treated by chemotherapy and surgery (chemo+surgery); 115 patients treated by surgery alone). The relationship between IHPoT, prognosis, chemotherapy survival benefit, and clinicopathological variables was assessed. About 97 (44.5%) and 121 (55.5%) ECs showed high and low IHPoT, respectively. There was no significant difference in IHPoT between surgery (median [range], 0.1637 [0-3.17]) and chemo+surgery (median [range], 0.1692 [0-2.69]) patients (P = 0.43). Chemo+surgery patients with low IHPoT had a significantly longer survival than surgery patients (HR = 1.81, 95% CI: 1.20-2.75, P = 0.005). There was no survival difference between chemo+surgery and surgery patients with high IHPoT (HR = 1.15, 95% CI: 0.72-1.81, P = 0.566). This is the first study suggesting that IHPoT measured in the pretreatment biopsy can predict chemotherapy survival benefit in EC patients. IHPoT may represent a clinically useful biomarker for patient treatment stratification. Future studies should determine if pathologists can reliably estimate IHPoT.

DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial.

BACKGROUND: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS). AIM: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort. METHODS: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy. RESULTS: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059) CONCLUSIONS: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC.

Multicenter Study of Presentation, Management, and Postoperative and Long-Term Outcomes of Septegenerians and Octogenerians Undergoing Gastrectomy for Gastric Cancer.

BACKGROUND: The optimal treatment strategy for elderly patients with gastric cancer is still controversial. This study aimed to assess the impact of age on short- and long-term outcomes after treatment for primary gastric cancer. METHODS: From January 2004 to December 2014, a total of 507 patients underwent gastrectomy for gastric adenocarcinoma at two high-volume upper gastrointestinal (GI) centers. The patients were classified into three groups as follows: group A (patients ≤ 69 years old, n = 266), group B (patients 70-79 years old, n = 166), and group C (patients ≥ 80 years old, n = 75). Clinicopathologic characteristics as well as, short- and long-term outcomes were compared between the groups. RESULTS: The patients in groups B and C had more comorbidities, whereas the younger subjects (group A) had more advanced tumor stages. Less extensive surgery was performed in the groups B and C. Older patients (age ≥ 70 years) had more postoperative medical complications. Moreover, group C had a higher postoperative mortality rate (8.1%) than group A (1.8%) or group B (1.9%). In the multivariable analysis, age older than 80 years (group C) was a negative independent factor for overall survival (OS) (hazard ratio [HR], 2.36) compared with group A, whereas group B seemed to have a comparable risk (HR, 1.37). Notably, the three groups did not show significant differences in disease-related survival (DRS). CONCLUSION: The data suggest that patients 70-79 years of age show a risk of postoperative death comparable with that of younger subjects. However, patients older than 80 years should be carefully selected for surgical treatment due to the increased risk of postoperative mortality.

Do all the European surgeons perform the same D2? The need of D2 audit in Europe.

Although D2 lymphadenectomy is the standard of care for radical intent surgical treatment of gastric cancer, the real compliance with D2 dissection in Europe is still unknown. The aim of the present study is to analyze the variation in lymph-node harvesting reported after D2 dissection in European series and to present a European project aiming at evaluating the real compliance with D2 lymphadenectomy. A PubMed search for papers using the key words "D2 lymphadenectomy" and "gastric cancer" from 2008 to 2017 was undertaken. Only studies by European authors in English language reporting the number of retrieved lymph nodes after D2 lymphadenectomy were included. The results of literature review were descriptively reported. The literature survey yielded 16 studies: 2 RCTs, 3 observational multicentre studies, and 11 observational monocentric studies. A large variability was found in the number of retrieved nodes, which, overall, was the lowest in the surgical series from Eastern Europe (16.6 and 19.9 in the Lithuanian and Hungarian series, respectively) and the highest in an Italian RCT. The within-study variability was also quite high, especially in multicentre RCTs and observational studies. Sample size tended to have a larger effect on the variability of lymph nodes retrieved than on its actual value. However, in both cases, the relation was not significant, due to the low number of studies considered. There is a large variability in the number of retrieved nodes after D2 dissection in European series. This reflects, at least partly, different approaches to D2 lymphadenectomy by European surgeons and may be responsible of the different outcomes observed in patients with gastric cancer across Europe. Therefore, there is the need to standardize the practice of D2 gastrectomy in Europe and to define possible variations of D2 procedures according to tumour's characteristics.

Poor performance in incremental shuttle walk and cardiopulmonary exercise testing predicts poor overall survival for patients undergoing esophago-gastric resection.

INTRODUCTION: Esophageal and gastric cancer have a poor prognosis and surgical intervention is associated with considerable morbidity, highlighting the need for careful preoperative assessment. The Incremental Shuttle Walk Test (ISWT) and Cardiopulmonary exercise testing (CPET) can assess preoperative fitness. This study aims to investigate their correlation with both postoperative respiratory complications and overall survival. PATIENTS AND METHODS: Patients were identified who underwent esophageal or gastric resections for cancer between 2010 and 2014 and had ISWT and/or CPET assessments. Tumor differentiation, stage, postoperative respiratory complications, and outcome were documented and then correlated with the results of the preoperative fitness assessments. RESULTS: Neither the ISWT result, anaerobic threshold (AT) nor VO2 Max correlated well with perioperative complications. However, ISWT (p < 0.001), AT (p < 0.001) and VO2 Max (p < 0.001) all correlated strongly with overall survival. No patient with a score of less than 350 m on ISWT survived beyond 3 years. In a subset of patients with ISWT results both pre and post chemotherapy (n = 49), those that had an improvement in result had a 19% incidence of post-operative respiratory complications compared to 45% where the result did not change or declined, though due to small numbers this only approached significance (p = 0.08). CONCLUSION: ISWT and CPET can be useful preoperative tools to predict overall survival for patients undergoing esophago-gastric resection. Furthermore, patients that improve their functional status during chemotherapy seem to do better than those where it remains static or declines.